Clinical trial NCT01539291
Conditions: Chronic Lymphocytic Leukemia
Keywords: CLL CAL-101 CAL 101 GS-1101 GS 1101 PI3K Leukemia GS-US-312-0116 idelalisib
Sponsor: Gilead Sciences
Start date: 2012-10-03; Completion date: 2018-06-29
Enrollment: 161 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this extension study (GS-US-312-0117) that is a companion study to Study GS-US-312-0116 (NCT01539512), is to evaluate the effect of idelalisib on the onset, magnitude, and duration of tumor control. Randomization was done in study GS-US-312-0116, and carried forward to study GS-US-312-117.

Detailed description:

Arms: arm 1: Participants will receive idelalisib 300 mg twice daily (600 mg per day). arm 2: Participants will receive idelalisib 150 mg twice daily (300 mg per day)
Interventions: intervention 1: Idelalisib
Intervention descriptions: intervention 1: Idelalisib tablet(s) administered orally twice daily

Protocol documents:
SAP_008.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 3, Double-Blind Extension Study Evaluating the 
Efficacy and Safety of Two Different Dose Levels of 
Single-Agent Idelalisib (GS-1101) for Previously Treated 
Chronic Lymphocytic Leukemia
A Companion Trial to Study GS-US-312-0116: A Phase 3, 
Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in 
Combination with Rituximab for Previously Treated Chronic 
Lymphocytic Leukemia
Name of Test Drug:
Idelalisib (IDELA; GS-1101)
Study Number:
GS-US-312-0117
Protocol Version:
Version 3.0
Protocol Date:
10 September 2013
Analysis Type:
Interim (Blinded Portion of Study 312-0117)
Analysis Plan Version:
Final 1.0
Analysis Plan Date:
04 November 2013
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS .......................................................................................................................................2
LIST OF ABBREVIATIONS ................................................................................................................................4
1.
INTRODUCTION .........................................................................................................................................6
1.1.
Study Objectives ...............................................................................................................................6
1.2.
Study Design.....................................................................................................................................7
1.3.
Sample Size and Power...................................................................................................................11
2.
TYPE OF PLANNED ANALYSIS .............................................................................................................12
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.....................................................................13
3.1.
Analysis Sets...................................................................................................................................13
3.1.1.
Intent-to-Treat Analysis Set ..........................................................................................13
3.1.2.
Pharmacokinetic/Pharmacodynamic Analysis Sets.......................................................13
3.2.
Strata and Covariates ......................................................................................................................13
3.3.
Examination of Subject Subsets......................................................................................................13
3.4.
Missing Data and Outliers...............................................................................................................13
3.5.
Data Handling Conventions and Transformations ..........................................................................14
3.5.1.
Data Handling for Efficacy Endpoints ..........................................................................14
3.5.2.
Data Handling for Laboratory data ...............................................................................15
3.6.
Visit Windows ................................................................................................................................15
3.6.1.
Analysis Windows ........................................................................................................15
3.6.2.
Selection of Data in the Event of Multiple Records in a Window ................................15
4.
SUBJECT DISPOSITION...........................................................................................................................16
4.1.
Subject Enrollment..........................................................................................................................16
4.2.
Disposition of Subjects ...................................................................................................................16
4.3.
Extent of Exposure..........................................................................................................................16
4.3.1.
Duration of Exposure to Study Drugs ...........................................................................16
4.3.2.
Adherence with idelalisib..............................................................................................17
4.4.
Protocol Deviations.........................................................................................................................17
5.
BASELINE DATA......................................................................................................................................18
5.1.
Demographics and Baseline Characteristics ...................................................................................18
5.2.
Medical History ..............................................................................................................................18
6.
EFFICACY ANALYSES ............................................................................................................................19
6.1.
Efficacy Endpoints..........................................................................................................................20
6.1.1.
Definition of Efficacy Endpoints ..................................................................................20
6.1.2.
Analysis Methods for Efficacy Endpoints.....................................................................21
6.1.3.
Between-Study Comparisons ........................................................................................25
6.2.
Changes From Protocol-Specified Efficacy Analyses ....................................................................25
7.
SAFETY ANALYSES.................................................................................................................................26
7.1.
Adverse Events and Deaths.............................................................................................................26
7.1.1.
Adverse Event Dictionary.............................................................................................26
7.1.2.
Adverse Event Severity.................................................................................................26
7.1.3.
Relationship of Adverse Events to Study Drug.............................................................26
7.1.4.
Serious Adverse Events.................................................................................................27
7.1.5.
Treatment-Emergent Adverse Events ...........................................................................27
7.1.6.
Summaries of Adverse Events and Deaths....................................................................27


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7.2.
Laboratory Evaluations...................................................................................................................29
7.2.1.
Summaries of Numeric Laboratory Results ..................................................................29
7.2.2.
Summaries of Categorical Laboratory Results..............................................................29
7.2.3.
Graded Laboratory Values ............................................................................................29
7.2.4.
Shift in CTCAE Grade Relative to Baseline .................................................................30
7.2.5.
Transaminase elevations ...............................................................................................30
7.3.
Concomitant Medications ...............................................................................................................31
7.4.
Body Weight and Vital Signs..........................................................................................................31
7.5.
Oxygen Saturation Levels...............................................................................................................31
7.6.
Other Safety Measures....................................................................................................................32
7.7.
Changes From Protocol-Specified Safety Analyses........................................................................32
8.
PHARMACOKINETIC ANALYSES .........................................................................................................33
9.
PHARMACDYNAMIC ANALYSES.........................................................................................................34
10.
REFERENCES ............................................................................................................................................35
11.
SOFTWARE................................................................................................................................................36
12.
SAP REVISION ..........................................................................................................................................37
13.
APPENDICES .............................................................................................................................................38
Appendix 1.
Table of Contents for Statistical Tables, Figures, and Listings.....................................39
Appendix 2.
Schedule of Study Procedures.......................................................................................48


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LIST OF ABBREVIATIONS
AE
adverse event
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATC
Anatomical-Therapeutic-Chemical classification 
BID
twice per day
BMI
body mass index
BOR
best overall response
CDF
cumulative distribution function
CI
confidence interval
CIRS
cumulative Illness Rating Scale
CLL
chronic lymphocytic leukemia
CR
complete response
CSR
clinical study report
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
DMC
data monitoring committee
DOR
duration of response
DSPH
Drug Safety and Public Health
eCRF
electronic case report form
ECG
electrocardiogram
EDC
electronic data capture
EOT
end of treatment
EQ-5D
EuroQoL Five-Dimension utility measure
EWB
emotional well-being
FACT-Leu
Functional Assessment of Cancer Therapy: Leukemia
FWB
functional well-being 
HLGT
high-level group term
HLT
high-level term
HRQL
health-related quality of life
IRC
independent review committee
ITT
intent to treat
IWCLL
International Workshop on CLL
IWRS
interactive web response system
LD
longest diameter
LLT
low level term


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LIST OF ABBREVIATIONS (CONTINUED)
LNR
lymph node response
LPD
longest perpendicular diameter
LVD
longest vertical dimension
LymS
lymphoma subscale
MedDRA
Medical Dictionary for Regulatory Activities
MID
minimally important difference
MRI
magnetic resonance imaging
ND
no disease
NE
not evaluable
ORR
overall response rate
OS
overall survival
PD
progressive disease
PK
pharmacokinetic
PK/PD
pharmacokinetic/pharmacodynamic
PI3K
phosphatidylinositol 3-kinase
PI3K
phosphatidylinositol 3-kinase p110isoform
PFS
progression-free survival
PPD
product of the perpendicular diameters
PR
partial response
PT
preferred term
PWB
physical well-being
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SOC
system organ class 
SPD
sum of the products of the perpendicular diameters 
StD
standard deviation
SWB
social/family well-being
TEAE
treatment-emergent adverse event
TOI
trial outcome index
TTR
time to response
WHODRUG
World Health Organization Drug Dictionary


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1.
INTRODUCTION
This document details the planned analysis for the blinded portion of 
Study GS-US-312-0117, a Phase 3, double-blind extension study evaluating the efficacy and 
safety of 2 different dose levels of single-agent idelalisib for previously treated chronic 
lymphocytic leukemia (CLL) patients. Related documents are the study protocol and 
electronic case report form (eCRF).
1.1.
Study Objectives
Study Objectives

To evaluate the effect of idelalisib on the onset, magnitude, and 
duration of tumor control

To compare tumor control in subjects receiving rituximab alone in 
Study GS-US-312-0116 to that observed in the same subjects when 
receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject well-being, 
including overall survival (OS), health-related quality of life 
(HRQL), and performance status

To assess the effects of idelalisib on disease-associated biomarkers 
and to evaluate potential mechanisms of resistance to idelalisib

To characterize exposure to idelalisib as determined by treatment 
administration and evaluation of idelalisib plasma concentrations 
over time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with 
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1.2.
Study Design
Design 
Configuratio
n and Subject 
Population
Study GS-US-312-0117 is a separate, multicenter, 2-arm, double-blind, 
parallel-group extension study that is a companion trial to 
Study GS-US-312-0116; in this trial, compliant subjects from 
GS-US-312-0116 who are tolerating primary study therapy but 
experience definitive CLL progression are eligible to receive active 
blinded idelalisib therapy at the standard dose or a higher dose, with 
allocation based on the original primary study randomization. In the event 
GS-US-312-0116 is stopped early due to overwhelming efficacy 
following an interim analysis or at the final analysis, subjects who are on 
Study GS-US-312-0116 at that time may transition to GS-US-312-0117. 
Additionally, GS-US-312-0117 will become an open-label study offering 
idelalisib 150mg BID to GS-US-312-0116 subjects who were randomized 
to placebo, and subjects randomized to idelalisib will continue idelalisib 
at 150mg BID.
Target Population: Subjects in the primary Phase 3 study 
(GS-US-312-0116) who are compliant, are tolerating primary study therapy, 
and 1) have definitive progression of CLL while receiving primary study 
drug therapy (idelalisib /placebo) or 2) are actively participating in 
Study GS-US-312-0116 at the time the study is stopped, including if 
stopped early due to overwhelming efficacy following an interim analysis.
Treatment 
Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117)


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Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID
Key 
Eligibility 
Criteria
Key Inclusion Criteria
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while receiving 
study drug therapy (idelalisib /placebo) in Study GS-US-312-0116. 
Note: Definitive disease progression is CLL progression based on 
standard criteria and occurring for any reason (ie, increasing 
lymphadenopathy, organomegaly, or bone marrow involvement; 
decreasing platelet count, hemoglobin, or neutrophil count; or 
worsening of disease-related symptoms) other than lymphocytosis. 
Subjects must have confirmation by the sponsor working in 
collaboration with an independent review committee (IRC) that the 
disease has progressed on the primary clinical trial
(Study GS-US-312-0116) before receiving secondary idelalisib therapy 
on this extension trial (Study GS-US-312-0117).
3) Presence of measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures 2.0 cm in the longest diameter [LD] and 
1.0 cm in the longest perpendicular diameter [LPD] as assessed by 
computed tomography [CT] or magnetic resonance imaging [MRI]).
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab 
and/or idelalisib/placebo) and no intervening or continuing therapy 
(including radiotherapy, chemotherapy, immunotherapy, or 
investigational therapy) for the treatment of CLL. Note: Subjects may 
receive corticosteroids to manage CLL manifestations.
5) The time from permanent cessation of Study GS-US-312-0116 
treatment (rituximab and/or idelalisib/placebo) and the initiation of 
Study GS-US-312-0117 therapy is 12 weeks. Note: Study procedures 
performed as part of Study GS-US-312-0116 need not be repeated and 
can be used as screening procedures for Study GS-US-312-0117 if 
performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.


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7) Required baseline laboratory data (within 4 weeks prior to initiation of 
study treatment) as shown in the table below. Note: Confirmation 
should be considered for out-of-range values to determine if the 
abnormality is real or artifactual. Values should be obtained within 
the screening period and should generally be the most recent 
measurement obtained. Subjects with any degree of neutropenia, 
thrombocytopenia, or anemia due to CLL or prior therapy may enroll.
Key Exclusion Criteria
1) Known histological transformation from CLL to an aggressive 
lymphoma (ie, Richter transformation). 
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at the 
time of the start of study treatment (Visit 2). Note: Subjects with 
localized fungal infections of skin or nails are eligible. Subjects may 
be receiving prophylactic antiviral or antibacterial therapies at the 
discretion of the investigator; anti-pneumocystis prophylaxis is 
encouraged. 
3) Pregnancy or breastfeeding. 
4) Intentional breaking of the blind in Study GS-US-312-0116 by the 
investigator or the study subject.
5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical condition, 
surgical history, physical finding, electrocardiogram (ECG) finding, or 
laboratory abnormality that, in the investigator’s opinion, could 
adversely affect the safety of the subject or impair the assessment of 
study results.
In the event Study GS-US-312-0116 is stopped early, subjects who are 
actively participating in Study GS-US-312-0116 will become eligible for 
this study, provided the following inclusion are met: 
1) Participation in Study GS-US-312-0116 within 12 weeks of enrollment 
onto GS-US-312-0117.
2) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening visit 
(Visit 1) throughout the study and for 30 days from the last dose of 
study drug. 
3) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of study 
drug (Visit 2) throughout the study and for 90 days following the last 
dose of study drug and to refrain from sperm donation from the start of 
study drug (Visit 2) throughout the study and for 90 days following the 
last dose of study drug.


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4) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, familial, 
or geographical factors that might preclude adequate study participation 
should be considered.
5) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature of 
the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study 
participation.
Study 
Periods/
Phases
Clinic/laboratory visits will occur every 2 weeks for the first 12 weeks, 
every 4 weeks between Weeks 12 and 24, and every 6 weeks between 
Weeks 24 and 48. Subjects continuing on study drug past Week 48 will 
have clinic visits every 12 weeks. Subjects will be assessed for safety at 
each visit. Subjects will be assessed for CLL disease status by physical and 
laboratory examinations at each visit and by CT or MRI at Weeks 8, 16, 24, 
36, and 48 and every 12 weeks thereafter.
Schedule of Assessments
The schedule of assessments is located in Appendix 2 of this SAP.
Treatment 
Assignment

Assignment to Arm A or Arm B with allocation based on the 
original primary study randomization

Implementation through an interactive web response system 
(IWRS)
Site and/or 
Stratum 
Enrollment Limits
Study will be conducted at approximately 90 centers in the United 
States and in Europe.  
Study Duration
Study drug will be taken continuously until the earliest of subject 
withdrawal from study drug, definitive progression of CLL, 
intolerable study drug-related toxicity, pregnancy, substantial 
noncompliance with study procedures, or study discontinuation.


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1.3.
Sample Size and Power
Planned Sample 
Size
Total of up to ~160 subjects (up to ~80 subjects per treatment arm)
Power Statement
The sample size for this extension study is not based upon a formal 
statistical hypothesis. The upper bound of the sample size in this study 
is determined by the sample size of the preceding primary clinical trial
(Study GS-US-312-0116). Assuming a ~10% dropout rate during 
Study GS-US-312-0116 and a further ~10% dropout rate in the 
transition from the primary study to the extension study, ~160 subjects 
are expected to be enrolled into Study GS-US-312-0117.
Actual Enrollment 
and Impact on 
Power
Not applicable at this point in the study.


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2.
TYPE OF PLANNED ANALYSIS
The data monitoring committee (DMC) will have access to serious adverse events requiring 
expedited reporting and will be provided with accumulating safety data on a regular basis. 
Interim safety reviews will be conducted by the DMC in conjunction with safety reviews of 
the primary clinical trial (Study GS-US-312-0116). Thus, interim safety reviews will be 
performed by the DMC at intervals of ~6 months; the specific frequency of these reviews 
will depend upon the rate at which the trials are enrolled, the nature of any emerging safety 
signals, and monitoring recommendations from the DMC. At each review, all available 
safety data will be summarized and evaluated. 
The efficacy analysis of the blinded portion of this clinical trial (Study GS-US-312-0117) is 
planned to take place at the time of the final blinded analysis of the primary study 
(GS-US-312-0116). Once outstanding data queries have been resolved, the database will be 
finalized for the blinded portion, and the blind will be broken.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
3.1.
Analysis Sets
3.1.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set includes all subjects who receive 1 dose of idelalisib.
This analysis set will be used for both the efficacy and safety analyses.
3.1.2.
Pharmacokinetic/Pharmacodynamic Analysis Sets
The pharmacokinetic/pharmacodynamic (PK/PD) analysis sets include data from subjects in 
the ITT analysis set who have the necessary baseline and on-study measurements to provide
interpretable results for the specific parameters of interest.
These analysis sets will be used in the analyses of idelalisib plasma concentrations.
3.2.
Strata and Covariates
Not applicable
3.3.
Examination of Subject Subsets
Not applicable
3.4.
Missing Data and Outliers
Missing Data
A missing data point for a given study visit may be due to any of the following reasons:

A visit occurred in the window but data were not collected or were unusable

A visit did not occur in the window

A subject permanently discontinued from the study before reaching the window
In general, values for missing data will not be imputed unless methods for handling missing 
data are specified.
Missing data in Functional Assessment of Cancer Therapy: Leukemia (FACT- Leu) will be 
handled according to the administration and scoring guidelines.  
Outliers
No data will be excluded from the analyses, including any outliers.


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3.5.
Data Handling Conventions and Transformations

By-subject listings will be created for important variables in each eCRF module, and will 
be presented for subjects in the ITT analysis set and sorted by subject number, visit, and 
time (if applicable).  

Summary tables for continuous variables will contain the following statistics: 
N (number in analysis set), n (number with data), mean, standard deviation (StD), 
median, Q1, Q3, minimum, and maximum.  The same number of decimal places as in the 
raw data will be presented when reporting minimum and maximum, 1 more decimal 
place than in the raw data will be presented when reporting mean, median and 2 more 
decimal places than in the raw data will be presented when reporting StD.  

Summary tables for categorical variables for baseline and safety data will include: 
N, n, percentage.  The tables for efficacy endpoints will include standard error, and 
95% confidence intervals (CI) on the percentage, where appropriate.  Unless otherwise 
indicated, 95% CIs for binary variables will be calculated using the binomial distribution. 
The denominator for the percentages will be the number of subjects in the ITT analysis 
set at the same treatment or total as appropriate, unless otherwise specified.  Missing data 
will be included as a row in tables where it is appropriate.  All percentages will be 
presented as 1-decimal point, unless otherwise specified.  Percent equal to 100 will be 
presented as 100% and percent will not be presented for zero frequencies.  

Tables and figures will be displayed by visit (as appropriate) for each treatment group 
and total (as appropriate).

Data from all sites will be pooled for all analyses.

Analyses will be based upon the observed data unless methods for handling missing data 
are specified.

Unscheduled visits will only be included in listings and the best or worst post-baseline 
summary. Unscheduled visits will not be included in the by-visit summary tables, unless 
otherwise specified.

For Kaplan-Meier estimates, the 95% CIs will be calculated using the Greenwood’s 
formula with (complementary) log-log transformation.
3.5.1.
Data Handling for Efficacy Endpoints

If there is a significant degree of non-normality for a continuous endpoint, analyses may 
be performed on log-transformed data or using nonparametric methods, as appropriate. 

Analyses will generally focus on evaluation of outcomes within each treatment arm; 
formal analyses comparing outcomes in Arm A to those in Arm B are not planned.


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3.5.2.
Data Handling for Laboratory data 
Laboratory data that are continuous in nature but are less than the lower limit of quantitation 
or above the upper limit of quantitation will be imputed as follows:

A value that is 1 unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the data is reported in the form of “<x” (x is considered the limit 
of quantitation). For example, if the values are reported as <50 and <5.0, then values of 
49 and 4.9 will be used for calculation of summary statistics, respectively. However, for 
direct bilirubin, a value of “<0.1” will be treated as 0.05 for calculation of summary 
statistics. 

A value that is 1 unit above the limit of quantitation will be used for calculation of 
descriptive statistics if the data is reported in the form of “>x” (x is considered the limit 
of quantitation). For example, if the values are reported as >50 and >5.0, then values of 
51 and 5.1 will be used for calculation of summary statistics, respectively. 

The limit of quantitation will be used for calculation of descriptive statistics if the data is 
reported in the form of “≤ x” or “≥ x” (x is considered as the limit of quantitation).
3.6.
Visit Windows
3.6.1.
Analysis Windows
For parameters that will be summarized by visit, the nominal visit as recorded on the eCRF 
will be used. For parameters assessed at the end of treatment (EOT) visit, the assessment 
results will be assigned to the next scheduled visit where the respective data were scheduled 
to be collected for summary. There will be no additional analysis windowing done based on 
the assessment date. Unscheduled visit prior to the first dosing will be included for the 
calculation of baseline values. Unscheduled scans will be used for determination of the time-
to-event and tumor response efficacy endpoints.
3.6.2.
Selection of Data in the Event of Multiple Records in a Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value per visit, 
whereas a time-to-event analysis would not require 1 value per analysis window but rather 
1 value for the study. Unless otherwise noted throughout the rest of this document, when a 
single value is needed, the following rule(s) will be used:

If more than 1 assessment occurs during the same nominal visit, select the record closest 
to the nominal day for that visit.

If there are 2 assessments that are equidistant from the nominal day, the data of the 
assessment after the scheduled study day will be used.

The last measurement will be used if multiple measurements are all taken on the same 
day.  


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment
A listing of all treated subjects will be generated to describe site, subject number, 
first treatment date, actual treatment arm, exposure of idelalisib, the reason for discontinuing 
study treatment, and the reason for discontinuing study. A by-subject listing for subjects who 
were screened but not treated will be listed separately.
4.2.
Disposition of Subjects
A summary of subject disposition will be provided by treatment group.  This summary will 
present number of subjects: 

treated with study drug

ongoing treatment with study drug

discontinued the study drug (with summary of reason for not completing)

ongoing on study

completed the study  (summary of reason for study completion) 

discontinued the study (with summary of reasons for not completing)

discontinued the long-term follow-up (with summary of reasons for not completing)
The denominator for the percentages of subjects in each category will be the number of 
subjects in the ITT analysis set. No inferential statistics will be generated. 
4.3.
Extent of Exposure
4.3.1.
Duration of Exposure to Study Drugs
Duration of exposure to idelalisib will be defined as (min(last idelalisib dosing date
[ie, captured on study drug completion CRF page], data cutoff date) – first idelalisib dosing
date in Study GS-US-312-0117 + 1), regardless of temporary interruptions in study drug 
administration, and will be expressed in months. Duration of exposure to idelalisib will be 
summarized for the ITT analysis set using descriptive statistics and as the number and 
percentage of subjects exposed for at least 1 day, 2, 4, 6, and 12 months, and every 6 months 
thereafter. 
Number and percentage of subjects who had idelalisib dose modification (dose reduction and 
dose re-escalation) will also be summarized. Idelalisib dosing records, drug accountability 
(dispense and return) records, and dose modification records will be listed in details.


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4.3.2.
Adherence with idelalisib
Adherence (%) with idelalisib will be calculated as:
Adherence (%) = {sum of pills dispensed minus pills returned} divided by {sum over all 
dosing period of (total daily pills x dosing duration)}, taking into account 
investigator-prescribed interruptions.
Descriptive statistics for adherence along with the number and percentage of subjects 
belonging to adherence categories (eg, < 75% or ≥ 75%) will be provided by treatment group 
for the ITT analysis set. No inferential statistics will be provided.
4.4.
Protocol Deviations
Protocol deviations will be categorized before database finalization by Gilead. The important 
(major) protocol deviations will be summarized by type of deviation in the clinical study 
report (CSR) based on the ITT analysis set.  A listing will be provided for all protocol 
deviations.


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5.
BASELINE DATA
5.1.
Demographics and Baseline Characteristics
Demographics including gender, race, ethnicity, age (years), weight (kg), height (cm), and 
body mass index (BMI, kg/m2) will be summarized for the ITT analysis set.  Gender, race,
ethnicity, and karnofsky performance status will be summarized by using summary statistics 
for categorical variables.  Age (years), weight (kg), and height (cm) will be summarized 
using summary statistics for continuous variables.  Age will be calculated as the number of 
years between date of birth and date of first dose in Study GS-US-312-0117.
Age (years) = (date of first dose – date of birth+1) / 365. 25 (round down to an integer)
BMI (kg/m2) = weight / (height)2 (round to 1 decimal point)
Number and percentage of subjects <65 and 65 years will also be summarized. A data 
listing will be presented for the above demographic data.
5.2.
Medical History
Total cumulative illness rating scale (CIRS) scores assessed in IWRS and CIRS score by 
organ systems will be summarized using descriptive statistics and presented by treatment 
group based on the ITT analysis set. In addition, the number (%) of subjects with CIRS > 6 
and ≤ 6 will be summarized.
A by-subject listing of medical history will be provided.


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6.
EFFICACY ANALYSES 
An IRC was established for this study and includes primary board-certified radiologists and a 
board-certified adjudicating radiologist from a pool of radiologists, and an independent 
board-certified hematologist or oncologist to perform an independent review of response and 
disease progression for each subject.  The review will comprise an assessment of 
radiographic images and prospectively defined clinical data acquired during the study
according to the Gilead Protocol GS-US-312-0117 Imaging Charter.  The determination of 
CLL response and progression will be based on standardized criteria promulgated by the
International Workshop on CLL {12154}, as specifically modified for this study to reflect 
current recommendations which consider the mechanism of action of idelalisib and similar 
drugs {22541}. The findings of the IRC will be considered primary for analyses of tumor 
control endpoints.
Unless otherwise specified, time-to-event analyses will be performed with reference to the 
date of first treatment on this study (GS-US-312-0117). Similarly, evaluations of on-therapy 
changes will reference the baseline values obtained prior to treatment in this extension study.


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6.1.
Efficacy Endpoints
6.1.1.
Definition of Efficacy Endpoints

Progression-free survival (PFS) – defined as the interval from the start of study drug to 
the earlier of the first documentation of definitive disease progression or death from any 
cause; definitive disease progression is CLL progression based on standard criteria 
{12154}, {22541} other than lymphocytosis alone.

Overall response rate (ORR) – defined as the proportion of subjects who achieve a 
complete response (CR) or partial response (PR)

Lymph node response (LNR) rate – defined as the proportion of subjects who achieve a 
≥50% decrease from baseline in the sum of the products of the greatest perpendicular 
diameters (SPD) of index lesions per IRC assessments

CR rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from the start of study drug to the first 
documentation of CR or PR

Duration of response (DOR) – defined as the interval from the first documentation of CR 
or PR to the earlier of the first documentation of definitive disease progression or death 
from any cause

Percent change in lymph node area – defined as the percent change from baseline in the 
SPD of index lesions

Splenomegaly response rate – defined as the proportion of subjects with a 50% decrease 
(minimum 2 cm) from baseline in the enlargement of the spleen in its longest vertical 
dimension (LVD) or to ≤ 12 cm by imaging.

Hepatomegaly response rate – defined as the proportion of subjects with a 50% decrease 
(minimum 2 cm) from baseline in the enlargement of the liver in its LVD or to ≤ 18 cm 
by imaging.

Absolute lymphocyte count (ALC) response rate – defined as the proportion of subjects 
with baseline lymphocytosis (ALC ≥ 4 x 109/L) who achieve an on-study ALC 
<4 x 109/L or demonstrate a ≥50% decrease in ALC from baseline

Platelet response rate – defined as the proportion of subjects with baseline 
thrombocytopenia (platelet count <100 x 109/L) who achieve an on-study platelet count 
≥100 x 109/L or demonstrate a ≥ 50% increase in platelet count from baseline without 
need for exogenous growth factors. Platelet values collected within 4 weeks after the 
first dosing date will be excluded from the platelet response rate evaluation.


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
Hemoglobin response rate – defined as the proportion of subjects with baseline anemia 
(hemoglobin <110 g/L [11.0 g/dL]) who achieve an on-study hemoglobin ≥110 g/L 
(11.0 g/dL) or demonstrate a ≥ 50% increase in hemoglobin from baseline without red 
blood cell transfusions or need for exogenous growth factors. Hemoglobin values 
collected within 4 weeks after the first dosing date will be excluded from the hemoglobin 
response rate evaluation.

Neutrophil response rate – defined as the proportion of subjects with baseline neutropenia 
(absolute neutrophil count [ANC] ≤1.5 x 109/L) who achieve an ANC >1.5 x 109/L or 
demonstrate a≥ 50% increase in ANC from baseline without need for exogenous growth 
factors. ANC values collected within 4 weeks after the first dosing date, 2 weeks after 
receiving G-CSF or other growth factors, and 4 weeks after receiving Neulasta will be 
excluded from the neutrophil response rate evaluation.

OS – defined as the interval from the date of first study drug in Study GS-US-312-0117
to death from any cause during the study

Change from baseline in HRQL domain and symptom scores based on FACT-Leu

Changes from baseline in Karnofsky performance status

Change from baseline in overall health and single-item dimension scores as assessed 
using the EuroQoL Five-Dimension (EQ-5D) utility measure
6.1.2.
Analysis Methods for Efficacy Endpoints
6.1.2.1.
Progression-Free Survival
PFS will be described in the ITT analysis set using Kaplan-Meier methods by treatment 
group. The Kaplan-Meier curve will also be plotted. 
The date of definitive CLL progression will be the timepoint at which progression is 
first identified by relevant objective radiographic or clinical data. Data will be censored on 
the date of the last tumor assessment (including assessments with a not evaluable [NE]
outcome) for subjects:

who do not have disease progression or die after study discontinuation, or

who start new anti-tumor therapy prior to documented disease progression, or

who have 2 consecutive missing tumor assessments before disease progression or 
death.
Subjects without adequate baseline tumor response evaluation will be censored on the 
first dosing date. 


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6.1.2.2.
Overall response rate
Responses will be categorized as CR, PR, stable disease (SD), or progressive disease (PD).  
In addition, a response category of not evaluable (NE) is provided for situations in which 
there is inadequate information to otherwise categorize response status. A response category 
of no disease (ND) is included for situations in which there is no evidence of tumor either at 
baseline or on treatment. 
The proportion of subjects who achieve a CR or PR will be presented with 95% CI by 
treatment group. In the calculation of response rates, subjects who do not have sufficient 
baseline or on-study tumor assessment to characterize response will be included in the 
denominator. 
The ORR analysis will be evaluated using the IRC assessments based on the ITT analysis set. 
6.1.2.3.
Lymph node response rate
LNR rate will be presented with 95% CI by treatment group. Only subjects that have both
baseline and ≥1 evaluable post-baseline SPD will be included for this analysis.
6.1.2.4.
Complete response rate
The same analyses as specified for ORR in Section 6.1.2.1 will be performed for the CR rate. 
6.1.2.5.
Time to response and duration of response
TTR and DOR will be evaluated using IRC assessments based on ITT subjects who achieve a 
CR or PR. Descriptive statistics will be provided for TTR. DOR will be summarized using 
Kaplan-Meier methods (medians, Q1, Q3, and corresponding 95% CIs) and the 
Kaplan-Meier curves will also be provided by treatment group.
For the DOR analysis, data will be censored on the date of the last tumor assessment 
(including assessments with a NE outcome) for subjects:

who do not have disease progression or die after study discontinuation, or

who start new anti-tumor therapy prior to documented disease progression, or

who have 2 consecutive missing tumor assessments before disease progression or 
death.
6.1.2.6.
Best percent change in lymph node area
The best percent change in SPD from baseline during the study will be summarized using 
descriptive statistics. The summary is based on ITT subjects with sufficient baseline and 
on-study tumor measurements for the SPD calculation per IRC. The best percent change 


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from baseline in SPD is defined as the largest decrease in tumor size during the study. The 
baseline SPD will be the last value prior to the start of study treatment.  Note that for subjects 
who only have increases in tumor size from baseline, the smallest increase will be considered 
as the best change from baseline in SPD. Waterfall plots of best on-study percent change in 
SPD will be provided for each treatment group using IRC data. 
6.1.2.7.
Other categorical endpoints
Splenomegaly response rate, hepatomegaly response rate, ALC response rate, platelet 
response rate, hemoglobin response rate, and neutrophil response rate will be presented with
95% CIs. In the calculation of response rates, only subjects who have relevant abnormality, 
sufficient baseline and post-baseline assessments to characterize response will be included in 
the analysis.
6.1.2.8.
Overall Survival 
OS will be described in the ITT analysis set using Kaplan-Meier methods by treatment 
group. The Kaplan-Meier curve will also be plotted.
Data from surviving subjects will be censored at the last time that the subject was known to 
be alive on study.
6.1.2.9.
Health-Related Quality of Life
The Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) questionnaire 
includes subscales for physical well-being (PWB, 7 items), social/family well-being 
(SWB, 7 items), emotional well-being (EWB, 6 items), functional well-being 
(FWB, 7 items), and additional concerns (Lymphoma Subscale, LymS, 15 items).  The 
FACT-Leu scoring guide identifies those negatively stated items that must be reversed before 
being added to obtain subscale totals. Negatively stated items are reversed by subtracting the 
response from “4”.  After reversing proper items, all subscale items are summed to a total, 
which is the subscale score.  For all FACT-Leu scales and symptom indices, the higher score 
is associated with the better quality of life. The scores in the following items need to be 
reversed:

Physical well-being: all individual items

Social/family well-being: none

Emotional well-being: 5 individual items (except for the second item, “I am satisfied with 
how I am coping with my illness”)

Functional well-being: none

Additional concerns: all individual items 


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The subscale scores will be a summation of each individual item score.  If ≤ 50% of item 
scores are missing, the subscale score will be calculated by multiplying the sum of the item 
scores by the number of items in the subscale, then divided by the number of non-missing 
item scores.  This imputes the missing scores by the mean of the non-missing scores within a 
subscale.
Prorated subscale score = [sum of item scores] x [N of items in subscale] / [N of items 
answered]
The following composite scores will be derived from the above subscale total scores:

Trial Outcome Index (TOI, score range: 0-116) = PWB + FWB + LymS

FACT_Leu Total Score (score range: 0-168) = PWB + SWB + EWB + FWB + LymS
The total scores will be set to missing if 20% or more of the included items are missing or 
any of the component subscales are missing. TOI scores are set to missing if any of the 
component subscales are missing.
The mean and change from baseline in mean scores to each subsequent assessment will be
summarized for the subscale and composite scores. The best change from baseline during the
study, defined as the highest positive value among all post-baseline visits minus the baseline 
value, will also be summarized.
Each subject’s FACT-Leu subscales (ie, PWB, EWB, SWB, and FWB) scores at each 
assessment will be compared to their baseline scores. The minimally important difference 
(MID) for these subscales is 3 points {26297}. An increase of at least 3 points will be 
required as a definition of symptom improvement and a decline of at least 3 points will 
define symptom worsening. The cumulative distribution function (CDF) of best (or worst) 
change from baseline will be provided. For the MID improvement comparison, subjects with 
baseline score >57 will be excluded (ie, subjects with no room for improvement). Time to 
symptom response will be assessed by defining the first occurrence of symptom 
improvement as an event. Subjects who do not experience a symptom improvement 
compared to baseline will be censored at their last available PRO assessment time.
A data listing for each individual item, the subscale scores, and the composite scores will be 
presented for each subject at each visit.
6.1.2.10.
Karnofsky performance status
The Karnofsky performance status scores and the change from baseline scores to each 
subsequent assessment will be summarized.  The best and worst changes from baseline 
during the study will also be summarized.  The best change from baseline is defined as the 
highest change score at post baseline.  The worst change from baseline is defined as the 
lowest change score at post baseline.


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6.1.2.11.
EQ-5D 
The EQ-5D questionnaire data will be scored, processed, and standardized according to the 
user manual. As for the FACT-Leu, data will be analyzed using appropriate methods 
specified in the user manual to account for incomplete completion of questionnaires. Data 
collected from the EQ-5D will not be reconciled with adverse event or laboratory data or 
with FACT-Leu findings.
6.1.3.
Between-Study Comparisons
To evaluate the benefits of single-agent idelalisib relative to single-agent rituximab in the 
same subjects, between-study analyses of Study GS-US-312-0116 and GS-US-312-0117 will 
be performed among subjects who participate in Arm B of both studies.
Baseline characteristics (eg, age, CIRS, etc.) and selected efficacy endpoints (eg, PFS, ORR, 
OS, TTR, etc.) will be summarized for Study GS-US-312-0117 relative to those in
Study GS-US-312-0116.
6.2.
Changes From Protocol-Specified Efficacy Analyses
The per-protocol analysis set and the safety analysis set are no longer applicable. The ITT 
analysis set will be used for both efficacy and safety analyses.
The following analyses will be removed as they are deemed to be less informative: 
Changes from baseline in HRQL parameters or in performance status in the 2 treatment 
groups will be described by treatment group considering both: 1) all subjects that have 
baseline and at least one post-baseline assessment for HRQL or performance status with the 
worst score assigned to those subjects who have progressed or died at the timepoint, and 2) 
all subjects that have baseline and at least one post-baseline assessment for HRQL or 
performance status who have not progressed or died at the timepoint. 


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
The focus of adverse event (AE) summarization will be on treatment-emergent AEs 
(TEAEs). All AEs and deaths happened on study will be summarized by treatment arms and 
will be listed in detail based on the ITT analysis set.
7.1.1.
Adverse Event Dictionary
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
System organ class (SOC), high level group term (HLGT), high level term (HLT), preferred 
term (PT), and lower level term (LLT) will be attached to the clinical database.
7.1.2.
Adverse Event Severity
The severity of AEs will be graded by the investigator according to the common terminology 
criteria for adverse events (CTCAE), Version 4.03, whenever possible.  If a CTCAE criterion 
does not exist, the grade corresponding to the appropriate adjective will be used by the 
investigator to describe the maximum intensity of the AE.  The severity grade will be 
categorized as:

Grade 1 (mild)

Grade 2 (moderate) 

Grade 3 (severe)

Grade 4 (life threatening), or 

Grade 5 (fatal)
A missing severity grade will be considered as missing.
7.1.3.
Relationship of Adverse Events to Study Drug
The relationship of an adverse event to idelalisib should be assessed using clinical judgment 
by the investigator, describing the event as either unrelated or related. Events for which the 
investigator did not record relationship to study drug will be considered related to study drug. 
Data listings will show relationship as missing. 


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7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) are those identified as serious in the clinical database. The 
clinical database will be reconciled with the SAE database from the Drug Safety and Public 
Health (DSPH) Department before database finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent
TEAEs are events in a given study period that meet one of the following criteria:

Events with onset dates on or after the start of treatment and up to 30 days after the 
permanent discontinuation of the study treatment. 

The continuing AEs diagnosed prior to the start of treatment and worsening in severity 
grade, or non-serious AEs at baseline which become serious, or AEs resulting in 
treatment discontinuation after the start of treatment.
7.1.5.2.
Incomplete Dates
All AEs with partial onset or stop dates will be identified and the partial dates will be 
imputed as follows:

For AE onset date: If day and month are missing but year is available, then the imputed 
day and month will be 01Jan or the first dosing date if they have the same year, 
whichever is later.  If day is missing but the month and year are available, then the 
imputed day will be the first day of the month or the first dosing date if they have the 
same month and year, whichever is later.  

For AE stop date: If day and month are missing but year is available, then the imputed 
day and month will be 31Dec or 30 days after the last dose of study treatment if they have 
the same year, whichever is earlier.  If day is missing but the month and year are 
available, then the imputed day will be the last day of the month or 30 days after the last 
dose of study treatment if they have the same month and year, whichever is earlier.
7.1.6.
Summaries of Adverse Events and Deaths
A brief summary of TEAEs by treatment arms will show the number and percentage of 
subjects who (1) had any AE, (2) had any Grade ≥3 AE, (3) had any IDELA-related AE, 
(4) had any Grade ≥3 IDELA-related AE, (5) had any SAE, (6) had any IDELA-related SAE, 
(7) discontinued from study drug due to an AE, (8) dose interruption or modification due to 
an AE, (9) death due to AEs (10) on-study deaths and (11) all deaths including long-term 
follow up.


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Summaries (number and percentage of subjects) of TEAEs (by SOC, HLT and PT) will be 
provided by treatment arms using the ITT analysis set as follows:

AEs

AEs by CTCAE Grade

Grade ≥3 AE 

IDELA-related AEs

SAEs

IDELA-related SAEs 

AEs leading to IDELA reduction

AEs leading to permanent discontinuation from IDELA

AEs leading to death
Multiple events will be counted once only per subject in each summary. For data 
presentation, SOC, HLT and PT will be sorted by decreasing frequency based on treatment 
Arm A (high-dose Idelalisib). For summaries by severity grade, the most severe event will be 
selected. In addition to the presentation by SOC and HLT, each summary will also be 
presented by preferred term only, ordered by decreasing frequency. 
In addition to the by-treatment summaries, data listings will be provided for the following:

All AEs (with a variable indicating whether the event is treatment-emergent)

SAEs (with a variable indicating whether the event is treatment-emergent)

AEs leading to discontinuation of study drug

Deaths
Relative day from first dose date will be provided for each AE in the listings.  If the AE onset 
date is after the first dose date, the relative day will be calculated as (AE onset date - first 
dose date + 1), however, if the AE onset date is prior to the first dose date, the relative day 
will be calculated as (first dose date – AE onset date).  


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7.2.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed 
data and will be reported using SI units. The focus of laboratory data summarization will be 
on treatment-emergent laboratory abnormalities using the ITT analysis set. 
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (sample size, mean, standard deviation, median, Q1, Q3, minimum and 
maximum) will be provided for each laboratory test specified in the study protocol as 
follows:

Baseline values 

Values at each post-baseline visit

Change from baseline at each post-baseline visit
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.6.2. In addition, mean change from baseline (standard error) and 
median (Q1/Q3) for all lab parameters will be plotted over time by treatment arms.
7.2.2.
Summaries of Categorical Laboratory Results
Laboratory data that are categorical will be summarized using number and percentage of 
subjects in the study with the given response at baseline and each scheduled post-dose 
assessment by treatment arms.
7.2.3.
Graded Laboratory Values
Applicable hematological and serum biochemistry laboratory data will be programmatically 
graded according to CTCAE, Version 4.03 severity grade [grade laboratory results as 
Grade 0, mild (Grade 1), moderate (Grade 2), severe (Grade 3), or life threatening (Grade 4)]. 
Grade 0 includes all values that do not meet criteria for an abnormality of at least Grade 1. 
Some laboratory tests have criteria for both increased and decreased levels; analyses for each 
direction (ie, increased, decreased) will be presented separately. For all laboratory tests 
except for lipids (cholesterol and triglyceride), lab normal ranges will override CTC grade 
criteria (ie, all labs within normal ranges will be programmatically assigned a CTCAE grade 
of 0) when lab normal ranges overlaps with CTC grade criteria.
7.2.3.1.
Treatment-Emergent Laboratory Abnormalities
A treatment-emergent laboratory abnormality is defined as an abnormality that, compared to 
baseline, worsens by ≥1 grade in the period from the first dose of study drug to 30 days after 
the last dose of study treatment. If baseline data are missing, then any graded abnormality 
(ie, an abnormality that is Grade ≥1 in severity) will be considered treatment-emergent.


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7.2.3.2.
Summaries of Laboratory Abnormalities
Summary (number and percentage of subjects) of baseline and worst post-baseline 
treatment-emergent laboratory abnormalities will be provided by treatment arms. Subjects 
will be categorized according to most severe abnormality grade.
For all summaries of laboratory abnormalities, the denominator is the number of subjects in 
the ITT analysis set.  A listing of treatment-emergent Grade ≥ 3 laboratory abnormalities will 
be provided.
7.2.4.
Shift in CTCAE Grade Relative to Baseline
Shift tables will be presented by showing change in CTCAE severity grade from baseline to 
the worst grade post baseline.
7.2.5.
Transaminase elevations
Analyses of transaminase elevations will be based on laboratory values using the ITT 
analysis set. Number and percentage of subjects will be summarized by treatment arms for 
subjects:

with Grade 3 or 4 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) 
elevation 

with Grade 3 or 4 ALT/AST elevation resolved to both ALT/AST of Grade 1 or less

re-challenged after dose interruption due to Grade 3 or 4 ALT/AST elevation

with recurrence of Grade 3 or 4 ALT/AST elevation among re-challenged

with recurrent Grade 3 or 4 ALT/AST elevation resolved to both ALT/AST of Grade 1 or 
less
Kaplan-Meier curves and estimates will be provided for time to onset of first Grade 3 or 4 
treatment-emergent ALT/AST elevations. Time to onset of first event is defined as time from 
start of study treatment to the start date of first Grade 3 or 4 treatment-emergent ALT/AST 
elevation, ie, time in weeks is calculated as (start date of first occurrence – date of first dose 
of study drug +1). In the absence of an event, the censoring date applied will be the earliest 
from the following dates: last dose date (if treatment discontinued) + 30 days, analysis data 
cut-off date and death date.
For subjects with at least 1 episode of Grade 3 or 4 ALT/AST elevation, time to resolution of 
first episode of treatment-emergent Grade 3 or 4 ALT/AST elevation to Grade 1 or less will 
be summarized using Kaplan-Meier estimates. The same censoring rule described above for 
time to onset will be used. In addition, the same analysis will be performed for subjects who 
are re-challenged due to Grade 3 or 4 treatment-emergent ALT/AST elevations.


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7.3.
Concomitant Medications
Concomitant medications will be coded by means of the World Health Organization Drug 
Dictionary (WHODRUG) dictionary, Q1 2011 into Anatomical-Therapeutic-Chemical 
classification (ATC) codes.  
Concomitant medications are defined as any medications meeting the following criteria:

Starting on or after the first dose of study drug up to 30 days post the last dose

Starting before and continuing after the first dose of study drug up to 30 days post the last 
dose
The incomplete dates handling method used for AE summaries will be used for concomitant 
medication summaries (Section 7.1.5.2).
Prior medications are defined as any medications stopped before the first dose of study drug.
Summaries of the number and percentage of subjects who used prior and concomitant
medications will be presented in tabular form by preferred drug name based on the ITT 
analysis set.  The summary tables will be sorted by descending frequency based on treatment 
Arm A (high-dose idelalisib).  Subjects will only be counted once for multiple drug use (by
preferred drug name) per subject.  
Concomitant medications started on/-after the start of study medication or ongoing
medications will be flagged on the prior and concomitant medication data listing. 
The summaries and listings will be based on the ITT analysis set. 
7.4.
Body Weight and Vital Signs
Body weight at each visit, and change from baseline in body weight will be summarized for 
the ITT analysis set using descriptive statistics by treatment group for each post baseline 
analysis window. In the case of multiple values in an analysis window, data will be selected 
for analysis as described in Section 3.6.2 Selection of Data in the Event of Multiple Records 
in a Window. No inferential statistics will be generated.
7.5.
Oxygen Saturation Levels
Oxygen percent saturation and its change from baseline will be summarized for the ITT
analysis set using descriptive statistics by treatment group and by visit. The number and 
percentage of subjects who achieve the lowest value below 92% and ≥5% decrease from 
baseline in oxygen percent saturation will be summarized by treatment group. Subjects will 
be characterized only once for each of these categorizations, based on their lowest value 
observed.


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7.6.
Other Safety Measures
Physical examination results will be summarized by body system and visit.  All results will 
be listed. 
A data listing will be provided for subjects experiencing pregnancy during the study.
7.7.
Changes From Protocol-Specified Safety Analyses
Not applicable


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8.
PHARMACOKINETIC ANALYSES
Bioanalytical analyses will be performed independently so that the study team and 
investigators will not have knowledge of data from individual subjects. Idelalisib plasma 
concentrations immediately pre-dose and at 1.5 hours after administration of the dose of 
study drug at each relevant clinic visit will be summarized by treatment and visit using 
descriptive statistics.


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9.
PHARMACDYNAMIC ANALYSES
A separate biomarker analysis plan will be prepared to detail pharmacodynamics and 
biomarker analyses.


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10.
REFERENCES
12154
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et 
al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a 
report from the International Workshop on Chronic Lymphocytic Leukemia 
(IWCLL) updating the National Cancer Institute-Working Group (NCI-WG) 1996 
guidelines. Blood 2008;111 (12):5446-56.
22541
Cheson BD, Byrd JC, Rai KR, Kay NE, O'Brien SM, Flinn IW, et al. Novel 
targeted agents and the need to refine clinical end points in chronic lymphocytic 
leukemia. J Clin Oncol 2012;30 (23):2820-2.
26297
Yost KJ, Eton DT. Combining distribution- and anchor-based approaches to 
determine minimally important differences: the FACIT experience. Evaluation & 
the health professions 2005;28 (2):172-91.


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11.
SOFTWARE
SAS® Software Version 9.2. SAS Institute Inc., Cary, NC, USA.


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12.
SAP REVISION
Revision Date
(dd month, yyyy)
Section
Summary of Revision
Reason for Revision


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13.
APPENDICES
Appendix 1.
Table of Contents for Statistical Tables, Figures, and Listings
Appendix 2.
Schedule of Study Procedures


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Appendix 1.
Table of Contents for Statistical Tables, Figures, and Listings
Table 
Number
Title
Analysis Set
Subject Disposition
ITT
Analysis Sets
ITT
Important Protocol Deviations
ITT
Subject Demographics and Baseline Characteristics
ITT 
Subject Demographics and Baseline Characteristics (Between-Study 
Analysis)
ITT 
CIRS Scores
ITT
CIRS Scores (Between-Study Analysis)
ITT
Study Drug (IDELA/Placebo) Exposure
ITT
Progression-free Survival - IRC Assessment
ITT
Progression-free Survival - IRC Assessment (Between-Study Analysis)
ITT
Overall Response Rate (ORR) - IRC assessment
ITT
Overall Response Rate (ORR) - IRC assessment (Between-Study Analysis)
ITT
Lymph Node Response (LNR) Rate - IRC assessment
ITT
Lymph Node Response (LNR) Rate - IRC assessment (Between-Study 
Analysis)
ITT
Complete Response (CR) Rate - IRC assessment
ITT
Overall Survival (OS)
ITT
Time to Response (TTR) - IRC Assessment
ITT
Time to Response (TTR) - IRC Assessment (Between-Study Analysis)
ITT
Duration of Response (DOR) - IRC Assessment
ITT
Duration of Response (DOR) - IRC Assessment (Between-Study Analysis)
ITT
Best Percent Change in SPD - IRC assessment
ITT
Best Percent Change in SPD - IRC assessment (Between-Study Analysis)
ITT
Splenomegaly Response Rate - IRC assessment
ITT
Splenomegaly Response Rate - IRC assessment (Between-Study Analysis)
ITT
Hepatomegaly Response Rate - IRC Assessments
ITT
Hepatomegaly Response Rate - IRC Assessments (Between-Study 
Analysis)
ITT
ALC Response Rate
ITT
ALC Response Rate (Between-Study Analysis)
ITT
Platelet Response Rate
ITT


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Table 
Number
Title
Analysis Set
Platelet Response Rate (Between-Study Analysis)
ITT
Hemoglobin Response Rate
ITT
Hemoglobin Response Rate (Between-Study Analysis)
ITT
Neutrophil Response Rate
ITT
Neutrophil Response Rate (Between-Study Analysis)
ITT
CLL Assessment by CT/MRI - Investigator assessment
ITT
Health Related Quality of Life (HRQL) – Summary of Change in FACT-
Leu Subscale Scores
ITT
Health Related Quality of Life (HRQL) - Summary of Symptom 
Improvement/Worsening in FACT-Leu Subscale Scores
ITT
Change in Karnofsky Performance Status
ITT
Change in EuroQoL Five Dimension Utility Measure
ITT
Overall Summary of Adverse Events
ITT
TEAEs by MedDRA SOC, HLT and PT
ITT
TEAEs by MedDRA SOC, HLT, PT and CTCAE Grade
ITT
TEAEs Related to IDELA/Placebo by MedDRA SOC, HLT and PT
ITT
TEAEs Related to Rituximab by MedDRA SOC, HLT and PT
ITT
Grade ≥ 3 TEAEs by MedDRA SOC, HLT and PT
ITT
Grade ≥ 3 TEAEs Related to IDELA by MedDRA SOC, HLT and PT
ITT
Serious TEAEs by MedDRA SOC, HLT and PT
ITT
Serious TEAEs Related to IDELA by MedDRA SOC, HLT and PT
ITT
TEAEs Leading to Reduction of IDELA by MedDRA SOC, HLT, PT and 
CTCAE grade
ITT
TEAEs Leading to IDELA Discontinuation by MedDRA SOC, HLT and 
PT
ITT
TEAEs Leading to Death by MedDRA SOC, HLT and PT term
ITT
TEAEs by MedDRA PT and CTCAE Grade
ITT
All Grade and Grade ≥ 3 TEAEs by MedDRA PT
ITT
All Grade and Grade ≥ 3 TEAEs Related to IDELA by MedDRA PT
ITT
Serious TEAEs by MedDRA PT 
ITT
TEAEs Leading to Reduction of IDELA by MedDRA PT and CTCAE 
grade
ITT
TEAEs Leading to IDELA Discontinuation by MedDRA PT
ITT
TEAEs Leading to Death by MedDRA PT
ITT


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Table 
Number
Title
Analysis Set
Death On Study
ITT
Deaths On Study and Long-term Follow up
ITT
Prior Medications
ITT
Concomitant Medications
ITT
Hematology: Summary of Actual Values and Change from Baseline
ITT
Hematology: Treatment-Emergent Laboratory Abnormalities
ITT
Hematology: Shift from Baseline to worst CTCAE Severity Grade
ITT
Serum Chemistry: Summary of Actual Values and Change from Baseline
ITT
Serum Chemistry: Treatment-Emergent Laboratory Abnormalities 
ITT
Serum Chemistry: Shift from Baseline to worst CTCAE Severity Grade
ITT
Summary of Transaminase Elevations
ITT
Time to Onset and Time to Resolution of Transaminase Elevations
ITT
Urinalysis: Summary of Actual Values at Baseline
ITT
Immunoglobulin: Summary of Actual Values and Change from Baseline
ITT
Oxygen Saturation: Summary of Actual Values and Change from Baseline
ITT
Decrease of Oxygen Saturation Level
ITT
Physical Examination
ITT


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Listing 
Number
Title
Analysis Set
Screen Failures
Subject Disposition
ITT
Analysis Set
ITT
Major Protocol Deviations
ITT
Subject Demographics and Baseline Characteristics
ITT
CIRS Score
ITT
IDELA Accountability
ITT
Study Drug Administration
ITT
IDELA Interruption and Modification
ITT
Tumor Assessment: Measurable Lesions - IRC Assessment
ITT
Tumor Assessment: Non-Measurable Lesions - IRC Assessment
ITT
Tumor Response Assessment - IRC Assessment
ITT
CLL Assessment by Physical Examination – Investigator Assessment
ITT
CLL Assessment by CT/MRI scan – Investigator Assessment
ITT
Tumor Response Assessment - Investigator Assessment
ITT
Progression Free Survival
ITT
Overall Survival
ITT
Duration of Response
ITT
Time to First Response
ITT
Overall Tumor Response Assessment
ITT
Bone Marrow Aspirate and Biopsy
ITT
Health Related Quality of Life (HRQL) - FACT-Leu Scores
ITT
Karnofsky Performance Status
ITT
EuroQoL Five-Dimension 
ITT
Laboratory Tests: Hematology
ITT
Laboratory Tests: Chemistry
ITT
Laboratory Tests: Urinalysis
ITT
Laboratory Tests: Immunoglobulin
ITT
Treatment-Emergent Laboratory Abnormalities
ITT
Transaminase Elevations
ITT
Treatment Emergent Adverse Events
ITT
Non-Treatment Emergent Adverse Events
ITT


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Listing 
Number
Title
Analysis Set
Serious Treatment Emergent Adverse Events
ITT
TEAEs Leading to Interruption or Modification of IDELA
ITT
TEAEs Leading to IDELA Discontinuation
ITT
Adverse Events Leading to Death
ITT
All Deaths
ITT
Vital Sign and Oxygen Saturation
ITT
Prior and Concomitant Medications
ITT
Concomitant Therapy
ITT
Transfusion Log
ITT
Hospitalization
ITT
Pregnancy
ITT
Long term Follow up Contact
ITT
Comment
ITT


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Figure
Number
Title
Analysis Set
Kaplan-Meier Curve of Progression Free Survival – IRC Assessment
ITT
Forest Plot of Overall Response Rate (ORR) and 95% Confidence Interval 
(CI) – IRC Assessment
ITT
Forest Plot of Lymph Node Response Rate and 95% Confidence Interval 
(CI) – IRC Assessment
ITT
Forest Plot of Complete Response (CR) Rate and 95% Confidence Interval 
(CI) – IRC Assessment
ITT
Kaplan-Meier Curve of Overall Survival
ITT
Kaplan-Meier Curve of Duration of Response – IRC Assessment
ITT
Kaplan-Meier Curve of Time to Response – IRC Assessment
ITT
Waterfall Plot of Best Percent Change from Baseline in SPD
ITT
Cummulative Distribution Fuction of Best Change from Baseline: FACT-
Leu Physical Well-being
ITT
Cummulative Distribution Fuction of Worst Change from Baseline: FACT-
Leu Physical Well-being
ITT
Cummulative Distribution Fuction of Best Change from Baseline: FACT-
Leu Social/Family Well-being
ITT
Cummulative Distribution Fuction of Worst Change from Baseline: FACT-
Leu Social/Family Well-being
ITT
Cummulative Distribution Fuction of Best Change from Baseline: FACT-
Leu Emotional Well-being
ITT
Cummulative Distribution Fuction of Worst Change from Baseline: FACT-
Leu Emotional Well-being
ITT
Cummulative Distribution Fuction of Best Change from Baseline: FACT-
Leu Functional Well-being
ITT
Cumulative Distribution Function of Worst Change from Baseline: FACT-
Leu Functional Well-being
ITT
Cumulative Distribution Function of Best Change from Baseline: FACT-
Leu Additional Concerns
ITT
Cummulative Distribution Function of Worst Change from Baseline: 
FACT-Leu Additional Concerns
ITT
Volcano Plot of Treatment-Emergent Adverse Events
ITT
Volcano Plot of Treatment-Emergent Laboratory Abnormalities
ITT
Kaplan-Meier Curve of Time to Onset of First Grade 3 or 4 ALT/AST 
Elevation
ITT
Kaplan-Meier Curve of Time to Onset of First Grade 3 or 4 ALT/AST 
Elevation – Rechallenged Subjects Only
ITT


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Figure
Number
Title
Analysis Set
Kaplan-Meier Curve of Time to Resolution of First Grade 3 or 4 ALT/AST 
Elevation
ITT
Kaplan-Meier Curve of Time to Resolution of First Grade 3 or 4 ALT/AST 
Elevation – Rechallenged Subjects Only
ITT
Median and Q1/Q3 Over Time: Albumin (g/L)
ITT
Median and Q1/Q3 Over Time: Alkaline Phosphatase (U/L)
ITT
Median and Q1/Q3 Over Time: ALT (U/L)
ITT
Median and Q1/Q3 Over Time: AST (U/L)
ITT
Median and Q1/Q3 Over Time: Chloride (mmol/L)
ITT
Median and Q1/Q3 Over Time: Creatinine (umol/L)
ITT
Median and Q1/Q3 Over Time: GGT (U/L)
ITT
Median and Q1/Q3 Over Time: Glucose (mmol/L)
ITT
Median and Q1/Q3 Over Time: Phosphorus (mmol/L)
ITT
Median and Q1/Q3 Over Time: Creatinine (umol/L)
ITT
Median and Q1/Q3 Over Time: Potassium (mmol/L)
ITT
Median and Q1/Q3 Over Time: Sodium (mmol/L)
ITT
Median and Q1/Q3 Over Time: Total Bilirubin (umol/L)
ITT
Median and Q1/Q3 Over Time: Total Protein (g/L)
ITT
Median and Q1/Q3 Over Time: Triglycerides (mmol/L)
ITT
Median and Q1/Q3 Over Time: Basophils (K/uL)
ITT
Median and Q1/Q3 Over Time: Eosinophils (K/uL)
ITT
Median and Q1/Q3 Over Time: Hematocrit (%)
ITT
Median and Q1/Q3 Over Time: Hemoglobin (g/L)
ITT
Median and Q1/Q3 Over Time: Lymphocytes (10^9/L)
ITT
Median and Q1/Q3 Over Time: Monocytes (10^9/L)
ITT
Median and Q1/Q3 Over Time: Neutrophils (10^9/L)
ITT
Median and Q1/Q3 Over Time: Platelets (10^9/L)
ITT
Median and Q1/Q3 Over Time: RBC (10^12/L)
ITT
Median and Q1/Q3 Over Time: WBC (10^9/L)
ITT
Mean and SE Over Time: Albumin (g/L)
ITT
Mean and SE Over Time: Alkaline Phosphatase (U/L)
ITT
Mean and SE Over Time: ALT (U/L)
ITT
Mean and SE Over Time: AST (U/L)
ITT


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Figure
Number
Title
Analysis Set
Mean and SE Over Time: Chloride (mmol/L)
ITT
Mean and SE Over Time: Creatinine (umol/L)
ITT
Mean and SE Over Time: GGT (U/L)
ITT
Mean and SE Over Time: Glucose (mmol/L)
ITT
Mean and SE Over Time: Phosphorus (mmol/L)
ITT
Mean and SE Over Time: Creatinine (umol/L)
ITT
Mean and SE Over Time: Potassium (mmol/L)
ITT
Mean and SE Over Time: Sodium (mmol/L)
ITT
Mean and SE Over Time: Total Bilirubin (umol/L)
ITT
Mean and SE Over Time: Total Protein (g/L)
ITT
Mean and SE Over Time: Triglycerides (mmol/L)
ITT
Mean and SE Over Time: Basophils (K/uL)
ITT
Mean and SE Over Time: Eosinophils (K/uL)
ITT
Mean and SE Over Time: Hematocrit (%)
ITT
Mean and SE Over Time: Hemoglobin (g/L)
ITT
Mean and SE Over Time: Lymphocytes (10^9/L)
ITT
Mean and SE Over Time: Monocytes (10^9/L)
ITT
Mean and SE Over Time: Neutrophils (10^9/L)
ITT
Mean and SE Over Time: Platelets (10^9/L)
ITT
Mean and SE Over Time: RBC (10^12/L)
ITT
Mean and SE Over Time: WBC (10^9/L)
ITT
Mean Change From Baseline: Albumin (g/L)
ITT
Mean Change From Baseline: Alkaline Phosphatase (U/L)
ITT
Mean Change From Baseline: ALT (U/L)
ITT
Mean Change From Baseline: AST (U/L)
ITT
Mean Change From Baseline: Chloride (mmol/L)
ITT
Mean Change From Baseline: Creatinine (umol/L)
ITT
Mean Change From Baseline: GGT (U/L)
ITT
Mean Change From Baseline: Glucose (mmol/L)
ITT
Mean Change From Baseline: Phosphorus (mmol/L)
ITT
Mean Change From Baseline: Creatinine (umol/L)
ITT
Mean Change From Baseline: Potassium (mmol/L)
ITT


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Figure
Number
Title
Analysis Set
Mean Change From Baseline: Sodium (mmol/L)
ITT
Mean Change From Baseline: Total Bilirubin (umol/L)
ITT
Mean Change From Baseline: Total Protein (g/L)
ITT
Mean Change From Baseline: Triglycerides (mmol/L)
ITT
Mean Change From Baseline: Basophils (K/uL)
ITT
Mean Change From Baseline: Eosinophils (K/uL)
ITT
Mean Change From Baseline: Hematocrit (%)
ITT
Mean Change From Baseline: Hemoglobin (g/L)
ITT
Mean Change From Baseline: Lymphocytes (10^9/L)
ITT
Mean Change From Baseline: Monocytes (10^9/L)
ITT
Mean Change From Baseline: Neutrophils (10^9/L)
ITT
Mean Change From Baseline: Platelets (10^9/L)
ITT
Mean Change From Baseline: RBC (10^12/L)
ITT
Mean Change From Baseline: WBC (10^9/L)
ITT


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Appendix 2.
Schedule of Study Procedures
Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4
5a
6
7a
8
9
10
11
12
13
14
15
16+
End of 
Study
30 
days
Long-
term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12 
Weeks
Study Day
Within 
-28 
Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within 
+30 
days
To  
+5 
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Informed consent
X
CIRS assessment
X
β-HCG (women of childbearing 
potential)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CLL peripheral blood evaluation
X
X
CLL serology
X
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Genotyping and expression analysis
X
X
HRQL/healthy utility – FACT-
Leu/EQ-5D
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exam (includes nodes, liver, 
spleen)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Oxygen saturation (by pulse oximetry)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Circulating cells
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4
5a
6
7a
8
9
10
11
12
13
14
15
16+
End of 
Study
30 
days
Long-
term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12 
Weeks
Study Day
Within 
-28 
Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within 
+30 
days
To  
+5 
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Biomarkers
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Igs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug administration in clinic
Xb
X
X
X
X
X
X
X
Idelalisib pharmacokineticsb
X
X
X
X
X
X
X
X
Study drug dispensing/accountingb
X
X
X
X
X
X
X
X
X
X
X
Radiology assessment (CT/MRI)d
X
X
X
X
X
X
X
X
Bone marrow biopsy/aspiratec
X
X
X
X
X
X
X
X
Post-treatment CLL therapy
X
Long-term follow-up 
X
a
Following unblinding of the study, visits 3, 5, and 7 will not be applicable for subjects who were randomized to idelalisib on Study GS-US-312-0116
b
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll following unblinding, may have idelalisib treatment (and associated PK testing) delayed at 
the Investigator’s discretion until the time of disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib treatment
c
At screening, to be performed at investigator discretion to determine extent of CLL involvement and bone marrow cellularity. Post-screening, to be performed to confirm CR 
or PD; if the subject does not otherwise meet criteria for CR or if the nature of PD does not require bone marrow confirmations, it is not necessary to obtain a follow-up bone 
marrow biopsy/aspirate
d
Following unblinding of the study, the imaging schedule will follow standard of care for subjects who were randomized to idelalisib on Study GS-US-312-0116 and subjects 
who were randomized to placebo on Study GS-US-312-0116 and enroll on Study GS-US-312-0117 will follow local standard of care for follow-up imaging until initiation of 
idelalisib, at which time the per-protocol schedule will be followed
Abbreviations: -HCG=beta human chorionic gonadotropin, CIRS=chronic illness rating scale, CLL=chronic lymphocytic leukemia, CR=complete response, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy- Leukemia, HRQL= health-related 
quality of life, Ig=immunoglobulin, IWRS=interactive web response system, MRI= magnetic resonance imaging.

Prot_010.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and 
Safety of Two Different Dose Levels of Single-Agent Idelalisib
(GS-1101) for Previously Treated Chronic Lymphocytic Leukemia
A Companion Trial to Study GS-US-312-0116: A Phase 3, Randomized, 
Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of Idelalisib (GS-1101) in Combination with Rituximab for 
Previously Treated Chronic Lymphocytic Leukemia
Sponsor:
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102
USA
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
EudraCT Number:
101254
2011-006293-72
Indication:
Chronic Lymphocytic Leukemia 
Protocol ID:
GS-US-312-0117
Gilead Sciences
Medical Monitor:
Name:
Telephone:
Office Fax:
Mobile Telephone:
E-mail:
Protocol Version/Date:
Version 1.0 (Original)
23 January 2012
Version 2.0 (Amendment 1)
23 January 2013
Version 3.0 (Amendment 2)
10 September 2013
Version 4.0 (Amendment 3)
16 December 2013
Version 5.0 (Amendment 4)
27 May 2014
Version 6.0 (Amendment 5)
10 October 2014
Version 7.0 (Amendment 6)
28 March 2016
Version 8.0 (Amendment 7)
05 August 2016
Version 9.0 (Amendment 8)
24 October 2016
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or under 
control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable institutional review board 
or independent ethics committee. This information is only to be used by you in connection with 
authorized clinical studies of the investigational drug described in the protocol. You must not 
disclose any of the information to others without written authorization from Gilead Sciences, Inc., 
except to the extent necessary to obtain informed consent from those persons to whom the drug may 
be administered.
PPD
PPD
PPD
PPD
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................6
LIST OF IN-TEXT FIGURES ......................................................................................................................................6
PROTOCOL SYNOPSIS ..............................................................................................................................................7
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................19
1.
INTRODUCTION ..............................................................................................................................................23
1.1.
Chronic Lymphocytic Leukemia............................................................................................................23
1.2.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies....................................................................24
1.3.
Idelalisib (formerly GS-1101)................................................................................................................25
1.3.1.
General Information .............................................................................................................25
1.3.2.
Safety Pharmacology............................................................................................................25
1.3.3.
Nonclinical Pharmacology and Metabolism.........................................................................26
1.3.4.
Toxicology ...........................................................................................................................27
1.3.5.
Idelalisib Clinical Studies.....................................................................................................27
1.4.
Summary and Justification for the Current Study ..................................................................................31
2.
STUDY DESIGN................................................................................................................................................34
2.1.
Design Overview and Study Schema .....................................................................................................34
2.2.
Design Rationale ....................................................................................................................................35
3.
OBJECTIVES AND ENDPOINTS ....................................................................................................................37
3.1.
Endpoints ...............................................................................................................................................37
3.1.1.
Tumor Control......................................................................................................................37
3.1.2.
Patient Well-Being ...............................................................................................................38
3.1.3.
Pharmacodynamic Markers of Drug Activity and Resistance..............................................39
3.1.4.
Exposure...............................................................................................................................39
3.1.5.
Safety....................................................................................................................................39
3.1.6.
Pharmacoeconomics.............................................................................................................39
3.2.
Endpoint Selection Rationale.................................................................................................................39
3.2.1.
Tumor Control Endpoints.....................................................................................................39
3.2.2.
Measures of Patient Well-Being...........................................................................................42
3.2.3.
Pharmacodynamic Markers of Drug Activity and Resistance..............................................43
3.2.4.
Assessments of Exposure .....................................................................................................45
3.2.5.
Evaluations of Safety............................................................................................................45
3.2.6.
Pharmacoeconomic Measures ..............................................................................................46
4.
SUBJECT POPULATION..................................................................................................................................47
4.1.
Number of Subjects................................................................................................................................47
4.2.
Subject Selection Criteria.......................................................................................................................47
4.2.1.
Inclusion Criteria..................................................................................................................47
4.2.2.
Exclusion Criteria.................................................................................................................49
4.3.
Enrollment Criteria Rationale ................................................................................................................50
5.
TREATMENT OF SUBJECTS ..........................................................................................................................51
5.1.
Enrollment..............................................................................................................................................51
5.1.1.
Interactive Web Response System .......................................................................................51
5.1.2.
Treatment Assignment .........................................................................................................51
5.1.3.
Blinding................................................................................................................................52


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5.2.
Investigational Study Drug (Idelalisib/Placebo) ....................................................................................53
5.2.1.
Description ...........................................................................................................................53
5.2.2.
Source...................................................................................................................................53
5.2.3.
Packaging and Labeling .......................................................................................................53
5.2.4.
Storage and Handling...........................................................................................................54
5.2.5.
Dispensing............................................................................................................................54
5.2.6.
Return...................................................................................................................................55
5.2.7.
Accountability......................................................................................................................55
5.2.8.
Overdose Precautions...........................................................................................................55
5.2.9.
Inadvertent Exposure and Spill Precautions.........................................................................56
5.3.
Study Drug Administration....................................................................................................................56
5.3.1.
Premedication.......................................................................................................................56
5.3.2.
Administration Instructions..................................................................................................56
5.3.3.
Dosing Schedule...................................................................................................................56
5.3.4.
Dose Levels..........................................................................................................................56
5.3.5.
Dose Schedule Interruptions and Vomited Doses ................................................................57
5.3.6.
Safety Monitoring and Study Drug Interruption/Dose Modification ...................................57
5.4.
Evaluation, Intervention, and Drug Discontinuation for Specific Adverse Events or 
Conditions ..............................................................................................................................................61
5.4.1.
Dermatological Events .........................................................................................................61
5.4.2.
Gastrointestinal Events.........................................................................................................62
5.4.3.
Hepatic Events......................................................................................................................64
5.4.4.
Hematological and Immunological Events...........................................................................65
5.4.5.
Infectious Events..................................................................................................................65
5.4.6.
Progressive Multifocal Leukoencephalopathy .....................................................................66
5.4.7.
Pulmonary Events ................................................................................................................66
5.4.8.
Secondary Malignancies.......................................................................................................67
5.4.9.
Tumor Lysis Syndrome........................................................................................................67
5.4.10.
Pregnancy, Lactation, and Reproduction..............................................................................67
5.4.11.
Ultraviolet Exposure ............................................................................................................68
5.4.12.
Further Safety Information...................................................................................................69
5.5.
Emergency Unblinding ..........................................................................................................................69
5.6.
Concomitant and Supportive Therapy....................................................................................................69
5.6.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments............................................................................................................................70
5.6.2.
Antibiotics............................................................................................................................70
5.6.3.
Antiemetics and Antidiarrheals............................................................................................70
5.6.4.
Contraception .......................................................................................................................70
5.6.5.
Corticosteroids .....................................................................................................................72
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin..............................................72
5.6.7.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism..................................................72
5.6.8.
Drugs that undergo CYP3A-Dependent Metabolism...........................................................73
5.6.9.
Immunization .......................................................................................................................73
5.6.10.
Surgery .................................................................................................................................73
5.6.11.
Diet.......................................................................................................................................73
5.7.
Duration of Study Drug..........................................................................................................................73
5.8.
Discontinuation of Study Drug ..............................................................................................................73
5.9.
Discontinuation from Study ...................................................................................................................74
5.10.
Study Treatment Rationale.....................................................................................................................75
6.
STUDY PROCEDURES ....................................................................................................................................77
6.1.
Enrollment and Study Management Procedures ....................................................................................77
6.1.1.
Subject Recruitment .............................................................................................................77
6.1.2.
Subject Compensation for Participation...............................................................................77


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6.1.3.
Screening..............................................................................................................................77
6.2.
Explanation of Study Visits....................................................................................................................78
6.2.1.
Visit 1 and Screening Period (Clinic Visit)..........................................................................79
6.2.2.
Visit 2 (Day 1) (Clinic Visit)................................................................................................81
6.2.3.
Visit 3 (Day 15) (Clinic Visit)..............................................................................................82
6.2.4.
Visit 4 (Day 29) (Clinic Visit)..............................................................................................83
6.2.5.
Visit 5 (Day 43) (Clinic Visit)..............................................................................................85
6.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit) .....................................................................86
6.2.7.
Visit 7 (Day 71) (Laboratory Visit)......................................................................................87
6.2.8.
Visit 8 (Day 85) (Clinic Visit)..............................................................................................88
6.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit) ...................................................................90
6.2.10.
Visit 10 (Day 141) (Clinic Visit)..........................................................................................92
6.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit) .................................................................94
6.2.12.
Visit 12 (Day 211) (Clinic Visit)..........................................................................................96
6.2.13.
Visit 13 (Day 253) (Clinic and Radiology Visit) .................................................................97
6.2.14.
Visit 14 (Day 295) (Clinic Visit)..........................................................................................98
6.2.15.
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks) (Clinic 
and Radiology Visits)...........................................................................................................99
6.2.16.
End-of-Study Visit (Clinic Visit) .......................................................................................101
6.2.17.
30 Day and Long-Term Follow-up.....................................................................................102
6.3.
Sample Storage.....................................................................................................................................102
6.4.
Blood Collection ..................................................................................................................................103
6.5.
Study Procedure Rationale...................................................................................................................103
7.
EFFICACY ASSESSMENTS...........................................................................................................................104
7.1.
Tumor Status Assessments...................................................................................................................104
7.2.
Method of Assessment .........................................................................................................................104
7.3.
Timing of Assessments ........................................................................................................................104
7.4.
Identification and Measurement of Tumor Lesions and Organomegaly ..............................................105
7.4.1.
Index Lesions .....................................................................................................................105
7.4.2.
Spleen and Liver.................................................................................................................106
7.4.3.
Non-Index Lesions .............................................................................................................106
7.5.
Definitions of Tumor Response and Progression.................................................................................106
7.5.1.
Complete Response............................................................................................................107
7.5.2.
Partial Response .................................................................................................................107
7.5.3.
Stable Disease ....................................................................................................................108
7.5.4.
Definitive Progressive Disease...........................................................................................108
7.5.5.
Non-Evaluable....................................................................................................................110
7.5.6.
No Disease .........................................................................................................................110
7.5.7.
Lymphocytosis During Therapy.........................................................................................111
7.5.8.
Documentation of Definitive CLL Progression..................................................................111
8.
SAFETY ASSESSMENTS...............................................................................................................................112
8.1.
Adverse Event Definitions ...................................................................................................................112
8.1.1.
Adverse Event ....................................................................................................................112
8.1.2.
Serious Adverse Event .......................................................................................................113
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .......................................................................114
8.2.
Assessment of Adverse Events and Serious Adverse Events...............................................................114
8.2.1.
Assessment of Causality for Study Drugs and Procedures.................................................115
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.....................................................................................................................115
8.4.
Gilead Reporting Requirements...........................................................................................................116
8.5.
Grading of the Severity of an Adverse Event.......................................................................................116


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8.6.
Adverse Event Reporting Period..........................................................................................................117
8.7.
Adverse Event Reporting Requirements ..............................................................................................117
8.7.1.
Site Reporting Requirements..............................................................................................117
8.7.2.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population.........................................................119
8.8.
Special Situations Reporting Requirements.........................................................................................119
8.8.1.
Definitions of Special Situations........................................................................................119
8.9.
Instructions for Reporting Special Situations.......................................................................................120
8.9.1.
Instructions for Reporting Pregnancies ..............................................................................120
8.9.2.
Reporting Other Special Situations ....................................................................................121
9.
STATISTICAL CONSIDERATIONS..............................................................................................................122
9.1.
Analysis Objectives..............................................................................................................................122
9.2.
Analysis Endpoints...............................................................................................................................122
9.3.
Analysis Conventions...........................................................................................................................122
9.3.1.
Analysis Sets ......................................................................................................................122
9.3.2.
Data Handling Conventions ...............................................................................................123
9.4.
Analysis Plan........................................................................................................................................125
9.4.1.
Subject Disposition and Baseline Characteristics...............................................................125
9.4.2.
Efficacy Analyses...............................................................................................................126
9.4.3.
Exposure and Safety Analyses ...........................................................................................127
9.4.4.
Other Analyses ...................................................................................................................129
9.5.
Sample Size..........................................................................................................................................130
9.6.
Timing of Analyses..............................................................................................................................131
10.
RESPONSIBILITIES........................................................................................................................................132
10.1.
Investigator Responsibilities ................................................................................................................132
10.1.1.
Compliance with Ethical and Regulatory Guidelines.........................................................132
10.1.2.
Institutional Review Board/Independent Ethics Committee ..............................................132
10.1.3.
Informed Consent...............................................................................................................133
10.1.4.
Confidentiality....................................................................................................................133
10.1.5.
Study Files and Retention of Records and Biological Samples..........................................133
10.1.6.
Case Report Forms.............................................................................................................135
10.1.7.
Drug Accountability...........................................................................................................135
10.1.8.
Inspections..........................................................................................................................136
10.1.9.
Protocol Compliance..........................................................................................................136
10.2.
Sponsor Responsibilities ......................................................................................................................136
10.2.1.
Protocol Modifications.......................................................................................................136
10.2.2.
Communications with Regulatory Authorities...................................................................136
10.2.3.
Data Management ..............................................................................................................137
10.2.4.
Study Reporting and Publication........................................................................................137
10.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................138
10.3.1.
Access to Information for Monitoring................................................................................138
10.3.2.
Access to Information for Auditing or Inspections ............................................................138
10.3.3.
Public Notification of Study Conduct ................................................................................138
10.3.4.
Study Discontinuation........................................................................................................138
10.4.
Study Committees ................................................................................................................................139
10.4.1.
Data Monitoring Committee ..............................................................................................139
10.4.2.
Independent Review Committee ........................................................................................140
11.
REFERENCES .................................................................................................................................................141
12.
APPENDICES ..................................................................................................................................................151


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Appendix 1.
Investigator Signature Page..................................................................................................152
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) ...................................153
Appendix 3.
Performance Status Scoring System.....................................................................................156
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D) ........................................................................................157
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance ............................................159
Appendix 6.
Cumulative Illness Rating Scale (CIRS) ..............................................................................160
Appendix 7.
Schedule of Study Procedures..............................................................................................162
LIST OF IN-TEXT TABLES
Table 4-1.
Required Screening Laboratory Values..................................................................................48
Table 5-1.
Study Drug Dose Levels.........................................................................................................57
Table 5-2.
Recommendations and Requirements for Study Drug Dose Modifications Based on 
Type and Severity of Treatment-Related Adverse Events or Laboratory 
Abnormalities .........................................................................................................................58
Table 5-3.
Protocol-Recommended Contraceptive Methods ...................................................................71
Table 5-4.
Known Strong Inducers of CYP3A........................................................................................72
Table 6-1.
Procedures and Assessments at Visit 1 (During Screening Period)........................................80
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1) .....................................................................81
Table 6-3.
Procedures and Assessments at Visit 3 (Day 15) ...................................................................82
Table 6-4.
Procedures and Assessments at Visit 4 (Day 29) ...................................................................83
Table 6-5.
Procedures and Assessments at Visit 5 (Day 43) ...................................................................85
Table 6-6.
Procedures and Assessments at Visit 6 (Day 57) ...................................................................86
Table 6-7.
Procedures and Assessments at Visit 7 (Day 71) ...................................................................87
Table 6-8.
Procedures and Assessments at Visit 8 (Day 85) ...................................................................88
Table 6-9.
Procedures and Assessments at Visit 9 (Day 113) .................................................................90
Table 6-10.
Procedures and Assessments at Visit 10 (Day 141) ...............................................................92
Table 6-11.
Procedures and Assessments at Visit 11 (Day 169) ...............................................................94
Table 6-12.
Procedures and Assessments at Visit 12 (Day 211) ...............................................................96
Table 6-13.
Procedures and Assessments at Visit 13 (Day 253) ...............................................................97
Table 6-14.
Procedures and Assessments at Visit 14 (Day 295) ...............................................................98
Table 6-15.
Procedures and Assessments at Visit 15 and Subsequent Visits (Day 337 and Every 
12 Weeks)...............................................................................................................................99
Table 6-16.
Procedures and Assessments at End-of-Study Visit.............................................................101
Table 8-1.
Grading of Adverse Event Severity......................................................................................117
Table 8-2.
Site Reporting Requirements for Adverse Events ................................................................118
Table 8-3.
Contact Information for Reporting Serious Adverse Events ................................................119
LIST OF IN-TEXT FIGURES
Figure 2-1.
Study Design ..........................................................................................................................34
Figure 5-1.
Kaplan-Meler Time to Diarrhea or Colitis .............................................................................63


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102, USA
Study Title:
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and 
Safety of Two Different Dose Levels of Single-Agent Idelalisib
(GS-1101) as Therapy for Patients with Previously Treated Chronic 
Lymphocytic Leukemia
A Companion Study to Study GS-US-312-0116: A Phase 3, Randomized, 
Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of Idelalisib (GS-1101) in Combination with Rituximab as 
Therapy for Patients with Previously Treated Chronic Lymphocytic 
Leukemia
Study Centers 
Planned:
Approximately 90 centers in the United States and in Europe
IND Number:
EudraCT Number:
101254
2011-006293-72
Objectives:

To evaluate the effect of idelalisib (formerly GS-1101) on the onset, 
magnitude, and duration of tumor control

To compare tumor control in subjects receiving rituximab alone in 
Study GS-US-312-0116 to that observed in the same subjects when 
receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject well-being, 
including overall survival (OS), health-related quality of life 
(HRQL), and performance status

To assess the effects of idelalisib on disease-associated biomarkers 
and to evaluate potential mechanisms of resistance to idelalisib

To characterize exposure to idelalisib as determined by treatment 
administration and evaluation of idelalisib plasma concentrations 
over time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with 
administration of idelalisib


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Study Design:
This study is being conducted as part of an overall clinical program 
evaluating the efficacy and safety of idelalisib in the therapy of patients 
with previously treated chronic lymphocytic leukemia (CLL).
Within this program, the primary clinical trial (Study GS-US-312-0116)
is a Phase 3, multicenter, 2-arm, randomized, double-blind, 
placebo-controlled, parallel-group study.
This clinical trial (Study GS-US-312-0117) is a separate, multicenter, 
2-arm, double-blind, parallel-group extension study that is a companion 
trial to Study GS-US-312-0116; in this trial, compliant subjects from 
GS-US-312-0116 who are tolerating primary study therapy but 
experience definitive CLL progression are eligible to receive active 
blinded idelalisib therapy at the standard dose or a higher dose, with 
allocation based on the original primary study randomization. In the 
event GS-US-312-0116 is stopped early due to overwhelming efficacy 
following an interim analysis or at the final analysis, subjects who are on 
Study GS-US-312-0116 at that time may transition to GS-US-312-0117. 
Additionally, GS-US-312-0117 will become an open-label study
offering idelalisib 150 mg BID to GS-US-312-0116 subjects who were
randomized to placebo, and subjects randomized to idelalisib will 
continue idelalisib at 150 mg BID.
Study Schema:
Treatment Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117)


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Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID
Treatment Assignment

Assignment to Arm A or Arm B with allocation based on the 
original primary study randomization

Implementation through an interactive web response system (IWRS)
Stratification
Not applicable for Study GS-US-312-0117
Number of 
Subjects Planned:
Total of up to ~180 subjects (up to ~90 subjects per treatment arm)
Target 
Population:
Subjects in the primary Phase 3 study (GS-US-312-0116) who are 
compliant, are tolerating primary study therapy, and 1) have definitive 
progression of CLL while receiving primary study drug therapy 
(idelalisib/placebo) or 2) are actively participating in 
Study GS-US-312-0116 at the time the study is stopped, including if 
stopped early due to overwhelming efficacy following an interim analysis.
Duration of 
Treatment:
Study drug will be taken continuously until the earliest of subject 
withdrawal from study drug, definitive progression of CLL, intolerable 
study drug-related toxicity, pregnancy, substantial noncompliance with 
study procedures, or study discontinuation. Idelalisib administration will
be continued only in subjects whose benefit-risk profile is deemed 
positive by the investigator.
Diagnosis and 
Main Eligibility 
Criteria:
Inclusion Criteria
Subjects must meet all of the following conditions to be eligible for 
enrollment into the study:
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while 
receiving study drug therapy (idelalisib /placebo) in 
Study GS-US-312-0116. Note: Definitive disease progression is 
CLL progression based on standard criteria and occurring for any 
reason (ie, increasing lymphadenopathy, organomegaly, or bone 
marrow involvement; decreasing platelet count, hemoglobin, or 
neutrophil count; or worsening of disease-related symptoms) other 
than lymphocytosis. Subjects must have confirmation by the 
sponsor working in collaboration with an independent review 
committee (IRC) that the disease has progressed on the primary 
clinical trial (Study GS-US-312-0116) before receiving secondary 
idelalisib therapy on this extension trial (Study GS-US-312-0117).


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3) Presence of measurable lymphadenopathy (defined as the presence 
of ≥1 nodal lesion that measures 2.0 cm in the longest diameter 
[LD] and 1.0 cm in the longest perpendicular diameter [LPD] as 
assessed by computed tomography [CT] or magnetic resonance 
imaging [MRI]).
4) Permanent cessation of Study GS-US-312-0116 treatment 
(rituximab and/or idelalisib/placebo) and no intervening or 
continuing therapy (including radiotherapy, chemotherapy, 
immunotherapy, or investigational therapy) for the treatment of 
CLL. Note: Subjects may receive corticosteroids to manage CLL 
manifestations.
5) The time from permanent cessation of Study GS-US-312-0116 
treatment (rituximab and/or idelalisib/placebo) and the initiation of 
Study GS-US-312-0117 therapy is 12 weeks. Note: Study 
procedures performed as part of Study GS-US-312-0116 need not 
be repeated and can be used as screening procedures for 
Study GS-US-312-0117 if performed within 4 weeks prior to 
initiation of study drug therapy on Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation 
of study treatment) as shown in the table below. Note: Confirmation 
should be considered for out-of-range values to determine if the 
abnormality is real or artifactual. Values should be obtained within 
the screening period and should generally be the most recent 
measurement obtained. Subjects with any degree of neutropenia, 
thrombocytopenia, or anemia due to CLL or prior therapy may 
enroll.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCr
a
>30 ml/min
Pregnancy
-HCGb
Negative
a
As calculated by the Cockcroft-Gault formula {Cockcroft et al 1976}
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or 
urine dipstick pregnancy test must be negative at randomization (Visit 2)
Abbreviations: -HCG=beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
eCCr=estimated creatinine clearance, ULN=upper limit of normal


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8) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening 
visit (Visit 1) throughout the study and for 30 days from the last dose 
of study drug. Note: A female subject is considered to be of 
childbearing potential unless she has had a hysterectomy, bilateral 
tubal ligation, or bilateral oophorectomy; has medically 
documented ovarian failure (with serum estradiol and 
follicle-stimulating hormone [FSH] levels within the institutional 
postmenopausal range and a negative serum or urine -HCG), or 
is menopausal (defined as age ≥54 years with amenorrhea for 
>12 months or amenorrhea for >6 months with serum estradiol 
and FSH levels within the institutional postmenopausal range).
9) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of 
study drug (Visit 2) throughout the study and for 90 days following 
the last dose of study drug and to refrain from sperm donation from 
the start of study drug (Visit 2) throughout the study and for 90 days 
following the last dose of study drug. Note: A male subject is 
considered able to father a child unless he has had a bilateral 
vasectomy with documented aspermia or a bilateral orchiectomy, 
or has ongoing testicular suppression with a depot luteinizing 
hormone- releasing hormone (LH-RH) agonist 
(eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), 
or triptorelin pamoate [Trelstar®]).
10) In the judgment of the investigator, participation in the protocol 
offers an acceptable benefit-to-risk ratio when considering current 
CLL disease status, medical condition, and the potential benefits and 
risks of alternative treatments for CLL.
11) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, 
familial, or geographical factors that might preclude adequate 
study participation should be considered.
12) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study 
participation.


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Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be 
enrolled in this study:
1) Known histological transformation from CLL to an aggressive 
lymphoma (ie, Richter transformation). 
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at 
the time of the start of study treatment (Visit 2). Note: Subjects with 
localized fungal infections of skin or nails are eligible. Subjects 
may be receiving prophylactic antiviral or antibacterial therapies at 
the discretion of the investigator; anti-pneumocystis prophylaxis is 
encouraged. 
3) Pregnancy or breastfeeding.
4) Intentional breaking of the blind in Study GS-US-312-0116 by the 
investigator or the study subject.
5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical condition, 
surgical history, physical finding, electrocardiogram (ECG) finding, 
or laboratory abnormality that, in the investigator’s opinion, could 
adversely affect the safety of the subject or impair the assessment of 
study results.
In the event Study GS-US-312-0116 is stopped early, subjects who are 
actively participating in Study GS-US-312-0116 will become eligible for 
this study, provided the following inclusion are met:
1) Participation in Study GS-US-312-0116 within 12 weeks of 
enrollment onto GS-US-312-0117.
2) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening 
visit (Visit 1) throughout the study and for 30 days from the last dose 
of study drug. 
3) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of
study drug (Visit 2) throughout the study and for 90 days following 
the last dose of study drug and to refrain from sperm donation from 
the start of study drug (Visit 2) throughout the study and for 90 days 
following the last dose of study drug.
4) In the judgment of the investigator, participation in the protocol 
offers an acceptable benefit-to-risk ratio when considering current 
CLL disease status, medical condition, and the potential benefits and 
risks of alternative treatments for CLL.


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5) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, 
familial, or geographical factors that might preclude adequate 
study participation should be considered.
6) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study 
participation.
Study Procedures/
Frequency:
Clinic/laboratory visits will occur every 2 weeks for the first 12 weeks, 
every 4 weeks between Weeks 12 and 24, and every 6 weeks between 
Weeks 24 and 48. Subjects continuing on study drug past Week 48 will 
have clinic visits every 12 weeks. Subjects will be assessed for safety at 
each visit. Subjects will be assessed for CLL disease status by physical 
and laboratory examinations at each visit and by CT or MRI at 
Weeks 8, 16, 24, 36, and 48 and every 12 weeks thereafter.
Following unblinding of the study:

Subjects who were randomized to idelalisib on 
Study GS-US-312-0116 and who received ≥24 weeks idelalisib will 
complete Visit 16+ twelve weeks from the date of their last 
radiology assessment (CT/MRI) and study visits will continue every 
12 weeks thereafter. Visits 3 through 15 will not be required.

Subjects who have received < 24 weeks idelalisib will have all 
Study GS-US-312-0117 assessments completed per the 
Schedule of Procedures until they have received idelalisib for 
24 weeks cumulative across both studies. After completion of 
24 weeks of cumulative idelalisib treatment, Visit 16+ will be 
conducted 12 weeks from the date of their last radiology assessment 
(CT/MRI), after which time study visits will occur every 12 weeks.
Test Therapy, Dose, 
and Mode of 
Administration:
Blinded Portion

Arm A: Idelalisib, 300 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be provided 
as 2 tablets of active idelalisib for oral administration

Arm B: Idelalisib, 150 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be provided 
as 1 tablet of active idelalisib and 1 tablet of placebo for oral 
administration


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Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID
Note: At the Investigator’s discretion, subjects who were randomized 
to placebo on study GS-US-312-0116 may delay initiation of idelalisib 
following enrollment on Study GS-US-312-0117 until the time of 
disease progression or until the investigator determines that the 
subject would benefit from initiation of idelalisib treatment
Reference Therapy, 
Dose, and Mode of 
Administration:
Not applicable
Criteria for 
Evaluation:
Tumor Control

Progression-free survival (PFS) – defined as the interval from the 
start of study therapy to the earlier of the first documentation of 
definitive disease progression or death from any cause; definitive 
disease progression is CLL progression based on standard criteria 
other than lymphocytosis alone

Overall response rate (ORR) – defined as the proportion of subjects 
who achieve a complete response (CR) or partial response (PR)

Lymph node response rate – defined as the proportion of subjects 
who achieve a 50% decrease from baseline in the sum of the 
products of the greatest perpendicular diameters (SPD) of index 
lesions

CR rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from start of study 
therapy to the first documentation of CR or PR

Duration of response (DOR) – defined as the interval from the 
first documentation of CR or PR to the earlier of the first 
documentation of definitive disease progression or death from any 
cause

Percent change in lymph node area – defined as the percent change 
from baseline in the SPD of index lymph nodes

Splenomegaly response rate – defined as the proportion of subjects 
with baseline splenomegaly who achieve an on-study normalization 
or a 50% decrease (minimum 2 cm) from baseline in the 
enlargement of the splenic LVD (by imaging)


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
Hepatomegaly response rate – defined as the proportion of subjects 
with baseline hepatomegaly who achieve an on-study normalization 
or a 50% decrease (minimum 2 cm) from baseline the hepatic 
longest vertical dimension (LVD) (by imaging)

ALC response rate – defined as the proportion of subjects with 
baseline lymphocytosis (ALC4 x 109/L) who achieve an on-study 
ALC <4 x 109/L or demonstrate a 50% decrease in ALC from 
baseline (ALC values within 4 weeks post-baseline will be excluded 
from the ALC response rate evaluation)

Platelet response rate – defined as the proportion of subjects with 
baseline thrombocytopenia (platelet count <100 x 109/L) who 
achieve an on-study platelet count 100 x 109/L or demonstrate a 
50% increase in platelet count from baseline without need for 
exogenous growth factors (Platelet values within 4 weeks 
post-baseline or within 8 days post transfusion will be excluded from 
the platelet response rate evaluation)

Hemoglobin response rate – defined as the proportion of subjects 
with baseline anemia (hemoglobin <110 g/L [11.0 g/dL]) who 
achieve an on-study hemoglobin 110 g/L (11.0 g/dL) or 
demonstrate a 50% increase in hemoglobin from baseline without 
red blood cell transfusions or need for exogenous growth factors 
(eg erythropoietin)

Neutrophil response rate – defined as the proportion of subjects with 
baseline neutropenia (absolute neutrophil count [ANC] ≤1.5 x 109/L) 
who achieve an ANC >1.5 x 109/L or demonstrate a 50% increase 
in ANC from baseline without need for exogenous growth factors 
(eg, G-CSF)
Patient Well-Being

Overall survival (OS) – defined as the interval from start of study 
therapy to death from any cause

Change from baseline in HRQL domain and symptom scores based 
on the Functional Assessment of Cancer Therapy: 
Leukemia (FACT-Leu) (See Appendix 2)

Changes from baseline in Karnofsky performance status 
(See Appendix 3)
Pharmacodynamic Markers of Drug Activity and Resistance

Changes from baseline in PI3K/AKT/mTOR pathway activation as a 
measure of PI3Kpathway activity

Changes from baseline in the plasma concentrations of 
disease-associated chemokines and cytokines


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Exposure

Study drug administration as assessed by prescribing records and 
compliance as assessed by quantification of used and unused drug

Trough (pre-dose) and peak (~1.5-hour samples) of idelalisib plasma 
concentrations as assessed by a validated bioanalytical method
Safety

Overall safety profile of each regimen characterized by the type, 
frequency, severity, timing of onset, duration, and relationship to 
study therapy of any adverse events or abnormalities of laboratory 
tests; serious adverse events; or adverse events leading to 
discontinuation of study drug
Pharmacoeconomics

Change in health status – defined as the change from baseline in 
overall health and single-item dimension scores as assessed using the 
EuroQoL Five-Dimension (EQ-5D) utility measure

Health resource measures, including resource utilization, total costs,
and measures of cost per unit of benefit (eg, cost per additional 
progression-free month, cost per quality-adjusted life-year)
Statistical Methods:
Appropriate data analysis sets will be defined. The intent-to-treat (ITT) 
analysis set will include data from all subjects who receive 1 dose of 
any study therapy on this study; in this data set, study drug assignment 
(high-dose or standard-dose idelalisib) will be designated according to 
the planned allocation to this study. A safety analysis set will comprise 
data from subjects in the ITT analysis set with treatment assignments 
designated according to the actual study drug (high-dose or 
standard-dose idelalisib) received. Other analysis sets [per-protocol (PP) 
and pharmacodynamic/pharmacokinetic analysis sets] will be used for 
certain analyses as well.
Subject characteristics and study results will be described and 
summarized by treatment arm and assessment for the relevant analysis 
sets. Descriptive summaries will be prepared to show sample size, mean, 
standard deviation, 95% confidence intervals (CIs) on the mean, median, 
minimum, and maximum for continuous variables and counts, 
percentages, and 95% CIs on the percentage for categorical variables.
An independent review committee (IRC) will review radiographic data 
and pertinent clinical data in order to provide expert evaluation of tumor 
status. The findings of the IRC will be considered primary for analyses 
of PFS and other tumor control endpoints.


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For endpoints relating to tumor control, patient well-being, and 
biomarkers, analyses will be done based on ITT, PP or 
pharmacodynamic data sets, as appropriate. Blinded portion of the study 
analyses will be presented in the following two groups:

IDELA 300 mg BID: Subjects who have PD per IRC confirmation in 
Arm A of Study GS-US-312-0116 and subsequently enroll into 
Study GS-US-312-0117 to receive IDELA 300 mg BID during the 
double-blind portion of the study

Placebo in GS-US-312-0116 + IDELA 150 mg BID in 
GS-US-312-0117: Subjects who have PD per IRC confirmation in 
Arm B of Study GS-US-312-0116 and subsequently enroll in 
Study GS-US-312-0117 to receive IDELA 150 mg BID during the 
double-blind portion of the study.
After unblinding, open-label extension study analyses will be presented 
in the following 4 groups:

IDELA 150 mg BID: Subjects who are randomized to Arm A in 
Study GS-US-312-0116 and transition to Study GS-US-312-0117 
during the open-label portion of the study to continue IDELA 
150 mg BID

Placebo in GS-US-312-0116 + IDELA 150 mg BID (open-label): 
Subjects who are randomized to Arm B in Study GS-US-312-0116 
and transition to receive IDELA 150 mg BID during the open-label 
portion of the study

IDELA 300 mg BID: Subjects who have PD per IRC confirmation in 
Arm A of Study GS-US-312-0116 and subsequently enroll 
Study GS-US-312-0117 to receive IDELA 300 mg BID during the 
double-blind portion of the study

Placebo in GS-US-312-0116 + IDELA 150 mg BID in 
GS-US-312-0117: Subjects who have PD per IRC confirmation in 
Arm B of Study GS-US-312-0116 and subsequently enroll 
Study GS-US-312-0117 to receive IDELA 150 mg BID during the 
double-blind portion of the study. Analyses will focus on evaluation 
of outcomes within each treatment arm and will be descriptive in 
nature; formal comparisons of outcomes between arms are not 
planned. Time-to-event endpoints will be summarized using 
Kaplan-Meier methods; medians, ranges, and the corresponding 
95% CI will be presented. Continuous and categorical variables will 
also be summarized as appropriate. Changes from baseline in 
categorical variables and changes from baseline in continuous 
endpoints will be analyzed using appropriate methods.


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Efficacy outcomes among subjects receiving rituximab alone in 
Study GS-US-312-0116 will be evaluated relative to those same 
outcomes among the same subjects receiving standard-dose idelalisib 
alone in Study GS-US-312-0117. 
Based on the safety analysis set, information regarding study drug 
administration, study drug compliance, safety variables, and post-study 
therapies will be described and summarized. Using data from the 
pharmacokinetic analysis set, idelalisib plasma concentrations will also 
be described and summarized.
Sample Size Calculation
The sample size for this extension study is not based upon a formal 
statistical hypothesis. The upper bound of the sample size in this study is 
determined by the sample size of the preceding primary clinical trial
(Study GS-US-312-0116) in which ~180 subjects (~90 per arm) are 
expected to be enrolled. Assuming a ~10% dropout rate during 
Study GS-US-312-0116 and a further ~10% dropout rate in the 
transition from the primary study to the extension study, ~180 subjects 
are expected to be enrolled into Study GS-US-312-0117.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP), 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
-HCG
Beta human chorionic gonadotropin
ABCG2
adenosine triphosphate-binding cassette sub-family G member 2 (see also BCRP)
AKT
AKT (a serine/threonine protein kinase)
ALC
absolute lymphocyte count
ALL
acute lymphocytic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
ATC
Anatomical-Therapeutic-Chemical classification system for drugs 
BCRP
breast cancer resistance protein (see also ABCG2)
BID
twice per day
BTK
Bruton tyrosine kinase
CAL-101
Former name for GS-1101
CCL
chemokine (C-C motif) ligand
CFR
Code of Federal Regulations
CI
confidence interval
CIRS
Cumulative Illness Rating Scale
CLL
chronic lymphocytic leukemia
cGMP
current Good Manufacturing Practice
Cmax
maximum concentration
CMV
cytomegalovirus
CR
complete response
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough concentration
CXCL
chemokine (C-X-C motif) ligand
CYP
cytochrome P450 enzyme
DLCO
diffusing capacity of the lung for carbon monoxide
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DOR
duration of response
DSPH
Gilead Sciences Department of Safety and Public Health
ECG
electrocardiogram


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eCCr
estimated creatinine clearance
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EQ-5D
EuroQoL Five-Dimension utility measure
FACT-Leu
Functional Assessment of Cancer Therapy: Leukemia questionnaire
FCεRI
high-affinity IgE receptor
FDA
United States Food and Drug Administration
FDAMA
Food and Drug Modernization Act
FDG
fluorodeoxyglucose (18F)
FISH
fluorescence in-situ hybridization,
FSH
follicle-stimulating hormone
G-CSF
granulocyte colony-stimulating factor
GGT
gamma-glutamyltransferase
GLP
Good Laboratory Practice
GM-CSF
granulocyte-macrophage colony-stimulating factor
HBc antibody
anti-hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
hERG
human ether-à-go-go-related gene
HL
Hodgkin lymphoma
HIV
human immunodeficiency virus
HRQL
health-related quality of life
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
idelalisib
formerly CAL-101 and GS-1101
IEC
independent ethics committee
Ig
immunoglobulin (including subtypes A, E, G, and M)
IgHV
immunoglobulin heavy chain variable region
IND
Investigational New Drug (application)
iNHL
indolent non-Hodgkin lymphoma
INR
international normalized ratio
IRB
institutional review board
IRC
independent review committee
ITT
intention to treat
IUD
intrauterine device
IWCLL
International Workshop on CLL
IWRS
interactive web response system
JAK
Janus kinase


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K2-EDTA
potassium-ethylenediaminetetraacetic acid
LD
longest diameter
LDH
lactate dehydrogenase
LH-RH
luteinizing hormone-releasing hormone
LLN
lower limit of normal
LPD
longest perpendicular diameter
LVD
longest vertical dimension
MTD
maximum tolerated dose
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mTOR
mammalian target of rapamycin
ND
no disease
NHL
non-Hodgkin lymphoma
NOAEL
no-observed-adverse effect level
NOEL
no-observed-effect level
OCT
organic cation transporter
ORR
overall response rate
OS
overall survival
pAKT
phosphorylated AKT
PCR
polymerase chain reaction
PD
progressive disease
PET
positron-emission tomography
PFS
progression-free survival
PI3K
phosphatidylinositol 3-kinase
PI3K
phosphatidylinositol 3-kinase p110isoform
PJP
Pneumocystis jiroveci pneumonia
PML
progressive multifocal leukoencephalopathy
PP
per-protocol
PPD
product of the perpendicular diameters
PRO
patient-reported outcome
PR
partial response
PT
prothrombin time
PVA
polyvinyl alcohol
PVC/PCTFE
polyvinyl chloride/polychlorotrifluoroethylene
QD
once per day
QT (interval)
measure of time between start of Q wave and end of T wave in electrical cycle of heart
RNA
ribonucleic acid
SADR
serious adverse drug reaction
SD
stable disease


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SPD
sum of the products of the perpendicular diameters of measured lymph nodes
SSC
study steering committee
SJS
Stevens-Johnson Syndrome
SUSAR
suspected, unexpected, serious adverse reaction
SYK
spleen tyrosine kinase
t1/2
half-life
TEN
Toxic Epidermal Necrolysis
Tmax
time of maximum concentration
TTR
time to response
UGT
uridine 5'-diphospho-glucuronosyltransferase
ULN
upper limit of normal
WHODRUG
World Health Organization Drug Dictionary
ZAP-70
zeta-associated protein 70


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1.
INTRODUCTION
1.1.
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is a neoplasia resulting from the progressive accumulation 
of functionally incompetent monoclonal B lymphocytes in blood, bone marrow, lymph nodes, 
spleen, and liver {Dighiero et al 2008}. CLL constitutes the most commonly occurring leukemia 
in Europe and the United States {Sant et al 2010, Surveillance Epidemiology and End Results 
(SEER) Program 2011}. While some patients never require treatment, many will need therapy 
for disfiguring or obstructing lymphadenopathy, debilitating constitutional B symptoms 
(fevers, night sweats, fatigue, weight loss) {Redaelli et al 2004}, or recurrent cytopenias and 
infections {Keating et al 2002b, Perkins et al 2002}. CLL is largely a disease of the elderly; at 
diagnosis, 70% of patients are 65 years of age and the median age is 72 years {Surveillance 
Epidemiology and End Results (SEER) Program 2011}.
In younger and relatively healthy patients with CLL, chemoimmunotherapy regimens that 
include the anti-CD20 monoclonal antibody, rituximab, are commonly employed to control 
disease manifestations {Gribben et al 2011}. Such combination therapies are effective in 
providing durable remissions {Byrd et al 2005, Fischer et al 2011, Hallek et al 2010, Iannitto et 
al 2011, Robak et al 2010}. However, while rituximab is usually well tolerated {Gentile et al 
2010}, the chemotherapeutic agents (typically fludarabine, cyclophosphamide, or bendamustine) 
in such regimens are acutely cytotoxic, induce permanent bone marrow compromise, and can 
cause secondary malignancies {Carney et al 2010, Kyasa et al 2004, Tam et al 2008}. 
Furthermore, in elderly patients or in those with comorbid conditions, such regimens are 
associated with less efficacy and greater toxicity {Eichhorst et al 2009b, Goede et al 2011, Tam 
et al 2008}.
Increasing attention has been paid to the problem of treating patients with CLL who have 
comorbidities. Because of the relatively late age of diagnosis, a large proportion (~90%) of 
patients with CLL have co-morbidities and a substantial proportion (~45%) have major chronic 
conditions such as coronary artery disease, diabetes, or chronic obstructive pulmonary disease 
{Thurmes et al 2008}. At the time the disease is first identified, ~25% of patients with CLL do 
not meet conventional criteria for participation in clinical studies containing cytotoxic agents 
{Thurmes et al 2008}. By the time treatment is necessary or during treatment for CLL, patients 
continue to advance in age and have new or worsening chronic conditions; as a result, the 
proportion of patients with comorbidities increases during the course of the illness. Such patients 
have been substantially underrepresented in clinical trials due to concerns regarding the ability of 
such patients to tolerate intensive chemoimmunotherapy {Eichhorst et al 2009a, Thurmes et al 
2008}. Instruments such as the Cumulative Illness Rating Scale (CIRS) {Linn et al 1968} are 
now being applied in order to categorize patient populations as fit or relatively unfit and to 
evaluate regimens tailored to these groups of patients {Del Giudice et al 2011, Eichhorst et al 
2009a, Hallek et al 2010}.


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Health constraints in older or compromised patients have prompted noncytotoxic approaches to 
therapy. Alternative immunotherapeutics, such as the monoclonal antibodies, alemtuzumab
{Keating et al 2002a} or ofatumumab {Wierda et al 2010}, have been developed. However the 
therapeutic utility of these drugs is modest; median progression-free survival (PFS) values in 
patients with recurrent CLL have been 4.7 months and 5.8 months, respectively. Moreover, these 
treatments can have clinical liabilities. Alemtuzumab causes extreme immunosuppression that 
leads to frequent opportunistic infection. Administration of the large amounts of protein 
recommended in ofatumumab product labeling results in frequent infusion reactions and 
cumbersome infusion schedules.
In view of these issues, repeated use of rituximab monotherapy or rituximab-corticosteroid 
combinations have been advocated in treatment guidelines for older or frail patients with 
recurrent CLL {Eichhorst et al 2010, Zelenetz et al 2011}. While single-agent rituximab use can 
offer palliative benefit with good tolerability in some patients with previously treated CLL, 
tumor control is not lasting, especially in patients with bulky adenopathy {Gentile et al 2010}. 
Addition of high-dose corticosteroids to rituximab can extend median PFS up to 12 months, but 
this combination is commonly associated with severe hyperglycemia and frequent 
life-threatening or fatal infections {Bowen et al 2007, Dungarwalla et al 2008}. New,
noncytotoxic, well-tolerated, and convenient therapies that can successfully be combined with 
rituximab or given as single-agent therapy are needed in order to enhance and prolong tumor 
control in patients with comorbid conditions.
1.2.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies
Phosphatidylinositol 3-kinases (PI3Ks) are enzymes that regulate several cellular functions 
including motility, proliferation, and survival {Okkenhaug et al 2003b}. PI3K activation recruits 
and activates numerous intracellular signaling enzymes. The most important of these is the 
serine/threonine kinase, AKT, which mediates a positive pleiotropic effect on cell survival, 
proliferation, growth, and metabolism {Engelman et al 2006} acting by signaling through 
mammalian target of rapamycin (mTOR) {Hay 2005, Osaki et al 2004}.
PI3K signaling is mediated by 4 catalytic isoforms of the p110 subunit of the enzyme - , , , 
and . While potentially important in multiple cell types, PI3K p110(PI3K) shows an 
expression pattern that is particularly prominent in cells of hematopoietic origin 
{Vanhaesebroeck et al 2005}. Mice deficient in PI3Khave no gross abnormalities, are fertile, 
fecund, and live a normal life span without an increased susceptibility to infections {Okkenhaug 
et al 2003a}. However, the B-lymphocyte population in these animals shows a decrease in 
maturation, diminished receptor-induced proliferation, and increased susceptibility to apoptotic 
cell death. Conversely, mice with aberrantly elevated PI3K signaling develop lymphadenopathy 
and have an increased incidence of lymphoma {Donahue et al 2004}. In CLL, sustained 
activation of the PI3K/AKT/mTOR pathway has been shown to promote malignant B-cell 
survival through mechanisms that are dependent on the PI3Kisoform {Cuni et al 2004, Herman 
et al 2010, Lannutti et al 2011}.


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Knowledge of the critical importance of PI3Kδ in B-cell biology and neoplasia has encouraged a 
search for inhibitors of this enzyme that could provide new options in the therapy of lymphoid 
malignancies, including CLL.
1.3.
Idelalisib (formerly GS-1101)
1.3.1.
General Information
Idelalisib was approved in the US on July 23, 2014 and in the European Union on 
September 18, 2014. Refer to local labeling for the approved indication statements and dosing 
recommendations.
Gilead Sciences, Inc has developed novel drugs that can suppress tumor growth through 
targeting of PI3Kδ activity. High-throughput screening was the basis for the discovery of novel 
agents that selectively inhibit PI3Kfunction but spare other PI3K isoforms and other kinases. 
Chemical optimization, pharmacological characterization, and toxicological evaluation have led 
to identification of idelalisib (also known as GS-1101), a 415-dalton, orally bioavailable, 
new chemical entity with potential clinical utility in the treatment of cancers.
In primary tumor samples and in cell lines derived from patients with CLL, indolent 
non-Hodgkin lymphoma (iNHL), mantle cell lymphoma (MCL), B-cell acute lymphocytic 
leukemia (ALL), or Hodgkin lymphoma (HL), idelalisib induces dose-dependent reductions in 
AKT phosphorylation {Herman et al 2010, Lannutti et al 2011, Meadows et al 2010}. In 
addition, idelalisib disrupts the PI3Kactivation and supportive intercellular signaling observed 
when CLL or HL cells are cocultured with stromal cells {Hoellenriegel et al 2011, Meadows et 
al 2010}. These effects have therapeutic consequences. In multiple lymphoid primary tumors and 
malignant cell lines, idelalisib enhances apoptosis and concentration-dependent cell killing when 
applied as a single agent and increases the therapeutic efficacy of other antineoplastic agents 
when given in combination {Hoellenriegel et al 2011, Meadows et al 2011}. In preclinical 
systems, coadministration of idelalisib with rituximab has not impaired rituximab-mediated 
activity {Herman et al 2010}.
1.3.2.
Safety Pharmacology
In vitro and in vivo safety pharmacology studies with idelalisib have demonstrated a favorable 
non-clinical safety profile. These studies indicate that the drug may minimally slow bone marrow 
progenitor proliferation and differentiation and that it has expected inhibitory effects on 
B-cell response to antigen challenge. However, the data indicate that idelalisib is unlikely to 
cause serious off-target effects or adverse effects on critical organ systems. Idelalisib has no 
meaningful effect on the human ether-à-go-go-related gene (hERG) channel, indicating that 
idelalisib would not be expected to induce clinical QT prolongation.
The drug has also proved well tolerated in standard in vivo Good Laboratory Practice (GLP) 
studies of pharmacological safety. A functional observation battery in rats revealed no adverse 
effects on behavior or on autonomic, neuromuscular, or sensorimotor function. In a 
cardiopulmonary function study in awake, telemeterized male beagle dogs, single doses of 


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idelalisib induced no meaningful abnormalities in pulmonary, cardiovascular, arterial blood gas, 
or electrocardiographic (ECG) (including QT interval) parameters. In an assessment of bacterial 
challenge in rats, idelalisib enhanced, rather than impaired, the phagocytic host clearance of 
staphylococcal bacteria.
1.3.3.
Nonclinical Pharmacology and Metabolism
Consistent with the moderate to high bioavailability seen in nonclinical species, idelalisib shows 
high permeability across human Caco-2 cell monolayers.  At lower concentrations, the reverse 
permeability at low concentration exceeds forward permeability, indicating efflux driven by 
transporters (eg, human P-glycoprotein (MDR1) and breast cancer resistance protein [BCRP]); 
idelalisib is a substrate for the efflux transporters MDR1 and BCRP; however, the permeability 
increases in a concentration-dependent manner, resulting in a lower efflux ratio at higher, 
clinically relevant concentrations of idelalisib.
Idelalisib exhibits moderately high plasma protein binding in mouse, rat, dog, and human. In dog 
and human plasma, the protein binding is concentration-independent between 1 and 20 µM. 
Protein binding in human plasma is slightly higher than in mouse, rat, and dog plasma, which 
have comparable free fractions.  In human plasma, idelalisib and GS-563117 
(the major metabolite of idelalisib) have an average free fraction of ~16% and ~12%, respectively.
After oral administration of 14C-idelalisib to rats and dogs, radioactivity is widely distributed, but 
relatively excluded from bone, brain, spinal cord, and eye lens in rats and from brain and eyes in 
dogs. In rats, the radioactivity declines steadily and most tissues have undetectable levels by 
72 hours post dose.  In bile duct-cannulated rats and dogs, ≥69% of radioactivity is recovered in 
bile and urine, indicating high absorption of idelalisib in vivo.
In hepatic tissues from nonclinical species, idelalisib is primarily metabolized by 
aldehyde oxidase, CYP3A, and UGT1A4.  In vitro metabolism in dog and human yields 
3 primary oxidative metabolites and 5 primary glucuronides. Of these, the oxidative product 
GS-563117 is the predominant metabolite in vitro and in vivo. In preclinical species, plasma 
levels of GS-563117 are below those of idelalisib. In humans, GS-563117 
(only circulating metabolite and formed via aldehyde oxidase) plasma levels significantly exceed 
those of idelalisib. After oral administration of 14C-idelalisib to rats and dogs, biliary excretion 
appears to be the major route of elimination of idelalisib and its metabolites as the majority of 
radioactivity is found in feces or bile and little in urine.
Idelalisib is not a substrate for the renal transporters OCT2, OAT1, and OAT3 or the 
hepatic uptake transporters OATP1B1 and OATP1B3.  GS-563117 is not a substrate for 
OATP1B1 and OATP1B3.
Idelalisib is not an inhibitor of CYP1A, CYP2B6, CYP2C9, and CYP2D6, and at concentrations 
above those observed clinically, is an inhibitor of CYP2C8 (IC50 = 13 µM), CYP2C19 
(IC50 = 76 µM), and CYP3A (IC50 = 44 µM). GS-563117 is not an inhibitor of CYP1A, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and a competitive and time dependent 
inhibitor of CYP3A (IC50 = 3.1 µM), (KI = 0.18 µM, kinact = 0.033 min-1 with midazolam as 
the probe substrate).


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In vitro, idelalisib is not an inhibitor of the transporters BCRP, OCT2, OAT1, and OAT3, and is 
an inhibitor of MDR1 (IC50 = 7.7 µM), OATP1B1 (IC50 = 10.1 µM), OATP1B3 (IC50 = 7.0 µM), 
and, at concentrations above those observed clinically, of glucuronosyltransferase UGT1A1 
(IC50 = 42.0 µM). GS-563117 is not an inhibitor of MDR1, BCRP, OATP1B1, OATP1B3, 
OAT1, OAT3, and OCT2, and at concentrations above those observed clinically, an inhibitor of 
UGT1A1 (IC50 = 16.8 µM).
Any potential clinical implications of these metabolism studies were evaluated in a formal 
drug-drug interaction study (GS-US-313-0130) which evaluated the effect of idelalisib on 
cytochrome P450 3A and the drug transporters P-gp, OATP1B1, and OATP1B3. 
Study GS-US-313-0130 also evaluated the impact of an inducer of metabolizing enzymes and 
transporters (rifampin) on the PK of idelalisib in healthy human subjects. Findings from this 
study are presented in Section 1.3.5.1.
1.3.4.
Toxicology
The toxicological profile of idelalisib was well characterized through the conduct of single dose, 
repeat dose, developmental and reproductive, and genetic toxicology and local tolerance studies. 
The primary target organ toxicities following repeated dosing include the lymphoid, hepatic, 
male reproductive systems in rats and dogs, and gastrointestinal system in dogs. Adverse effects 
in the lymphoid system were primarily the result of on target pharmacology resulting in 
decreased lymphocytes in multiple lymphoid organs, primarily involving B-cell regions. Liver 
effects were transient and reversible with continued dosing and did not result in chronic liver 
injury. Reduction in sperm numbers in males were reversible and did not impact fertility or 
reproductive performance.  Gastrointestinal effects in dogs were minor, superficial, and 
considered secondary to effects on lymphocytes in Peyer’s Patches. Idelalisib was shown to be 
teratogenic and associated with embryo-fetal lethality. Effects on the reproductive system have 
been reported for inhibitors which target other isoforms of PI3K. The dose-dependence and 
potential of idelalisib to selectively inhibit additional PI3K isoforms may be responsible for the 
off-target toxicity. Additionally, the drug may have the potential to produce phototoxic reactions 
in humans. These findings represent toxicities that can be monitored, are considered clinically 
manageable, or are considered acceptable risks in the intended patient population.
Further details on the toxicology of idelalisib can be found in the Idelalisib 
Investigator’s Brochure (IB).
1.3.5.
Idelalisib Clinical Studies
1.3.5.1.
Phase 1 Studies in Healthy Subjects and in Patients with Allergic Rhinitis
Various studies in healthy subjects have evaluated safety, pharmacokinetics, food effect, and the 
potential for drug interactions of idelalisib with CYP3A4 inhibitors {Webb et al 2010}.


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Safety results from these studies indicated that idelalisib was well tolerated when administered to 
healthy subjects at single doses through 400 mg (the highest dose level tested) and was also 
generally well tolerated when administered to healthy subjects over 7 days at dose levels through 
200 mg/dose BID (the highest dose level tested). Dosing with 200 mg/dose BID for 7 days 
resulted in a skin rash in 3 out of 6 subjects; histological findings were consistent with a 
delayed-type hypersensitivity maculopapular exanthema. Rashes have sometimes occurred in 
patients with hematological malignancies receiving idelalisib, but have not typically proved 
dose- or treatment-limiting. In placebo-controlled single-dose and multiple-dose trials, repeated 
ECG evaluations performed in tandem with pharmacokinetic monitoring showed no evidence of 
drug-, dose-, or exposure-dependent effects on cardiac rhythm or cardiac intervals 
(eg, QT interval). Pharmacokinetic results indicated that idelalisib appeared rapidly in plasma 
with a median Tmax of 1 to 1.5 hours. Cmax and AUC increased in a less-than-dose-proportional 
manner and mean t1/2 values were across the dose range were 6.5 to 9.8 hours.
Idelalisib dosing after a high-fat, high-calorie meal delayed median time of 
maximum concentration (Tmax) from 0.75 hours to 3 hours; mean Cmax was unaffected and 
mean AUC was ~40% higher. These changes in idelalisib exposures are considered 
modest/clinically non-relevant; thus, idelalisib may be given with or without food.
Idelalisib is metabolized in humans primarily by aldehyde oxidase, with some involvement of 
CYP3A4 and UGT1A4. Accordingly, when idelalisib was administered following 4 days of daily 
dosing with ketoconazole (a potent inhibitor of CYP3A4), modest/moderate increases in mean 
idelalisib Cmax and AUC values of ~30% and ~80% higher, respectively, which is not considered 
to be clinically relevant and suggesting that idelalisib is a weak CYP3A substrate. GS-563117 is 
formed from idelalisib primarily via aldehyde oxidase.
The 14C-labeled idelalisib human mass balance results showed that the drug has moderate to high 
oral bioavailability. Idelalisib is eliminated mainly via hepatic metabolism and biliary excretion 
in the feces (~78% of dose); recovery in urine was < 15%. GS-563117, the only circulating 
metabolite observed in human plasma, was also observed in urine and feces.
Results from the drug interaction/probe Study GS-US-313-0130 indicate that idelalisib does not 
affect the pharmacokinetics of substrates of Pgp, BCRP, OATP1B1 or OATP1B3 transporters. 
Idelalisib is not expected to affect the exposures of coadministered agents via transporter 
mediated interactions.
The exposures (AUC) of probe CYP3A substrate, midazolam, increased ~5-fold upon 
coadministration with idelalisib, driven by competitive and time-dependent CYP3A inhibition by 
GS-563117, the only circulating metabolite of idelalisib. Coadministration of the highly potent 
CYP3A inducer rifampin resulted in a ~75% reduction in idelalisib systemic exposures, likely 
driven by a higher relative contribution of CYP3A to overall idelalisib clearance under the 
induced state.


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Pharmacodynamic results showed that a idelalisib dose of 200 mg inhibited ex vivo basophil 
activation via the PI3K-specific, high-affinity immunoglobulin (Ig)E receptor (anti-FCR1) in 
basophils collected from healthy volunteers. The findings were confirmed when the drug was 
assessed over 7 days in a Phase 1b study in subjects with allergic rhinitis. In this study, idelalisib
at a dose level of 100 mg/dose BID showed clinical and pharmacodynamic activity 
(attenuating adverse responses to allergenic challenge and decreasing markers of inflammation) 
and was well tolerated.
1.3.5.2.
Phase 1 Studies in Patients with Hematological Malignancies
1.3.5.2.1.
Phase 1 Monotherapy Study in Patients with Hematological Malignancies
A Phase 1 dose-ranging study (Study 101-02) of single-agent idelalisib extended safety and 
pharmacokinetic observations; documented the clinical and pharmacodynamic activity of 
idelalisib in subjects with iNHL, MCL, and CLL; and provided dosing information in support of 
further development {Brown et al 2011, Coutre et al 2011, Kahl et al 2011}. In this study, 
idelalisib was administered in cohorts of subjects across a range of dose levels from 50 mg/dose 
BID to 350 mg/dose BID. Idelalisib administration was continued as long as individual subjects 
were safely benefitting from therapy. Subjects were evaluated in 4-week cycles; response and 
progression assessments were based on standard criteria {Hallek et al 2008}.
A total of 191 subjects were enrolled to the study at dose levels of 50 mg BID (n=17), 
150 mg QD (n=16), 100 mg BID (n=25), 150 mg BID (n=45), 200 mg BID (n=35), 
350 mg BID (n=17), and 300 mg QD (n=19). An additional cohort was also enrolled to receive 
idelalisib 150 mg BID in 28 day cycles (21 days on idelalisib/7 days off [n=17]). Subject
characteristics were as follows: males/females n=139 (73%)/52 (27%) with median age of 
64.5 (range 32-91) years. Diagnoses included: CLL, n=54 (28%); iNHL, n=64 (34%); aggressive 
NHL (MCL and DLBCL), n=49 (26%); AML, n=12 (6%); and MM, n=12 (6%). Categorization 
of disease by response to the last prior therapy included: refractory, n=111 (58%); 
relapsed, n=79 (42%); and unknown, n=1 (1%).  The median (range) number of prior therapies 
was 5 (1-14). Among subjects with iNHL and CLL, the majority had received prior rituximab 
and prior alkylating agent therapy.
Adverse events were usually mild to moderate and not clearly idelalisib-related. Among 
Grade ≥3 adverse events, pneumonias and diarrhea were notable. Pneumonia was observed in 
23 (12%) subjects, primarily in subjects with CLL. In most instances, these findings were 
considered bacterial in origin, based either on culture results or on response to conventional 
antibiotics. Grade ≥3 adverse events of diarrhea were seen in 11 subjects (5.8%). Other 
Grade ≥3 events included rash in 3 (1.6%) subjects. The relative contributions of disease-related 
factors, toxicity from prior therapies or ongoing supportive care, and idelalisib to these events 
was not clear.
Grade ≥3 hematological laboratory abnormalities have included neutropenia, n=46 (24%); 
thrombocytopenia, n=27 (14%), anemia, n=14 (7.3%), and lymphopenia 13 (6.8%); with 
12 subjects (6.3%) having febrile neutropenia.  The occurrence of these events was greater in 
subjects with leukemia, particularly in those with pre-existing hematological abnormalities due 
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Consistent with the observations in the 28-day dog toxicology study, reversible Grade ≥3 
ALT/AST elevations occurred in 28 (15%) subjects and have been attributed to idelalisib. Onset 
generally occurred between 2 to 16 weeks after idelalisib initiation and resolution was usually 
seen 2 to 6 weeks after idelalisib interruption.  After resolution of ALT/AST increases, 
14 subjects were rechallenged at the same or a reduced dose of idelalisib and 9 (64%) of these 
subjects were able to resume treatment without recurrence of transaminase elevations.
Two (1.0%) subjects had ≥ 2 x ULN elevations in bilirubin in the context of Grade ≥3 
elevated AST/ALT, both of whom had confounding factors (recent history of biliary obstruction 
or concomitant use of potentially hepatotoxic medications) so that a definitive causal relationship 
to idelalisib could not be established.
Pharmacokinetic analyses indicated that the increase in Cmax and AUC0-6h with dose was less 
than dose-proportional, with modest increases above the dose level of 150 mg BID.
Pharmacodynamic data supported drug activity.  In subjects with NHL, plasma concentrations of 
chemokines CCL22 and CCL17 were elevated at baseline and showed significant decreases 
within 1 cycle of idelalisib treatment (p<0.001 for both comparisons). Flow cytometry of CLL 
cells from subjects showed that idelalisib reduced constitutive expression of phosphorylated 
AKT to background levels when measured after 1 week of treatment (p<0.0001), demonstrating 
pharmacodynamic inhibition of activated PI3K signaling.  Plasma concentrations of 
chemokines CCL3, CCL4, and CXCL13 were elevated in CLL subjects at baseline and 
decreased significantly within 1 cycle of idelalisib administration (p<0.001 for all comparisons).
Tumor reductions meeting antitumor response criteria were not observed in subjects with AML 
or MM. One of 11 subjects with DLBCL achieved a PR.  In 104 subjects with iNHL and MCL, 
idelalisib induced PRs at all dose levels, with respective ORRs in enrolled subjects of 
29/64 (45%) for iNHL and 16/40 (40%) for MCL. The median DOR has not been reached in 
subjects with iNHL; 19 subjects continued to receive idelalisib in a long-term extension study. 
The median [range] DOR was 2.7 months [1 month to 8 months] in subjects with MCL; 
6 MCL subjects continued to receive idelalisib in a long-term extension study.
In subjects with CLL, idelalisib reduced lymphadenopathy in almost all subjects; 
44/54 (81.5%) achieved a lymph node response (≥50% reduction in target nodal lesions). An 
initial increase in peripheral absolute lymphocyte counts of >50% from baseline was observed in 
some subjects; increases were maximal during the first 2 cycles and decreased thereafter; the 
pattern suggested drug-mediated lymphocyte redistribution.  In 54 subjects with CLL, 
39/54 (72%) achieved a PR (includes PR with lymphocytosis).  The median DOR was not 
reached; 23 subjects continued to receive idelalisib in a long-term extension study.
1.3.5.2.2.
Phase 1 Combination Study in Patients with Hematological Malignancies
A separate Phase 1 trial (Study 101-07) has evaluated the safety and preliminary activity of 
idelalisib given in combination with rituximab to subjects with recurrent iNHL or CLL {Brown 
et al 2011, Leonard et al 2011}.


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In this study, rituximab was administered at a standard dose of 375 mg/m2 per infusion weekly 
for 8 weeks in all subjects. Idelalisib was started simultaneously with the rituximab, first at a 
dose level of 100 mg/dose BID (n=13) and then at a dose level of 150 mg/dose BID (n=12) and 
was administered continuously to both subjects with CLL (n=13) and subjects with iNHL (n=12)
for as long as individual subjects were safely benefiting from therapy. Subjects were evaluated in 
4-week cycles; response and progression assessments were based on standard criteria {Hallek et 
al 2008}.
Among the subjects with CLL, the median age was 63 and ranged to 85 years. Bulky tumors 
(1 lymph node 5 cm in diameter) were present in 63% of the subjects. The median number of 
prior therapies by disease was 2 and ranged up to 8 prior treatments. All had received prior 
rituximab and the majority had received prior fludarabine or alkylating agents. Approximately 
one-third of subjects had CLL that was refractory to the last prior therapy. At the time of data 
cut-off, therapy had been administered for a median of 5 cycles, ranging up to 12 cycles 
(ie, 48 weeks).
No idelalisib-related dose-limiting toxicities were observed within the tested subject cohorts. 
Grade 3-4 adverse events largely comprised background events resulting from pre-existing 
disease- or treatment-related conditions or from intercurrent illness. Among subjects with CLL, 
2 (15%) developed pneumonia. For subjects receiving idelalisib together with rituximab, 
Grade 3-4 elevations in ALT/AST were not observed in those with CLL, although 
3 subjects (25%) of those with iNHL had such events.
The idelalisib plus rituximab combination showed a high level of antitumor activity in both 
subjects with CLL and those with iNHL. Altogether 92% of subjects with CLL receiving the 
combination of idelalisib and rituximab had reductions in nodal size and 77% showed a 
lymph node response (50% reduction in index nodal lesions). Although concomitant 
administration of rituximab did not eliminate the redistribution lymphocytosis that is associated 
with idelalisib, it blunted the magnitude of the change. As a result, the overall response rate 
(ORR) was also 77% among subjects participating in this study. At the time of last data analysis, 
PFS through 48 weeks was 70% and a median PFS had not yet been observed.
Collectively, the emerging data from this study support further evaluation of idelalisib together 
with rituximab in subjects with CLL and indicate that co-administration of idelalisib with 
rituximab is tolerable when using idelalisib at full dose, ie, at a starting dose level of 
150 mg/dose BID.
For additional or updated information, please refer to the current version of the IB.
1.4.
Summary and Justification for the Current Study
Gilead Sciences is conducting this Phase 3 study program to evaluate the efficacy and safety of 
idelalisib in patients with previously treated, recurrent CLL. Collectively the data derived from 
the primary clinical trial (Study GS-US-312-0116) and from this extension trial 
(Study GS-US-312-0117) address the activity of idelalisib together with rituximab, the activity 
of idelalisib when given alone, and the potential for dose-dependent restoration of drug activity 
in subjects who have disease that appears to be drug resistant.


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The design and conduct of this clinical trial program is supported by knowledge of the 
demographics of patients with CLL, the natural history and current therapies for the disease, and 
the nonclinical and clinical information regarding idelalisib. The collective data support the 
following conclusions:

CLL is a serious, disabling, and potentially life-threatening disorder of older patients that 
requires sequential treatment with agents that provide alternative mechanisms of tumor 
control. Existing cytotoxic agents have serious acute and chronic toxicities, making them less 
suitable for frail or unfit patients. Single-agent rituximab can offer disease palliation with 
good tolerability in some patients with relapsed CLL but tumor control is not lasting, 
especially in patients with bulky adenopathy. Development of a non-cytotoxic combination 
therapy of idelalisib with rituximab or a monotherapy regimen of idelalisib that can address 
disease pathogenesis with a new mechanism of action and might offer complementary 
nodal and peripheral blood activity would address an unmet medical need, particularly when 
applied in patients with substantial comorbidities or myelosuppression from prior 
chemotherapies.

PI3Kδ over-expression plays an important role in CLL biology. Further evaluation of 
idelalisib as a potential treatment for CLL has sound scientific rationale founded on 
knowledge of the actions of the drug to selectively abrogate PI3Kδ activity and to inhibit 
malignant cell growth and stromal cell signaling in nonclinical models of CLL. These data 
are supported by clinical documentation of idelalisib inhibition of PI3Kδ signaling in patients 
with CLL.

The potential for clinical efficacy of idelalisib monotherapy or of idelalisib plus rituximab in 
patients with relapsed or refractory CLL is supported by the observed antitumor activity of 
idelalisib - given alone or in combination with rituximab - in patients with heavily pretreated 
CLL and iNHL.

The safety of advancing development of the idelalisib monotherapy and of a regimen of 
idelalisib plus rituximab in this Phase 3 clinical trial program is well supported by safety 
pharmacology and toxicology studies and by Phase 1 single-agent and combination safety 
data obtained in healthy volunteers and in subjects with lymphoid cancers.

Dose-safety, dose-exposure, and dose-activity relationships identified in Phase 1 studies
support the dosing regimen and dose modification provisions in this study.

Observations relating to patterns of CLL response among subjects receiving idelalisib alone 
or in combination with rituximab in Phase 1 trials provide the foundation for efficacy
monitoring in this trial. Of particular note is that idelalisib mobilizes CLL cells from tissues 
into the peripheral blood. This characteristic pharmacological action is prominent early in 
therapy but can persist over time and should not be confused with disease progression in 
patients who have persistent control of other CLL-related signs and symptoms. For this 
reason, in this Phase 3 study program, subjects will be continued on therapy until the 
occurrence of definitive disease progression, ie, disease progression that is manifest by 
worsening CLL-related signs or symptoms other than lymphocytosis alone. 


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
Thorough nonclinical and clinical characterization of the type, severity, manifestations, and 
expected timing of adverse events establish the safety monitoring plan in this trial program.

The scientific correlative work performed in prior preclinical and clinical studies provides 
strong scientific underpinnings for the companion laboratory studies to be performed as a 
component of this clinical trial program.

Given the seriousness of previously treated CLL in patients with substantial comorbidity, and 
the aggregate potential benefits considered in the context of potential risks, further 
development of idelalisib in this Phase 3 clinical trial program is justified.
The rationale for specific design features is provided in relevant sections of the protocol, 
including Section 3.2 (Endpoint Selection Rationale), Section 2.2 (Design Rationale), 
Section 4.3 (Enrollment Criteria Rationale), Section 5.10 (Study Treatment Rationale), and 
Section 6.5 (Study Procedure Rationale).


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2.
STUDY DESIGN
2.1.
Design Overview and Study Schema
This study is being conducted as part of an overall clinical program that is evaluating the efficacy 
and safety of idelalisib in the therapy of patients with previously treated CLL (see Figure 2-1). 
Within this program, the primary clinical trial (Study GS-US-312-0116) is a Phase 3, 
multicenter, 2-arm, randomized, double-blind, placebo-controlled, parallel-group study. This 
clinical trial (Study GS-US-312-0117) is a separate, multicenter, 2-arm, double-blind, 
parallel-group extension study that is a companion study to the primary study.
Figure 2-1.
Study Design
Candidates for the primary study will be adults with previously treated recurrent CLL who have 
measurable lymphadenopathy, require therapy for CLL, have experienced CLL progression 
<24 months since the completion of the last prior therapy, and are currently not sufficiently fit to 
receive cytotoxic therapy because of chemotherapy-induced bone marrow damage or 
comorbidities.
Primary study subjects will be stratified based on 17p deletion and/or a p53 mutation status 
(either vs neither), immunoglobulin heavy chain variable region (IgHV) mutation status 
(unmutated vs mutated), and any prior therapy with an anti-CD20 therapeutic monoclonal 
antibody (yes vs no) and randomized in a 1:1 ratio to receive 1 of the 2 treatment arms.
In the primary study, subjects will be administered rituximab intravenously in the clinic starting 
at a dose of 375 mg/m2 on Day 1 (Week 0) and will continue with a dose of 500 mg/m2 on 
Day 15 (Week 2), Day 29 (Week 4), Day 43 (Week 6), Day 57 (Week 8), Day 85 (Week 12), 
Day 113 (Week 16), Day 141 (Week 20) (for a total of 8 infusions). Rituximab will be
administered until the earliest of subject withdrawal from study, definitive progression of CLL, 
intolerable rituximab-related toxicity, pregnancy, substantial noncompliance with study 
procedures, study discontinuation, or a maximum of 8 infusions.


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Idelalisib or placebo will be taken orally, BID continuously. Subjects will continue whichever 
study drug (idelalisib/placebo or rituximab) continues to be tolerated, even if the other drug has 
been discontinued due to toxicity.
If permanent discontinuation of study drug, occurs prior to definitive progression of CLL, 
subjects shall remain on study until definitive progression of CLL or withdrawal from the study 
for reasons specified in Section 5.7.
Compliant subjects who are tolerating therapy but who develop definitive disease progression in 
the primary clinical trial (Study GS-US-312-0116) can consider enrollment in this separate 
companion extension trial (Study GS-US-312-0117). In the extension trial, subjects will take 
active blinded idelalisib therapy, either at a higher starting dose or at the standard starting dose, 
with allocation based on the original primary study randomization. Following unblinding of 
Study GS-US-312-0116, subjects will be allowed to enter Study GS-US-312-0117 in the absence 
of evidence of disease progression and will take 150 mg BID idelalisib regardless of treatment 
assignment in Study GS-US-312-0116.
The primary objective of Study GS-US-312-0116 will be to evaluate the effect of the addition of 
idelalisib to rituximab on PFS. Secondary and tertiary objectives will focus on determining the 
effect of the addition of idelalisib to rituximab on the onset, magnitude, and duration of tumor 
control; overall survival (OS); health-related quality of life (HRQL); changes in subject 
performance status; disease-associated biomarkers and potential mechanisms of resistance; 
treatment administration; safety; and health resource utilization. In Study GS-US-312-0117, the 
same endpoints will be assessed as in Study GS-US-312-0116; the focus of the analysis will be 
largely descriptive except for the within-subject assessment of treatment effects among subjects 
receiving first rituximab alone and then idelalisib alone on Arm B of each trial. No formal 
comparisons of outcomes in Arm A vs Arm B are planned within Study GS-US-312-0117.
2.2.
Design Rationale
The randomized, add-on design for the primary trial (Study GS-US-312-0116) is customary in 
the comparative evaluation of new therapies for cancer. While this design provides idelalisib
efficacy and safety information only in the context of administration of a companion 
antineoplastic agent, it is appropriate because it documents the incremental benefit and toxicity 
of the investigational therapy in the context of a controlled clinical trial while ensuring that all 
participants receive potentially active treatment.
This separate extension trial (Study GS-US-312-0117) enhances subject acceptance of 
randomization in the primary study and provides further information regarding idelalisib
efficacy, resistance, and safety. Among subjects in Arm A, escalation to a higher dose level 
allows evaluation of dose-dependent resistance and a determination if a higher dose can 
reestablish disease control. The safety data obtained in these subjects will add to the overall 
safety database. Among subjects randomized to Arm B in the primary study, evaluation of 
idelalisib at a starting dose of 150 mg/dose BID in the extension study may permit a 
within-subject assessment of the treatment effects with single-agent idelalisib relative to the 
effects previously observed with rituximab alone. Of importance, the extension study maintains 


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the partial blinding of the primary study, thus minimizing the bias that might occur if the overall 
design entailed only a 1-way crossover to open-label idelalisib among subjects who had received 
placebo on Arm B of the primary study. To ensure confirmation of disease progression, tumor 
size data collected from the primary study will be subjected to independent review by an 
independent review committee (IRC) (see Section 10.4.2); subjects will continue with study 
therapy pending confirmation of progression status by the sponsor working in collaboration with 
the IRC. Subjects must have confirmation that the disease has progressed on the primary study 
before being permitted to receive secondary idelalisib therapy on the extension study, or in the 
event the primary study is stopped, subjects who have not yet progressed may enroll on the 
extension study to receive 150 mg BID idelalisib.


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3.
OBJECTIVES AND ENDPOINTS

To evaluate the effect of idelalisib on the onset, magnitude, and duration of tumor control

To compare tumor control in subjects receiving rituximab alone in Study GS-US-312-0116 to 
that observed in the same subjects when receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject well-being, including overall survival 
(OS), health-related quality of life (HRQL), and performance status

To assess the effects of idelalisib on disease-associated biomarkers and to evaluate potential 
mechanisms of resistance to idelalisib

To characterize exposure to idelalisib as determined by treatment administration and 
evaluation of idelalisib plasma concentrations over time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with administration of idelalisib
3.1.
Endpoints
3.1.1.
Tumor Control

Progression-free survival (PFS) – defined as the interval from the start of study therapy to the 
earlier of the first documentation of definitive disease progression or death from any cause; 
definitive disease progression is CLL progression based on standard criteria other than 
lymphocytosis alone

ORR – defined as the proportion of subjects who achieve a CR or partial response (PR) 

Lymph node response rate – defined as the proportion of subjects who achieve a 
50% decrease from baseline in the SPD of index lymph nodes

CR rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from start of study therapy to the first 
documentation of CR or PR

Duration of response (DOR) – defined as the interval from the first documentation of 
CR or PR to the earlier of the first documentation of definitive disease progression or death 
from any cause


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
Percent change in lymph node area – defined as the percent change from baseline in the sum 
of the products of the greatest perpendicular diameters (SPD) of index lymph nodes

Splenomegaly response rate – defined as the proportion of subjects with baseline 
splenomegaly who achieve an on-study normalization or a 50% decrease (minimum 2 cm) 
from baseline in the enlargement of the splenic LVD (by imaging)

Hepatomegaly response rate – defined as the proportion of subjects with baseline 
hepatomegaly who achieve an on-study normalization or a 50% decrease (minimum 2 cm) 
from baseline in the hepatic longest vertical dimension (LVD) (by imaging)

ALC response rate – defined as the proportion of subjects with baseline lymphocytosis 
(ALC4 x 109/L) who achieve an on-study ALC <4 x 109/L or demonstrate a 50% decrease 
in ALC from baseline; ALC values within 4 weeks post-baseline will be excluded from the 
ALC response rate evaluation

Platelet response rate – defined as the proportion of subjects with baseline thrombocytopenia 
(platelet count <100 x 109/L) who achieve an on-study platelet count 100 x 109/L or 
demonstrate a 50% increase in platelet count from baseline; platelet values within 4 weeks 
post-baseline or after 8 days post transfusion will be excluded from the platelet response rate 
evaluation

Hemoglobin response rate – defined as the proportion of subjects with baseline anemia 
(hemoglobin <110 g/L [11.0 g/dL]) who achieve an on-study hemoglobin 110 g/L 
(11.0 g/dL) or demonstrate a 50% increase in hemoglobin from baseline; hemoglobin 
values within 4 weeks post-baseline or after 4 weeks of receiving packed cell/whole blood 
transfusion or after 6 weeks of receiving exogenous growth factors (e.g., Darbepoetin alfa) 
will be excluded for the hemoglobin response evaluation

Neutrophil response rate – defined as the proportion of subjects with baseline neutropenia 
(absolute neutrophil count [ANC] ≤1.5 x 109/L) who achieve an ANC >1.5 x 109/L or 
demonstrate a 50% increase in ANC from baseline; ANC values within 4 weeks of 
post-baseline or after 2 weeks of receiving exogenous growth factors 
(e.g., Filgrastim, G-CSF, Lenograstim) or after 4 weeks of receiving Neulasta were excluded 
for response evaluation
3.1.2.
Patient Well-Being

Overall survival (OS) – defined as the interval from start of study therapy to death from any 
cause

Change from baseline in HRQL domain and symptom scores based on the 
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) (see Appendix 2)

Changes from baseline in Karnofsky performance status – defined as the change from 
baseline in the performance status (see Appendix 3)


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3.1.3.
Pharmacodynamic Markers of Drug Activity and Resistance

Changes from baseline in PI3K/AKT/mTOR pathway activation as a measure of PI3K
pathway activity

Changes from baseline in the plasma concentrations of disease-associated chemokines and 
cytokines
3.1.4.
Exposure

Study drug administration as assessed by prescribing records and compliance as assessed by 
quantification of used and unused drug

Trough (pre-dose) and peak (1.5-hour samples) of idelalisib plasma concentrations as 
assessed by a validated bioanalytical method
3.1.5.
Safety

Overall safety profile of each study treatment regimen characterized by the type, frequency, 
severity, timing of onset, duration, and relationship to study therapy of any adverse events or 
abnormalities of laboratory tests; serious adverse events; or adverse events leading to 
discontinuation of study drug
3.1.6.
Pharmacoeconomics

Change in health status – defined as the change from baseline in overall health and 
single-item dimension scores as assessed using the EuroQoL Five-Dimension (EQ-5D) utility 
measure (Appendix 4)

Health resource measures, including resource utilization, total costs, and measures of 
cost per unit of benefit (eg, cost per additional progression-free month, 
cost per quality-adjusted life-year)
3.2.
Endpoint Selection Rationale
The proposed endpoints have been chosen based on relevance to the pathophysiology and 
clinical manifestations of CLL, the known pharmacology of idelalisib, and the goals of the study 
in documenting idelalisib benefit-to-risk ratio. These types of endpoints have been employed in 
prior studies in CLL and can be evaluated with acceptable reliability and accuracy.
3.2.1.
Tumor Control Endpoints
Assessments of the magnitude and duration of changes in tumor size are routinely employed in 
registration-directed oncology clinical studies to determine therapeutic effect. Unlike OS, these 
endpoints directly assess the ability of the drug to control the malignancy. Such assessments are 
also integral to treatment decisions; because subjects are being treated until disease progression, 


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repeated tumor assessment must be performed in order to define the proper duration of treatment 
for each study participant. Standard response and progression criteria have been established by 
the International Workshop on CLL (IWCLL) {Hallek et al 2008}; the assessments of treatment 
effects in this study will be based on these criteria, taking into account the specific pharmacology 
of idelalisib.
In CLL, disease-related nodal enlargement is a major cause of patient discomfort and can cause
organ dysfunction {Dighiero et al 2008}. Extensive lymphadenopathy constitutes a reason to 
treat CLL and controlling the size of pathologically enlarged lymph nodes is an important 
therapeutic goal for improving patient well-being and relieving obstructive symptoms {Hallek et 
al 2008}. Given that the natural history of recurrent CLL is inexorable nodal growth, enhancing 
tumor shrinkage and prolonging tumor control provides strong evidence of pharmacological 
activity.
Endpoints of overall tumor control as evaluated in this trial are customarily assessed and reported 
in studies of new therapies in patients with cancer. PFS offers a well established outcome 
measure that directly measures treatment effect, conveys important longitudinal information 
regarding tumor control, can be characterized in all subjects using intention-to-treat (ITT) 
principles, and is readily analyzed using statistical methods such as Kaplan-Meier techniques. 
ORR provides an integrated assessment of the magnitude and extent of changes in 
lymphadenopathy, organomegaly, bone marrow infiltration, and bone marrow function that 
conveniently categorizes and describes treatment effects. TTR and DOR are important in 
characterizing the rapidity of achieving tumor shrinkage and the duration of tumor control. 
Beyond providing descriptions on overall response assessment using ORR, this protocol will also 
seek to characterize the individual components of response that are important in assessment of 
CLL {Hallek et al 2008}. Thus, changes in lymph node area and in the proportion of subjects 
having a lymph node response will be analyzed. In addition, among subjects who enter the study 
with splenomegaly or hepatomegaly, the proportion of subjects who achieve substantial (50%) 
reductions in spleen or liver size will be assessed. Similarly, the proportions of subjects who 
experience improvements in ALC, platelets, hemoglobin, and neutrophil counts will be 
characterized in order to provide specific insight into the degree to which therapy alters these 
individual parameters.
Because idelalisib mobilizes CLL cells from tissues into the peripheral blood as part of its 
pharmacological effect, there is a risk of falsely declaring a subject to have experienced disease 
progression if lymphocyte count is considered as the sole basis for potential CLL worsening. To 
account for this potential problem, changes in lymphocyte count will not be considered in 
determining whether a subject has progressive disease, ie, subjects will only be declared to have 
progressive CLL if they meet any of the IWCLL criteria for progressive disease other than 
lymphocytosis alone. Thus, subjects with worsening lymphadenopathy, organomegaly, bone 
marrow involvement, progressive cytopenias, appearance of new disease, or transformation to an 
aggressive lymphoid malignancy histology (eg, Richter syndrome) will be considered to have 
progressed. Subjects with lymphocytosis without any of these other events will not be considered 
to have progressed. Given that lymphocytosis has no prognostic significance in patients with 
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considered a reason to treat in patients with CLL {Eichhorst et al 2010, Hallek et al 2008, 
Zelenetz et al 2011}, this approach does not jeopardize subject safety or subsequent therapy. 
Furthermore, it will allow complete collection of all response and progression data (both 
considering lymphocytosis and ignoring lymphocytosis) with the intent of providing complete 
information for regulatory authority review.
The current IWCLL guidelines indicate that physical examination is generally sufficient to 
evaluate nodal response and progression in patients with CLL {Hallek et al 2008} but that 
radiographic assessments may be appropriate in clinical trials. Computed tomography (CT) is 
considered the preferred imaging method unless patients have contraindications that require use 
of magnetic resonance imaging (MRI). Given the low fluorodeoxyglucose (FDG) avidity of 
CLL, positron- emission tomography (PET) does not have a role in evaluation of this disease. 
The incremental benefits of using radiographic imaging are limited in patients undergoing 
long-term follow-up following first-line therapy {Blum et al 2007, Eichhorst et al 2011}. 
However, in the patients with advanced CLL and bulky adenopathy such as those who will be 
enrolled to this trial, it is known that CT scans commonly detect bulky intra-abdominal 
lymphadenopathy and splenomegaly that would be missed by palpation alone and that the 
presence of large-volume, intra-abdominal disease of the nodes and spleen is associated with a 
poor prognosis {Norin et al 2010}. Thus, while use of CT confers greater radiation exposure, 
subjects have the chance to benefit from radiographic imaging because it will offer more 
accurate information regarding their response to protocol therapy and the appropriate duration of 
protocol treatment. Having this information is particularly important in this trial because PI3K
inhibition precludes use of lymphocyte counts as evidence for disease progression. In addition, 
the risk is offset by the fact that the trial subjects will primarily be patients who have already 
received more potent mutagens (eg, purine analogs, alkylating agents), and all of whom have 
advanced cancer and limited treatment options at study entry. Based on published data {Keating 
et al 2002a, Wierda et al 2010}, median OS for patients with comparably advanced CLL is 
<18 months, so the long-term secondary malignancy risk from CT-related radiation exposure is 
very low. Finally, in the context of a registration-directed pivotal trial of a new drug with a new 
mechanism of action, radiographic imaging is critically important to provide reassurance 
regarding subject safety and trial validity. In this regard, CT evaluations of the lung can be used 
retrospectively to assess for radiographic evidence of drug-induced lung changes {Maroto et al 
2011, White et al 2010}. Furthermore, CT measurements have greater accuracy and 
reproducibility than palpation, are subject to independent expert review, and can be audited 
against electronic case report form (eCRF) information.
The timing of radiographic tumor assessments has been carefully considered. To avoid 
duplication, the CT scan documenting CLL progression in Study GS-US-312-0116 will serve as 
the baseline CT scan for Study GS-US-312-0117. Among patients receiving idelalisib in 
Phase 1b/2 studies who experienced a nodal response (50% regression in tumor area), such 
responses were observed with the first 16 week of therapy {Coutre et al 2011, Leonard et al 
2011}; the planned timing of tumor assessments (at Weeks 8, 16, 24, 36, 48 and then every 
12 weeks thereafter) in this study fits with this known timing of changes in lymph node size 
during idelalisib therapy. Scans at 8-week intervals during the first 24 weeks allow efficient 
documentation of response. During this period, early documentation of disease progression 


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allows subjects who are not benefiting from study therapy to move rapidly to alternative 
treatments. After 24 weeks on study or after 24 weeks cumulative treatment with idelalisib 
across Study GS-US-312-0116 and Study GS-US-312-0117, the reduction in the frequency of 
CT scans (to 12-week intervals) reduces the overall protocol burden for subjects while still 
allowing characterization of the expected median PFS in this trial. As outlined in Section 7.3, 
iodine-containing or gadolinium contrast material may be omitted in subjects for whom use of a 
contrast agent would be medically contraindicated.
3.2.2.
Measures of Patient Well-Being
3.2.2.1.
Overall Survival
While OS provides an ultimate measure of patient well-being, it has not routinely been used as 
the primary endpoint in CLL clinical trials. Unlike PFS, it does not specifically measure 
drug-mediated tumor control, and thus provides only an indirect assessment of treatment effect. 
Depending upon the treatment setting, long OS times in patients with CLL can preclude use of 
this endpoint as an efficient method for understanding drug benefits. In both the front-line and 
recurrent disease settings, post-study treatments can influence OS in unpredictable ways, 
potentially confounding differences between treatment groups.
However, given the life-threatening nature of systemic malignancy, documentation of OS is 
customary in oncology therapeutic clinical trials, including those evaluating subjects with 
recurrent CLL {Keating et al 2002a, Wierda et al 2010}. Evaluation of OS in this study 
continues the survival assessment from the primary study (Study GS-US-312-0116). The study 
program as a whole (considering both the primary randomized trial and secondary extension 
study) offers the potential to better understand OS and causes of death in a frail population of 
patients with both CLL, considering the consequences of the disease and comorbidities.
3.2.2.2.
Health-Related Quality of Life
Direct patient reporting of outcomes using standardized methods has become an increasingly 
important component of therapeutic assessment. Evaluation of patient-reported outcomes (PROs) 
is particularly relevant in patients who cannot be cured of disease {Reeve et al 2007}. PRO 
questionnaires have been previously used in CLL to understand how patients differ from the 
general population in terms of health concerns {Eichhorst et al 2007, Else et al 2008, Holzner et 
al 2004, Shanafelt et al 2007}, to understand differences in perceptions of well-being in younger 
vs older patients {Else et al 2008, Levin et al 2007}, to determine how treatment affects HRQL 
{Catovsky et al 2007, Efficace et al 2008, Eichhorst et al 2007}, and to assess the 
pharmacoeconomic cost of improvements in HRQL {Stephens et al 2005}.
Patients with CLL have overtly impaired well-being relative to comparable controls {Eichhorst 
et al 2007, Else et al 2008, Holzner et al 2004, Shanafelt et al 2007}. Fatigue is cited as a 
common complaint, being present in the substantial majority of patients. Impairment of HRQL 
prior to any treatment is apparent in those with B symptoms or in patients with anemia, 
supporting the concept of initiating treatment when patients experience symptomatic disease. 
Factors associated with lower overall HRQL have included older age, greater fatigue, severity of 


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co-morbid health conditions, advanced stage, and ongoing treatment for CLL {Shanafelt et al 
2007}. Younger patients appear to have worse emotional and social well-being but older patients 
experience worse physical HRQL {Levin et al 2007}. In comparative evaluation of 
chemotherapy-containing regimens, differences in HRQL between therapies (eg, fludarabine vs 
fludarabine-cyclophosphamide vs chlorambucil) reflected differences in toxicity while improved 
HRQL was associated with greater efficacy {Catovsky et al 2007, Eichhorst et al 2007}.
In this study, it is postulated that idelalisib-mediated tumor control will be correlated with greater 
positive changes in HRQL and that assessments of the drug’s safety profile will be supported by 
HRQL evaluations. The FACT-Leu (Appendix 2) has been selected to evaluate such outcomes 
for the study. The FACT-Leu comprises a general HRQL measure for patients receiving cancer 
treatment that yields a total score and subscales for physical, functional, social/family and 
emotional well-being {Cella et al 1993} and a diagnosis-specific measure for patients with 
leukemia {Webster et al 2002}. The FACT-Leu was developed to assess symptoms (eg, fevers, 
chills, night sweats, nodal swelling, fatigue) specifically relevant to patients with leukemia. 
FACT instruments have documented psychometric properties {Brucker et al 2005, Cella et al 
2005, Cella et al 1993, Victorson et al 2008, Webster et al 2002}.
The FACT-Leu instrument is available in appropriate languages for this study. FACT-Leu data 
will be obtained at baseline and during each investigational clinic visit during treatment. Having 
FACT-Leu data concurrent with tumor response information will allow an evaluation of the 
potential relationship between tumor response and symptomatic changes as reported by patients. 
To avoid biasing HRQL results, the FACT-Leu will be administered at each visit before other 
procedures are performed and before any study information is conveyed to the subject.
3.2.2.3.
Changes in Performance Status
Performance status evaluation provides an integrated assessment of patient well-being before, 
during, and after treatment and, ideally, may indicate how drug efficacy and toxicity affect 
patient functioning. In patients with CLL performance status can be predictive of PFS or OS 
{Hallek et al 1996, Sorensen et al 1997, Youngson et al 1995}.
In this study, it is hypothesized that idelalisib-mediated tumor control will be correlated with 
changes in performance status and that assessments of the drug’s safety profile might be 
supported by performance status evaluations. The well-established, reliable, and validated 
Karnofsky performance score {Karnofsky et al 1949, Schag et al 1984, Yates et al 1980}
(see Appendix 3) will be employed in the trial for characterization of the subject population and 
repeated assessment of performance status.
3.2.3.
Pharmacodynamic Markers of Drug Activity and Resistance
In CLL, disease-related perturbations in inflammatory status can be clinically overt; patients 
often develop bothersome B symptoms (fevers, night sweats, and weight loss) that are 
characteristic of excessive systemic inflammation {Redaelli et al 2004}. Consistent with such 
disease manifestations, the PI3K/AKT/mTOR pathway is constitutively overactive in 
circulating CLL cells {Coutre et al 2011}. In addition, chemokines and cytokines that are 


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markers of aberrant B-cell trafficking or perturbations in inflammation are overexpressed by 
CLL tissues or by stromal cells and circulate in plasma {Burger 2010, Coutre et al 2011}. In 
Phase 1 studies of idelalisib it has been confirmed that idelalisib largely normalizes AKT
phosphorylation and induces dose-dependent reductions in plasma concentrations of circulating 
chemokines and cytokines in patients with CLL {Coutre et al 2011}.
In this study, it is hypothesized that incremental changes in these biomarkers provide direct 
evidence of mechanism-specific idelalisib effects on PI3Kδ activity or indirectly document drug 
effects on overall tumor cell volume. In either case, improvements in these pharmacodynamic 
measures provide corroborative evidence in support of idelalisib pharmacological activity; 
conversely, worsening of these biomarkers may indicate acquisition of resistance to idelalisib. In 
addition, it is possible that disease-or inflammation-related biomarkers may provide corollary 
information relating to the adverse effects of idelalisib on the liver; such data might allow better 
prediction of which subjects might be most susceptible to ALT/AST elevations during idelalisib
treatment. Finally, it can also be postulated that genetic, protein, or metabolic changes in CLL 
cells could provide signatures that would correlate with drug sensitivity and resistance.
Based on these considerations, this study will evaluate PI3K/AKT/mTOR pathway activation 
status in CLL cells. For this purpose, blood will be evaluated by flow cytometry using a 
clinically validated assay {Hoellenriegel et al 2011}. CLL cells will be identified using anti-CD5 
and anti-CD19 antibodies. AKT activation will be determined by quantifying phosphorylation at 
the Ser473 and Thr308 AKT sites using specific anti-pAKT Thr308 and anti-pAKT
Ser473 antibodies. Additional assessments of PI3K/AKT/mTOR pathway signaling 
(eg, evaluating phosphorylation state for other downstream enzymes) may also be explored.
Plasma will be collected for assessment of circulating concentrations of relevant chemokines and 
cytokines with a particular focus on CCL2, CCL3, CCL4, CXCL12, CXCL13, CCL17, CCL19, 
CCL21, CCL22, sCD40 ligand, tumor necrosis factor-α, and C-reactive protein. In addition 
serum markers of iron metabolism (eg, hepcidin, iron, ferritin, transferrin) that might provide 
markers linking disease-related inflammation with perturbations of liver iron and sensitivity to 
liver injury will be evaluated {Ferrucci et al 2010, Nemeth et al 2003}. Clinically validated 
assays (eg, enzyme-linked immunosorbent assays [ELISAs]) will be used to measure circulating 
concentrations of chemokines and cytokines at baseline and during the course of idelalisib
therapy.
CLL cell deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein will be collected at 
baseline and at the conclusion of a subject’s treatment on study. DNA and RNA samples will be 
analyzed using gene array technologies to evaluate for changes in DNA mutations or in 
RNA expression patterns that might be associated with intrinsic or acquired resistance to study 
treatments. Similarly, protein will be evaluated for state-specific changes in protein 
phosphorylation to evaluate for differences in pathway activation at baseline or during therapy 
that might be associated with differences in response or in acquisition of resistance to therapy.


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3.2.4.
Assessments of Exposure
3.2.4.1.
Study Drug Administration and Compliance
Evaluation of study drug administration and compliance provides context for assessments of 
safety, pharmacokinetics, and pharmacological activity. Evaluations of treatment administration 
and modifications from planned therapy document the influence of treatment-emergent adverse 
events on prescribing practice. Compliance assessment offers a general indication of patients’ 
acceptance of therapy, integrating factors of tolerability, palatability, and convenience.
In this study, information regarding planned treatment and modification from planned treatment 
(eg, dose reductions and interruptions) will be kept. The compliance of the subject will be 
verified by accounting for used and unused drug.
3.2.4.2.
Pharmacokinetics
Given the intent of this protocol to assess longer-term dosing, collection of plasma for idelalisib
concentrations is important for evaluating exposure over time. These data may allow correlations 
of exposure with measures of efficacy, toxicity, and resistance. Because the idelalisib
pharmacokinetic profile has been well characterized in Phase 1 studies, limited plasma sampling 
will be performed in this study. Samples will be collected pre-dose and 1.5 hours post-dose 
relative to the morning administration of idelalisib. Based on discussions with investigators, 
collecting more than 2 samples in the morning is not considered reasonable given the need to 
minimize time requirements for study participants and to avoid substantial inconvenience for 
clinic staff.
Evaluation of idelalisib plasma concentrations will be performed using liquid chromatography 
with tandem mass spectrometry. The method has been fully validated in the context of prior 
Phase 1 studies. Plasma samples will be retained for potential later analyses of idelalisib
metabolites.
3.2.5.
Evaluations of Safety
In defining the therapeutic relevance of a drug in a particular clinical setting, it is imperative that 
its safety profile be fully characterized. As is conventional in all clinical studies, proper 
description of each adverse event or laboratory abnormality requires an understanding of the 
type, incidence, timing, severity, and relatedness to study drug. While information on all reported 
adverse events will be collected, listed, and summarized, particular focus will be placed on 
monitoring and reporting adverse events and laboratory abnormalities that were encountered in 
the prior toxicology studies and clinical experience with idelalisib. Safety parameters of specific 
interest in reporting study results will include those relating to bone marrow function, 
dermatological events, gastrointestinal inflammation, infection, pulmonary events 
(eg, pneumonia/pneumonitis), and liver injury. Additional scrutiny will be applied to 
Grade 3-4 adverse events, to adverse events causing interruption or discontinuation of idelalisib, 
and to serious adverse events.


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In addition, the protocol will evaluate for potential adverse idelalisib effects on laboratory 
parameters of immune function; the absolute number of CD4+, CD5+,CD8+, CD16/CD56+, 
CD19+, and CD20+ cells will be assessed by flow cytometry. Serum concentrations of IgA, IgE, 
IgG, and IgM will be obtained.
For consistency of interpretation, adverse events will be coded using the standard 
Medical Dictionary for Regulatory Activities (MedDRA) [http://www.meddramsso.com]), and 
the severity adverse events and laboratory abnormalities will be graded using the well-defined 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). 
Standard definitions for seriousness will be applied (see Section 8.1.2).
3.2.6.
Pharmacoeconomic Measures
It is increasingly important to understand the potential cost implications of introducing a new 
medication into patient care for CLL {Hornberger et al 2012, Main et al 2010}. In order to 
analyze the pharmacoeconomic consequences of idelalisib administration, data will be collected 
regarding the health status of subjects and regarding health care resource utilization.
Heath status information will be obtained with the EQ-5D, which is a self-administered, generic, 
indirect utility measure {The EuroQol Group 1990} (Appendix 4). The EQ-5D consists of a 
visual analogue scale on which subjects are asked to rate their current overall health status and 
5 single-item dimensions which ask subjects to rate their health in terms of mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression. For each of the 5 items, patients must 
choose between 3 levels of difficulty in accomplishing tasks in that dimension. The visual analog 
scale is then used in combination with the dimension scores to generate a health utility score that 
can be incorporated into analyses of cost effectiveness. The EQ-5D has been successfully used in 
the evaluation of patients with B-cell and other cancers {Doorduijn et al 2005, Witzens-Harig et 
al 2009, Yang et al 2010}.
The EQ-5D instrument is available in appropriate languages for this study. EQ-5D data will be 
obtained at baseline and during each investigational clinic visit during treatment. The EQ-5D 
will be administered immediately after administration of the FACT-Leu instrument, before other 
procedures are performed and before any study information is conveyed to the subject. The 
EQ-5D instrument takes only 5 minutes to complete.
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach will be to combine the resource utilization data from the trial with data on 
unit prices (collected separately) to estimate total costs. The costs will be described relative to 
the health care findings as measured by duration of tumor control, the symptom-free survival 
period, and/or utility outcomes or some other appropriate measure of clinical benefits.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects
The planned sample size is ~160 subjects but will be bounded by the number of subjects enrolled 
to the primary clinical trial (Study GS-US-312-0116).
4.2.
Subject Selection Criteria
Subjects in the primary Phase 3 study (GS-US-312-0116) who are compliant, are tolerating 
primary study therapy, and 1) have definitive progression of CLL while receiving primary study 
drug therapy (idelalisib /placebo) or 2) are actively participating in Study GS-US-312-0116 at 
the time the study is stopped, including if stopped early due to overwhelming efficacy following 
an interim analysis are eligible to enroll in the extension study. Eligibility criteria may not be 
waived by the investigator and conformance to the eligibility criteria is subject to review in the 
case of a Good Clinical Practice (GCP) or a regulatory authority audit. Any questions regarding a 
subject’s eligibility should be discussed with the study sponsor medical monitor prior to 
enrollment.
4.2.1.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while receiving study drug therapy 
(idelalisib/placebo) in Study GS-US-312-0116. Note: Definitive disease progression is CLL 
progression based on standard criteria and occurring for any reason 
(ie, increasing lymphadenopathy, organomegaly, or bone marrow involvement; 
decreasing platelet count, hemoglobin, or neutrophil count; or worsening of 
disease-related symptoms) other than lymphocytosis. Subjects must have confirmation by 
the sponsor working in collaboration with an independent review committee (IRC) that the 
disease has progressed on the clinical trial (Study GS-US-312-0116) before receiving
secondary idelalisib therapy on this extension trial (Study GS-US-312-0117).
3) Presence of radiographically measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures 2.0 cm in the longest diameter [LD] and 1.0 cm in the 
longest perpendicular diameter [LPD] as assessed by CT or MRI).
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab and idelalisib/placebo) 
and no intervening or continuing therapy (including radiotherapy, chemotherapy, 
immunotherapy, or investigational therapy) for the treatment of CLL. Note: Subjects may 
receive corticosteroids to manage CLL manifestations.


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5) The time from permanent cessation of Study GS-US-312-0116 treatment (rituximab and/or
idelalisib/placebo) and the initiation of Study GS-US-312-0117 therapy is 12 weeks. 
Note: Study procedures performed as part of Study GS-US-312-0116 need not be repeated 
and can be used as screening procedures for Study GS-US-312-0117 if performed within 
4 weeks prior to initiation of study drug therapy on Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation of study treatment) as 
shown in the table below. Note: Confirmation should be considered for out-of-range values 
to determine if the abnormality is real or artifactual. Values should be obtained within the 
screening period and should generally be the most recent measurement obtained. Subjects 
with any degree of neutropenia, thrombocytopenia, or anemia due to CLL or prior therapy 
may enroll.
Table 4-1.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCra
>30 ml/min
Pregnancy
-HCGb
Negative
a
As calculated by the Cockcroft-Gault formula (see Appendix 5) {Cockcroft et al 1976}
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or 
urine dipstick pregnancy test must be negative at start of study treatment (Visit 2)
Abbreviations: -HCG= beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
eCCr=estimated creatinine clearance, ULN=upper limit of normal
8) For female subjects of childbearing potential, willingness to use a protocol-recommended 
method of contraception (as outlined in Section 5.6.4) from the screening visit (Visit 1) 
throughout the study and for 30 days following the last dose of study drug.
Note: A female subject is considered to be of childbearing potential unless she has had a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically 
documented ovarian failure (with serum estradiol and follicle-stimulating hormone [FSH] 
levels within the institutional postmenopausal range and a negative serum or 
urine HCG), or is menopausal (age ≥54 with amenorrhea for >12 months or 
amenorrhea for >6 months with serum estradiol and FSH levels within the institutional 
postmenopausal range).
9) For male subjects of childbearing potential having intercourse with females of childbearing 
potential, willingness to use a protocol-recommended method of contraception 
(as outlined in Section 5.6.4) from the start of study drug (Visit 2) throughout the study and 
for 90 days following the last dose of study drug and to refrain from sperm donation from the 
start of study drug (Visit 2) throughout the study and for 90 days following the last dose of 
study drug. Note: A male subject is considered able to father a child unless he has had a 


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bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or has ongoing 
testicular suppression with a depot luteinizing hormone- releasing hormone (LH-RH) 
agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate  [Lupron®]), or 
triptorelin pamoate [Trelstar®]).
10) In the judgment of the investigator, participation in the protocol offers an acceptable 
benefit-to-risk ratio when considering current CLL disease status, medical condition, and the 
potential benefits and risks of alternative treatments for CLL. 
11) Willingness and ability to comply with scheduled visits, drug administration plan, imaging 
studies, laboratory tests, other study procedures, and study restrictions. 
Note: Psychological, social, familial, or geographical factors that might preclude adequate 
study participation should be considered.
12) Evidence of a personally signed informed consent indicating that the subject is aware of the 
neoplastic nature of the disease and has been informed of the procedures to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study participation.
4.2.2.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
1) Known histological transformation from CLL to an aggressive lymphoma 
(ie, Richter transformation). Note: Biopsy documentation of the absence or presence of 
transformation is not required.
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of the start of 
study treatment (Visit 2). Note: Subjects with localized fungal infections of skin or nails are 
eligible. Subjects may be receiving prophylactic antiviral or antibacterial therapies at the 
discretion of the investigator; anti-pneumocystis prophylaxis is encouraged. For subjects 
who are at substantial risk of an infection (eg, influenza) that may be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of 
protocol therapy.
3) Pregnancy or breastfeeding. 
4) Intentional breaking of the blind in Study GS-US-312-0116 by the investigator or the study 
subject.
5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical condition, surgical history, physical 
finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the 
investigator’s opinion, could adversely affect the safety of the subject or impair the 
assessment of study results.


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4.3.
Enrollment Criteria Rationale
The eligibility criteria are designed to limit enrollment to subjects who participated in the 
primary clinical trial (Study GS-US-312-0116), are compliant, have been generally able to 
tolerate study therapy and study procedures, and have experienced definitive CLL progression 
while receiving study treatment (rituximab and/or idelalisib/placebo) in the primary study or who 
are actively participating in Study GS-US-312-0116 at the time the study is stopped, including if 
stopped early due to overwhelming efficacy.
The requirement of measurable lymphadenopathy to enter the blinded portion of the study 
ensures that subjects have disease that can adequately be assessed for evidence of drug activity. 
Prior therapy provisions are intended to ensure that subjects are transitioning directly from 
Study GS-US-312-0116 to Study GS-US-312-0117 without receiving intervening treatments. 
The stipulation of 12-week interval from Study GS-US-312-0116 treatment until 
Study GS-US-312-0117 treatment precludes excessively protracted intervals between 
participation in the 2 studies but also permits sufficient time for clinicians and subjects to 
determine whether participation is appropriate. 
In the blinded portion of the study, to ensure that subjects are not so acutely ill from 
life-threatening comorbidities that they require hospitalization and stabilization, subjects with 
Karnofsky performance scores <40 (ie, those who are bed-bound or hospitalized) will not be 
enrolled. Baseline laboratory evaluations are designed to limit participation to subjects who have 
not developed serious organ compromise that would pose a safety risk or confound the 
interpretation of adverse effects. Pregnancy testing and restrictions on eligibility relating to 
reproduction, pregnancy, and nursing are important because idelalisib is a new chemical entity 
with teratogenic effects in rats and it is unknown if it may have adverse effects on conception, on 
fetal development, or on the health of a breast-feeding child. To minimize missing data and 
premature discontinuations, subjects should have sufficient psychological and social resources to 
comply with study procedures and restrictions. Consistent with GCP guidelines, subjects must 
provide informed consent before initiation of any study procedures.


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5.
TREATMENT OF SUBJECTS
5.1.
Enrollment
5.1.1.
Interactive Web Response System
An IWRS will be employed to manage the conduct of the trial. The IWRS will be used to 
maintain a central log documenting enrollment, to manage dose modifications, to assess current 
inventories of study drug, to initiate any necessary resupply of study drug, and to document 
discontinuation of study.
5.1.2.
Treatment Assignment
After a subject has completed the necessary documentation of definitive CLL progression in the 
primary clinical trial (GS-US-312-0116) and has been confirmed to be eligible, the subject can 
be entered into this trial (Study GS-US-312-0117). In order to obtain a treatment arm allocation 
for a subject, a site representative will access the IWRS and supply the system with the required
information.
Subjects will be assigned to either of the following treatment assignments with allocation based 
on the original primary study randomization:
Treatment Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117)
Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly enrolled subjects will 
receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly enrolled subjects will 
receive 150 mg BID
Note: At the Investigator’s discretion, subjects who were randomized to placebo on 
Study GS-US-312-0116 may delay initiation of idelalisib following enrollment on 
Study GS-US-312-0117 until the time of disease progression or until the investigator 
determines that the subject would benefit from initiation of idelalisib treatment.


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Treatment Assignment

Assignment to Arm A or Arm B with allocation based on the original primary study 
randomization

Implementation through an interactive web response system (IWRS)
The IWRS will assign blister card, or bottle numbers and instructions for dispensing of blinded 
study drug (high-dose or standard-dose idelalisib). It is anticipated that subjects will usually 
begin study drug immediately at Visit 2 of the study.
5.1.3.
Blinding
During the blinded portion of the study, the identity of the treatments will be concealed by 
central blinding of study drug assignments. Blinding will be accomplished through use of a 
placebo that is well-matched to the active drug in appearance, packaging, labeling, and schedule 
of administration (see Section 5.2.1). During the study, subjects, caregivers, investigational site 
personnel, Gilead Sciences study team members, and all other study personnel will remain 
blinded to the identity of the treatment assignments; these assignments will be available only to 
the IWRS, the data monitoring committee (DMC) for the study, an independent bioanalytical 
group that supports the DMC, and drug safety personnel who are not part of the study team.
Unblinding an individual subject’s treatment assignment during the study will only occur in the 
case of subject emergencies (see Section 5.5) or in the event the study is discontinued by the
Sponsor, a Regulatory Agency, or an IRB or EC (see Section 5.9). Where required by local 
regulation, expedited reporting of serious adverse events to specific regulatory authorities will 
include information regarding the study drug treatment assignment 
(high-dose or standard-dose idelalisib); this will be done in such a way that subjects, 
investigational site personnel, institutional review board/independent ethics committees 
(IRB/IEC), and study team members remain blinded as to the treatment assignment for the 
subject described in the adverse event report.
The unblinded analysis of the study will be performed when the database is completed and 
locked following unblinding of Study GS-US-312-0116 and Study GS-US-312-0117. The final 
analysis of the open label portion of the study will occur once the open label portion is stopped.
While bioanalytical assays to determine idelalisib concentrations may be performed prior to 
unblinding, pharmacokinetic data that would allow identification of treatment assignments for 
individual subjects will not be available to the study team until after the blind is broken and the 
primary analysis has occurred. Except for emergency unblinding, individual subjects, caregivers, 
and site personnel will not be informed of the treatment assignments until the implications of 
revealing such data for the overall idelalisib study program have been determined by the clinical 
project leader for the idelalisib development program.


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5.2.
Investigational Study Drug (Idelalisib/Placebo)
5.2.1.
Description
Subjects allocated to Arm A in the blinded portion of the study will be provided with 2 tablets of 
active idelalisib for oral administration at each dose. Each tablet contains 150 mg or 100 mg of 
active idelalisib. The 150-mg tablets will be used for initial therapy; the 100-mg tablets are 
provided for use by those subjects who require a dose reduction (see Table 5-1).
Subjects allocated to Arm B in the blinded portion of the study will be provided with 1 tablet of 
active idelalisib and 1 tablet of placebo for oral administration at each dose. Each active tablet 
contains 150 mg or 100 mg of active idelalisib. The 150-mg tablets (and matching placebo) will 
be used for initial therapy; the 100-mg tablets (and matching placebo) are provided for use by 
those subjects who require a dose reduction.
In the open-label portion of the study, subjects will be provided with 150 mg tablets of idelalisib.
The 150-mg tablets are pink, oval-shaped film-coated, and include the following inactive 
excipients: microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, 
sodium starch glycolate, magnesium stearate, red iron oxide, polyethylene glycol, talc, 
polyvinyl alcohol (PVA), and titanium dioxide. The 100-mg tablets are orange, oval shaped film-
coated, and include the following inactive excipients: microcrystalline cellulose, hydroxypropyl 
cellulose, croscarmellose sodium, sodium starch glycolate, magnesium stearate, FD&C Yellow 
#6/Sunset Yellow FCF aluminum lake, polyethylene glycol, talc, PVA, and titanium dioxide.
The placebo tablets match the active idelalisib formulations in appearance. The placebo tablets 
matching the 150-mg tablets are pink, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium stearate, 
red iron oxide, polyethylene glycol, talc, PVA, and titanium dioxide. The placebo tablets 
matching the 100-mg tablets are orange, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium stearate, 
FD&C Yellow #6/Sunset Yellow FCF aluminum lake, polyethylene glycol, talc, PVA and 
titanium dioxide.
5.2.2.
Source
Both active idelalisib and placebo will be supplied free of charge by Gilead Sciences.
5.2.3.
Packaging and Labeling
During the blinded portion of the study, study drug (idelalisib or idelalisib/placebo) will be 
provided in blister cards. The blister cards are made of polyvinyl chloride/
polychlorotrifluoroethylene (PVC/PCTFE) film and have aluminum foil lidding materials. Each 
blister card contains 120 tablets (4-week supply plus a modest overage) of one of the relevant 
dose strengths. The 100-mg or 150-mg and matching placebo tablets will be combined in order 
to obtain the daily doses to be used in this study. Thus, in Arm A, the 300-mg idelalisib dose will 


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be obtained by administering two 150-mg tablets and the 200-mg idelalisib dose will be obtained 
by administering two 100-mg tablets. In Arm B, the 150-mg idelalisib dose will be obtained by 
administering one 150-mg tablet and one placebo tablet and the 100-mg idelalisib dose will be 
obtained by administering one 100-mg tablet and one placebo tablet.
Each blister card will have a unique number. Labeling for blister cards dispensed to subjects in 
Arm A will appear identical to blister cards dispensed to subjects in Arm B, and may include 
either idelalisib or placebo.
When the primary study (GS-US-312-0116) is stopped including if early after an 
interim analysis, GS-US-312-0116 active study subjects will become eligible for participation on 
Study GS-US-312-0117. Active GS-US-312-0117 study subjects will be transitioned to 
open-label idelalisib at this time. Each bottle contains 60 tablets 
(4 week supply plus a modest overage) of one of the relevant dose strengths (150 mg, 100 mg) 
and a polyester coil. Bottles are white and are made of high-density polyethylene. Each bottle is 
closed with a white, continuous-thread, child-resistant, polypropylene screw cap fitted with an 
induction-sealed, aluminum-faced liner.
All labels for study drugs to be distributed to centers in the United States, the EU, and other 
countries will meet all applicable requirements of the United States Food and Drug 
Administration (FDA), the EU Annex 13 of Current Good Manufacturing Practice (cGMP) 
(Manufacture of Investigational Medicinal Products, July 2010), and/or other local regulations as 
applicable.
5.2.4.
Storage and Handling
Blister cards or bottles containing tablets of study drug (idelalisib or idelalisib/placebo) should
be stored at controlled room temperature (ie, ~25 °C, with a range of 15 to 30 °C). While the 
stability of study drug tablets stored at controlled room temperature has been confirmed, brief 
excursions to temperatures as low as -20 °C or as high as 40 °C (eg, during shipping) will not 
adversely affect the drug. Updated stability data will be provided to the sites, as appropriate.
5.2.5.
Dispensing
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing 
study drug according to the IWRS directions. It is planned that drug will be dispensed at 4-week 
intervals through the first 24 weeks of treatment and at 12-week intervals thereafter, or on a 
frequency consistent with the subject’s visit schedule. Sufficient study drug will be provided for 
each study period at the beginning of the period. Multiple blister cards or bottles may be 
dispensed at a single visit. Tablets should be kept in the original blister cards or bottles provided
until they are self-administered by the subject.
At the time of starting study treatment, the IWRS will provide the clinic staff with the blister 
card numbers designating the blister cards to be dispensed, or the quantity of open-label bottles 
to be dispensed. The clinic staff (eg, pharmacist or other qualified person) will write the subject 
number on each blister card or bottle that is dispensed. Immediately before dispensing, the clinic 
staff will write the blister card or bottle number in the study drug administration record 
corresponding to the subject number.


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5.2.6.
Return
The study drug should be retrieved from each subject at the end of each dispensing interval. The 
quantity of study drug and the date returned by the subject should be recorded in the study drug 
accountability records. When possible, all study drug returned by the subject should be retained 
for review by the study site monitor prior to return to Gilead Sciences or destruction.
5.2.7.
Accountability
The disposition of all study drug should be documented from the time of receipt at the site 
through subject dispensing and return.
Study personnel must ensure that all study drug is kept in a secure locked area with access 
limited to authorized personnel. The study drug must not be used outside the context of this 
protocol. Under no circumstances should the investigator or site personnel supply study drug to 
other investigators or clinics, or allow the study drug to be used other than as directed by this 
protocol.
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by Gilead Sciences or its designee, including, but not limited to, 
the date received, lot number, amount received, and the disposition of all study drug. Upon 
receipt of a drug shipment, the shipment must be logged into the IWRS. Study drug 
accountability records must also be maintained that include the subject number to whom the 
study drug was dispensed and the date, quantity and lot number of the study drug dispensed.
Depending upon the decision of Gilead Sciences, remaining unused study drug supply will be 
returned to Gilead Sciences or its designee after the study is completed or will be discarded or 
destroyed at the clinical site. If the study drug is discarded or destroyed at the clinical site, 
standard institutional policy should be followed. Records documenting the date of study drug 
shipping or destruction, relevant lot numbers, and amount shipped or destroyed should be 
maintained.
5.2.8.
Overdose Precautions
In Phase 1 studies, an MTD for idelalisib was not reached when the drug was administered 
continuously at dose levels through 350 mg/dose BID (700 mg per day) {Coutre et al 2011, Kahl 
et al 2011}. However, in this protocol, an overdose is defined as administration of more than the 
prescribed daily dose (ie, >600 mg in a single day). In a subject who experiences an overdose 
consideration should be given as to whether idelalisib administration should be temporarily 
interrupted. If the overdose ingestion is recent and substantial, and if there are no medical 
contraindications, use of gastric lavage or induction of emesis may be considered. Observation 
for any symptomatic side effects should be instituted, and biochemical and hematological 
parameters should be followed closely (consistent with the protocol or more frequently, as 
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The Gilead Sciences medical monitor should be contacted if a study drug overdose occurs. Cases 
of study drug overdose will result in specific reporting requirements (see Section 8.8).
5.2.9.
Inadvertent Exposure and Spill Precautions
Based on available data from nonclinical studies, idelalisib does not appear to be acutely toxic, 
genotoxic, or irritative at levels that are likely to result from inadvertent exposure to the contents 
of broken tablets. However, personnel handling the drug should use reasonable precautions to 
avoid eye contact, skin contact, inhalation, or ingestion of the study drug product. For further 
information regarding inadvertent exposure and spill precautions, please consult the idelalisib
investigator brochure.
5.3.
Study Drug Administration
5.3.1.
Premedication
No specific premedications or supporting medications are required in conjunction with study 
drug administration.
5.3.2.
Administration Instructions
The prescribed dose of study drug (idelalisib/placebo) should be taken orally. At each dose 
administration, the tablet number corresponding to the appropriate dose of study drug is to be 
swallowed whole with 100 to 200 mL (~ 4 to 8 ounces) of water. In case of breakage of the 
tablets in the oral cavity, additional water should be taken as a rinse. 
Study drug may be taken with or without food. There are no known dietary restrictions related to 
study drug use.
5.3.3.
Dosing Schedule
Study drug should be taken on a BID schedule at approximately the same times each day. Ideally,
doses should be taken at ~12-hour intervals (eg, at ~7 AM and at ~7 PM). While it is realized 
that variations in dosing schedule may occur in the outpatient setting, the prescribed regimen 
should be followed as closely as possible, especially in the clinic.
At specified clinic visits, the study drug will be administered in the clinic with dosing 
appropriately timed relative to blood sampling for idelalisib pharmacokinetics. As detailed in 
Section 6.2, clinic staff should record idelalisib administration information, including the exact 
clock time of each dose, for doses of study drug administered in the clinic or hospital. Thereafter, 
subjects will be given an adequate supply of tablets to take at home.
5.3.4.
Dose Levels
Study drug dose levels for Arm A and Arm B are described in Table 5-1. The lower dose level
(Dose Level -1) is provided in case a subject requires a study drug dose modification.


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Table 5-1.
Study Drug Dose Levels
Treatment Arm
Starting Dose
Dose Level -1
Arm A
300 mg/dose BID
200 mg/dose BID
Arm B
150 mg/dose BID
100 mg/dose BID
Abbreviation: BID=twice per day
When the primary study (GS-US-312-0116) is stopped, and GS-US-312-0116 active study 
subjects become eligible for participation on Study GS-US-312-0117 subjects will be enrolled 
into Study GS-US-312-0117 at open label 150 mg BID. Subjects already participating in 
Study GS-US-312-0117 will remain on the same dose.
5.3.5.
Dose Schedule Interruptions and Vomited Doses
Subjects who have a delay in administration of a dose of the study drug of <6 hours should take 
the planned dose as soon as possible after the intended time of administration. For subjects who 
have a delay in administration of study drug of 6 hours, the dose should not be taken. Study 
drug administration may continue but the missed dose should not be made up and the planned 
timing of subsequent study drug dosing should not be altered.
Vomited doses may be retaken, but only if the tablet is visible in the vomitus.
5.3.6.
Safety Monitoring and Study Drug Interruption/Dose Modification
Subjects must be monitored closely for adverse events or laboratory abnormalities during the
course of the study. Reference should be made to the CTCAE, Version 4.03 for grading the 
severity of adverse events and laboratory abnormalities.
Recommendations and requirements for modifications of the dosing regimens based on the drug 
and the type and severity of adverse events or laboratory abnormalities are provided in Table 5-2
below. The dose modification instructions focus on the types of events most commonly 
attributed to each of the study agents. Required dose modifications and actions provided in 
Table 5-2 must be followed based on the type and severity of adverse avent. The 
recommendations provided in Table 5-2 comprise only guidelines; variations from these 
recommendations may be warranted based on an investigator’s individual judgment in 
considering potential risks, benefits, and therapeutic alternatives available to each subject.
Consistent with Table 5-2, if a subject experiences an adverse event that is suspected to be 
related to study drug and requires a dose modification during the course of study therapy, then 
study drug administration should be held, as necessary, until the adverse event resolves or 
stabilizes to an acceptable degree Thereafter, study drug may be reinstituted, but the dose should 
be modified per(Table 5-1 and Table 5-2). If the adverse event occurs again, reinitiation of 
therapy may be attempted if the investigator feels that a second rechallenge is medically 
appropriate. If the subject cannot tolerate idelalisib at Dose Level -1 after 2 rechallenges, then 
the subject should be discontinued from study drug therapy unless continued therapy is discussed 
with the Gilead Sciences medical monitor.


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After the study drug dose is reduced, the dose need not be re-escalated, even if there is minimal 
or no toxicity with the reduced dose. However, if the subject tolerates the lower dose level of 
study drug for ≥4 weeks then the dose level may be increased to the starting dose level 
(see Table 5-1) at the discretion of the investigator. Such re-escalation may be particularly 
warranted if further evaluation reveals that the adverse event that led to the dose reduction was 
not study-drug-related. The starting dose level should not intentionally be exceeded in this study.
Whenever possible, any dose adjustment of study drug should be discussed between the 
investigator and the Gilead Sciences medical monitor prior to implementation. To implement 
either a dose reduction or a dose reescalation, the investigator/study staff member will call the 
IWRS, enter the subject number, and inform the IWRS of the need for dose titration. The IWRS 
will provide details regarding the study drug to be dispensed to the subject. The appropriate 
clinic staff should instruct the subject/caregiver about the change in dose.
Recommendations for dose modification based on the type and severity of adverse events or 
laboratory abnormalities are provided in Table 5-2 below.
Table 5-2.
Recommendations and Requirements for Study Drug Dose 
Modifications Based on Type and Severity of Treatment-Related 
Adverse Events or Laboratory Abnormalities
NCI CTCAE Gradea
Recommendation
Idelalisib
HEMATOLOGICAL ADVERSE EVENTS
Neutropenia
Grade 2 neutropenia
Recommended Action: Maintain current dose level and schedule.
Grade 3 neutropenia
Required Action: Blood counts should be monitored at least weekly until ANC < Grade 2.
Recommended Action: Maintain current idelalisib dose level and schedule.
Grade 4 neutropenia
(or occurrence of 
neutropenic fever 
or infection)
Required Action: Withhold idelalisib.
Required Action:Monitor blood counts at least weekly until ANC < Grade 2 
Recommended Action: May resume idelalisib at lower dose level at investigator discretion.
Neutropenia should be managed according to established clinical guidelines.
Thrombocytopenia
Grade 3
Recommended Action: Maintain current dose level and schedule.
Grade 4
Required Action: Withhold idelalisib for bruising or bleeding until Grade 3. 
Recommended Action: May resume idelalisib at initial or lower dose level at investigator 
discretion.
NON-HEMATOLOGICAL ADVERSE EVENTS
Rash
Grade 1
Recommended Action: Maintain current dose level and schedule.
Grade 2
Recommended Action: Maintain current dose level and schedule.


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NCI CTCAE Gradea
Recommendation
Idelalisib
Grade ≥3 
Required Action: Withhold idelalisib until Grade 1. 
Recommended Action: Resume at lower dose level or discontinue idelalisib at 
investigator discretion.
Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN)
Any Grade
Required Action: Discontinue idelalisib. Interrupt coadministered medications potentially 
associated with SJS/TEN.  Institute treatment per institutional standards.
Gastrointestinal Inflammation/Diarrhea
Grade 1
Required Action: Obtain history of onset and duration of diarrhea, including description,
number of stools, stool composition (e.g., watery, bloody, nocturnal), travel history, 
dietary changes and a medication review to identify possible diarrheogenic agents.
Required Action: Perform physical examination including assessment for fever, dizziness, 
abdominal pain/cramping, and weakness (e.g., evaluate for sepsis, bowel obstruction, 
dehydration).
Recommended Action: Provide anti-diarrheal (eg, loperamide) and maintain current 
idelalisib dose level and schedule.
Grade 2 diarrhea or 
colitis (unless clinical 
diagnosis is 
established from 
medical history and 
physical examination)
Required Action: Obtain history of onset and duration of diarrhea, including description,
number of stools, and stool composition (e.g., watery, bloody, nocturnal), travel history, 
dietary changes and a medication review to identify possible diarrheogenic agents.
Required Action: Perform physical examination including assessment for fever, dizziness, 
abdominal pain/cramping, and weakness (e.g., evaluate for sepsis, bowel obstruction, 
dehydration).
Required Action: For Grade 2 colitis or diarrhea (unless clinical diagnosis is established 
from medical history and physical examination), perform stool culture for routine 
pathogens (Salmonella, Shigella, Campylobacter species, Clostridium difficile toxin, 
Rotavirus, Cytomegalovirus, Adenovirus), ova and parasites (Cryptosporidium parvum, 
Isospora belli, Enterocytozoon bieneusi, Septata intestinalis, Strongyloides, Microsporidia, 
Entamoeba histolytica, Cyclospora), and Giardia antigen.
Recommended Action: For persistent Grade 2 colitis or diarrhea without clear etiology 
(clostridium difficile enterocolitis), endoscopy with biopsyb is strongly recommended to 
assess by immunohistochemistry (IHC) and PCR for CMV, Adenovirus.  (Optional: If 
ileal biopsy is performed, consider Acid Fast Bacillus staining.)
Recommended Action: Provide anti-diarrheal (eg, loperamide). Consider addition of anti-
inflammatory agent (eg, sulfasalazine, budesonide). Maintain current idelalisib dose level 
and schedule.


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NCI CTCAE Gradea
Recommendation
Idelalisib
Grade ≥ 3 diarrhea or 
colitis or persistent 
grade 2 diarrhea or 
colitis without clear 
etiology
Required Action: Withhold idelalisib. 
Required Action: Obtain history of onset and duration of diarrhea, including description,
number of stools, stool composition (e.g., watery, bloody, nocturnal), travel history, 
dietary changes and a medication review to identify possible diarrheogenic agents.
Required Action: Perform physical examination including assessment for fever, dizziness, 
abdominal pain/cramping, and weakness (e.g., evaluate for sepsis, bowel obstruction, 
dehydration).
Required Action: For Grade 3 colitis or diarrhea (unless clinical diagnosis is established 
from medical history and physical examination), perform stool culture for routine 
pathogens (Salmonella, Shigella, Campylobacter species, Clostridium difficile toxin, 
Rotavirus, Cytomegalovirus, Adenovirus), ova and parasites (Cryptosporidium parvum, 
Isospora belli, Enterocytozoon bieneusi, Septata intestinalis, Strongyloides, Microsporidia, 
Entamoeba histolytica, Cyclospora), and Giardia antigen.
Recommended Action: For Grade 3 colitis or diarrhea without clear etiology (eg, 
clostridium difficile enterocolitis), endoscopy with biopsyb isstrongly recommended to 
assess by immunohistochemistry (IHC) and PCR for CMV, Adenovirus. . (Optional: If 
ileal biopsy is performed, consider Acid Fast Bacillus staining.)
Recommended Action: At Grade 1, may resume idelalisib at lower dose level or 
discontinue at investigator discretion.
Recommended Action: Provide anti-diarrheal (eg, loperamide) and/or addition of 
anti-inflammatory agent (eg, sulfasalazine, budesonide).
Hepatic Adverse Events (elevations in ALT, AST, or bilirubin)
Grade 1
(ALT/AST3xULN)
(Bilirubin1.5xULN)
Recommended Action: Maintain current dose level and schedule.
Grade 2
(ALT/AST>3-5xULN)
(Bilirubin>1.5-
3xULN)
Recommended Action: Monitor ALT, AST, ALP, and bilirubin at least 1x per week until 
all abnormalities are Grade ≤ 1; thereafter maintain current dose level.
Grade 3
(ALT/AST>5-20xUL
N)
(Bilirubin>3-10xULN)
Recommended Action: Withhold idelalisib. 
Recommended Action: Monitor ALT, AST, ALP, and bilirubin at least 1x per week until 
all abnormalities are Grade 1. 
Recommended Action: If bilirubin abnormality was Grade <3, resume idelalisib at same 
dose level. If bilirubin abnormality was Grade >3, resume at lower dose level.
Grade 4
(ALT/AST>20xULN)
(Bilirubin>10xULN)
Required Action: Withhold idelalisib. 
Required Action: Monitor ALT, AST, ALP, and bilirubin at least 1x per week until all
abnormalities are Grade 1. 
Required Action: If bilirubin abnormality was Grade 4, discontinue idelalisib.
Required Action: If bilirubin abnormality was Grade <4, if drug is restarted then resume 
idelalisib at lower dose level. 


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NCI CTCAE Gradea
Recommendation
Idelalisib
Pneumonitis (with new onset or worsening baseline dyspnea, cough, or hypoxia without obvious infectious 
cause)
Grade 1  
(asymptomatic)
Required Action: Withhold idelalisib until resolution to baseline.
May resume at lower dose level or discontinue idelalisib at investigator discretion.
Grade ≥ 2
Required Action: Discontinue idelalisib permanently in subjects with any severity of 
symptomatic pneumonitis and institute therapy as clinically appropriate.
Pneumocystis jirovecci pneumonia (PJP)
Any Grade
Required Action: Discontinue idelalisib
Unequivocal CMV infectionc
Any Grade
Required Action: Interrupt idelalisib upon unequivocal clinical or laboratory evidence of 
CMV infection.
Required Action: Treat according to established clinical guidelines.
Required Action: If the benefits of resuming idelalisib are judged to outweigh the risks, 
consideration should be given to administering pre-emptive CMV therapy.
Other Nonhematological Adverse Events
Grade 2
Recommended Action: Maintain current dose level and schedule.
Grade 3
Recommended Action: Withhold idelalisib until Grade 1. May resume idelalisib at initial 
or lower dose level or discontinue idelalisib at investigator discretion.
a
CTCAE, Version 4.03.
b
Refer to 5.4.2.2 for recommendations if the differentiation between small-bowel and large-bowel diarrhea is unclear
c
CMV should be diagnosed using clinical or laboratory criteria per established institutional standard
Abbreviations:  ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST= aspartate aminotransferase, 
CTCAE=Common Terminology Criteria for Adverse Events, CMV=cytomegalovirus, G-CSF=granulocyte colony-stimulating 
factor, NCI=National Cancer Institute, ULN=upper limit of normal
5.4.
Evaluation, Intervention, and Drug Discontinuation for Specific Adverse 
Events or Conditions
5.4.1.
Dermatological Events
Subjects receiving idelalisib with ≥ Grade 3 rash have generally presented with a maculopapular 
rash on the trunk and extremities that is occasionally associated with fever and/or pruritus and 
responded to treatment with diphenhydramine and/or topical or oral corticosteroids. 
For subjects who develop Grade ≥3 rash for which an underlying etiology cannot be identified 
(e.g., infection, co suspect drug), study drug must be interrupted. 
Severe cutaneous reactions, including fatal events of Stevens-Johnson syndrome (SJS) and toxic 
epidermal necrolysis (TEN), have been reported in subjects receiving idelalisib. Assessment of 
potential causal association between idelalisib and the occurrence of SJS or TEN has been 
confounded by the coadministration of antineoplastic agents (e.g., bendamustine, rituximab) 


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and/or other concomitant medications known to be associated with SJS or TEN (e.g., allopurinol).
If SJS or TEN is suspected, idelalisib and all coadministered medications associated with SJS or 
TEN should be interrupted and the subject treated accordingly. 
Subjects should be monitored for the development of SJS, TEN, or other severe cutaneous 
reactions and idelalisib treatment should be discontinued if such events occur.
Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab. 
These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid 
dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis {Genentech Inc 2011}. 
The onset of these reactions has varied from 1 to 13 weeks following initiation of rituximab 
exposure. The safety of readministration of rituximab to patients with severe mucocutaneous 
reactions has not been determined; thus, for subjects experiencing a severe mucocutaneous 
reaction, rituximab should be discontinued.
Among patients receiving bendamustine, skin reactions have been reported in clinical trials and 
post-marketing safety reports {Cephalon 2012}. These events have included rash, toxic skin 
reactions, bullous exanthema, and purpura {Gavini et al 2012}. Cases of Stevens-Johnson 
syndrome and toxic epidermal necrolysis have been reported when bendamustine was 
administered concomitantly with allopurinol and other medications known to cause these 
syndromes. There may be an increased risk of skin toxicity in subjects receiving bendamustine 
together with trimethoprim-sulfamethoxazole. Because of coadministration of other agents, the 
precise relationship of cutaneous adverse events to bendamustine has often been uncertain. 
Where skin reactions to bendamustine do occur, they may be progressive and increase in severity 
with further treatment. Therefore, patients with skin reactions should be monitored closely. If 
skin reactions are severe or progressive, bendamustine should be discontinued.
5.4.2.
Gastrointestinal Events
Isolated cases of gastrointestinal inflammation (eg, stomatitis, colitis, cecitis) have been noted in 
subjects receiving idelalisib. Rare cases of gastrointestinal perforation have occurred, generally 
in the setting of occult carcinoma, mesenteric embolus or diverticular disease.  Idelalisib must be
discontinued in subjects who experience bowel perforation.
Cholangitis manifest as hyperbilirubinemia out of proportion to serum transaminase elevations 
has been observed. While disease related factors, neutropenia, toxicity from prior therapies, 
effects of ongoing supportive care, or pre existing cholelithiasis may have initiated such events, 
it is possible that idelalisib played a contributory role. In such subjects, rechallenge with 
idelalisib has been possible and has not been associated with other severe adverse events. 
Subjects who have developed evidence of enteritis during idelalisib therapy have been 
successfully treated with antidiarrheals (eg, loperamide) and with enteric steroidal (eg, budesonide)
or non steroidal (eg sulfasalazine [Azulfidine®]) anti-inflammatory agents and have been able to 
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For study subjects who develop severe abdominal pain the possibility of a bowel obstruction or 
perforation should be considered. Appropriate clinical and radiographic examination should be 
performed and supportive care or surgical intervention should be considered. Upon recovery, 
rituximab may be resumed. 
Among patients receiving rituximab in combination with chemotherapy, rare instances of 
life-threatening bowel obstruction or perforation has been observed {Ram et al 2009}, primarily 
in patients with NHL. In post-marketing reports, the mean time to documented gastrointestinal 
perforation was 6 (range 1–77) days from start of chemoimmunotherapy. It is hard to draw a 
definite conclusion regarding the role of rituximab in these cases, as the affected patients had 
multiple risk factors including lymphomatous involvement of the gastrointestinal tract, other 
gastrointestinal disorders, and/or the risk of concomitant treatments with chemoradiotherapy and 
corticosteroids. Very isolated instances of inflammatory bowel disease have been seen in patients 
receiving rituximab {Ardelean et al 2010}.
5.4.2.1.
Investigation for Idelalisib Late Onset or Severe Diarrhea/Colitis
See CTCAE Version 4.03 for definitions of colitis and diarrhea.
Among idelalisib-treated patients who reported diarrhea or colitis, the median time to onset of 
any grade diarrhea or colitis was 1.9 months (range, 0.0–29.8), of grade 1 or 2 was 1.5 months 
(range, 0.0–15.2) and of grade 3 or 4 was 7.1 months (range, 0.5–29.8). Kaplan–Meier curves of 
time to onset of diarrhea or colitis are shown for all idelalisib- treated patients in Figure 5-1
{Coutre et al 2015}.
Figure 5-1.
Kaplan-Meler Time to Diarrhea or Colitis
Idelalisib-associated severe diarrhea responds poorly to antimotility agents however, median 
time to resolution ranged between 1 week and 1 month across trials following interruption of 
idelalisib treatment and, in some instances, initiation of corticosteroid treatment 
{Gilead Sciences Inc 2014}.


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5.4.2.2.
Differentiation Between Small-bowel and Large-bowel Diarrhea 
Differentiate between small-bowel and large-bowel diarrhea on a clinical basis if recommended.  
If unclear, consider upper and lower tract endoscopy with biopsy.

Small bowel diarrhea is characterized by large volume diarrhea (more than one per day), 
possibly associated dehydration, weight loss, and paraumbilical pain.   Consider an 
endoscopic small-bowel biopsy and evaluate other etiologies such as celiac disease.

Large-bowel diarrhea may present with lower pelvic pain, tenesmus, generally smaller stool 
volumes with gross blood frequently found in the stool. Consider a colonoscopic evaluation 
and biopsy.
5.4.3.
Hepatic Events
Transaminase Elevations: Consistent with observations in a dog toxicology study, reversible 
asymptomatic ALT/AST increases were also observed early in the idelalisib program in phase 1 
studies (101-02 and 101-07) in subjects with hematologic malignancies. Transaminase elevations 
generally occurred within 4 to 12 weeks of drug initiation, and resolved spontaneously over a 
period of 2 to 4 weeks with drug being continued for Grade 1 and 2 elevations and drug withheld 
for Grade 3 or 4 elevations until resolution. These early observations have been consistent with 
the ongoing experience with idelalisib treatment and transaminase elevations are now well 
characterized as most frequently asymptomatic, transient and occurring within the first 3 months 
of treatment.
Grade 1 or 2 elevations commonly resolve despite continued idelalisib treatment and Grade 3 or 
4 elevations can be managed by withholding idelalisib. Successful rechallenge after resolution at 
either the same or lower dose level of idelalisib has been achieved in the majority of subjects. 
There has been no evidence of impaired synthetic function. Close monitoring of hepatic 
laboratory tests during therapy is important to allow for appropriate idelalisib interruption and 
reinstitution so that subjects may continue with study drug treatment.
HBV Reactivation: HBV reactivation can occur in patients treated with anti-CD20 antibodies.  
Subjects who are HBc antibody positive/HBV DNA PCR negative at screening will be 
monitored for potential HBV reactivation (manifest as detectable HBV DNA by quantitative 
PCR). Although some subjects who are HBc antibody positive with negative PCR may have had 
passive transfer of antibody from intravenous IgG, it cannot be known for certain that any such 
subject did not have natural HBV infection. Therefore, all subjects will be tested monthly for the 
duration of anti-CD20 therapy and every 3 months for 1 year following the last dose of rituximab 
during study participation. Following the completion of study participation, monitoring for HBV 
reactivation will be conducted per standard of care at the discretion of the investigator. If there is 
evidence of HBV reactivation, immediately discontinue anti-CD20 and start appropriate 
treatment for HBV.  In the event of HBV reactivation, please contact the Medical Monitor 
regarding continuation of idelalisib.


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5.4.4.
Hematological and Immunological Events
In the Phase 1 experience with idelalisib in NHL and CLL, subjects with Grade3 neutropenia, 
anemia, and/or thrombocytopenia were enrolled to clinical trials. Decreased levels of neutrophil 
counts, hemoglobin, or platelet counts during therapy were largely due to minor fluctuations in 
these parameters among patients with pre-existing hematological abnormalities due to disease or 
prior therapy. Thus, idelalisib did not appear to induce overt myelosuppression. Obvious patterns 
of drug-mediated reductions in circulating CD4+ lymphocyte counts or suppression of serum 
IgG levels were also not observed.
Treatment-emergent Grade 3 or 4 neutropenia events, including febrile neutropenia, have occurred in 
subjects treated with idelalisib. For subjects who develop Grade 3 neutropenia, blood counts must be 
monitored weekly. For subjects who developGrade 4 neutropenia , idelalisib must be interrupted and 
blood counts monitored weekly until ANC is ≥ 0.5 Gi/L, at which point, idelalisib dosing may be 
resumed at 100 mg BID.  Neutropenia should be managed according to established clinical 
guidelines.
No modification of any drug for changes in circulating CD4+ counts or Ig levels is planned.
5.4.5.
Infectious Events
Patients with lymphoid cancers receiving idelalisib have developed serious and fatal infections 
during therapy. Opportunistic infections, most notably Pneumocystis jirovecii pneumonia (PJP) 
and CMV infection, have most frequently occurred within the first 6 months of treatment with 
idelalisib and are increased in the context of concurrent myelosuppressive therapy such as 
bendamustine.
Subjects must receive trimethoprim-sulfamethoxazole or other established prophylaxis for PJP 
throughout the course of idelalisib treatment, and must continue for 2 to 6 months after the last 
dose of idelalisib.  Prophylaxis must continue until the CD4+ T-cell count is documented to be 
>200 cells/mcL after idelalisib treatment ends. Subjects must permanently discontinue idelalisib 
upon diagnosis of PJP.
CMV surveillance for active disease (quantitative PCR or PP65 antigen) must be conducted 
approximately every 4 weeks throughout the course of idelalisib treatment. CMV viral load 
testing should be performed from the same specimen type whenever possible and caution should 
be exercised when comparing CMV viral load results across different testing centers. If 
unequivocal clinical or laboratory evidence of CMV infection is present, the subject must 
interrupt idelalisib treatment and undergo effective antiviral treatment according to established 
clinical guidelines. If the benefits of resuming idelalisib are judged to outweigh the risks, 
consideration should be given to administering pre-emptive CMV therapy.
Serious bacterial, fungal, and new or reactivated viral infections have occurred during and for 
~1 year following rituximab-based therapy {Gea-Banacloche 2010}. New or reactivated viral 
infections in patients receiving rituximab have included CMV, herpes simplex virus, parvovirus 
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In high-risk subjects (history of recurrent infection, allogeneic transplant, treatment with 
alemtuzumab, hypogammaglobulinemia) other infection prophylaxis should be considered per 
consensus guidelines. Administration of intravenous immunoglobulin is permitted per standard 
institutional practice {Raanani et al 2009}. For subjects who develop an infection, appropriate 
medical therapy should be instituted in a timely manner.
5.4.6.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) due to polyomavirus JC has been observed 
in patients who have received rituximab therapy {Carson et al 2009} for hematologic 
malignancies. The specific causal role of rituximab is unknown because many of these patients
had other risk factors (eg, low CD4+ counts) and the majority had received rituximab in 
combination with chemotherapy or as part of a hematopoietic stem cell transplant. Most cases of 
PML were diagnosed within 12 months of the last infusion of rituximab.
The diagnosis of PML should be considered in any subject presenting with new-onset or 
worsening neurologic manifestations, especially weakness or paralysis, vision loss, impaired 
speech, or cognitive deterioration. Evaluation of PML should include consultation with a 
neurologist, brain MRI, and lumbar puncture. In subjects diagnosed with PML, study drug 
should also be permanently discontinued.
5.4.7.
Pulmonary Events
Documented bacterial, fungal, viral, and pneumocystis pneumonias have been observed in 
patients receiving idelalisib, primarily in patients with CLL. Some study subjects receiving 
idelalisib alone or in combination have developed evidence of pneumonitis without documented 
pulmonary infection.
Rituximab-related noninfectious pneumonitis has been described {Subramanian et al 2010} with 
an incidence of ~4.3% {Salmasi et al 2010}. In patients developing rituximab-associated 
pneumonitis, the mean time from the first rituximab infusion to the onset of respiratory 
symptoms was 3 months, with a peak incidence after administration of a mean cumulative 
dosage of 1600 mg/m2 {Liote et al 2010}.
Given the potential for infectious or drug-related adverse events, clinicians should be particularly 
observant for evidence of respiratory events in subjects participating in this trial. Subjects who 
describe pulmonary symptoms (eg, dyspnea on exertion, cough, shortness of breath); manifest a 
decline from baseline of 5% in oxygen saturation, or demonstrate evidence of pulmonary 
inflammation (eg, focal or diffuse interstitial pattern or ground-glass opacities on chest CT)
should be evaluated. Potential bacterial, fungal, or viral etiologies should be assessed. 
Noninfectious etiologies such as pulmonary edema or thromboembolism should also be 
considered.
As appropriate for the clinical situation and culture results, subjects should be treated empirically 
or given specific antibiotics, antifungals, or antiviral agents for a cultured organism. Supportive 
care, including oxygen or mechanical ventilation, should be provided as necessary.


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For subjects with suspected Grade 1 pneumonitis, withhold idelalisib until resolution to baseline. 
Upon resolution to baseline, idelalisib may be resumed at lower dose level or discontinued at 
investigator discretion. For subjects with suspected Grade ≥ 2 pneumonitis (eg, new onset or 
worsening of baseline cough, dyspnea, hypoxia and/or a diffuse interstitial pattern or ground-
glass opacities on chest imaging without obvious infectious etiology), idelalisib must be 
discontinued permanently and therapy initiated as clinically appropriate.
5.4.8.
Secondary Malignancies
Subjects receiving idelalisib for CLL or iNHL have developed pre-malignant and secondary 
malignant diseases, such as basal cell carcinoma, myelodysplastic syndrome, myeloproliferative 
disorders, and more aggressive lymphoid malignancies (eg, have had Richter transformation). 
Generally this has occurred in subjects who have received multiple previous lines of therapy and 
when idelalisib is combined with other therapies such as rituximab or bendamustine. The specific 
association of the therapeutic agents with these types of events has not been determined.
There are reports of pre-malignant and malignant diseases that have developed in subjects who 
have been treated with bendamustine, including myelodysplastic syndrome, myeloproliferative 
disorders, acute myeloid leukemia, and bronchial carcinoma. The specific association of the 
therapeutic agents with these types of events has not been determined.
5.4.9.
Tumor Lysis Syndrome
Tumor lysis syndrome has not been observed with idelalisib monotherapy. 
Subjects with tumor lysis syndrome should receive rapid reversal of hyperkalemia, intravenous 
hydration, antihyperuricemic agents, and appropriate cardiac and renal support, including 
dialysis as indicated. Upon recovery to baseline functioning, such subjects should continue study 
treatment.
5.4.10.
Pregnancy, Lactation, and Reproduction
Idelalisib has induced embryo lethality and teratogenicity when administered to pregnant female 
rats at maternally toxic doses. However, definitive reproductive toxicology studies in animals 
have not yet been performed and the specific effects of idelalisib on human embryogenesis or 
fetal development are unknown. Whether idelalisib is excreted in human breast milk is unknown. 
General toxicology studies in rats and dogs indicated dose-dependent reductions in testicular 
weights, with persistent minimal to mild degeneration of the seminiferous tubules and decreased 
spermatozoa in rats and hypospermatogenesis in dogs. The implications of these testicular 
changes for animal or human fertility are unknown.
Given the preliminary nature of data regarding the risks to a fetus or infant as a result of 
exposure to idelalisib, women of reproductive potential entering this study must have a negative 
serum pregnancy test at baseline and must not be breastfeeding. Males and females of 
childbearing potential should abstain from sexual intercourse or use an effective form of 
contraception (see Section 5.6.4). If a female study participant becomes pregnant or decides to 
breastfeed during the course of the study, all study therapy must be discontinued.


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5.4.10.1.
PJP Prophylaxis
Trimethoprim sulfamethoxazole is rated a Pregnancy category C.  In rats, oral doses of 
533 mg/kg or 200 mg/kg produced teratologic effects manifested mainly as cleft palates. 
One survey found no congenital abnormalities in 35 children whose mothers had received oral 
sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter. Because 
sulfamethoxazole and trimethoprim may interfere with folic acid metabolism it should be used 
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Dapsone is rated a Pregnancy Category C.  Extensive, but uncontrolled experience and 
two published surveys on the use of Dapsone in pregnant women have not shown that Dapsone 
increases the risk of fetal abnormalities if administered during all trimesters of pregnancy or can 
affect reproduction capacity. Because of the lack of animal studies or controlled human 
experience, Dapsone should be given to a pregnant woman only if clearly needed. Dapsone is 
excreted in breast milk in substantial amounts. Hemolytic reactions can occur in neonates. 
Because of the potential for tumorgenicity shown for Dapsone in animal studies a decision 
should be made whether to discontinue nursing or discontinue the drug taking into account the 
importance of drug to the mother.
Atovaquone is rated a Pregnancy Category C.  Atovaquone is teratogenic and did not cause 
reproductive toxicity in rats at plasma concentrations up to 2 to 3 times the estimated human 
exposure. Atovaquone can cause maternal toxicity in rabbits at plasma concentrations that were 
approximately one half the estimated human exposure. Mean fetal body lengths and weights were 
decreased and there were higher numbers of early resorption and post-implantation loss per dam. It is 
not clear whether these effects are caused by atovaquone directly or are secondary to maternal 
toxicity. Concentrations of atovaquone in rabbit fetuses averaged 30% of the concurrent maternal 
plasma concentrations.  There are no adequate and well-controlled studies in pregnant women. 
Atovaquone should be used during pregnancy only if the potential benefit justifies the potential risk 
to the fetus. It is not known whether atovaquone is excreted into human milk. Because many drugs 
are excreted into human milk, caution should be exercised when Atovaquone is administered to a 
nursing woman. In a rat study, atovaquone concentrations in the milk were 30% of the concurrent 
atovaquone concentrations in the maternal plasma.
Aerosolized Pentamidine (NebuPent) is a Pregnancy Category C.  There are no adequate and well 
controlled studies of NebuPent in pregnant women. One literature report indicated that intravenously 
administered pentamidine in pregnant rats at 4 mg/kg/day was embryolethal; teratogenicity was not 
observed in this study. It is unknown whether pentamidine administered via the aerosolized route 
crosses the placenta at clinically significant concentrations. It is not known whether NebuPent can 
cause fetal harm when administered to a pregnant woman. NebuPent should be given to a pregnant 
woman only if clearly needed.  It is not known whether NebuPent is excreted in human milk.  
NebuPent should not be given to a nursing mother unless the potential benefits are judged to 
outweigh the unknown risks.
5.4.11.
Ultraviolet Exposure
In vitro studies indicate enhanced cytotoxicity when embryonic murine fibroblasts treated with 
GS-563117 (the major metabolite of idelalisib) are simultaneously exposed to ultraviolet light. 
While nonclinical findings suggest the hypothetical potential for phototoxicity in humans, 


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available clinical data do not reveal a photosafety concern. Although specific clinical correlates 
for these nonclinical data are not available, investigators and study subjects should be observant 
for the possibility that study participants may have exaggerated sunburn reactions 
(eg, burning, erythema, exudation, vesicles, blistering, edema) involving areas of skin exposed to 
ultraviolet light.
5.4.12.
Further Safety Information
Further safety information regarding the study drug may be found in the investigator brochure 
for idelalisib. 
5.5.
Emergency Unblinding
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IWRS system 
for that subject. Gilead recommends but does not require that the investigator contact the 
Gilead medical monitor before breaking the blind. Treatment assignment should remain blinded 
unless that knowledge is necessary to determine subject emergency medical care. The rationale 
for unblinding must be clearly explained in source documentation and on the case report 
form/ electronic case report form (CRF/eCRF), along with the date on which the treatment 
assignment was obtained. The investigator is requested to contact the Gilead medical monitor 
promptly in case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).
5.6.
Concomitant and Supportive Therapy
To the extent possible, administration of any prescription or over-the-counter drug products other 
than study medication should be minimized during the study period. Subjects should be 
discouraged from use of street drugs, herbal remedies, self-prescribed drugs, tobacco products, or 
excessive alcohol at any time during the clinical study.
If considered necessary for the subject’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator. The decision to 
authorize the use of any drug other than study drug should take into account subject safety, the 
medical need, the potential for drug interactions, the possibility for masking symptoms of a more 
significant underlying event, and whether use of the drug will compromise the outcome or 
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Subjects should be instructed about the importance of the need to inform the clinic staff of the 
use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and during 
the course of the study. Any concomitant drugs taken by a subject during the course of the study 
and the reason for use should be recorded on the eCRFs.
Information regarding use or restrictions on specific concomitant medications, dietary measures, 
or other interventions is provided below.
5.6.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments
Except for corticosteroids (see Section 5.6.5), no other systemic anticancer therapies (including 
but not limited to chemotherapy, radiation, antibody therapy, immunotherapy, or other 
experimental therapies) of any kind are permitted. Subjects are not allowed to participate 
concurrently in any other therapeutic clinical study.
5.6.2.
Antibiotics
Investigators must initiate antibiotic prophylaxis against pneumocystis infection 
(eg, with trimethoprim-sulfamethoxazole, dapsone, aerosolized pentamidine, or atovaquone)
beginning prior to study drug administration. Such support may also offer the benefit of reducing
the risk for other bacterial infections {Green et al 2007}. Investigator discretion and local 
practices or guidelines may be followed.
For subjects who develop an infection, appropriate medical therapy (with antibiotics, antifungals, 
or antiviral) or other interventions should be instituted. Whenever appropriate, subjects may 
continue with study drug during treatment for the infection; however, subjects who develop PJP
must permanently discontinue study drug.
5.6.3.
Antiemetics and Antidiarrheals
Drug-related nausea and/or vomiting have not been commonly observed with idelalisib in prior 
studies. However, subjects who experience nausea or vomiting while on study therapy may 
receive antiemetics based on the judgment of the treating physician and local institutional 
practices. At the occurrence of persistent nausea or vomiting of severity Grade 1, it is suggested 
that the subject receive an oral or transdermal serotonin antagonist (eg, dolasetron, granisetron, 
ondansetron, tropisetron, palonosetron). Other classes of antiemetic medications that may be 
employed include dopamine antagonists or benzodiazepines. As needed, subjects may be 
prescribed loperamide (Imodium® or others) or diphenoxylate and atropine (Lomotil®) to control 
diarrheal symptoms.
5.6.4.
Contraception
In the context of this protocol, a female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, a bilateral tubal ligation, or a bilateral oophorectomy; has 
medically documented ovarian failure (with serum estradiol and FSH levels within the 


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institutional postmenopausal range and a negative serum or urine HCG); or is menopausal 
(age ≥54 years with amenorrhea for >12 months or amenorrhea for >6 months with serum 
estradiol and FSH levels within the institutional postmenopausal range).
Sexually active females of childbearing potential must agree to use a protocol-recommended 
method of contraception during heterosexual intercourse throughout the study treatment period 
and for 30 days following the last dose of the study drug. The investigator should counsel 
subjects on the most effective methods for avoiding pregnancy during the trial. 
Protocol-recommended contraceptive methods are described in Table 5-3.
Table 5-3.
Protocol-Recommended Contraceptive Methods
Individual Methods
Combination Methods
Hormonal Methods
(One method to be used
with a barrier method)
Barrier Methods
(Both of these methods to be used OR
one of these methods to be used
with a hormonal method)
IUD

Copper T 380A IUD

LNg 20 IUD
Tubal sterilization
Hysterectomy
Estrogen and progesterone

Oral contraceptives

Transdermal patch

Vaginal ring
Progesterone

Injection

Implant

Diaphragm with spermicidea

Male condom(with spermicidea)
a
If available/approved for use in the specific country
Abbreviation: IUD=intrauterine device
In the context of this protocol, a male subject is considered able to father a child unless he has 
had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or is receiving
ongoing testicular suppression with a depot luteinizing hormone-releasing hormone (LH-RH) 
agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or 
triptorelin pamoate [Trelstar®]).
Sexually active male subjects who can father a child must accept continuous heterosexual 
abstinence as a lifestyle choice; limit intercourse to female partners who are surgically sterile, 
post-menopausal, or using effective contraception (as noted in Table 5-3); or agree to use a 
protocol-recommended method of contraception during heterosexual intercourse throughout the 
study treatment period and for 90 days following discontinuation of the study drug
(as noted in Table 5-3). 
The Gilead Sciences medical monitor should be consulted regarding any questions relating to 
childbearing status or contraception.


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5.6.5.
Corticosteroids
Subjects may receive topical, inhaled, enteric, or systemic corticosteroids while on study. It 
should be realized that the use of systemic corticosteroids in patients with CLL may confound 
interpretation of antitumor effects mediated by study drug therapy. However, subjects who 
develop conditions that may be alleviated by systemic corticosteroid therapy are permitted to 
receive such drugs and are not required to discontinue study participation.
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin
Granulocyte-macrophage colony-stimulating factor (GM-CSF) should not be administered given 
the potential for GM-CSF-related inflammatory symptoms.
G-CSF (filgrastim, PEG-filgrastim, lenograstim) may be administered in response to 
Grade 4 neutropenia or neutropenic complications; use should be particularly considered if 
providing hematopoietic support might help to maintain study drug treatment (see Table 5-2).
While erythropoietic agents (eg, erythropoietin or darbepoetin) may be administered for 
Grade 3 anemia, their use in this study is discouraged given the potential to confound 
assessments of improvements in bone marrow function related to study drug.
Reference may be made to the American Society of Clinical Oncology guidelines {Rizzo et al 
2008, Smith et al 2006}.
5.6.7.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism
Idelalisib is metabolized primarily via aldehyde oxidase and in part by CYP3A. A clinical 
drug-drug interaction study indicated that administration of a potent CYP3A inhibitor together 
with idelalisib resulted in a ~80% increase in idelalisib plasma exposures (AUC) 
(see Section 1.3.5.1), which is not considered to be clinically relevant and suggesting that 
idelalisib is a weak CYP3A substrate. Preliminary data indicate when coadministered with 
rifampin, a highly potent inducer of CYP3A, idelalisib exposures are ~75% lower. 
Coadministration of potent inducers of CYP3A with idelalisib should be avoided; a list of strong 
inducers is provided in Table 5-4:
Table 5-4.
Known Strong Inducers of CYP3A
Effect on CYP3A
Drug Class
Medications
Strong CYP3A Inducers
Antimycobacterial
Rifampin
Anticonvulsants
carbamazepine, phenytoin
Foods/herbs
St. John’s wort
Abbreviation: CYP=cytochrome P450 enzyme


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5.6.8.
Drugs that undergo CYP3A-Dependent Metabolism
The major metabolite of idelalisib, GS-563117, is a reversible and time dependent inhibitor of 
CYP3A; accordingly coadministration of idelalisib with midazolam, a probe CYP3A substrate, 
resulted in a ~5-fold increase in midazolam systemic exposure (AUC), indicating that idelalisib 
is a strong inhibitor of CYP3A. Coadministration of CYP3A substrates with idelalisib may result 
in an increase in their systemic exposures (eg, antiarrhythmics, calcium channel blockers, 
benzodiazepines, certain HMG-CoA reductase inhibitors, phosphodiesterase-5 (PDE5) 
inhibitors, warfarin). Avoid coadministration of drugs that are narrow therapeutic index CYP3A 
substrates (eg, alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, fentanyl, 
quinidine, ergotamine, dihydroergotamine, astemizole, terfenadine) with idelalisib.
5.6.9.
Immunization
Because of its actions to inhibit PI3Kδ-dependent B-cell function, high doses of idelalisib can 
impair primary or secondary responses to immunization in animals.
The specific clinical relevance of these findings with idelalisib is unknown. However, for 
subjects who are at substantial risk of an infection (eg, influenza) that might be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of study 
therapy.
Of note, the safety of immunization with live viral vaccines following idelalisib therapy has not 
been studied and vaccination with live virus vaccines during study treatment is not 
recommended.
5.6.10.
Surgery
There are no known effects of idelalisib on coagulation or wound healing. Pending receipt of 
additional information, study drug may be continued in the peri-procedural period in subjects 
who require surgery or invasive procedures.
5.6.11.
Diet
There are no specific dietary restrictions in the study. Study drug may be taken with or without food.
5.7.
Duration of Study Drug
Subjects may continue receiving study drug until the occurrence of any events requiring study 
drug discontinuation as defined in Section 5.8.
5.8.
Discontinuation of Study Drug
All study participants may receive study drug indefinitely; however:

Any subject has the right to discontinue study drug at any time.

Any subject who has objective evidence based on IRC review of definitive CLL progression
will discontinue study drug.


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
Any subject unable to tolerate a second rechallenge with protocol-described, dose-modified 
idelalisib at Dose Level –1 (see Section 5.2) should discontinue study drug.

Any subject who becomes pregnant or begins breastfeeding should discontinue study drug.

Any subject who becomes significantly noncompliant with study drug administration, study 
procedures, or study requirements should discontinue study drug.

Any subject for whom the blind is intentionally broken by the subject or the study site should 
discontinue study drug (only applicable to the blinded portion of the study).

The investigator, in consultation with the Gilead Sciences medical monitor, may discontinue
study drug, if, it is not in the subject’s best interest to continue.

If allowed by local regulations, Gilead Sciences may transition subjects from study drug to 
commercial drug supply when idelalisib becomes commercially available in the country 
where the subject is living.

Any subject who is diagnosed with any grade of SJS or TEN, Grade ≥2 pneumonitis, or PJP
must discontinue study drug.
Any subject whose benefit-risk profile is not deemed positive by the investigator should 
discontinue study drug.
Subjects who permanently discontinue study drug for a reason other than disease progression 
(as determined by the IRC) shall continue with assessments per the schedule of procedures until 
disease progression or until another anticancer or experimental therapy is initiated.
5.9.
Discontinuation from Study
Subject study participation will be ended due to any of the following reasons:

Adverse event.

Disease progression.

Withdrawal of consent.

Significant subject noncompliance with study drug administration, study procedures, or study 
requirements.

Initiation of any additional systemic anticancer therapies (other than corticosteroids, 
see Section 5.6.5) including chemotherapy, radiation, antibody therapy, immunotherapy, or 
other experimental treatment.

Physician’s decision to remove the subject from the study.

Pregnancy.

The subject is lost to follow-up.


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
Death.

Discontinuation of study by the Sponsor, a Regulatory Agency, or an IRB or EC.
5.10.
Study Treatment Rationale
Subjects will be assigned to treatment (Arm A or Arm B) in this study based on their 
randomization in the primary study. The 1:1 randomization in the primary trial
(GS-US-312-0116) ensures that sufficient Arm B subjects will cross over from 
rituximab alone to single-agent idelalisib at the 150-mg/dose BID starting dose level in this 
extension trial (GS-US-312-0117) to allow an adequate evaluation of efficacy and safety in this 
trial. The randomization and allocation processes will be established and performed through an 
IWRS; the intent is to maximize the integrity and security of the subject disposition and to ensure 
appropriate access and convenience-of-use by the investigational sites.
Double blinding is included to provide protection against biased interpretations of efficacy and 
safety data by subjects, caregivers, investigators, Gilead Sciences personnel, or others involved 
in study conduct.
Selection of the idelalisib treatment regimen (including starting dose level, dose-modifications 
and supportive care, schedule, duration, and conditions of administration) for this study program 
has been based primarily on safety, exposure, and activity profiles from previous Phase 1 clinical 
studies involving healthy volunteers, patients with allergic rhinitis, and patients with 
refractory/relapsed lymphoid malignancies {Coutre et al 2011, Kahl et al 2011, Webb et al 
2010}. The following information was considered in selecting the study drug dosing regimen for 
the primary study and this companion extension study:

Idelalisib was symptomatically well tolerated in patients with lymphoid malignancies receiving 
dose levels of 50 mg/dose BID through 350 mg/dose BID (the highest dose level tested). No
specific MTD was apparent over the dose range tested. However, monitorable, reversible 
transaminase elevations were observed in some patients and may have been more frequent at 
higher dose levels (~10% rate among patients with CLL receiving starting doses of 
150 mg/dose). Thus, while doses through 350 mg/dose BID are tolerable, the starting dose 
of 150 mg/dose BID appears to appropriately balance safety with efficacy in idelalisib-naïve 
subjects. The starting dose of 300 mg/dose BID in this study also appears appropriate for 
evaluation; it is lower than the dose level of 350 mg/dose BID that has been tolerable in prior 
studies and is likely to be suitable in subjects who have already been tolerating idelalisib
therapy at 100 mg/dose BID. 

Upon disease progression, permitting escalation from 150 mg/dose BID to 300 mg/dose BID 
among subjects allocated to Arm A offers a systematic evaluation of higher doses in subjects 
who are tolerating idelalisib treatment and might benefit from increased PI3Kinhibition. 
The pharmacological basis for considering such an intervention is based on the concept that 
some individuals might have lower-than-expected plasma exposures or dose-dependent 
resistance to the compound at 150 mg/dose BID and might benefit from a higher dose. 


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The intent is to determine if the higher dose can reestablish disease control or whether 
absolute resistance to PI3Kinhibition has been acquired. The safety data obtained in these 
subjects would add to the overall safety database.

In an allergic rhinitis study, idelalisib induced statistically significant improvements in 
clinical and pharmacodynamic endpoints when administered at 100 mg/dose BID over 
7 days. These data support the pharmacological relevance of idelalisib-mediated 
PI3Kδ inhibition when administered at the dose-levels to be used in this study.

A positive correlation was noted between idelalisib dose and measures of tumor control and 
chemokine normalization in patients with B-cell malignancies. The majority of patients 
appear to have tumor responses and protracted PFS when receiving starting doses of 
100 mg/dose BID. Thus, treatment with a idelalisib at a starting dose of 150 mg/dose BID 
appears to offer most patients the potential to benefit from therapy and the dose level of 
300 mg/dose BID may provide additional benefit in patients with disease resistance as 
systematically evaluated in this trial. 

Increases in idelalisib plasma Cmax, AUC, and Ctrough values were less than dose-proportional 
in subjects with lymphoid malignancies; the dose-exposure evaluation indicated modest 
increases in plasma exposure at dose levels >150 mg BID.  Thus, administration of starting 
doses of idelalisib of 150 mg/dose BID appears appropriate to ensure adequate exposure in 
the majority of patients. 

In Phase 1 studies, the mean plasma t1/2 of idelalisib was ~6.5 to 9.8 hours across all dose 
levels and there was no substantive plasma accumulation over 7 or 28 days.

The changes in exposure observed when administering idelalisib after a high-fat, high-calorie 
meal are modest (~40% increase in mean AUC with no change in mean Cmax). 
Thus, idelalisib can be administered with or without food. 

The idelalisib dose modification provisions described in the protocol are designed to balance 
a primary concern for subject safety with the potential for observing pharmacological and 
antitumor activity in circumstances under which a subject experiencing an adverse event may 
still be able to continue on therapy at a lower idelalisib dose level. The enhanced monitoring 
to be performed and the actions to be taken in response to toxicity are based on experience 
with interruption, dose-modification, rechallenge, and re-escalation already piloted in 
idelalisib Phase 1 trials. In addition, idelalisib antitumor activity has been observed in the 
Phase 1 studies across all dose levels tested, including doses in the range of the modified 
dose levels planned for this protocol. Thus, use of the lower dose level to accommodate 
individual subject tolerability in this protocol is justified because subjects receiving such an
idelalisib dose level still have the potential for benefit.

In both the primary and extension studies, study treatment will be continued for each subject
until the occurrence of disease progression. Such a strategy is considered appropriate under 
the assumption that persistent interference with PI3Ksignaling is likely to extend treatment 
effect. In addition, this design permits collection of further single-agent safety information 
and thus is likely to enhance understanding of the overall safety profile of idelalisib. 


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6.
STUDY PROCEDURES
6.1.
Enrollment and Study Management Procedures
6.1.1.
Subject Recruitment
Study candidates are limited to those subjects who participated in the primary clinical trial
(Study GS-US-312-0116) and meet the entry criteria for this trial (Study GS-US-312-0117).
Subjects will be enrolled from investigational sites in the United States and Europe. The site 
principal investigator, designated sub-investigators, or other designees will discuss the possibility 
of participation directly with subjects who participated in the primary study.
The study sponsor will post a description of the study on the ClinicalTrials.gov website. Any 
promotional information generated by the sponsor or investigational sites will be submitted for 
IRB/IEC review.
6.1.2.
Subject Compensation for Participation
For subjects requesting such assistance, reasonable reimbursements for the costs of travel 
required to participate in this study will be provided by the study sponsor. To receive payment 
for travel, subjects will need to submit the original travel receipts to the research study staff at 
the investigational site.
However, other than medical care that may be provided, subjects will not be paid for 
participation in the study. Payments for such items as lost wages, disability, discomfort due to 
injury, or meals obtained while waiting at the clinical research center will not be provided. 
Through the informed consent process, study candidates will be notified that their insurance 
company could be charged for standard care that is a component of this research study and that 
subjects may be responsible for co-payments and deductible payments that are typical for their 
insurance coverage.
6.1.3.
Screening
The investigator must inform each prospective subject of the nature of the study, explain the 
potential risks, and obtain written informed consent from the subject and/or a legal guardian 
prior to performing any study-related screening procedures. At the time the study candidate signs 
the informed consent, a site representative should access the IWRS to indicate that a study 
candidate is being screened. The user will need to supply the IWRS with required information 
identifying the site and the subject number as already assigned in Study GS-US-312-0116.
Any consented subject who is excluded from the study before initiation of study treatment will 
be considered a screen failure. All screen failures must be documented along with an adequate 
description of the reason the subject was considered a screen failure. If available, information 
should be provided as to why the subject did not meet eligibility criteria, withdrew consent, 
experienced an intercurrent illness, or had other events that precluded treatment on this study.


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6.2.
Explanation of Study Visits
The specific study procedures to be conducted for each subject enrolled in the study are 
presented in tabular form in Appendix 7 and are described in the sections that follow. Additional 
information on the study procedures is provided in the study manual.
For visits at which HRQL and healthy utility data are obtained, it is important that the subject be 
administered the FACT-Leu and the EQ-5D before any other procedures are performed and 
before any study-related information is communicated to the subject; this is necessary to avoid 
biasing the PRO responses provided by the subject. Once the subject has completed the 
FACT-Leu and the EQ-5D assessments, the remaining procedures may be performed.
At visits involving idelalisib administration and pharmacokinetic sampling in the clinic, care 
should be taken to perform procedures with the appropriate timing relative to idelalisib
administration. The actual sample collection times of pharmacokinetic blood specimens should 
be recorded. If a heparinized venous catheter is placed for sample collection in order to avoid 
repeated needle sticks, at least 2 mL of blood should be removed and discarded prior to each 
sample collection in order to avoid heparin contamination of the sample.
At the visit designated as a laboratory-only visit (Visit 7), subjects will have laboratory 
assessments that may be performed at the investigational site or at an accredited local laboratory 
or clinic that is convenient for the subject/caregiver. If blood is collected at a local laboratory, 
samples are not to be analyzed at the local laboratory. For these visits, subjects and/or caregivers 
will be provided with central laboratory kits that will contain materials necessary for the 
collection and shipment of the laboratory samples by the local laboratory clinic to the central 
laboratory.
Local lab results may be requested in the event central laboratory results are not available for 
assessment of disease response, progression, or the evaluation of a significant event. In addition 
to clinical assessments of tumor status, CT or MRI imaging of the neck, chest, abdomen, and 
pelvis will be performed as a component of tumor assessments during the study based on the 
rationale provided in Section 3.2.1.
Following unblinding of the study:

Subjects who were randomized to idelalisib on Study GS-US-312-0116 and who received 
≥24 weeks idelalisib will complete Visit 16+ twelve weeks from the date of their last 
radiology assessment (CT/MRI) and study visits will continue every 12 weeks thereafter.
Visits 3 through 15 will not be required.

Subjects who have received < 24 weeks of idelalisib will have all Study GS-US-312-0117 
assessments completed per the Schedule of Procedures until they have received idelalisib for 
24 weeks cumulative across both studies. After completion of 24 weeks of cumulative 
idelalisib treatment, Visit 16+ will be conducted 12 weeks from the date of their last 
radiology assessment (CT/MRI), after which time study visits will occur every 12 weeks.


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6.2.1.
Visit 1 and Screening Period (Clinic Visit)
The initial screening visit is designated as Visit 1. At Visit 1, the investigator must inform each 
prospective study participant of the nature of the study, explain the potential risks, and obtain 
written informed consent from the study candidate and/or legal guardian prior to performing any 
study-related screening procedures. Once the informed consent document has been signed, the 
subject may undergo the screening procedures.
In order to optimize scheduling convenience for the subject and for the investigational staff, 
study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be 
used as screening procedures for Study GS-US-312-0117 if performed within 4 weeks prior to 
initiation of study drug therapy on Study GS-US-312-0117. In addition, screening procedures 
may be performed over as many days as necessary provided that screening is completed within 
4 weeks prior to initiation of study drug therapy on Study GS-US-312-0117.
The tests and evaluations outline in Table 6-1 will be performed at Visit 1 or during the 
screening period prior to initiation of study treatment.


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Table 6-1.
Procedures and Assessments at Visit 1 (During Screening Period)
Assessment or Procedure
Explanationa
Informed consent
To be obtained before any screening procedures are initiated
IWRS access
Access IWRS to document that subject is in screening and provide the subject number
from Study GS-US-312-0116
CIRS assessment
Recording of current comorbid conditions using the CIRS scoring instrument
(see Appendix 6)
Concomitant medications
Recording of ongoing concomitant medication use
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including height, weight, evidence of palpable lymphadenopathy, hepatomegaly, 
and/or splenomegaly
Serum β-HCG
Women of childbearing potential only
CLL peripheral blood 
evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 
12 trisomy; DNA mutational analysis for p53, IgHV (including IgHV3-21), and other 
genes of interest in CLL (eg, Notch); flow cytometry for CD5, CD10, CD11c, CD19, 
CD20, CD23, CD38, CD45, kappa and lambda light chains, and ZAP-70; 
cytology for karyotyping.
CLL serology
Serum 2 microglobulin
 
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis, to be scheduled with 
4 weeks prior to initiation of study treatment at Visit 2
Bone marrow biopsy and 
aspirate
To be performed at investigator discretion to determine extent of CLL involvement 
and bone marrow cellularity.
a
Study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be used as screening 
procedures for Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117.
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase,
AST=aspartate aminotransferase, CIRS=cumulative illness rating scale, CLL=chronic lymphocytic leukemia, CT=computed 
tomography, DNA=deoxyribonucleic acid, FISH= fluorescence in-situ hybridization, GGT=gamma--glutamyltransferase, 
Ig=immunoglobulin, IgHV=immunoglobulin heavy chain variable region, IWRS=interactive web response system, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging, RNA=ribonucleic acid, ZAP-70=zeta-associated protein 70
PPD


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6.2.2.
Visit 2 (Day 1) (Clinic Visit)
Subjects will be assessed to determine if they still meet eligibility criteria and can initiate study 
treatment. Study drug holds from primary study GS-US-312-0116 may continue as medically 
appropriate. The procedures outlined in Table 6-2 will be performed at Visit 2 (Day 1).
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
β-HCG
For women of child-bearing potential only; serum -HCG or urine dipstick pregnancy 
test must be negative prior to initial study treatment
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics
(with recording of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration
Study drug administrationa
First dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib
pharmacokineticsa
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensinga
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding study 
drug dosing at next full 
clinic visita
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 3.
a
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll on Study GS-US-312-0117 following 
unblinding may have idelalisib treatment (and associated PK testing) delayed at the Investigator’s discretion until the time of 
disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib treatment
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response 
system, LDH=lactate dehydrogenase, RNA=ribonucleic acid


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6.2.3.
Visit 3 (Day 15) (Clinic Visit)
The procedures outlined in Table 6-3 will be performed at Visit 3 (Day 15 [±2 days]).
Table 6-3.
Procedures and Assessments at Visit 3 (Day 15)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib pharmacokinetics
Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose). Pre-dose 
collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to document subject visit
Study Therapy Administration
Study drug administration
Study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Instruction regarding study 
drug dosing at next full 
clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 4.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase,
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, HRQL=health-related 
quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, LDH=lactate dehydrogenase


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6.2.4.
Visit 4 (Day 29) (Clinic Visit)
The procedures outlined in Table 6-4 will be performed at Visit 4 (Day 29 [±2 days]).
Table 6-4.
Procedures and Assessments at Visit 4 (Day 29)
Assessment or Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 3
Concomitant medications
Recording of concomitant medication used since Visit 3
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, IgM
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics
(with recording of the date and actual clock time of the date and actual clock time of 
blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration and Dispensing
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)


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Assessment or Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 5.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.5.
Visit 5 (Day 43) (Clinic Visit)
The procedures outlined in Table 6-5 will be performed at Visit 5 (Day 43 [±2 days]).
Table 6-5.
Procedures and Assessments at Visit 5 (Day 43)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
IWRS access
Access of IWRS to document subject visit
Post-Therapy Procedures and Assessments
Instruction regarding study 
drug dosing at next full 
clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 6.
Scheduling of Visit 6 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 6.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, 
LDH=lactate dehydrogenase


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6.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit)
The procedures outlined in Table 6-6 will be performed at Visit 6 (Day 57 [±2 days]).
Table 6-6.
Procedures and Assessments at Visit 6 (Day 57)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted.
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 5
Concomitant medications
Recording of concomitant medication used since Visit 5
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and 
CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug bottle number


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Assessment or Procedure
Explanation
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 8.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging
6.2.7.
Visit 7 (Day 71) (Laboratory Visit)
The procedures outlined in Table 6-7 will be performed at Visit 7 (Day 71 [±2 days]).
Table 6-7.
Procedures and Assessments at Visit 7 (Day 71)
Assessment or Procedure
Explanation
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including ALT, AST, ALP, GGT, total bilirubin, LDH
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
GGT=gamma-glutamyltransferase, LDH=lactate dehydrogenase


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6.2.8.
Visit 8 (Day 85) (Clinic Visit)
The procedures outlined in Table 6-8 will be performed at Visit 8 (Day 85 [±2 days]).
Table 6-8.
Procedures and Assessments at Visit 8 (Day 85)
Assessment or Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 6
Concomitant medications
Recording of concomitant medication used since Visit 6
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM, 
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration and Dispensing
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)


Idelalisib
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Final
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Assessment or Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 9.
Scheduling of Visit 9 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 9.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit)
The procedures outlined in Table 6-9 will be performed at Visit 9 (Day 113 [±3 days]).
Table 6-9.
Procedures and Assessments at Visit 9 (Day 113)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit the assessment should be done even if study drug has been interrupted.
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 8
Concomitant medications
Recording of concomitant medication used since Visit 8
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and 
CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number


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Final
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Version 9.0
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Assessment or Procedure
Explanation
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 10.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.10.
Visit 10 (Day 141) (Clinic Visit)
The procedures outlined in Table 6-10 will be performed at Visit 10 (Day 141 [±3 days]).
Table 6-10.
Procedures and Assessments at Visit 10 (Day 141)
Assessment or Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 9
Concomitant medications
Recording of concomitant medication used since Visit 9
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug  blister card number
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)


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Assessment or Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 11.
Scheduling of Visit 11 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 11.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit)
The procedures outlined in Table 6-11 will be performed at Visit 11 (Day 169 [±3 days]). 
Table 6-11.
Procedures and Assessments at Visit 11 (Day 169)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted. 
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant medications
Recording of concomitant medication used since Visit 10
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card numbers


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Assessment or Procedure
Explanation
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for 
self-administration at home.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.12.
Visit 12 (Day 211) (Clinic Visit)
The procedures outlined in Table 6-12 will be performed at Visit 12 (Day 211 [±3 days]).
Table 6-12.
Procedures and Assessments at Visit 12 (Day 211)
Assessment or Procedure
Explanation
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 11
Concomitant medications
Recording of concomitant medication used since Visit 11
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit
Study drug administration
Subject to continue with study drug as prescribed.
Scheduling of Visit 13 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 13.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.13.
Visit 13 (Day 253) (Clinic and Radiology Visit)
The procedures outlined in Table 6-13 will be performed at Visit 13 (Day 253 [±3 days]).
Table 6-13.
Procedures and Assessments at Visit 13 (Day 253)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted.
During-Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant medications
Recording of concomitant medication used since Visit 10
Study drug return/
accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study drug administration
Subject to continue with study drug as prescribed.
Study drug dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for 
self-administration at home.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.14.
Visit 14 (Day 295) (Clinic Visit)
The procedures outlined in Table 6-14 will be performed at Visit 14 (Day 295 [±3 days]).
Table 6-14.
Procedures and Assessments at Visit 14 (Day 295)
Assessment or Procedure
Explanation
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant medications
Recording of concomitant medication used since Visit 10
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit
Study drug administration
Subject to continue with study drug as prescribed.
Scheduling of Visit 15 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 15.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.15.
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks)
(Clinic and Radiology Visits)
The procedures outlined in Table 6-15 will be performed at Visit 15 (Day 337 [±3 days]) and 
every 12 weeks thereafter [±7 Days]).
Table 6-15.
Procedures and Assessments at Visit 15 and Subsequent Visits
(Day 337 and Every 12 Weeks)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted.
During-Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since prior visit
Concomitant medications
Recording of concomitant medication used since prior visit
Study drug return/
accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
CMV viral load
CMV viral load testing approximately every 4 weeks throughout the course of 
idelalisib treatment
Circulating cells
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Immune monitoring
Lymphocyte subset panel using flow cytometry (immunophenotyping), 
serum CH50 level
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines


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Assessment or Procedure
Explanation
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study drug administration
Subject to continue with study drug as prescribed.
Study drug dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for 
self-administration at home
PJP prophylaxis
Subjects must receive trimethoprim-sulfamethoxazole or other established 
prophylaxis for PJP throughout the course of idelalisib treatment.  Subjects must 
permanently discontinue idelalisib upon diagnosis of PJP.
Scheduling of next visit 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for next 
clinic visit (every 12 weeks).
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CMV=cytomegalovirus, CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, 
FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related 
quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, PJP= Pneumocystis 
jirovecii pneumonia


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6.2.16.
End-of-Study Visit (Clinic Visit)
At the time of discontinuation from the study, the subject should have the procedures and 
assessments performed as documented in Table 6-16. An end-of-study CT/MRI tumor 
assessment should be performed unless the subject already has radiographic confirmation of 
definitive disease progression or a CT/MRI has been performed within 4 weeks prior to the 
end-of-study visit.
Table 6-16.
Procedures and Assessments at End-of-Study Visit
Assessment or Procedure
Explanation
Radiology assessmenta
CT or MRI imaging of neck, chest, abdomen, and pelvis
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed
Adverse events 
Recording of adverse events occurring since prior visit; if a clinically significant 
adverse event or abnormal result is observed that is not resolved by the 
end-of-treatment visit, repeat evaluations should be performed to document resolution 
or stabilization of the abnormality
Concomitant medications
Recording of concomitant medication used since prior visit
Study drug return/
accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Serum β-HCG
Women of childbearing potential only
CLL peripheral blood 
evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 
12 trisomy; DNA mutational analysis for p53, IgHV (including IgHV3-21), and other 
genes of interest in CLL (eg, Notch); flow cytometry for CD5, CD10, CD11c, CD19, 
CD20, CD23, CD38, CD45, kappa and lambda light chains, and ZAP-70; 
cytology for karyotyping
CLL serology
Serum 2 microglobulin
 
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
PPD


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Assessment or Procedure
Explanation
Circulating cells
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Immune monitoring
Lymphocyte subset panel using flow cytometry (immunophenotyping), serum CH50 
level
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
PJP prophylaxis
Subjects must receive trimethoprim-sulfamethoxazole or other established 
prophylaxis for PJP after completion of idelalisib treatment until the CD4+ T-cell 
count is > 200 cells/mcL, at which point PJP prophylaxis may be discontinued.
IWRS
Access IWRS to document that subject has permanently discontinued study therapy
and to indicate whether subject agrees to continue to undergo long-term follow-up
a
An end-of-study CT/MRI tumor assessment should be performed unless the subject has per-protocol CT/MRI assessments 
4 weeks prior to end-of-study discontinuation.
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, CLL=chronic lymphocytic leukemia, CT=computed tomography, FISH= fluorescence in-situ 
hybridization, GGT=gamma-glutamyltransferase, IgHV=immunoglobulin heavy-chain variable-region, IWRS=interactive web 
response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, PJP= Pneumocystis jirovecii pneumonia,
RNA=ribonucleic acid, ZAP-70=zeta-associated protein 70
6.2.17.
30 Day and Long-Term Follow-up
A 30 Day follow-up visit will be performed 30 (+ 5) days following the end-of-study visit; 
however, it may be waived for subjects who have permanently discontinued study drug and have 
had a study visit >30 days after the last dose of study drug.
Long-term, follow-up will be requested of all subjects who withdraw from study for any reason.
The long-term follow-up for survival will be conducted at ~6-month intervals for 5 years, 
starting at the end-of-study visit. Information may be gathered during a routine clinic visit or 
other contact with the subject, or via telephone. Information gathered will include medical status, 
anti-tumor treatments, secondary malignancies, and survival.
6.3.
Sample Storage
 
 
 
 
 
PPD


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6.4.
Blood Collection
The maximum amount of blood to be drawn at a visit ~115 mL and the total amount of blood to 
be drawn over the initial 52-week study period (including the 4-week screening period and 
through Week 48 of the study including a possible end-of-therapy visit) is ~560 mL. For a 
40-kg person (the smallest participant expected to enroll in the study), this equates to 
maximum blood volume per body weight per visit of ~2.8 mL/kg and a total blood volume 
per body weight per average 6-week period of ~1.6 mL/kg. These quantities of blood are within 
accepted limits of 3.0 mL/kg of body weight for a single blood draw and 7.0 mL/kg of 
body weight for a 6-week period.
Specific details regarding blood sample collection and processing requirements will be provided 
separately in the study manual.
 
 
 
6.5.
Study Procedure Rationale
The planned study assessments and timing have been selected as appropriate for screening of 
subjects, for determination of idelalisib-related or disease-related toxicities, for dose 
modification during the study, for characterization of drug exposure and desired pharmacological 
effects, and for evaluation of drug activity. The scheduling of testing is designed to collect a 
complete safety and pharmacology data set while maintaining subject tolerance of study 
procedures. The planned schedule of tumor assessments is consistent with expected rate of 
changes and appropriately balances precise measurement of tumor control with the expense and 
subject inconvenience associated with clinical and radiological procedures. For discussion of the 
rationale for endpoint selection, see Section 3.2.
PPD


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7.
EFFICACY ASSESSMENTS
7.1.
Tumor Status Assessments
The determination of CLL response and progression will be based on standardized IWCLL
criteria {Hallek et al 2008}, as specifically modified for this study to reflect current 
recommendations which consider the mechanism of action of idelalisib and similar drugs 
{Cheson et al 2012}. Treatment decisions by the investigator in this study will be based on these 
assessments. Radiographic and clinical tumor assessments will be subject to independent 
confirmation by the IRC (see Section 10.4.2).
7.2.
Method of Assessment
In addition to clinical examination, imaging-based evaluation will be used in this study in all 
subjects enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI 
scanning may be used at the investigator’s discretion in subjects for whom this may be a 
preferred alternative to CT scanning; however, if MRI is performed, a non-contrast CT of the 
chest should be performed. Contrast-enhanced scanning is preferred, but iodine-containing or 
gadolinium contrast material may be omitted in subjects for whom use of a contrast agent would 
be medically contraindicated. Chest x-ray, ultrasound, endoscopy, laparoscopy, PET, 
radionuclide scans, or tumor markers will not be considered for response assessment.
For radiographic evaluations, the same method of assessment and the same technique 
(eg, scan type, scanner, subject position, dose of contrast, injection/scan interval) should be used 
to characterize each identified and reported lesion at baseline and during study treatment and 
follow-up.
All relevant clinical and radiographic information required to make each tumor status assessment 
must be made available for source verification and for submission to the IRC 
(see Section 10.4.2).
7.3.
Timing of Assessments
All baseline clinical and CT/MRI tumor assessments should be performed within 4 weeks prior 
to initiation of study drug therapy. In order to optimize scheduling convenience for the subject 
and for the investigational staff, clinical and CT/MRI tumor assessments performed as part of 
Study GS-US-312-0116 need not be repeated and can be used as baseline tumor assessments for 
Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117. Clinical tumor assessments should be performed at each clinical visit. 
On-study CT/MRI tumor assessments should be performed at ~8- to 12-week intervals as 
dictated by the study protocol. An end-of-study CT/MRI tumor assessment should be performed 
unless the subject has per-protocol CT/MRI assessments 4 weeks prior. If a subject 
permanently discontinues study drug prior to objective documentation of CLL progression, 
investigators should continue further follow-up at ~12-week intervals until CLL progression is 
documented by the central IRC.


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7.4.
Identification and Measurement of Tumor Lesions and Organomegaly
7.4.1.
Index Lesions
At baseline, up to 6 lymph nodes should be selected as index lesions that will be used to 
quantitate the status of the disease during study treatment. Ideally, the index lesions should be 
located in disparate regions of the body. Only peripheral nodes need be selected as index lesions. 
However, it is optimal if mediastinal and retroperitoneal areas of disease are assessed whenever 
these sites are involved.
Index lesions will be measured and recorded at baseline and at the stipulated intervals. The 
cross-sectional dimensions (the largest cross-sectional diameter, ie, the LD × LPD) will be 
recorded (in cm) for each index lesion. The product of the perpendicular diameters (PPD) 
(in cm2) for each index lesion and the sum of the products (SPDs) (in cm2) for all index lesions 
will be calculated and recorded. The baseline SPDs will be used as references by which tumor 
response will be characterized during treatment. The nadir LD of individual lesions and the nadir 
SPD will be used as references by which CLL progression will be characterized. All LD and 
LPD diameters will be reported in centimenters and all PPDs and SPDs will be reported in 
centimeters squared.
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable at 
baseline. A lymph node lesion is considered abnormal if it has a single diameter that is 1.5 cm 
and is considered measurable if it has 2 perpendicular diameters that can be accurately measured 
in cross section with the LD being 1.0 cm and the LPD also being 1.0 cm.
At follow-up time points, the LDs for individual lesions and the SPD of all nodal index lesions 
will be considered. Because nodal index lesions that have one or both diameters 
>0 cm and 1.0 cm cannot be reliably measured, a default value of 1.0 cm will be assigned for 
each diameter that meets these criteria and the resulting PPD will be used in SPD calculations. 
Based on this convention, a CR may be achieved even if an SPD value is >0 cm2, 
(ie, if all lymph nodes measure <1.0 cm2).
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD will be considered 
progressive disease.
In cases in which a large lymph node mass has split into multiple components, all 
subcomponents regardless of size will be used in calculating the SPD. Progression of the lesion 
will be based on the SPD of sub-components. Lesion sub-components will have the true PPDs 
calculated. Similarly, lesion sub-components that are visible but neither abnormal nor 
measurable will have the default PPD of 1.0 cm2 (1.0 cm 1.0 cm) used in calculating the SPD.
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer 
be separated by this boundary, the newly merged lesion will be measured bi-dimensionally.


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7.4.2.
Spleen and Liver
Both the spleen and liver will be assessed by CT/MRI scan at baseline and at the stipulated 
intervals during treatment. The baseline and nadir values for the longest vertical dimension 
(LVD) of each organ will be used as reference to further characterize the objective tumor 
response of the measurable dimensions of the CLL during treatment. All spleen and liver LVD 
measurements should be recorded in centimeters.
By imaging, the spleen will be considered enlarged if it is >12 cm in LVD {Asghar et al 2011, 
Bezerra et al 2005}.
For subjects with splenomegaly at baseline or at the splenic LVD nadir, respective response and 
progression evaluations of the spleen will consider only changes relative to the enlargement of 
the spleen at baseline or nadir, not changes relative to the total splenic LVD.
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen in its LVD or 
decrease to ≤12 cm in the LVD, is required for declaration of a splenomegaly response. 
Conversely, an increase in splenic enlargement by ≥50% from nadir 
(with a minimum 2 cm increase) is required for declaration of splenic progression.
By imaging, the liver will be considered enlarged if it is >18 cm in LVD {Erturk et al 2006}.
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the liver in its LVD or 
decrease to ≤ 18 cm in the LVD is required for declaration of a hepatomegaly response. 
Conversely, an increase in liver enlargement by ≥50% from nadir 
(with a minimum 2 cm increase) is required for declaration of hepatic progression.
7.4.3.
Non-Index Lesions
Any other measurable and abnormal nodal lesions not selected for quantitation as index lesions 
may be considered non-index lesions. In addition, non-measurable evidence of CLL such as 
nodal lesions with both diameters <1.0 cm, extra-nodal lesions, bone lesions, leptomeningeal 
disease, ascites, pleural or pericardial effusions, lymphangitis of the skin or lung, abdominal 
masses that are not confirmed and followed by imaging techniques, cystic lesions, previously 
irradiated lesions, lesions with artifacts, and may be considered as non-index disease.
The presence or absence of non-index disease should be recorded at baseline and at the stipulated 
intervals during treatment. If present at baseline, up to 6 non-index lesions should be recorded. 
The non-index disease at baseline will be used as a general reference to further characterize 
regression or progression of CLL during assessments of the objective tumor response during 
treatment. Measurements are not required and these lesions should be followed as 
“present” or “absent”.
7.5.
Definitions of Tumor Response and Progression
Responses will be categorized by the IRC as CR, PR, SD, or PD. In addition, a response category 
of not evaluable (NE) is provided for situations in which there is inadequate information to 
otherwise categorize response status. A response category of no disease (ND) is included for 
situations in which there is absence of tumor both at baseline and on treatment.


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The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until disease/recurrence progression (taking as a reference 
for disease progression the smallest measurements recorded since treatment started). Subjects 
with a best overall response of NE or ND will be counted in the denominators in calculations of 
tumor response rates.
7.5.1.
Complete Response
To satisfy criteria for a CR, all of the following criteria must be met:

No evidence of new disease

ALC in peripheral blood of <4 x 109/L

Regression of all index nodal masses to normal size (1.5 cm in the LD)

Normal spleen and liver size

Regression to normal of all nodal non-index disease and disappearance of all detectable 
non-nodal, non-index disease

Morphologically negative bone marrow defined as <30% of nucleated cells being lymphoid 
cells and no lymphoid nodules in a bone marrow sample that is normocellular for age

Peripheral blood counts meeting all of the following criteria:
ANC >1.5 x 109/L without need for exogenous growth factors (eg, G-CSF)
Platelet count 100 x 109/L without need for exogenous growth factors or transfusions
Hemoglobin 110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (eg, erythropoietin)
Note: Subjects who fulfill all the criteria for a CR (including bone marrow criteria) but who 
have a persistent anemia, thrombocytopenia, or neutropenia or a hypocellular bone marrow 
that is related to prior or ongoing drug toxicity (and not to CLL) will be considered as a CR 
with incomplete marrow recovery (CRi).
7.5.2.
Partial Response
To satisfy criteria for a PR, all of the following criteria must be met:

No evidence of new disease

A change in disease status meeting 2 of the following criteria, with 2 exceptions in which 
only 1 criterion is needed: (1) Only lymphadenopathy is present at baseline; 
(2) Only lymphadenopathy and lymphocytosis are present at baseline. In these 2 cases, only 
lymphadenopathy must improve to the extent specified below:


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In a subject with baseline lymphocytosis (ALC4 x 109/L), a decrease in 
peripheral blood ALC by 50% from baseline or a decrease to <4 x 109/L
A decrease by 50% from the baseline in the SPD of the index nodal lesions
In a subject with enlargement of the spleen at baseline, a splenomegaly response, defined 
as a ≥50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen or 
decrease to ≤12 cm in the LVD by imaging
In a subject with enlargement of the liver at baseline, a hepatomegaly response, defined 
as a ≥50% decrease (minimum 2 cm) from baseline in the enlargement of the liver or 
decrease to ≤18 cm in the LVD by imaging
A decrease by 50% from baseline in the CLL marrow infiltrate or in 
B-lymphoid nodules

No index, splenic, liver, or non-index disease with worsening that meets the criteria for 
definitive PD

Peripheral blood counts meeting 1 of the following criteria:
ANC >1.5 x 109/L or 50% increase over baseline without need for exogenous growth 
factors (eg, G-CSF)
Platelet count 100 x 109/L or 50% increase over baseline without need for 
exogenous growth factors or transfusions
Hemoglobin 110 g/L (11.0 g/dL) or 50% increase over baseline without red blood cell 
transfusions or need for exogenous growth factors (eg, erythropoietin)
7.5.3.
Stable Disease
To satisfy criteria for stable disease (SD), the following criteria must be met:

No evidence of new disease

There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD
7.5.4.
Definitive Progressive Disease
The occurrence of any of the following events indicates definitive PD:

Evidence of any new disease:
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD


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New or recurrent splenomegaly, with a minimum LVD of 14 cm
New or recurrent hepatomegaly, with a minimum LVD of 20 cm
Unequivocal reappearance of an extra-nodal lesion that had resolved
A new unequivocal extra-nodal lesion of any size
New non-index disease (eg, effusions, ascites, or other organ abnormalities 
related to CLL)
Note: Isolated new effusions, ascites, or other organ abnormalities are not sufficient evidence 
alone of PD unless histologically confirmed. Thus, a declaration of PD should not be made if 
this is the only manifestation of apparently new disease.

Evidence of worsening of index lesions, spleen or liver, or non-index disease:
Increase by 50% from the nadir in the SPD of index lesions
Increase from the nadir by 50% in the LD of an individual node or extra-nodal mass that 
now has an LD of >1.5 cm and an LPD of > 1.0 cm
Splenic progression, defined as an increase in splenic enlargement by 50% from nadir 
(with a minimum 2 cm increase and a minimum LVD of 14 cm)
Hepatic progression, defined as an increase in hepatic enlargement by 50% from nadir 
(with a minimum 2 cm increase and minimum LVD of 20 cm)
Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or other 
organ abnormalities related to CLL) 
Transformation to a more aggressive histology (eg, Richter syndrome) as established by 
lymph node or other tissue biopsy, or fluid cytology (with the biopsy or fluid cytology 
date being considered the date of CLL progression if the subject has no earlier objective 
documentation of CLL progression).

Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to an 
autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an infiltrate of 
clonal CLL cells
The current platelet count is <100 x 109/L and there has been a decrease by >50% from 
the highest on-study platelet count
The current hemoglobin is <110 g/L (11.0 g/dL) and there has been a 
decrease by >20 g/L (2 g/dL) from the highest on-study hemoglobin


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Note: If there is uncertainty regarding whether there is true progression, the subject should 
continue study treatment and remain under close observation 
(eg, evaluated at 4-week intervals) pending confirmation of progression status by the IRC. In 
particular, worsening of constitutional symptoms in the absence of objective evidence of 
worsening CLL will not be considered definitive disease progression; in such subjects, both 
CLL-related and non-CLL-related causes for the constitutional symptoms should be 
considered. Worsening of disease during temporary interruption of study treatment 
(eg, for intercurrent illness) is not necessarily indicative of resistance to study treatment. In 
these instances, CT/MRI or other relevant evaluations should be considered in order to 
document whether definitive disease progression has occurred. If subsequent evaluations 
suggest that the subject has experienced persistent definitive CLL progression, then the date of 
progression should be the timepoint at which progression was first objectively documented.
7.5.5.
Non-Evaluable
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE:

There are no images or inadequate or missing images

Images of the liver and spleen are missing at that time point (with the exception that absence 
of splenic images will not result in an NE designation in a subject known to have 
undergone splenectomy).
Note: A time-point will be considered to have a response of NE if any index lesion is missing. 
PD may be assigned at any time point regardless of the extent of missing index or 
non-index lesions. Missing non-index lesions will not impact the ability to assess for response 
or disease progression.
7.5.6.
No Disease
Subjects have a status of ND if all of the following conditions occur:

No index disease noted at baseline or on-treatment 

No non-index disease noted at baseline or on-treatment.

No enlargement of the liver or spleen at baseline or on-treatment

No abnormalities of peripheral blood counts (elevated ALC or abnormally low ANC, 
platelet count, or hemoglobin) and no evidence of CLL in bone marrow (if available) at 
baseline or on treatment


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7.5.7.
Lymphocytosis During Therapy
Idelalisib can mobilize CLL cells from tissues into the peripheral blood. This characteristic 
pharmacological action can be prominent early in therapy but can persist over time and should 
not be confused with disease progression in subjects who have persistent control of other 
CLL-related signs and symptoms. In the absence of other objective evidence of disease 
progression, lymphocytosis alone will not preclude subjects from meeting the criteria for PR if 
other criteria for PR are met and will not be considered evidence of disease progression if 
occurring in isolation. Subjects with lymphocytosis should be continued on study drug until the 
occurrence of definitive disease progression (ie, disease progression that is manifest by 
worsening CLL-related signs other than lymphocytosis alone), or the occurrence of another 
reason to discontinue study therapy as described in Section 5.8.
7.5.8.
Documentation of Definitive CLL Progression
Of importance, CLL response and progression data collected from the primary study will be 
subjected to IRC review (see Section 10.4.2). Subjects must have confirmation by the sponsor 
working in collaboration with the IRC that the disease has progressed on the primary clinical 
trial (Study GS-US-312-0116) before being permitted to receive secondary idelalisib therapy 
on this extension trial (GS-US-312-0117). Subjects should continue study drug pending 
confirmation of progression status. CT/MRI should be attempted in order to document definitive 
disease progression by the IRC. The end-of study scan from the primary study can serve as the 
baseline scan for the extension study if obtained within the specific screening period for the 
extension study. If obtained within the specified screening period for the extension study, this 
scan can serve as the baseline scan for the extension study.


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8.
SAFETY ASSESSMENTS
8.1.
Adverse Event Definitions
8.1.1.
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical product which; does not necessarily have a causal relationship 
with study drug administration or usage. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Lymphocytosis

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 5.2.8)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
In this study, any of the following events will be considered an adverse event:

Any complication that occurs as a result of a protocol-mandated procedure 
(eg, venipuncture, biopsy) in the screening, on-treatment, or post-treatment periods.

Any pre-existing condition that increases in severity or changes in nature during or as a 
consequence of study drug administration. Worsening manifestations of the underlying 
cancer (eg, increase in pain, tumor flare reaction, tumor lysis syndrome) may be considered 
adverse events in this study.


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
Any injury or accident occurring during the screening, on-treatment, or post-treatment 
periods. If a medical condition is known to have caused the injury or accident 
(eg, a fall secondary to dizziness), the medical condition (dizziness) and the accident (fall) 
should be reported as 2 separate adverse events. 

Any abnormality in physiological testing or a physical examination finding that requires 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test).

Any laboratory (eg, clinical chemistry, hematology, urinalysis) or investigational abnormality 
(eg, ECG, X-ray) independent of the underlying medical condition that requires clinical
intervention, results in further investigation (beyond ordering a repeat [confirmatory] test), or 
leads to investigational medicinal product interruption or discontinuation unless it is
associated with an already reported clinical event. If the laboratory abnormality is part of a 
syndrome, the syndrome or diagnosis (eg, anemia) not the laboratory result 
(eg, decreased hemoglobin) should be recorded. 

A complication related to pregnancy or termination of a pregnancy (see Section 5.4.10 for 
additional information).
8.1.2.
Serious Adverse Event
A serious adverse event (SAE) is defined as an event that results in any of the following:

Death

Life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization.

Persistent or significant disability/incapacity.

A congenital anomaly/birth defect

A medically important event or reaction. Such events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the outcomes listed above. Examples of such events 
might include:
Allergic bronchospasm requiring intensive treatment in an emergency room or at home
New cancers or blood dyscrasias
Convulsions that do not result in hospitalization
Development of drug dependency or drug abuse


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Medical and scientific judgment must be exercised to determine whether such an event is 
reportable under expedited reporting rules.
Infections resulting from contaminated medicinal product will be considered a medically 
important event and subject to expedited reporting requirements.
Given the endpoints of the study, in order to maintain the integrity of the study the following 
events that are assessed as unrelated to IMP will not be considered SAEs:

Progression of CLL

Death related to progression of CLL
Disease progression and death from disease progression should be reported as SAEs by the 
investigator only if it is assessed that the IMPs caused or contributed to the disease progression 
(i.e., by a means other than lack of effect). Unrelated disease progression and death due to 
disease progression should be captured on the eCRF.
These events will be reported, as appropriate, in the final clinical study report and in any relevant 
aggregate safety reports. The safety information from this study will also be reviewed by an 
independent DMC on an ongoing basis. The DMC can have access to partially blinded or 
unblinded data in order to determine if it is safe to continue the study according to the protocol.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Section 8.5. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result 
(ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 5.4.
8.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.


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8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting.
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed from screening 
onwards.
All AEs, regardless of cause or relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP must be reported to the CRF/eCRF database as 
instructed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported.
All AEs should be followed up until resolution if possible. If by the last day on study 
(including the off-study medication follow-up period) the AE has not resolved, then the AE will 
be followed up until the investigator and/or Gilead Sciences determine that the subject's 
condition is stable. However, Gilead Sciences may request that certain AEs be followed until 
resolution.


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Investigators are not obligated to actively seek SAEs after the above period. However, if the 
investigator learns of any SAEs that occur after study participation has concluded and the event 
is deemed relevant to the use of IMP, he/she should promptly document and report the event to 
Gilead DSPH.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.

At the time of study start, SAEs will be reported using a paper serious adverse event 
reporting form. During the study conduct, sites may transition to an electronic SAE (eSAE) 
system. Gilead will notify sites in writing and provide training and account information prior 
to implementing an eSAE system.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by faxing 
the report form within 24 hours of the investigator’s knowledge of the event to the attention 
of Gilead DSPH or to the designated CRO.
8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to expedite 
to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the 
EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide 
regulatory agencies and the relevant IEC in concerned Member States of applicable SUSARs as 
outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the IRB or IEC of SUSAR reports as soon as is practical, where this is 
required by local regulatory agencies, and in accordance with the local institutional policy.
8.5.
Grading of the Severity of an Adverse Event
The severity of adverse events will be graded using the CTCAE, Version 4.03 (provided in 
study manual and available at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). For 
each episode, the highest severity grade attained should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or 
Grade 5 (fatal) to describe the maximum intensity of the adverse event. For purposes of 
consistency with the CTCAE, these intensity grades are defined in Table 8-1.


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Table 8-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Sign or symptom is present, but it is easily tolerated, is not expected to have a 
clinically significant effect on the subject’s overall health and well-being, does not 
interfere with the subject’s usual function, and is not likely to require medical 
attention.
Grade 2
Moderate
Sign or symptom causes interference with usual activity or affect clinical status, and 
may require medical intervention.
Grade 3
Severe
Sign or symptom is incapacitating or significantly affects clinical status and likely 
requires medical intervention and/or close follow-up.
Grade 4
Life-threatening
Sign or symptom results in a potential threat to life.
Grade 5
Fatal
Sign or symptom results in death.
The distinction between the seriousness and the severity of an adverse event should be noted. 
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For 
example, a headache may be severe in intensity, but would not be classified as serious unless it 
met one of the criteria for serious events listed in Section 8.1.2 above.
8.6.
Adverse Event Reporting Period
The start of the adverse event reporting for a study subject will coincide with signing of the 
informed consent for Study GS-US-312-0117. Any new adverse events occurring thereafter 
should not be reported within Study GS-US-312-0116, but instead should be reported within
Study GS-US-312-0117. The end of the adverse-event-reporting period for 
Study GS-US-312-0117 occurs 30 days after the discontinuation from study drug or when any 
ongoing drug-related adverse events and/or serious adverse events have resolved or become 
stable. A subject withdrawn from the study because of an adverse event must be followed until 
the clinical outcome from the adverse event is determined. The investigator should use
appropriate judgment in ordering additional tests as necessary to monitor the resolution of events 
ongoing at the completion of study treatment. Gilead Sciences may request that certain adverse 
events be followed longer.
Investigators are not obligated to actively seek information regarding the occurrence of new 
serious adverse events beginning after the 30-day post-study period. However, if the investigator 
learns of such a serious adverse event and that event is deemed relevant to the use of the study 
drug, he/she should promptly document and report the event. A longer reporting period applies in 
the case of pregnancy (see Section 8.9.1)
8.7.
Adverse Event Reporting Requirements
8.7.1.
Site Reporting Requirements
Classification of an event as serious or nonserious (see Section 8.1.2) determines the reporting 
procedures to be followed by the site.


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Site reporting requirements for adverse events are summarized in Table 8-2, below.
Table 8-2.
Site Reporting Requirements for Adverse Events
Classification
Reporting Time
Reporting Action
Serious
Within 24 hours
Fax report on designated serious adverse event report form 
to PPD Pharmacovigilancea, and to the site IRB/IEC, 
as per local IRB/IEC requirements; include copies of 
relevant source documentsb (eg, progress notes, 
autopsy reports, laboratory and diagnostic test results, 
discharge summaries) in communication to 
PPD Pharmacovigilancea
Per eCRF submission procedurec
Record and submit information on appropriate eCRFs
Nonserious
Per eCRF submission procedure
Record and submit information on appropriate eCRFs
a
See contact information in Table 8-3 below.
b
Subject name, address, and other personal identifiers should be obscured but without losing the traceability of a document to 
the study subject identifiers.
c
CLL progression or death due to CLL progression should be reported by the investigator as a serious adverse event only if it 
is assessed that the study drugs caused or contributed to the CLL progression (ie, by a means other than lack of effect). 
Unrelated events of CLL progression should be captured on the appropriate eCRF. 
Abbreviations: CLL = chronic lymphocytic leukemia, eCRF=case report form, IRB/IEC= Institutional Review Board/
Independent Ethics Committee
For serious adverse events, in addition to completing the adverse event portion of the eCRF, the 
serious adverse event report form must also be completed. The information in the adverse event 
portion of the eCRF page and the serious adverse event report form(s) must match or be 
reconciled. Where the same data are collected, the forms must be completed in a consistent 
manner. For example, the same adverse event term should be used on both forms. Particularly for 
fatal or life-threatening events, copies of progress notes, autopsy reports, laboratory and 
diagnostic test results, discharge summaries, and other relevant documents should be faxed when 
requested and applicable. Follow-up information to the serious adverse event should be clearly 
documented as “follow up” in the serious adverse event report form and must be faxed to these 
same parties. Gilead Sciences may request additional information from the investigator to ensure 
the timely completion of accurate safety reports.
The subject’s name, address, and other personal identity information should be obscured on any 
source documents (eg, progress notes, nurses’ notes, laboratory and diagnostic test results, 
discharge summaries). Only the subject’s study number, initials, or date of birth are to be 
provided.
The serious adverse event report form must be communicated to PPD Pharmacovigilance and to 
the site IRB/IEC (if required by local regulations) within 24 hours. In the rare event that the 
investigator does not become aware of the occurrence of a serious adverse event immediately 
(for example, if a subject initially seeks treatment elsewhere), the investigator is to report the 
event within 24 hours after learning of it and to document his/her first awareness of the adverse 
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Contact details for PPD Pharmacovigilance and for the Gilead study medical monitor are 
provided in Table 8-3:
Table 8-3.
Contact Information for Reporting Serious Adverse Events
Function
Contact Information
PPD Pharmacovigilance
(US)
Facsimile:
PPD Pharmacovigilance
(International)
Facsimile:
Gilead Sciences
Medical Monitor
Name:
Title: 
Medical Monitor, Clinical Research
Telephone:
Facsimile:
E-mail:
8.7.2.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population
To maintain the integrity of the study, progression of CLL and death related to progression of 
CLL will not be reported to Gilead Sciences as serious adverse events unless it is assessed that 
the study drug caused or contributed to CLL progression or death related to CLL progression 
(ie, by a means other than lack of effect). These events will be exempt from global expedited 
reporting requirements for the duration of the study because they define the primary efficacy 
endpoint for this study. All events of progression of CLL and death related to progression of 
CLL, regardless of relationship to study drug, will be reported in the eCRFs and, as appropriate, 
in the final clinical study report and in any relevant aggregate safety reports. Disease progression 
information from this study will be reviewed by an independent DMC on an ongoing basis.
8.8.
Special Situations Reporting Requirements
8.8.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, lack of 
effect reports and pregnancy reports regardless of an associated AE. Also includes reports of 
adverse reactions in infants following exposure from breastfeeding, and reports of adverse 
reactions associated with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following possible maternal or paternal 
exposure to the medicinal product.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
PPD
PPD
PPD
PPD
PPD
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Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Lack of effect is defined as a situation where there is apparent failure of the medicinal product or 
medical technology to bring about the intended beneficial effect on the individual in a defined 
population with a given medical problem, under ideal conditions of use.
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
8.9.
Instructions for Reporting Special Situations
8.9.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (ie, signs the informed consent) and throughout the study, including the 
post study drug follow-up period, to the  or Gilead DSPH ] using the pregnancy report form 
within 24 hours of becoming aware of the pregnancy. Refer to the CRF/eCRF completion 
guidelines for full instructions on the mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE, and therefore should be reported as 
such. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must be 
reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to PPD Pharmacovigilance or Gilead DSPH using 
the pregnancy outcome report form. If the end of the pregnancy occurs after the study has been 
completed, the outcome should be reported directly to Gilead DSPH. Gilead DSPH 
contact information is as follows: Email:
 and Fax:
PPD
PPD


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Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to PPD Pharmacovigilance 
or Gilead DSPH using the pregnancy and pregnancy outcome forms within 24 hours. Monitoring 
of the subject should continue until the conclusion of the pregnancy. If the end of the pregnancy 
occurs after the study has been completed, the outcome should be reported directly to 
Gilead DSPH, fax number
 or email 
8.9.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to PPD Pharmacovigilance or Gilead DSPH within 24 hours of the investigator 
becoming aware of the situation. These reports must consist of situations that involve study IMP, 
but do not apply to concomitant medications. Except for situations that result in AEs, special 
situations involving concomitant medications will not be reported. Any inappropriate use of 
medications prohibited by this protocol should not be reported as “misuse,” but may be more 
appropriately documented as a protocol deviation.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.
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9.
STATISTICAL CONSIDERATIONS
9.1.
Analysis Objectives
As described in Section 3, the objectives of this clinical trial will focus on determining the effect 
of idelalisib on the onset, magnitude, and duration of tumor control; measures of patient 
well-being (including OS, HRQL; and changes in subject performance status); disease-associated 
biomarkers and potential mechanisms of resistance; treatment administration; safety; and health 
resource utilization.
9.2.
Analysis Endpoints
The endpoints of the study are defined in Section 3.1, grouped in categories relating to tumor 
control, patient well-being, pharmacodynamic markers of drug activity and resistance, exposure, 
safety, and pharmacoeconomics.
9.3.
Analysis Conventions
9.3.1.
Analysis Sets
9.3.1.1.
Intent-to-Treat Analysis Set
The ITT analysis set includes all subjects who receive 1 dose of any study treatment 
(high-dose idelalisib or standard-dose idelalisib). In the ITT analysis set, study drug assignment 
will be designated according to planned allocation in this study, regardless of whether subjects 
receive a different study therapy from that to which they were allocated.
This analysis set will be used in the analyses of subject characteristics and all the tumor control 
and patient well-being endpoints. Subjects in the ITT analysis set who do not have sufficient 
baseline or on-study tumor status information to be adequately assessed for response status will 
be included in the denominators in the calculation of response rates.
9.3.1.2.
Per-Protocol Analysis Set
The PP analysis set includes data from subjects in the ITT analysis set who meet the general 
criteria defining the target population for this study, are adherent to the protocol, are compliant 
with study drug treatment, and are evaluable for relevant efficacy endpoints. Treatment 
assignment will be designated according to the actual treatment received. The specific 
classification of subjects to be included in the PP analysis set will be included in the statisticial 
analysis plan which will be finalized prior to the database lock.
The PP analysis set will be used in sensitivity analyses of these tumor control and patient 
well-being endpoints: PFS, ORR, lymph node response rate, OS and CR rate.


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9.3.1.3.
Safety Analysis Set
A safety analysis set will include subjects in the ITT analysis set grouped for analyses with 
treatment assignments designated according to the actual study drug received.
This analysis set will be used in the analyses of safety variables as well as study treatment 
administration, and health economic variables.
9.3.1.4.
Pharmacodynamic and/or Pharmacokinetic Analysis Sets
The pharmacodynamic and/or pharmacokinetic analysis sets include data from subjects in the 
safety analysis set who have the necessary baseline and on-study measurements to provide 
interpretable results for the specific parameters of interest. 
These analysis sets will be used in the analyses of AKT phosphorylation, chemokines/cytokines, 
and idelalisib plasma concentrations.
9.3.2.
Data Handling Conventions
9.3.2.1.
General Methods 
By-subject listings will be created for important variables from each eCRF module. 
Summary tables for continuous variables will contain the following statistics: 
N (number in population), n (number with data), mean, standard deviation, 
95% confidence intervals (CIs) on the mean, median, minimum, and maximum. Summary tables 
for categorical variables will include: N, n, percentage, and 95% CIs on the percentage. Unless 
otherwise indicated, 95% CIs for binary variables will be calculated using the binomial 
distribution (exact method) and will be 2-sided. Data will be described and summarized by 
relevant treatment arm, analysis set, and timepoint. As appropriate, changes from baseline to 
each subsequent timepoint will be described and summarized by treatment arm. Similarly, as 
appropriate, the best change from baseline during the study will also be described and 
summarized by treatment arm. Graphical techniques (eg, waterfall plots, 
Kaplan-Meier curves, line plots) may be used when such methods are appropriate and 
informative.
Data from all sites will be pooled for all analyses. Analyses will be based upon the observed data 
unless methods for handling missing data are specified. If there is a significant degree of 
non-normality, analyses may be performed on log-transformed data or nonparametric tests may 
be applied, as appropriate.
9.3.2.2.
Double-Blinded Portion of the Study Analyses
Efficacy and safety data collected during the blinded portion of Study GS-US-312-0117 will be 
presented in the following 2 groups:


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
IDELA 300 mg BID: Subjects who have PD per IRC confirmation in Arm A of 
Study GS-US-312-0116 and subsequently enroll into Study GS-US-312-0117 to receive 
IDELA 300 mg BID during the double-blind portion of the study

Placebo in Study GS-US-312-0116 + IDELA 150 mg BID in Study GS-US-312-0117: 
Subjects who have PD per IRC confirmation in Arm B of Study GS-US-312-0116 and 
subsequently enroll Study GS-US-312-0117 to receive IDELA 150 mg BID during the 
double-blind portion of the study
All analyses will be performed based on the data collected during the blinded-portion of the 
extension study. Time-to-event analyses will reference to the date of first treatment on this 
clinical trial (Study GS-US-312-0117). Similarly, evaluations of on-therapy changes will 
reference the baseline values obtained prior to treatment in this study. The baseline value used in 
each analysis will be the last (most recent) pre-treatment value. Analyses will be descriptive in 
nature and formal comparisons of outcomes in the 2 groups are not planned.
9.3.2.3.
Open-Label Extension Study Analyses
GS-US-312-0117 will become an open-label study offering idelalisib 150 mg BID to 
GS-US-312-0116 subjects who were randomized to Arm B. Subjects randomized to Arm A will 
continue idelalisib at 150 mg BID. Efficacy and safety data collected during the primary and 
open-label extension studies will be presented in the following 4 groups:

IDELA 150 mg BID: Subjects who are randomized to Arm A in Study GS-US-312-0116 and 
transition to Study GS-US-312-0117 during the open-label portion of the study to continue 
IDELA 150 mg BID

Placebo in GS-US-312-0116 + IDELA 150 mg BID (open-label): Subjects who are 
randomized to Arm B in Study GS-US-312-0116 and transition to receive 
IDELA 150 mg BID during the open-label portion of the study

IDELA 300 mg BID: Subjects who have PD per IRC confirmation in Arm A of 
Study GS-US-312-0116 and subsequently enroll Study GSUS-312-0117 to receive 
IDELA 300 mg BID during double-blind portion of the study

Placebo in GS-US-312-0116 + IDELA 150 mg BID in GS-US-312-0117: Subjects who have 
PD per IRC confirmation in Arm B of Study GS-US-312-0116 and subsequently enroll 
Study GS-US-312-0117 to receive IDELA 150 mg BID during double-blind portion of the 
study.
Depending on the endpoints, analyses may be based on the combined data from both primary and 
extension studies or data from the extension study alone. Analyses will be descriptive in nature 
and formal comparisons of outcomes in the 4 groups are not planned. A separate statistical 
analysis plan will be created for the open-label portion of the study.


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9.3.2.4.
Calculation of Tumor Control and Patient Well-Being Variables
Tumor control assessments will be based on standardized IWCLL criteria {Cheson et al 2012, 
Hallek et al 2008}, as specifically modified for this study considering the pharmacology of 
idelalisib. The individual and composite endpoints of response and progression 
(considering changes in lymph node area, liver and spleen size, bone marrow, platelet counts, 
hemoglobin, neutrophil counts, and peripheral blood lymphocyte counts) will be determined. 
Tumor control will be documented at each assessment by response category (eg, CR, PR, SD, 
definitive PD, NE, ND) as defined for each response parameter, SPD value, percentage change in 
SPD values from baseline or nadir, date that response is first documented and date of definitive 
CLL progression.
The date of definitive CLL progression will be the timepoint at which progression is 
first identified by relevant objective radiographic or laboratory data. Because of the characteristic 
redistribution lymphocytosis that is expected with PI3Kinhibition, lymphocyte count will be 
ignored in the evaluation of progression. Changes in tumor status as provided by the investigator 
and changes in tumor status as adjudicated by the IRC (see Section 10.4.2) will be described. 
The findings of the IRC will be considered primary for analyses of all tumor control endpoints.
The following censoring conventions will be applied:

PFS and DOR: Data from surviving, non-progressing subjects will be censored at the earliest 
of the time of initiation of antitumor treatment other than the study treatment or the last time 
that lack of definitive CLL progression was objectively documented. Data from subjects who 
have CLL progression or die after 2 consecutive missing tumor assessments will be 
censored at the last time prior to the missing assessments that lack of definitive CLL 
progression was objectively documented.

OS: Data from surviving subjects will be censored at the last time that the subject was known 
to be alive.
9.4.
Analysis Plan
9.4.1.
Subject Disposition and Baseline Characteristics
A listing of all ITT analysis subjects will be generated to describe site, subject number, 
first screening date, first treatment date, allocated study drug assignment, actual study drug 
assignment, the longest duration of study drug treatment, and the reason for discontinuing study 
treatment. Available information on subjects who were screened or registered but not treated will 
be listed separately. A table will be created summarizing these categories in terms of number and 
percent for the ITT analysis set.
Subject baseline characteristics will be listed and summarized by treatment arm for the 
ITT analysis set. As appropriate for the specific variable, subject baseline characteristics
acquired in Study GS-US-312-0116 will be referenced in Study GS-US-312-0117.


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9.4.2.
Efficacy Analyses
9.4.2.1.
Time-to-Event Tumor Control and Survival Endpoints
PFS, DOR and OS will be described in the ITT analysis set using Kaplan-Meier methods by 
treatment group. Medians, ranges, and corresponding 95% CIs will be presented.
The Cox regression approach may be used to explore the influence of the primary study 
stratification factors and other baseline characteristics on PFS and OS. The stratification 
variables from the primary study and additional baseline subject characteristics may be included 
as covariates, focusing on those with expected prognostic significance.
9.4.2.2.
Categorical Endpoints
Response rates, lymph node response rate, splenomegaly response rate, 
hepatomegaly response rate, ALC response rate, platelet response rate, hemoglobin response 
rate, and neutrophil response rate will be described. In the calculation of response rates, subjects 
who do not have sufficient baseline or on-study tumor assessment to characterize response will 
be included in the denominator. For all analyses, the corresponding 95% CIs will be presented.
The potential influence of subject baseline characteristics on response rates may be explored
with multiple logistic regression modeling.
9.4.2.3.
Continuous Endpoints
Changes in lymph node area and changes in performance status, PI3K/AKT/mTOR pathway 
activation, and plasma chemokines/cytokines will be assessed by treatment group. Both changes 
from baseline to each subsequent timepoint and best overall on-study changes will be analyzed 
using appropriate methods (eg, analysis of covariance [ANCOVA] or paired t-tests). Means and 
standard errors will be presented.
9.4.2.4.
Health-Related Quality of Life and Performance Status
The FACT-Leu questionnaire data will be scored and processed according to the user manual. 
Missing items in a subscale will be imputed consistent with the user manual instructions. Data 
collected from the FACT-Leu instrument will not be reconciled with adverse event or laboratory 
data or with EQ-D5 findings.
As a baseline, the last value obtained prior to receiving the first idelalisib dose of 
150 mg and 300 mg will be used, depending on the treatment group assigned.
The mean and change from baseline in mean scores to each subsequent assessment will be 
summarized for the FACT-Lym subscale and composite scores. The best change from baseline 
during the study, defined as the highest positive value among all post-baseline visits minus 
the baseline value, will also be summarized.


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9.4.3.
Exposure and Safety Analyses
9.4.3.1.
Treatment Administration and Study Drug Compliance
Descriptive information will be provided by treatment arm regarding the number of doses of 
study therapy prescribed, the total number of doses taken, the percent of expected doses taken, 
the number of days of treatment, and the number and timing of prescribed dose reductions and 
interruptions.
Study drug compliance will be described by treatment arm in terms of the proportion of study 
drug actually taken based on returned pill count relative to the amount that was dispensed 
(taking into account physician-prescribed reductions and interruptions).
9.4.3.2.
Idelalisib Plasma Concentrations
Bioanalytical analyses will performed independently so that the study team and investigators will 
not have knowledge of data from individual subjects. Idelalisib plasma concentrations 
immediately pre-dose and at 1.5 hours after administration of the dose of study drug at each 
relevant clinic visit will be summarized by treatment and visit using descriptive statistics.
9.4.3.3.
Prior, Concomitant, and Post-Treatment Medication Use
Prior, concomitant, and post-treatment medications will be coded by means of the 
World Health Organization Drug Dictionary (WHODRUG) dictionary into 
Anatomical-Therapeutic-Chemical classification (ATC) codes.
Descriptions of prior medication use will be focused on drugs and regimens used as treatments 
for CLL. Information regarding CLL therapy that was administered prior to 
Study GS-US-312-0116 will be referenced in reporting the results of Study GS-US-312-0117. In 
addition, relevant treatment administration information collected during Study GS-US-312-0116 
will be referenced in reporting the results of this study. As appropriate and if available, 
information on the sequencing, type, dose, schedule, timing, duration of use, and efficacy of 
prior regimens will be provided, focusing particularly on findings observed in 
Study GS-US-312-0116.
The type and timing of use of concomitant medications will be listed and summarized by type 
and treatment arm. Information regarding the type and use of specific supportive medications 
(eg, pneumocystis prophylaxis, hematopoietic growth factors, corticosteroids) during study 
treatment will be described.
The number, type, and timing of post-study-treatment regimens for CLL will be summarized by 
treatment arm, characterizing the disposition of all subjects who were eligible for post-study 
treatment and also those who were not eligible for post-study treatment (eg, subjects who are 
never treated at all, die while on study treatment, are still on study, are lost to follow-up, etc).


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9.4.3.4.
Adverse Events
All adverse events will be listed. The focus of adverse event summarization will be on 
treatment-emergent adverse events. A treatment-emergent adverse event is defined as an adverse 
event that occurs or worsens in the period from the first dose of study treatment to 30 days after 
the last dose of study treatment.
Adverse events will be classified using MedDRA (http://www.meddramsso.com) with 
descriptions by System Organ Class, High-Level Group Term, High-Level Term, 
Preferred Term, and Lower-Level Term. The severity of adverse events will be graded by the 
investigator according to the CTCAE, Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf), 
whenever possible. If a CTCAE criterion does not exist for a specific type of adverse event, the 
grade corresponding to the appropriate adjective will be used by the investigator to describe the 
maximum intensity of the adverse event: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), 
Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the adverse event to the study 
drug will be categorized as related or unrelated.
Treatment-emergent adverse events will be summarized by treatment arm and by visit. 
Summary tables will be presented to show the number of subjects reporting treatment-emergent 
adverse events by severity grade and corresponding percentages. A subject who reports multiple 
treatment-emergent adverse events within the same Preferred Term (or System Organ Class) is 
counted only once for that Preferred Term (or System Organ Class) using the worst severity 
grade. Adverse event descriptions will be presented by decreasing frequency for a given 
System Organ Class and Preferred Term.
Separate listings and summaries will be prepared for the following types of treatment-emergent 
adverse events:

Study-drug-related adverse events

Adverse events that are Grade 3 in severity

Adverse events leading to study drug interruption and/or dose modification

Adverse events leading to study drug discontinuation

Serious adverse events (with categorization of the primary reason that the adverse event is 
considered serious, eg, death, hospitalization, etc)
Separate listings and summaries will be prepared for long-term follow-up safety data 
(see Section 6.2.17).
9.4.3.5.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed data. 
The focus of laboratory data summarization will be on treatment-emergent laboratory 
abnormalities. A treatment-emergent laboratory abnormality is defined as an abnormality that, 


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compared to baseline, worsens by 1 grade in the period from the first dose of study drug to
30 days after the last dose of study drug. If baseline data are missing, then any graded 
abnormality (ie, an abnormality that is Grade 1 in severity) will be considered treatment 
emergent. Hematological, serum biochemistry, and urine data will be programmatically graded 
according to CTCAE severity grade, when applicable. For parameters for which a CTCAE scale 
does not exist, reference ranges from the central laboratory will be used to determine 
programmatically if a laboratory parameter is below, within, or above the normal range for the 
subject’s age, sex, etc.
Hematological and serum biochemistry and their changes from baseline will be summarized by 
treatment arm and by visit. Summary tables will be presented for each relevant assay to show the 
number of subjects by CTCAE severity grade with corresponding percentages. For parameters 
for which a CTCAE scale does not exist, the frequency of subjects with values below, within, 
and above the normal ranges will be summarized. Subjects will be characterized only once for a 
given assay, based on their worst severity grade observed during a period of interest 
(eg, during the study or from baseline to a particular visit).
Shift tables for hematology and serum biochemistry will also be presented by showing change in 
CTCAE severity grade from baseline to the worst grade post baseline. Separate listings and 
summaries will be prepared for laboratory abnormalities that are Grade 3 in severity.
9.4.3.6.
Oxygen Saturation Values
All oxygen saturation data will be listed. Summaries of oxygen saturation data will be based on 
observed data and will be reported as % saturation. Data and changes from baseline will be 
summarized by treatment arm and by visit. Summary tables will be presented for values 
below 92% and for declines from baseline of 5% to show the number of subjects with 
corresponding percentages. Subjects will be characterized only once for each of these 
categorizations, based on their lowest value observed during a period of interest 
(eg, during the study or from baseline to a particular visit).
9.4.4.
Other Analyses
9.4.4.1.
Between-Study Comparisons
It is expected that patients with a progressive malignancy like CLL will normally fare better with 
an earlier therapy than with a later therapy. However, if the converse situation proves true –
eg, if an investigational treatment (idelalisib) administered later shows similar or greater benefit 
than a standard treatment (rituximab) administered earlier – strong evidence of investigational 
drug effect is demonstrated. Evaluating data derived from the same study subjects during their 
sequential participation in 2 clinical trials offers unique analytical challenges. However, in this 
integrated Phase 3 study program, it is likely that comparing baseline characteristics and 
outcomes among Arm B subjects participating in Study GS-US-312-0116 and 
Study GS-US-312-0117 will be informative. Such an evaluation characterizes how the subjects
and the CLL disease process change with time and treatment. In addition, such an analysis 
provides relevant supporting information documenting the benefits of single-agent idelalisib
relative to single-agent rituximab in the same subjects.


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Accordingly, baseline characteristics, time-to-event efficacy variables (eg, PFS, TTR, DOR), 
categorical variables (eg, ORR, lymph node response rate, splenomegaly response rate, 
hepatomegaly response rate), and continuous variables (eg, percentage changes in 
lymph node area; changes in performance status, PI3K/AKT/mTOR pathway activation and 
plasma chemokines/cytokines)  may be evaluated between Study GS-US-312-0116 and 
Study GS-US-312-0117 for Arm B subjects.
9.4.4.2.
Health Care Resource Utilization
The EQ-D5 questionnaire data will be scored, processed, and standardized according to the user 
manual. Change from baseline in EQ-5D visual analogue scale and EQ-5D index will be 
summarized. As for the FACT-Leu, data will be analyzed using appropriate methods to account 
for incomplete completion of questionnaires. Data collected from the EQ-D5 will not be 
reconciled with adverse event or laboratory data or with FACT-Leu findings.
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach to the health economic analysis will be to combine the resource utilization 
data from the trial with data on unit prices (collected separately) to estimate total costs.
The perspective of this analysis will be that of the third-party payer(s) and the hospital over a 
lifetime horizon in the base case. The costs will be described relative to the health care findings 
as measured by duration of tumor control, the symptom-free survival period, life-years, utility 
outcomes, or other measure of appropriate clinical benefits. In order to facilitate the calculation 
of utilities for use in the cost effectiveness analyses, the health status of subjects will be 
evaluated using PFS, Karnofsky performance status, FACT-Leu, and EQ-5D.
9.4.4.3.
Data Explorations
Changes in biomarkers during acquisition of resistance will be evaluated descriptively. Data 
explorations may be performed to evaluate potential associations between subject characteristics 
and outcome measures. Explorations may be performed to assess the potential associations 
between different outcomes measures (eg, relationships between HRQL changes and 
clinical/radiographic endpoints of tumor control).
9.5.
Sample Size
The sample size for this extension study is not based upon a formal statistical hypothesis. The 
upper bound of the sample size in this study is determined by the sample size of the preceding 
primary study (Study GS-US-312-0116) in which ~220 subjects (~110 per arm) are expected to 
be enrolled. It is estimated that this extension study (Study GS-US-312-0117) will have a total 
idelalisib-treated N~180 (assuming a ~10% dropout rate during Study GS-US-312-0116 and a 
further ~10% dropout rate in the transition from the primary study to the extension study).


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9.6.
Timing of Analyses
The DMC will have access to serious adverse events requiring expedited reporting and will be 
provided with accumulating safety data on a regular basis. Interim safety reviews will be 
conducted by the DMC in conjunction with safety reviews of the primary clinical trial
(Study GS-US-312-0116) if applicable. Thus, interim safety reviews will be performed by the 
DMC at intervals of ~6 months; the specific frequency of these reviews will depend upon the 
rate at which the trials are enrolled, the nature of any emerging safety signals, and monitoring 
recommendations from the DMC. At each review, all available safety data will be summarized 
and evaluated.
An interim efficacy analysis of this clinical trial (Study GS-US-312-0117) is planned to take 
place at the time of the final blinded analysis of the primary study (GS-US-312-0116). The intent 
is to provide the data from this extension study in support of regulatory review of data from the 
primary study. An analysis of efficacy and safety may be performed to satisfy regulatory 
requirements and to perform long-term efficacy, safety and OS follow-up. The timing of the final 
analysis is expected to occur within 48 months of accrual of the final subject to 
Study GS-US-312-0117.


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
Compliance with Ethical and Regulatory Guidelines
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), with ICH guidelines, or with the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the study subject. These 
standards are consistent with the European Union Clinical Trials Directive 2001/20/EC and 
Good Clinical Practice Directive 2005/28/EC. The investigator will ensure adherence to the 
basic principles of GCP as outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and 
Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 1993, 
“Retention of Bioavailability and Bioequivalence Testing Samples.”
Because this is a “covered” clinical trial, the investigator will ensure adherence to 
21 CFR, Part 54, 1998; a covered clinical trial is any “study of a drug or device in humans 
submitted in a marketing application or reclassification petition subject to this part that the 
applicant or FDA relies on to establish that the product is effective (including studies that show 
equivalence to an effective product) or that make a significant contribution to the demonstration 
of safety.” This requires that investigators and all sub-investigators must provide documentation 
of their financial interest or arrangements with Gilead Sciences, or proprietary interests in the 
drug being studied. This documentation must be provided before participation of the investigator 
and any subinvestigator in the trial. The investigator or subinvestigator agrees to notify 
Gilead Sciences of any change in reportable financial interests during the study and for 1 year 
following completion of the study. Study completion is defined as the date that the last subject 
has completed the protocol-defined activities.
10.1.2.
Institutional Review Board/Independent Ethics Committee
This protocol and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) will be submitted by the investigator to an IRB (for sites enrolling in 
the United States) and to an IEC for sites enrolling outside of the United States). Approval from 
the IRB/IEC must be obtained before starting the study and should be documented in a letter to 
the investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.
Any modifications or amendments made to the protocol after receipt of the initial IRB/IEC
approval must also be submitted to the IRB/IEC for approval before implementation. Only 
changes necessary to eliminate apparent immediate hazards to the subjects may be initiated prior 
to IRB/IEC approval. In that event, the investigator must notify the IRB/IEC and Gilead Sciences
in writing within 5 working days after implementation.


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The investigator shall submit a progress report, at least once yearly, to the IRB/IEC, and must 
provide a copy to Gilead Sciences. As soon as possible after completion or termination of the 
study, the investigator will submit a final report to the IRB/IEC and to Gilead Sciences. This 
report should include the dates of initiation and completion of the trial, a description of any 
changes in study procedures or amendments to the protocol, any deviations from the protocol, 
the number and type of subjects evaluated, the number of subjects who discontinued 
(and the reasons for discontinuation), the number of subjects who completed the trial, and the 
results of the trial, including a description of any adverse events. Gilead Sciences will assist the 
investigator in the preparation of this report, as needed.
10.1.3.
Informed Consent
After adequately, explaining the aims, methods, objectives, and potential hazards of the study 
and before undertaking any study-related procedures, the investigator is responsible for obtaining 
written informed consent from each individual participating in this study. The investigator must 
utilize an IRB/IEC-approved consent form for documenting written informed consent. Each 
informed consent will be appropriately signed and dated by the subject or the subject’s legally 
authorized representative and the person obtaining consent.
The approved informed consent must not be changed without prior approval by Gilead Sciences
and the IRB/IEC.
10.1.4.
Confidentiality
The investigator must assure that each subject’s anonymity will be strictly maintained and that 
each subject’s identity is protected from unauthorized parties. Only subject initials, date of birth, 
and an identification code (but no subject names) should be recorded on any form or biological 
sample submitted to the Gilead Sciences or designees (eg, laboratories), or to the IRB/IEC.
However, sufficient information must be retained at the site to permit sample data and data in the 
database to be connected with the unique subject number assigned to each study participant.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the idelalisib investigator brochure, this protocol, eCRFs, the investigational new drug, 
and any other study information, remain the sole and exclusive property of Gilead Sciences
during the conduct of the study and thereafter. This information is not to be disclosed to any 
third party (except employees or agents directly involved in the conduct of the study or 
as required by law) without prior written consent from Gilead Sciences. The investigator further 
agrees to take all reasonable precautions to prevent the disclosure by any employee or agent of 
the study site to any third party or otherwise into the public domain.
10.1.5.
Study Files and Retention of Records and Biological Samples
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator’s study file, and 
(2) subject clinical source documents.


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The investigator’s study file will contain the protocol/amendments, eCRF and query forms, the 
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data referenced in the monitoring plan for the study, and should include 
sequential notes containing at least the following information for each subject:

Subject identification (name, date of birth, gender)

Documentation that subject meets eligibility criteria, eg, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria)

Participation in trial (including trial number)

Trial discussed and date of informed consent

Dates of all visits

Documentation that protocol-specific procedures were performed

Results of efficacy parameters, as required by the protocol

Start and end date (including dose regimen) of trial medication (including relevant drug 
dispensing and return information)

Record of all adverse events and other safety parameters (including start and end date, 
causality and intensity)

Concomitant medication (including start and end date and dose if relevant dose changes 
occur)

Date of trial completion and reason for discontinuation, if applicable
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (ie, the United States, Europe, 
or Japan) and until there are no pending or contemplated marketing applications in an 
ICH region; or, if no application is filed or if the application is not approved for such indication, 
until 2 years after the investigation is discontinued and regulatory authorities have been notified. 
Investigators may be required to retain documents longer if required by applicable regulatory 
requirements, by local regulations, or by an agreement with Gilead Sciences. The investigator 
must notify Gilead Sciences before destroying any clinical study records. The investigator will 
promptly notify Gilead Sciences in the event of accidental loss or destruction of any study 
records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead Sciences must be notified in advance.


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If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead Sciences
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site.
Biological samples including tissue and blood samples collected as a study procedure or as 
standard of care during study participation will be stored and maintained by the investigator until 
notification is received from Gilead Sciences that the retained samples and records no longer 
required. The investigator must obtain written permission from Gilead Sciences before disposing 
of any retained samples. The investigator should promptly notify Gilead Sciences in the event of 
accidental loss or destruction of any study samples. With the permission of Gilead Sciences, the 
retained samples may be transferred to an acceptable designee, such as another investigator, 
another institution, a contract storage site, or to Gilead Sciences.
10.1.6.
Case Report Forms
An eCRF is required and must be completed for each enrolled subject, with all required study 
data accurately recorded such that the information matches the data contained in medical records 
(eg, physicians’ notes, nurses’ notes, clinic charts, or other study-specific source documents). As 
required by the protocol, eCRFs should also be completed for those subjects who fail to complete 
the study (even during the screening period). If a subject withdraws from the study, the reason 
must be noted on the eCRF. If a subject is withdrawn from the study because of a 
treatment-limiting adverse event, thorough efforts should be made to clearly document the 
outcome.
The eCRFs for this study will exist within a Web-based electronic data capture (EDC) system. 
After the investigator or the investigator’s designees (eg, research coordinators) have been 
appropriately trained, they will be given access to the EDC system and will enter the data 
required by the protocol into the EDC system. Any change of data will be made via the 
EDC system, with all changes tracked by the system to provide an audit trail.
The eCRF must be completed and signed by the principal investigator or subinvestigator 
(as appropriate) within a reasonable time period after data collection. This signature serves to 
attest that the information contained in the eCRF is true.
10.1.7.
Drug Accountability
As described in the relevant section (see Section 5.2.7), the investigator is responsible for 
ensuring adequate accountability of all used and unused investigational medicinal product, 
placebos, and comparators. This responsibility includes acknowledgment of receipt of each 
shipment of study product (quantity and condition), subject dispensing records, and returned or 
destroyed study product. Dispensing records will document quantities received from 
Gilead Sciences and quantities dispensed to subjects, including lot number, date dispensed, 
subject identifier number, subject initials, and the initials of the person dispensing the 
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At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Sciences’ requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRB/IECs, 
and to regulatory authority or health authority inspectors. It is important that the investigator and 
relevant institutional personnel are available during monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, will be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB/IEC in 
accordance with local requirements. Except as noted in Section 10.1.2, IRB/IEC approval must 
be obtained before changes can be implemented.
10.2.2.
Communications with Regulatory Authorities
Gilead Sciences, working either directly or through designees, will assume responsibility for 
regulatory interactions with relevant regulatory authorities. Gilead Sciences will maintain an 
IND for idelalisib in support of the study in the United States and will maintain similar 
regulatory applications with other regulatory authorities, as required for conduct of the study. In 
fulfilling this responsibility, Gilead Sciences (or a designee) will collect, assemble, and 
communicate all required regulatory documents (eg, Form FDA 1572, investigator financial 
disclosure forms, protocol and protocol amendments, investigator brochures, informed consent 
documents, annual reports) as required by regulation. Gilead Sciences (or a designee) will also 
assume responsibility for adverse event reporting to regulatory authorities as described in 
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10.2.3.
Data Management
Electronic data capture will be used to enter study data eCRFs and to transfer the data into a 
study-specific electronic database. During the data collection process, automated quality 
assurance programs will be used to identify missing data, selected protocol violations, 
out-of-range data, and other data inconsistencies. Requests for data clarification or correction 
will be forwarded to the investigative site for resolution. As appropriate, eCRFs, listings, tables, 
and SAS datasets will be provided to the investigational sites for review.
Quality assurance and quality control systems will be implemented and maintained according to 
written standard operating procedures to ensure that the data are generated, recorded, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements. Data 
collection and storage systems will provide audit trail, security mechanisms, and electronic 
signature capabilities that meet the requirements of FDA Title 21 of CFR Part 11 regarding 
electronic records and electronic signatures.
Data security will be controlled through appropriate and specific restriction of access only to data 
and systems required by individual users to accomplish their roles in the data management 
process. Individual login and password protections will be employed at study sites and at 
Gilead Sciences or its designee. The database will exist on physically secured servers. Data 
backups will be done regularly and will be stored in separate facilities. Printed documents 
relating to the study will be secured when not under review.
10.2.4.
Study Reporting and Publication
Gilead Sciences may make information obtained during this study available in order to further 
the scientific or business needs of the company or as required by law or regulation. In this 
regard, Gilead Sciences may provide study information to private or public organizations 
(eg, business partners, collaborators, consultants, CROs, investors, other physicians who are 
conducting similar studies, funding organizations, regulatory authorities, or other 
government authorities).
Gilead Sciences will prepare a clinical study report for submission to relevant regulatory 
agencies. Gilead Sciences will ensure that the report meets the standards set out in the 
ICH Guideline for Structure and Content of Clinical Study Reports (ICH E3). An abbreviated 
report may be prepared in certain cases, as appropriate.
Gilead Sciences intends that the data from this study will be presented and published. 
Gilead Sciences will work in collaboration with the principal investigators in preparing 
presentations and writing manuscripts for publication.

Investigators may publish or present the results of the study generated by their individual site 
either with the advanced written consent of Gilead or > 2 years after the completion of this 
extension study (GS-US-312-0117) at all participating institutions.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information (see Section 10.1.4).


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The investigator will submit to Gilead Sciences any proposed publication or presentation along 
with the respective scientific journal or presentation forum prior to submission of the publication 
(at least 30 days prior to manuscripts and 15 days prior for abstracts and oral presentations). The 
investigator will comply with Gilead Sciences’ request to delete references to its confidential 
information (other than the study results) in any paper or presentation. If deemed necessary by 
Gilead Sciences, the investigator also agrees to withhold publication or presentation for an 
additional 60 days in order to obtain patent protection.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the eCRFs for consistency.
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.
10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences may conduct inspections or audits 
of the clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.
10.3.3.
Public Notification of Study Conduct
Consistent with Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and 
with requirements of the International Committee of Medical Journal Editors (ICMJE) as a 
condition of consideration for publication of study results, Gilead Sciences will be responsible 
for ensuring that this protocol is listed at the ClinicalTrials.gov website (or equivalent) and that 
information at the website relating to study design and conduct is appropriately updated during 
the course of the study. In order to facilitate this process, investigators will need to supply 
Gilead Sciences with appropriate contact information for study site personnel.
10.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authorities and IRB/IECs. In terminating the study, Gilead Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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10.4.
Study Committees
10.4.1.
Data Monitoring Committee
A DMC, operating autonomously from Gilead Sciences, the clinical investigators, and the SSC, 
will be responsible for providing independent recommendations to Gilead Sciences about 
evolving risk-benefit observed in the course of the study and any modifications required during 
the course of the study. The DMC will consist of a biostatistician and 2 physicians experienced 
in treating patients with lymphoid malignancies. The DMC will be chaired by one of these 
individuals. DMC members must not be actively involved in study design, conduct, or subject
accrual and must not have financial, proprietary, professional, or other interests that may affect 
impartial, independent decision-making. Specialists may be invited to participate as non-voting 
members at any time if additional expertise is desired. The DMC will formally interact with the 
external SSC members through the sharing of meeting minutes. Informal interactions between 
the DMC and external SSC members will be limited. The DMC will operate under a charter 
developed as a collaborative document between Gilead Sciences and the DMC. It is expected 
that the members of the DMC will be the same as those for the primary study 
(Study GS-US-312-0116). 
The primary responsibility of the DMC is to protect the safety and welfare of subjects 
participating in this clinical trial and to ensure the integrity of the clinical trial. In general, the 
DMC will be responsible for:

Reviewing the general progress of the study as regards subject accrual, study conduct, and 
protocol violations

Examining accumulated safety, efficacy, and other relevant data at prespecified points during 
the course of the study 

Reviewing major study design modifications prior to implementation of those modifications

Making recommendations concerning continuation, modification, interruption, or termination 
of each study

Advising the company on changes to informed consent documents

Proposing updates to the DMC monitoring plan, changes in the DMC membership, actions to 
be taken relating to conflict of interest or confidentiality breaches, the need for additional 
expertise during DMC deliberations, revisions to the DMC charter, or alterations in the 
support provided to the DMC

Providing expert advice to the Gilead Science medical monitor on an ad hoc basis regarding 
matters such as safety concerns or diagnostic evaluations in individual subjects
Based on the results of its deliberations during the course of the study, the DMC can recommend 
appropriate actions (eg, continuation of the study unchanged, continuation of the study with 
modifications in design or monitoring plan, interruption of study accrual, study termination).


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10.4.2.
Independent Review Committee
An IRC will be established to provide a blinded review of radiographic data and pertinent 
clinical data in order to provide expert interpretation of changes in tumor status. The IRC will 
include 1 independent board-certified radiologist and 1 independent board-certified 
hematologist or oncologist, and will be managed by a CRO selected by Gilead Sciences. The 
review of radiographic and clinical data by the IRC will be performed on an ongoing basis until 
the primary analysis . The specifics of the IRC’s processes and reading methods will be 
described in an independent review charter developed by the contracted imaging facility in 
conjunction with Gilead Sciences. The same organization that is providing IRC services for 
Study GS-US-312-0116 will provide IRC services for this study.


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11.
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12.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
Appendix 3.
Performance Status Scoring System
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D)
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Appendix 6.
Cumulative Illness Rating Scale (CIRS)
Appendix 7.
Schedule of Study Procedures


PPD
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Version 9.0 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
199 EAST .BLAINE STREET 
SEATTLE, WA98102 
STUDY ACKNOWLEDGEMENT 
A Phase 3, Double--Blind Extension Study Evaluating the Efficacy and Safety of 
Two Different Dose Levels of Single-Agenl Idelalisib (GS-1 J 0 I) for Previously Treated 
Chronic Lymphocytic Leukemia 
GS-US-312-0117, Version 9 (Amendment 8), 24 October 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this 8DDLO..Yal.'---------. 
Signature 
Dafe 
/ 
LNVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator 
Printed Name 
Date 
CONFIDENTIAL 
Page 152 
Signature 
Site Number 
24 October2016 


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Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
FACT-Leu (Version 4) 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
PHYSICAL WELL-BEING 
GPI 
I have a lack of energy . . . . . . . . . . . . . . . 
GPl 
l have nausea 
.... ............ 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
GP4 
I have pain ...... ..... , 
......... ......................... 
GP5 
l am bothered by side effects of treatment 
01'6 
I feel ill . 
. ···················· 
GP7 
1 am forced to spend time in bed 
SOCIAL/FAMILY WELL-BEING 
OS! 
I feel close to my friends ...... 
.................. 
GS1 
I get emotional support from my family 
GS3 
1 get support from my friends .... 
GS4 
My family has accepted my illness 
GS5 
1 am satisfied with family communication about my 
illness .................... 
GS6 
I feel close to my partner (or the person who is my main 
support) . 
QI 
Regardless o_fyour current level of sexual activity. please 
answer the following question. ffyou prefer not to answer it, 
please mark this box 0 and go to the next section. 
GS7 
I am satisfied with my sex life ......................................... 
Engh !l.h (Universal) 
C~nglu 1987, 1997 
Not 
A little 
Some-
Quite 
at all 
bit 
what 
a bit 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
Not 
A little 
Some-
Quite 
at all 
bit 
what 
a bit 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
19 Novcmlx:r 1007 
Page I of3 


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FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
EMOTIONAL WELL-BEING 
GEl 
I feel sad ..... ................................ , 
GE2 
I am satisfied with how I am coping with my illness .... 
GE3 
I am losing hope in the fight against my illness 
GE4 
I feel nervous 
................... , 
GE5 
I worry about dying . . . . . . . . . . . . . . . . . . . . . . . . 
GE6 
I worry that my condition will get worse 
FUNCTIONAL WELL-BEING 
GFI 
I am able to work (include work at home) 
GF2 
My work (include work at home) is fulfilling ... 
GF3 
I am able to enjoy life ...... 
................. , ...... 
GF4 
1 have accepted my illness ... ................. 
GF5 
1 am sleeping well 
................................. 
GF6 
I am enjoying the things 1 usually do for fun 
GF7 
I am content with the quality of my life right now 
Enghsh (Universal) 
Cop}'right 1987, 1997 
Not 
A little 
Some-
at all 
bit 
what 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Not 
A little 
Some-
at all 
bit 
what 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
19 November 1007 
Page 2 ofJ 


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FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
ADDITIONAL CONCERNS 
Not 
A little 
Some-
at all 
bit 
what 
BRM3 
I am bothered by fevers (episodes of high body 
temperature) 
...... ........ . 
0 
2 
Pl 
I have certai n parts of my body where I experience pain.... 
0 
2 
BRMl 
ES3 
LEU I 
THI 
Till 
Hll2 
BMT6 
Cl 
C6 
An7 
N3 
LEm 
LEU6 
BRM9 
I am bothered by the chills .. .......... ... . 
I have night sweats .............................. .. 
I am bothered by lumps or swelling in certain parts of 
my body (e.g., neck, armpits, or groin) 
I bleed easily . 
1 bruise easily . 
I feel weak all over. 
I get tired easily 
I am losing weight 
I have a good appetite .......... ............ .. 
I am able to do my usual activities 
I worry about getting infections ......................... . 
I feel uncertain about my future health .................... .. 
1 worry that I might get new symptoms of my illness 
I have emotional ups and downs 
LEU7 
I feel isolated from others because of my illness or 
treatment 
Enghsh (Universal) 
Cop}'right 1987, 1997 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
19 November 1007 
Page 3 ofJ 


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Appendix 3.
Performance Status Scoring System
Karnofsky Performance Status
General Description
Score
Specific Description
Able to carry on normal activity and 
to work; no special care needed.
100
Normal; no complaints;
no evidence of disease.
90
Able to carry on normal activity;
minor signs or symptoms of disease.
80
Normal activity with effort;
some signs or symptoms of disease.
Unable to work; able to live at home 
and care for most personal needs; 
varying amount of assistance 
needed.
70
Cares for self;
unable to carry on normal activity or to do active work.
60
Requires occasional assistance,
but is able to care for most of personal needs.
50
Requires considerable assistance and frequent medical care.
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly.
40
Disabled; requires special care and assistance.
30
Severely disabled;
hospital admission is indicated although death not imminent.
20
Very sick; hospital admission necessary;
active supportive treatment necessary.
10
Moribund; fatal processes progressing rapidly.
0
Dead


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Appendix 4.
EuroQoL-5 Dimensions (EQ-5D)
Sample


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Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Formulas for calculating the estimated creatinine clearance (eCcr) are provided in the table 
below. The formula appropriate to the units in which serum creatinine was measured and the 
subject’s gender should be used.
Cockcroft-Gault Formulas for Calculating Estimated Creatinine Clearance
Serum
Creatinine Units
Gender
Formula
mg/dL
Males
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1
72 subject serum creatinine [mg/dl]
Females
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 0.85
72 subject serum creatinine [mg/dl]
M/dL
Males
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.23
Subject serum creatinine [mg/dl]
Females
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.04
Subject serum creatinine [mg/dl]
Abbreviation: eCcr=estimated creatinine clearance


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Appendix 6.
Cumulative Illness Rating Scale (CIRS)
The CIRS used in this protocol is designed to provide an assessment of recurrent or ongoing 
chronic comorbid conditions, classified by 14 organ systems. Using the drop-down lists of 
organ-specific diagnoses, please select any conditions present in the study subject. If the subject
has a recurrent or ongoing chronic conditions that are not described in the list for a given organ 
system, please indicate the name of the conditions under “other chronic condition” for that organ 
system. Please take into account that CLL-induced discomfort, symptoms, or disability should 
not be considered. If additional explanation would be helpful, text comments may be inserted.
CIRS List of Comorbid Conditions
Organ System
Diagnosis
Comment
Cardiac
Chronic heart failure
Angina pectoris
Medically relevant arrhythmia
Valve dysfunction
Congenital heart disease
Cardiomyopathy
Myocarditis
Chronic pericarditis
Endocarditis
Other chronic cardiac condition:
Other chronic cardiac condition:
Vascular
Hypertension
Thrombosis
Peripheral diabetic microvascular disease
Peripheral artery disease
Aortic aneurysm
Aortitis
Raynaud disease
Vasculitis
Other chronic vascular condition:
Other chronic vascular condition


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Organ System
Diagnosis
Comment
Hematological/
immunological
Sickle cell anemia
Hemoglobinopathy
Polycythemia
Thrombocythemia
Hemophilia
Paroxysmal nocturnal hemoglobinuria
Thrombotic thrombocytopenic purpura
Dysfibrinogenemia
HIV
Other chronic hematological or 
immunological condition:
Other chronic hematological or 
immunological condition
Abbreviation: CIRS=Cumulative Illness Rating Scale
For each condition selected from the CIRS List of Comorbid Conditions, please rate the severity 
of that condition. For the severity rating, please use the scoring guidelines shown in the table 
below, considering the magnitude of symptoms, how manageable the condition is, and the extent 
of intervention required:
CIRS Rating Scale
Score
Severity
Findings
1
Mild
Mild discomfort, symptoms or disability
Easy to control
Requiring either no therapy/medication or only as needed
2
Moderate
Moderate  discomfort, symptoms or disability
Manageable
Requiring daily treatment or first-line therapy
3
Severe
Severe discomfort, symptoms or disability
Hard to control
Requiring second-line therapy or multiple medications
4
Extremely severe
Life threatening, permanently disabling disability, causing organ failure
Poorly manageable
Requiring urgent intervention or resistant to therapy
Abbreviation: CIRS=Cumulative Illness Rating Scale


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Appendix 7.
Schedule of Study Procedures
Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4 a
5a
6 a
7a
8 a
9 a
10 a
11 a
12 a
13 a
14 a
15 a
16+e
End
of
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28 Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30 days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Informed consent
X
CIRS assessment
X
β-HCG
(women of 
childbearing 
potential)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CLL peripheral 
blood evaluation
X
X
CLL serology
X
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HRQL/
healthy utility –
FACT-Leu/EQ-5D
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exam
(includes nodes, 
liver, spleen)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PPD


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Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4 a
5a
6 a
7a
8 a
9 a
10 a
11 a
12 a
13 a
14 a
15 a
16+e
End
of
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28 Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30 days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Oxygen saturation
(by pulse 
oximetry)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Circulating cells/
Immune 
monitoringb
X
X
X
X
X
X
X
X
X
X
X
X
X
Xb
Biomarkers
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Igsb
X
X
X
X
X
X
X
X
X
X
X
X
X
Xb
Study drug
administration in 
clinic
X
X
X
X
X
X
X
X
Idelalisib
pharmacokinetics c
X
X
X
X
X
X
X
X
Study drug
dispensing/
accounting c
X
X
X
X
X
X
X
X
X
X
X
Radiology 
assessment 
(CT/MRI)
X
Xf
Xf
Xf
Xf
Xf
Xf
X f,g
Bone marrow 
biopsy/
aspirate d
X
X
X
X
X
X
X
X
CMV viral loadh
X


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Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4 a
5a
6 a
7a
8 a
9 a
10 a
11 a
12 a
13 a
14 a
15 a
16+e
End
of
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28 Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30 days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
PJP prophylaxisi, j
Xi
Xj
CD4+ T-cell countj
(related to PJP 
prophylaxis)
Xj
Post-treatment 
CLL therapy
X
Long-term 
follow-up 
X
a
Following unblinding of the study, the visit schedule will be modified per Section 6.2 and Visits 3 – 15 may not be applicable for subjects who were randomized to idelalisib 
on Study GS-US-312-0116 or who were randomized to placebo on GS-US-312-0116 and have received 24 weeks cumulative treatment with idelalisib
b
Circulating cells/Immune monitoring  and Serum Igs should be performed at the the End of Study visit
c
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll following unblinding, may have idelalisib treatment (and associated PK testing) delayed at 
the Investigator’s discretion until the time of disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib treatment
d
At screening, to be performed at investigator discretion to determine extent of CLL involvement and bone marrow cellularity. Post-screening, to be performed to confirm 
response category in subjects with potential CR or to confirm a hematologically-based disease progression; if the subject does not otherwise meet criteria for CR or if the 
nature of PD does not require bone marrow confirmations, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate
e
Following unblinding, Visit 16+ may be completed prior to 48 weeks as subjects transition to a Q12 week visit schedule 
f
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the assessment should be done even if study drug has been interrupted
g
An end-of-study CT/MRI tumor assessment should be performed unless the subject already has radiographic confirmation of definitive disease progression < 4 weeks prior to 
study discontinuation
h
CMV viral load should be performed approximately every 4 weeks throughout idelalisib treatment.  If unequivocal clinical or laboratory evidence of CMV infection is 
present, the subject must interrupt idelalisib treatment and undergo effective antiviral treatment according to established clinical guidelines.
i
PJP prophylaxis:  subjects must receive trimethoprim-sulfamethoxazole or other established prophylaxis for PJP throughout the course of idelalisib treatment and for 2 to 6 
months after the last dose of idelalisib.  Subjects must permanently discontinue idelalisib upon diagnosis of PJP. Prophylaxis will continue for 2 to 6 months after the last dose of 
idelalisib and until the CD4+ T-cell count is documented to be >200 cells/mcL after idelalisib treatment ends. 
j
CD4+ T-cell countl (related to PJP prophylaxis):  PJP prophylaxis will continue until the CD4+ T-cell count is documented to be >200 cells/mcL after idelalisib treatment ends.
Abbreviations: -HCG=beta human chorionic gonadotropin, CIRS=chronic illness rating scale, CLL=chronic lymphocytic leukemia, CMV=cytomegalovirus, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy- Leukemia, HRQL= health-related quality of life, 
Ig=immunoglobulin, IWRS=interactive web response system, MRI= magnetic resonance imaging, PJP= Pneumocystis jirovecii pneumonia.

Prot_007.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and 
Safety of Two Different Dose Levels of Single-Agent Idelalisib
(GS-1101) for Previously Treated Chronic Lymphocytic Leukemia
A Companion Trial to Study GS-US-312-0116: A Phase 3, Randomized, 
Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of Idelalisib (GS-1101) in Combination with Rituximab for 
Previously Treated Chronic Lymphocytic Leukemia
Sponsor:
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102
USA
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
EudraCT Number:
101254
2011-006293-72
Indication:
Chronic Lymphocytic Leukemia 
Protocol ID:
GS-US-312-0117
Gilead Sciences
Medical Monitor:
Name:
Telephone:
Office Fax:
Mobile Telephone:
E-mail:
Protocol Version/Date:
Version 1.0 (Original)
23 January 2012
Version 2.0 (Amendment 1)
23 January 2013
Version 3.0 (Amendment 2)
10 September 2013
Version 4.0 (Amendment 3)
16 December 2013
Version 5.0 (Amendment 4)
27 May 2014
Version 6.0 (Amendment 5)
10 October 2014
Version 7.0 (Amendment 6)
28 March 2016
Version 8.0 (Amendment 7)
05 August 2016
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or under 
control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable institutional review board 
or independent ethics committee. This information is only to be used by you in connection with 
authorized clinical studies of the investigational drug described in the protocol. You must not 
disclose any of the information to others without written authorization from Gilead Sciences, Inc., 
except to the extent necessary to obtain informed consent from those persons to whom the drug may 
be administered.
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................6
LIST OF IN-TEXT FIGURES ......................................................................................................................................6
PROTOCOL SYNOPSIS ..............................................................................................................................................7
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................19
1.
INTRODUCTION ..............................................................................................................................................23
1.1.
Chronic Lymphocytic Leukemia............................................................................................................23
1.2.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies....................................................................24
1.3.
Idelalisib (formerly GS-1101)................................................................................................................25
1.3.1.
General Information .............................................................................................................25
1.3.2.
Safety Pharmacology............................................................................................................25
1.3.3.
Nonclinical Pharmacology and Metabolism.........................................................................26
1.3.4.
Toxicology ...........................................................................................................................27
1.3.5.
Idelalisib Clinical Studies.....................................................................................................27
1.4.
Summary and Justification for the Current Study ..................................................................................31
2.
STUDY DESIGN................................................................................................................................................34
2.1.
Design Overview and Study Schema .....................................................................................................34
2.2.
Design Rationale ....................................................................................................................................35
3.
OBJECTIVES AND ENDPOINTS ....................................................................................................................37
3.1.
Endpoints ...............................................................................................................................................37
3.1.1.
Tumor Control......................................................................................................................37
3.1.2.
Patient Well-Being ...............................................................................................................38
3.1.3.
Pharmacodynamic Markers of Drug Activity and Resistance..............................................39
3.1.4.
Exposure...............................................................................................................................39
3.1.5.
Safety....................................................................................................................................39
3.1.6.
Pharmacoeconomics.............................................................................................................39
3.2.
Endpoint Selection Rationale.................................................................................................................39
3.2.1.
Tumor Control Endpoints.....................................................................................................39
3.2.2.
Measures of Patient Well-Being...........................................................................................42
3.2.3.
Pharmacodynamic Markers of Drug Activity and Resistance..............................................43
3.2.4.
Assessments of Exposure .....................................................................................................45
3.2.5.
Evaluations of Safety............................................................................................................45
3.2.6.
Pharmacoeconomic Measures ..............................................................................................46
4.
SUBJECT POPULATION..................................................................................................................................47
4.1.
Number of Subjects................................................................................................................................47
4.2.
Subject Selection Criteria.......................................................................................................................47
4.2.1.
Inclusion Criteria..................................................................................................................47
4.2.2.
Exclusion Criteria.................................................................................................................49
4.3.
Enrollment Criteria Rationale ................................................................................................................50
5.
TREATMENT OF SUBJECTS ..........................................................................................................................51
5.1.
Enrollment..............................................................................................................................................51
5.1.1.
Interactive Web Response System .......................................................................................51
5.1.2.
Treatment Assignment .........................................................................................................51
5.1.3.
Blinding................................................................................................................................52


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5.2.
Investigational Study Drug (Idelalisib/Placebo) ....................................................................................53
5.2.1.
Description ...........................................................................................................................53
5.2.2.
Source...................................................................................................................................53
5.2.3.
Packaging and Labeling .......................................................................................................53
5.2.4.
Storage and Handling...........................................................................................................54
5.2.5.
Dispensing............................................................................................................................54
5.2.6.
Return...................................................................................................................................55
5.2.7.
Accountability......................................................................................................................55
5.2.8.
Overdose Precautions...........................................................................................................55
5.2.9.
Inadvertent Exposure and Spill Precautions.........................................................................56
5.3.
Study Drug Administration ....................................................................................................................56
5.3.1.
Premedication.......................................................................................................................56
5.3.2.
Administration Instructions..................................................................................................56
5.3.3.
Dosing Schedule...................................................................................................................56
5.3.4.
Dose Levels..........................................................................................................................56
5.3.5.
Dose Schedule Interruptions and Vomited Doses ................................................................57
5.3.6.
Safety Monitoring and Study Drug Interruption/Dose Modification ...................................57
5.4.
Evaluation, Intervention, and Drug Discontinuation for Specific Adverse Events or 
Conditions ..............................................................................................................................................62
5.4.1.
Dermatological Events .........................................................................................................62
5.4.2.
Gastrointestinal Events.........................................................................................................63
5.4.3.
Hepatic Events......................................................................................................................64
5.4.4.
Hematological and Immunological Events...........................................................................65
5.4.5.
Infectious Events..................................................................................................................65
5.4.6.
Progressive Multifocal Leukoencephalopathy .....................................................................66
5.4.7.
Pulmonary Events ................................................................................................................66
5.4.8.
Secondary Malignancies.......................................................................................................67
5.4.9.
Tumor Lysis Syndrome........................................................................................................67
5.4.10.
Pregnancy, Lactation, and Reproduction..............................................................................68
5.4.11.
Ultraviolet Exposure ............................................................................................................69
5.4.12.
Further Safety Information...................................................................................................69
5.5.
Emergency Unblinding ..........................................................................................................................69
5.6.
Concomitant and Supportive Therapy....................................................................................................70
5.6.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments............................................................................................................................70
5.6.2.
Antibiotics............................................................................................................................70
5.6.3.
Antiemetics and Antidiarrheals............................................................................................71
5.6.4.
Contraception .......................................................................................................................71
5.6.5.
Corticosteroids .....................................................................................................................72
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin..............................................72
5.6.7.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism..................................................73
5.6.8.
Drugs that undergo CYP3A-Dependent Metabolism...........................................................73
5.6.9.
Immunization .......................................................................................................................74
5.6.10.
Surgery .................................................................................................................................74
5.6.11.
Diet.......................................................................................................................................74
5.7.
Duration of Study Drug..........................................................................................................................74
5.8.
Discontinuation of Study Drug ..............................................................................................................74
5.9.
Discontinuation from Study ...................................................................................................................75
5.10.
Study Treatment Rationale.....................................................................................................................76
6.
STUDY PROCEDURES ....................................................................................................................................78
6.1.
Enrollment and Study Management Procedures ....................................................................................78
6.1.1.
Subject Recruitment .............................................................................................................78
6.1.2.
Subject Compensation for Participation...............................................................................78


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6.1.3.
Screening..............................................................................................................................78
6.2.
Explanation of Study Visits....................................................................................................................79
6.2.1.
Visit 1 and Screening Period (Clinic Visit)..........................................................................80
6.2.2.
Visit 2 (Day 1) (Clinic Visit)................................................................................................82
6.2.3.
Visit 3 (Day 15) (Clinic Visit)..............................................................................................83
6.2.4.
Visit 4 (Day 29) (Clinic Visit)..............................................................................................84
6.2.5.
Visit 5 (Day 43) (Clinic Visit)..............................................................................................86
6.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit) .....................................................................87
6.2.7.
Visit 7 (Day 71) (Laboratory Visit)......................................................................................88
6.2.8.
Visit 8 (Day 85) (Clinic Visit)..............................................................................................89
6.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit) ...................................................................91
6.2.10.
Visit 10 (Day 141) (Clinic Visit)..........................................................................................93
6.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit) .................................................................95
6.2.12.
Visit 12 (Day 211) (Clinic Visit)..........................................................................................97
6.2.13.
Visit 13 (Day 253) (Clinic and Radiology Visit) .................................................................98
6.2.14.
Visit 14 (Day 295) (Clinic Visit)..........................................................................................99
6.2.15.
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks) (Clinic 
and Radiology Visits).........................................................................................................100
6.2.16.
End-of-Study Visit (Clinic Visit) .......................................................................................102
6.2.17.
30 Day and Long-Term Follow-up.....................................................................................103
6.3.
Sample Storage.....................................................................................................................................103
6.4.
Blood Collection ..................................................................................................................................104
6.5.
Study Procedure Rationale...................................................................................................................104
7.
EFFICACY ASSESSMENTS...........................................................................................................................105
7.1.
Tumor Status Assessments...................................................................................................................105
7.2.
Method of Assessment .........................................................................................................................105
7.3.
Timing of Assessments ........................................................................................................................105
7.4.
Identification and Measurement of Tumor Lesions and Organomegaly ..............................................106
7.4.1.
Index Lesions .....................................................................................................................106
7.4.2.
Spleen and Liver.................................................................................................................107
7.4.3.
Non-Index Lesions .............................................................................................................107
7.5.
Definitions of Tumor Response and Progression.................................................................................107
7.5.1.
Complete Response............................................................................................................108
7.5.2.
Partial Response .................................................................................................................108
7.5.3.
Stable Disease ....................................................................................................................109
7.5.4.
Definitive Progressive Disease...........................................................................................109
7.5.5.
Non-Evaluable....................................................................................................................111
7.5.6.
No Disease .........................................................................................................................111
7.5.7.
Lymphocytosis During Therapy.........................................................................................112
7.5.8.
Documentation of Definitive CLL Progression..................................................................112
8.
SAFETY ASSESSMENTS...............................................................................................................................113
8.1.
Adverse Event Definitions ...................................................................................................................113
8.1.1.
Adverse Event ....................................................................................................................113
8.1.2.
Serious Adverse Event .......................................................................................................114
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .......................................................................115
8.2.
Assessment of Adverse Events and Serious Adverse Events...............................................................115
8.2.1.
Assessment of Causality for Study Drugs and Procedures.................................................116
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.....................................................................................................................116
8.4.
Gilead Reporting Requirements...........................................................................................................117
8.5.
Grading of the Severity of an Adverse Event.......................................................................................117


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8.6.
Adverse Event Reporting Period..........................................................................................................118
8.7.
Adverse Event Reporting Requirements ..............................................................................................118
8.7.1.
Site Reporting Requirements..............................................................................................118
8.7.2.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population.........................................................120
8.8.
Special Situations Reporting Requirements.........................................................................................120
8.8.1.
Definitions of Special Situations........................................................................................120
8.9.
Instructions for Reporting Special Situations.......................................................................................121
8.9.1.
Instructions for Reporting Pregnancies ..............................................................................121
8.9.2.
Reporting Other Special Situations ....................................................................................122
9.
STATISTICAL CONSIDERATIONS..............................................................................................................123
9.1.
Analysis Objectives..............................................................................................................................123
9.2.
Analysis Endpoints...............................................................................................................................123
9.3.
Analysis Conventions...........................................................................................................................123
9.3.1.
Analysis Sets ......................................................................................................................123
9.3.2.
Data Handling Conventions ...............................................................................................124
9.4.
Analysis Plan........................................................................................................................................126
9.4.1.
Subject Disposition and Baseline Characteristics...............................................................126
9.4.2.
Efficacy Analyses...............................................................................................................127
9.4.3.
Exposure and Safety Analyses ...........................................................................................128
9.4.4.
Other Analyses ...................................................................................................................130
9.5.
Sample Size..........................................................................................................................................131
9.6.
Timing of Analyses..............................................................................................................................132
10.
RESPONSIBILITIES........................................................................................................................................133
10.1.
Investigator Responsibilities ................................................................................................................133
10.1.1.
Compliance with Ethical and Regulatory Guidelines.........................................................133
10.1.2.
Institutional Review Board/Independent Ethics Committee ..............................................133
10.1.3.
Informed Consent...............................................................................................................134
10.1.4.
Confidentiality....................................................................................................................134
10.1.5.
Study Files and Retention of Records and Biological Samples..........................................134
10.1.6.
Case Report Forms.............................................................................................................136
10.1.7.
Drug Accountability...........................................................................................................136
10.1.8.
Inspections..........................................................................................................................137
10.1.9.
Protocol Compliance..........................................................................................................137
10.2.
Sponsor Responsibilities ......................................................................................................................137
10.2.1.
Protocol Modifications.......................................................................................................137
10.2.2.
Communications with Regulatory Authorities...................................................................137
10.2.3.
Data Management ..............................................................................................................138
10.2.4.
Study Reporting and Publication........................................................................................138
10.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................139
10.3.1.
Access to Information for Monitoring................................................................................139
10.3.2.
Access to Information for Auditing or Inspections ............................................................139
10.3.3.
Public Notification of Study Conduct ................................................................................139
10.3.4.
Study Discontinuation........................................................................................................139
10.4.
Study Committees ................................................................................................................................140
10.4.1.
Data Monitoring Committee ..............................................................................................140
10.4.2.
Independent Review Committee ........................................................................................141
11.
REFERENCES .................................................................................................................................................142
12.
APPENDICES ..................................................................................................................................................152


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Appendix 1.
Investigator Signature Page..................................................................................................153
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) ...................................154
Appendix 3.
Performance Status Scoring System.....................................................................................157
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D) ........................................................................................158
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance ............................................160
Appendix 6.
Cumulative Illness Rating Scale (CIRS) ..............................................................................161
Appendix 7.
Schedule of Study Procedures..............................................................................................163
LIST OF IN-TEXT TABLES
Table 4-1.
Required Screening Laboratory Values..................................................................................48
Table 5-1.
Study Drug Dose Levels.........................................................................................................57
Table 5-2.
Recommendations and Requirements for Study Drug Dose Modifications Based on 
Type and Severity of Treatment-Related Adverse Events or Laboratory 
Abnormalities .........................................................................................................................58
Table 5-3.
Protocol-Recommended Contraceptive Methods ...................................................................72
Table 5-4.
Known Strong Inducers of CYP3A........................................................................................73
Table 6-1.
Procedures and Assessments at Visit 1 (During Screening Period)........................................81
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1) .....................................................................82
Table 6-3.
Procedures and Assessments at Visit 3 (Day 15) ...................................................................83
Table 6-4.
Procedures and Assessments at Visit 4 (Day 29) ...................................................................84
Table 6-5.
Procedures and Assessments at Visit 5 (Day 43) ...................................................................86
Table 6-6.
Procedures and Assessments at Visit 6 (Day 57) ...................................................................87
Table 6-7.
Procedures and Assessments at Visit 7 (Day 71) ...................................................................88
Table 6-8.
Procedures and Assessments at Visit 8 (Day 85) ...................................................................89
Table 6-9.
Procedures and Assessments at Visit 9 (Day 113) .................................................................91
Table 6-10.
Procedures and Assessments at Visit 10 (Day 141) ...............................................................93
Table 6-11.
Procedures and Assessments at Visit 11 (Day 169) ...............................................................95
Table 6-12.
Procedures and Assessments at Visit 12 (Day 211) ...............................................................97
Table 6-13.
Procedures and Assessments at Visit 13 (Day 253) ...............................................................98
Table 6-14.
Procedures and Assessments at Visit 14 (Day 295) ...............................................................99
Table 6-15.
Procedures and Assessments at Visit 15 and Subsequent Visits (Day 337 and Every 
12 Weeks).............................................................................................................................100
Table 6-16.
Procedures and Assessments at End-of-Study Visit.............................................................102
Table 8-1.
Grading of Adverse Event Severity......................................................................................118
Table 8-2.
Site Reporting Requirements for Adverse Events ................................................................119
Table 8-3.
Contact Information for Reporting Serious Adverse Events ................................................120
LIST OF IN-TEXT FIGURES
Figure 2-1.
Study Design ..........................................................................................................................34
Figure 5-1.
Kaplan-Meler Time to Diarrhea or Colitis .............................................................................64


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102, USA
Study Title:
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and 
Safety of Two Different Dose Levels of Single-Agent Idelalisib
(GS-1101) as Therapy for Patients with Previously Treated Chronic 
Lymphocytic Leukemia
A Companion Study to Study GS-US-312-0116: A Phase 3, Randomized, 
Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of Idelalisib (GS-1101) in Combination with Rituximab as 
Therapy for Patients with Previously Treated Chronic Lymphocytic 
Leukemia
Study Centers 
Planned:
Approximately 90 centers in the United States and in Europe
IND Number:
EudraCT Number:
101254
2011-006293-72
Objectives:

To evaluate the effect of idelalisib (formerly GS-1101) on the onset, 
magnitude, and duration of tumor control

To compare tumor control in subjects receiving rituximab alone in 
Study GS-US-312-0116 to that observed in the same subjects when 
receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject well-being, 
including overall survival (OS), health-related quality of life 
(HRQL), and performance status

To assess the effects of idelalisib on disease-associated biomarkers 
and to evaluate potential mechanisms of resistance to idelalisib

To characterize exposure to idelalisib as determined by treatment 
administration and evaluation of idelalisib plasma concentrations 
over time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with 
administration of idelalisib


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Study Design:
This study is being conducted as part of an overall clinical program 
evaluating the efficacy and safety of idelalisib in the therapy of patients 
with previously treated chronic lymphocytic leukemia (CLL).
Within this program, the primary clinical trial (Study GS-US-312-0116)
is a Phase 3, multicenter, 2-arm, randomized, double-blind, 
placebo-controlled, parallel-group study.
This clinical trial (Study GS-US-312-0117) is a separate, multicenter, 
2-arm, double-blind, parallel-group extension study that is a companion 
trial to Study GS-US-312-0116; in this trial, compliant subjects from 
GS-US-312-0116 who are tolerating primary study therapy but 
experience definitive CLL progression are eligible to receive active 
blinded idelalisib therapy at the standard dose or a higher dose, with 
allocation based on the original primary study randomization. In the 
event GS-US-312-0116 is stopped early due to overwhelming efficacy 
following an interim analysis or at the final analysis, subjects who are on 
Study GS-US-312-0116 at that time may transition to GS-US-312-0117. 
Additionally, GS-US-312-0117 will become an open-label study
offering idelalisib 150 mg BID to GS-US-312-0116 subjects who were
randomized to placebo, and subjects randomized to idelalisib will 
continue idelalisib at 150 mg BID.
Study Schema:
Treatment Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117)


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Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID
Treatment Assignment

Assignment to Arm A or Arm B with allocation based on the 
original primary study randomization

Implementation through an interactive web response system (IWRS)
Stratification
Not applicable for Study GS-US-312-0117
Number of 
Subjects Planned:
Total of up to ~180 subjects (up to ~90 subjects per treatment arm)
Target 
Population:
Subjects in the primary Phase 3 study (GS-US-312-0116) who are 
compliant, are tolerating primary study therapy, and 1) have definitive 
progression of CLL while receiving primary study drug therapy 
(idelalisib/placebo) or 2) are actively participating in 
Study GS-US-312-0116 at the time the study is stopped, including if 
stopped early due to overwhelming efficacy following an interim analysis.
Duration of 
Treatment:
Study drug will be taken continuously until the earliest of subject 
withdrawal from study drug, definitive progression of CLL, intolerable 
study drug-related toxicity, pregnancy, substantial noncompliance with 
study procedures, or study discontinuation. Idelalisib administration will
be continued only in subjects whose benefit-risk profile is deemed 
positive by the investigator.
Diagnosis and 
Main Eligibility 
Criteria:
Inclusion Criteria
Subjects must meet all of the following conditions to be eligible for 
enrollment into the study:
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while 
receiving study drug therapy (idelalisib /placebo) in 
Study GS-US-312-0116. Note: Definitive disease progression is 
CLL progression based on standard criteria and occurring for any 
reason (ie, increasing lymphadenopathy, organomegaly, or bone 
marrow involvement; decreasing platelet count, hemoglobin, or 
neutrophil count; or worsening of disease-related symptoms) other 
than lymphocytosis. Subjects must have confirmation by the 
sponsor working in collaboration with an independent review 
committee (IRC) that the disease has progressed on the primary 


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clinical trial (Study GS-US-312-0116) before receiving secondary 
idelalisib therapy on this extension trial (Study GS-US-312-0117).
3) Presence of measurable lymphadenopathy (defined as the presence 
of ≥1 nodal lesion that measures 2.0 cm in the longest diameter 
[LD] and 1.0 cm in the longest perpendicular diameter [LPD] as 
assessed by computed tomography [CT] or magnetic resonance 
imaging [MRI]).
4) Permanent cessation of Study GS-US-312-0116 treatment 
(rituximab and/or idelalisib/placebo) and no intervening or 
continuing therapy (including radiotherapy, chemotherapy, 
immunotherapy, or investigational therapy) for the treatment of 
CLL. Note: Subjects may receive corticosteroids to manage CLL 
manifestations.
5) The time from permanent cessation of Study GS-US-312-0116 
treatment (rituximab and/or idelalisib/placebo) and the initiation of 
Study GS-US-312-0117 therapy is 12 weeks. Note: Study 
procedures performed as part of Study GS-US-312-0116 need not 
be repeated and can be used as screening procedures for 
Study GS-US-312-0117 if performed within 4 weeks prior to 
initiation of study drug therapy on Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation 
of study treatment) as shown in the table below. Note: Confirmation 
should be considered for out-of-range values to determine if the 
abnormality is real or artifactual. Values should be obtained within 
the screening period and should generally be the most recent 
measurement obtained. Subjects with any degree of neutropenia, 
thrombocytopenia, or anemia due to CLL or prior therapy may 
enroll.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCr
a
>30 ml/min
Pregnancy
-HCGb
Negative
a
As calculated by the Cockcroft-Gault formula {Cockcroft et al 1976}
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or 
urine dipstick pregnancy test must be negative at randomization (Visit 2)
Abbreviations: -HCG=beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
eCCr=estimated creatinine clearance, ULN=upper limit of normal


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8) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening 
visit (Visit 1) throughout the study and for 30 days from the last dose 
of study drug. Note: A female subject is considered to be of 
childbearing potential unless she has had a hysterectomy, bilateral 
tubal ligation, or bilateral oophorectomy; has medically 
documented ovarian failure (with serum estradiol and 
follicle-stimulating hormone [FSH] levels within the institutional 
postmenopausal range and a negative serum or urine -HCG), or 
is menopausal (defined as age ≥54 years with amenorrhea for 
>12 months or amenorrhea for >6 months with serum estradiol 
and FSH levels within the institutional postmenopausal range).
9) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of 
study drug (Visit 2) throughout the study and for 90 days following 
the last dose of study drug and to refrain from sperm donation from 
the start of study drug (Visit 2) throughout the study and for 90 days 
following the last dose of study drug. Note: A male subject is 
considered able to father a child unless he has had a bilateral 
vasectomy with documented aspermia or a bilateral orchiectomy, 
or has ongoing testicular suppression with a depot luteinizing 
hormone- releasing hormone (LH-RH) agonist 
(eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), 
or triptorelin pamoate [Trelstar®]).
10) In the judgment of the investigator, participation in the protocol 
offers an acceptable benefit-to-risk ratio when considering current 
CLL disease status, medical condition, and the potential benefits and 
risks of alternative treatments for CLL.
11) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, 
familial, or geographical factors that might preclude adequate 
study participation should be considered.
12) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study 
participation.


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Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be 
enrolled in this study:
1) Known histological transformation from CLL to an aggressive 
lymphoma (ie, Richter transformation). 
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at 
the time of the start of study treatment (Visit 2). Note: Subjects with 
localized fungal infections of skin or nails are eligible. Subjects 
may be receiving prophylactic antiviral or antibacterial therapies at 
the discretion of the investigator; anti-pneumocystis prophylaxis is 
encouraged. 
3) Pregnancy or breastfeeding.
4) Intentional breaking of the blind in Study GS-US-312-0116 by the 
investigator or the study subject.
5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical condition, 
surgical history, physical finding, electrocardiogram (ECG) finding, 
or laboratory abnormality that, in the investigator’s opinion, could 
adversely affect the safety of the subject or impair the assessment of 
study results.
In the event Study GS-US-312-0116 is stopped early, subjects who are 
actively participating in Study GS-US-312-0116 will become eligible for 
this study, provided the following inclusion are met:
1) Participation in Study GS-US-312-0116 within 12 weeks of 
enrollment onto GS-US-312-0117.
2) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening 
visit (Visit 1) throughout the study and for 30 days from the last dose 
of study drug. 
3) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of
study drug (Visit 2) throughout the study and for 90 days following 
the last dose of study drug and to refrain from sperm donation from 
the start of study drug (Visit 2) throughout the study and for 90 days 
following the last dose of study drug.
4) In the judgment of the investigator, participation in the protocol 
offers an acceptable benefit-to-risk ratio when considering current 
CLL disease status, medical condition, and the potential benefits and 
risks of alternative treatments for CLL.


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5) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, 
familial, or geographical factors that might preclude adequate 
study participation should be considered.
6) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study 
participation.
Study Procedures/
Frequency:
Clinic/laboratory visits will occur every 2 weeks for the first 12 weeks, 
every 4 weeks between Weeks 12 and 24, and every 6 weeks between 
Weeks 24 and 48. Subjects continuing on study drug past Week 48 will 
have clinic visits every 12 weeks. Subjects will be assessed for safety at 
each visit. Subjects will be assessed for CLL disease status by physical 
and laboratory examinations at each visit and by CT or MRI at 
Weeks 8, 16, 24, 36, and 48 and every 12 weeks thereafter.
Following unblinding of the study:

Subjects who were randomized to idelalisib on 
Study GS-US-312-0116 and who received ≥24 weeks idelalisib will 
complete Visit 16+ twelve weeks from the date of their last 
radiology assessment (CT/MRI) and study visits will continue every 
12 weeks thereafter. Visits 3 through 15 will not be required.

Subjects who have received < 24 weeks idelalisib will have all 
Study GS-US-312-0117 assessments completed per the 
Schedule of Procedures until they have received idelalisib for 
24 weeks cumulative across both studies. After completion of 
24 weeks of cumulative idelalisib treatment, Visit 16+ will be 
conducted 12 weeks from the date of their last radiology assessment 
(CT/MRI), after which time study visits will occur every 12 weeks.
Test Therapy, Dose, 
and Mode of 
Administration:
Blinded Portion

Arm A: Idelalisib, 300 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be provided 
as 2 tablets of active idelalisib for oral administration

Arm B: Idelalisib, 150 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be provided 
as 1 tablet of active idelalisib and 1 tablet of placebo for oral 
administration


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Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID
Note: At the Investigator’s discretion, subjects who were randomized 
to placebo on study GS-US-312-0116 may delay initiation of idelalisib 
following enrollment on Study GS-US-312-0117 until the time of 
disease progression or until the investigator determines that the 
subject would benefit from initiation of idelalisib treatment
Reference Therapy, 
Dose, and Mode of 
Administration:
Not applicable
Criteria for 
Evaluation:
Tumor Control

Progression-free survival (PFS) – defined as the interval from the 
start of study therapy to the earlier of the first documentation of 
definitive disease progression or death from any cause; definitive 
disease progression is CLL progression based on standard criteria 
other than lymphocytosis alone

Overall response rate (ORR) – defined as the proportion of subjects 
who achieve a complete response (CR) or partial response (PR)

Lymph node response rate – defined as the proportion of subjects 
who achieve a 50% decrease from baseline in the sum of the 
products of the greatest perpendicular diameters (SPD) of index 
lesions

CR rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from start of study 
therapy to the first documentation of CR or PR

Duration of response (DOR) – defined as the interval from the 
first documentation of CR or PR to the earlier of the first 
documentation of definitive disease progression or death from any 
cause

Percent change in lymph node area – defined as the percent change 
from baseline in the SPD of index lymph nodes

Splenomegaly response rate – defined as the proportion of subjects 
with baseline splenomegaly who achieve an on-study normalization 
or a 50% decrease (minimum 2 cm) from baseline in the 
enlargement of the splenic LVD (by imaging)


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
Hepatomegaly response rate – defined as the proportion of subjects 
with baseline hepatomegaly who achieve an on-study normalization 
or a 50% decrease (minimum 2 cm) from baseline the hepatic 
longest vertical dimension (LVD) (by imaging)

ALC response rate – defined as the proportion of subjects with 
baseline lymphocytosis (ALC4 x 109/L) who achieve an on-study 
ALC <4 x 109/L or demonstrate a 50% decrease in ALC from 
baseline (ALC values within 4 weeks post-baseline will be excluded 
from the ALC response rate evaluation)

Platelet response rate – defined as the proportion of subjects with 
baseline thrombocytopenia (platelet count <100 x 109/L) who 
achieve an on-study platelet count 100 x 109/L or demonstrate a 
50% increase in platelet count from baseline without need for 
exogenous growth factors (Platelet values within 4 weeks 
post-baseline or within 8 days post transfusion will be excluded from 
the platelet response rate evaluation)

Hemoglobin response rate – defined as the proportion of subjects 
with baseline anemia (hemoglobin <110 g/L [11.0 g/dL]) who 
achieve an on-study hemoglobin 110 g/L (11.0 g/dL) or 
demonstrate a 50% increase in hemoglobin from baseline without 
red blood cell transfusions or need for exogenous growth factors 
(eg erythropoietin)

Neutrophil response rate – defined as the proportion of subjects with 
baseline neutropenia (absolute neutrophil count [ANC] ≤1.5 x 109/L) 
who achieve an ANC >1.5 x 109/L or demonstrate a 50% increase 
in ANC from baseline without need for exogenous growth factors 
(eg, G-CSF)
Patient Well-Being

Overall survival (OS) – defined as the interval from start of study 
therapy to death from any cause

Change from baseline in HRQL domain and symptom scores based 
on the Functional Assessment of Cancer Therapy: 
Leukemia (FACT-Leu) (See Appendix 2)

Changes from baseline in Karnofsky performance status 
(See Appendix 3)
Pharmacodynamic Markers of Drug Activity and Resistance

Changes from baseline in PI3K/AKT/mTOR pathway activation as a 
measure of PI3Kpathway activity

Changes from baseline in the plasma concentrations of 
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Exposure

Study drug administration as assessed by prescribing records and 
compliance as assessed by quantification of used and unused drug

Trough (pre-dose) and peak (~1.5-hour samples) of idelalisib plasma 
concentrations as assessed by a validated bioanalytical method
Safety

Overall safety profile of each regimen characterized by the type, 
frequency, severity, timing of onset, duration, and relationship to 
study therapy of any adverse events or abnormalities of laboratory 
tests; serious adverse events; or adverse events leading to 
discontinuation of study drug
Pharmacoeconomics

Change in health status – defined as the change from baseline in 
overall health and single-item dimension scores as assessed using the 
EuroQoL Five-Dimension (EQ-5D) utility measure

Health resource measures, including resource utilization, total costs, 
and measures of cost per unit of benefit (eg, cost per additional 
progression-free month, cost per quality-adjusted life-year)
Statistical Methods:
Appropriate data analysis sets will be defined. The intent-to-treat (ITT) 
analysis set will include data from all subjects who receive 1 dose of 
any study therapy on this study; in this data set, study drug assignment 
(high-dose or standard-dose idelalisib) will be designated according to 
the planned allocation to this study. A safety analysis set will comprise 
data from subjects in the ITT analysis set with treatment assignments 
designated according to the actual study drug (high-dose or 
standard-dose idelalisib) received. Other analysis sets [per-protocol (PP) 
and pharmacodynamic/pharmacokinetic analysis sets] will be used for 
certain analyses as well.
Subject characteristics and study results will be described and 
summarized by treatment arm and assessment for the relevant analysis 
sets. Descriptive summaries will be prepared to show sample size, mean, 
standard deviation, 95% confidence intervals (CIs) on the mean, median, 
minimum, and maximum for continuous variables and counts, 
percentages, and 95% CIs on the percentage for categorical variables.
An independent review committee (IRC) will review radiographic data 
and pertinent clinical data in order to provide expert evaluation of tumor 
status. The findings of the IRC will be considered primary for analyses 
of PFS and other tumor control endpoints.


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For endpoints relating to tumor control, patient well-being, and 
biomarkers, analyses will be done based on ITT, PP or 
pharmacodynamic data sets, as appropriate. Blinded portion of the study 
analyses will be presented in the following two groups:

IDELA 300 mg BID: Subjects who have PD per IRC confirmation in 
Arm A of Study GS-US-312-0116 and subsequently enroll into 
Study GS-US-312-0117 to receive IDELA 300 mg BID during the 
double-blind portion of the study

Placebo in GS-US-312-0116 + IDELA 150 mg BID in 
GS-US-312-0117: Subjects who have PD per IRC confirmation in 
Arm B of Study GS-US-312-0116 and subsequently enroll in 
Study GS-US-312-0117 to receive IDELA 150 mg BID during the 
double-blind portion of the study.
After unblinding, open-label extension study analyses will be presented 
in the following 4 groups:

IDELA 150 mg BID: Subjects who are randomized to Arm A in 
Study GS-US-312-0116 and transition to Study GS-US-312-0117 
during the open-label portion of the study to continue IDELA 
150 mg BID

Placebo in GS-US-312-0116 + IDELA 150 mg BID (open-label): 
Subjects who are randomized to Arm B in Study GS-US-312-0116 
and transition to receive IDELA 150 mg BID during the open-label 
portion of the study

IDELA 300 mg BID: Subjects who have PD per IRC confirmation in 
Arm A of Study GS-US-312-0116 and subsequently enroll 
Study GS-US-312-0117 to receive IDELA 300 mg BID during the 
double-blind portion of the study

Placebo in GS-US-312-0116 + IDELA 150 mg BID in 
GS-US-312-0117: Subjects who have PD per IRC confirmation in 
Arm B of Study GS-US-312-0116 and subsequently enroll 
Study GS-US-312-0117 to receive IDELA 150 mg BID during the 
double-blind portion of the study. Analyses will focus on evaluation 
of outcomes within each treatment arm and will be descriptive in 
nature; formal comparisons of outcomes between arms are not 
planned. Time-to-event endpoints will be summarized using 
Kaplan-Meier methods; medians, ranges, and the corresponding 
95% CI will be presented. Continuous and categorical variables will 
also be summarized as appropriate. Changes from baseline in 
categorical variables and changes from baseline in continuous 
endpoints will be analyzed using appropriate methods.


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Efficacy outcomes among subjects receiving rituximab alone in 
Study GS-US-312-0116 will be evaluated relative to those same 
outcomes among the same subjects receiving standard-dose idelalisib 
alone in Study GS-US-312-0117. 
Based on the safety analysis set, information regarding study drug 
administration, study drug compliance, safety variables, and post-study 
therapies will be described and summarized. Using data from the 
pharmacokinetic analysis set, idelalisib plasma concentrations will also 
be described and summarized.
Sample Size Calculation
The sample size for this extension study is not based upon a formal 
statistical hypothesis. The upper bound of the sample size in this study is 
determined by the sample size of the preceding primary clinical trial
(Study GS-US-312-0116) in which ~180 subjects (~90 per arm) are 
expected to be enrolled. Assuming a ~10% dropout rate during 
Study GS-US-312-0116 and a further ~10% dropout rate in the 
transition from the primary study to the extension study, ~180 subjects 
are expected to be enrolled into Study GS-US-312-0117.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP), 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
-HCG
Beta human chorionic gonadotropin
ABCG2
adenosine triphosphate-binding cassette sub-family G member 2 (see also BCRP)
AKT
AKT (a serine/threonine protein kinase)
ALC
absolute lymphocyte count
ALL
acute lymphocytic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
ATC
Anatomical-Therapeutic-Chemical classification system for drugs 
BCRP
breast cancer resistance protein (see also ABCG2)
BID
twice per day
BTK
Bruton tyrosine kinase
CAL-101
Former name for GS-1101
CCL
chemokine (C-C motif) ligand
CFR
Code of Federal Regulations
CI
confidence interval
CIRS
Cumulative Illness Rating Scale
CLL
chronic lymphocytic leukemia
cGMP
current Good Manufacturing Practice
Cmax
maximum concentration
CMV
cytomegalovirus
CR
complete response
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough concentration
CXCL
chemokine (C-X-C motif) ligand
CYP
cytochrome P450 enzyme
DLCO
diffusing capacity of the lung for carbon monoxide
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DOR
duration of response
DSPH
Gilead Sciences Department of Safety and Public Health
ECG
electrocardiogram


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eCCr
estimated creatinine clearance
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EQ-5D
EuroQoL Five-Dimension utility measure
FACT-Leu
Functional Assessment of Cancer Therapy: Leukemia questionnaire
FCεRI
high-affinity IgE receptor
FDA
United States Food and Drug Administration
FDAMA
Food and Drug Modernization Act
FDG
fluorodeoxyglucose (18F)
FISH
fluorescence in-situ hybridization,
FSH
follicle-stimulating hormone
G-CSF
granulocyte colony-stimulating factor
GGT
gamma-glutamyltransferase
GLP
Good Laboratory Practice
GM-CSF
granulocyte-macrophage colony-stimulating factor
HBc antibody
anti-hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
hERG
human ether-à-go-go-related gene
HL
Hodgkin lymphoma
HIV
human immunodeficiency virus
HRQL
health-related quality of life
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
idelalisib
formerly CAL-101 and GS-1101
IEC
independent ethics committee
Ig
immunoglobulin (including subtypes A, E, G, and M)
IgHV
immunoglobulin heavy chain variable region
IND
Investigational New Drug (application)
iNHL
indolent non-Hodgkin lymphoma
INR
international normalized ratio
IRB
institutional review board
IRC
independent review committee
ITT
intention to treat
IUD
intrauterine device
IWCLL
International Workshop on CLL
IWRS
interactive web response system
JAK
Janus kinase


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K2-EDTA
potassium-ethylenediaminetetraacetic acid
LD
longest diameter
LDH
lactate dehydrogenase
LH-RH
luteinizing hormone-releasing hormone
LLN
lower limit of normal
LPD
longest perpendicular diameter
LVD
longest vertical dimension
MTD
maximum tolerated dose
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mTOR
mammalian target of rapamycin
ND
no disease
NHL
non-Hodgkin lymphoma
NOAEL
no-observed-adverse effect level
NOEL
no-observed-effect level
OCT
organic cation transporter
ORR
overall response rate
OS
overall survival
pAKT
phosphorylated AKT
PCR
polymerase chain reaction
PD
progressive disease
PET
positron-emission tomography
PFS
progression-free survival
PI3K
phosphatidylinositol 3-kinase
PI3K
phosphatidylinositol 3-kinase p110isoform
PJP
Pneumocystis jiroveci pneumonia
PML
progressive multifocal leukoencephalopathy
PP
per-protocol
PPD
product of the perpendicular diameters
PRO
patient-reported outcome
PR
partial response
PT
prothrombin time
PVA
polyvinyl alcohol
PVC/PCTFE
polyvinyl chloride/polychlorotrifluoroethylene
QD
once per day
QT (interval)
measure of time between start of Q wave and end of T wave in electrical cycle of heart
RNA
ribonucleic acid
SADR
serious adverse drug reaction
SD
stable disease


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SPD
sum of the products of the perpendicular diameters of measured lymph nodes
SSC
study steering committee
SJS
Stevens-Johnson Syndrome
SUSAR
suspected, unexpected, serious adverse reaction
SYK
spleen tyrosine kinase
t1/2
half-life
TEN
Toxic Epidermal Necrolysis
Tmax
time of maximum concentration
TTR
time to response
UGT
uridine 5'-diphospho-glucuronosyltransferase
ULN
upper limit of normal
WHODRUG
World Health Organization Drug Dictionary
ZAP-70
zeta-associated protein 70


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1.
INTRODUCTION
1.1.
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is a neoplasia resulting from the progressive accumulation 
of functionally incompetent monoclonal B lymphocytes in blood, bone marrow, lymph nodes, 
spleen, and liver {Dighiero et al 2008}. CLL constitutes the most commonly occurring leukemia 
in Europe and the United States {Sant et al 2010}, {Surveillance Epidemiology and End Results 
(SEER) Program 2011}. While some patients never require treatment, many will need therapy 
for disfiguring or obstructing lymphadenopathy, debilitating constitutional B symptoms 
(fevers, night sweats, fatigue, weight loss) {Redaelli et al 2004}, or recurrent cytopenias and 
infections {Perkins et al 2002}, {Keating et al 2002b}. CLL is largely a disease of the elderly; at 
diagnosis, 70% of patients are 65 years of age and the median age is 72 years {Surveillance 
Epidemiology and End Results (SEER) Program 2011}.
In younger and relatively healthy patients with CLL, chemoimmunotherapy regimens that 
include the anti-CD20 monoclonal antibody, rituximab, are commonly employed to control 
disease manifestations {Gribben et al 2011}. Such combination therapies are effective in 
providing durable remissions {Byrd et al 2005}, {Hallek et al 2010}, {Robak et al 2010}, 
{Fischer et al 2011}, {Iannitto et al 2011}. However, while rituximab is usually well tolerated 
{Gentile et al 2010}, the chemotherapeutic agents (typically fludarabine, cyclophosphamide, 
or bendamustine) in such regimens are acutely cytotoxic, induce permanent bone marrow 
compromise, and can cause secondary malignancies {Kyasa et al 2004}, {Tam et al 2008}, 
{Carney et al 2010}. Furthermore, in elderly patients or in those with comorbid conditions, such 
regimens are associated with less efficacy and greater toxicity {Tam et al 2008}, {Eichhorst et al 
2009b}, {Goede et al 2011}.
Increasing attention has been paid to the problem of treating patients with CLL who have 
comorbidities. Because of the relatively late age of diagnosis, a large proportion (~90%) of 
patients with CLL have co-morbidities and a substantial proportion (~45%) have major chronic 
conditions such as coronary artery disease, diabetes, or chronic obstructive pulmonary disease 
{Thurmes et al 2008}. At the time the disease is first identified, ~25% of patients with CLL do 
not meet conventional criteria for participation in clinical studies containing cytotoxic agents 
{Thurmes et al 2008}. By the time treatment is necessary or during treatment for CLL, patients 
continue to advance in age and have new or worsening chronic conditions; as a result, the 
proportion of patients with comorbidities increases during the course of the illness. Such patients 
have been substantially underrepresented in clinical trials due to concerns regarding the ability of 
such patients to tolerate intensive chemoimmunotherapy {Thurmes et al 2008}, {Eichhorst et al 
2009a}. Instruments such as the Cumulative Illness Rating Scale (CIRS) {Linn et al 1968} are 
now being applied in order to categorize patient populations as fit or relatively unfit and to 
evaluate regimens tailored to these groups of patients {Eichhorst et al 2009a}, {Hallek et al 
2010}, {Del Giudice et al 2011}.


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Health constraints in older or compromised patients have prompted noncytotoxic approaches to 
therapy. Alternative immunotherapeutics, such as the monoclonal antibodies, alemtuzumab
{Keating et al 2002a} or ofatumumab {Wierda et al 2010}, have been developed. However the 
therapeutic utility of these drugs is modest; median progression-free survival (PFS) values in 
patients with recurrent CLL have been 4.7 months and 5.8 months, respectively. Moreover, these 
treatments can have clinical liabilities. Alemtuzumab causes extreme immunosuppression that 
leads to frequent opportunistic infection. Administration of the large amounts of protein 
recommended in ofatumumab product labeling results in frequent infusion reactions and 
cumbersome infusion schedules.
In view of these issues, repeated use of rituximab monotherapy or rituximab-corticosteroid 
combinations have been advocated in treatment guidelines for older or frail patients with 
recurrent CLL {Eichhorst et al 2010}, {Zelenetz et al 2011}. While single-agent rituximab use 
can offer palliative benefit with good tolerability in some patients with previously treated CLL, 
tumor control is not lasting, especially in patients with bulky adenopathy {Gentile et al 2010}. 
Addition of high-dose corticosteroids to rituximab can extend median PFS up to 12 months, but 
this combination is commonly associated with severe hyperglycemia and frequent 
life-threatening or fatal infections {Bowen et al 2007}, {Dungarwalla et al 2008}. New,
noncytotoxic, well-tolerated, and convenient therapies that can successfully be combined with 
rituximab or given as single-agent therapy are needed in order to enhance and prolong tumor 
control in patients with comorbid conditions.
1.2.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies
Phosphatidylinositol 3-kinases (PI3Ks) are enzymes that regulate several cellular functions 
including motility, proliferation, and survival {Okkenhaug et al 2003b}. PI3K activation recruits 
and activates numerous intracellular signaling enzymes. The most important of these is the 
serine/threonine kinase, AKT, which mediates a positive pleiotropic effect on cell survival, 
proliferation, growth, and metabolism {Engelman et al 2006} acting by signaling through 
mammalian target of rapamycin (mTOR) {Hay 2005}, {Osaki et al 2004}.
PI3K signaling is mediated by 4 catalytic isoforms of the p110 subunit of the enzyme - , , , 
and . While potentially important in multiple cell types, PI3K p110(PI3K) shows an 
expression pattern that is particularly prominent in cells of hematopoietic origin 
{Vanhaesebroeck et al 2005}. Mice deficient in PI3Khave no gross abnormalities, are fertile, 
fecund, and live a normal life span without an increased susceptibility to infections {Okkenhaug 
et al 2003a}. However, the B-lymphocyte population in these animals shows a decrease in
maturation, diminished receptor-induced proliferation, and increased susceptibility to apoptotic 
cell death. Conversely, mice with aberrantly elevated PI3K signaling develop lymphadenopathy 
and have an increased incidence of lymphoma {Donahue et al 2004}. In CLL, sustained 
activation of the PI3K/AKT/mTOR pathway has been shown to promote malignant B-cell 
survival through mechanisms that are dependent on the PI3Kisoform {Cuni et al 2004}, 
{Herman et al 2010}, {Lannutti et al 2011}.


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Knowledge of the critical importance of PI3Kδ in B-cell biology and neoplasia has encouraged a 
search for inhibitors of this enzyme that could provide new options in the therapy of lymphoid 
malignancies, including CLL.
1.3.
Idelalisib (formerly GS-1101)
1.3.1.
General Information
Idelalisib was approved in the US on July 23, 2014 and in the European Union on 
September 18, 2014. Refer to local labeling for the approved indication statements and dosing 
recommendations.
Gilead Sciences, Inc has developed novel drugs that can suppress tumor growth through 
targeting of PI3Kδ activity. High-throughput screening was the basis for the discovery of novel 
agents that selectively inhibit PI3Kfunction but spare other PI3K isoforms and other kinases. 
Chemical optimization, pharmacological characterization, and toxicological evaluation have led 
to identification of idelalisib (also known as GS-1101), a 415-dalton, orally bioavailable, 
new chemical entity with potential clinical utility in the treatment of cancers.
In primary tumor samples and in cell lines derived from patients with CLL, indolent 
non-Hodgkin lymphoma (iNHL), mantle cell lymphoma (MCL), B-cell acute lymphocytic 
leukemia (ALL), or Hodgkin lymphoma (HL), idelalisib induces dose-dependent reductions in 
AKT phosphorylation {Herman et al 2010}, {Meadows et al 2010}, {Lannutti et al 2011}. In 
addition, idelalisib disrupts the PI3Kactivation and supportive intercellular signaling observed 
when CLL or HL cells are cocultured with stromal cells {Meadows et al 2010}, {Hoellenriegel 
et al 2011}. These effects have therapeutic consequences. In multiple lymphoid primary tumors
and malignant cell lines, idelalisib enhances apoptosis and concentration-dependent cell killing 
when applied as a single agent and increases the therapeutic efficacy of other antineoplastic 
agents when given in combination {Hoellenriegel et al 2011}, {Meadows et al 2011}. In 
preclinical systems, coadministration of idelalisib with rituximab has not impaired 
rituximab-mediated activity {Herman et al 2010}.
1.3.2.
Safety Pharmacology
In vitro and in vivo safety pharmacology studies with idelalisib have demonstrated a favorable 
non-clinical safety profile. These studies indicate that the drug may minimally slow bone marrow 
progenitor proliferation and differentiation and that it has expected inhibitory effects on 
B-cell response to antigen challenge. However, the data indicate that idelalisib is unlikely to 
cause serious off-target effects or adverse effects on critical organ systems. Idelalisib has no 
meaningful effect on the human ether-à-go-go-related gene (hERG) channel, indicating that 
idelalisib would not be expected to induce clinical QT prolongation.
The drug has also proved well tolerated in standard in vivo Good Laboratory Practice (GLP) 
studies of pharmacological safety. A functional observation battery in rats revealed no adverse 
effects on behavior or on autonomic, neuromuscular, or sensorimotor function. In a 
cardiopulmonary function study in awake, telemeterized male beagle dogs, single doses of 


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idelalisib induced no meaningful abnormalities in pulmonary, cardiovascular, arterial blood gas, 
or electrocardiographic (ECG) (including QT interval) parameters. In an assessment of bacterial 
challenge in rats, idelalisib enhanced, rather than impaired, the phagocytic host clearance of 
staphylococcal bacteria.
1.3.3.
Nonclinical Pharmacology and Metabolism
Consistent with the moderate to high bioavailability seen in nonclinical species, idelalisib shows 
high permeability across human Caco-2 cell monolayers.  At lower concentrations, the reverse 
permeability at low concentration exceeds forward permeability, indicating efflux driven by 
transporters (eg, human P-glycoprotein (MDR1) and breast cancer resistance protein [BCRP]); 
idelalisib is a substrate for the efflux transporters MDR1 and BCRP; however, the permeability 
increases in a concentration-dependent manner, resulting in a lower efflux ratio at higher, 
clinically relevant concentrations of idelalisib.
Idelalisib exhibits moderately high plasma protein binding in mouse, rat, dog, and human. In dog 
and human plasma, the protein binding is concentration-independent between 1 and 20 µM. 
Protein binding in human plasma is slightly higher than in mouse, rat, and dog plasma, which 
have comparable free fractions.  In human plasma, idelalisib and GS-563117 
(the major metabolite of idelalisib) have an average free fraction of ~16% and ~12%, respectively.
After oral administration of 14C-idelalisib to rats and dogs, radioactivity is widely distributed, but 
relatively excluded from bone, brain, spinal cord, and eye lens in rats and from brain and eyes in 
dogs. In rats, the radioactivity declines steadily and most tissues have undetectable levels by 
72 hours post dose.  In bile duct-cannulated rats and dogs, ≥69% of radioactivity is recovered in 
bile and urine, indicating high absorption of idelalisib in vivo.
In hepatic tissues from nonclinical species, idelalisib is primarily metabolized by 
aldehyde oxidase, CYP3A, and UGT1A4.  In vitro metabolism in dog and human yields 
3 primary oxidative metabolites and 5 primary glucuronides. Of these, the oxidative product 
GS-563117 is the predominant metabolite in vitro and in vivo. In preclinical species, plasma 
levels of GS-563117 are below those of idelalisib. In humans, GS-563117 
(only circulating metabolite and formed via aldehyde oxidase) plasma levels significantly exceed 
those of idelalisib. After oral administration of 14C-idelalisib to rats and dogs, biliary excretion 
appears to be the major route of elimination of idelalisib and its metabolites as the majority of 
radioactivity is found in feces or bile and little in urine.
Idelalisib is not a substrate for the renal transporters OCT2, OAT1, and OAT3 or the 
hepatic uptake transporters OATP1B1 and OATP1B3.  GS-563117 is not a substrate for 
OATP1B1 and OATP1B3.
Idelalisib is not an inhibitor of CYP1A, CYP2B6, CYP2C9, and CYP2D6, and at concentrations 
above those observed clinically, is an inhibitor of CYP2C8 (IC50 = 13 µM), CYP2C19 
(IC50 = 76 µM), and CYP3A (IC50 = 44 µM). GS-563117 is not an inhibitor of CYP1A, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and a competitive and time dependent 
inhibitor of CYP3A (IC50 = 3.1 µM), (KI = 0.18 µM, kinact = 0.033 min-1 with midazolam as 
the probe substrate).


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In vitro, idelalisib is not an inhibitor of the transporters BCRP, OCT2, OAT1, and OAT3, and is 
an inhibitor of MDR1 (IC50 = 7.7 µM), OATP1B1 (IC50 = 10.1 µM), OATP1B3 (IC50 = 7.0 µM), 
and, at concentrations above those observed clinically, of glucuronosyltransferase UGT1A1 
(IC50 = 42.0 µM). GS-563117 is not an inhibitor of MDR1, BCRP, OATP1B1, OATP1B3, 
OAT1, OAT3, and OCT2, and at concentrations above those observed clinically, an inhibitor of 
UGT1A1 (IC50 = 16.8 µM).
Any potential clinical implications of these metabolism studies were evaluated in a formal 
drug-drug interaction study (GS-US-313-0130) which evaluated the effect of idelalisib on 
cytochrome P450 3A and the drug transporters P-gp, OATP1B1, and OATP1B3. 
Study GS-US-313-0130 also evaluated the impact of an inducer of metabolizing enzymes and 
transporters (rifampin) on the PK of idelalisib in healthy human subjects. Findings from this 
study are presented in Section 1.3.5.1.
1.3.4.
Toxicology
The toxicological profile of idelalisib was well characterized through the conduct of single dose, 
repeat dose, developmental and reproductive, and genetic toxicology and local tolerance studies. 
The primary target organ toxicities following repeated dosing include the lymphoid, hepatic, 
male reproductive systems in rats and dogs, and gastrointestinal system in dogs. Adverse effects 
in the lymphoid system were primarily the result of on target pharmacology resulting in 
decreased lymphocytes in multiple lymphoid organs, primarily involving B-cell regions. Liver 
effects were transient and reversible with continued dosing and did not result in chronic liver 
injury. Reduction in sperm numbers in males were reversible and did not impact fertility or 
reproductive performance.  Gastrointestinal effects in dogs were minor, superficial, and 
considered secondary to effects on lymphocytes in Peyer’s Patches. Idelalisib was shown to be 
teratogenic and associated with embryo-fetal lethality. Effects on the reproductive system have 
been reported for inhibitors which target other isoforms of PI3K. The dose-dependence and 
potential of idelalisib to selectively inhibit additional PI3K isoforms may be responsible for the 
off-target toxicity. Additionally, the drug may have the potential to produce phototoxic reactions 
in humans. These findings represent toxicities that can be monitored, are considered clinically 
manageable, or are considered acceptable risks in the intended patient population.
Further details on the toxicology of idelalisib can be found in the Idelalisib 
Investigator’s Brochure (IB).
1.3.5.
Idelalisib Clinical Studies
1.3.5.1.
Phase 1 Studies in Healthy Subjects and in Patients with Allergic Rhinitis
Various studies in healthy subjects have evaluated safety, pharmacokinetics, food effect, and the 
potential for drug interactions of idelalisib with CYP3A4 inhibitors {Webb et al 2010}.


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Safety results from these studies indicated that idelalisib was well tolerated when administered to 
healthy subjects at single doses through 400 mg (the highest dose level tested) and was also 
generally well tolerated when administered to healthy subjects over 7 days at dose levels through 
200 mg/dose BID (the highest dose level tested). Dosing with 200 mg/dose BID for 7 days 
resulted in a skin rash in 3 out of 6 subjects; histological findings were consistent with a 
delayed-type hypersensitivity maculopapular exanthema. Rashes have sometimes occurred in 
patients with hematological malignancies receiving idelalisib, but have not typically proved 
dose- or treatment-limiting. In placebo-controlled single-dose and multiple-dose trials, repeated 
ECG evaluations performed in tandem with pharmacokinetic monitoring showed no evidence of 
drug-, dose-, or exposure-dependent effects on cardiac rhythm or cardiac intervals 
(eg, QT interval). Pharmacokinetic results indicated that idelalisib appeared rapidly in plasma 
with a median Tmax of 1 to 1.5 hours. Cmax and AUC increased in a less-than-dose-proportional 
manner and mean t1/2 values were across the dose range were 6.5 to 9.8 hours.
Idelalisib dosing after a high-fat, high-calorie meal delayed median time of 
maximum concentration (Tmax) from 0.75 hours to 3 hours; mean Cmax was unaffected and 
mean AUC was ~40% higher. These changes in idelalisib exposures are considered 
modest/clinically non-relevant; thus, idelalisib may be given with or without food.
Idelalisib is metabolized in humans primarily by aldehyde oxidase, with some involvement of 
CYP3A4 and UGT1A4. Accordingly, when idelalisib was administered following 4 days of daily 
dosing with ketoconazole (a potent inhibitor of CYP3A4), modest/moderate increases in mean 
idelalisib Cmax and AUC values of ~30% and ~80% higher, respectively, which is not considered 
to be clinically relevant and suggesting that idelalisib is a weak CYP3A substrate. GS-563117 is 
formed from idelalisib primarily via aldehyde oxidase.
The 14C-labeled idelalisib human mass balance results showed that the drug has moderate to high 
oral bioavailability. Idelalisib is eliminated mainly via hepatic metabolism and biliary excretion 
in the feces (~78% of dose); recovery in urine was < 15%. GS-563117, the only circulating 
metabolite observed in human plasma, was also observed in urine and feces.
Results from the drug interaction/probe Study GS-US-313-0130 indicate that idelalisib does not 
affect the pharmacokinetics of substrates of Pgp, BCRP, OATP1B1 or OATP1B3 transporters. 
Idelalisib is not expected to affect the exposures of coadministered agents via transporter 
mediated interactions.
The exposures (AUC) of probe CYP3A substrate, midazolam, increased ~5-fold upon 
coadministration with idelalisib, driven by competitive and time-dependent CYP3A inhibition by 
GS-563117, the only circulating metabolite of idelalisib. Coadministration of the highly potent 
CYP3A inducer rifampin resulted in a ~75% reduction in idelalisib systemic exposures, likely 
driven by a higher relative contribution of CYP3A to overall idelalisib clearance under the 
induced state.


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Pharmacodynamic results showed that a idelalisib dose of 200 mg inhibited ex vivo basophil 
activation via the PI3K-specific, high-affinity immunoglobulin (Ig)E receptor (anti-FCR1) in 
basophils collected from healthy volunteers. The findings were confirmed when the drug was 
assessed over 7 days in a Phase 1b study in subjects with allergic rhinitis. In this study, idelalisib
at a dose level of 100 mg/dose BID showed clinical and pharmacodynamic activity 
(attenuating adverse responses to allergenic challenge and decreasing markers of inflammation) 
and was well tolerated.
1.3.5.2.
Phase 1 Studies in Patients with Hematological Malignancies
1.3.5.2.1.
Phase 1 Monotherapy Study in Patients with Hematological Malignancies
A Phase 1 dose-ranging study (Study 101-02) of single-agent idelalisib extended safety and 
pharmacokinetic observations; documented the clinical and pharmacodynamic activity of 
idelalisib in subjects with iNHL, MCL, and CLL; and provided dosing information in support of 
further development {Brown et al 2011}, {Coutre et al 2011}, {Kahl et al 2011}. In this study, 
idelalisib was administered in cohorts of subjects across a range of dose levels from 50 mg/dose 
BID to 350 mg/dose BID. Idelalisib administration was continued as long as individual subjects 
were safely benefitting from therapy. Subjects were evaluated in 4-week cycles; response and 
progression assessments were based on standard criteria {Hallek et al 2008}.
A total of 191 subjects were enrolled to the study at dose levels of 50 mg BID (n=17), 
150 mg QD (n=16), 100 mg BID (n=25), 150 mg BID (n=45), 200 mg BID (n=35), 
350 mg BID (n=17), and 300 mg QD (n=19). An additional cohort was also enrolled to receive 
idelalisib 150 mg BID in 28 day cycles (21 days on idelalisib/7 days off [n=17]). Subject
characteristics were as follows: males/females n=139 (73%)/52 (27%) with median age of 
64.5 (range 32-91) years. Diagnoses included: CLL, n=54 (28%); iNHL, n=64 (34%); aggressive 
NHL (MCL and DLBCL), n=49 (26%); AML, n=12 (6%); and MM, n=12 (6%). Categorization 
of disease by response to the last prior therapy included: refractory, n=111 (58%); 
relapsed, n=79 (42%); and unknown, n=1 (1%).  The median (range) number of prior therapies 
was 5 (1-14). Among subjects with iNHL and CLL, the majority had received prior rituximab 
and prior alkylating agent therapy.
Adverse events were usually mild to moderate and not clearly idelalisib-related. Among 
Grade ≥3 adverse events, pneumonias and diarrhea were notable. Pneumonia was observed in 
23 (12%) subjects, primarily in subjects with CLL. In most instances, these findings were 
considered bacterial in origin, based either on culture results or on response to conventional 
antibiotics. Grade ≥3 adverse events of diarrhea were seen in 11 subjects (5.8%). Other 
Grade ≥3 events included rash in 3 (1.6%) subjects. The relative contributions of disease-related 
factors, toxicity from prior therapies or ongoing supportive care, and idelalisib to these events 
was not clear.
Grade ≥3 hematological laboratory abnormalities have included neutropenia, n=46 (24%); 
thrombocytopenia, n=27 (14%), anemia, n=14 (7.3%), and lymphopenia 13 (6.8%); with 
12 subjects (6.3%) having febrile neutropenia.  The occurrence of these events was greater in 
subjects with leukemia, particularly in those with pre-existing hematological abnormalities due 
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Consistent with the observations in the 28-day dog toxicology study, reversible Grade ≥3 
ALT/AST elevations occurred in 28 (15%) subjects and have been attributed to idelalisib. Onset 
generally occurred between 2 to 16 weeks after idelalisib initiation and resolution was usually 
seen 2 to 6 weeks after idelalisib interruption.  After resolution of ALT/AST increases, 
14 subjects were rechallenged at the same or a reduced dose of idelalisib and 9 (64%) of these 
subjects were able to resume treatment without recurrence of transaminase elevations.
Two (1.0%) subjects had ≥ 2 x ULN elevations in bilirubin in the context of Grade ≥3 
elevated AST/ALT, both of whom had confounding factors (recent history of biliary obstruction 
or concomitant use of potentially hepatotoxic medications) so that a definitive causal relationship 
to idelalisib could not be established.
Pharmacokinetic analyses indicated that the increase in Cmax and AUC0-6h with dose was less 
than dose-proportional, with modest increases above the dose level of 150 mg BID.
Pharmacodynamic data supported drug activity.  In subjects with NHL, plasma concentrations of 
chemokines CCL22 and CCL17 were elevated at baseline and showed significant decreases 
within 1 cycle of idelalisib treatment (p<0.001 for both comparisons). Flow cytometry of CLL 
cells from subjects showed that idelalisib reduced constitutive expression of phosphorylated 
AKT to background levels when measured after 1 week of treatment (p<0.0001), demonstrating 
pharmacodynamic inhibition of activated PI3K signaling.  Plasma concentrations of 
chemokines CCL3, CCL4, and CXCL13 were elevated in CLL subjects at baseline and 
decreased significantly within 1 cycle of idelalisib administration (p<0.001 for all comparisons).
Tumor reductions meeting antitumor response criteria were not observed in subjects with AML 
or MM. One of 11 subjects with DLBCL achieved a PR.  In 104 subjects with iNHL and MCL, 
idelalisib induced PRs at all dose levels, with respective ORRs in enrolled subjects of 
29/64 (45%) for iNHL and 16/40 (40%) for MCL. The median DOR has not been reached in 
subjects with iNHL; 19 subjects continued to receive idelalisib in a long-term extension study. 
The median [range] DOR was 2.7 months [1 month to 8 months] in subjects with MCL; 
6 MCL subjects continued to receive idelalisib in a long-term extension study.
In subjects with CLL, idelalisib reduced lymphadenopathy in almost all subjects; 
44/54 (81.5%) achieved a lymph node response (≥50% reduction in target nodal lesions). An 
initial increase in peripheral absolute lymphocyte counts of >50% from baseline was observed in 
some subjects; increases were maximal during the first 2 cycles and decreased thereafter; the 
pattern suggested drug-mediated lymphocyte redistribution.  In 54 subjects with CLL, 
39/54 (72%) achieved a PR (includes PR with lymphocytosis).  The median DOR was not 
reached; 23 subjects continued to receive idelalisib in a long-term extension study.
1.3.5.2.2.
Phase 1 Combination Study in Patients with Hematological Malignancies
A separate Phase 1 trial (Study 101-07) has evaluated the safety and preliminary activity of 
idelalisib given in combination with rituximab to subjects with recurrent iNHL or CLL {Brown 
et al 2011}, {Leonard et al 2011}.


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In this study, rituximab was administered at a standard dose of 375 mg/m2 per infusion weekly 
for 8 weeks in all subjects. Idelalisib was started simultaneously with the rituximab, first at a 
dose level of 100 mg/dose BID (n=13) and then at a dose level of 150 mg/dose BID (n=12) and 
was administered continuously to both subjects with CLL (n=13) and subjects with iNHL (n=12)
for as long as individual subjects were safely benefiting from therapy. Subjects were evaluated in 
4-week cycles; response and progression assessments were based on standard criteria {Hallek et 
al 2008}.
Among the subjects with CLL, the median age was 63 and ranged to 85 years. Bulky tumors 
(1 lymph node 5 cm in diameter) were present in 63% of the subjects. The median number of 
prior therapies by disease was 2 and ranged up to 8 prior treatments. All had received prior 
rituximab and the majority had received prior fludarabine or alkylating agents. Approximately 
one-third of subjects had CLL that was refractory to the last prior therapy. At the time of data 
cut-off, therapy had been administered for a median of 5 cycles, ranging up to 12 cycles 
(ie, 48 weeks).
No idelalisib-related dose-limiting toxicities were observed within the tested subject cohorts. 
Grade 3-4 adverse events largely comprised background events resulting from pre-existing 
disease- or treatment-related conditions or from intercurrent illness. Among subjects with CLL, 
2 (15%) developed pneumonia. For subjects receiving idelalisib together with rituximab, 
Grade 3-4 elevations in ALT/AST were not observed in those with CLL, although 
3 subjects (25%) of those with iNHL had such events.
The idelalisib plus rituximab combination showed a high level of antitumor activity in both 
subjects with CLL and those with iNHL. Altogether 92% of subjects with CLL receiving the 
combination of idelalisib and rituximab had reductions in nodal size and 77% showed a 
lymph node response (50% reduction in index nodal lesions). Although concomitant 
administration of rituximab did not eliminate the redistribution lymphocytosis that is associated 
with idelalisib, it blunted the magnitude of the change. As a result, the overall response rate 
(ORR) was also 77% among subjects participating in this study. At the time of last data analysis, 
PFS through 48 weeks was 70% and a median PFS had not yet been observed.
Collectively, the emerging data from this study support further evaluation of idelalisib together 
with rituximab in subjects with CLL and indicate that co-administration of idelalisib with 
rituximab is tolerable when using idelalisib at full dose, ie, at a starting dose level of 
150 mg/dose BID.
For additional or updated information, please refer to the current version of the IB.
1.4.
Summary and Justification for the Current Study
Gilead Sciences is conducting this Phase 3 study program to evaluate the efficacy and safety of 
idelalisib in patients with previously treated, recurrent CLL. Collectively the data derived from 
the primary clinical trial (Study GS-US-312-0116) and from this extension trial 
(Study GS-US-312-0117) address the activity of idelalisib together with rituximab, the activity 
of idelalisib when given alone, and the potential for dose-dependent restoration of drug activity 
in subjects who have disease that appears to be drug resistant.


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The design and conduct of this clinical trial program is supported by knowledge of the 
demographics of patients with CLL, the natural history and current therapies for the disease, and 
the nonclinical and clinical information regarding idelalisib. The collective data support the 
following conclusions:

CLL is a serious, disabling, and potentially life-threatening disorder of older patients that 
requires sequential treatment with agents that provide alternative mechanisms of tumor 
control. Existing cytotoxic agents have serious acute and chronic toxicities, making them less 
suitable for frail or unfit patients. Single-agent rituximab can offer disease palliation with 
good tolerability in some patients with relapsed CLL but tumor control is not lasting, 
especially in patients with bulky adenopathy. Development of a non-cytotoxic combination 
therapy of idelalisib with rituximab or a monotherapy regimen of idelalisib that can address 
disease pathogenesis with a new mechanism of action and might offer complementary 
nodal and peripheral blood activity would address an unmet medical need, particularly when 
applied in patients with substantial comorbidities or myelosuppression from prior 
chemotherapies.

PI3Kδ over-expression plays an important role in CLL biology. Further evaluation of 
idelalisib as a potential treatment for CLL has sound scientific rationale founded on 
knowledge of the actions of the drug to selectively abrogate PI3Kδ activity and to inhibit 
malignant cell growth and stromal cell signaling in nonclinical models of CLL. These data 
are supported by clinical documentation of idelalisib inhibition of PI3Kδ signaling in patients 
with CLL.

The potential for clinical efficacy of idelalisib monotherapy or of idelalisib plus rituximab in 
patients with relapsed or refractory CLL is supported by the observed antitumor activity of 
idelalisib - given alone or in combination with rituximab - in patients with heavily pretreated 
CLL and iNHL.

The safety of advancing development of the idelalisib monotherapy and of a regimen of 
idelalisib plus rituximab in this Phase 3 clinical trial program is well supported by safety 
pharmacology and toxicology studies and by Phase 1 single-agent and combination safety 
data obtained in healthy volunteers and in subjects with lymphoid cancers.

Dose-safety, dose-exposure, and dose-activity relationships identified in Phase 1 studies
support the dosing regimen and dose modification provisions in this study.

Observations relating to patterns of CLL response among subjects receiving idelalisib alone 
or in combination with rituximab in Phase 1 trials provide the foundation for efficacy
monitoring in this trial. Of particular note is that idelalisib mobilizes CLL cells from tissues 
into the peripheral blood. This characteristic pharmacological action is prominent early in 
therapy but can persist over time and should not be confused with disease progression in 
patients who have persistent control of other CLL-related signs and symptoms. For this 
reason, in this Phase 3 study program, subjects will be continued on therapy until the 
occurrence of definitive disease progression, ie, disease progression that is manifest by 
worsening CLL-related signs or symptoms other than lymphocytosis alone. 


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
Thorough nonclinical and clinical characterization of the type, severity, manifestations, and 
expected timing of adverse events establish the safety monitoring plan in this trial program.

The scientific correlative work performed in prior preclinical and clinical studies provides 
strong scientific underpinnings for the companion laboratory studies to be performed as a 
component of this clinical trial program.

Given the seriousness of previously treated CLL in patients with substantial comorbidity, and 
the aggregate potential benefits considered in the context of potential risks, further 
development of idelalisib in this Phase 3 clinical trial program is justified.
The rationale for specific design features is provided in relevant sections of the protocol, 
including Section 3.2 (Endpoint Selection Rationale), Section 2.2 (Design Rationale), 
Section 4.3 (Enrollment Criteria Rationale), Section 5.10 (Study Treatment Rationale), and 
Section 6.5 (Study Procedure Rationale).


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2.
STUDY DESIGN
2.1.
Design Overview and Study Schema
This study is being conducted as part of an overall clinical program that is evaluating the efficacy 
and safety of idelalisib in the therapy of patients with previously treated CLL (see Figure 2-1). 
Within this program, the primary clinical trial (Study GS-US-312-0116) is a Phase 3, 
multicenter, 2-arm, randomized, double-blind, placebo-controlled, parallel-group study. This 
clinical trial (Study GS-US-312-0117) is a separate, multicenter, 2-arm, double-blind, 
parallel-group extension study that is a companion study to the primary study.
Figure 2-1.
Study Design
Candidates for the primary study will be adults with previously treated recurrent CLL who have 
measurable lymphadenopathy, require therapy for CLL, have experienced CLL progression 
<24 months since the completion of the last prior therapy, and are currently not sufficiently fit to 
receive cytotoxic therapy because of chemotherapy-induced bone marrow damage or 
comorbidities.
Primary study subjects will be stratified based on 17p deletion and/or a p53 mutation status 
(either vs neither), immunoglobulin heavy chain variable region (IgHV) mutation status 
(unmutated vs mutated), and any prior therapy with an anti-CD20 therapeutic monoclonal 
antibody (yes vs no) and randomized in a 1:1 ratio to receive 1 of the 2 treatment arms.
In the primary study, subjects will be administered rituximab intravenously in the clinic starting 
at a dose of 375 mg/m2 on Day 1 (Week 0) and will continue with a dose of 500 mg/m2 on 
Day 15 (Week 2), Day 29 (Week 4), Day 43 (Week 6), Day 57 (Week 8), Day 85 (Week 12), 
Day 113 (Week 16), Day 141 (Week 20) (for a total of 8 infusions). Rituximab will be
administered until the earliest of subject withdrawal from study, definitive progression of CLL, 
intolerable rituximab-related toxicity, pregnancy, substantial noncompliance with study 
procedures, study discontinuation, or a maximum of 8 infusions.


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Idelalisib or placebo will be taken orally, BID continuously. Subjects will continue whichever 
study drug (idelalisib/placebo or rituximab) continues to be tolerated, even if the other drug has 
been discontinued due to toxicity.
If permanent discontinuation of study drug, occurs prior to definitive progression of CLL, 
subjects shall remain on study until definitive progression of CLL or withdrawal from the study 
for reasons specified in Section 5.7.
Compliant subjects who are tolerating therapy but who develop definitive disease progression in 
the primary clinical trial (Study GS-US-312-0116) can consider enrollment in this separate 
companion extension trial (Study GS-US-312-0117). In the extension trial, subjects will take 
active blinded idelalisib therapy, either at a higher starting dose or at the standard starting dose, 
with allocation based on the original primary study randomization. Following unblinding of 
Study GS-US-312-0116, subjects will be allowed to enter Study GS-US-312-0117 in the absence 
of evidence of disease progression and will take 150 mg BID idelalisib regardless of treatment 
assignment in Study GS-US-312-0116.
The primary objective of Study GS-US-312-0116 will be to evaluate the effect of the addition of 
idelalisib to rituximab on PFS. Secondary and tertiary objectives will focus on determining the 
effect of the addition of idelalisib to rituximab on the onset, magnitude, and duration of tumor 
control; overall survival (OS); health-related quality of life (HRQL); changes in subject 
performance status; disease-associated biomarkers and potential mechanisms of resistance; 
treatment administration; safety; and health resource utilization. In Study GS-US-312-0117, the 
same endpoints will be assessed as in Study GS-US-312-0116; the focus of the analysis will be 
largely descriptive except for the within-subject assessment of treatment effects among subjects 
receiving first rituximab alone and then idelalisib alone on Arm B of each trial. No formal 
comparisons of outcomes in Arm A vs Arm B are planned within Study GS-US-312-0117.
2.2.
Design Rationale
The randomized, add-on design for the primary trial (Study GS-US-312-0116) is customary in 
the comparative evaluation of new therapies for cancer. While this design provides idelalisib
efficacy and safety information only in the context of administration of a companion 
antineoplastic agent, it is appropriate because it documents the incremental benefit and toxicity 
of the investigational therapy in the context of a controlled clinical trial while ensuring that all 
participants receive potentially active treatment.
This separate extension trial (Study GS-US-312-0117) enhances subject acceptance of 
randomization in the primary study and provides further information regarding idelalisib
efficacy, resistance, and safety. Among subjects in Arm A, escalation to a higher dose level 
allows evaluation of dose-dependent resistance and a determination if a higher dose can 
reestablish disease control. The safety data obtained in these subjects will add to the overall 
safety database. Among subjects randomized to Arm B in the primary study, evaluation of 
idelalisib at a starting dose of 150 mg/dose BID in the extension study may permit a 
within-subject assessment of the treatment effects with single-agent idelalisib relative to the 
effects previously observed with rituximab alone. Of importance, the extension study maintains 


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the partial blinding of the primary study, thus minimizing the bias that might occur if the overall 
design entailed only a 1-way crossover to open-label idelalisib among subjects who had received 
placebo on Arm B of the primary study. To ensure confirmation of disease progression, tumor 
size data collected from the primary study will be subjected to independent review by an 
independent review committee (IRC) (see Section 10.4.2); subjects will continue with study 
therapy pending confirmation of progression status by the sponsor working in collaboration with 
the IRC. Subjects must have confirmation that the disease has progressed on the primary study 
before being permitted to receive secondary idelalisib therapy on the extension study, or in the 
event the primary study is stopped, subjects who have not yet progressed may enroll on the 
extension study to receive 150 mg BID idelalisib.


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3.
OBJECTIVES AND ENDPOINTS

To evaluate the effect of idelalisib on the onset, magnitude, and duration of tumor control

To compare tumor control in subjects receiving rituximab alone in Study GS-US-312-0116 to 
that observed in the same subjects when receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject well-being, including overall survival 
(OS), health-related quality of life (HRQL), and performance status

To assess the effects of idelalisib on disease-associated biomarkers and to evaluate potential 
mechanisms of resistance to idelalisib

To characterize exposure to idelalisib as determined by treatment administration and 
evaluation of idelalisib plasma concentrations over time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with administration of idelalisib
3.1.
Endpoints
3.1.1.
Tumor Control

Progression-free survival (PFS) – defined as the interval from the start of study therapy to the 
earlier of the first documentation of definitive disease progression or death from any cause; 
definitive disease progression is CLL progression based on standard criteria other than 
lymphocytosis alone

ORR – defined as the proportion of subjects who achieve a CR or partial response (PR) 

Lymph node response rate – defined as the proportion of subjects who achieve a 
50% decrease from baseline in the SPD of index lymph nodes

CR rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from start of study therapy to the first 
documentation of CR or PR

Duration of response (DOR) – defined as the interval from the first documentation of 
CR or PR to the earlier of the first documentation of definitive disease progression or death 
from any cause


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
Percent change in lymph node area – defined as the percent change from baseline in the sum 
of the products of the greatest perpendicular diameters (SPD) of index lymph nodes

Splenomegaly response rate – defined as the proportion of subjects with baseline 
splenomegaly who achieve an on-study normalization or a 50% decrease (minimum 2 cm) 
from baseline in the enlargement of the splenic LVD (by imaging)

Hepatomegaly response rate – defined as the proportion of subjects with baseline 
hepatomegaly who achieve an on-study normalization or a 50% decrease (minimum 2 cm) 
from baseline in the hepatic longest vertical dimension (LVD) (by imaging)

ALC response rate – defined as the proportion of subjects with baseline lymphocytosis 
(ALC4 x 109/L) who achieve an on-study ALC <4 x 109/L or demonstrate a 50% decrease 
in ALC from baseline; ALC values within 4 weeks post-baseline will be excluded from the 
ALC response rate evaluation

Platelet response rate – defined as the proportion of subjects with baseline thrombocytopenia 
(platelet count <100 x 109/L) who achieve an on-study platelet count 100 x 109/L or 
demonstrate a 50% increase in platelet count from baseline; platelet values within 4 weeks 
post-baseline or after 8 days post transfusion will be excluded from the platelet response rate 
evaluation

Hemoglobin response rate – defined as the proportion of subjects with baseline anemia 
(hemoglobin <110 g/L [11.0 g/dL]) who achieve an on-study hemoglobin 110 g/L 
(11.0 g/dL) or demonstrate a 50% increase in hemoglobin from baseline; hemoglobin 
values within 4 weeks post-baseline or after 4 weeks of receiving packed cell/whole blood 
transfusion or after 6 weeks of receiving exogenous growth factors (e.g., Darbepoetin alfa) 
will be excluded for the hemoglobin response evaluation

Neutrophil response rate – defined as the proportion of subjects with baseline neutropenia 
(absolute neutrophil count [ANC] ≤1.5 x 109/L) who achieve an ANC >1.5 x 109/L or 
demonstrate a 50% increase in ANC from baseline; ANC values within 4 weeks of 
post-baseline or after 2 weeks of receiving exogenous growth factors 
(e.g., Filgrastim, G-CSF, Lenograstim) or after 4 weeks of receiving Neulasta were excluded 
for response evaluation
3.1.2.
Patient Well-Being

Overall survival (OS) – defined as the interval from start of study therapy to death from any 
cause

Change from baseline in HRQL domain and symptom scores based on the 
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) (see Appendix 2)

Changes from baseline in Karnofsky performance status – defined as the change from 
baseline in the performance status (see Appendix 3)


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3.1.3.
Pharmacodynamic Markers of Drug Activity and Resistance

Changes from baseline in PI3K/AKT/mTOR pathway activation as a measure of PI3K
pathway activity

Changes from baseline in the plasma concentrations of disease-associated chemokines and 
cytokines
3.1.4.
Exposure

Study drug administration as assessed by prescribing records and compliance as assessed by 
quantification of used and unused drug

Trough (pre-dose) and peak (1.5-hour samples) of idelalisib plasma concentrations as 
assessed by a validated bioanalytical method
3.1.5.
Safety

Overall safety profile of each study treatment regimen characterized by the type, frequency, 
severity, timing of onset, duration, and relationship to study therapy of any adverse events or 
abnormalities of laboratory tests; serious adverse events; or adverse events leading to 
discontinuation of study drug
3.1.6.
Pharmacoeconomics

Change in health status – defined as the change from baseline in overall health and 
single-item dimension scores as assessed using the EuroQoL Five-Dimension (EQ-5D) utility 
measure (Appendix 4)

Health resource measures, including resource utilization, total costs, and measures of 
cost per unit of benefit (eg, cost per additional progression-free month,
cost per quality-adjusted life-year)
3.2.
Endpoint Selection Rationale
The proposed endpoints have been chosen based on relevance to the pathophysiology and 
clinical manifestations of CLL, the known pharmacology of idelalisib, and the goals of the study 
in documenting idelalisib benefit-to-risk ratio. These types of endpoints have been employed in 
prior studies in CLL and can be evaluated with acceptable reliability and accuracy.
3.2.1.
Tumor Control Endpoints
Assessments of the magnitude and duration of changes in tumor size are routinely employed in 
registration-directed oncology clinical studies to determine therapeutic effect. Unlike OS, these 
endpoints directly assess the ability of the drug to control the malignancy. Such assessments are 
also integral to treatment decisions; because subjects are being treated until disease progression, 


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repeated tumor assessment must be performed in order to define the proper duration of treatment 
for each study participant. Standard response and progression criteria have been established by 
the International Workshop on CLL (IWCLL) {Hallek et al 2008}; the assessments of treatment 
effects in this study will be based on these criteria, taking into account the specific pharmacology 
of idelalisib.
In CLL, disease-related nodal enlargement is a major cause of patient discomfort and can cause 
organ dysfunction {Dighiero et al 2008}. Extensive lymphadenopathy constitutes a reason to 
treat CLL and controlling the size of pathologically enlarged lymph nodes is an important 
therapeutic goal for improving patient well-being and relieving obstructive symptoms {Hallek et 
al 2008}. Given that the natural history of recurrent CLL is inexorable nodal growth, enhancing 
tumor shrinkage and prolonging tumor control provides strong evidence of pharmacological 
activity.
Endpoints of overall tumor control as evaluated in this trial are customarily assessed and reported 
in studies of new therapies in patients with cancer. PFS offers a well established outcome 
measure that directly measures treatment effect, conveys important longitudinal information 
regarding tumor control, can be characterized in all subjects using intention-to-treat (ITT) 
principles, and is readily analyzed using statistical methods such as Kaplan-Meier techniques. 
ORR provides an integrated assessment of the magnitude and extent of changes in 
lymphadenopathy, organomegaly, bone marrow infiltration, and bone marrow function that 
conveniently categorizes and describes treatment effects. TTR and DOR are important in 
characterizing the rapidity of achieving tumor shrinkage and the duration of tumor control. 
Beyond providing descriptions on overall response assessment using ORR, this protocol will also 
seek to characterize the individual components of response that are important in assessment of 
CLL {Hallek et al 2008}. Thus, changes in lymph node area and in the proportion of subjects 
having a lymph node response will be analyzed. In addition, among subjects who enter the study 
with splenomegaly or hepatomegaly, the proportion of subjects who achieve substantial (50%) 
reductions in spleen or liver size will be assessed. Similarly, the proportions of subjects who 
experience improvements in ALC, platelets, hemoglobin, and neutrophil counts will be 
characterized in order to provide specific insight into the degree to which therapy alters these 
individual parameters.
Because idelalisib mobilizes CLL cells from tissues into the peripheral blood as part of its 
pharmacological effect, there is a risk of falsely declaring a subject to have experienced disease 
progression if lymphocyte count is considered as the sole basis for potential CLL worsening. To 
account for this potential problem, changes in lymphocyte count will not be considered in 
determining whether a subject has progressive disease, ie, subjects will only be declared to have 
progressive CLL if they meet any of the IWCLL criteria for progressive disease other than 
lymphocytosis alone. Thus, subjects with worsening lymphadenopathy, organomegaly, bone 
marrow involvement, progressive cytopenias, appearance of new disease, or transformation to an 
aggressive lymphoid malignancy histology (eg, Richter syndrome) will be considered to have 
progressed. Subjects with lymphocytosis without any of these other events will not be considered 
to have progressed. Given that lymphocytosis has no prognostic significance in patients with 
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generally considered a reason to treat in patients with CLL {Hallek et al 2008}, {Eichhorst et al 
2010}, {Zelenetz et al 2011}, this approach does not jeopardize subject safety or subsequent 
therapy. Furthermore, it will allow complete collection of all response and progression data (both 
considering lymphocytosis and ignoring lymphocytosis) with the intent of providing complete 
information for regulatory authority review.
The current IWCLL guidelines indicate that physical examination is generally sufficient to 
evaluate nodal response and progression in patients with CLL {Hallek et al 2008} but that 
radiographic assessments may be appropriate in clinical trials. Computed tomography (CT) is 
considered the preferred imaging method unless patients have contraindications that require use 
of magnetic resonance imaging (MRI). Given the low fluorodeoxyglucose (FDG) avidity of 
CLL, positron- emission tomography (PET) does not have a role in evaluation of this disease. 
The incremental benefits of using radiographic imaging are limited in patients undergoing 
long-term follow-up following first-line therapy {Blum et al 2007}, {Eichhorst et al 2011}. 
However, in the patients with advanced CLL and bulky adenopathy such as those who will be 
enrolled to this trial, it is known that CT scans commonly detect bulky intra-abdominal 
lymphadenopathy and splenomegaly that would be missed by palpation alone and that the 
presence of large-volume, intra-abdominal disease of the nodes and spleen is associated with a 
poor prognosis {Norin et al 2010}. Thus, while use of CT confers greater radiation exposure, 
subjects have the chance to benefit from radiographic imaging because it will offer more 
accurate information regarding their response to protocol therapy and the appropriate duration of 
protocol treatment. Having this information is particularly important in this trial because PI3K
inhibition precludes use of lymphocyte counts as evidence for disease progression. In addition, 
the risk is offset by the fact that the trial subjects will primarily be patients who have already 
received more potent mutagens (eg, purine analogs, alkylating agents), and all of whom have 
advanced cancer and limited treatment options at study entry. Based on published data {Keating 
et al 2002a} {Wierda et al 2010}, median OS for patients with comparably advanced CLL is 
<18 months, so the long-term secondary malignancy risk from CT-related radiation exposure is 
very low. Finally, in the context of a registration-directed pivotal trial of a new drug with a new 
mechanism of action, radiographic imaging is critically important to provide reassurance 
regarding subject safety and trial validity. In this regard, CT evaluations of the lung can be used 
retrospectively to assess for radiographic evidence of drug-induced lung changes {White et al 
2010}, {Maroto et al 2011}. Furthermore, CT measurements have greater accuracy and 
reproducibility than palpation, are subject to independent expert review, and can be audited 
against electronic case report form (eCRF) information.
The timing of radiographic tumor assessments has been carefully considered. To avoid 
duplication, the CT scan documenting CLL progression in Study GS-US-312-0116 will serve as 
the baseline CT scan for Study GS-US-312-0117. Among patients receiving idelalisib in 
Phase 1b/2 studies who experienced a nodal response (50% regression in tumor area), such 
responses were observed with the first 16 week of therapy {Coutre et al 2011}, {Leonard et al 
2011}; the planned timing of tumor assessments (at Weeks 8, 16, 24, 36, 48 and then every 
12 weeks thereafter) in this study fits with this known timing of changes in lymph node size 
during idelalisib therapy. Scans at 8-week intervals during the first 24 weeks allow efficient 
documentation of response. During this period, early documentation of disease progression 


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allows subjects who are not benefiting from study therapy to move rapidly to alternative 
treatments. After 24 weeks on study or after 24 weeks cumulative treatment with idelalisib 
across Study GS-US-312-0116 and Study GS-US-312-0117, the reduction in the frequency of 
CT scans (to 12-week intervals) reduces the overall protocol burden for subjects while still 
allowing characterization of the expected median PFS in this trial. As outlined in Section 7.3, 
iodine-containing or gadolinium contrast material may be omitted in subjects for whom use of a 
contrast agent would be medically contraindicated.
3.2.2.
Measures of Patient Well-Being
3.2.2.1.
Overall Survival
While OS provides an ultimate measure of patient well-being, it has not routinely been used as 
the primary endpoint in CLL clinical trials. Unlike PFS, it does not specifically measure 
drug-mediated tumor control, and thus provides only an indirect assessment of treatment effect. 
Depending upon the treatment setting, long OS times in patients with CLL can preclude use of 
this endpoint as an efficient method for understanding drug benefits. In both the front-line and 
recurrent disease settings, post-study treatments can influence OS in unpredictable ways, 
potentially confounding differences between treatment groups.
However, given the life-threatening nature of systemic malignancy, documentation of OS is 
customary in oncology therapeutic clinical trials, including those evaluating subjects with 
recurrent CLL {Keating et al 2002a}, {Wierda et al 2010}. Evaluation of OS in this study 
continues the survival assessment from the primary study (Study GS-US-312-0116). The study 
program as a whole (considering both the primary randomized trial and secondary extension 
study) offers the potential to better understand OS and causes of death in a frail population of 
patients with both CLL, considering the consequences of the disease and comorbidities.
3.2.2.2.
Health-Related Quality of Life
Direct patient reporting of outcomes using standardized methods has become an increasingly 
important component of therapeutic assessment. Evaluation of patient-reported outcomes (PROs) 
is particularly relevant in patients who cannot be cured of disease {Reeve et al 2007}. PRO 
questionnaires have been previously used in CLL to understand how patients differ from the 
general population in terms of health concerns {Holzner et al 2004}, {Eichhorst et al 2007}, 
{Shanafelt et al 2007}, {Else et al 2008}, to understand differences in perceptions of well-being 
in younger vs older patients {Levin et al 2007}, {Else et al 2008}, to determine how treatment 
affects HRQL {Catovsky et al 2007}, {Eichhorst et al 2007}, {Efficace et al 2008}, and to assess 
the pharmacoeconomic cost of improvements in HRQL {Stephens et al 2005}.
Patients with CLL have overtly impaired well-being relative to comparable controls {Holzner et 
al 2004}, {Eichhorst et al 2007}, {Shanafelt et al 2007}, {Else et al 2008}. Fatigue is cited as a 
common complaint, being present in the substantial majority of patients. Impairment of HRQL 
prior to any treatment is apparent in those with B symptoms or in patients with anemia, 
supporting the concept of initiating treatment when patients experience symptomatic disease. 
Factors associated with lower overall HRQL have included older age, greater fatigue, severity of 


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co-morbid health conditions, advanced stage, and ongoing treatment for CLL {Shanafelt et al 
2007}. Younger patients appear to have worse emotional and social well-being but older patients 
experience worse physical HRQL {Levin et al 2007}. In comparative evaluation of 
chemotherapy-containing regimens, differences in HRQL between therapies (eg, fludarabine vs 
fludarabine-cyclophosphamide vs chlorambucil) reflected differences in toxicity while improved 
HRQL was associated with greater efficacy {Catovsky et al 2007}, {Eichhorst et al 2007}.
In this study, it is postulated that idelalisib-mediated tumor control will be correlated with greater 
positive changes in HRQL and that assessments of the drug’s safety profile will be supported by 
HRQL evaluations. The FACT-Leu (Appendix 2) has been selected to evaluate such outcomes 
for the study. The FACT-Leu comprises a general HRQL measure for patients receiving cancer 
treatment that yields a total score and subscales for physical, functional, social/family and 
emotional well-being {Cella et al 1993} and a diagnosis-specific measure for patients with 
leukemia {Webster et al 2002}. The FACT-Leu was developed to assess symptoms (eg, fevers, 
chills, night sweats, nodal swelling, fatigue) specifically relevant to patients with leukemia. 
FACT instruments have documented psychometric properties {Cella et al 1993}, {Webster et al 
2002}, {Brucker et al 2005}, {Cella et al 2005}, {Victorson et al 2008}.
The FACT-Leu instrument is available in appropriate languages for this study. FACT-Leu data 
will be obtained at baseline and during each investigational clinic visit during treatment. Having 
FACT-Leu data concurrent with tumor response information will allow an evaluation of the 
potential relationship between tumor response and symptomatic changes as reported by patients. 
To avoid biasing HRQL results, the FACT-Leu will be administered at each visit before other 
procedures are performed and before any study information is conveyed to the subject.
3.2.2.3.
Changes in Performance Status
Performance status evaluation provides an integrated assessment of patient well-being before, 
during, and after treatment and, ideally, may indicate how drug efficacy and toxicity affect 
patient functioning. In patients with CLL performance status can be predictive of PFS or OS 
{Sorensen et al 1997}, {Hallek et al 1996}, {Youngson et al 1995}.
In this study, it is hypothesized that idelalisib-mediated tumor control will be correlated with 
changes in performance status and that assessments of the drug’s safety profile might be 
supported by performance status evaluations. The well-established, reliable, and validated 
Karnofsky performance score {Karnofsky et al 1949}, {Yates et al 1980}, {Schag et al 1984}
(see Appendix 3) will be employed in the trial for characterization of the subject population and 
repeated assessment of performance status.
3.2.3.
Pharmacodynamic Markers of Drug Activity and Resistance
In CLL, disease-related perturbations in inflammatory status can be clinically overt; patients 
often develop bothersome B symptoms (fevers, night sweats, and weight loss) that are 
characteristic of excessive systemic inflammation {Redaelli et al 2004}. Consistent with such 
disease manifestations, the PI3K/AKT/mTOR pathway is constitutively overactive in 
circulating CLL cells {Coutre et al 2011}. In addition, chemokines and cytokines that are 


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markers of aberrant B-cell trafficking or perturbations in inflammation are overexpressed by 
CLL tissues or by stromal cells and circulate in plasma {Burger 2010}, {Coutre et al 2011}. In 
Phase 1 studies of idelalisib it has been confirmed that idelalisib largely normalizes AKT
phosphorylation and induces dose-dependent reductions in plasma concentrations of circulating 
chemokines and cytokines in patients with CLL {Coutre et al 2011}.
In this study, it is hypothesized that incremental changes in these biomarkers provide direct 
evidence of mechanism-specific idelalisib effects on PI3Kδ activity or indirectly document drug 
effects on overall tumor cell volume. In either case, improvements in these pharmacodynamic 
measures provide corroborative evidence in support of idelalisib pharmacological activity; 
conversely, worsening of these biomarkers may indicate acquisition of resistance to idelalisib. In 
addition, it is possible that disease-or inflammation-related biomarkers may provide corollary 
information relating to the adverse effects of idelalisib on the liver; such data might allow better 
prediction of which subjects might be most susceptible to ALT/AST elevations during idelalisib
treatment. Finally, it can also be postulated that genetic, protein, or metabolic changes in CLL 
cells could provide signatures that would correlate with drug sensitivity and resistance.
Based on these considerations, this study will evaluate PI3K/AKT/mTOR pathway activation 
status in CLL cells. For this purpose, blood will be evaluated by flow cytometry using a 
clinically validated assay {Hoellenriegel et al 2011}. CLL cells will be identified using anti-CD5 
and anti-CD19 antibodies. AKT activation will be determined by quantifying phosphorylation at 
the Ser473 and Thr308 AKT sites using specific anti-pAKT Thr308 and anti-pAKT
Ser473 antibodies. Additional assessments of PI3K/AKT/mTOR pathway signaling 
(eg, evaluating phosphorylation state for other downstream enzymes) may also be explored.
Plasma will be collected for assessment of circulating concentrations of relevant chemokines and 
cytokines with a particular focus on CCL2, CCL3, CCL4, CXCL12, CXCL13, CCL17, CCL19, 
CCL21, CCL22, sCD40 ligand, tumor necrosis factor-α, and C-reactive protein. In addition 
serum markers of iron metabolism (eg, hepcidin, iron, ferritin, transferrin) that might provide 
markers linking disease-related inflammation with perturbations of liver iron and sensitivity to 
liver injury will be evaluated {Nemeth et al 2003}, {Ferrucci et al 2010}. Clinically validated 
assays (eg, enzyme-linked immunosorbent assays [ELISAs]) will be used to measure circulating 
concentrations of chemokines and cytokines at baseline and during the course of idelalisib
therapy.
CLL cell deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein will be collected at 
baseline and at the conclusion of a subject’s treatment on study. DNA and RNA samples will be 
analyzed using gene array technologies to evaluate for changes in DNA mutations or in 
RNA expression patterns that might be associated with intrinsic or acquired resistance to study 
treatments. Similarly, protein will be evaluated for state-specific changes in protein 
phosphorylation to evaluate for differences in pathway activation at baseline or during therapy 
that might be associated with differences in response or in acquisition of resistance to therapy.


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3.2.4.
Assessments of Exposure
3.2.4.1.
Study Drug Administration and Compliance
Evaluation of study drug administration and compliance provides context for assessments of 
safety, pharmacokinetics, and pharmacological activity. Evaluations of treatment administration 
and modifications from planned therapy document the influence of treatment-emergent adverse 
events on prescribing practice. Compliance assessment offers a general indication of patients’ 
acceptance of therapy, integrating factors of tolerability, palatability, and convenience.
In this study, information regarding planned treatment and modification from planned treatment 
(eg, dose reductions and interruptions) will be kept. The compliance of the subject will be 
verified by accounting for used and unused drug.
3.2.4.2.
Pharmacokinetics
Given the intent of this protocol to assess longer-term dosing, collection of plasma for idelalisib
concentrations is important for evaluating exposure over time. These data may allow correlations 
of exposure with measures of efficacy, toxicity, and resistance. Because the idelalisib
pharmacokinetic profile has been well characterized in Phase 1 studies, limited plasma sampling 
will be performed in this study. Samples will be collected pre-dose and 1.5 hours post-dose 
relative to the morning administration of idelalisib. Based on discussions with investigators, 
collecting more than 2 samples in the morning is not considered reasonable given the need to 
minimize time requirements for study participants and to avoid substantial inconvenience for 
clinic staff.
Evaluation of idelalisib plasma concentrations will be performed using liquid chromatography 
with tandem mass spectrometry. The method has been fully validated in the context of prior 
Phase 1 studies. Plasma samples will be retained for potential later analyses of idelalisib
metabolites.
3.2.5.
Evaluations of Safety
In defining the therapeutic relevance of a drug in a particular clinical setting, it is imperative that 
its safety profile be fully characterized. As is conventional in all clinical studies, proper 
description of each adverse event or laboratory abnormality requires an understanding of the 
type, incidence, timing, severity, and relatedness to study drug. While information on all reported 
adverse events will be collected, listed, and summarized, particular focus will be placed on 
monitoring and reporting adverse events and laboratory abnormalities that were encountered in 
the prior toxicology studies and clinical experience with idelalisib. Safety parameters of specific 
interest in reporting study results will include those relating to bone marrow function, 
dermatological events, gastrointestinal inflammation, infection, pulmonary events 
(eg, pneumonia/pneumonitis), and liver injury. Additional scrutiny will be applied to 
Grade 3-4 adverse events, to adverse events causing interruption or discontinuation of idelalisib, 
and to serious adverse events.


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In addition, the protocol will evaluate for potential adverse idelalisib effects on laboratory 
parameters of immune function; the absolute number of CD4+, CD5+,CD8+, CD16/CD56+, 
CD19+, and CD20+ cells will be assessed by flow cytometry. Serum concentrations of IgA, IgE, 
IgG, and IgM will be obtained.
For consistency of interpretation, adverse events will be coded using the standard 
Medical Dictionary for Regulatory Activities (MedDRA) [http://www.meddramsso.com]), and 
the severity adverse events and laboratory abnormalities will be graded using the well-defined 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). 
Standard definitions for seriousness will be applied (see Section 8.1.2).
3.2.6.
Pharmacoeconomic Measures
It is increasingly important to understand the potential cost implications of introducing a new 
medication into patient care for CLL {Main et al 2010}, {Hornberger et al 2012}. In order to 
analyze the pharmacoeconomic consequences of idelalisib administration, data will be collected 
regarding the health status of subjects and regarding health care resource utilization.
Heath status information will be obtained with the EQ-5D, which is a self-administered, generic, 
indirect utility measure {The EuroQol Group 1990} (Appendix 4). The EQ-5D consists of a 
visual analogue scale on which subjects are asked to rate their current overall health status and 
5 single-item dimensions which ask subjects to rate their health in terms of mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression. For each of the 5 items, patients must 
choose between 3 levels of difficulty in accomplishing tasks in that dimension. The visual analog 
scale is then used in combination with the dimension scores to generate a health utility score that 
can be incorporated into analyses of cost effectiveness. The EQ-5D has been successfully used in 
the evaluation of patients with B-cell and other cancers {Doorduijn et al 2005}, {Witzens-Harig 
et al 2009}, {Yang et al 2010}.
The EQ-5D instrument is available in appropriate languages for this study. EQ-5D data will be 
obtained at baseline and during each investigational clinic visit during treatment. The EQ-5D 
will be administered immediately after administration of the FACT-Leu instrument, before other 
procedures are performed and before any study information is conveyed to the subject. The 
EQ-5D instrument takes only 5 minutes to complete.
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach will be to combine the resource utilization data from the trial with data on 
unit prices (collected separately) to estimate total costs. The costs will be described relative to 
the health care findings as measured by duration of tumor control, the symptom-free survival 
period, and/or utility outcomes or some other appropriate measure of clinical benefits.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects
The planned sample size is ~160 subjects but will be bounded by the number of subjects enrolled 
to the primary clinical trial (Study GS-US-312-0116).
4.2.
Subject Selection Criteria
Subjects in the primary Phase 3 study (GS-US-312-0116) who are compliant, are tolerating 
primary study therapy, and 1) have definitive progression of CLL while receiving primary study 
drug therapy (idelalisib /placebo) or 2) are actively participating in Study GS-US-312-0116 at 
the time the study is stopped, including if stopped early due to overwhelming efficacy following 
an interim analysis are eligible to enroll in the extension study. Eligibility criteria may not be 
waived by the investigator and conformance to the eligibility criteria is subject to review in the 
case of a Good Clinical Practice (GCP) or a regulatory authority audit. Any questions regarding a 
subject’s eligibility should be discussed with the study sponsor medical monitor prior to 
enrollment.
4.2.1.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while receiving study drug therapy 
(idelalisib/placebo) in Study GS-US-312-0116. Note: Definitive disease progression is CLL 
progression based on standard criteria and occurring for any reason 
(ie, increasing lymphadenopathy, organomegaly, or bone marrow involvement; 
decreasing platelet count, hemoglobin, or neutrophil count; or worsening of 
disease-related symptoms) other than lymphocytosis. Subjects must have confirmation by 
the sponsor working in collaboration with an independent review committee (IRC) that the 
disease has progressed on the clinical trial (Study GS-US-312-0116) before receiving
secondary idelalisib therapy on this extension trial (Study GS-US-312-0117).
3) Presence of radiographically measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures 2.0 cm in the longest diameter [LD] and 1.0 cm in the 
longest perpendicular diameter [LPD] as assessed by CT or MRI).
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab and idelalisib/placebo) 
and no intervening or continuing therapy (including radiotherapy, chemotherapy, 
immunotherapy, or investigational therapy) for the treatment of CLL. Note: Subjects may 
receive corticosteroids to manage CLL manifestations.


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5) The time from permanent cessation of Study GS-US-312-0116 treatment (rituximab and/or
idelalisib/placebo) and the initiation of Study GS-US-312-0117 therapy is 12 weeks. 
Note: Study procedures performed as part of Study GS-US-312-0116 need not be repeated 
and can be used as screening procedures for Study GS-US-312-0117 if performed within 
4 weeks prior to initiation of study drug therapy on Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation of study treatment) as 
shown in the table below. Note: Confirmation should be considered for out-of-range values 
to determine if the abnormality is real or artifactual. Values should be obtained within the 
screening period and should generally be the most recent measurement obtained. Subjects 
with any degree of neutropenia, thrombocytopenia, or anemia due to CLL or prior therapy 
may enroll.
Table 4-1.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCra
>30 ml/min
Pregnancy
-HCGb
Negative
a
As calculated by the Cockcroft-Gault formula (see Appendix 5) {Cockcroft et al 1976}
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or 
urine dipstick pregnancy test must be negative at start of study treatment (Visit 2)
Abbreviations: -HCG= beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
eCCr=estimated creatinine clearance, ULN=upper limit of normal
8) For female subjects of childbearing potential, willingness to use a protocol-recommended 
method of contraception (as outlined in Section 5.6.4) from the screening visit (Visit 1) 
throughout the study and for 30 days following the last dose of study drug.
Note: A female subject is considered to be of childbearing potential unless she has had a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically 
documented ovarian failure (with serum estradiol and follicle-stimulating hormone [FSH] 
levels within the institutional postmenopausal range and a negative serum or 
urine HCG), or is menopausal (age ≥54 with amenorrhea for >12 months or 
amenorrhea for >6 months with serum estradiol and FSH levels within the institutional 
postmenopausal range).
9) For male subjects of childbearing potential having intercourse with females of childbearing 
potential, willingness to use a protocol-recommended method of contraception 
(as outlined in Section 5.6.4) from the start of study drug (Visit 2) throughout the study and 
for 90 days following the last dose of study drug and to refrain from sperm donation from the 
start of study drug (Visit 2) throughout the study and for 90 days following the last dose of 
study drug. Note: A male subject is considered able to father a child unless he has had a 


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bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or has ongoing 
testicular suppression with a depot luteinizing hormone- releasing hormone (LH-RH) 
agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate  [Lupron®]), or 
triptorelin pamoate [Trelstar®]).
10) In the judgment of the investigator, participation in the protocol offers an acceptable 
benefit-to-risk ratio when considering current CLL disease status, medical condition, and the 
potential benefits and risks of alternative treatments for CLL. 
11) Willingness and ability to comply with scheduled visits, drug administration plan, imaging 
studies, laboratory tests, other study procedures, and study restrictions. 
Note: Psychological, social, familial, or geographical factors that might preclude adequate 
study participation should be considered.
12) Evidence of a personally signed informed consent indicating that the subject is aware of the 
neoplastic nature of the disease and has been informed of the procedures to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study participation.
4.2.2.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
1) Known histological transformation from CLL to an aggressive lymphoma 
(ie, Richter transformation). Note: Biopsy documentation of the absence or presence of 
transformation is not required.
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of the start of 
study treatment (Visit 2). Note: Subjects with localized fungal infections of skin or nails are 
eligible. Subjects may be receiving prophylactic antiviral or antibacterial therapies at the 
discretion of the investigator; anti-pneumocystis prophylaxis is encouraged. For subjects 
who are at substantial risk of an infection (eg, influenza) that may be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of 
protocol therapy.
3) Pregnancy or breastfeeding. 
4) Intentional breaking of the blind in Study GS-US-312-0116 by the investigator or the study 
subject.
5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical condition, surgical history, physical 
finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the 
investigator’s opinion, could adversely affect the safety of the subject or impair the 
assessment of study results.


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4.3.
Enrollment Criteria Rationale
The eligibility criteria are designed to limit enrollment to subjects who participated in the 
primary clinical trial (Study GS-US-312-0116), are compliant, have been generally able to 
tolerate study therapy and study procedures, and have experienced definitive CLL progression 
while receiving study treatment (rituximab and/or idelalisib/placebo) in the primary study or who 
are actively participating in Study GS-US-312-0116 at the time the study is stopped, including if 
stopped early due to overwhelming efficacy.
The requirement of measurable lymphadenopathy to enter the blinded portion of the study 
ensures that subjects have disease that can adequately be assessed for evidence of drug activity. 
Prior therapy provisions are intended to ensure that subjects are transitioning directly from 
Study GS-US-312-0116 to Study GS-US-312-0117 without receiving intervening treatments. 
The stipulation of 12-week interval from Study GS-US-312-0116 treatment until 
Study GS-US-312-0117 treatment precludes excessively protracted intervals between 
participation in the 2 studies but also permits sufficient time for clinicians and subjects to 
determine whether participation is appropriate. 
In the blinded portion of the study, to ensure that subjects are not so acutely ill from 
life-threatening comorbidities that they require hospitalization and stabilization, subjects with 
Karnofsky performance scores <40 (ie, those who are bed-bound or hospitalized) will not be 
enrolled. Baseline laboratory evaluations are designed to limit participation to subjects who have 
not developed serious organ compromise that would pose a safety risk or confound the 
interpretation of adverse effects. Pregnancy testing and restrictions on eligibility relating to 
reproduction, pregnancy, and nursing are important because idelalisib is a new chemical entity 
with teratogenic effects in rats and it is unknown if it may have adverse effects on conception, on 
fetal development, or on the health of a breast-feeding child. To minimize missing data and 
premature discontinuations, subjects should have sufficient psychological and social resources to 
comply with study procedures and restrictions. Consistent with GCP guidelines, subjects must 
provide informed consent before initiation of any study procedures.


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5.
TREATMENT OF SUBJECTS
5.1.
Enrollment
5.1.1.
Interactive Web Response System
An IWRS will be employed to manage the conduct of the trial. The IWRS will be used to 
maintain a central log documenting enrollment, to manage dose modifications, to assess current 
inventories of study drug, to initiate any necessary resupply of study drug, and to document 
discontinuation of study.
5.1.2.
Treatment Assignment
After a subject has completed the necessary documentation of definitive CLL progression in the
primary clinical trial (GS-US-312-0116) and has been confirmed to be eligible, the subject can 
be entered into this trial (Study GS-US-312-0117). In order to obtain a treatment arm allocation 
for a subject, a site representative will access the IWRS and supply the system with the required 
information.
Subjects will be assigned to either of the following treatment assignments with allocation based 
on the original primary study randomization:
Treatment Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117)
Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly enrolled subjects will 
receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly enrolled subjects will 
receive 150 mg BID
Note: At the Investigator’s discretion, subjects who were randomized to placebo on 
Study GS-US-312-0116 may delay initiation of idelalisib following enrollment on 
Study GS-US-312-0117 until the time of disease progression or until the investigator 
determines that the subject would benefit from initiation of idelalisib treatment.


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Treatment Assignment

Assignment to Arm A or Arm B with allocation based on the original primary study 
randomization

Implementation through an interactive web response system (IWRS)
The IWRS will assign blister card, or bottle numbers and instructions for dispensing of blinded 
study drug (high-dose or standard-dose idelalisib). It is anticipated that subjects will usually 
begin study drug immediately at Visit 2 of the study.
5.1.3.
Blinding
During the blinded portion of the study, the identity of the treatments will be concealed by 
central blinding of study drug assignments. Blinding will be accomplished through use of a 
placebo that is well-matched to the active drug in appearance, packaging, labeling, and schedule 
of administration (see Section 5.2.1). During the study, subjects, caregivers, investigational site 
personnel, Gilead Sciences study team members, and all other study personnel will remain 
blinded to the identity of the treatment assignments; these assignments will be available only to 
the IWRS, the data monitoring committee (DMC) for the study, an independent bioanalytical 
group that supports the DMC, and drug safety personnel who are not part of the study team.
Unblinding an individual subject’s treatment assignment during the study will only occur in the 
case of subject emergencies (see Section 5.5) or in the event the study is discontinued by the
Sponsor, a Regulatory Agency, or an IRB or EC (see Section 5.9). Where required by local 
regulation, expedited reporting of serious adverse events to specific regulatory authorities will 
include information regarding the study drug treatment assignment 
(high-dose or standard-dose idelalisib); this will be done in such a way that subjects, 
investigational site personnel, institutional review board/independent ethics committees 
(IRB/IEC), and study team members remain blinded as to the treatment assignment for the 
subject described in the adverse event report.
The unblinded analysis of the study will be performed when the database is completed and 
locked following unblinding of Study GS-US-312-0116 and Study GS-US-312-0117. The final 
analysis of the open label portion of the study will occur once the open label portion is stopped.
While bioanalytical assays to determine idelalisib concentrations may be performed prior to 
unblinding, pharmacokinetic data that would allow identification of treatment assignments for 
individual subjects will not be available to the study team until after the blind is broken and the 
primary analysis has occurred. Except for emergency unblinding, individual subjects, caregivers, 
and site personnel will not be informed of the treatment assignments until the implications of 
revealing such data for the overall idelalisib study program have been determined by the clinical 
project leader for the idelalisib development program.


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5.2.
Investigational Study Drug (Idelalisib/Placebo)
5.2.1.
Description
Subjects allocated to Arm A in the blinded portion of the study will be provided with 2 tablets of 
active idelalisib for oral administration at each dose. Each tablet contains 150 mg or 100 mg of 
active idelalisib. The 150-mg tablets will be used for initial therapy; the 100-mg tablets are 
provided for use by those subjects who require a dose reduction (see Table 5-1).
Subjects allocated to Arm B in the blinded portion of the study will be provided with 1 tablet of 
active idelalisib and 1 tablet of placebo for oral administration at each dose. Each active tablet 
contains 150 mg or 100 mg of active idelalisib. The 150-mg tablets (and matching placebo) will 
be used for initial therapy; the 100-mg tablets (and matching placebo) are provided for use by 
those subjects who require a dose reduction.
In the open-label portion of the study, subjects will be provided with 150 mg tablets of idelalisib.
The 150-mg tablets are pink, oval-shaped film-coated, and include the following inactive 
excipients: microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, 
sodium starch glycolate, magnesium stearate, red iron oxide, polyethylene glycol, talc, 
polyvinyl alcohol (PVA), and titanium dioxide. The 100-mg tablets are orange, oval shaped film-
coated, and include the following inactive excipients: microcrystalline cellulose, hydroxypropyl 
cellulose, croscarmellose sodium, sodium starch glycolate, magnesium stearate, FD&C Yellow 
#6/Sunset Yellow FCF aluminum lake, polyethylene glycol, talc, PVA, and titanium dioxide.
The placebo tablets match the active idelalisib formulations in appearance. The placebo tablets 
matching the 150-mg tablets are pink, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium stearate, 
red iron oxide, polyethylene glycol, talc, PVA, and titanium dioxide. The placebo tablets 
matching the 100-mg tablets are orange, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium stearate, 
FD&C Yellow #6/Sunset Yellow FCF aluminum lake, polyethylene glycol, talc, PVA and 
titanium dioxide.
5.2.2.
Source
Both active idelalisib and placebo will be supplied free of charge by Gilead Sciences.
5.2.3.
Packaging and Labeling
During the blinded portion of the study, study drug (idelalisib or idelalisib/placebo) will be 
provided in blister cards. The blister cards are made of polyvinyl chloride/
polychlorotrifluoroethylene (PVC/PCTFE) film and have aluminum foil lidding materials. Each 
blister card contains 120 tablets (4-week supply plus a modest overage) of one of the relevant 
dose strengths. The 100-mg or 150-mg and matching placebo tablets will be combined in order 
to obtain the daily doses to be used in this study. Thus, in Arm A, the 300-mg idelalisib dose will 


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be obtained by administering two 150-mg tablets and the 200-mg idelalisib dose will be obtained 
by administering two 100-mg tablets. In Arm B, the 150-mg idelalisib dose will be obtained by 
administering one 150-mg tablet and one placebo tablet and the 100-mg idelalisib dose will be 
obtained by administering one 100-mg tablet and one placebo tablet.
Each blister card will have a unique number. Labeling for blister cards dispensed to subjects in 
Arm A will appear identical to blister cards dispensed to subjects in Arm B, and may include 
either idelalisib or placebo.
When the primary study (GS-US-312-0116) is stopped including if early after an 
interim analysis, GS-US-312-0116 active study subjects will become eligible for participation on 
Study GS-US-312-0117. Active GS-US-312-0117 study subjects will be transitioned to 
open-label idelalisib at this time. Each bottle contains 60 tablets 
(4 week supply plus a modest overage) of one of the relevant dose strengths (150 mg, 100 mg) 
and a polyester coil. Bottles are white and are made of high-density polyethylene. Each bottle is 
closed with a white, continuous-thread, child-resistant, polypropylene screw cap fitted with an 
induction-sealed, aluminum-faced liner.
All labels for study drugs to be distributed to centers in the United States, the EU, and other 
countries will meet all applicable requirements of the United States Food and Drug 
Administration (FDA), the EU Annex 13 of Current Good Manufacturing Practice (cGMP) 
(Manufacture of Investigational Medicinal Products, July 2010), and/or other local regulations as 
applicable.
5.2.4.
Storage and Handling
Blister cards or bottles containing tablets of study drug (idelalisib or idelalisib/placebo) should
be stored at controlled room temperature (ie, ~25 °C, with a range of 15 to 30 °C). While the 
stability of study drug tablets stored at controlled room temperature has been confirmed, brief 
excursions to temperatures as low as -20 °C or as high as 40 °C (eg, during shipping) will not 
adversely affect the drug. Updated stability data will be provided to the sites, as appropriate.
5.2.5.
Dispensing
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing 
study drug according to the IWRS directions. It is planned that drug will be dispensed at 4-week 
intervals through the first 24 weeks of treatment and at 12-week intervals thereafter, or on a 
frequency consistent with the subject’s visit schedule. Sufficient study drug will be provided for 
each study period at the beginning of the period. Multiple blister cards or bottles may be 
dispensed at a single visit. Tablets should be kept in the original blister cards or bottles provided
until they are self-administered by the subject.
At the time of starting study treatment, the IWRS will provide the clinic staff with the blister 
card numbers designating the blister cards to be dispensed, or the quantity of open-label bottles 
to be dispensed. The clinic staff (eg, pharmacist or other qualified person) will write the subject 
number on each blister card or bottle that is dispensed. Immediately before dispensing, the clinic 
staff will write the blister card or bottle number in the study drug administration record 
corresponding to the subject number.


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5.2.6.
Return
The study drug should be retrieved from each subject at the end of each dispensing interval. The 
quantity of study drug and the date returned by the subject should be recorded in the study drug 
accountability records. When possible, all study drug returned by the subject should be retained 
for review by the study site monitor prior to return to Gilead Sciences or destruction.
5.2.7.
Accountability
The disposition of all study drug should be documented from the time of receipt at the site 
through subject dispensing and return.
Study personnel must ensure that all study drug is kept in a secure locked area with access 
limited to authorized personnel. The study drug must not be used outside the context of this 
protocol. Under no circumstances should the investigator or site personnel supply study drug to 
other investigators or clinics, or allow the study drug to be used other than as directed by this 
protocol.
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by Gilead Sciences or its designee, including, but not limited to, 
the date received, lot number, amount received, and the disposition of all study drug. Upon 
receipt of a drug shipment, the shipment must be logged into the IWRS. Study drug 
accountability records must also be maintained that include the subject number to whom the 
study drug was dispensed and the date, quantity and lot number of the study drug dispensed.
Depending upon the decision of Gilead Sciences, remaining unused study drug supply will be 
returned to Gilead Sciences or its designee after the study is completed or will be discarded or 
destroyed at the clinical site. If the study drug is discarded or destroyed at the clinical site, 
standard institutional policy should be followed. Records documenting the date of study drug 
shipping or destruction, relevant lot numbers, and amount shipped or destroyed should be 
maintained.
5.2.8.
Overdose Precautions
In Phase 1 studies, an MTD for idelalisib was not reached when the drug was administered 
continuously at dose levels through 350 mg/dose BID (700 mg per day) {Coutre et al 2011}, 
{Kahl et al 2011}. However, in this protocol, an overdose is defined as administration of more 
than the prescribed daily dose (ie, >600 mg in a single day). In a subject who experiences an 
overdose consideration should be given as to whether idelalisib administration should be 
temporarily interrupted. If the overdose ingestion is recent and substantial, and if there are no 
medical contraindications, use of gastric lavage or induction of emesis may be considered. 
Observation for any symptomatic side effects should be instituted, and biochemical and 
hematological parameters should be followed closely (consistent with the protocol or more 
frequently, as needed). Appropriate supportive management to mitigate adverse effects should be 
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The Gilead Sciences medical monitor should be contacted if a study drug overdose occurs. Cases 
of study drug overdose will result in specific reporting requirements (see Section 8.8).
5.2.9.
Inadvertent Exposure and Spill Precautions
Based on available data from nonclinical studies, idelalisib does not appear to be acutely toxic, 
genotoxic, or irritative at levels that are likely to result from inadvertent exposure to the contents 
of broken tablets. However, personnel handling the drug should use reasonable precautions to 
avoid eye contact, skin contact, inhalation, or ingestion of the study drug product. For further 
information regarding inadvertent exposure and spill precautions, please consult the idelalisib
investigator brochure.
5.3.
Study Drug Administration
5.3.1.
Premedication
No specific premedications or supporting medications are required in conjunction with study 
drug administration.
5.3.2.
Administration Instructions
The prescribed dose of study drug (idelalisib/placebo) should be taken orally. At each dose 
administration, the tablet number corresponding to the appropriate dose of study drug is to be 
swallowed whole with 100 to 200 mL (~ 4 to 8 ounces) of water. In case of breakage of the 
tablets in the oral cavity, additional water should be taken as a rinse. 
Study drug may be taken with or without food. There are no known dietary restrictions related to 
study drug use.
5.3.3.
Dosing Schedule
Study drug should be taken on a BID schedule at approximately the same times each day. Ideally,
doses should be taken at ~12-hour intervals (eg, at ~7 AM and at ~7 PM). While it is realized 
that variations in dosing schedule may occur in the outpatient setting, the prescribed regimen 
should be followed as closely as possible, especially in the clinic.
At specified clinic visits, the study drug will be administered in the clinic with dosing 
appropriately timed relative to blood sampling for idelalisib pharmacokinetics. As detailed in 
Section 6.2, clinic staff should record idelalisib administration information, including the exact 
clock time of each dose, for doses of study drug administered in the clinic or hospital. Thereafter, 
subjects will be given an adequate supply of tablets to take at home.
5.3.4.
Dose Levels
Study drug dose levels for Arm A and Arm B are described in Table 5-1. The lower dose level
(Dose Level -1) is provided in case a subject requires a study drug dose modification.


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Table 5-1.
Study Drug Dose Levels
Treatment Arm
Starting Dose
Dose Level -1
Arm A
300 mg/dose BID
200 mg/dose BID
Arm B
150 mg/dose BID
100 mg/dose BID
Abbreviation: BID=twice per day
When the primary study (GS-US-312-0116) is stopped, and GS-US-312-0116 active study 
subjects become eligible for participation on Study GS-US-312-0117 subjects will be enrolled 
into Study GS-US-312-0117 at open label 150 mg BID. Subjects already participating in 
Study GS-US-312-0117 will remain on the same dose.
5.3.5.
Dose Schedule Interruptions and Vomited Doses
Subjects who have a delay in administration of a dose of the study drug of <6 hours should take 
the planned dose as soon as possible after the intended time of administration. For subjects who 
have a delay in administration of study drug of 6 hours, the dose should not be taken. Study 
drug administration may continue but the missed dose should not be made up and the planned 
timing of subsequent study drug dosing should not be altered.
Vomited doses may be retaken, but only if the tablet is visible in the vomitus.
5.3.6.
Safety Monitoring and Study Drug Interruption/Dose Modification
Subjects must be monitored closely for adverse events or laboratory abnormalities during the
course of the study. Reference should be made to the CTCAE, Version 4.03 for grading the 
severity of adverse events and laboratory abnormalities.
Recommendations and requirements for modifications of the dosing regimens based on the drug 
and the type and severity of adverse events or laboratory abnormalities are provided in Table 5-2
below. The dose modification instructions focus on the types of events most commonly 
attributed to each of the study agents. Required dose modifications and actions provided in 
Table 5-2 must be followed based on the type and severity of adverse avent. The 
recommendations provided in Table 5-2 comprise only guidelines; variations from these 
recommendations may be warranted based on an investigator’s individual judgment in 
considering potential risks, benefits, and therapeutic alternatives available to each subject.
Consistent with Table 5-2, if a subject experiences an adverse event that is suspected to be 
related to study drug and requires a dose modification during the course of study therapy, then 
study drug administration should be held, as necessary, until the adverse event resolves or 
stabilizes to an acceptable degree Thereafter, study drug may be reinstituted, but the dose should 
be modified per(Table 5-1 and Table 5-2). If the adverse event occurs again, reinitiation of 
therapy may be attempted if the investigator feels that a second rechallenge is medically 
appropriate. If the subject cannot tolerate idelalisib at Dose Level -1 after 2 rechallenges, then 
the subject should be discontinued from study drug therapy unless continued therapy is discussed 
with the Gilead Sciences medical monitor.


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After the study drug dose is reduced, the dose need not be re-escalated, even if there is minimal 
or no toxicity with the reduced dose. However, if the subject tolerates the lower dose level of 
study drug for ≥4 weeks then the dose level may be increased to the starting dose level 
(see Table 5-1) at the discretion of the investigator. Such re-escalation may be particularly 
warranted if further evaluation reveals that the adverse event that led to the dose reduction was 
not study-drug-related. The starting dose level should not intentionally be exceeded in this study.
Whenever possible, any dose adjustment of study drug should be discussed between the 
investigator and the Gilead Sciences medical monitor prior to implementation. To implement 
either a dose reduction or a dose reescalation, the investigator/study staff member will call the 
IWRS, enter the subject number, and inform the IWRS of the need for dose titration. The IWRS 
will provide details regarding the study drug to be dispensed to the subject. The appropriate 
clinic staff should instruct the subject/caregiver about the change in dose.
Recommendations for dose modification based on the type and severity of adverse events or 
laboratory abnormalities are provided in Table 5-2 below.
Table 5-2.
Recommendations and Requirements for Study Drug Dose 
Modifications Based on Type and Severity of Treatment-Related 
Adverse Events or Laboratory Abnormalities
NCI CTCAE Gradea
Recommendation
Idelalisib
HEMATOLOGICAL ADVERSE EVENTS
Neutropenia
Grade 2 neutropenia
Recommended Action: Maintain current dose level and schedule.
Grade 3 neutropenia
Required Action: Blood counts should be monitored at least weekly until ANC < Grade 2.
Recommended Action: Maintain current idelalisib dose level and schedule.
Grade 4 neutropenia
(or occurrence of 
neutropenic fever 
or infection)
Required Action: Withhold idelalisib.
Required Action:Monitor blood counts at least weekly until ANC < Grade 2 
Recommended Action: May resume idelalisib at lower dose level at investigator discretion.
Neutropenia should be managed according to established clinical guidelines.
Thrombocytopenia
Grade 3
Recommended Action: Maintain current dose level and schedule.
Grade 4
Required Action: Withhold idelalisib for bruising or bleeding until Grade 3. 
Recommended Action: May resume idelalisib at initial or lower dose level at investigator 
discretion.
NON-HEMATOLOGICAL ADVERSE EVENTS
Rash
Grade 1
Recommended Action: Maintain current dose level and schedule.
Grade 2
Recommended Action: Maintain current dose level and schedule.


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NCI CTCAE Gradea
Recommendation
Idelalisib
Grade ≥3 
Required Action: Withhold idelalisib until Grade 1. 
Recommended Action: Resume at lower dose level or discontinue idelalisib at 
investigator discretion.
Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN)
Any Grade
Required Action: Discontinue idelalisib. Interrupt coadministered medications potentially 
associated with SJS/TEN.  Institute treatment per institutional standards.
Gastrointestinal Inflammation/Diarrhea
Grade 1
Required Action: Obtain history of onset and duration of diarrhea, including description,
number of stools, stool composition (e.g., watery, bloody, nocturnal), travel history, 
dietary changes and a medication review to identify possible diarrheogenic agents.
Required Action: Perform physical examination including assessment for fever, dizziness, 
abdominal pain/cramping, and weakness (e.g., evaluate for sepsis, bowel obstruction, 
dehydration).
Recommended Action: Provide anti-diarrheal (eg, loperamide) and maintain current 
idelalisib dose level and schedule.
Grade 2 diarrhea or 
colitis (unless clinical 
diagnosis is 
established from 
medical history and 
physical examination)
Required Action: Obtain history of onset and duration of diarrhea, including description,
number of stools, and stool composition (e.g., watery, bloody, nocturnal), travel history, 
dietary changes and a medication review to identify possible diarrheogenic agents.
Required Action: Perform physical examination including assessment for fever, dizziness, 
abdominal pain/cramping, and weakness (e.g., evaluate for sepsis, bowel obstruction, 
dehydration).
Required Action: For Grade 2 colitis or diarrhea (unless clinical diagnosis is established 
from medical history and physical examination), perform stool culture for routine 
pathogens (Salmonella, Shigella, Campylobacter species, Clostridium difficile toxin, 
Rotavirus, Cytomegalovirus, Adenovirus), ova and parasites (Cryptosporidium parvum, 
Isospora belli, Enterocytozoon bieneusi, Septata intestinalis, Strongyloides, Microsporidia, 
Entamoeba histolytica, Cyclospora), and Giardia antigen.
Recommended Action: For persistent Grade 2 colitis or diarrhea without clear etiology 
(clostridium difficile enterocolitis), endoscopy with biopsyb is strongly recommended to 
assess by immunohistochemistry (IHC) and PCR for CMV, Adenovirus.  (Optional: If 
ileal biopsy is performed, consider Acid Fast Bacillus staining.)
Recommended Action: Provide anti-diarrheal (eg, loperamide). Consider addition of anti-
inflammatory agent (eg, sulfasalazine, budesonide). Maintain current idelalisib dose level 
and schedule.


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NCI CTCAE Gradea
Recommendation
Idelalisib
Grade ≥ 3 diarrhea or 
colitis or persistent 
grade 2 diarrhea or 
colitis without clear 
etiology
Required Action: Withhold idelalisib. 
Required Action: Obtain history of onset and duration of diarrhea, including description,
number of stools, stool composition (e.g., watery, bloody, nocturnal), travel history, 
dietary changes and a medication review to identify possible diarrheogenic agents.
Required Action: Perform physical examination including assessment for fever, dizziness, 
abdominal pain/cramping, and weakness (e.g., evaluate for sepsis, bowel obstruction, 
dehydration).
Required Action: For Grade 3 colitis or diarrhea (unless clinical diagnosis is established 
from medical history and physical examination), perform stool culture for routine 
pathogens (Salmonella, Shigella, Campylobacter species, Clostridium difficile toxin, 
Rotavirus, Cytomegalovirus, Adenovirus), ova and parasites (Cryptosporidium parvum, 
Isospora belli, Enterocytozoon bieneusi, Septata intestinalis, Strongyloides, Microsporidia, 
Entamoeba histolytica, Cyclospora), and Giardia antigen.
Recommended Action: For Grade 3 colitis or diarrhea without clear etiology (eg, 
clostridium difficile enterocolitis), endoscopy with biopsyb isstrongly recommended to 
assess by immunohistochemistry (IHC) and PCR for CMV, Adenovirus. . (Optional: If 
ileal biopsy is performed, consider Acid Fast Bacillus staining.)
Recommended Action: At Grade 1, may resume idelalisib at lower dose level or 
discontinue at investigator discretion.
Recommended Action: Provide anti-diarrheal (eg, loperamide) and/or addition of 
anti-inflammatory agent (eg, sulfasalazine, budesonide).
Hepatic Adverse Events (elevations in ALT, AST, or bilirubin)
Grade 1
(ALT/AST3xULN)
(Bilirubin1.5xULN)
Recommended Action: Maintain current dose level and schedule.
Grade 2
(ALT/AST>3-5xULN)
(Bilirubin>1.5-
3xULN)
Recommended Action: Monitor ALT, AST, ALP, and bilirubin at least 1x per week until 
all abnormalities are Grade ≤ 1; thereafter maintain current dose level.
Grade 3
(ALT/AST>5-20xUL
N)
(Bilirubin>3-10xULN)
Recommended Action: Withhold idelalisib. 
Recommended Action: Monitor ALT, AST, ALP, and bilirubin at least 1x per week until 
all abnormalities are Grade 1. 
Recommended Action: If bilirubin abnormality was Grade <3, resume idelalisib at same 
dose level. If bilirubin abnormality was Grade >3, resume at lower dose level.
Grade 4
(ALT/AST>20xULN)
(Bilirubin>10xULN)
Required Action: Withhold idelalisib. 
Required Action: Monitor ALT, AST, ALP, and bilirubin at least 1x per week until all 
abnormalities are Grade 1. 
Required Action: If bilirubin abnormality was Grade 4, discontinue idelalisib.
Required Action: If bilirubin abnormality was Grade <4, if drug is restarted then resume 
idelalisib at lower dose level. 


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NCI CTCAE Gradea
Recommendation
Idelalisib
Pneumonitis (dyspnea, cough, hypoxia without obvious infectious cause)
Grade 1
Recommended Action: Withhold idelalisib until resolution to baseline. May resume at 
lower dose level or discontinue idelalisib at investigator discretion. 
Grade 2
Required Action: Interrupt or discontinue idelalisib 
Recommended Action: Consider supportive care, including oxygen or mechanical
ventilation, and provide as necessary.
Recommended Action: Consider bronchoscopy to evaluate for PJP, CMV and other 
organisms (bacterial and viral)
Recommended Action: Consider treatment with systemic corticosteroids.
Recommended Action: Consider empiric treatment of pneumocystis if bronchoscopy 
is contraindicated
Recommended Action: Upon resolution, may resume idelalisib at lower dose level at 
investigator discretion and/or Gilead medical monitor agreement
Grade 3
Required Action: Interrupt or discontinue idelalisib.
Recommended Action: Consider supportive care, including oxygen, systemic steroids, or 
mechanical ventilation, and provide as necessary.
Recommended Action: Consider bronchoscopy to evaluate for PJP, CMV and other 
organisms (bacterial and viral)
Recommended Action: Consider treatment with systemic corticosteroids.
Recommended Action: Consider empiric treatment of pneumocystis if bronchoscopy 
is contraindicated
Recommended Action: Upon resolution, may resume idelalisib at lower dose level at 
investigator discretion and/or Gilead medical monitor agreement
Pneumocystis jirovecci pneumonia (PJP)
Any Grade
Required Action: Discontinue idelalisib
Unequivocal CMV infectionc
Any Grade
Required Action: Interrupt idelalisib upon unequivocal clinical or laboratory evidence of 
CMV infection.
Required Action: Treat according to established clinical guidelines.
Required Action: If the benefits of resuming idelalisib are judged to outweigh the risks, 
consideration should be given to administering pre-emptive CMV therapy.
Other Nonhematological Adverse Events
Grade 2
Recommended Action: Maintain current dose level and schedule.
Grade 3
Recommended Action: Withhold idelalisib until Grade 1. May resume idelalisib at initial 
or lower dose level or discontinue idelalisib at investigator discretion.
a
CTCAE, Version 4.03.
b
Refer to 5.4.2.2 for recommendations if the differentiation between small-bowel and large-bowel diarrhea is unclear
c
CMV should be diagnosed using clinical or laboratory criteria per established institutional standard
Abbreviations:  ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST= aspartate aminotransferase, 
CTCAE=Common Terminology Criteria for Adverse Events, CMV=cytomegalovirus, G-CSF=granulocyte colony-stimulating 
factor, NCI=National Cancer Institute, ULN=upper limit of normal


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5.4.
Evaluation, Intervention, and Drug Discontinuation for Specific Adverse 
Events or Conditions
5.4.1.
Dermatological Events
Subjects receiving idelalisib with ≥ Grade 3 rash have generally presented with a maculopapular 
rash on the trunk and extremities that is occasionally associated with fever and/or pruritus and 
responded to treatment with diphenhydramine and/or topical or oral corticosteroids. 
For subjects who develop Grade ≥3 rash for which an underlying etiology cannot be identified 
(e.g., infection, co suspect drug), study drug must be interrupted. 
Severe cutaneous reactions, including fatal events of Stevens-Johnson syndrome (SJS) and toxic 
epidermal necrolysis (TEN), have been reported in subjects receiving idelalisib. Assessment of 
potential causal association between idelalisib and the occurrence of SJS or TEN has been 
confounded by the coadministration of antineoplastic agents (e.g., bendamustine, rituximab) 
and/or other concomitant medications known to be associated with SJS or TEN (e.g., allopurinol).
If SJS or TEN is suspected, idelalisib and all coadministered medications associated with SJS or 
TEN should be interrupted and the subject treated accordingly. 
Subjects should be monitored for the development of SJS, TEN, or other severe cutaneous 
reactions and idelalisib treatment should be discontinued if such events occur.
Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab. 
These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid 
dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis {Genentech Inc 2011}. 
The onset of these reactions has varied from 1 to 13 weeks following initiation of rituximab 
exposure. The safety of readministration of rituximab to patients with severe mucocutaneous 
reactions has not been determined; thus, for subjects experiencing a severe mucocutaneous 
reaction, rituximab should be discontinued.
Among patients receiving bendamustine, skin reactions have been reported in clinical trials and 
post-marketing safety reports {Cephalon 2012}. These events have included rash, toxic skin 
reactions, bullous exanthema, and purpura {Gavini et al 2012}. Cases of Stevens-Johnson 
syndrome and toxic epidermal necrolysis have been reported when bendamustine was 
administered concomitantly with allopurinol and other medications known to cause these 
syndromes. There may be an increased risk of skin toxicity in subjects receiving bendamustine 
together with trimethoprim-sulfamethoxazole. Because of coadministration of other agents, the 
precise relationship of cutaneous adverse events to bendamustine has often been uncertain. 
Where skin reactions to bendamustine do occur, they may be progressive and increase in severity 
with further treatment. Therefore, patients with skin reactions should be monitored closely. If 
skin reactions are severe or progressive, bendamustine should be discontinued.


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5.4.2.
Gastrointestinal Events
Isolated cases of gastrointestinal inflammation (eg, stomatitis, colitis, cecitis) have been noted in 
subjects receiving idelalisib. Rare cases of gastrointestinal perforation have occurred, generally 
in the setting of occult carcinoma, mesenteric embolus or diverticular disease.  Idelalisib must be 
discontinued in subjects who experience bowel perforation.
Cholangitis manifest as hyperbilirubinemia out of proportion to serum transaminase elevations 
has been observed. While disease related factors, neutropenia, toxicity from prior therapies, 
effects of ongoing supportive care, or pre existing cholelithiasis may have initiated such events, 
it is possible that idelalisib played a contributory role. In such subjects, rechallenge with 
idelalisib has been possible and has not been associated with other severe adverse events. 
Subjects who have developed evidence of enteritis during idelalisib therapy have been 
successfully treated with antidiarrheals (eg, loperamide) and with enteric steroidal (eg, budesonide)
or non steroidal (eg sulfasalazine [Azulfidine®]) anti-inflammatory agents and have been able to 
continue or resume idelalisib.
For study subjects who develop severe abdominal pain the possibility of a bowel obstruction or 
perforation should be considered. Appropriate clinical and radiographic examination should be 
performed and supportive care or surgical intervention should be considered. Upon recovery, 
rituximab may be resumed. 
Among patients receiving rituximab in combination with chemotherapy, rare instances of 
life-threatening bowel obstruction or perforation has been observed {Ram et al 2009}, primarily 
in patients with NHL. In post-marketing reports, the mean time to documented gastrointestinal 
perforation was 6 (range 1–77) days from start of chemoimmunotherapy. It is hard to draw a 
definite conclusion regarding the role of rituximab in these cases, as the affected patients had 
multiple risk factors including lymphomatous involvement of the gastrointestinal tract, other 
gastrointestinal disorders, and/or the risk of concomitant treatments with chemoradiotherapy and 
corticosteroids. Very isolated instances of inflammatory bowel disease have been seen in patients 
receiving rituximab {Ardelean et al 2010}.
5.4.2.1.
Investigation for Idelalisib Late Onset or Severe Diarrhea/Colitis
See CTCAE Version 4.03 for definitions of colitis and diarrhea.
Among idelalisib-treated patients who reported diarrhea or colitis, the median time to onset of 
any grade diarrhea or colitis was 1.9 months (range, 0.0–29.8), of grade 1 or 2 was 1.5 months 
(range, 0.0–15.2) and of grade 3 or 4 was 7.1 months (range, 0.5–29.8). Kaplan–Meier curves of 
time to onset of diarrhea or colitis are shown for all idelalisib- treated patients in Figure 5-1
{Coutre et al 2015}.


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Figure 5-1.
Kaplan-Meler Time to Diarrhea or Colitis
Idelalisib-associated severe diarrhea responds poorly to antimotility agents however, median 
time to resolution ranged between 1 week and 1 month across trials following interruption of 
idelalisib treatment and, in some instances, initiation of corticosteroid treatment 
{Gilead Sciences Inc 2014}.
5.4.2.2.
Differentiation Between Small-bowel and Large-bowel Diarrhea 
Differentiate between small-bowel and large-bowel diarrhea on a clinical basis if recommended.  
If unclear, consider upper and lower tract endoscopy with biopsy.

Small bowel diarrhea is characterized by large volume diarrhea (more than one per day), 
possibly associated dehydration, weight loss, and paraumbilical pain.   Consider an 
endoscopic small-bowel biopsy and evaluate other etiologies such as celiac disease.

Large-bowel diarrhea may present with lower pelvic pain, tenesmus, generally smaller stool 
volumes with gross blood frequently found in the stool. Consider a colonoscopic evaluation 
and biopsy.
5.4.3.
Hepatic Events
Transaminase Elevations: Consistent with observations in a dog toxicology study, reversible 
asymptomatic ALT/AST increases were also observed early in the idelalisib program in phase 1 
studies (101-02 and 101-07) in subjects with hematologic malignancies. Transaminase elevations 
generally occurred within 4 to 12 weeks of drug initiation, and resolved spontaneously over a 
period of 2 to 4 weeks with drug being continued for Grade 1 and 2 elevations and drug withheld 
for Grade 3 or 4 elevations until resolution. These early observations have been consistent with 
the ongoing experience with idelalisib treatment and transaminase elevations are now well 
characterized as most frequently asymptomatic, transient and occurring within the first 3 months 
of treatment.


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Grade 1 or 2 elevations commonly resolve despite continued idelalisib treatment and Grade 3 or 
4 elevations can be managed by withholding idelalisib. Successful rechallenge after resolution at 
either the same or lower dose level of idelalisib has been achieved in the majority of subjects. 
There has been no evidence of impaired synthetic function. Close monitoring of hepatic 
laboratory tests during therapy is important to allow for appropriate idelalisib interruption and 
reinstitution so that subjects may continue with study drug treatment.
HBV Reactivation: HBV reactivation can occur in patients treated with anti-CD20 antibodies.  
Subjects who are HBc antibody positive/HBV DNA PCR negative at screening will be 
monitored for potential HBV reactivation (manifest as detectable HBV DNA by quantitative 
PCR). Although some subjects who are HBc antibody positive with negative PCR may have had 
passive transfer of antibody from intravenous IgG, it cannot be known for certain that any such 
subject did not have natural HBV infection. Therefore, all subjects will be tested monthly for the 
duration of anti-CD20 therapy and every 3 months for 1 year following the last dose of rituximab 
during study participation. Following the completion of study participation, monitoring for HBV 
reactivation will be conducted per standard of care at the discretion of the investigator. If there is 
evidence of HBV reactivation, immediately discontinue anti-CD20 and start appropriate 
treatment for HBV.  In the event of HBV reactivation, please contact the Medical Monitor 
regarding continuation of idelalisib.
5.4.4.
Hematological and Immunological Events
In the Phase 1 experience with idelalisib in NHL and CLL, subjects with Grade3 neutropenia, 
anemia, and/or thrombocytopenia were enrolled to clinical trials. Decreased levels of neutrophil 
counts, hemoglobin, or platelet counts during therapy were largely due to minor fluctuations in 
these parameters among patients with pre-existing hematological abnormalities due to disease or 
prior therapy. Thus, idelalisib did not appear to induce overt myelosuppression. Obvious patterns 
of drug-mediated reductions in circulating CD4+ lymphocyte counts or suppression of serum 
IgG levels were also not observed.
Treatment-emergent Grade 3 or 4 neutropenia events, including febrile neutropenia, have occurred in 
subjects treated with idelalisib. For subjects who develop Grade 3 neutropenia, blood counts must be 
monitored weekly. For subjects who developGrade 4 neutropenia , idelalisib must be interrupted and 
blood counts monitored weekly until ANC is ≥ 0.5 Gi/L, at which point, idelalisib dosing may be 
resumed at 100 mg BID.  Neutropenia should be managed according to established clinical 
guidelines.
No modification of any drug for changes in circulating CD4+ counts or Ig levels is planned.
5.4.5.
Infectious Events
Patients with lymphoid cancers receiving idelalisib have developed serious and fatal infections 
during therapy. Opportunistic infections, most notably Pneumocystis jirovecii pneumonia (PJP) 
and CMV infection, have most frequently occurred within the first 6 months of treatment with 
idelalisib and are increased in the context of concurrent myelosuppressive therapy such as 
bendamustine.


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Subjects must receive trimethoprim-sulfamethoxazole or other established prophylaxis for PJP 
throughout the course of idelalisib treatment, and must continue for 2 to 6 months after the last 
dose of idelalisib.  Prophylaxis must continue until the CD4+ T-cell count is documented to be 
>200 cells/mcL after idelalisib treatment ends. Subjects must permanently discontinue idelalisib 
upon diagnosis of PJP.
CMV surveillance for active disease (quantitative PCR or PP65 antigen) must be conducted 
approximately every 4 weeks throughout the course of idelalisib treatment. CMV viral load 
testing should be performed from the same specimen type whenever possible and caution should 
be exercised when comparing CMV viral load results across different testing centers. If 
unequivocal clinical or laboratory evidence of CMV infection is present, the subject must 
interrupt idelalisib treatment and undergo effective antiviral treatment according to established 
clinical guidelines. If the benefits of resuming idelalisib are judged to outweigh the risks, 
consideration should be given to administering pre-emptive CMV therapy.
Serious bacterial, fungal, and new or reactivated viral infections have occurred during and for 
~1 year following rituximab-based therapy {Gea-Banacloche 2010}. New or reactivated viral 
infections in patients receiving rituximab have included CMV, herpes simplex virus, parvovirus 
B19, varicella zoster virus, West Nile virus, HBV (see Section 5.4.3) and HCV.
In high-risk subjects (history of recurrent infection, allogeneic transplant, treatment with 
alemtuzumab, hypogammaglobulinemia) other infection prophylaxis should be considered per 
consensus guidelines. Administration of intravenous immunoglobulin is permitted per standard 
institutional practice {Raanani et al 2009}. For subjects who develop an infection, appropriate 
medical therapy should be instituted in a timely manner.
5.4.6.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) due to polyomavirus JC has been observed 
in patients who have received rituximab therapy {Carson et al 2009} for hematologic 
malignancies. The specific causal role of rituximab is unknown because many of these patients 
had other risk factors (eg, low CD4+ counts) and the majority had received rituximab in 
combination with chemotherapy or as part of a hematopoietic stem cell transplant. Most cases of 
PML were diagnosed within 12 months of the last infusion of rituximab.
The diagnosis of PML should be considered in any subject presenting with new-onset or 
worsening neurologic manifestations, especially weakness or paralysis, vision loss, impaired 
speech, or cognitive deterioration. Evaluation of PML should include consultation with a 
neurologist, brain MRI, and lumbar puncture. In subjects diagnosed with PML, study drug 
should also be permanently discontinued.
5.4.7.
Pulmonary Events
Documented bacterial, fungal, viral, and pneumocystis pneumonias have been observed in 
patients receiving idelalisib, primarily in patients with CLL. Some study subjects receiving 
idelalisib alone or in combination have developed evidence of pneumonitis without documented 
pulmonary infection.


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Rituximab-related noninfectious pneumonitis has been described {Subramanian et al 2010} with 
an incidence of ~4.3% {Salmasi et al 2010}. In patients developing rituximab-associated 
pneumonitis, the mean time from the first rituximab infusion to the onset of respiratory 
symptoms was 3 months, with a peak incidence after administration of a mean cumulative 
dosage of 1600 mg/m2 {Liote et al 2010}.
Given the potential for infectious or drug-related adverse events, clinicians should be particularly 
observant for evidence of respiratory events in subjects participating in this trial. Subjects who 
describe pulmonary symptoms (eg, dyspnea on exertion, cough, shortness of breath); manifest a 
decline from baseline of 5% in oxygen saturation, or demonstrate evidence of pulmonary 
inflammation (eg, focal or diffuse interstitial pattern or ground-glass opacities on chest CT)
should be evaluated. Potential bacterial, fungal, or viral etiologies should be assessed. 
Noninfectious etiologies such as pulmonary edema or thromboembolism should also be 
considered.
As appropriate for the clinical situation and culture results, subjects should be treated empirically 
or given specific antibiotics, antifungals, or antiviral agents for a cultured organism. Supportive 
care, including oxygen or mechanical ventilation, should be provided as necessary.
For subjects with suspected pneumonitis (eg, onset of cough, dyspnea, hypoxia and/or a diffuse 
interstitial pattern or ground-glass opacities on chest imaging without obvious infectious 
etiology), study drug should be interrupted. Supportive care, including oxygen or mechanical 
ventilation, should be considered and provided as necessary. Consider bronchoscopy to evaluate 
for PJP, CMV and other organisms (bacterial and viral).  Consider treatment with systemic 
corticosteroids.  Consider empiric treatment of pneumocystis if bronchoscopy is contraindicated. 
Upon resolution, may resume idelalisib at lower dose level at investigator discretion and
following discussion with Gilead medical monitor.
5.4.8.
Secondary Malignancies
Subjects receiving idelalisib for CLL or iNHL have developed pre-malignant and secondary 
malignant diseases, such as basal cell carcinoma, myelodysplastic syndrome, myeloproliferative 
disorders, and more aggressive lymphoid malignancies (eg, have had Richter transformation). 
Generally this has occurred in subjects who have received multiple previous lines of therapy and 
when idelalisib is combined with other therapies such as rituximab or bendamustine. The specific 
association of the therapeutic agents with these types of events has not been determined.
There are reports of pre-malignant and malignant diseases that have developed in subjects who 
have been treated with bendamustine, including myelodysplastic syndrome, myeloproliferative 
disorders, acute myeloid leukemia, and bronchial carcinoma. The specific association of the 
therapeutic agents with these types of events has not been determined.
5.4.9.
Tumor Lysis Syndrome
Tumor lysis syndrome has not been observed with idelalisib monotherapy. 


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Subjects with tumor lysis syndrome should receive rapid reversal of hyperkalemia, intravenous 
hydration, antihyperuricemic agents, and appropriate cardiac and renal support, including 
dialysis as indicated. Upon recovery to baseline functioning, such subjects should continue study 
treatment.
5.4.10.
Pregnancy, Lactation, and Reproduction
Idelalisib has induced embryo lethality and teratogenicity when administered to pregnant female 
rats at maternally toxic doses. However, definitive reproductive toxicology studies in animals 
have not yet been performed and the specific effects of idelalisib on human embryogenesis or 
fetal development are unknown. Whether idelalisib is excreted in human breast milk is unknown. 
General toxicology studies in rats and dogs indicated dose-dependent reductions in testicular 
weights, with persistent minimal to mild degeneration of the seminiferous tubules and decreased 
spermatozoa in rats and hypospermatogenesis in dogs. The implications of these testicular 
changes for animal or human fertility are unknown.
Given the preliminary nature of data regarding the risks to a fetus or infant as a result of 
exposure to idelalisib, women of reproductive potential entering this study must have a negative 
serum pregnancy test at baseline and must not be breastfeeding. Males and females of 
childbearing potential should abstain from sexual intercourse or use an effective form of 
contraception (see Section 5.6.4). If a female study participant becomes pregnant or decides to 
breastfeed during the course of the study, all study therapy must be discontinued.
5.4.10.1.
PJP Prophylaxis
Trimethoprim sulfamethoxazole is rated a Pregnancy category C.  In rats, oral doses of 
533 mg/kg or 200 mg/kg produced teratologic effects manifested mainly as cleft palates. 
One survey found no congenital abnormalities in 35 children whose mothers had received oral 
sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter. Because 
sulfamethoxazole and trimethoprim may interfere with folic acid metabolism it should be used 
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Dapsone is rated a Pregnancy Category C.  Extensive, but uncontrolled experience and 
two published surveys on the use of Dapsone in pregnant women have not shown that Dapsone 
increases the risk of fetal abnormalities if administered during all trimesters of pregnancy or can 
affect reproduction capacity. Because of the lack of animal studies or controlled human 
experience, Dapsone should be given to a pregnant woman only if clearly needed. Dapsone is 
excreted in breast milk in substantial amounts. Hemolytic reactions can occur in neonates. 
Because of the potential for tumorgenicity shown for Dapsone in animal studies a decision 
should be made whether to discontinue nursing or discontinue the drug taking into account the 
importance of drug to the mother.
Atovaquone is rated a Pregnancy Category C.  Atovaquone is teratogenic and did not cause 
reproductive toxicity in rats at plasma concentrations up to 2 to 3 times the estimated human 
exposure. Atovaquone can cause maternal toxicity in rabbits at plasma concentrations that were 
approximately one half the estimated human exposure. Mean fetal body lengths and weights were 


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decreased and there were higher numbers of early resorption and post-implantation loss per dam. It is 
not clear whether these effects are caused by atovaquone directly or are secondary to maternal 
toxicity. Concentrations of atovaquone in rabbit fetuses averaged 30% of the concurrent maternal 
plasma concentrations.  There are no adequate and well-controlled studies in pregnant women. 
Atovaquone should be used during pregnancy only if the potential benefit justifies the potential risk 
to the fetus. It is not known whether atovaquone is excreted into human milk. Because many drugs 
are excreted into human milk, caution should be exercised when Atovaquone is administered to a 
nursing woman. In a rat study, atovaquone concentrations in the milk were 30% of the concurrent 
atovaquone concentrations in the maternal plasma.
Aerosolized Pentamidine (NebuPent) is a Pregnancy Category C.  There are no adequate and well 
controlled studies of NebuPent in pregnant women. One literature report indicated that intravenously 
administered pentamidine in pregnant rats at 4 mg/kg/day was embryolethal; teratogenicity was not 
observed in this study. It is unknown whether pentamidine administered via the aerosolized route 
crosses the placenta at clinically significant concentrations. It is not known whether NebuPent can 
cause fetal harm when administered to a pregnant woman. NebuPent should be given to a pregnant 
woman only if clearly needed.  It is not known whether NebuPent is excreted in human milk.  
NebuPent should not be given to a nursing mother unless the potential benefits are judged to 
outweigh the unknown risks.
5.4.11.
Ultraviolet Exposure
In vitro studies indicate enhanced cytotoxicity when embryonic murine fibroblasts treated with 
GS-563117 (the major metabolite of idelalisib) are simultaneously exposed to ultraviolet light. 
While nonclinical findings suggest the hypothetical potential for phototoxicity in humans, 
available clinical data do not reveal a photosafety concern. Although specific clinical correlates 
for these nonclinical data are not available, investigators and study subjects should be observant 
for the possibility that study participants may have exaggerated sunburn reactions 
(eg, burning, erythema, exudation, vesicles, blistering, edema) involving areas of skin exposed to 
ultraviolet light.
5.4.12.
Further Safety Information
Further safety information regarding the study drug may be found in the investigator brochure 
for idelalisib. 
5.5.
Emergency Unblinding
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IWRS system 
for that subject. Gilead recommends but does not require that the investigator contact the 
Gilead medical monitor before breaking the blind. Treatment assignment should remain blinded 
unless that knowledge is necessary to determine subject emergency medical care. The rationale 
for unblinding must be clearly explained in source documentation and on the case report 
form/ electronic case report form (CRF/eCRF), along with the date on which the treatment 
assignment was obtained. The investigator is requested to contact the Gilead medical monitor 
promptly in case of any treatment unblinding.


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Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).
5.6.
Concomitant and Supportive Therapy
To the extent possible, administration of any prescription or over-the-counter drug products other 
than study medication should be minimized during the study period. Subjects should be 
discouraged from use of street drugs, herbal remedies, self-prescribed drugs, tobacco products, or 
excessive alcohol at any time during the clinical study.
If considered necessary for the subject’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator. The decision to 
authorize the use of any drug other than study drug should take into account subject safety, the 
medical need, the potential for drug interactions, the possibility for masking symptoms of a more 
significant underlying event, and whether use of the drug will compromise the outcome or 
integrity of the study
Subjects should be instructed about the importance of the need to inform the clinic staff of the 
use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and during 
the course of the study. Any concomitant drugs taken by a subject during the course of the study 
and the reason for use should be recorded on the eCRFs.
Information regarding use or restrictions on specific concomitant medications, dietary measures, 
or other interventions is provided below.
5.6.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments
Except for corticosteroids (see Section 5.6.5), no other systemic anticancer therapies (including 
but not limited to chemotherapy, radiation, antibody therapy, immunotherapy, or other 
experimental therapies) of any kind are permitted. Subjects are not allowed to participate 
concurrently in any other therapeutic clinical study.
5.6.2.
Antibiotics
Investigators must initiate antibiotic prophylaxis against pneumocystis infection 
(eg, with trimethoprim-sulfamethoxazole, dapsone, aerosolized pentamidine, or atovaquone)
beginning prior to study drug administration. Such support may also offer the benefit of reducing
the risk for other bacterial infections {Green et al 2007}. Investigator discretion and local 
practices or guidelines may be followed.


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For subjects who develop an infection, appropriate medical therapy (with antibiotics, antifungals, 
or antiviral) or other interventions should be instituted. Whenever appropriate, subjects may 
continue with study drug during treatment for the infection; however, subjects who develop PJP
must permanently discontinue study drug.
5.6.3.
Antiemetics and Antidiarrheals
Drug-related nausea and/or vomiting have not been commonly observed with idelalisib in prior 
studies. However, subjects who experience nausea or vomiting while on study therapy may 
receive antiemetics based on the judgment of the treating physician and local institutional 
practices. At the occurrence of persistent nausea or vomiting of severity Grade 1, it is suggested 
that the subject receive an oral or transdermal serotonin antagonist (eg, dolasetron, granisetron, 
ondansetron, tropisetron, palonosetron). Other classes of antiemetic medications that may be 
employed include dopamine antagonists or benzodiazepines. As needed, subjects may be 
prescribed loperamide (Imodium® or others) or diphenoxylate and atropine (Lomotil®) to control 
diarrheal symptoms.
5.6.4.
Contraception
In the context of this protocol, a female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, a bilateral tubal ligation, or a bilateral oophorectomy; has 
medically documented ovarian failure (with serum estradiol and FSH levels within the 
institutional postmenopausal range and a negative serum or urine HCG); or is menopausal 
(age ≥54 years with amenorrhea for >12 months or amenorrhea for >6 months with serum 
estradiol and FSH levels within the institutional postmenopausal range).
Sexually active females of childbearing potential must agree to use a protocol-recommended 
method of contraception during heterosexual intercourse throughout the study treatment period 
and for 30 days following the last dose of the study drug. The investigator should counsel 
subjects on the most effective methods for avoiding pregnancy during the trial. 
Protocol-recommended contraceptive methods are described in Table 5-3.


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Table 5-3.
Protocol-Recommended Contraceptive Methods
Individual Methods
Combination Methods
Hormonal Methods
(One method to be used
with a barrier method)
Barrier Methods
(Both of these methods to be used OR
one of these methods to be used
with a hormonal method)
IUD

Copper T 380A IUD

LNg 20 IUD
Tubal sterilization
Hysterectomy

Estrogen and 
progesteroneOral 
contraceptives

Transdermal patch

Vaginal ring
Progesterone

Injection

Implant

Diaphragm with spermicidea

Male condom(with spermicidea)
a
If available/approved for use in the specific country
Abbreviation: IUD=intrauterine device
In the context of this protocol, a male subject is considered able to father a child unless he has 
had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or is receiving
ongoing testicular suppression with a depot luteinizing hormone-releasing hormone (LH-RH) 
agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or 
triptorelin pamoate [Trelstar®]).
Sexually active male subjects who can father a child must accept continuous heterosexual 
abstinence as a lifestyle choice; limit intercourse to female partners who are surgically sterile, 
post-menopausal, or using effective contraception (as noted in Table 5-3); or agree to use a 
protocol-recommended method of contraception during heterosexual intercourse throughout the 
study treatment period and for 90 days following discontinuation of the study drug
(as noted in Table 5-3). 
The Gilead Sciences medical monitor should be consulted regarding any questions relating to 
childbearing status or contraception.
5.6.5.
Corticosteroids
Subjects may receive topical, inhaled, enteric, or systemic corticosteroids while on study. It 
should be realized that the use of systemic corticosteroids in patients with CLL may confound 
interpretation of antitumor effects mediated by study drug therapy. However, subjects who 
develop conditions that may be alleviated by systemic corticosteroid therapy are permitted to 
receive such drugs and are not required to discontinue study participation.
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin
Granulocyte-macrophage colony-stimulating factor (GM-CSF) should not be administered given 
the potential for GM-CSF-related inflammatory symptoms.


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G-CSF (filgrastim, PEG-filgrastim, lenograstim) may be administered in response to 
Grade 4 neutropenia or neutropenic complications; use should be particularly considered if 
providing hematopoietic support might help to maintain study drug treatment (see Table 5-2).
While erythropoietic agents (eg, erythropoietin or darbepoetin) may be administered for 
Grade 3 anemia, their use in this study is discouraged given the potential to confound 
assessments of improvements in bone marrow function related to study drug.
Reference may be made to the American Society of Clinical Oncology guidelines {Rizzo et al 
2008}, {Smith et al 2006}.
5.6.7.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism
Idelalisib is metabolized primarily via aldehyde oxidase and in part by CYP3A. A clinical 
drug-drug interaction study indicated that administration of a potent CYP3A inhibitor together 
with idelalisib resulted in a ~80% increase in idelalisib plasma exposures (AUC) 
(see Section 1.3.5.1), which is not considered to be clinically relevant and suggesting that 
idelalisib is a weak CYP3A substrate. Preliminary data indicate when coadministered with 
rifampin, a highly potent inducer of CYP3A, idelalisib exposures are ~75% lower. 
Coadministration of potent inducers of CYP3A with idelalisib should be avoided; a list of strong 
inducers is provided in Table 5-4:
Table 5-4.
Known Strong Inducers of CYP3A
Effect on CYP3A
Drug Class
Medications
Strong CYP3A Inducers
Antimycobacterial
Rifampin
Anticonvulsants
carbamazepine, phenytoin
Foods/herbs
St. John’s wort
Abbreviation: CYP=cytochrome P450 enzyme
5.6.8.
Drugs that undergo CYP3A-Dependent Metabolism
The major metabolite of idelalisib, GS-563117, is a reversible and time dependent inhibitor of 
CYP3A; accordingly coadministration of idelalisib with midazolam, a probe CYP3A substrate, 
resulted in a ~5-fold increase in midazolam systemic exposure (AUC), indicating that idelalisib 
is a strong inhibitor of CYP3A. Coadministration of CYP3A substrates with idelalisib may result 
in an increase in their systemic exposures (eg, antiarrhythmics, calcium channel blockers, 
benzodiazepines, certain HMG-CoA reductase inhibitors, phosphodiesterase-5 (PDE5) 
inhibitors, warfarin). Avoid coadministration of drugs that are narrow therapeutic index CYP3A 
substrates (eg, alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, fentanyl, 
quinidine, ergotamine, dihydroergotamine, astemizole, terfenadine) with idelalisib.


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5.6.9.
Immunization
Because of its actions to inhibit PI3Kδ-dependent B-cell function, high doses of idelalisib can 
impair primary or secondary responses to immunization in animals.
The specific clinical relevance of these findings with idelalisib is unknown. However, for 
subjects who are at substantial risk of an infection (eg, influenza) that might be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of study 
therapy.
Of note, the safety of immunization with live viral vaccines following idelalisib therapy has not 
been studied and vaccination with live virus vaccines during study treatment is not 
recommended.
5.6.10.
Surgery
There are no known effects of idelalisib on coagulation or wound healing. Pending receipt of 
additional information, study drug may be continued in the peri-procedural period in subjects 
who require surgery or invasive procedures.
5.6.11.
Diet
There are no specific dietary restrictions in the study. Study drug may be taken with or without 
food.
5.7.
Duration of Study Drug
Subjects may continue receiving study drug until the occurrence of any events requiring study 
drug discontinuation as defined in Section 5.8.
5.8.
Discontinuation of Study Drug
All study participants may receive study drug indefinitely; however:

Any subject has the right to discontinue study drug at any time.

Any subject who has objective evidence based on IRC review of definitive CLL progression
will discontinue study drug.

Any subject unable to tolerate a second rechallenge with protocol-described, dose-modified 
idelalisib at Dose Level –1 (see Section 5.2) should discontinue study drug.

Any subject who becomes pregnant or begins breastfeeding should discontinue study drug.

Any subject who becomes significantly noncompliant with study drug administration, study 
procedures, or study requirements should discontinue study drug.


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
Any subject for whom the blind is intentionally broken by the subject or the study site should 
discontinue study drug (only applicable to the blinded portion of the study).

The investigator, in consultation with the Gilead Sciences medical monitor, may discontinue
study drug, if, it is not in the subject’s best interest to continue.

If allowed by local regulations, Gilead Sciences may transition subjects from study drug to 
commercial drug supply when idelalisib becomes commercially available in the country 
where the subject is living.

Any subject who is diagnosed with any grade of SJS or TEN, Grade ≥2 pneumonitis, or PJP
must discontinue study drug.
Any subject whose benefit-risk profile is not deemed positive by the investigator should 
discontinue study drug.
Subjects who permanently discontinue study drug for a reason other than disease progression 
(as determined by the IRC) shall continue with assessments per the schedule of procedures until 
disease progression or until another anticancer or experimental therapy is initiated.
5.9.
Discontinuation from Study
Subject study participation will be ended due to any of the following reasons:

Adverse event.

Disease progression.

Withdrawal of consent.

Significant subject noncompliance with study drug administration, study procedures, or study 
requirements.

Initiation of any additional systemic anticancer therapies (other than corticosteroids, 
see Section 5.6.5) including chemotherapy, radiation, antibody therapy, immunotherapy, or 
other experimental treatment.

Physician’s decision to remove the subject from the study.

Pregnancy.

The subject is lost to follow-up.

Death.

Discontinuation of study by the Sponsor, a Regulatory Agency, or an IRB or EC.


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5.10.
Study Treatment Rationale
Subjects will be assigned to treatment (Arm A or Arm B) in this study based on their 
randomization in the primary study. The 1:1 randomization in the primary trial
(GS-US-312-0116) ensures that sufficient Arm B subjects will cross over from 
rituximab alone to single-agent idelalisib at the 150-mg/dose BID starting dose level in this 
extension trial (GS-US-312-0117) to allow an adequate evaluation of efficacy and safety in this 
trial. The randomization and allocation processes will be established and performed through an 
IWRS; the intent is to maximize the integrity and security of the subject disposition and to ensure 
appropriate access and convenience-of-use by the investigational sites.
Double blinding is included to provide protection against biased interpretations of efficacy and 
safety data by subjects, caregivers, investigators, Gilead Sciences personnel, or others involved 
in study conduct.
Selection of the idelalisib treatment regimen (including starting dose level, dose-modifications 
and supportive care, schedule, duration, and conditions of administration) for this study program 
has been based primarily on safety, exposure, and activity profiles from previous Phase 1 clinical 
studies involving healthy volunteers, patients with allergic rhinitis, and patients with 
refractory/relapsed lymphoid malignancies {Webb et al 2010}, {Coutre et al 2011}, {Kahl et al 
2011}. The following information was considered in selecting the study drug dosing regimen for 
the primary study and this companion extension study:

Idelalisib was symptomatically well tolerated in patients with lymphoid malignancies receiving 
dose levels of 50 mg/dose BID through 350 mg/dose BID (the highest dose level tested). No
specific MTD was apparent over the dose range tested. However, monitorable, reversible 
transaminase elevations were observed in some patients and may have been more frequent at 
higher dose levels (~10% rate among patients with CLL receiving starting doses of 
150 mg/dose). Thus, while doses through 350 mg/dose BID are tolerable, the starting dose 
of 150 mg/dose BID appears to appropriately balance safety with efficacy in idelalisib-naïve 
subjects. The starting dose of 300 mg/dose BID in this study also appears appropriate for 
evaluation; it is lower than the dose level of 350 mg/dose BID that has been tolerable in prior 
studies and is likely to be suitable in subjects who have already been tolerating idelalisib
therapy at 100 mg/dose BID. 

Upon disease progression, permitting escalation from 150 mg/dose BID to 300 mg/dose BID 
among subjects allocated to Arm A offers a systematic evaluation of higher doses in subjects 
who are tolerating idelalisib treatment and might benefit from increased PI3Kinhibition. 
The pharmacological basis for considering such an intervention is based on the concept that 
some individuals might have lower-than-expected plasma exposures or dose-dependent 
resistance to the compound at 150 mg/dose BID and might benefit from a higher dose. The 
intent is to determine if the higher dose can reestablish disease control or whether absolute 
resistance to PI3Kinhibition has been acquired. The safety data obtained in these subjects 
would add to the overall safety database.


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
In an allergic rhinitis study, idelalisib induced statistically significant improvements in 
clinical and pharmacodynamic endpoints when administered at 100 mg/dose BID over 
7 days. These data support the pharmacological relevance of idelalisib-mediated 
PI3Kδ inhibition when administered at the dose-levels to be used in this study.

A positive correlation was noted between idelalisib dose and measures of tumor control and 
chemokine normalization in patients with B-cell malignancies. The majority of patients 
appear to have tumor responses and protracted PFS when receiving starting doses of 
100 mg/dose BID. Thus, treatment with a idelalisib at a starting dose of 150 mg/dose BID 
appears to offer most patients the potential to benefit from therapy and the dose level of 
300 mg/dose BID may provide additional benefit in patients with disease resistance as 
systematically evaluated in this trial. 

Increases in idelalisib plasma Cmax, AUC, and Ctrough values were less than dose-proportional 
in subjects with lymphoid malignancies; the dose-exposure evaluation indicated modest 
increases in plasma exposure at dose levels >150 mg BID.  Thus, administration of starting 
doses of idelalisib of 150 mg/dose BID appears appropriate to ensure adequate exposure in 
the majority of patients. 

In Phase 1 studies, the mean plasma t1/2 of idelalisib was ~6.5 to 9.8 hours across all dose 
levels and there was no substantive plasma accumulation over 7 or 28 days.

The changes in exposure observed when administering idelalisib after a high-fat, high-calorie 
meal are modest (~40% increase in mean AUC with no change in mean Cmax). 
Thus, idelalisib can be administered with or without food. 

The idelalisib dose modification provisions described in the protocol are designed to balance 
a primary concern for subject safety with the potential for observing pharmacological and 
antitumor activity in circumstances under which a subject experiencing an adverse event may 
still be able to continue on therapy at a lower idelalisib dose level. The enhanced monitoring 
to be performed and the actions to be taken in response to toxicity are based on experience 
with interruption, dose-modification, rechallenge, and re-escalation already piloted in 
idelalisib Phase 1 trials. In addition, idelalisib antitumor activity has been observed in the 
Phase 1 studies across all dose levels tested, including doses in the range of the modified 
dose levels planned for this protocol. Thus, use of the lower dose level to accommodate 
individual subject tolerability in this protocol is justified because subjects receiving such an
idelalisib dose level still have the potential for benefit.

In both the primary and extension studies, study treatment will be continued for each subject
until the occurrence of disease progression. Such a strategy is considered appropriate under 
the assumption that persistent interference with PI3Ksignaling is likely to extend treatment 
effect. In addition, this design permits collection of further single-agent safety information 
and thus is likely to enhance understanding of the overall safety profile of idelalisib. 


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6.
STUDY PROCEDURES
6.1.
Enrollment and Study Management Procedures
6.1.1.
Subject Recruitment
Study candidates are limited to those subjects who participated in the primary clinical trial
(Study GS-US-312-0116) and meet the entry criteria for this trial (Study GS-US-312-0117).
Subjects will be enrolled from investigational sites in the United States and Europe. The site 
principal investigator, designated sub-investigators, or other designees will discuss the possibility 
of participation directly with subjects who participated in the primary study.
The study sponsor will post a description of the study on the ClinicalTrials.gov website. Any 
promotional information generated by the sponsor or investigational sites will be submitted for 
IRB/IEC review.
6.1.2.
Subject Compensation for Participation
For subjects requesting such assistance, reasonable reimbursements for the costs of travel 
required to participate in this study will be provided by the study sponsor. To receive payment 
for travel, subjects will need to submit the original travel receipts to the research study staff at 
the investigational site.
However, other than medical care that may be provided, subjects will not be paid for 
participation in the study. Payments for such items as lost wages, disability, discomfort due to 
injury, or meals obtained while waiting at the clinical research center will not be provided. 
Through the informed consent process, study candidates will be notified that their insurance 
company could be charged for standard care that is a component of this research study and that 
subjects may be responsible for co-payments and deductible payments that are typical for their 
insurance coverage.
6.1.3.
Screening
The investigator must inform each prospective subject of the nature of the study, explain the 
potential risks, and obtain written informed consent from the subject and/or a legal guardian 
prior to performing any study-related screening procedures. At the time the study candidate signs 
the informed consent, a site representative should access the IWRS to indicate that a study 
candidate is being screened. The user will need to supply the IWRS with required information 
identifying the site and the subject number as already assigned in Study GS-US-312-0116.
Any consented subject who is excluded from the study before initiation of study treatment will 
be considered a screen failure. All screen failures must be documented along with an adequate 
description of the reason the subject was considered a screen failure. If available, information 
should be provided as to why the subject did not meet eligibility criteria, withdrew consent, 
experienced an intercurrent illness, or had other events that precluded treatment on this study.


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6.2.
Explanation of Study Visits
The specific study procedures to be conducted for each subject enrolled in the study are 
presented in tabular form in Appendix 7 and are described in the sections that follow. Additional 
information on the study procedures is provided in the study manual.
For visits at which HRQL and healthy utility data are obtained, it is important that the subject be 
administered the FACT-Leu and the EQ-5D before any other procedures are performed and 
before any study-related information is communicated to the subject; this is necessary to avoid 
biasing the PRO responses provided by the subject. Once the subject has completed the 
FACT-Leu and the EQ-5D assessments, the remaining procedures may be performed.
At visits involving idelalisib administration and pharmacokinetic sampling in the clinic, care 
should be taken to perform procedures with the appropriate timing relative to idelalisib
administration. The actual sample collection times of pharmacokinetic blood specimens should 
be recorded. If a heparinized venous catheter is placed for sample collection in order to avoid 
repeated needle sticks, at least 2 mL of blood should be removed and discarded prior to each 
sample collection in order to avoid heparin contamination of the sample.
At the visit designated as a laboratory-only visit (Visit 7), subjects will have laboratory 
assessments that may be performed at the investigational site or at an accredited local laboratory 
or clinic that is convenient for the subject/caregiver. If blood is collected at a local laboratory, 
samples are not to be analyzed at the local laboratory. For these visits, subjects and/or caregivers
will be provided with central laboratory kits that will contain materials necessary for the 
collection and shipment of the laboratory samples by the local laboratory clinic to the central 
laboratory.
Local lab results may be requested in the event central laboratory results are not available for 
assessment of disease response, progression, or the evaluation of a significant event. In addition 
to clinical assessments of tumor status, CT or MRI imaging of the neck, chest, abdomen, and 
pelvis will be performed as a component of tumor assessments during the study based on the 
rationale provided in Section 3.2.1.
Following unblinding of the study:

Subjects who were randomized to idelalisib on Study GS-US-312-0116 and who received 
≥24 weeks idelalisib will complete Visit 16+ twelve weeks from the date of their last 
radiology assessment (CT/MRI) and study visits will continue every 12 weeks thereafter.
Visits 3 through 15 will not be required.

Subjects who have received < 24 weeks of idelalisib will have all Study GS-US-312-0117 
assessments completed per the Schedule of Procedures until they have received idelalisib for 
24 weeks cumulative across both studies. After completion of 24 weeks of cumulative 
idelalisib treatment, Visit 16+ will be conducted 12 weeks from the date of their last 
radiology assessment (CT/MRI), after which time study visits will occur every 12 weeks.


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6.2.1.
Visit 1 and Screening Period (Clinic Visit)
The initial screening visit is designated as Visit 1. At Visit 1, the investigator must inform each 
prospective study participant of the nature of the study, explain the potential risks, and obtain 
written informed consent from the study candidate and/or legal guardian prior to performing any 
study-related screening procedures. Once the informed consent document has been signed, the 
subject may undergo the screening procedures.
In order to optimize scheduling convenience for the subject and for the investigational staff, 
study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be 
used as screening procedures for Study GS-US-312-0117 if performed within 4 weeks prior to 
initiation of study drug therapy on Study GS-US-312-0117. In addition, screening procedures 
may be performed over as many days as necessary provided that screening is completed within 
4 weeks prior to initiation of study drug therapy on Study GS-US-312-0117.
The tests and evaluations outline in Table 6-1 will be performed at Visit 1 or during the 
screening period prior to initiation of study treatment.


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Table 6-1.
Procedures and Assessments at Visit 1 (During Screening Period)
Assessment or Procedure
Explanationa
Informed consent
To be obtained before any screening procedures are initiated
IWRS access
Access IWRS to document that subject is in screening and provide the subject number
from Study GS-US-312-0116
CIRS assessment
Recording of current comorbid conditions using the CIRS scoring instrument
(see Appendix 6)
Concomitant medications
Recording of ongoing concomitant medication use
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including height, weight, evidence of palpable lymphadenopathy, hepatomegaly, 
and/or splenomegaly
Serum β-HCG
Women of childbearing potential only
CLL peripheral blood 
evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 
12 trisomy; DNA mutational analysis for p53, IgHV (including IgHV3-21), and other 
genes of interest in CLL (eg, Notch); flow cytometry for CD5, CD10, CD11c, CD19, 
CD20, CD23, CD38, CD45, kappa and lambda light chains, and ZAP-70; 
cytology for karyotyping.
CLL serology
Serum 2 microglobulin
 
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis, to be scheduled with 
4 weeks prior to initiation of study treatment at Visit 2
Bone marrow biopsy and 
aspirate
To be performed at investigator discretion to determine extent of CLL involvement 
and bone marrow cellularity.
a
Study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be used as screening 
procedures for Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117.
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase,
AST=aspartate aminotransferase, CIRS=cumulative illness rating scale, CLL=chronic lymphocytic leukemia, CT=computed 
tomography, DNA=deoxyribonucleic acid, FISH= fluorescence in-situ hybridization, GGT=gamma--glutamyltransferase, 
Ig=immunoglobulin, IgHV=immunoglobulin heavy chain variable region, IWRS=interactive web response system, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging, RNA=ribonucleic acid, ZAP-70=zeta-associated protein 70
PPD


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6.2.2.
Visit 2 (Day 1) (Clinic Visit)
Subjects will be assessed to determine if they still meet eligibility criteria and can initiate study 
treatment. Study drug holds from primary study GS-US-312-0116 may continue as medically 
appropriate. The procedures outlined in Table 6-2 will be performed at Visit 2 (Day 1).
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
β-HCG
For women of child-bearing potential only; serum -HCG or urine dipstick pregnancy 
test must be negative prior to initial study treatment
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics
(with recording of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration
Study drug administrationa
First dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib
pharmacokineticsa
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensinga
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding study 
drug dosing at next full 
clinic visita
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 3.
a
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll on Study GS-US-312-0117 following 
unblinding may have idelalisib treatment (and associated PK testing) delayed at the Investigator’s discretion until the time of 
disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib treatment
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response 
system, LDH=lactate dehydrogenase, RNA=ribonucleic acid


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6.2.3.
Visit 3 (Day 15) (Clinic Visit)
The procedures outlined in Table 6-3 will be performed at Visit 3 (Day 15 [±2 days]).
Table 6-3.
Procedures and Assessments at Visit 3 (Day 15)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib pharmacokinetics
Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose). Pre-dose 
collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to document subject visit
Study Therapy Administration
Study drug administration
Study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Instruction regarding study 
drug dosing at next full 
clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 4.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase,
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, HRQL=health-related 
quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, LDH=lactate dehydrogenase


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6.2.4.
Visit 4 (Day 29) (Clinic Visit)
The procedures outlined in Table 6-4 will be performed at Visit 4 (Day 29 [±2 days]).
Table 6-4.
Procedures and Assessments at Visit 4 (Day 29)
Assessment or Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 3
Concomitant medications
Recording of concomitant medication used since Visit 3
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, IgM
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics
(with recording of the date and actual clock time of the date and actual clock time of 
blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration and Dispensing
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)


Idelalisib
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Assessment or Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 5.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.5.
Visit 5 (Day 43) (Clinic Visit)
The procedures outlined in Table 6-5 will be performed at Visit 5 (Day 43 [±2 days]).
Table 6-5.
Procedures and Assessments at Visit 5 (Day 43)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
IWRS access
Access of IWRS to document subject visit
Post-Therapy Procedures and Assessments
Instruction regarding study 
drug dosing at next full 
clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 6.
Scheduling of Visit 6 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 6.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, 
LDH=lactate dehydrogenase


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Version 8.0
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6.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit)
The procedures outlined in Table 6-6 will be performed at Visit 6 (Day 57 [±2 days]).
Table 6-6.
Procedures and Assessments at Visit 6 (Day 57)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted.
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 5
Concomitant medications
Recording of concomitant medication used since Visit 5
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and 
CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug bottle number


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Assessment or Procedure
Explanation
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 8.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging
6.2.7.
Visit 7 (Day 71) (Laboratory Visit)
The procedures outlined in Table 6-7 will be performed at Visit 7 (Day 71 [±2 days]).
Table 6-7.
Procedures and Assessments at Visit 7 (Day 71)
Assessment or Procedure
Explanation
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including ALT, AST, ALP, GGT, total bilirubin, LDH
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
GGT=gamma-glutamyltransferase, LDH=lactate dehydrogenase


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6.2.8.
Visit 8 (Day 85) (Clinic Visit)
The procedures outlined in Table 6-8 will be performed at Visit 8 (Day 85 [±2 days]).
Table 6-8.
Procedures and Assessments at Visit 8 (Day 85)
Assessment or Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 6
Concomitant medications
Recording of concomitant medication used since Visit 6
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM, 
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration and Dispensing
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 8.0
CONFIDENTIAL
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Assessment or Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 9.
Scheduling of Visit 9 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 9.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit)
The procedures outlined in Table 6-9 will be performed at Visit 9 (Day 113 [±3 days]).
Table 6-9.
Procedures and Assessments at Visit 9 (Day 113)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the
visit the assessment should be done even if study drug has been interrupted.
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since Visit 8
Concomitant medications
Recording of concomitant medication used since Visit 8
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and 
CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number


Idelalisib
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Final
Gilead Sciences, Inc.
Version 8.0
CONFIDENTIAL
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Assessment or Procedure
Explanation
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 10.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.10.
Visit 10 (Day 141) (Clinic Visit)
The procedures outlined in Table 6-10 will be performed at Visit 10 (Day 141 [±3 days]).
Table 6-10.
Procedures and Assessments at Visit 10 (Day 141)
Assessment or Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 9
Concomitant medications
Recording of concomitant medication used since Visit 9
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug  blister card number
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)


Idelalisib
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CONFIDENTIAL
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Assessment or Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 11.
Scheduling of Visit 11 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 11.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit)
The procedures outlined in Table 6-11 will be performed at Visit 11 (Day 169 [±3 days]). 
Table 6-11.
Procedures and Assessments at Visit 11 (Day 169)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted. 
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant medications
Recording of concomitant medication used since Visit 10
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card numbers


Idelalisib
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Final
Gilead Sciences, Inc.
Version 8.0
CONFIDENTIAL
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Assessment or Procedure
Explanation
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for 
self-administration at home.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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Gilead Sciences, Inc.
Version 8.0
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6.2.12.
Visit 12 (Day 211) (Clinic Visit)
The procedures outlined in Table 6-12 will be performed at Visit 12 (Day 211 [±3 days]).
Table 6-12.
Procedures and Assessments at Visit 12 (Day 211)
Assessment or Procedure
Explanation
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 11
Concomitant medications
Recording of concomitant medication used since Visit 11
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit
Study drug administration
Subject to continue with study drug as prescribed.
Scheduling of Visit 13 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 13.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.13.
Visit 13 (Day 253) (Clinic and Radiology Visit)
The procedures outlined in Table 6-13 will be performed at Visit 13 (Day 253 [±3 days]).
Table 6-13.
Procedures and Assessments at Visit 13 (Day 253)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted.
During-Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant medications
Recording of concomitant medication used since Visit 10
Study drug return/
accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study drug administration
Subject to continue with study drug as prescribed.
Study drug dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for 
self-administration at home.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.14.
Visit 14 (Day 295) (Clinic Visit)
The procedures outlined in Table 6-14 will be performed at Visit 14 (Day 295 [±3 days]).
Table 6-14.
Procedures and Assessments at Visit 14 (Day 295)
Assessment or Procedure
Explanation
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant medications
Recording of concomitant medication used since Visit 10
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit
Study drug administration
Subject to continue with study drug as prescribed.
Scheduling of Visit 15 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 15.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.15.
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks)
(Clinic and Radiology Visits)
The procedures outlined in Table 6-15 will be performed at Visit 15 (Day 337 [±3 days]) and 
every 12 weeks thereafter [±7 Days]).
Table 6-15.
Procedures and Assessments at Visit 15 and Subsequent Visits
(Day 337 and Every 12 Weeks)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted.
During-Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since prior visit
Concomitant medications
Recording of concomitant medication used since prior visit
Study drug return/
accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
CMV viral load
CMV viral load testing approximately every 4 weeks throughout the course of 
idelalisib treatment
Circulating cells
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Immune monitoring
Lymphocyte subset panel using flow cytometry (immunophenotyping), 
serum CH50 level
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines


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Assessment or Procedure
Explanation
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study drug administration
Subject to continue with study drug as prescribed.
Study drug dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for 
self-administration at home
PJP prophylaxis
Subjects must receive trimethoprim-sulfamethoxazole or other established 
prophylaxis for PJP throughout the course of idelalisib treatment.  Subjects must 
permanently discontinue idelalisib upon diagnosis of PJP.
Scheduling of next visit 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for next 
clinic visit (every 12 weeks).
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CMV=cytomegalovirus, CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, 
FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related 
quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, PJP= Pneumocystis 
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6.2.16.
End-of-Study Visit (Clinic Visit)
At the time of discontinuation from the study, the subject should have the procedures and 
assessments performed as documented in Table 6-16. An end-of-study CT/MRI tumor 
assessment should be performed unless the subject already has radiographic confirmation of 
definitive disease progression or a CT/MRI has been performed within 4 weeks prior to the 
end-of-study visit.
Table 6-16.
Procedures and Assessments at End-of-Study Visit
Assessment or Procedure
Explanation
Radiology assessmenta
CT or MRI imaging of neck, chest, abdomen, and pelvis
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed
Adverse events 
Recording of adverse events occurring since prior visit; if a clinically significant 
adverse event or abnormal result is observed that is not resolved by the 
end-of-treatment visit, repeat evaluations should be performed to document resolution 
or stabilization of the abnormality
Concomitant medications
Recording of concomitant medication used since prior visit
Study drug return/
accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Serum β-HCG
Women of childbearing potential only
CLL peripheral blood 
evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 
12 trisomy; DNA mutational analysis for p53, IgHV (including IgHV3-21), and other 
genes of interest in CLL (eg, Notch); flow cytometry for CD5, CD10, CD11c, CD19, 
CD20, CD23, CD38, CD45, kappa and lambda light chains, and ZAP-70; 
cytology for karyotyping
CLL serology
Serum 2 microglobulin
 
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
PPD


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Assessment or Procedure
Explanation
Circulating cells
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Immune monitoring
Lymphocyte subset panel using flow cytometry (immunophenotyping), serum CH50 
level
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
PJP prophylaxis
Subjects must receive trimethoprim-sulfamethoxazole or other established 
prophylaxis for PJP after completion of idelalisib treatment until the CD4+ T-cell 
count is > 200 cells/mcL, at which point PJP prophylaxis may be discontinued.
IWRS
Access IWRS to document that subject has permanently discontinued study therapy
and to indicate whether subject agrees to continue to undergo long-term follow-up
a
An end-of-study CT/MRI tumor assessment should be performed unless the subject has per-protocol CT/MRI assessments 
4 weeks prior to end-of-study discontinuation.
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, CLL=chronic lymphocytic leukemia, CT=computed tomography, FISH= fluorescence in-situ 
hybridization, GGT=gamma-glutamyltransferase, IgHV=immunoglobulin heavy-chain variable-region, IWRS=interactive web 
response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, PJP= Pneumocystis jirovecii pneumonia,
RNA=ribonucleic acid, ZAP-70=zeta-associated protein 70
6.2.17.
30 Day and Long-Term Follow-up
A 30 Day follow-up visit will be performed 30 (+ 5) days following the end-of-study visit; 
however, it may be waived for subjects who have permanently discontinued study drug and have 
had a study visit >30 days after the last dose of study drug.
Long-term, follow-up will be requested of all subjects who withdraw from study for any reason.
The long-term follow-up for survival will be conducted at ~6-month intervals for 5 years, 
starting at the end-of-study visit. Information may be gathered during a routine clinic visit or 
other contact with the subject, or via telephone. Information gathered will include medical status, 
anti-tumor treatments, secondary malignancies, and survival.
6.3.
Sample Storage
 
 
 
 
 
PPD


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6.4.
Blood Collection
The maximum amount of blood to be drawn at a visit ~115 mL and the total amount of blood to 
be drawn over the initial 52-week study period (including the 4-week screening period and 
through Week 48 of the study including a possible end-of-therapy visit) is ~560 mL. For a 
40-kg person (the smallest participant expected to enroll in the study), this equates to 
maximum blood volume per body weight per visit of ~2.8 mL/kg and a total blood volume 
per body weight per average 6-week period of ~1.6 mL/kg. These quantities of blood are within 
accepted limits of 3.0 mL/kg of body weight for a single blood draw and 7.0 mL/kg of 
body weight for a 6-week period.
Specific details regarding blood sample collection and processing requirements will be provided 
separately in the study manual.
 
 
 
6.5.
Study Procedure Rationale
The planned study assessments and timing have been selected as appropriate for screening of 
subjects, for determination of idelalisib-related or disease-related toxicities, for dose 
modification during the study, for characterization of drug exposure and desired pharmacological 
effects, and for evaluation of drug activity. The scheduling of testing is designed to collect a 
complete safety and pharmacology data set while maintaining subject tolerance of study 
procedures. The planned schedule of tumor assessments is consistent with expected rate of 
changes and appropriately balances precise measurement of tumor control with the expense and 
subject inconvenience associated with clinical and radiological procedures. For discussion of the 
rationale for endpoint selection, see Section 3.2.
PPD


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7.
EFFICACY ASSESSMENTS
7.1.
Tumor Status Assessments
The determination of CLL response and progression will be based on standardized IWCLL
criteria {Hallek et al 2008}, as specifically modified for this study to reflect current 
recommendations which consider the mechanism of action of idelalisib and similar drugs 
{Cheson et al 2012}. Treatment decisions by the investigator in this study will be based on these 
assessments. Radiographic and clinical tumor assessments will be subject to independent 
confirmation by the IRC (see Section 10.4.2).
7.2.
Method of Assessment
In addition to clinical examination, imaging-based evaluation will be used in this study in all 
subjects enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI 
scanning may be used at the investigator’s discretion in subjects for whom this may be a 
preferred alternative to CT scanning; however, if MRI is performed, a non-contrast CT of the 
chest should be performed. Contrast-enhanced scanning is preferred, but iodine-containing or 
gadolinium contrast material may be omitted in subjects for whom use of a contrast agent would 
be medically contraindicated. Chest x-ray, ultrasound, endoscopy, laparoscopy, PET, 
radionuclide scans, or tumor markers will not be considered for response assessment.
For radiographic evaluations, the same method of assessment and the same technique 
(eg, scan type, scanner, subject position, dose of contrast, injection/scan interval) should be used 
to characterize each identified and reported lesion at baseline and during study treatment and 
follow-up.
All relevant clinical and radiographic information required to make each tumor status assessment 
must be made available for source verification and for submission to the IRC 
(see Section 10.4.2).
7.3.
Timing of Assessments
All baseline clinical and CT/MRI tumor assessments should be performed within 4 weeks prior 
to initiation of study drug therapy. In order to optimize scheduling convenience for the subject 
and for the investigational staff, clinical and CT/MRI tumor assessments performed as part of 
Study GS-US-312-0116 need not be repeated and can be used as baseline tumor assessments for 
Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117. Clinical tumor assessments should be performed at each clinical visit. 
On-study CT/MRI tumor assessments should be performed at ~8- to 12-week intervals as 
dictated by the study protocol. An end-of-study CT/MRI tumor assessment should be performed 
unless the subject has per-protocol CT/MRI assessments 4 weeks prior. If a subject 
permanently discontinues study drug prior to objective documentation of CLL progression, 
investigators should continue further follow-up at ~12-week intervals until CLL progression is 
documented by the central IRC.


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7.4.
Identification and Measurement of Tumor Lesions and Organomegaly
7.4.1.
Index Lesions
At baseline, up to 6 lymph nodes should be selected as index lesions that will be used to 
quantitate the status of the disease during study treatment. Ideally, the index lesions should be 
located in disparate regions of the body. Only peripheral nodes need be selected as index lesions. 
However, it is optimal if mediastinal and retroperitoneal areas of disease are assessed whenever 
these sites are involved.
Index lesions will be measured and recorded at baseline and at the stipulated intervals. The 
cross-sectional dimensions (the largest cross-sectional diameter, ie, the LD × LPD) will be 
recorded (in cm) for each index lesion. The product of the perpendicular diameters (PPD) 
(in cm2) for each index lesion and the sum of the products (SPDs) (in cm2) for all index lesions 
will be calculated and recorded. The baseline SPDs will be used as references by which tumor 
response will be characterized during treatment. The nadir LD of individual lesions and the nadir 
SPD will be used as references by which CLL progression will be characterized. All LD and 
LPD diameters will be reported in centimenters and all PPDs and SPDs will be reported in 
centimeters squared.
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable at 
baseline. A lymph node lesion is considered abnormal if it has a single diameter that is 1.5 cm 
and is considered measurable if it has 2 perpendicular diameters that can be accurately measured 
in cross section with the LD being 1.0 cm and the LPD also being 1.0 cm.
At follow-up time points, the LDs for individual lesions and the SPD of all nodal index lesions 
will be considered. Because nodal index lesions that have one or both diameters 
>0 cm and 1.0 cm cannot be reliably measured, a default value of 1.0 cm will be assigned for 
each diameter that meets these criteria and the resulting PPD will be used in SPD calculations. 
Based on this convention, a CR may be achieved even if an SPD value is >0 cm2, 
(ie, if all lymph nodes measure <1.0 cm2).
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD will be considered 
progressive disease.
In cases in which a large lymph node mass has split into multiple components, all 
subcomponents regardless of size will be used in calculating the SPD. Progression of the lesion 
will be based on the SPD of sub-components. Lesion sub-components will have the true PPDs 
calculated. Similarly, lesion sub-components that are visible but neither abnormal nor 
measurable will have the default PPD of 1.0 cm2 (1.0 cm 1.0 cm) used in calculating the SPD.
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer 
be separated by this boundary, the newly merged lesion will be measured bi-dimensionally.


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7.4.2.
Spleen and Liver
Both the spleen and liver will be assessed by CT/MRI scan at baseline and at the stipulated 
intervals during treatment. The baseline and nadir values for the longest vertical dimension 
(LVD) of each organ will be used as reference to further characterize the objective tumor 
response of the measurable dimensions of the CLL during treatment. All spleen and liver LVD 
measurements should be recorded in centimeters.
By imaging, the spleen will be considered enlarged if it is >12 cm in LVD {Bezerra et al 2005}, 
{Asghar et al 2011}.
For subjects with splenomegaly at baseline or at the splenic LVD nadir, respective response and 
progression evaluations of the spleen will consider only changes relative to the enlargement of 
the spleen at baseline or nadir, not changes relative to the total splenic LVD.
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen in its LVD or 
decrease to ≤12 cm in the LVD, is required for declaration of a splenomegaly response. 
Conversely, an increase in splenic enlargement by ≥50% from nadir 
(with a minimum 2 cm increase) is required for declaration of splenic progression.
By imaging, the liver will be considered enlarged if it is >18 cm in LVD {Erturk et al 2006}.
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the liver in its LVD or 
decrease to ≤ 18 cm in the LVD is required for declaration of a hepatomegaly response. 
Conversely, an increase in liver enlargement by ≥50% from nadir 
(with a minimum 2 cm increase) is required for declaration of hepatic progression.
7.4.3.
Non-Index Lesions
Any other measurable and abnormal nodal lesions not selected for quantitation as index lesions 
may be considered non-index lesions. In addition, non-measurable evidence of CLL such as 
nodal lesions with both diameters <1.0 cm, extra-nodal lesions, bone lesions, leptomeningeal 
disease, ascites, pleural or pericardial effusions, lymphangitis of the skin or lung, abdominal 
masses that are not confirmed and followed by imaging techniques, cystic lesions, previously 
irradiated lesions, lesions with artifacts, and may be considered as non-index disease.
The presence or absence of non-index disease should be recorded at baseline and at the stipulated 
intervals during treatment. If present at baseline, up to 6 non-index lesions should be recorded. 
The non-index disease at baseline will be used as a general reference to further characterize 
regression or progression of CLL during assessments of the objective tumor response during 
treatment. Measurements are not required and these lesions should be followed as 
“present” or “absent”.
7.5.
Definitions of Tumor Response and Progression
Responses will be categorized by the IRC as CR, PR, SD, or PD. In addition, a response category 
of not evaluable (NE) is provided for situations in which there is inadequate information to 
otherwise categorize response status. A response category of no disease (ND) is included for 
situations in which there is absence of tumor both at baseline and on treatment.


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The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until disease/recurrence progression (taking as a reference 
for disease progression the smallest measurements recorded since treatment started). Subjects 
with a best overall response of NE or ND will be counted in the denominators in calculations of 
tumor response rates.
7.5.1.
Complete Response
To satisfy criteria for a CR, all of the following criteria must be met:

No evidence of new disease

ALC in peripheral blood of <4 x 109/L

Regression of all index nodal masses to normal size (1.5 cm in the LD)

Normal spleen and liver size

Regression to normal of all nodal non-index disease and disappearance of all detectable 
non-nodal, non-index disease

Morphologically negative bone marrow defined as <30% of nucleated cells being lymphoid 
cells and no lymphoid nodules in a bone marrow sample that is normocellular for age

Peripheral blood counts meeting all of the following criteria:
ANC >1.5 x 109/L without need for exogenous growth factors (eg, G-CSF)
Platelet count 100 x 109/L without need for exogenous growth factors or transfusions
Hemoglobin 110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (eg, erythropoietin)
Note: Subjects who fulfill all the criteria for a CR (including bone marrow criteria) but who 
have a persistent anemia, thrombocytopenia, or neutropenia or a hypocellular bone marrow 
that is related to prior or ongoing drug toxicity (and not to CLL) will be considered as a CR 
with incomplete marrow recovery (CRi).
7.5.2.
Partial Response
To satisfy criteria for a PR, all of the following criteria must be met:

No evidence of new disease

A change in disease status meeting 2 of the following criteria, with 2 exceptions in which 
only 1 criterion is needed: (1) Only lymphadenopathy is present at baseline; 
(2) Only lymphadenopathy and lymphocytosis are present at baseline. In these 2 cases, only 
lymphadenopathy must improve to the extent specified below:


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In a subject with baseline lymphocytosis (ALC4 x 109/L), a decrease in 
peripheral blood ALC by 50% from baseline or a decrease to <4 x 109/L
A decrease by 50% from the baseline in the SPD of the index nodal lesions
In a subject with enlargement of the spleen at baseline, a splenomegaly response, defined 
as a ≥50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen or 
decrease to ≤12 cm in the LVD by imaging
In a subject with enlargement of the liver at baseline, a hepatomegaly response, defined 
as a ≥50% decrease (minimum 2 cm) from baseline in the enlargement of the liver or 
decrease to ≤18 cm in the LVD by imaging
A decrease by 50% from baseline in the CLL marrow infiltrate or in 
B-lymphoid nodules

No index, splenic, liver, or non-index disease with worsening that meets the criteria for 
definitive PD

Peripheral blood counts meeting 1 of the following criteria:
ANC >1.5 x 109/L or 50% increase over baseline without need for exogenous growth 
factors (eg, G-CSF)
Platelet count 100 x 109/L or 50% increase over baseline without need for 
exogenous growth factors or transfusions
Hemoglobin 110 g/L (11.0 g/dL) or 50% increase over baseline without red blood cell 
transfusions or need for exogenous growth factors (eg, erythropoietin)
7.5.3.
Stable Disease
To satisfy criteria for stable disease (SD), the following criteria must be met:

No evidence of new disease

There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD
7.5.4.
Definitive Progressive Disease
The occurrence of any of the following events indicates definitive PD:

Evidence of any new disease:
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD


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New or recurrent splenomegaly, with a minimum LVD of 14 cm
New or recurrent hepatomegaly, with a minimum LVD of 20 cm
Unequivocal reappearance of an extra-nodal lesion that had resolved
A new unequivocal extra-nodal lesion of any size
New non-index disease (eg, effusions, ascites, or other organ abnormalities 
related to CLL)
Note: Isolated new effusions, ascites, or other organ abnormalities are not sufficient evidence 
alone of PD unless histologically confirmed. Thus, a declaration of PD should not be made if 
this is the only manifestation of apparently new disease.

Evidence of worsening of index lesions, spleen or liver, or non-index disease:
Increase by 50% from the nadir in the SPD of index lesions
Increase from the nadir by 50% in the LD of an individual node or extra-nodal mass that 
now has an LD of >1.5 cm and an LPD of > 1.0 cm
Splenic progression, defined as an increase in splenic enlargement by 50% from nadir 
(with a minimum 2 cm increase and a minimum LVD of 14 cm)
Hepatic progression, defined as an increase in hepatic enlargement by 50% from nadir 
(with a minimum 2 cm increase and minimum LVD of 20 cm)
Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or other 
organ abnormalities related to CLL) 
Transformation to a more aggressive histology (eg, Richter syndrome) as established by 
lymph node or other tissue biopsy, or fluid cytology (with the biopsy or fluid cytology 
date being considered the date of CLL progression if the subject has no earlier objective 
documentation of CLL progression).

Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to an 
autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an infiltrate of 
clonal CLL cells
The current platelet count is <100 x 109/L and there has been a decrease by >50% from 
the highest on-study platelet count
The current hemoglobin is <110 g/L (11.0 g/dL) and there has been a 
decrease by >20 g/L (2 g/dL) from the highest on-study hemoglobin


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Note: If there is uncertainty regarding whether there is true progression, the subject should 
continue study treatment and remain under close observation 
(eg, evaluated at 4-week intervals) pending confirmation of progression status by the IRC. In 
particular, worsening of constitutional symptoms in the absence of objective evidence of 
worsening CLL will not be considered definitive disease progression; in such subjects, both 
CLL-related and non-CLL-related causes for the constitutional symptoms should be 
considered. Worsening of disease during temporary interruption of study treatment 
(eg, for intercurrent illness) is not necessarily indicative of resistance to study treatment. In 
these instances, CT/MRI or other relevant evaluations should be considered in order to 
document whether definitive disease progression has occurred. If subsequent evaluations 
suggest that the subject has experienced persistent definitive CLL progression, then the date of 
progression should be the timepoint at which progression was first objectively documented.
7.5.5.
Non-Evaluable
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE:

There are no images or inadequate or missing images

Images of the liver and spleen are missing at that time point (with the exception that absence 
of splenic images will not result in an NE designation in a subject known to have 
undergone splenectomy).
Note: A time-point will be considered to have a response of NE if any index lesion is missing. 
PD may be assigned at any time point regardless of the extent of missing index or 
non-index lesions. Missing non-index lesions will not impact the ability to assess for response 
or disease progression.
7.5.6.
No Disease
Subjects have a status of ND if all of the following conditions occur:

No index disease noted at baseline or on-treatment 

No non-index disease noted at baseline or on-treatment.

No enlargement of the liver or spleen at baseline or on-treatment

No abnormalities of peripheral blood counts (elevated ALC or abnormally low ANC, 
platelet count, or hemoglobin) and no evidence of CLL in bone marrow (if available) at 
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7.5.7.
Lymphocytosis During Therapy
Idelalisib can mobilize CLL cells from tissues into the peripheral blood. This characteristic 
pharmacological action can be prominent early in therapy but can persist over time and should 
not be confused with disease progression in subjects who have persistent control of other 
CLL-related signs and symptoms. In the absence of other objective evidence of disease 
progression, lymphocytosis alone will not preclude subjects from meeting the criteria for PR if 
other criteria for PR are met and will not be considered evidence of disease progression if 
occurring in isolation. Subjects with lymphocytosis should be continued on study drug until the 
occurrence of definitive disease progression (ie, disease progression that is manifest by 
worsening CLL-related signs other than lymphocytosis alone), or the occurrence of another 
reason to discontinue study therapy as described in Section 5.8.
7.5.8.
Documentation of Definitive CLL Progression
Of importance, CLL response and progression data collected from the primary study will be 
subjected to IRC review (see Section 10.4.2). Subjects must have confirmation by the sponsor 
working in collaboration with the IRC that the disease has progressed on the primary clinical 
trial (Study GS-US-312-0116) before being permitted to receive secondary idelalisib therapy 
on this extension trial (GS-US-312-0117). Subjects should continue study drug pending 
confirmation of progression status. CT/MRI should be attempted in order to document definitive 
disease progression by the IRC. The end-of study scan from the primary study can serve as the 
baseline scan for the extension study if obtained within the specific screening period for the 
extension study. If obtained within the specified screening period for the extension study, this 
scan can serve as the baseline scan for the extension study.


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8.
SAFETY ASSESSMENTS
8.1.
Adverse Event Definitions
8.1.1.
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical product which; does not necessarily have a causal relationship 
with study drug administration or usage. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Lymphocytosis

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 5.2.8)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
In this study, any of the following events will be considered an adverse event:

Any complication that occurs as a result of a protocol-mandated procedure 
(eg, venipuncture, biopsy) in the screening, on-treatment, or post-treatment periods.

Any pre-existing condition that increases in severity or changes in nature during or as a 
consequence of study drug administration. Worsening manifestations of the underlying 
cancer (eg, increase in pain, tumor flare reaction, tumor lysis syndrome) may be considered 
adverse events in this study.


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
Any injury or accident occurring during the screening, on-treatment, or post-treatment 
periods. If a medical condition is known to have caused the injury or accident 
(eg, a fall secondary to dizziness), the medical condition (dizziness) and the accident (fall) 
should be reported as 2 separate adverse events. 

Any abnormality in physiological testing or a physical examination finding that requires 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test).

Any laboratory (eg, clinical chemistry, hematology, urinalysis) or investigational abnormality 
(eg, ECG, X-ray) independent of the underlying medical condition that requires clinical
intervention, results in further investigation (beyond ordering a repeat [confirmatory] test), or 
leads to investigational medicinal product interruption or discontinuation unless it is
associated with an already reported clinical event. If the laboratory abnormality is part of a 
syndrome, the syndrome or diagnosis (eg, anemia) not the laboratory result 
(eg, decreased hemoglobin) should be recorded. 

A complication related to pregnancy or termination of a pregnancy (see Section 5.4.10 for 
additional information).
8.1.2.
Serious Adverse Event
A serious adverse event (SAE) is defined as an event that results in any of the following:

Death

Life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization.

Persistent or significant disability/incapacity.

A congenital anomaly/birth defect

A medically important event or reaction. Such events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the outcomes listed above. Examples of such events 
might include:
Allergic bronchospasm requiring intensive treatment in an emergency room or at home
New cancers or blood dyscrasias
Convulsions that do not result in hospitalization
Development of drug dependency or drug abuse


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Medical and scientific judgment must be exercised to determine whether such an event is 
reportable under expedited reporting rules.
Infections resulting from contaminated medicinal product will be considered a medically 
important event and subject to expedited reporting requirements.
Given the endpoints of the study, in order to maintain the integrity of the study the following 
events that are assessed as unrelated to IMP will not be considered SAEs:

Progression of CLL

Death related to progression of CLL
Disease progression and death from disease progression should be reported as SAEs by the 
investigator only if it is assessed that the IMPs caused or contributed to the disease progression 
(i.e., by a means other than lack of effect). Unrelated disease progression and death due to 
disease progression should be captured on the eCRF.
These events will be reported, as appropriate, in the final clinical study report and in any relevant 
aggregate safety reports. The safety information from this study will also be reviewed by an 
independent DMC on an ongoing basis. The DMC can have access to partially blinded or 
unblinded data in order to determine if it is safe to continue the study according to the protocol.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Section 8.5. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result 
(ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 5.4.
8.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.


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8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting.
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed from screening 
onwards.
All AEs, regardless of cause or relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP must be reported to the CRF/eCRF database as 
instructed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported.
All AEs should be followed up until resolution if possible. If by the last day on study 
(including the off-study medication follow-up period) the AE has not resolved, then the AE will 
be followed up until the investigator and/or Gilead Sciences determine that the subject's 
condition is stable. However, Gilead Sciences may request that certain AEs be followed until 
resolution.


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Investigators are not obligated to actively seek SAEs after the above period. However, if the 
investigator learns of any SAEs that occur after study participation has concluded and the event 
is deemed relevant to the use of IMP, he/she should promptly document and report the event to 
Gilead DSPH.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.

At the time of study start, SAEs will be reported using a paper serious adverse event 
reporting form. During the study conduct, sites may transition to an electronic SAE (eSAE) 
system. Gilead will notify sites in writing and provide training and account information prior 
to implementing an eSAE system.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by faxing 
the report form within 24 hours of the investigator’s knowledge of the event to the attention 
of Gilead DSPH or to the designated CRO.
8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to expedite 
to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the 
EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide 
regulatory agencies and the relevant IEC in concerned Member States of applicable SUSARs as 
outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the IRB or IEC of SUSAR reports as soon as is practical, where this is 
required by local regulatory agencies, and in accordance with the local institutional policy.
8.5.
Grading of the Severity of an Adverse Event
The severity of adverse events will be graded using the CTCAE, Version 4.03 (provided in 
study manual and available at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). For 
each episode, the highest severity grade attained should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or 
Grade 5 (fatal) to describe the maximum intensity of the adverse event. For purposes of 
consistency with the CTCAE, these intensity grades are defined in Table 8-1.


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Table 8-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Sign or symptom is present, but it is easily tolerated, is not expected to have a 
clinically significant effect on the subject’s overall health and well-being, does not 
interfere with the subject’s usual function, and is not likely to require medical 
attention.
Grade 2
Moderate
Sign or symptom causes interference with usual activity or affect clinical status, and 
may require medical intervention.
Grade 3
Severe
Sign or symptom is incapacitating or significantly affects clinical status and likely 
requires medical intervention and/or close follow-up.
Grade 4
Life-threatening
Sign or symptom results in a potential threat to life.
Grade 5
Fatal
Sign or symptom results in death.
The distinction between the seriousness and the severity of an adverse event should be noted. 
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For 
example, a headache may be severe in intensity, but would not be classified as serious unless it 
met one of the criteria for serious events listed in Section 8.1.2 above.
8.6.
Adverse Event Reporting Period
The start of the adverse event reporting for a study subject will coincide with signing of the 
informed consent for Study GS-US-312-0117. Any new adverse events occurring thereafter 
should not be reported within Study GS-US-312-0116, but instead should be reported within
Study GS-US-312-0117. The end of the adverse-event-reporting period for 
Study GS-US-312-0117 occurs 30 days after the discontinuation from study drug or when any 
ongoing drug-related adverse events and/or serious adverse events have resolved or become 
stable. A subject withdrawn from the study because of an adverse event must be followed until 
the clinical outcome from the adverse event is determined. The investigator should use 
appropriate judgment in ordering additional tests as necessary to monitor the resolution of events 
ongoing at the completion of study treatment. Gilead Sciences may request that certain adverse 
events be followed longer.
Investigators are not obligated to actively seek information regarding the occurrence of new 
serious adverse events beginning after the 30-day post-study period. However, if the investigator 
learns of such a serious adverse event and that event is deemed relevant to the use of the study 
drug, he/she should promptly document and report the event. A longer reporting period applies in 
the case of pregnancy (see Section 8.9.1)
8.7.
Adverse Event Reporting Requirements
8.7.1.
Site Reporting Requirements
Classification of an event as serious or nonserious (see Section 8.1.2) determines the reporting 
procedures to be followed by the site.


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Site reporting requirements for adverse events are summarized in Table 8-2, below.
Table 8-2.
Site Reporting Requirements for Adverse Events
Classification
Reporting Time
Reporting Action
Serious
Within 24 hours
Fax report on designated serious adverse event report form 
to PPD Pharmacovigilancea, and to the site IRB/IEC, 
as per local IRB/IEC requirements; include copies of 
relevant source documentsb (eg, progress notes, 
autopsy reports, laboratory and diagnostic test results, 
discharge summaries) in communication to 
PPD Pharmacovigilancea
Per eCRF submission procedurec
Record and submit information on appropriate eCRFs
Nonserious
Per eCRF submission procedure
Record and submit information on appropriate eCRFs
a
See contact information in Table 8-3 below.
b
Subject name, address, and other personal identifiers should be obscured but without losing the traceability of a document to
the study subject identifiers.
c
CLL progression or death due to CLL progression should be reported by the investigator as a serious adverse event only if it 
is assessed that the study drugs caused or contributed to the CLL progression (ie, by a means other than lack of effect). 
Unrelated events of CLL progression should be captured on the appropriate eCRF. 
Abbreviations: CLL = chronic lymphocytic leukemia, eCRF=case report form, IRB/IEC= Institutional Review Board/
Independent Ethics Committee
For serious adverse events, in addition to completing the adverse event portion of the eCRF, the 
serious adverse event report form must also be completed. The information in the adverse event 
portion of the eCRF page and the serious adverse event report form(s) must match or be 
reconciled. Where the same data are collected, the forms must be completed in a consistent 
manner. For example, the same adverse event term should be used on both forms. Particularly for 
fatal or life-threatening events, copies of progress notes, autopsy reports, laboratory and 
diagnostic test results, discharge summaries, and other relevant documents should be faxed when 
requested and applicable. Follow-up information to the serious adverse event should be clearly 
documented as “follow up” in the serious adverse event report form and must be faxed to these 
same parties. Gilead Sciences may request additional information from the investigator to ensure 
the timely completion of accurate safety reports.
The subject’s name, address, and other personal identity information should be obscured on any 
source documents (eg, progress notes, nurses’ notes, laboratory and diagnostic test results, 
discharge summaries). Only the subject’s study number, initials, or date of birth are to be 
provided.
The serious adverse event report form must be communicated to PPD Pharmacovigilance and to 
the site IRB/IEC (if required by local regulations) within 24 hours. In the rare event that the 
investigator does not become aware of the occurrence of a serious adverse event immediately 
(for example, if a subject initially seeks treatment elsewhere), the investigator is to report the 
event within 24 hours after learning of it and to document his/her first awareness of the adverse 
event.


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Contact details for PPD Pharmacovigilance and for the Gilead study medical monitor are 
provided in Table 8-3:
Table 8-3.
Contact Information for Reporting Serious Adverse Events
Function
Contact Information
PPD Pharmacovigilance
(US)
Facsimile:
PPD Pharmacovigilance
(International)
Facsimile:
 
Gilead Sciences
Medical Monitor
Name:
Title: 
Medical Monitor, Clinical Research
Telephone:
Facsimile:
E-mail:
8.7.2.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population
To maintain the integrity of the study, progression of CLL and death related to progression of 
CLL will not be reported to Gilead Sciences as serious adverse events unless it is assessed that 
the study drug caused or contributed to CLL progression or death related to CLL progression 
(ie, by a means other than lack of effect). These events will be exempt from global expedited 
reporting requirements for the duration of the study because they define the primary efficacy 
endpoint for this study. All events of progression of CLL and death related to progression of 
CLL, regardless of relationship to study drug, will be reported in the eCRFs and, as appropriate, 
in the final clinical study report and in any relevant aggregate safety reports. Disease progression 
information from this study will be reviewed by an independent DMC on an ongoing basis.
8.8.
Special Situations Reporting Requirements
8.8.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, lack of 
effect reports and pregnancy reports regardless of an associated AE. Also includes reports of
adverse reactions in infants following exposure from breastfeeding, and reports of adverse 
reactions associated with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following possible maternal or paternal 
exposure to the medicinal product.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Lack of effect is defined as a situation where there is apparent failure of the medicinal product or 
medical technology to bring about the intended beneficial effect on the individual in a defined 
population with a given medical problem, under ideal conditions of use.
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
8.9.
Instructions for Reporting Special Situations
8.9.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (ie, signs the informed consent) and throughout the study, including the 
post study drug follow-up period, to the  or Gilead DSPH ] using the pregnancy report form 
within 24 hours of becoming aware of the pregnancy. Refer to the CRF/eCRF completion 
guidelines for full instructions on the mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE, and therefore should be reported as 
such. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must be 
reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to PPD Pharmacovigilance or Gilead DSPH using 
the pregnancy outcome report form. If the end of the pregnancy occurs after the study has been 
completed, the outcome should be reported directly to Gilead DSPH. Gilead DSPH 
contact information is as follows: Email:
 and Fax:
PPD
PPD


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Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to PPD Pharmacovigilance 
or Gilead DSPH using the pregnancy and pregnancy outcome forms within 24 hours. Monitoring 
of the subject should continue until the conclusion of the pregnancy. If the end of the pregnancy 
occurs after the study has been completed, the outcome should be reported directly to 
Gilead DSPH, fax number
 or email 
8.9.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to PPD Pharmacovigilance or Gilead DSPH within 24 hours of the investigator 
becoming aware of the situation. These reports must consist of situations that involve study IMP, 
but do not apply to concomitant medications. Except for situations that result in AEs, special 
situations involving concomitant medications will not be reported. Any inappropriate use of 
medications prohibited by this protocol should not be reported as “misuse,” but may be more 
appropriately documented as a protocol deviation.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.
PPD
PPD


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9.
STATISTICAL CONSIDERATIONS
9.1.
Analysis Objectives
As described in Section 3, the objectives of this clinical trial will focus on determining the effect 
of idelalisib on the onset, magnitude, and duration of tumor control; measures of patient 
well-being (including OS, HRQL; and changes in subject performance status); disease-associated 
biomarkers and potential mechanisms of resistance; treatment administration; safety; and health 
resource utilization.
9.2.
Analysis Endpoints
The endpoints of the study are defined in Section 3.1, grouped in categories relating to tumor 
control, patient well-being, pharmacodynamic markers of drug activity and resistance, exposure, 
safety, and pharmacoeconomics.
9.3.
Analysis Conventions
9.3.1.
Analysis Sets
9.3.1.1.
Intent-to-Treat Analysis Set
The ITT analysis set includes all subjects who receive 1 dose of any study treatment 
(high-dose idelalisib or standard-dose idelalisib). In the ITT analysis set, study drug assignment 
will be designated according to planned allocation in this study, regardless of whether subjects 
receive a different study therapy from that to which they were allocated.
This analysis set will be used in the analyses of subject characteristics and all the tumor control 
and patient well-being endpoints. Subjects in the ITT analysis set who do not have sufficient 
baseline or on-study tumor status information to be adequately assessed for response status will 
be included in the denominators in the calculation of response rates.
9.3.1.2.
Per-Protocol Analysis Set
The PP analysis set includes data from subjects in the ITT analysis set who meet the general 
criteria defining the target population for this study, are adherent to the protocol, are compliant 
with study drug treatment, and are evaluable for relevant efficacy endpoints. Treatment 
assignment will be designated according to the actual treatment received. The specific 
classification of subjects to be included in the PP analysis set will be included in the statisticial 
analysis plan which will be finalized prior to the database lock.
The PP analysis set will be used in sensitivity analyses of these tumor control and patient 
well-being endpoints: PFS, ORR, lymph node response rate, OS and CR rate.


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9.3.1.3.
Safety Analysis Set
A safety analysis set will include subjects in the ITT analysis set grouped for analyses with 
treatment assignments designated according to the actual study drug received.
This analysis set will be used in the analyses of safety variables as well as study treatment 
administration, and health economic variables.
9.3.1.4.
Pharmacodynamic and/or Pharmacokinetic Analysis Sets
The pharmacodynamic and/or pharmacokinetic analysis sets include data from subjects in the 
safety analysis set who have the necessary baseline and on-study measurements to provide 
interpretable results for the specific parameters of interest. 
These analysis sets will be used in the analyses of AKT phosphorylation, chemokines/cytokines, 
and idelalisib plasma concentrations.
9.3.2.
Data Handling Conventions
9.3.2.1.
General Methods 
By-subject listings will be created for important variables from each eCRF module. 
Summary tables for continuous variables will contain the following statistics: 
N (number in population), n (number with data), mean, standard deviation, 
95% confidence intervals (CIs) on the mean, median, minimum, and maximum. Summary tables 
for categorical variables will include: N, n, percentage, and 95% CIs on the percentage. Unless 
otherwise indicated, 95% CIs for binary variables will be calculated using the binomial 
distribution (exact method) and will be 2-sided. Data will be described and summarized by 
relevant treatment arm, analysis set, and timepoint. As appropriate, changes from baseline to 
each subsequent timepoint will be described and summarized by treatment arm. Similarly, as 
appropriate, the best change from baseline during the study will also be described and 
summarized by treatment arm. Graphical techniques (eg, waterfall plots, 
Kaplan-Meier curves, line plots) may be used when such methods are appropriate and 
informative.
Data from all sites will be pooled for all analyses. Analyses will be based upon the observed data 
unless methods for handling missing data are specified. If there is a significant degree of 
non-normality, analyses may be performed on log-transformed data or nonparametric tests may 
be applied, as appropriate.
9.3.2.2.
Double-Blinded Portion of the Study Analyses
Efficacy and safety data collected during the blinded portion of Study GS-US-312-0117 will be 
presented in the following 2 groups:


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
IDELA 300 mg BID: Subjects who have PD per IRC confirmation in Arm A of 
Study GS-US-312-0116 and subsequently enroll into Study GS-US-312-0117 to receive 
IDELA 300 mg BID during the double-blind portion of the study

Placebo in Study GS-US-312-0116 + IDELA 150 mg BID in Study GS-US-312-0117: 
Subjects who have PD per IRC confirmation in Arm B of Study GS-US-312-0116 and 
subsequently enroll Study GS-US-312-0117 to receive IDELA 150 mg BID during the 
double-blind portion of the study
All analyses will be performed based on the data collected during the blinded-portion of the 
extension study. Time-to-event analyses will reference to the date of first treatment on this 
clinical trial (Study GS-US-312-0117). Similarly, evaluations of on-therapy changes will 
reference the baseline values obtained prior to treatment in this study. The baseline value used in 
each analysis will be the last (most recent) pre-treatment value. Analyses will be descriptive in 
nature and formal comparisons of outcomes in the 2 groups are not planned.
9.3.2.3.
Open-Label Extension Study Analyses
GS-US-312-0117 will become an open-label study offering idelalisib 150 mg BID to 
GS-US-312-0116 subjects who were randomized to Arm B. Subjects randomized to Arm A will 
continue idelalisib at 150 mg BID. Efficacy and safety data collected during the primary and 
open-label extension studies will be presented in the following 4 groups:

IDELA 150 mg BID: Subjects who are randomized to Arm A in Study GS-US-312-0116 and 
transition to Study GS-US-312-0117 during the open-label portion of the study to continue 
IDELA 150 mg BID

Placebo in GS-US-312-0116 + IDELA 150 mg BID (open-label): Subjects who are 
randomized to Arm B in Study GS-US-312-0116 and transition to receive 
IDELA 150 mg BID during the open-label portion of the study

IDELA 300 mg BID: Subjects who have PD per IRC confirmation in Arm A of 
Study GS-US-312-0116 and subsequently enroll Study GSUS-312-0117 to receive 
IDELA 300 mg BID during double-blind portion of the study

Placebo in GS-US-312-0116 + IDELA 150 mg BID in GS-US-312-0117: Subjects who have 
PD per IRC confirmation in Arm B of Study GS-US-312-0116 and subsequently enroll 
Study GS-US-312-0117 to receive IDELA 150 mg BID during double-blind portion of the 
study.
Depending on the endpoints, analyses may be based on the combined data from both primary and 
extension studies or data from the extension study alone. Analyses will be descriptive in nature 
and formal comparisons of outcomes in the 4 groups are not planned. A separate statistical 
analysis plan will be created for the open-label portion of the study.


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9.3.2.4.
Calculation of Tumor Control and Patient Well-Being Variables
Tumor control assessments will be based on standardized IWCLL criteria {Hallek et al 2008}
{Cheson et al 2012}, as specifically modified for this study considering the pharmacology of 
idelalisib. The individual and composite endpoints of response and progression 
(considering changes in lymph node area, liver and spleen size, bone marrow, platelet counts, 
hemoglobin, neutrophil counts, and peripheral blood lymphocyte counts) will be determined. 
Tumor control will be documented at each assessment by response category (eg, CR, PR, SD, 
definitive PD, NE, ND) as defined for each response parameter, SPD value, percentage change in 
SPD values from baseline or nadir, date that response is first documented and date of definitive 
CLL progression.
The date of definitive CLL progression will be the timepoint at which progression is 
first identified by relevant objective radiographic or laboratory data. Because of the characteristic 
redistribution lymphocytosis that is expected with PI3Kinhibition, lymphocyte count will be 
ignored in the evaluation of progression. Changes in tumor status as provided by the investigator 
and changes in tumor status as adjudicated by the IRC (see Section 10.4.2) will be described. 
The findings of the IRC will be considered primary for analyses of all tumor control endpoints.
The following censoring conventions will be applied:

PFS and DOR: Data from surviving, non-progressing subjects will be censored at the earliest 
of the time of initiation of antitumor treatment other than the study treatment or the last time 
that lack of definitive CLL progression was objectively documented. Data from subjects who 
have CLL progression or die after 2 consecutive missing tumor assessments will be 
censored at the last time prior to the missing assessments that lack of definitive CLL 
progression was objectively documented.

OS: Data from surviving subjects will be censored at the last time that the subject was known 
to be alive.
9.4.
Analysis Plan
9.4.1.
Subject Disposition and Baseline Characteristics
A listing of all ITT analysis subjects will be generated to describe site, subject number, 
first screening date, first treatment date, allocated study drug assignment, actual study drug 
assignment, the longest duration of study drug treatment, and the reason for discontinuing study 
treatment. Available information on subjects who were screened or registered but not treated will 
be listed separately. A table will be created summarizing these categories in terms of number and 
percent for the ITT analysis set.
Subject baseline characteristics will be listed and summarized by treatment arm for the 
ITT analysis set. As appropriate for the specific variable, subject baseline characteristics
acquired in Study GS-US-312-0116 will be referenced in Study GS-US-312-0117.


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9.4.2.
Efficacy Analyses
9.4.2.1.
Time-to-Event Tumor Control and Survival Endpoints
PFS, DOR and OS will be described in the ITT analysis set using Kaplan-Meier methods by 
treatment group. Medians, ranges, and corresponding 95% CIs will be presented.
The Cox regression approach may be used to explore the influence of the primary study 
stratification factors and other baseline characteristics on PFS and OS. The stratification 
variables from the primary study and additional baseline subject characteristics may be included 
as covariates, focusing on those with expected prognostic significance.
9.4.2.2.
Categorical Endpoints
Response rates, lymph node response rate, splenomegaly response rate, 
hepatomegaly response rate, ALC response rate, platelet response rate, hemoglobin response 
rate, and neutrophil response rate will be described. In the calculation of response rates, subjects 
who do not have sufficient baseline or on-study tumor assessment to characterize response will 
be included in the denominator. For all analyses, the corresponding 95% CIs will be presented.
The potential influence of subject baseline characteristics on response rates may be explored
with multiple logistic regression modeling.
9.4.2.3.
Continuous Endpoints
Changes in lymph node area and changes in performance status, PI3K/AKT/mTOR pathway 
activation, and plasma chemokines/cytokines will be assessed by treatment group. Both changes 
from baseline to each subsequent timepoint and best overall on-study changes will be analyzed 
using appropriate methods (eg, analysis of covariance [ANCOVA] or paired t-tests). Means and 
standard errors will be presented.
9.4.2.4.
Health-Related Quality of Life and Performance Status
The FACT-Leu questionnaire data will be scored and processed according to the user manual. 
Missing items in a subscale will be imputed consistent with the user manual instructions. Data 
collected from the FACT-Leu instrument will not be reconciled with adverse event or laboratory 
data or with EQ-D5 findings.
As a baseline, the last value obtained prior to receiving the first idelalisib dose of 
150 mg and 300 mg will be used, depending on the treatment group assigned.
The mean and change from baseline in mean scores to each subsequent assessment will be 
summarized for the FACT-Lym subscale and composite scores. The best change from baseline 
during the study, defined as the highest positive value among all post-baseline visits minus 
the baseline value, will also be summarized.


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9.4.3.
Exposure and Safety Analyses
9.4.3.1.
Treatment Administration and Study Drug Compliance
Descriptive information will be provided by treatment arm regarding the number of doses of 
study therapy prescribed, the total number of doses taken, the percent of expected doses taken, 
the number of days of treatment, and the number and timing of prescribed dose reductions and 
interruptions.
Study drug compliance will be described by treatment arm in terms of the proportion of study 
drug actually taken based on returned pill count relative to the amount that was dispensed 
(taking into account physician-prescribed reductions and interruptions).
9.4.3.2.
Idelalisib Plasma Concentrations
Bioanalytical analyses will performed independently so that the study team and investigators will 
not have knowledge of data from individual subjects. Idelalisib plasma concentrations 
immediately pre-dose and at 1.5 hours after administration of the dose of study drug at each 
relevant clinic visit will be summarized by treatment and visit using descriptive statistics.
9.4.3.3.
Prior, Concomitant, and Post-Treatment Medication Use
Prior, concomitant, and post-treatment medications will be coded by means of the 
World Health Organization Drug Dictionary (WHODRUG) dictionary into 
Anatomical-Therapeutic-Chemical classification (ATC) codes.
Descriptions of prior medication use will be focused on drugs and regimens used as treatments 
for CLL. Information regarding CLL therapy that was administered prior to 
Study GS-US-312-0116 will be referenced in reporting the results of Study GS-US-312-0117. In 
addition, relevant treatment administration information collected during Study GS-US-312-0116 
will be referenced in reporting the results of this study. As appropriate and if available, 
information on the sequencing, type, dose, schedule, timing, duration of use, and efficacy of 
prior regimens will be provided, focusing particularly on findings observed in 
Study GS-US-312-0116.
The type and timing of use of concomitant medications will be listed and summarized by type 
and treatment arm. Information regarding the type and use of specific supportive medications 
(eg, pneumocystis prophylaxis, hematopoietic growth factors, corticosteroids) during study 
treatment will be described.
The number, type, and timing of post-study-treatment regimens for CLL will be summarized by 
treatment arm, characterizing the disposition of all subjects who were eligible for post-study 
treatment and also those who were not eligible for post-study treatment (eg, subjects who are 
never treated at all, die while on study treatment, are still on study, are lost to follow-up, etc).


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9.4.3.4.
Adverse Events
All adverse events will be listed. The focus of adverse event summarization will be on 
treatment-emergent adverse events. A treatment-emergent adverse event is defined as an adverse 
event that occurs or worsens in the period from the first dose of study treatment to 30 days after 
the last dose of study treatment.
Adverse events will be classified using MedDRA (http://www.meddramsso.com) with 
descriptions by System Organ Class, High-Level Group Term, High-Level Term, 
Preferred Term, and Lower-Level Term. The severity of adverse events will be graded by the 
investigator according to the CTCAE, Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf), 
whenever possible. If a CTCAE criterion does not exist for a specific type of adverse event, the 
grade corresponding to the appropriate adjective will be used by the investigator to describe the 
maximum intensity of the adverse event: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), 
Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the adverse event to the study 
drug will be categorized as related or unrelated.
Treatment-emergent adverse events will be summarized by treatment arm and by visit. 
Summary tables will be presented to show the number of subjects reporting treatment-emergent 
adverse events by severity grade and corresponding percentages. A subject who reports multiple 
treatment-emergent adverse events within the same Preferred Term (or System Organ Class) is 
counted only once for that Preferred Term (or System Organ Class) using the worst severity 
grade. Adverse event descriptions will be presented by decreasing frequency for a given 
System Organ Class and Preferred Term.
Separate listings and summaries will be prepared for the following types of treatment-emergent 
adverse events:

Study-drug-related adverse events

Adverse events that are Grade 3 in severity

Adverse events leading to study drug interruption and/or dose modification

Adverse events leading to study drug discontinuation

Serious adverse events (with categorization of the primary reason that the adverse event is 
considered serious, eg, death, hospitalization, etc)
Separate listings and summaries will be prepared for long-term follow-up safety data 
(see Section 6.2.17).
9.4.3.5.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed data. 
The focus of laboratory data summarization will be on treatment-emergent laboratory 
abnormalities. A treatment-emergent laboratory abnormality is defined as an abnormality that, 


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compared to baseline, worsens by 1 grade in the period from the first dose of study drug to
30 days after the last dose of study drug. If baseline data are missing, then any graded 
abnormality (ie, an abnormality that is Grade 1 in severity) will be considered treatment 
emergent. Hematological, serum biochemistry, and urine data will be programmatically graded 
according to CTCAE severity grade, when applicable. For parameters for which a CTCAE scale 
does not exist, reference ranges from the central laboratory will be used to determine 
programmatically if a laboratory parameter is below, within, or above the normal range for the 
subject’s age, sex, etc.
Hematological and serum biochemistry and their changes from baseline will be summarized by 
treatment arm and by visit. Summary tables will be presented for each relevant assay to show the 
number of subjects by CTCAE severity grade with corresponding percentages. For parameters 
for which a CTCAE scale does not exist, the frequency of subjects with values below, within, 
and above the normal ranges will be summarized. Subjects will be characterized only once for a 
given assay, based on their worst severity grade observed during a period of interest 
(eg, during the study or from baseline to a particular visit).
Shift tables for hematology and serum biochemistry will also be presented by showing change in 
CTCAE severity grade from baseline to the worst grade post baseline. Separate listings and 
summaries will be prepared for laboratory abnormalities that are Grade 3 in severity.
9.4.3.6.
Oxygen Saturation Values
All oxygen saturation data will be listed. Summaries of oxygen saturation data will be based on 
observed data and will be reported as % saturation. Data and changes from baseline will be 
summarized by treatment arm and by visit. Summary tables will be presented for values 
below 92% and for declines from baseline of 5% to show the number of subjects with 
corresponding percentages. Subjects will be characterized only once for each of these 
categorizations, based on their lowest value observed during a period of interest 
(eg, during the study or from baseline to a particular visit).
9.4.4.
Other Analyses
9.4.4.1.
Between-Study Comparisons
It is expected that patients with a progressive malignancy like CLL will normally fare better with 
an earlier therapy than with a later therapy. However, if the converse situation proves true –
eg, if an investigational treatment (idelalisib) administered later shows similar or greater benefit 
than a standard treatment (rituximab) administered earlier – strong evidence of investigational 
drug effect is demonstrated. Evaluating data derived from the same study subjects during their 
sequential participation in 2 clinical trials offers unique analytical challenges. However, in this 
integrated Phase 3 study program, it is likely that comparing baseline characteristics and 
outcomes among Arm B subjects participating in Study GS-US-312-0116 and 
Study GS-US-312-0117 will be informative. Such an evaluation characterizes how the subjects
and the CLL disease process change with time and treatment. In addition, such an analysis 
provides relevant supporting information documenting the benefits of single-agent idelalisib
relative to single-agent rituximab in the same subjects.


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Accordingly, baseline characteristics, time-to-event efficacy variables (eg, PFS, TTR, DOR), 
categorical variables (eg, ORR, lymph node response rate, splenomegaly response rate, 
hepatomegaly response rate), and continuous variables (eg, percentage changes in 
lymph node area; changes in performance status, PI3K/AKT/mTOR pathway activation and 
plasma chemokines/cytokines)  may be evaluated between Study GS-US-312-0116 and 
Study GS-US-312-0117 for Arm B subjects.
9.4.4.2.
Health Care Resource Utilization
The EQ-D5 questionnaire data will be scored, processed, and standardized according to the user 
manual. Change from baseline in EQ-5D visual analogue scale and EQ-5D index will be 
summarized. As for the FACT-Leu, data will be analyzed using appropriate methods to account 
for incomplete completion of questionnaires. Data collected from the EQ-D5 will not be 
reconciled with adverse event or laboratory data or with FACT-Leu findings.
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach to the health economic analysis will be to combine the resource utilization 
data from the trial with data on unit prices (collected separately) to estimate total costs.
The perspective of this analysis will be that of the third-party payer(s) and the hospital over a 
lifetime horizon in the base case. The costs will be described relative to the health care findings 
as measured by duration of tumor control, the symptom-free survival period, life-years, utility 
outcomes, or other measure of appropriate clinical benefits. In order to facilitate the calculation 
of utilities for use in the cost effectiveness analyses, the health status of subjects will be 
evaluated using PFS, Karnofsky performance status, FACT-Leu, and EQ-5D.
9.4.4.3.
Data Explorations
Changes in biomarkers during acquisition of resistance will be evaluated descriptively. Data 
explorations may be performed to evaluate potential associations between subject characteristics 
and outcome measures. Explorations may be performed to assess the potential associations 
between different outcomes measures (eg, relationships between HRQL changes and 
clinical/radiographic endpoints of tumor control).
9.5.
Sample Size
The sample size for this extension study is not based upon a formal statistical hypothesis. The 
upper bound of the sample size in this study is determined by the sample size of the preceding 
primary study (Study GS-US-312-0116) in which ~220 subjects (~110 per arm) are expected to 
be enrolled. It is estimated that this extension study (Study GS-US-312-0117) will have a total 
idelalisib-treated N~180 (assuming a ~10% dropout rate during Study GS-US-312-0116 and a 
further ~10% dropout rate in the transition from the primary study to the extension study).


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9.6.
Timing of Analyses
The DMC will have access to serious adverse events requiring expedited reporting and will be 
provided with accumulating safety data on a regular basis. Interim safety reviews will be 
conducted by the DMC in conjunction with safety reviews of the primary clinical trial
(Study GS-US-312-0116) if applicable. Thus, interim safety reviews will be performed by the 
DMC at intervals of ~6 months; the specific frequency of these reviews will depend upon the 
rate at which the trials are enrolled, the nature of any emerging safety signals, and monitoring 
recommendations from the DMC. At each review, all available safety data will be summarized 
and evaluated.
An interim efficacy analysis of this clinical trial (Study GS-US-312-0117) is planned to take 
place at the time of the final blinded analysis of the primary study (GS-US-312-0116). The intent 
is to provide the data from this extension study in support of regulatory review of data from the 
primary study. An analysis of efficacy and safety may be performed to satisfy regulatory 
requirements and to perform long-term efficacy, safety and OS follow-up. The timing of the final
analysis is expected to occur within 48 months of accrual of the final subject to 
Study GS-US-312-0117.


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
Compliance with Ethical and Regulatory Guidelines
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), with ICH guidelines, or with the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the study subject. These 
standards are consistent with the European Union Clinical Trials Directive 2001/20/EC and 
Good Clinical Practice Directive 2005/28/EC. The investigator will ensure adherence to the 
basic principles of GCP as outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and 
Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 1993, 
“Retention of Bioavailability and Bioequivalence Testing Samples.”
Because this is a “covered” clinical trial, the investigator will ensure adherence to 
21 CFR, Part 54, 1998; a covered clinical trial is any “study of a drug or device in humans 
submitted in a marketing application or reclassification petition subject to this part that the 
applicant or FDA relies on to establish that the product is effective (including studies that show 
equivalence to an effective product) or that make a significant contribution to the demonstration 
of safety.” This requires that investigators and all sub-investigators must provide documentation 
of their financial interest or arrangements with Gilead Sciences, or proprietary interests in the 
drug being studied. This documentation must be provided before participation of the investigator 
and any subinvestigator in the trial. The investigator or subinvestigator agrees to notify 
Gilead Sciences of any change in reportable financial interests during the study and for 1 year 
following completion of the study. Study completion is defined as the date that the last subject 
has completed the protocol-defined activities.
10.1.2.
Institutional Review Board/Independent Ethics Committee
This protocol and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) will be submitted by the investigator to an IRB (for sites enrolling in 
the United States) and to an IEC for sites enrolling outside of the United States). Approval from 
the IRB/IEC must be obtained before starting the study and should be documented in a letter to 
the investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.
Any modifications or amendments made to the protocol after receipt of the initial IRB/IEC
approval must also be submitted to the IRB/IEC for approval before implementation. Only 
changes necessary to eliminate apparent immediate hazards to the subjects may be initiated prior 
to IRB/IEC approval. In that event, the investigator must notify the IRB/IEC and Gilead Sciences
in writing within 5 working days after implementation.


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The investigator shall submit a progress report, at least once yearly, to the IRB/IEC, and must 
provide a copy to Gilead Sciences. As soon as possible after completion or termination of the 
study, the investigator will submit a final report to the IRB/IEC and to Gilead Sciences. This 
report should include the dates of initiation and completion of the trial, a description of any 
changes in study procedures or amendments to the protocol, any deviations from the protocol, 
the number and type of subjects evaluated, the number of subjects who discontinued 
(and the reasons for discontinuation), the number of subjects who completed the trial, and the 
results of the trial, including a description of any adverse events. Gilead Sciences will assist the 
investigator in the preparation of this report, as needed.
10.1.3.
Informed Consent
After adequately, explaining the aims, methods, objectives, and potential hazards of the study 
and before undertaking any study-related procedures, the investigator is responsible for obtaining 
written informed consent from each individual participating in this study. The investigator must 
utilize an IRB/IEC-approved consent form for documenting written informed consent. Each 
informed consent will be appropriately signed and dated by the subject or the subject’s legally 
authorized representative and the person obtaining consent.
The approved informed consent must not be changed without prior approval by Gilead Sciences
and the IRB/IEC.
10.1.4.
Confidentiality
The investigator must assure that each subject’s anonymity will be strictly maintained and that 
each subject’s identity is protected from unauthorized parties. Only subject initials, date of birth, 
and an identification code (but no subject names) should be recorded on any form or biological 
sample submitted to the Gilead Sciences or designees (eg, laboratories), or to the IRB/IEC.
However, sufficient information must be retained at the site to permit sample data and data in the 
database to be connected with the unique subject number assigned to each study participant.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the idelalisib investigator brochure, this protocol, eCRFs, the investigational new drug, 
and any other study information, remain the sole and exclusive property of Gilead Sciences
during the conduct of the study and thereafter. This information is not to be disclosed to any 
third party (except employees or agents directly involved in the conduct of the study or 
as required by law) without prior written consent from Gilead Sciences. The investigator further 
agrees to take all reasonable precautions to prevent the disclosure by any employee or agent of 
the study site to any third party or otherwise into the public domain.
10.1.5.
Study Files and Retention of Records and Biological Samples
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator’s study file, and 
(2) subject clinical source documents.


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The investigator’s study file will contain the protocol/amendments, eCRF and query forms, the 
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data referenced in the monitoring plan for the study, and should include 
sequential notes containing at least the following information for each subject:

Subject identification (name, date of birth, gender)

Documentation that subject meets eligibility criteria, eg, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria)

Participation in trial (including trial number)

Trial discussed and date of informed consent

Dates of all visits

Documentation that protocol-specific procedures were performed

Results of efficacy parameters, as required by the protocol

Start and end date (including dose regimen) of trial medication (including relevant drug 
dispensing and return information)

Record of all adverse events and other safety parameters (including start and end date, 
causality and intensity)

Concomitant medication (including start and end date and dose if relevant dose changes 
occur)

Date of trial completion and reason for discontinuation, if applicable
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (ie, the United States, Europe, 
or Japan) and until there are no pending or contemplated marketing applications in an 
ICH region; or, if no application is filed or if the application is not approved for such indication, 
until 2 years after the investigation is discontinued and regulatory authorities have been notified. 
Investigators may be required to retain documents longer if required by applicable regulatory 
requirements, by local regulations, or by an agreement with Gilead Sciences. The investigator 
must notify Gilead Sciences before destroying any clinical study records. The investigator will 
promptly notify Gilead Sciences in the event of accidental loss or destruction of any study 
records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead Sciences must be notified in advance.


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If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead Sciences
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site.
Biological samples including tissue and blood samples collected as a study procedure or as 
standard of care during study participation will be stored and maintained by the investigator until 
notification is received from Gilead Sciences that the retained samples and records no longer 
required. The investigator must obtain written permission from Gilead Sciences before disposing 
of any retained samples. The investigator should promptly notify Gilead Sciences in the event of 
accidental loss or destruction of any study samples. With the permission of Gilead Sciences, the 
retained samples may be transferred to an acceptable designee, such as another investigator, 
another institution, a contract storage site, or to Gilead Sciences.
10.1.6.
Case Report Forms
An eCRF is required and must be completed for each enrolled subject, with all required study 
data accurately recorded such that the information matches the data contained in medical records 
(eg, physicians’ notes, nurses’ notes, clinic charts, or other study-specific source documents). As 
required by the protocol, eCRFs should also be completed for those subjects who fail to complete 
the study (even during the screening period). If a subject withdraws from the study, the reason 
must be noted on the eCRF. If a subject is withdrawn from the study because of a 
treatment-limiting adverse event, thorough efforts should be made to clearly document the 
outcome.
The eCRFs for this study will exist within a Web-based electronic data capture (EDC) system. 
After the investigator or the investigator’s designees (eg, research coordinators) have been 
appropriately trained, they will be given access to the EDC system and will enter the data 
required by the protocol into the EDC system. Any change of data will be made via the 
EDC system, with all changes tracked by the system to provide an audit trail.
The eCRF must be completed and signed by the principal investigator or subinvestigator 
(as appropriate) within a reasonable time period after data collection. This signature serves to 
attest that the information contained in the eCRF is true.
10.1.7.
Drug Accountability
As described in the relevant section (see Section 5.2.7), the investigator is responsible for 
ensuring adequate accountability of all used and unused investigational medicinal product, 
placebos, and comparators. This responsibility includes acknowledgment of receipt of each 
shipment of study product (quantity and condition), subject dispensing records, and returned or 
destroyed study product. Dispensing records will document quantities received from 
Gilead Sciences and quantities dispensed to subjects, including lot number, date dispensed, 
subject identifier number, subject initials, and the initials of the person dispensing the 
medication.


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At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Sciences’ requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRB/IECs, 
and to regulatory authority or health authority inspectors. It is important that the investigator and 
relevant institutional personnel are available during monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, will be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB/IEC in 
accordance with local requirements. Except as noted in Section 10.1.2, IRB/IEC approval must 
be obtained before changes can be implemented.
10.2.2.
Communications with Regulatory Authorities
Gilead Sciences, working either directly or through designees, will assume responsibility for 
regulatory interactions with relevant regulatory authorities. Gilead Sciences will maintain an 
IND for idelalisib in support of the study in the United States and will maintain similar 
regulatory applications with other regulatory authorities, as required for conduct of the study. In 
fulfilling this responsibility, Gilead Sciences (or a designee) will collect, assemble, and 
communicate all required regulatory documents (eg, Form FDA 1572, investigator financial 
disclosure forms, protocol and protocol amendments, investigator brochures, informed consent 
documents, annual reports) as required by regulation. Gilead Sciences (or a designee) will also 
assume responsibility for adverse event reporting to regulatory authorities as described in 
Section 8.7.2.


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10.2.3.
Data Management
Electronic data capture will be used to enter study data eCRFs and to transfer the data into a 
study-specific electronic database. During the data collection process, automated quality 
assurance programs will be used to identify missing data, selected protocol violations, 
out-of-range data, and other data inconsistencies. Requests for data clarification or correction 
will be forwarded to the investigative site for resolution. As appropriate, eCRFs, listings, tables, 
and SAS datasets will be provided to the investigational sites for review.
Quality assurance and quality control systems will be implemented and maintained according to 
written standard operating procedures to ensure that the data are generated, recorded, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements. Data 
collection and storage systems will provide audit trail, security mechanisms, and electronic 
signature capabilities that meet the requirements of FDA Title 21 of CFR Part 11 regarding 
electronic records and electronic signatures.
Data security will be controlled through appropriate and specific restriction of access only to data 
and systems required by individual users to accomplish their roles in the data management 
process. Individual login and password protections will be employed at study sites and at 
Gilead Sciences or its designee. The database will exist on physically secured servers. Data 
backups will be done regularly and will be stored in separate facilities. Printed documents 
relating to the study will be secured when not under review.
10.2.4.
Study Reporting and Publication
Gilead Sciences may make information obtained during this study available in order to further 
the scientific or business needs of the company or as required by law or regulation. In this 
regard, Gilead Sciences may provide study information to private or public organizations 
(eg, business partners, collaborators, consultants, CROs, investors, other physicians who are 
conducting similar studies, funding organizations, regulatory authorities, or other 
government authorities).
Gilead Sciences will prepare a clinical study report for submission to relevant regulatory 
agencies. Gilead Sciences will ensure that the report meets the standards set out in the 
ICH Guideline for Structure and Content of Clinical Study Reports (ICH E3). An abbreviated 
report may be prepared in certain cases, as appropriate.
Gilead Sciences intends that the data from this study will be presented and published. 
Gilead Sciences will work in collaboration with the principal investigators in preparing 
presentations and writing manuscripts for publication.

Investigators may publish or present the results of the study generated by their individual site 
either with the advanced written consent of Gilead or > 2 years after the completion of this 
extension study (GS-US-312-0117) at all participating institutions.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information (see Section 10.1.4).


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The investigator will submit to Gilead Sciences any proposed publication or presentation along 
with the respective scientific journal or presentation forum prior to submission of the publication 
(at least 30 days prior to manuscripts and 15 days prior for abstracts and oral presentations). The 
investigator will comply with Gilead Sciences’ request to delete references to its confidential 
information (other than the study results) in any paper or presentation. If deemed necessary by 
Gilead Sciences, the investigator also agrees to withhold publication or presentation for an 
additional 60 days in order to obtain patent protection.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the eCRFs for consistency.
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.
10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences may conduct inspections or audits 
of the clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.
10.3.3.
Public Notification of Study Conduct
Consistent with Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and 
with requirements of the International Committee of Medical Journal Editors (ICMJE) as a 
condition of consideration for publication of study results, Gilead Sciences will be responsible 
for ensuring that this protocol is listed at the ClinicalTrials.gov website (or equivalent) and that 
information at the website relating to study design and conduct is appropriately updated during 
the course of the study. In order to facilitate this process, investigators will need to supply 
Gilead Sciences with appropriate contact information for study site personnel.
10.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authorities and IRB/IECs. In terminating the study, Gilead Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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10.4.
Study Committees
10.4.1.
Data Monitoring Committee
A DMC, operating autonomously from Gilead Sciences, the clinical investigators, and the SSC, 
will be responsible for providing independent recommendations to Gilead Sciences about 
evolving risk-benefit observed in the course of the study and any modifications required during 
the course of the study. The DMC will consist of a biostatistician and 2 physicians experienced 
in treating patients with lymphoid malignancies. The DMC will be chaired by one of these 
individuals. DMC members must not be actively involved in study design, conduct, or subject
accrual and must not have financial, proprietary, professional, or other interests that may affect 
impartial, independent decision-making. Specialists may be invited to participate as non-voting 
members at any time if additional expertise is desired. The DMC will formally interact with the 
external SSC members through the sharing of meeting minutes. Informal interactions between 
the DMC and external SSC members will be limited. The DMC will operate under a charter 
developed as a collaborative document between Gilead Sciences and the DMC. It is expected 
that the members of the DMC will be the same as those for the primary study 
(Study GS-US-312-0116). 
The primary responsibility of the DMC is to protect the safety and welfare of subjects 
participating in this clinical trial and to ensure the integrity of the clinical trial. In general, the 
DMC will be responsible for:

Reviewing the general progress of the study as regards subject accrual, study conduct, and 
protocol violations

Examining accumulated safety, efficacy, and other relevant data at prespecified points during 
the course of the study 

Reviewing major study design modifications prior to implementation of those modifications

Making recommendations concerning continuation, modification, interruption, or termination 
of each study

Advising the company on changes to informed consent documents

Proposing updates to the DMC monitoring plan, changes in the DMC membership, actions to 
be taken relating to conflict of interest or confidentiality breaches, the need for additional 
expertise during DMC deliberations, revisions to the DMC charter, or alterations in the 
support provided to the DMC

Providing expert advice to the Gilead Science medical monitor on an ad hoc basis regarding 
matters such as safety concerns or diagnostic evaluations in individual subjects
Based on the results of its deliberations during the course of the study, the DMC can recommend 
appropriate actions (eg, continuation of the study unchanged, continuation of the study with 
modifications in design or monitoring plan, interruption of study accrual, study termination).


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10.4.2.
Independent Review Committee
An IRC will be established to provide a blinded review of radiographic data and pertinent 
clinical data in order to provide expert interpretation of changes in tumor status. The IRC will 
include 1 independent board-certified radiologist and 1 independent board-certified 
hematologist or oncologist, and will be managed by a CRO selected by Gilead Sciences. The 
review of radiographic and clinical data by the IRC will be performed on an ongoing basis until 
the primary analysis . The specifics of the IRC’s processes and reading methods will be 
described in an independent review charter developed by the contracted imaging facility in 
conjunction with Gilead Sciences. The same organization that is providing IRC services for 
Study GS-US-312-0116 will provide IRC services for this study.


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11.
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Holzner B, Kemmler G, Kopp M, Nguyen-Van-Tam D, Sperner-Unterweger B, Greil R. Quality 
of life of patients with chronic lymphocytic leukemia: results of a longitudinal 
investigation over 1 yr. Eur J Haematol 2004;72 (6):381-9.
Hornberger J, Reyes C, Shewade A, Lerner S, Friedmann M, Han L, et al. Cost-effectiveness of 
adding rituximab to fludarabine and cyclophosphamide for the treatment of 
previously untreated chronic lymphocytic leukemia. Leuk Lymphoma 2012;53 
(2):225-34.
Iannitto E, Morabito F, Mancuso S, Gentile M, Montanini A, Augello A, et al. Bendamustine 
with or without rituximab in the treatment of relapsed chronic lymphocytic 
leukaemia: an Italian retrospective study. Br J Haematol 2011;153 (3):351-7.
Kahl B, Byrd J, Flinn I, Wagner-Johnston N, Spurgeon S, al E. Significant Clinical Activity Of 
Cal-101, An Isoform-Selective Inhibitor Of Phosphatidylinositol 3 Kinase P110D, 
In Patients With Relapsed Or Refractory Indolent And Mantle Cell Lymphoma 
[Abstract 350] 11th Triennial International Conference on malignant Lymphoma 
(Icml). Lugano, Swizterland: 2011:


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Karnofsky DA, Burchenal JH. The Clinical Evaluation of Chemotherapeutic Agents in Cancer. 
In: MacLeod CM, ed.  Evaluation of Chemotherapeutic Agents. New York, NY: 
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Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, et al. Therapeutic role of alemtuzumab 
(Campath-1H) in patients who have failed fludarabine: results of a large 
international study. Blood 2002a;99 (10):3554-61.
Keating MJ, O'Brien S, Kontoyiannis D, Plunkett W, Koller C, Beran M, et al. Results of first 
salvage therapy for patients refractory to a fludarabine regimen in chronic 
lymphocytic leukemia. Leuk Lymphoma 2002b;43 (9):1755-62.
Kyasa MJ, Hazlett L, Parrish RS, Schichman SA, Zent CS. Veterans with chronic lymphocytic 
leukemia/small lymphocytic lymphoma (CLL/SLL) have a markedly increased 
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Lannutti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B, Johnson AJ, et al. CAL-101, a 
p110delta-selective phosphatidylinositol-3-kinase (PI3K) inhibitor for the 
treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. 
Blood 2011;117 (2):591-4.
Leonard JM, Schreeder M, Coutre S, Flinn I, Wagner-Johnston N, et al. A phase 1 study of 
CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110D, 
in combination with anti-CD20 monoclonal antibody therapy and/or 
bendamustine in patients with previously treated B-cel malignancies [Abstract]. 
11th Triennial International Conference on Malignant Lymphoma (ICML); 2011 
June 15; Lugano, Switzerland. 
Levin TT, Li Y, Riskind J, Rai K. Depression, anxiety and quality of life in a chronic 
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pneumonitis in patients with advanced renal cell carcinoma treated with 
temsirolimus. J Clin Oncol 2011;29 (13):1750-6.


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Meadows SA, Kashishia A, Miller LL, Lannutti BJ. CAL 101, a specific inhibitor of 
phosphatidylinositol-3-kinase-delta (PI3Kd), attenuates pathway signaling, 
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International Conference on Malignant Lymphoma; 2011 15-18 June; Lugano, 
Switzerland. Ann Oncol. 2011 Jun; 22(Suppl 4). 
Meadows SA, Kashishian A, Johnson D, Diehl V, Lannutti BJ. CAL-101, a potent selective 
inhibitor of the p110delta isoform of phosphatidylinositol-3-kinase, attenuates 
pathway signaling, induces apoptosis, and overcomes signals from the 
microenvironment in cellular models of Hodgkin lymphoma [Abstract 3926]. 
Blood (ASH Annual Meeting Abstracts) 2010;116.
Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative 
mediator of anemia of inflammation, is a type II acute-phase protein. Blood 
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targeted mice. Biochemical Society transactions 2003a;31 (Pt 1):270-4.
Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and 
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fludarabine-refractory B-cell chronic lymphocytic leukemia and small 
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Ram R, Ben-Bassat I, Shpilberg O, Polliack A, Raanani P. The late adverse events of rituximab 
therapy--rare but there! Leuk Lymphoma 2009;50 (7):1083-95.
Redaelli A, Laskin BL, Stephens JM, Botteman MF, Pashos CL. The clinical and 
epidemiological burden of chronic lymphocytic leukaemia. European journal of 
cancer care 2004;13 (3):279-87.


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Reeve BB, Burke LB, Chiang YP, Clauser SB, Colpe LJ, Elias JW, et al. Enhancing 
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epoetin and darbepoetin in patients with cancer: 2007 American Society of 
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Rituximab plus fludarabine and cyclophosphamide prolongs progression-free 
survival compared with fludarabine and cyclophosphamide alone in previously 
treated chronic lymphocytic leukemia. J Clin Oncol 2010;28 (10):1756-65.
Salmasi G, Li M, Sivabalasundaram V, Kukreti V, Crump M, Kuruvilla J. A retrospective study 
on the incidence of rituximab-related interstitial pneumonitis in patients 
undergoing immunochemotherapy for non-Hodgkin lymphoma [Abstract 3094]. 
Blood (ASH Annual Meeting Abstracts) 2010;116.
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Stephens JM, Gramegna P, Laskin B, Botteman MF, Pashos CL. Chronic lymphocytic leukemia: 
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12.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
Appendix 3.
Performance Status Scoring System
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D)
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Appendix 6.
Cumulative Illness Rating Scale (CIRS)
Appendix 7.
Schedule of Study Procedures


PPD
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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
199 EAST BLAINE STREET 
SEATTLE, WA 98102 
STUDY ACKNOWLEDGEMENT 
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and Safety of 
Two Different Dose Levels of Single-Agent Idelalisib (GS-1101) for Previously Treated 
Chronic Lymphocytic Leukemia 
GS-US-312-0117, Version 8 (Amendment 7), 05 August 2016 
This protocol has been approved b} Gilead Sciences, Inc. The following signature documents 
this approvaL 
~--:-::--:-------~·· 
Gilead Sciences Medical Monitor 
INVESTIGATOR STATEMENT 
1 have read the protocol, including all appendices, and 1 agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies ofthe protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator 
Printed Name 
Date 
CONFlDENTIAL 
Page 153 
Signature 
Site Number 
05 August 2016 


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Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
FACT-Leu (Version 4) 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
PHYSICAL WELL-BEING 
GPI 
I have a lack of energy . . . . . . . . . . . . . . . 
GPl 
l have nausea 
.... ............ 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
GP4 
I have pain ...... ..... , 
......... ......................... 
GP5 
l am bothered by side effects of treatment 
01'6 
I feel ill . 
. ···················· 
GP7 
1 am forced to spend time in bed 
SOCIAL/FAMILY WELL-BEING 
OS! 
I feel close to my friends ...... 
.................. 
GS1 
I get emotional support from my family 
GS3 
1 get support from my friends .... 
GS4 
My family has accepted my illness 
GS5 
1 am satisfied with family communication about my 
illness .................... 
GS6 
I feel close to my partner (or the person who is my main 
support) . 
QI 
Regardless o_fyour current level of sexual activity. please 
answer the following question. ffyou prefer not to answer it, 
please mark this box 0 and go to the next section. 
GS7 
I am satisfied with my sex life ......................................... 
Engh !l.h (Universal) 
C~nglu 1987, 1997 
Not 
A little 
Some-
Quite 
at all 
bit 
what 
a bit 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
Not 
A little 
Some-
Quite 
at all 
bit 
what 
a bit 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
19 Novcmlx:r 1007 
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FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
EMOTIONAL WELL-BEING 
GEl 
I feel sad ..... ................................ , 
GE2 
I am satisfied with how I am coping with my illness .... 
GE3 
I am losing hope in the fight against my illness 
GE4 
I feel nervous 
................... , 
GE5 
I worry about dying . . . . . . . . . . . . . . . . . . . . . . . . 
GE6 
I worry that my condition will get worse 
FUNCTIONAL WELL-BEING 
GFI 
I am able to work (include work at home) 
GF2 
My work (include work at home) is fulfilling ... 
GF3 
I am able to enjoy life ...... 
................. , ...... 
GF4 
1 have accepted my illness ... ................. 
GF5 
1 am sleeping well 
................................. 
GF6 
I am enjoying the things 1 usually do for fun 
GF7 
I am content with the quality of my life right now 
Enghsh (Universal) 
Cop}'right 1987, 1997 
Not 
A little 
Some-
at all 
bit 
what 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Not 
A little 
Some-
at all 
bit 
what 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
19 November 1007 
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FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
ADDITIONAL CONCERNS 
Not 
A little 
Some-
at all 
bit 
what 
BRM3 
I am bothered by fevers (episodes of high body 
temperature) 
...... ........ . 
0 
2 
Pl 
I have certai n parts of my body where I experience pain.... 
0 
2 
BRMl 
ES3 
LEU I 
THI 
Till 
Hll2 
BMT6 
Cl 
C6 
An7 
N3 
LEm 
LEU6 
BRM9 
I am bothered by the chills .. .......... ... . 
I have night sweats .............................. .. 
I am bothered by lumps or swelling in certain parts of 
my body (e.g., neck, armpits, or groin) 
I bleed easily . 
1 bruise easily . 
I feel weak all over. 
I get tired easily 
I am losing weight 
I have a good appetite .......... ............ .. 
I am able to do my usual activities 
I worry about getting infections ......................... . 
I feel uncertain about my future health .................... .. 
1 worry that I might get new symptoms of my illness 
I have emotional ups and downs 
LEU7 
I feel isolated from others because of my illness or 
treatment 
Enghsh (Universal) 
Cop}'right 1987, 1997 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
19 November 1007 
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Appendix 3.
Performance Status Scoring System
Karnofsky Performance Status
General Description
Score
Specific Description
Able to carry on normal activity and 
to work; no special care needed.
100
Normal; no complaints;
no evidence of disease.
90
Able to carry on normal activity;
minor signs or symptoms of disease.
80
Normal activity with effort;
some signs or symptoms of disease.
Unable to work; able to live at home 
and care for most personal needs; 
varying amount of assistance 
needed.
70
Cares for self;
unable to carry on normal activity or to do active work.
60
Requires occasional assistance,
but is able to care for most of personal needs.
50
Requires considerable assistance and frequent medical care.
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly.
40
Disabled; requires special care and assistance.
30
Severely disabled;
hospital admission is indicated although death not imminent.
20
Very sick; hospital admission necessary;
active supportive treatment necessary.
10
Moribund; fatal processes progressing rapidly.
0
Dead


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Appendix 4. 
EuroQoL-5 Dimensions (EQ-SD) 
By placmg a clleckmark m one box in each group below. please ind.t~ate wbJch 
stat~mems b~1 describe your own health sEate today. 
Mobility 
I have no proWems in •11alking about 
I ha1:e some p oblems r walking about 
I am corrlir.ed to bed 
Self-Care 
I ~ve no problems wim self-care 
I have some probrems washing o dress g- myself 
I am unabla to ~'ash or dress myseli 
Usual Activities (e.g., work, study, housework, family, or leisure activities) 
I have no problems with perorming my usual ac1ivlties 
I hiwe some prob ems •1f'i1h perlormiJ'Ig my usua( activities 
I am unable to ~erform my usuaJ actvites 
Pain/Discomfort 
I have no pain o: discomfon 
I ha'o·e moderate pail or discorrrott 
I h.ave eldreme pa.n or rLsoomfort 
Anxiety!Oe pression 
I am n~ anxious ot de~ressed 
I am moderately anxi01.1s or depressed 
I am extremely anxious or depressed 
CONFIDENTIAL 
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D 
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D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
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05 August 2016 


Idelalisib 
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To help people say bow good or bad a health state LS, 
we have drawn a scale (rather bke a thennometer) on 
which the best stare you can un.agine 1S marked 100 
and the worsr stare you can imagine is marked 0. 
We \Vould like you to mdicate on this scale how good 
or bad your own health is today. in your opinion. 
Please do this by drawmg a line from the box below 
to wlllcbever pomt on the scale indicates how good or 
bad your health state is today. 
CONFIDENTIAL 
Yow· own 
hPalth statl' 
toda~· 
Page 159 
B~ 
imagmable 
health SUll! 
tOO 
T 
0 
\Vm"t 
ima:inab!e 
huhh:;ute 
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Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Formulas for calculating the estimated creatinine clearance (eCcr) are provided in the table 
below. The formula appropriate to the units in which serum creatinine was measured and the 
subject’s gender should be used.
Cockcroft-Gault Formulas for Calculating Estimated Creatinine Clearance
Serum
Creatinine Units
Gender
Formula
mg/dL
Males
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1
72 subject serum creatinine [mg/dl]
Females
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 0.85
72 subject serum creatinine [mg/dl]
M/dL
Males
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.23
Subject serum creatinine [mg/dl]
Females
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.04
Subject serum creatinine [mg/dl]
Abbreviation: eCcr=estimated creatinine clearance


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Appendix 6.
Cumulative Illness Rating Scale (CIRS)
The CIRS used in this protocol is designed to provide an assessment of recurrent or ongoing 
chronic comorbid conditions, classified by 14 organ systems. Using the drop-down lists of 
organ-specific diagnoses, please select any conditions present in the study subject. If the subject
has a recurrent or ongoing chronic conditions that are not described in the list for a given organ 
system, please indicate the name of the conditions under “other chronic condition” for that organ 
system. Please take into account that CLL-induced discomfort, symptoms, or disability should 
not be considered. If additional explanation would be helpful, text comments may be inserted.
CIRS List of Comorbid Conditions
Organ System
Diagnosis
Comment
Cardiac
Chronic heart failure
Angina pectoris
Medically relevant arrhythmia
Valve dysfunction
Congenital heart disease
Cardiomyopathy
Myocarditis
Chronic pericarditis
Endocarditis
Other chronic cardiac condition:
Other chronic cardiac condition:
Vascular
Hypertension
Thrombosis
Peripheral diabetic microvascular disease
Peripheral artery disease
Aortic aneurysm
Aortitis
Raynaud disease
Vasculitis
Other chronic vascular condition:
Other chronic vascular condition


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Organ System
Diagnosis
Comment
Hematological/
immunological
Sickle cell anemia
Hemoglobinopathy
Polycythemia
Thrombocythemia
Hemophilia
Paroxysmal nocturnal hemoglobinuria
Thrombotic thrombocytopenic purpura
Dysfibrinogenemia
HIV
Other chronic hematological or 
immunological condition:
Other chronic hematological or 
immunological condition
Abbreviation: CIRS=Cumulative Illness Rating Scale
For each condition selected from the CIRS List of Comorbid Conditions, please rate the severity 
of that condition. For the severity rating, please use the scoring guidelines shown in the table 
below, considering the magnitude of symptoms, how manageable the condition is, and the extent 
of intervention required:
CIRS Rating Scale
Score
Severity
Findings
1
Mild
Mild discomfort, symptoms or disability
Easy to control
Requiring either no therapy/medication or only as needed
2
Moderate
Moderate  discomfort, symptoms or disability
Manageable
Requiring daily treatment or first-line therapy
3
Severe
Severe discomfort, symptoms or disability
Hard to control
Requiring second-line therapy or multiple medications
4
Extremely severe
Life threatening, permanently disabling disability, causing organ failure
Poorly manageable
Requiring urgent intervention or resistant to therapy
Abbreviation: CIRS=Cumulative Illness Rating Scale


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Appendix 7.
Schedule of Study Procedures
Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4 a
5a
6 a
7a
8 a
9 a
10 a
11 a
12 a
13 a
14 a
15 a
16+e
End
of
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28 Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30 days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Informed consent
X
CIRS assessment
X
β-HCG
(women of 
childbearing 
potential)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CLL peripheral 
blood evaluation
X
X
CLL serology
X
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HRQL/
healthy utility –
FACT-Leu/EQ-5D
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exam
(includes nodes, 
liver, spleen)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PPD


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Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4 a
5a
6 a
7a
8 a
9 a
10 a
11 a
12 a
13 a
14 a
15 a
16+e
End
of
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28 Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30 days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Oxygen saturation
(by pulse 
oximetry)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Circulating cells/
Immune 
monitoringb
X
X
X
X
X
X
X
X
X
X
X
X
X
Xb
Biomarkers
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Igsb
X
X
X
X
X
X
X
X
X
X
X
X
X
Xb
Study drug
administration in 
clinic
X
X
X
X
X
X
X
X
Idelalisib
pharmacokinetics c
X
X
X
X
X
X
X
X
Study drug
dispensing/
accounting c
X
X
X
X
X
X
X
X
X
X
X
Radiology 
assessment 
(CT/MRI)
X
Xf
Xf
Xf
Xf
Xf
Xf
X f,g
Bone marrow 
biopsy/
aspirate d
X
X
X
X
X
X
X
X
CMV viral loadh
X


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Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4 a
5a
6 a
7a
8 a
9 a
10 a
11 a
12 a
13 a
14 a
15 a
16+e
End
of
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28 Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30 days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
PJP prophylaxisi, j
Xi
Xj
CD4+ T-cell countj
(related to PJP 
prophylaxis)
Xj
Post-treatment 
CLL therapy
X
Long-term 
follow-up 
X
a
Following unblinding of the study, the visit schedule will be modified per Section 6.2 and Visits 3 – 15 may not be applicable for subjects who were randomized to idelalisib 
on Study GS-US-312-0116 or who were randomized to placebo on GS-US-312-0116 and have received 24 weeks cumulative treatment with idelalisib
b
Circulating cells/Immune monitoring  and Serum Igs should be performed at the the End of Study visit
c
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll following unblinding, may have idelalisib treatment (and associated PK testing) delayed at 
the Investigator’s discretion until the time of disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib treatment
d
At screening, to be performed at investigator discretion to determine extent of CLL involvement and bone marrow cellularity. Post-screening, to be performed to confirm 
response category in subjects with potential CR or to confirm a hematologically-based disease progression; if the subject does not otherwise meet criteria for CR or if the 
nature of PD does not require bone marrow confirmations, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate
e
Following unblinding, Visit 16+ may be completed prior to 48 weeks as subjects transition to a Q12 week visit schedule 
f
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the assessment should be done even if study drug has been interrupted
g
An end-of-study CT/MRI tumor assessment should be performed unless the subject already has radiographic confirmation of definitive disease progression < 4 weeks prior to 
study discontinuation
h
CMV viral load should be performed approximately every 4 weeks throughout idelalisib treatment.  If unequivocal clinical or laboratory evidence of CMV infection is 
present, the subject must permanently discontinue idelalisib treatment and undergo effective antiviral treatment according to established clinical guidelines.
i
PJP prophylaxis:  subjects must receive trimethoprim-sulfamethoxazole or other established prophylaxis for PJP throughout the course of idelalisib treatment and for 2 to 6 
months after the last dose of idelalisib.  Subjects must permanently discontinue idelalisib upon diagnosis of PJP. Prophylaxis will continue for 2 to 6 months after the last dose of 
idelalisib and until the CD4+ T-cell count is documented to be >200 cells/mcL after idelalisib treatment ends. 
j
CD4+ T-cell countl (related to PJP prophylaxis):  PJP prophylaxis will continue until the CD4+ T-cell count is documented to be >200 cells/mcL after idelalisib treatment ends.
Abbreviations: -HCG=beta human chorionic gonadotropin, CIRS=chronic illness rating scale, CLL=chronic lymphocytic leukemia, CMV=cytomegalovirus, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy- Leukemia, HRQL= health-related quality of life, 
Ig=immunoglobulin, IWRS=interactive web response system, MRI= magnetic resonance imaging, PJP= Pneumocystis jirovecii pneumonia.

Prot_003.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy 
and Safety of Two Different Dose Levels of Single-Agent 
Idelalisib (GS-1101) for Previously Treated Chronic Lymphocytic 
Leukemia
A Companion Trial to Study GS-US-312-0116: A Phase 3, 
Randomized, Double-Blind, Placebo-Controlled Study Evaluating 
the Efficacy and Safety of Idelalisib (GS-1101) in Combination 
with Rituximab for Previously Treated Chronic Lymphocytic 
Leukemia
Sponsor:
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102
USA
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
101254
EudraCT Number:
2011-006293-72
Indication:
Chronic Lymphocytic Leukemia 
Protocol ID:
GS-US-312-0117
Gilead Sciences Medical 
Monitor:
Name:
Office Telephone:
Office Fax:
Mobile Telephone:
E-mail:
Protocol Version/Date:
Version 1.0 (Original)
23 January 2012
Version 2.0 (Amendment 1)
23 January 2013 
Version 3.0 (Amendment 2)
10 September 2013
Version 4.0 (Amendment 3)
16 December 2013
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable institutional 
review board or independent ethics committee. This information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You must not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS .......................................................................................................................................2
LIST OF IN-TEXT TABLES.................................................................................................................................6
LIST OF IN-TEXT FIGURES ...............................................................................................................................6
PROTOCOL SYNOPSIS .......................................................................................................................................7
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................................18
1.
INTRODUCTION .......................................................................................................................................22
Chronic Lymphocytic Leukemia.....................................................................................................22
1.1.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies.............................................................23
1.2.
Idelalisib (formerly GS-1101).........................................................................................................24
1.3.
1.3.1.
Discovery and Efficacy Pharmacology .........................................................................24
1.3.2.
Safety Pharmacology.....................................................................................................24
1.3.3.
Nonclinical Pharmacology and Metabolism..................................................................25
1.3.4.
Toxicology ....................................................................................................................26
1.3.5.
Idelalisib Clinical Studies..............................................................................................26
Summary and Justification for the Current Study...........................................................................31
1.4.
2.
STUDY DESIGN.........................................................................................................................................33
Design Overview and Study Schema ..............................................................................................33
2.1.
Design Rationale.............................................................................................................................34
2.2.
3.
OBJECTIVES AND ENDPOINTS .............................................................................................................36
Endpoints ........................................................................................................................................36
3.1.
3.1.1.
Tumor Control...............................................................................................................36
3.1.2.
Patient Well-Being ........................................................................................................37
3.1.3.
Pharmacodynamic Markers of Drug Activity and Resistance.......................................37
3.1.4.
Exposure........................................................................................................................38
3.1.5.
Safety.............................................................................................................................38
3.1.6.
Pharmacoeconomics......................................................................................................38
Endpoint Selection Rationale..........................................................................................................38
3.2.
3.2.1.
Tumor Control Endpoints..............................................................................................38
3.2.2.
Measures of Patient Well-Being....................................................................................41
3.2.3.
Pharmacodynamic Markers of Drug Activity and Resistance.......................................42
3.2.4.
Assessments of Exposure..............................................................................................43
3.2.5.
Evaluations of Safety.....................................................................................................44
3.2.6.
Pharmacoeconomic Measures .......................................................................................45
4.
SUBJECT POPULATION...........................................................................................................................46
Number of Subjects.........................................................................................................................46
4.1.
Subject Selection Criteria................................................................................................................46
4.2.
4.2.1.
Inclusion Criteria...........................................................................................................46
4.2.2.
Exclusion Criteria..........................................................................................................48
Enrollment Criteria Rationale .........................................................................................................49
4.3.
5.
TREATMENT OF SUBJECTS ...................................................................................................................50
Enrollment.......................................................................................................................................50
5.1.
5.1.1.
Interactive Web Response System ................................................................................50
5.1.2.
Treatment Assignment ..................................................................................................50
5.1.3.
Blinding.........................................................................................................................51


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Investigational Study Drug (Idelalisib/Placebo) .............................................................................52
5.2.
5.2.1.
Description ....................................................................................................................52
5.2.2.
Source............................................................................................................................52
5.2.3.
Packaging and Labeling ................................................................................................52
5.2.4.
Storage and Handling....................................................................................................53
5.2.5.
Dispensing.....................................................................................................................53
5.2.6.
Return............................................................................................................................54
5.2.7.
Accountability...............................................................................................................54
5.2.8.
Overdose Precautions....................................................................................................54
5.2.9.
Inadvertent Exposure and Spill Precautions..................................................................55
Study Drug Administration.............................................................................................................55
5.3.
5.3.1.
Premedication................................................................................................................55
5.3.2.
Administration Instructions...........................................................................................55
5.3.3.
Dosing Schedule............................................................................................................55
5.3.4.
Dose Levels...................................................................................................................55
5.3.5.
Dose Schedule Interruptions and Vomited Doses.........................................................56
5.3.6.
Safety Monitoring and Study Drug Interruption/Dose Modification ............................56
Recommendations for Evaluation, Intervention, and Drug Discontinuation for Specific 
5.4.
Adverse Events or Conditions.........................................................................................................59
5.4.1.
Dermatological Events ..................................................................................................59
5.4.2.
Gastrointestinal Events..................................................................................................60
5.4.3.
Hepatic Events...............................................................................................................61
5.4.4.
Hematological and Immunological Events....................................................................62
5.4.5.
Infectious Events...........................................................................................................62
5.4.6.
Progressive Multifocal Leukoencephalopathy ..............................................................63
5.4.7.
Pulmonary Events .........................................................................................................63
5.4.8.
Tumor Lysis Syndrome.................................................................................................64
5.4.9.
Pregnancy, Lactation, and Reproduction.......................................................................64
5.4.10.
Ultraviolet Exposure .....................................................................................................65
Emergency Unblinding ...................................................................................................................65
5.5.
Concomitant and Supportive Therapy.............................................................................................65
5.6.
5.6.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments.....................................................................................................................66
5.6.2.
Antibiotics.....................................................................................................................66
5.6.3.
Antiemetics and Antidiarrheals.....................................................................................66
5.6.4.
Contraception ................................................................................................................66
5.6.5.
Corticosteroids ..............................................................................................................68
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin.......................................68
5.6.7.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism...........................................68
5.6.8.
Drugs that undergo CYP3A-Dependent Metabolism....................................................69
5.6.9.
Immunization ................................................................................................................69
5.6.10.
Surgery..........................................................................................................................69
5.6.11.
Diet................................................................................................................................69
Duration of Study Drug...................................................................................................................69
5.7.
Discontinuation of Study Drug .......................................................................................................70
5.8.
Discontinuation from Study ............................................................................................................70
5.9.
Study Treatment Rationale..............................................................................................................71
5.10.
6.
STUDY PROCEDURES .............................................................................................................................74
Enrollment and Study Management Procedures .............................................................................74
6.1.
6.1.1.
Subject Recruitment ......................................................................................................74
6.1.2.
Subject Compensation for Participation........................................................................74
6.1.3.
Screening.......................................................................................................................74
Explanation of Study Visits.............................................................................................................75
6.2.


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6.2.1.
Visit 1 and Screening Period (Clinic Visit)...................................................................75
6.2.2.
Visit 2 (Day 1) (Clinic Visit).........................................................................................78
6.2.3.
Visit 3 (Day 15) (Clinic Visit).......................................................................................79
6.2.4.
Visit 4 (Day 29) (Clinic Visit).......................................................................................80
6.2.5.
Visit 5 (Day 43) (Clinic Visit).......................................................................................82
6.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit) ..............................................................83
6.2.7.
Visit 7 (Day 71) (Laboratory Visit)...............................................................................84
6.2.8.
Visit 8 (Day 85) (Clinic Visit).......................................................................................85
6.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit) ............................................................87
6.2.10.
Visit 10 (Day 141) (Clinic Visit)...................................................................................89
6.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit) ..........................................................91
6.2.12.
Visit 12 (Day 211) (Clinic Visit)...................................................................................93
6.2.13.
Visit 13 (Day 253) (Clinic and Radiology Visit) ..........................................................94
6.2.14.
Visit 14 (Day 295) (Clinic Visit)...................................................................................95
6.2.15.
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks) (Clinic 
and Radiology Visits)....................................................................................................96
6.2.16.
End-of-Study Visit (Clinic Visit) ..................................................................................97
6.2.17.
30 Day and Long-Term Follow-up................................................................................99
Sample Storage................................................................................................................................99
6.3.
Blood Collection .............................................................................................................................99
6.4.
Study Procedure Rationale............................................................................................................100
6.5.
7.
EFFICACY ASSESSMENTS....................................................................................................................101
Tumor Status Assessments............................................................................................................101
7.1.
Method of Assessment ..................................................................................................................101
7.2.
Timing of Assessments .................................................................................................................101
7.3.
Identification and Measurement of Tumor Lesions and Organomegaly.......................................102
7.4.
7.4.1.
Index Lesions ..............................................................................................................102
7.4.2.
Spleen and Liver..........................................................................................................103
7.4.3.
Non-Index Lesions ......................................................................................................103
Definitions of Tumor Response and Progression..........................................................................104
7.5.
7.5.1.
Complete Response.....................................................................................................104
7.5.2.
Partial Response..........................................................................................................105
7.5.3.
Stable Disease .............................................................................................................105
7.5.4.
Definitive Progressive Disease....................................................................................106
7.5.5.
Non-Evaluable.............................................................................................................107
7.5.6.
No Disease ..................................................................................................................107
7.5.7.
Lymphocytosis During Therapy..................................................................................108
7.5.8.
Documentation of Definitive CLL Progression...........................................................108
8.
SAFETY ASSESSMENTS........................................................................................................................109
Adverse Event Definitions ............................................................................................................109
8.1.
8.1.1.
Adverse Event .............................................................................................................109
8.1.2.
Serious Adverse Event ................................................................................................110
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events ................................................................111
Assessment of Adverse Events and Serious Adverse Events........................................................111
8.2.
8.2.1.
Assessment of Causality for Study Drugs and Procedures..........................................112
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
8.3.
Adverse Events to Gilead..............................................................................................................112
Gilead Reporting Requirements....................................................................................................113
8.4.
Grading of the Severity of an Adverse Event................................................................................113
8.5.
Adverse Event Reporting Period...................................................................................................114
8.6.
Adverse Event Reporting Requirements .......................................................................................115
8.7.


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8.7.1.
Site Reporting Requirements.......................................................................................115
8.7.2.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population..................................................116
Special Situations Reporting Requirements..................................................................................117
8.8.
8.8.1.
Definitions of Special Situations.................................................................................117
Instructions for Reporting Special Situations................................................................................117
8.9.
8.9.1.
Instructions for Reporting Pregnancies .......................................................................117
8.9.2.
Reporting Other Special Situations .............................................................................118
9.
STATISTICAL CONSIDERATIONS.......................................................................................................119
Analysis Objectives.......................................................................................................................119
9.1.
Analysis Endpoints........................................................................................................................119
9.2.
Analysis Conventions....................................................................................................................119
9.3.
9.3.1.
Analysis Sets ...............................................................................................................119
9.3.2.
Data Handling Conventions ........................................................................................120
Analysis Plan.................................................................................................................................121
9.4.
9.4.1.
Subject Disposition and Baseline Characteristics........................................................121
9.4.2.
Efficacy Analyses........................................................................................................122
9.4.3.
Exposure and Safety Analyses ....................................................................................123
9.4.4.
Other Analyses............................................................................................................125
Sample Size...................................................................................................................................127
9.5.
Timing of Analyses.......................................................................................................................127
9.6.
10.
RESPONSIBILITIES.................................................................................................................................128
Investigator Responsibilities .........................................................................................................128
10.1.
10.1.1.
Compliance with Ethical and Regulatory Guidelines..................................................128
10.1.2.
Institutional Review Board/Independent Ethics Committee .......................................128
10.1.3.
Informed Consent........................................................................................................129
10.1.4.
Confidentiality.............................................................................................................129
10.1.5.
Study Files and Retention of Records and Biological Samples...................................130
10.1.6.
Case Report Forms......................................................................................................131
10.1.7.
Drug Accountability....................................................................................................131
10.1.8.
Inspections...................................................................................................................132
10.1.9.
Protocol Compliance...................................................................................................132
Sponsor Responsibilities...............................................................................................................132
10.2.
10.2.1.
Protocol Modifications................................................................................................132
10.2.2.
Communications with Regulatory Authorities............................................................132
10.2.3.
Data Management .......................................................................................................133
10.2.4.
Study Reporting and Publication.................................................................................133
Joint Investigator/Sponsor Responsibilities ..................................................................................134
10.3.
10.3.1.
Access to Information for Monitoring.........................................................................134
10.3.2.
Access to Information for Auditing or Inspections .....................................................134
10.3.3.
Public Notification of Study Conduct .........................................................................134
10.3.4.
Study Discontinuation.................................................................................................135
Study Committees.........................................................................................................................135
10.4.
10.4.1.
Data Monitoring Committee .......................................................................................135
10.4.2.
Independent Review Committee .................................................................................136
11.
REFERENCES ..........................................................................................................................................137
12.
APPENDICES ...........................................................................................................................................147
Appendix 1.
Investigator Signature Page.........................................................................................148
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)..........................149


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Appendix 3.
Performance Status Scoring System............................................................................152
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D) ...............................................................................153
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance ...................................155
Appendix 6.
Cumulative Illness Rating Scale (CIRS) .....................................................................156
Appendix 7.
Schedule of Study Procedures.....................................................................................158
LIST OF IN-TEXT TABLES
Table 4-1.
Required Screening Laboratory Values.........................................................................47
Table 5-1.
Study Drug Dose Levels................................................................................................56
Table 5-2.
Recommendations for Study Drug Dose Modifications Based on 
Type and Severity of Treatment-Related Adverse Events or 
Laboratory Abnormalities .............................................................................................58
Table 5-3.
Protocol-Recommended Contraceptive Methods..........................................................67
Table 5-4.
Known Strong Inducers of CYP3A...............................................................................68
Table 6-1.
Procedures and Assessments at Visit 1 (During Screening Period) ..............................77
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1) ............................................................78
Table 6-3.
Procedures and Assessments at Visit 3 (Day 15) ..........................................................79
Table 6-4.
Procedures and Assessments at Visit 4 (Day 29) ..........................................................80
Table 6-5.
Procedures and Assessments at Visit 5 (Day 43) ..........................................................82
Table 6-6.
Procedures and Assessments at Visit 6 (Day 57) ..........................................................83
Table 6-7.
Procedures and Assessments at Visit 7 (Day 71) ..........................................................84
Table 6-8.
Procedures and Assessments at Visit 8 (Day 85) ..........................................................85
Table 6-9.
Procedures and Assessments at Visit 9 (Day 113) ........................................................87
Table 6-10.
Procedures and Assessments at Visit 10 (Day 141) ......................................................89
Table 6-11.
Procedures and Assessments at Visit 11 (Day 169) ......................................................91
Table 6-12.
Procedures and Assessments at Visit 12 (Day 211) ......................................................93
Table 6-13.
Procedures and Assessments at Visit 13 (Day 253) ......................................................94
Table 6-14.
Procedures and Assessments at Visit 14 (Day 295) ......................................................95
Table 6-15.
Procedures and Assessments at Visit 15 and Subsequent Visits (Day 
337 and Every 12 Weeks) .............................................................................................96
Table 6-16.
Procedures and Assessments at End-of-Study Visit......................................................98
Table 8-1.
Grading of Adverse Event Severity.............................................................................114
Table 8-2.
Site Reporting Requirements for Adverse Events.......................................................115
Table 8-3.
Contact Information for Reporting Serious Adverse Events.......................................116
LIST OF IN-TEXT FIGURES
Figure 2-1.
Study Design .................................................................................................................33


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc
199 East Blaine Street
Seattle, WA 98102, USA
Study Title: 
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and 
Safety of Two Different Dose Levels of Single-Agent Idelalisib (GS-1101) 
as Therapy for Patients with Previously Treated Chronic Lymphocytic 
Leukemia
A Companion Study to Study GS-US-312-0116: A Phase 3, Randomized, 
Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety 
of Idelalisib (GS-1101) in Combination with Rituximab as Therapy for 
Patients with Previously Treated Chronic Lymphocytic Leukemia
Study Centers 
Planned:
Approximately 90 centers in the United States and in Europe
IND Number:
101254
EudraCT 
Number:
2011-006293-72
Objectives:

To evaluate the effect of idelalisib (formerly GS-1101) on the onset, 
magnitude, and duration of tumor control 

To compare tumor control in subjects receiving rituximab alone in 
Study GS-US-312-0116 to that observed in the same subjects when 
receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject well-being, 
including overall survival (OS), health-related quality of life (HRQL),
and performance status

To assess the effects of idelalisib on disease-associated biomarkers and 
to evaluate potential mechanisms of resistance to idelalisib

To characterize exposure to idelalisib as determined by treatment 
administration and evaluation of idelalisib plasma concentrations over 
time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with administration 
of idelalisib


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Study Design:
This study is being conducted as part of an overall clinical program 
evaluating the efficacy and safety of idelalisib in the therapy of patients with 
previously treated chronic lymphocytic leukemia (CLL). 
Within this program, the primary clinical trial (Study GS-US-312-0116) is a 
Phase 3, multicenter, 2-arm, randomized, double-blind, placebo-controlled, 
parallel-group study.
This clinical trial (Study GS-US-312-0117) is a separate, multicenter, 2-arm, 
double-blind, parallel-group extension study that is a companion trial to 
Study GS-US-312-0116; in this trial, compliant subjects from 
GS-US-312-0116 who are tolerating primary study therapy but experience 
definitive CLL progression are eligible to receive active blinded idelalisib
therapy at the standard dose or a higher dose, with allocation based on the 
original primary study randomization. In the event GS-US-312-0116 is 
stopped early due to overwhelming efficacy following an interim analysis or 
at the final analysis, subjects who are on Study GS-US-312-0116 at that time 
may transition to GS-US-312-0117.  Additionally, GS-US-312-0117 will 
become an open-label study offering idelalisib 150 mg BID to 
GS-US-312-0116 subjects who were randomized to placebo, and subjects 
randomized to idelalisib will continue idelalisib at 150 mg BID .
Study Schema:
Treatment Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117)


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Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID
Treatment Assignment

Assignment to Arm A or Arm B with allocation based on the original 
primary study randomization

Implementation through an interactive web response system (IWRS)
Stratification
Not applicable for Study GS-US-312-0117
Number of 
Subjects 
Planned:
Total of up to ~160 subjects (up to ~80 subjects per treatment arm)
Target 
Population
Subjects in the primary Phase 3 study (GS-US-312-0116) who are 
compliant, are tolerating primary study therapy, and 1) have definitive 
progression of CLL while receiving primary study drug therapy 
(idelalisib /placebo)  or 2) are actively participating in 
Study= GS-US-312-0116 at the time the study is stopped, including if 
stopped early due to overwhelming efficacy following an interim analysis.
Diagnosis and 
Main Eligibility 
Criteria:
Inclusion Criteria
Subjects must meet all of the following conditions to be eligible for 
enrollment into the study:
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while receiving 
study drug therapy (idelalisib /placebo) in Study GS-US-312-0116. 
Note: Definitive disease progression is CLL progression based on 
standard criteria and occurring for any reason (ie, increasing 
lymphadenopathy, organomegaly, or bone marrow involvement; 
decreasing platelet count, hemoglobin, or neutrophil count; or 
worsening of disease-related symptoms) other than lymphocytosis. 
Subjects must have confirmation by the sponsor working in 
collaboration with an independent review committee (IRC) that the 
disease has progressed on the primary clinical trial
(Study GS-US-312-0116) before receiving secondary idelalisib therapy 
on this extension trial (Study GS-US-312-0117).


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3) Presence of measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures 2.0 cm in the longest diameter [LD] and 
1.0 cm in the longest perpendicular diameter [LPD] as assessed by 
computed tomography [CT] or magnetic resonance imaging [MRI]).
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab 
and/or idelalisib/placebo) and no intervening or continuing therapy 
(including radiotherapy, chemotherapy, immunotherapy, or 
investigational therapy) for the treatment of CLL. Note: Subjects may 
receive corticosteroids to manage CLL manifestations.
5) The time from permanent cessation of Study GS-US-312-0116 treatment 
(rituximab and/or idelalisib/placebo) and the initiation of Study 
GS-US-312-0117 therapy is 12 weeks. Note: Study procedures 
performed as part of Study GS-US-312-0116 need not be repeated and 
can be used as screening procedures for Study GS-US-312-0117 if 
performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation of 
study treatment) as shown in the table below. Note: Confirmation 
should be considered for out-of-range values to determine if the 
abnormality is real or artifactual. Values should be obtained within the 
screening period and should generally be the most recent measurement 
obtained. Subjects with any degree of neutropenia, thrombocytopenia, 
or anemia due to CLL or prior therapy may enroll.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCr
a
>30 ml/min
Pregnancy
-HCGb
Negative 
a
As calculated by the Cockcroft-Gault formula {2202}
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or urine 
dipstick pregnancy test must be negative at randomization (Visit 2)
Abbreviations: -HCG=beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
eCCr=estimated creatinine clearance, ULN=upper limit of normal


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8) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening visit 
(Visit 1) throughout the study and for 30 days from the last dose of study 
drug. Note: A female subject is considered to be of childbearing 
potential unless she has had a hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy; has medically documented ovarian failure 
(with serum estradiol and follicle-stimulating hormone [FSH] levels 
within the institutional postmenopausal range and a negative serum or 
urine HCG), or is menopausal (defined as age >55 years with 
amenorrhea for >12 months or amenorrhea for >6 months with serum 
estradiol and FSH levels within the institutional postmenopausal 
range). 
9) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of study 
drug (Visit 2) throughout the study and for 90 days following the last 
dose of study drug and to refrain from sperm donation from the start of 
study drug (Visit 2) throughout the study and for 90 days following the 
last dose of study drug. Note: A male subject is considered able to 
father a child unless he has had a bilateral vasectomy with documented 
aspermia or a bilateral orchiectomy, or has ongoing testicular 
suppression with a depot luteinizing hormone- releasing hormone 
(LH-RH) agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate 
[Lupron®]), or triptorelin pamoate [Trelstar®]).
10) In the judgment of the investigator, participation in the protocol offers an 
acceptable benefit-to-risk ratio when considering current CLL disease 
status, medical condition, and the potential benefits and risks of 
alternative treatments for CLL. 
11) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, familial, 
or geographical factors that might preclude adequate study 
participation should be considered.
12) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature of the 
therapy, alternatives, potential benefits, possible side effects, potential 
risks and discomforts, and other pertinent aspects of study participation.


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Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be 
enrolled in this study:
1) Known histological transformation from CLL to an aggressive 
lymphoma (ie, Richter transformation). 
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at the 
time of the start of study treatment (Visit 2). Note: Subjects with 
localized fungal infections of skin or nails are eligible. Subjects may be 
receiving prophylactic antiviral or antibacterial therapies at the 
discretion of the investigator; anti-pneumocystis prophylaxis is 
encouraged. 
3) Pregnancy or breastfeeding. 
4) Intentional breaking of the blind in Study GS-US-312-0116 by the 
investigator or the study subject.
5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical condition, surgical 
history, physical finding, electrocardiogram (ECG) finding, or laboratory 
abnormality that, in the investigator’s opinion, could adversely affect the 
safety of the subject or impair the assessment of study results.
In the event Study GS-US-312-0116 is stopped early, subjects who are 
actively participating in Study GS-US-312-0116 will become eligible for this 
study, provided the following inclusion are met: Participation in Study 
GS-US-312-0116 within 12 weeks of enrollment onto GS-US-312-0117.
1) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening visit 
(Visit 1) throughout the study and for 30 days from the last dose of study 
drug. 
2) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of study 
drug (Visit 2) throughout the study and for 90 days following the last 
dose of study drug and to refrain from sperm donation from the start of 
study drug (Visit 2) throughout the study and for 90 days following the 
last dose of study drug. 
3) In the judgment of the investigator, participation in the protocol offers an 
acceptable benefit-to-risk ratio when considering current CLL disease 
status, medical condition, and the potential benefits and risks of 
alternative treatments for CLL. 


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4) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, familial, 
or geographical factors that might preclude adequate study participation 
should be considered.
5) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature of the 
therapy, alternatives, potential benefits, possible side effects, potential 
risks and discomforts, and other pertinent aspects of study participation.
Study 
Procedures/
Frequency:
Clinic/laboratory visits will occur every 2 weeks for the first 12 weeks, every 
4 weeks between Weeks 12 and 24, and every 6 weeks between Weeks 24 
and 48. Subjects continuing on study drug past Week 48 will have clinic 
visits every 12 weeks. Subjects will be assessed for safety at each visit. 
Subjects will be assessed for CLL disease status by physical and laboratory 
examinations at each visit and by CT or MRI at Weeks 8, 16, 24, 36, and 
48 and every 12 weeks thereafter.
Following unblinding of the study, subjects who were randomized to 
idelalisib on Study GS-US-312-0116 will not be required to have study visits 
3, 5, and 7 performed.
Test Therapy, 
Dose, and 
Mode of 
Administration:
Blinded Portion

Arm A: Idelalisib, 300 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be provided 
as 2 tablets of active idelalisib for oral administration

Arm B: Idelalisib, 150 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be provided 
as 1 tablet of active idelalisib and 1 tablet of placebo for oral 
administration
Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID
Note: At the Investigator’s discretion, subjects who were randomized to 
placebo on study GS-US-312-0116 may delay initiation of idelalisib 
following enrollment on Study GS-US-312-0117 until the time of disease 
progression or until the investigator determines that the subject would 
benefit from initiation of idelalisib treatment


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Reference 
Therapy, Dose, 
and Mode of 
Administration:
Not applicable
Duration of 
Treatment:
Study drug will be taken continuously until the earliest of subject withdrawal 
from study drug, definitive progression of CLL, intolerable study 
drug-related toxicity, pregnancy, substantial noncompliance with study 
procedures, or study discontinuation.
Criteria for 
Evaluation:
Tumor Control

Progression-free survival (PFS) – defined as the interval from the start 
of study therapy to the earlier of the first documentation of definitive 
disease progression or death from any cause; definitive disease 
progression is CLL progression based on standard criteria other than 
lymphocytosis alone

Overall response rate (ORR) – defined as the proportion of subjects 
who achieve a complete response (CR) or partial response (PR)

Lymph node response rate – defined as the proportion of subjects who 
achieve a 50% decrease from baseline in the sum of the products of 
the greatest perpendicular diameters (SPD) of index lesions

CR rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from start of study 
therapy to the first documentation of CR or PR

Duration of response (DOR) – defined as the interval from the 
first documentation of CR or PR to the earlier of the first 
documentation of definitive disease progression or death from any 
cause

Percent change in lymph node area – defined as the percent change 
from baseline in the SPD of index lymph nodes

Splenomegaly response rate – defined as the proportion of subjects 
with a 50% decrease (minimum 2 cm) from baseline in the enlargement 
of the spleen in its LVD or to <12 cm 

Hepatomegaly response rate – defined as the proportion of subjects 
with a 50% decrease (minimum 2 cm) from baseline in the enlargement 
of the liver in its LVD or <18 cm 

ALC response rate – defined as the proportion of subjects with baseline 
lymphocytosis (ALC4 x 109/L) who achieve an on-study ALC 
<4 x 109/L or demonstrate a 50% decrease in ALC from baseline


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
Platelet response rate – defined as the proportion of subjects with 
baseline thrombocytopenia (platelet count <100 x 109/L) who achieve 
an on-study platelet count 100 x 109/L or demonstrate a 
50% increase in platelet count from baseline

Hemoglobin response rate – defined as the proportion of subjects with 
baseline anemia (hemoglobin <110 g/L [11.0 g/dL]) who achieve an 
on-study hemoglobin 110 g/L (11.0 g/dL) or demonstrate a 
50% increase in hemoglobin from baseline

Neutrophil response rate – defined as the proportion of subjects with 
baseline neutropenia (absolute neutrophil count [ANC] ≤1.5 x 109/L) 
who achieve an ANC >1.5 x 109/L or demonstrate a 50% increase in 
ANC from baseline
Patient Well-Being

Overall survival (OS) – defined as the interval from start of study 
therapy to death from any cause

Change from baseline in HRQL domain and symptom scores based on
the Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
(See Appendix 2)

Changes from baseline in Karnofsky performance status
(See Appendix 3)
Pharmacodynamic Markers of Drug Activity and Resistance

Changes from baseline in PI3K/AKT/mTOR pathway activation as a 
measure of PI3Kpathway activity 

Changes from baseline in the plasma concentrations of 
disease-associated chemokines and cytokines
Exposure

Study drug administration as assessed by prescribing records and 
compliance as assessed by quantification of used and unused drug

Trough (pre-dose) and peak (1.5-hour samples) of idelalisib plasma 
concentrations as assessed by a validated bioanalytical method
Safety

Overall safety profile of each regimen characterized by the type, 
frequency, severity, timing of onset, duration, and relationship to study 
therapy of any adverse events or abnormalities of laboratory tests; 
serious adverse events; or adverse events leading to discontinuation of 
study drug


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Pharmacoeconomics

Change in health status – defined as the change from baseline in 
overall health and single-item dimension scores as assessed using the 
EuroQoL Five-Dimension (EQ-5D) utility measure 

Health resource measures, including resource utilization, total costs, 
and measures of cost per unit of benefit (eg, cost per additional 
progression-free month, cost per quality-adjusted life-year)
Statistical 
Methods:
Appropriate data analysis sets will be defined. The intent-to-treat (ITT) 
analysis set will include data from all subjects who receive 1 dose of any 
study therapy on this study; in this data set, study drug assignment 
(high-dose or standard-dose idelalisib) will be designated according to the 
planned allocation to this study. A safety analysis set will comprise data from 
subjects in the ITT analysis set with treatment assignments designated 
according to the actual study drug (high-dose or standard-dose idelalisib) 
received. Other analysis sets [per-protocol (PP) and 
pharmacodynamic/pharmacokinetic analysis sets] will be used for certain 
analyses as well.
Subject characteristics and study results will be described and summarized 
by treatment arm and assessment for the relevant analysis sets. Descriptive 
summaries will be prepared to show sample size, mean, standard deviation, 
95% confidence intervals (CIs) on the mean, median, minimum, and 
maximum for continuous variables and counts, percentages, and 95% CIs on 
the percentage for categorical variables.
An independent review committee (IRC) will review radiographic data and 
pertinent clinical data in order to provide expert evaluation of tumor status. 
The findings of the IRC will be considered primary for analyses of PFS and 
other tumor control endpoints.
For endpoints relating to tumor control, patient well-being, and biomarkers, 
analyses will be done based on ITT, PP or pharmacodynamic data sets, as 
appropriate. Time-to-event analyses will be performed with reference to the 
date of first treatment on this study (Study GS-US-312-0117). Similarly, 
evaluations of on-therapy changes will reference the baseline values 
obtained prior to treatment in this study. Analyses will focus on evaluation 
of outcomes within each treatment arm and will be largely descriptive in 
nature; formal comparisons of outcomes in Arm A vs Arm B are not 
planned. Time-to-event endpoints will be summarized using Kaplan-Meier 
methods; medians, ranges, and the corresponding 95% CI will be presented. 
Continuous and categorical variables will also be summarized as appropriate.
Changes from baseline in categorical variables and changes from baseline in 
continuous endpoints will be analyzed using appropriate methods.


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Efficacy outcomes among subjects receiving rituximab alone in 
Study GS-US-312-0116 will be evaluated relative to those same outcomes 
among the same subjects receiving standard-dose idelalisib alone in 
Study GS-US-312-0117. More specifically, time-to-event endpoints will be 
compared using the paired Prentice-Wilcoxon test; continuous endpoints will 
be compared using the paired t-test; and categorical or non-normal data will 
be compared using the Wilcoxon signed-rank test.
Based on the safety analysis set, information regarding study drug
administration, study drug compliance, safety variables, and post-study 
therapies will be described and summarized. Using data from the 
pharmacokinetic analysis set, idelalisib plasma concentrations will also be 
described and summarized.
Sample Size Calculation
The sample size for this extension study is not based upon a formal statistical 
hypothesis. The upper bound of the sample size in this study is determined 
by the sample size of the preceding primary clinical trial (Study GS-
US-312-0116) in which ~160 subjects (~80 per arm) are expected to be 
enrolled. Assuming a ~10% dropout rate during Study GS-US-312-0116 and 
a further ~10% dropout rate in the transition from the primary study to the 
extension study, ~130 subjects are expected to be enrolled into 
Study GS-US-312-0117.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP), 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
-HCG
Beta human chorionic gonadotropin
ABCG2
adenosine triphosphate-binding cassette sub-family G member 2 (see also BCRP)
AKT
AKT (a serine/threonine protein kinase)
ALC
absolute lymphocyte count
ALL
acute lymphocytic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
ATC
Anatomical-Therapeutic-Chemical classification system for drugs 
BCRP
breast cancer resistance protein (see also ABCG2)
BID
twice per day
BTK
Bruton tyrosine kinase
CAL-101
Former name for GS-1101
CCL
chemokine (C-C motif) ligand
CFR
Code of Federal Regulations
CI
confidence interval
CIRS
Cumulative Illness Rating Scale
CLL
chronic lymphocytic leukemia
cGMP
current Good Manufacturing Practice
Cmax
maximum concentration
CMV
cytomegalovirus
CR
complete response
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough concentration
CXCL
chemokine (C-X-C motif) ligand
CYP
cytochrome P450 enzyme
DLCO
diffusing capacity of the lung for carbon monoxide
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DOR
duration of response
DSPH
Gilead Sciences Department of Safety and Public Health
ECG
electrocardiogram


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
eCCr
estimated creatinine clearance
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EQ-5D
EuroQoL Five-Dimension utility measure
FACT-Leu
Functional Assessment of Cancer Therapy: Leukemia questionnaire
FCεRI
high-affinity IgE receptor
FDA
United States Food and Drug Administration
FDAMA
Food and Drug Modernization Act
FDG
fluorodeoxyglucose (18F)
FISH
fluorescence in-situ hybridization,
FSH
follicle-stimulating hormone
G-CSF
granulocyte colony-stimulating factor
GGT
gamma-glutamyltransferase
GLP
Good Laboratory Practice
GM-CSF
granulocyte-macrophage colony-stimulating factor
HBc antibody
anti-hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
hERG
human ether-à-go-go-related gene
HL
Hodgkin lymphoma
HIV
human immunodeficiency virus
HRQL
health-related quality of life
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
idelalisib
formerly CAL-101 and GS-1101
IEC
independent ethics committee
Ig
immunoglobulin (including subtypes A, E, G, and M)
IgHV
immunoglobulin heavy chain variable region
IND
Investigational New Drug (application)
iNHL
indolent non-Hodgkin lymphoma
INR
international normalized ratio
IRB
institutional review board
IRC
independent review committee
ITT
intention to treat
IUD
intrauterine device
IWCLL
International Workshop on CLL


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
IWRS
interactive web response system
JAK
Janus kinase
K2-EDTA
potassium-ethylenediaminetetraacetic acid
LD
longest diameter
LDH
lactate dehydrogenase
LH-RH
luteinizing hormone-releasing hormone
LLN
lower limit of normal
LPD
longest perpendicular diameter
LVD
longest vertical dimension
MTD
maximum tolerated dose
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mTOR
mammalian target of rapamycin
ND
no disease
NHL
non-Hodgkin lymphoma
NOAEL
no-observed-adverse effect level
NOEL
no-observed-effect level
OCT
organic cation transporter
ORR
overall response rate
OS
overall survival
pAKT
phosphorylated AKT
PCR
polymerase chain reaction
PD
progressive disease
PET
positron-emission tomography
PI3K
phosphatidylinositol 3-kinase
PI3K
phosphatidylinositol 3-kinase p110isoform
PFS
progression-free survival
PML
progressive multifocal leukoencephalopathy
PP
per-protocol
PPD
product of the perpendicular diameters
PRO
patient-reported outcome
PR
partial response
PT
prothrombin time
PVA
polyvinyl alcohol
PVC/PCTFE
polyvinyl chloride/polychlorotrifluoroethylene
QD
once per day
QT (interval)
measure of time between start of Q wave and end of T wave in electrical cycle of heart


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
RNA
ribonucleic acid
SADR
serious adverse drug reaction
SD
stable disease
SPD
sum of the products of the perpendicular diameters of measured lymph nodes
SSC
study steering committee
SUSAR
suspected, unexpected, serious adverse reaction
SYK
spleen tyrosine kinase
t1/2
half-life
Tmax
time of maximum concentration
TTR
time to response
UGT
uridine 5'-diphospho-glucuronosyltransferase
ULN
upper limit of normal
WHODRUG
World Health Organization Drug Dictionary
ZAP-70
zeta-associated protein 70


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1.
INTRODUCTION
Chronic Lymphocytic Leukemia
1.1.
Chronic lymphocytic leukemia (CLL) is a neoplasia resulting from the progressive accumulation 
of functionally incompetent monoclonal B lymphocytes in blood, bone marrow, lymph nodes, 
spleen, and liver {19448}. CLL constitutes the most commonly occurring leukemia in Europe and 
the United States {20169}, {17688}. While some patients never require treatment, many will need 
therapy for disfiguring or obstructing lymphadenopathy, debilitating constitutional B symptoms 
(fevers, night sweats, fatigue, weight loss) {20168}, or recurrent cytopenias and infections
{17828}, {19449}. CLL is largely a disease of the elderly; at diagnosis, 70% of patients are 
65 years of age and the median age is 72 years {17688}.
In younger and relatively healthy patients with CLL, chemoimmunotherapy regimens that 
include the anti-CD20 monoclonal antibody, rituximab, are commonly employed to control 
disease manifestations {17676}. Such combination therapies are effective in providing durable 
remissions {20163}, {20165}, {17687}, {20360}, {20359}. However, while rituximab is usually
well tolerated {19036}, the chemotherapeutic agents (typically fludarabine, cyclophosphamide, or 
bendamustine) in such regimens are acutely cytotoxic, induce permanent bone marrow 
compromise, and can cause secondary malignancies {26356}, {18997}, {17717}. Furthermore, in 
elderly patients or in those with comorbid conditions, such regimens are associated with less 
efficacy and greater toxicity {18997}, {19032}, {17674}.
Increasing attention has been paid to the problem of treating patients with CLL who have 
comorbidities. Because of the relatively late age of diagnosis, a large proportion (~90%) of 
patients with CLL have co-morbidities and a substantial proportion (~45%) have major chronic 
conditions such as coronary artery disease, diabetes, or chronic obstructive pulmonary disease 
{20525}. At the time the disease is first identified, ~25% of patients with CLL do not meet 
conventional criteria for participation in clinical studies containing cytotoxic agents {20525}. By 
the time treatment is necessary or during treatment for CLL, patients continue to advance in age 
and have new or worsening chronic conditions; as a result, the proportion of patients with 
comorbidities increases during the course of the illness. Such patients have been substantially 
underrepresented in clinical trials due to concerns regarding the ability of such patients to 
tolerate intensive chemoimmunotherapy {20525}, {20558}. Instruments such as the Cumulative 
Illness Rating Scale (CIRS) {21025} are now being applied in order to categorize patient 
populations as fit or relatively unfit and to evaluate regimens tailored to these groups of patients
{20558}, {20165}, {21059}.


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Health constraints in older or compromised patients have prompted noncytotoxic approaches to 
therapy. Alternative immunotherapeutics, such as the monoclonal antibodies, alemtuzumab
{17680} or ofatumumab {21022}, have been developed. However the therapeutic utility of these 
drugs is modest; median progression-free survival (PFS) values in patients with recurrent CLL 
have been 4.7 months and 5.8 months, respectively. Moreover, these treatments can have clinical 
liabilities. Alemtuzumab causes extreme immunosuppression that leads to frequent opportunistic 
infection. Administration of the large amounts of protein recommended in ofatumumab product 
labeling results in frequent infusion reactions and cumbersome infusion schedules.
In view of these issues, repeated use of rituximab monotherapy or rituximab-corticosteroid 
combinations have been advocated in treatment guidelines for older or frail patients with 
recurrent CLL {17670}, {19042}. While single-agent rituximab use can offer palliative benefit 
with good tolerability in some patients with previously treated CLL, tumor control is not lasting, 
especially in patients with bulky adenopathy {19036}. Addition of high-dose corticosteroids to 
rituximab can extend median PFS up to 12 months, but this combination is commonly associated 
with severe hyperglycemia and frequent life-threatening or fatal infections {19037}, {19035}.
New, noncytotoxic, well-tolerated, and convenient therapies that can successfully be combined 
with rituximab or given as single-agent therapy are needed in order to enhance and prolong 
tumor control in patients with comorbid conditions.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies
1.2.
Phosphatidylinositol 3-kinases (PI3Ks) are enzymes that regulate several cellular functions 
including motility, proliferation, and survival {23618}. PI3K activation recruits and activates 
numerous intracellular signaling enzymes. The most important of these is the serine/threonine 
kinase, AKT, which mediates a positive pleiotropic effect on cell survival, proliferation, growth, 
and metabolism {17720} acting by signaling through mammalian target of rapamycin (mTOR) 
{17678}, {17686}.
PI3K signaling is mediated by 4 catalytic isoforms of the p110 subunit of the enzyme - , , , 
and . While potentially important in multiple cell types, PI3K p110(PI3K) shows an 
expression pattern that is particularly prominent in cells of hematopoietic origin {17690}. Mice 
deficient in PI3Khave no gross abnormalities, are fertile, fecund, and live a normal life span 
without an increased susceptibility to infections {23619}. However, the B-lymphocyte population 
in these animals shows a decrease in maturation, diminished receptor-induced proliferation, and 
increased susceptibility to apoptotic cell death. Conversely, mice with aberrantly elevated PI3K 
signaling develop lymphadenopathy and have an increased incidence of lymphoma {17719}. In 
CLL, sustained activation of the PI3K/AKT/mTOR pathway has been shown to promote 
malignant B-cell survival through mechanisms that are dependent on the PI3Kisoform {24339}, 
{23399}, {19034}.
Knowledge of the critical importance of PI3Kδ in B-cell biology and neoplasia has encouraged a 
search for inhibitors of this enzyme that could provide new options in the therapy of lymphoid 
malignancies, including CLL.


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Idelalisib (formerly GS-1101)
1.3.
1.3.1.
Discovery and Efficacy Pharmacology
Gilead Sciences, Inc has developed novel drugs that can suppress tumor growth through 
targeting of PI3Kδ activity. High-throughput screening was the basis for the discovery of novel 
agents that selectively inhibit PI3Kfunction but spare other PI3K isoforms and other kinases. 
Chemical optimization, pharmacological characterization, and toxicological evaluation have led 
to identification of idelalisib (also known as GS-1101), a 415-dalton, orally bioavailable, new 
chemical entity with potential clinical utility in the treatment of cancers.
In primary tumor samples and in cell lines derived from patients with CLL, indolent 
non-Hodgkin lymphoma (iNHL), mantle cell lymphoma (MCL), B-cell acute lymphocytic 
leukemia (ALL), or Hodgkin lymphoma (HL), idelalisib induces dose-dependent reductions in 
AKT phosphorylation {23399}, {20167}, {19034}. In addition, idelalisib disrupts the PI3K
activation and supportive intercellular signaling observed when CLL or HL cells are cocultured 
with stromal cells {20167}, {23401}. These effects have therapeutic consequences. In multiple 
lymphoid primary tumors and malignant cell lines, idelalisib enhances apoptosis and 
concentration-dependent cell killing when applied as a single agent and increases the therapeutic 
efficacy of other antineoplastic agents when given in combination {23401}, {20902}. In 
preclinical systems, coadministration of idelalisib with rituximab has not impaired 
rituximab-mediated activity {23399}.
1.3.2.
Safety Pharmacology
In vitro and in vivo safety pharmacology studies with idelalisib have demonstrated a favorable 
non-clinical safety profile. These studies indicate that the drug may minimally slow bone marrow 
progenitor proliferation and differentiation and that it has expected inhibitory effects on B-cell
response to antigen challenge. However, the data indicate that idelalisib is unlikely to cause 
serious off-target effects or adverse effects on critical organ systems. idelalisib has no 
meaningful effect on the human ether-à-go-go-related gene (hERG) channel, indicating that 
idelalisib would not be expected to induce clinical QT prolongation.
The drug has also proved well tolerated in standard in vivo Good Laboratory Practice (GLP) 
studies of pharmacological safety. A functional observation battery in rats revealed no adverse 
effects on behavior or on autonomic, neuromuscular, or sensorimotor function. In a 
cardiopulmonary function study in awake, telemeterized male beagle dogs, single doses of 
idelalisib induced no meaningful abnormalities in pulmonary, cardiovascular, arterial blood gas, 
or electrocardiographic (ECG) (including QT interval) parameters. In an assessment of bacterial 
challenge in rats, idelalisib enhanced, rather than impaired, the phagocytic host clearance of 
staphylococcal bacteria.


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1.3.3.
Nonclinical Pharmacology and Metabolism
Consistent with the moderate to high bioavailability seen in nonclinical species, idelalisib shows 
high permeability across human Caco-2 cell monolayers.  At lower concentrations, the reverse 
permeability at low concentration exceeds forward permeability, indicating efflux driven by 
transporters (eg, human P-glycoprotein (MDR1) and breast cancer resistance protein [BCRP]); 
idelalisib is a substrate for the efflux transporters MDR1 and BCRP; however, the permeability 
increases in a concentration-dependent manner, resulting in a lower efflux ratio at higher, 
clinically relevant concentrations of idelalisib. 
Idelalisib exhibits moderately high plasma protein binding in mouse, rat, dog, and human.  In
dog and human plasma, the protein binding is concentration-independent between 1 and 20 µM.  
Protein binding in human plasma is slightly higher than in mouse, rat, and dog plasma, which 
have comparable free fractions.  In human plasma, idelalisib and GS-563117 (the major
metabolite of idelalisib) have an average free fraction of ~16% and ~12%, respectively.
After oral administration of 14C-idelalisib to rats and dogs, radioactivity is widely distributed, but 
relatively excluded from bone, brain, spinal cord, and eye lens in rats and from brain and eyes in 
dogs.  In rats, the radioactivity declines steadily and most tissues have undetectable levels by 
72 hours post dose.  In bile duct-cannulated rats and dogs, ≥ 69% of radioactivity is recovered in 
bile and urine, indicating high absorption of idelalisib in vivo.
In hepatic tissues from nonclinical species, idelalisib is primarily metabolized by aldehyde 
oxidase, CYP3A, and UGT1A4.  In vitro metabolism in dog and human yields 3 primary 
oxidative metabolites and 5 primary glucuronides.  Of these, the oxidative product GS-563117 is 
the predominant metabolite in vitro and in vivo.  In preclinical species, plasma levels of 
GS-563117 are below those of idelalisib.  In humans, GS-563117 (only circulating metabolite 
and formed via aldehyde oxidase) plasma levels significantly exceed those of idelalisib.  After 
oral administration of 14C-idelalisib to rats and dogs, biliary excretion appears to be the major 
route of elimination of idelalisib and its metabolites as the majority of radioactivity is found in 
feces or bile and little in urine.
Idelalisib is not a substrate for the renal transporters OCT2, OAT1, and OAT3 or the hepatic 
uptake transporters OATP1B1 and OATP1B3.  GS-563117 is not a substrate for OATP1B1 and 
OATP1B3.  
Idelalisib is not an inhibitor of CYP1A, CYP2B6, CYP2C9, and CYP2D6, and at concentrations 
above those observed clinically, is an inhibitor of CYP2C8 (IC50 = 13 µM), CYP2C19 
(IC50 = 76 µM), and CYP3A (IC50 = 44 µM). GS-563117 is not an inhibitor of CYP1A, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and a competitive and time dependent 
inhibitor of CYP3A (IC50 = 3.1 µM), (KI = 0.18 µM, kinact = 0.033 min-1 with midazolam as 
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In vitro, idelalisib is not an inhibitor of the transporters BCRP, OCT2, OAT1, and OAT3, and is 
an inhibitor of MDR1 (IC50 = 7.7 µM), OATP1B1 (IC50 = 10.1 µM), OATP1B3 (IC50 = 7.0 µM), 
and, at concentrations above those observed clinically, of glucuronosyltransferase UGT1A1 
(IC50 = 42.0 µM).  GS-563117 is not an inhibitor of MDR1, BCRP, OATP1B1, OATP1B3, 
OAT1, OAT3, and OCT2, and at concentrations above those observed clinically, an inhibitor of 
UGT1A1 (IC50 = 16.8 µM).
Any potential clinical implications of these metabolism studies were evaluated in a formal drug-
drug interaction study (GS-US-313-0130) which evaluated the effect of idelalisib on cytochrome 
P450 3A and the drug transporters P-gp, OATP1B1, and OATP1B3.  Study GS-US-313-0130 
also evaluated the impact of an inducer of metabolizing enzymes and transporters (rifampin) on 
the PK of idelalisib in healthy human subjects. Findings from this study are presented in 
Section 1.3.5.1.
1.3.4.
Toxicology
The toxicological profile of idelalisib was well characterized through the conduct of single dose, 
repeat dose, developmental and reproductive, and genetic toxicology and local tolerance studies.  
The primary target organ toxicities following repeated dosing include the lymphoid, hepatic, 
male reproductive systems in rats and dogs, and gastrointestinal system in dogs.  Adverse effects 
in the lymphoid system were primarily the result of on target pharmacology resulting in 
decreased lymphocytes in multiple lymphoid organs, primarily involving B-cell regions.  Liver 
effects were transient and reversible with continued dosing and did not result in chronic liver 
injury.  Reduction in sperm numbers in males were reversible and did not impact fertility or 
reproductive performance. Gastrointestinal effects in dogs were minor, superficial, and 
considered secondary to effects on lymphocytes in Peyer’s Patches.  Idelalisib was shown to be 
teratogenic and associated with embryo-fetal lethality.  Effects on the reproductive system have 
been reported for inhibitors which target other isoforms of PI3K.  The dose-dependence and 
potential of idelalisib to selectively inhibit additional PI3K isoforms may be responsible for the 
off-target toxicity.  Additionally, the drug may have the potential to produce phototoxic reactions 
in humans.  These findings represent toxicities that can be monitored, are considered clinically 
manageable, or are considered acceptable risks in the intended patient population.
Further details on the toxicology of idelalisib can be found in the Idelalisib Investigator’s 
Brochure (IB).
1.3.5.
Idelalisib Clinical Studies
1.3.5.1.
Phase 1 Studies in Healthy Subjects and in Patients with Allergic Rhinitis
Various studies in healthy subjectshave evaluatedsafety, pharmacokinetics, food effect, and the 
potential for drug interactions of idelalisib with CYP3A4 inhibitors {20361}. 


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Safety results from these studies indicated that idelalisib was well tolerated when administered to 
healthy subjects at single doses through 400 mg (the highest dose level tested) and was also 
generally well tolerated when administered to healthy subjects over 7 days at dose levels through 
200 mg/dose BID (the highest dose level tested). Dosing with 200 mg/dose BID for 7 days 
resulted in a skin rash in 3 out of 6 subjects; histological findings were consistent with a 
delayed-type hypersensitivity maculopapular exanthema. Rashes have sometimes occurred in 
patients with hematological malignancies receiving idelalisib, but have not typically proved 
dose- or treatment-limiting. In placebo-controlled single-dose and multiple-dose trials, repeated 
ECG evaluations performed in tandem with pharmacokinetic monitoring showed no evidence of 
drug-, dose-, or exposure-dependent effects on cardiac rhythm or cardiac intervals 
(eg, QT interval). Pharmacokinetic results indicated that idelalisib appeared rapidly in plasma 
with a median Tmax of 1 to 1.5 hours.  Cmax and AUC increased in a less-than-dose-proportional 
manner and mean t1/2 values were across the dose range were 6.5 to 9.8 hours.
Idelalisib dosing after a high-fat, high-calorie meal delayed median time of maximum 
concentration (Tmax) from 0.75 hours to 3 hours; mean Cmax was unaffected and mean AUC was 
~40% higher. These changes in idelalisib exposures are considered modest/clinically 
non-relevant; thus, idelalisib may be given with or without food.
Idelalisib is metabolized in humans primarily by aldehyde oxidase, with some involvement of 
CYP3A4 and UGT1A4. Accordingly, when idelalisib was administered following 4 days of daily 
dosing with ketoconazole (a potent inhibitor of CYP3A4), modest/moderate increases in mean 
idelalisib Cmax and AUC values of ~30% and ~80% higher, respectively, which is not considered 
to be clinically relevant and suggesting that idelalisib is a weak CYP3A substrate. GS-563117 is 
formed from idelalisib primarily via aldehyde oxidase.
The 14C-labeled idelalisib human mass balance results showed that the drug has moderate to high 
oral bioavailability. Idelalisib is eliminated mainly via hepatic metabolism and biliary excretion 
in the feces (~78% of dose); recovery in urine was < 15%. GS-563117, the only circulating 
metabolite observed in human plasma, was also observed in urine and feces. 
Results from the drug interaction/probe Study GS-US-313-0130 indicate that idelalisib does not 
affect the pharmacokinetics of substrates of Pgp, BCRP, OATP1B1 or OATP1B3 transporters. 
Idelalisib is not expected to affect the exposures of coadministered agents via transporter 
mediated interactions. 
The exposures (AUC) of probe CYP3A substrate, midazolam, increased ~5-fold upon 
coadministration with idelalisib, driven by competitive and time-dependent CYP3A inhibition by 
GS-563117, the only circulating metabolite of idelalisib. Coadministration of the highly potent 
CYP3A inducer rifampin resulted in a ~75% reduction in idelalisib systemic exposures, likely 
driven by a higher relative contribution of CYP3A to overall idelalisib clearance under the 
induced state.


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Pharmacodynamic results showed that a idelalisib dose of 200 mg inhibited ex vivo basophil 
activation via the PI3K-specific, high-affinity immunoglobulin (Ig)E receptor (anti-FCR1) in 
basophils collected from healthy volunteers. The findings were confirmed when the drug was 
assessed over 7 days in a Phase 1b study in subjects with allergic rhinitis. In this study, idelalisib
at a dose level of 100 mg/dose BID showed clinical and pharmacodynamic activity 
(attenuating adverse responses to allergenic challenge and decreasing markers of inflammation) 
and was well tolerated.
1.3.5.2.
Phase 1 Studies in Patients with Hematological Malignancies
1.3.5.2.1.
Phase 1 Monotherapy Study in Patients with Hematological Malignancies
A Phase 1 dose-ranging study (Study 101-02) of single-agent idelalisib extended safety and 
pharmacokinetic observations; documented the clinical and pharmacodynamic activity of 
idelalisib in subjects with iNHL, MCL, and CLL; and provided dosing information in support of 
further development {20397}, {21030}, {21036}. In this study, idelalisib was administered in 
cohorts of subjects across a range of dose levels from 50 mg/dose BID to 350 mg/dose BID. 
Idelalisib administration was continued as long as individual subjects were safely benefitting 
from therapy. Subjects were evaluated in 4-week cycles; response and progression assessments 
were based on standard criteria {12154}.
A total of 191 subjects were enrolled to the study at dose levels of 50 mg BID (n=17), 150 mg 
QD (n=16), 100 mg BID (n=25), 150 mg BID (n=45), 200 mg BID (n=35), 350 mg BID (n=17), 
and 300 mg QD (n=19). An additional cohort was also enrolled to receive idelalisib 150 mg BID 
in 28 day cycles (21 days on idelalisib/7 days off [n=17]). Subject characteristics were as 
follows: males/females n=139 (73%)/52 (27%) with median age of 64.5 (range 32-91) years.  
Diagnoses included: CLL, n=54 (28%); iNHL, n=64 (34%); aggressive NHL (MCL and 
DLBCL), n=49 (26%); AML, n=12 (6%); and MM, n=12 (6%).  Categorization of disease by 
response to the last prior therapy included: refractory, n=111 (58%); relapsed, n=79 (42%); and 
unknown, n=1 (1%).  The median (range) number of prior therapies was 5 (1-14). Among 
subjects with iNHL and CLL, the majority had received prior rituximab and prior alkylating 
agent therapy. 
Adverse events were usually mild to moderate and not clearly idelalisib-related.  Among 
Grade ≥3 adverse events, pneumonias and diarrhea were notable.  Pneumonia was observed in 
23 (12%) subjects, primarily in subjects with CLL.  In most instances, these findings were 
considered bacterial in origin, based either on culture results or on response to conventional 
antibiotics.  Grade ≥3 adverse events of diarrhea were seen in 11 subjects (5.8%).  Other 
Grade ≥3 events included rash in 3 (1.6%) subjects.  The relative contributions of disease-related 
factors, toxicity from prior therapies or ongoing supportive care, and idelalisib to these events 
was not clear.


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Grade ≥3 hematological laboratory abnormalities have included neutropenia, n=46 (24%); 
thrombocytopenia, n=27 (14%), anemia, n=14 (7.3%), and lymphopenia 13 (6.8%); with 
12 subjects (6.3%) having febrile neutropenia.  The occurrence of these events was greater in 
subjects with leukemia, particularly in those with pre-existing hematological abnormalities due 
to disease or prior therapy, commonly making attribution of these events to idelalisib uncertain.
Consistent with the observations in the 28-day dog toxicology study, reversible Grade ≥3 
ALT/AST elevations occurred in 28 (15%) subjects and have been attributed to idelalisib.  Onset 
generally occurred between 2 to 16 weeks after idelalisib initiation and resolution was usually 
seen 2 to 6 weeks after idelalisib interruption.  After resolution of ALT/AST increases, 
14 subjects were rechallenged at the same or a reduced dose of idelalisib and 9 (64%) of these 
subjects were able to resume treatment without recurrence of transaminase elevations.  
Two (1.0%) subjects had ≥ 2 x ULN elevations in bilirubin in the context of Grade ≥3 elevated 
AST / ALT, both of whom had confounding factors (recent history of biliary obstruction or 
concomitant use of potentially hepatotoxic medications) so that a definitive causal relationship to 
idelalisib could not be established. 
Pharmacokinetic analyses indicated that the increase in Cmax and AUC0-6h with dose was less 
than dose-proportional, with modest increases above the dose level of 150 mg BID.  
Pharmacodynamic data supported drug activity.  In subjects with NHL, plasma concentrations of 
chemokines CCL22 and CCL17 were elevated at baseline and showed significant decreases 
within 1 cycle of idelalisib treatment (p<0.001 for both comparisons).  Flow cytometry of CLL 
cells from subjects showed that idelalisib reduced constitutive expression of phosphorylated 
AKT to background levels when measured after 1 week of treatment (p<0.0001), demonstrating 
pharmacodynamic inhibition of activated PI3K signaling.  Plasma concentrations of chemokines 
CCL3, CCL4, and CXCL13 were elevated in CLL subjects at baseline and decreased 
significantly within 1 cycle of idelalisib administration (p<0.001 for all comparisons).
Tumor reductions meeting antitumor response criteria were not observed in subjects with AML 
or MM.  One of 11 subjects with DLBCL achieved a PR. In 104 subjects with iNHL and MCL, 
idelalisib induced PRs at all dose levels, with respective ORRs in enrolled subjects of 
29/64 (45%) for iNHL and 16/40 (40%) for MCL. The median DOR has not been reached in 
subjects with iNHL; 19 subjects continued to receive idelalisib in a long-term extension study.   
The median [range] DOR was 2.7 months [1 month to 8 months] in subjects with MCL; 6 MCL 
subjects continued to receive idelalisib in a long-term extension study. 
In subjects with CLL, idelalisib reduced lymphadenopathy in almost all subjects; 44/54 (81.5%) 
achieved a lymph node response (≥50% reduction in target nodal lesions).  An initial increase in 
peripheral absolute lymphocyte counts of >50% from baseline was observed in some subjects; 
increases were maximal during the first 2 cycles and decreased thereafter; the pattern suggested 
drug-mediated lymphocyte redistribution.  In 54 subjects with CLL, 39/54 (72%) achieved a PR 
(includes PR with lymphocytosis).  The median DOR was not reached; 23 subjects continued to 
receive idelalisib in a long-term extension study.  


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1.3.5.2.2.
Phase 1 Combination Study in Patients with Hematological Malignancies
A separate Phase 1 trial (Study 101-07) has evaluated the safety and preliminary activity of 
idelalisib given in combination with rituximab to subjects with recurrent iNHL or CLL {20397}, 
{19528}.
In this study, rituximab was administered at a standard dose of 375 mg/m2 per infusion weekly 
for 8 weeks in all subjects. Idelalisib was started simultaneously with the rituximab, first at a 
dose level of 100 mg/dose BID (n=13) and then at a dose level of 150 mg/dose BID (n=12) and 
was administered continuously to both subjects with CLL (n=13) and subjects with iNHL (n=12)
for as long as individual subjects were safely benefiting from therapy. Subjects were evaluated in 
4-week cycles; response and progression assessments were based on standard criteria {12154}.
Among the subjects with CLL, the median age was 63 and ranged to 85 years. Bulky tumors 
(1 lymph node 5 cm in diameter) were present in 63% of the subjects. The median number of 
prior therapies by disease was 2 and ranged up to 8 prior treatments. All had received prior 
rituximab and the majority had received prior fludarabine or alkylating agents. Approximately 
one-third of subjects had CLL that was refractory to the last prior therapy. At the time of data 
cut-off, therapy had been administered for a median of 5 cycles, ranging up to 12 cycles (ie, 48
weeks).
No idelalisib-related dose-limiting toxicities were observed within the tested subject cohorts. 
Grade 3-4 adverse events largely comprised background events resulting from pre-existing 
disease- or treatment-related conditions or from intercurrent illness. Among subjects with CLL, 
2 (15%) developed pneumonia. For subjects receiving idelalisib together with rituximab, 
Grade 3-4 elevations in ALT/AST were not observed in those with CLL, although 3 subjects 
(25%) of those with iNHL had such events.
The idelalisib plus rituximab combination showed a high level of antitumor activity in both 
subjects with CLL and those with iNHL. Altogether 92% of subjects with CLL receiving the 
combination of idelalisib and rituximab had reductions in nodal size and 77% showed a lymph 
node response (50% reduction in index nodal lesions). Although concomitant administration of 
rituximab did not eliminate the redistribution lymphocytosis that is associated with idelalisib, it 
blunted the magnitude of the change. As a result, the overall response rate (ORR) was also 
77% among subjects participating in this study. At the time of last data analysis, PFS through 
48 weeks was 70% and a median PFS had not yet been observed.
Collectively, the emerging data from this study support further evaluation of idelalisib together 
with rituximab in subjects with CLL and indicate that co-administration of idelalisib with 
rituximab is tolerable when using idelalisib at full dose, ie, at a starting dose level of 
150 mg/dose BID.


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Summary and Justification for the Current Study
1.4.
Gilead Sciences is conducting this Phase 3 study program to evaluate the efficacy and safety of 
idelalisib in patients with previously treated, recurrent CLL. Collectively the data derived from 
the primary clinical trial (Study GS-US-312-0116) and from this extension trial 
(Study GS-US-312-0117) address the activity of idelalisib together with rituximab, the activity 
of idelalisib when given alone, and the potential for dose-dependent restoration of drug activity 
in subjects who have disease that appears to be drug resistant.
The design and conduct of this clinical trial program is supported by knowledge of the 
demographics of patients with CLL, the natural history and current therapies for the disease, and 
the nonclinical and clinical information regarding idelalisib. The collective data support the 
following conclusions:

CLL is a serious, disabling, and potentially life-threatening disorder of older patients that 
requires sequential treatment with agents that provide alternative mechanisms of tumor 
control. Existing cytotoxic agents have serious acute and chronic toxicities, making them less 
suitable for frail or unfit patients. Single-agent rituximab can offer disease palliation with 
good tolerability in some patients with relapsed CLL but tumor control is not lasting, 
especially in patients with bulky adenopathy. Development of a non-cytotoxic combination 
therapy of idelalisib with rituximab or a monotherapy regimen of idelalisib that can address 
disease pathogenesis with a new mechanism of action and might offer complementary nodal 
and peripheral blood activity would address an unmet medical need, particularly when 
applied in patients with substantial comorbidities or myelosuppression from prior 
chemotherapies.

PI3Kδ over-expression plays an important role in CLL biology. Further evaluation of 
idelalisib as a potential treatment for CLL has sound scientific rationale founded on 
knowledge of the actions of the drug to selectively abrogate PI3Kδ activity and to inhibit 
malignant cell growth and stromal cell signaling in nonclinical models of CLL. These data 
are supported by clinical documentation of idelalisib inhibition of PI3Kδ signaling in patients 
with CLL.

The potential for clinical efficacy of idelalisib monotherapy or of idelalisib plus rituximab in 
patients with relapsed or refractory CLL is supported by the observed antitumor activity of 
idelalisib – given alone or in combination with rituximab - in patients with heavily pretreated 
CLL and iNHL.

The safety of advancing development of the idelalisib monotherapy and of a regimen of 
idelalisib plus rituximab in this Phase 3 clinical trial program is well supported by safety 
pharmacology and toxicology studies and by Phase 1 single-agent and combination safety 
data obtained in healthy volunteers and in subjects with lymphoid cancers. 

Dose-safety, dose-exposure, and dose-activity relationships identified in Phase 1 studies
support the dosing regimen and dose modification provisions in this study.


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
Observations relating to patterns of CLL response among subjects receiving idelalisib alone 
or in combination with rituximab in Phase 1 trials provide the foundation for efficacy
monitoring in this trial. Of particular note is that idelalisib mobilizes CLL cells from tissues 
into the peripheral blood. This characteristic pharmacological action is prominent early in 
therapy but can persist over time and should not be confused with disease progression in 
patients who have persistent control of other CLL-related signs and symptoms. For this 
reason, in this Phase 3 study program, subjects will be continued on therapy until the 
occurrence of definitive disease progression, ie, disease progression that is manifest by 
worsening CLL-related signs or symptoms other than lymphocytosis alone. 

Thorough nonclinical and clinical characterization of the type, severity, manifestations, and 
expected timing of adverse events establish the safety monitoring plan in this trial program.

The scientific correlative work performed in prior preclinical and clinical studies provides 
strong scientific underpinnings for the companion laboratory studies to be performed as a 
component of this clinical trial program.

Given the seriousness of previously treated CLL in patients with substantial comorbidity, and 
the aggregate potential benefits considered in the context of potential risks, further 
development of idelalisib in this Phase 3 clinical trial program is justified.
The rationale for specific design features is provided in relevant sections of the protocol, 
including Section 3.2 (Endpoint Selection Rationale), Section 2.2 (Design Rationale), Section 4.3
(Enrollment Criteria Rationale), Section 5.10 (Study Treatment Rationale), and Section 6.5
(Study Procedure Rationale).


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2.
STUDY DESIGN
Design Overview and Study Schema
2.1.
This study is being conducted as part of an overall clinical program that is evaluating the efficacy 
and safety of idelalisib in the therapy of patients with previously treated CLL (see Figure 2-1). 
Within this program, the primary clinical trial (Study GS-US-312-0116) is a Phase 3, 
multicenter, 2-arm, randomized, double-blind, placebo-controlled, parallel-group study. This 
clinical trial (Study GS-US-312-0117) is a separate, multicenter, 2-arm, double-blind, parallel-
group extension study that is a companion study to the primary study.
Figure 2-1.
Study Design
Candidates for the primary study will be adults with previously treated recurrent CLL who have 
measurable lymphadenopathy, require therapy for CLL, have experienced CLL progression 
<24 months since the completion of the last prior therapy, and are currently not sufficiently fit to 
receive cytotoxic therapy because of chemotherapy-induced bone marrow damage or 
comorbidities.
Primary study subjects will be stratified based on 17p deletion and/or a p53 mutation status 
(either vs neither), immunoglobulin heavy chain variable region (IgHV) mutation status 
(unmutated vs mutated), and any prior therapy with an anti-CD20 therapeutic monoclonal 
antibody (yes vs no) and randomized in a 1:1 ratio to receive 1 of the 2 treatment arms. 
In the primary study, subjects will be administered rituximab intravenously in the clinic starting 
at a dose of 375 mg/m2 on Day 1 (Week 0) and will continue with a dose of 500 mg/m2 on 
Day 15 (Week 2), Day 29 (Week 4), Day 43 (Week 6), Day 57 (Week 8), Day 85 (Week 12), 
Day 113 (Week 16), Day 141 (Week 20) (for a total of 8 infusions). Rituximab will be
administered until the earliest of subject withdrawal from study, definitive progression of CLL, 
intolerable rituximab-related toxicity, pregnancy, substantial noncompliance with study 
procedures, study discontinuation, or a maximum of 8 infusions.


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Idelalisib or placebo will be taken orally, BID continuously. Subjects will continue whichever 
study drug (idelalisib/placebo or rituximab) continues to be tolerated, even if the other drug has 
been discontinued due to toxicity.
If permanent discontinuation of study drug, occurs prior to definitive progression of CLL, 
subjects shall remain on study until definitive progression of CLL or withdrawal from the study 
for reasons specified in Section 5.7.
Compliant subjects who are tolerating therapy but who develop definitive disease progression in 
the primary clinical trial (Study GS-US-312-0116) can consider enrollment in this separate 
companion extension trial (Study GS-US-312-0117). In the extension trial, subjects will take 
active blinded idelalisib therapy, either at a higher starting dose or at the standard starting dose, 
with allocation based on the original primary study randomization.
The primary objective of Study GS-US-312-0116 will be to evaluate the effect of the addition of 
idelalisib to rituximab on PFS. Secondary and tertiary objectives will focus on determining the 
effect of the addition of idelalisib to rituximab on the onset, magnitude, and duration of tumor 
control; overall survival (OS); health-related quality of life (HRQL); changes in subject 
performance status; disease-associated biomarkers and potential mechanisms of resistance; 
treatment administration; safety; and health resource utilization. In Study GS-US-312-0117, the 
same endpoints will be assessed as in Study GS-US-312-0116; the focus of the analysis will be 
largely descriptive except for the within-subject assessment of treatment effects among subjects 
receiving first rituximab alone and then idelalisib alone on Arm B of each trial. No formal 
comparisons of outcomes in Arm A vs Arm B are planned within Study GS-US-312-0117.
Design Rationale
2.2.
The randomized, add-on design for the primary trial (Study GS-US-312-0116) is customary in 
the comparative evaluation of new therapies for cancer. While this design provides idelalisib
efficacy and safety information only in the context of administration of a companion 
antineoplastic agent, it is appropriate because it documents the incremental benefit and toxicity 
of the investigational therapy in the context of a controlled clinical trial while ensuring that all 
participants receive potentially active treatment.
This separate extension trial (Study GS-US-312-0117) enhances subject acceptance of 
randomization in the primary study and provides further information regarding idelalisib
efficacy, resistance, and safety. Among subjects in Arm A, escalation to a higher dose level 
allows evaluation of dose-dependent resistance and a determination if a higher dose can 
reestablish disease control. The safety data obtained in these subjects will add to the overall 
safety database. Among subjects randomized to Arm B in the primary study, evaluation of 
idelalisib at a starting dose of 150 mg/dose BID in the extension study may permit a 
within-subject assessment of the treatment effects with single-agent idelalisib relative to the 
effects previously observed with rituximab alone. Of importance, the extension study maintains 
the partial blinding of the primary study, thus minimizing the bias that might occur if the overall 
design entailed only a 1-way crossover to open-label idelalisib among subjects who had received 
placebo on Arm B of the primary study. To ensure confirmation of disease progression, tumor 


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size data collected from the primary study will be subjected to independent review by an 
independent review committee (IRC) (see Section 10.4.2); subjects will continue with study 
therapy pending confirmation of progression status by the sponsor working in collaboration with 
the IRC. Subjects must have confirmation that the disease has progressed on the primary study 
before being permitted to receive secondary idelalisib therapy on the extension study, or in the 
event the primary study is stopped, subjects who have not yet progressed may enroll on the 
extension study to receive 150 mg BID idelalisib.


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3.
OBJECTIVES AND ENDPOINTS

To evaluate the effect of idelalisib on the onset, magnitude, and duration of tumor control

To compare tumor control in subjects receiving rituximab alone in Study GS-US-312-0116 to 
that observed in the same subjects when receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject well-being, including overall survival 
(OS), health-related quality of life (HRQL), and performance status

To assess the effects of idelalisib on disease-associated biomarkers and to evaluate potential 
mechanisms of resistance to idelalisib

To characterize exposure to idelalisib as determined by treatment administration and 
evaluation of idelalisib plasma concentrations over time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with administration of idelalisib
Endpoints
3.1.
3.1.1.
Tumor Control

Progression-free survival (PFS) – defined as the interval from the start of study therapy to the 
earlier of the first documentation of definitive disease progression or death from any cause; 
definitive disease progression is CLL progression based on standard criteria other than 
lymphocytosis alone

ORR – defined as the proportion of subjects who achieve a CR or partial response (PR) 

Lymph node response rate – defined as the proportion of subjects who achieve a 
50% decrease from baseline in the SPD of index lymph nodes

CR rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from start of study therapy to the first 
documentation of CR or PR

Duration of response (DOR) – defined as the interval from the first documentation of CR or 
PR to the earlier of the first documentation of definitive disease progression or death from 
any cause

Percent change in lymph node area – defined as the percent change from baseline in the sum 
of the products of the greatest perpendicular diameters (SPD) of index lymph nodes


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
Splenomegaly response rate – defined as the proportion of subjects with a 50% decrease
(minimum 2 cm) from baseline in the enlargement of the spleen in its LVD or to 12 cm by 
imaging

Hepatomegaly response rate – defined as the proportion of subjects with a 50% decrease
(minimum 2 cm) from baseline in the enlargement of the liver in its LVD or to 18 cm by 
imaging

ALC response rate – defined as the proportion of subjects with baseline lymphocytosis 
(ALC4 x 109/L) who achieve an on-study ALC <4 x 109/L or demonstrate a 50% decrease 
in ALC from baseline

Platelet response rate – defined as the proportion of subjects with baseline thrombocytopenia 
(platelet count <100 x 109/L) who achieve an on-study platelet count 100 x 109/L or 
demonstrate a 50% increase in platelet count from baseline

Hemoglobin response rate – defined as the proportion of subjects with baseline anemia 
(hemoglobin <110 g/L [11.0 g/dL]) who achieve an on-study hemoglobin 110 g/L 
(11.0 g/dL) or demonstrate a 50% increase in hemoglobin from baseline

Neutrophil response rate – defined as the proportion of subjects with baseline neutropenia 
(absolute neutrophil count [ANC] ≤1.5 x 109/L) who achieve an ANC >1.5 x 109/L or 
demonstrate a 50% increase in ANC from baseline
3.1.2.
Patient Well-Being

Overall survival (OS) – defined as the interval from start of study therapy to death from any 
cause

Change from baseline in HRQL domain and symptom scores based on  the Functional 
Assessment of Cancer Therapy: Leukemia (FACT-Leu) (see Appendix 2) 

Changes from baseline in Karnofsky performance status – defined as the change from 
baseline in the performance status (see Appendix 3) 
3.1.3.
Pharmacodynamic Markers of Drug Activity and Resistance

Changes from baseline in PI3K/AKT/mTOR pathway activation as a measure of PI3K
pathway activity

Changes from baseline in the plasma concentrations of disease-associated chemokines and 
cytokines


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3.1.4.
Exposure

Study drug administration as assessed by prescribing records and compliance as assessed by 
quantification of used and unused drug

Trough (pre-dose) and peak (1.5-hour samples) of idelalisib plasma concentrations as 
assessed by a validated bioanalytical method
3.1.5.
Safety

Overall safety profile of each study treatment regimen characterized by the type, frequency, 
severity, timing of onset, duration, and relationship to study therapy of any adverse events or 
abnormalities of laboratory tests; serious adverse events; or adverse events leading to 
discontinuation of study drug
3.1.6.
Pharmacoeconomics

Change in health status – defined as the change from baseline in overall health and 
single-item dimension scores as assessed using the EuroQoL Five-Dimension (EQ-5D) utility 
measure (Appendix 4)

Health resource measures, including resource utilization, total costs, and measures of cost per 
unit of benefit (eg, cost per additional progression-free month, cost per quality-adjusted 
life-year)
Endpoint Selection Rationale
3.2.
The proposed endpoints have been chosen based on relevance to the pathophysiology and 
clinical manifestations of CLL, the known pharmacology of idelalisib, and the goals of the study 
in documenting idelalisib benefit-to-risk ratio. These types of endpoints have been employed in 
prior studies in CLL and can be evaluated with acceptable reliability and accuracy.
3.2.1.
Tumor Control Endpoints
Assessments of the magnitude and duration of changes in tumor size are routinely employed in 
registration-directed oncology clinical studies to determine therapeutic effect. Unlike OS, these 
endpoints directly assess the ability of the drug to control the malignancy. Such assessments are 
also integral to treatment decisions; because subjects are being treated until disease progression, 
repeated tumor assessment must be performed in order to define the proper duration of treatment 
for each study participant. Standard response and progression criteria have been established by 
the International Workshop on CLL (IWCLL) {12154}; the assessments of treatment effects in 
this study will be based on these criteria, taking into account the specific pharmacology of 
idelalisib.


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In CLL, disease-related nodal enlargement is a major cause of patient discomfort and can cause 
organ dysfunction {19448}. Extensive lymphadenopathy constitutes a reason to treat CLL and 
controlling the size of pathologically enlarged lymph nodes is an important therapeutic goal for 
improving patient well-being and relieving obstructive symptoms {12154}. Given that the natural 
history of recurrent CLL is inexorable nodal growth, enhancing tumor shrinkage and prolonging 
tumor control provides strong evidence of pharmacological activity. 
Endpoints of overall tumor control as evaluated in this trial are customarily assessed and reported 
in studies of new therapies in patients with cancer. PFS offers a well established outcome 
measure that directly measures treatment effect, conveys important longitudinal information 
regarding tumor control, can be characterized in all subjects using intention-to-treat (ITT) 
principles, and is readily analyzed using statistical methods such as Kaplan-Meier techniques. 
ORR provides an integrated assessment of the magnitude and extent of changes in 
lymphadenopathy, organomegaly, bone marrow infiltration, and bone marrow function that 
conveniently categorizes and describes treatment effects. TTR and DOR are important in 
characterizing the rapidity of achieving tumor shrinkage and the duration of tumor control. 
Beyond providing descriptions on overall response assessment using ORR, this protocol will also 
seek to characterize the individual components of response that are important in assessment of 
CLL {12154}. Thus, changes in lymph node area and in the proportion of subjects having a 
lymph node response will be analyzed. In addition, among subjects who enter the study with 
splenomegaly or hepatomegaly, the proportion of subjects who achieve substantial (50%) 
reductions in spleen or liver size will be assessed. Similarly, the proportions of subjects who 
experience improvements in ALC, platelets, hemoglobin, and neutrophil counts will be 
characterized in order to provide specific insight into the degree to which therapy alters these 
individual parameters. 
Because idelalisib mobilizes CLL cells from tissues into the peripheral blood as part of its 
pharmacological effect, there is a risk of falsely declaring a subject to have experienced disease 
progression if lymphocyte count is considered as the sole basis for potential CLL worsening. To 
account for this potential problem, changes in lymphocyte count will not be considered in 
determining whether a subject has progressive disease, ie, subjects will only be declared to have 
progressive CLL if they meet any of the IWCLL criteria for progressive disease other than 
lymphocytosis alone. Thus, subjects with worsening lymphadenopathy, organomegaly, bone 
marrow involvement, progressive cytopenias, appearance of new disease, or transformation to an 
aggressive lymphoid malignancy histology (eg, Richter syndrome) will be considered to have 
progressed. Subjects with lymphocytosis without any of these other events will not be considered 
to have progressed. Given that lymphocytosis has no prognostic significance in patients with 
relapsed/refractory disease {24682}, {24684} and is not generally considered a reason to treat in 
patients with CLL {12154}, {17670}, {19042}, this approach does not jeopardize subject safety or 
subsequent therapy. Furthermore, it will allow complete collection of all response and 
progression data (both considering lymphocytosis and ignoring lymphocytosis) with the intent of 
providing complete information for regulatory authority review.


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The current IWCLL guidelines indicate that physical examination is generally sufficient to 
evaluate nodal response and progression in patients with CLL {12154} but that radiographic 
assessments may be appropriate in clinical trials. Computed tomography (CT) is considered the 
preferred imaging method unless patients have contraindications that require use of magnetic 
resonance imaging (MRI). Given the low fluorodeoxyglucose (FDG) avidity of CLL, 
positron- emission tomography (PET) does not have a role in evaluation of this disease. The 
incremental benefits of using radiographic imaging are limited in patients undergoing long-term
follow-up following first-line therapy {24654}, {24663}. However, in the patients with advanced 
CLL and bulky adenopathy such as those who will be enrolled to this trial, it is known that CT 
scans commonly detect bulky intra-abdominal lymphadenopathy and splenomegaly that would 
be missed by palpation alone and that the presence of large-volume, intra-abdominal disease of 
the nodes and spleen is associated with a poor prognosis {24677}. Thus, while use of CT confers 
greater radiation exposure, subjects have the chance to benefit from radiographic imaging 
because it will offer more accurate information regarding their response to protocol therapy and 
the appropriate duration of protocol treatment. Having this information is particularly important 
in this trial because PI3Kinhibition precludes use of lymphocyte counts as evidence for disease 
progression. In addition, the risk is offset by the fact that the trial subjects will primarily be 
patients who have already received more potent mutagens (eg, purine analogs, alkylating agents), 
and all of whom have advanced cancer and limited treatment options at study entry. Based on 
published data {17680} {21022}, median OS for patients with comparably advanced CLL is 
<18 months, so the long-term secondary malignancy risk from CT-related radiation exposure is 
very low. Finally, in the context of a registration-directed pivotal trial of a new drug with a new 
mechanism of action, radiographic imaging is critically important to provide reassurance 
regarding subject safety and trial validity. In this regard, CT evaluations of the lung can be used 
retrospectively to assess for radiographic evidence of drug-induced lung changes {19673}, 
{19671}. Furthermore, CT measurements have greater accuracy and reproducibility than 
palpation, are subject to independent expert review, and can be audited against electronic case 
report form (eCRF) information.
The timing of radiographic tumor assessments has been carefully considered. To avoid 
duplication, the CT scan documenting CLL progression in Study GS-US-312-0116 will serve as 
the baseline CT scan for Study GS-US-312-0117. Among patients receiving idelalisib in 
Phase 1b/2 studies who experienced a nodal response (50% regression in tumor area), such 
responses were observed with the first 16 week of therapy {21030}, {19528}; the planned timing 
of tumor assessments (at Weeks 8, 16, 24, 36, 48 and then every 12 weeks on thereafter) in this 
study fits with this known timing of changes in lymph node size during idelalisib therapy. Scans 
at 8-week intervals during the first 24 weeks allow efficient documentation of response. During 
this period, early documentation of disease progression allows subjects who are not benefiting 
from study therapy to move rapidly to alternative treatments. After 24 weeks on study, the 
reduction in the frequency of CT scans (to 12-week intervals) reduces the overall protocol 
burden for subjects while still allowing characterization of the expected median PFS in this trial. 
As outlined in Section 7.3, iodine-containing or gadolinium contrast material may be omitted in 
subjects for whom use of a contrast agent would be medically contraindicated.


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3.2.2.
Measures of Patient Well-Being
3.2.2.1.
Overall Survival
While OS provides an ultimate measure of patient well-being, it has not routinely been used as 
the primary endpoint in CLL clinical trials. Unlike PFS, it does not specifically measure drug-
mediated tumor control, and thus provides only an indirect assessment of treatment effect. 
Depending upon the treatment setting, long OS times in patients with CLL can preclude use of 
this endpoint as an efficient method for understanding drug benefits. In both the front-line and 
recurrent disease settings, post-study treatments can influence OS in unpredictable ways, 
potentially confounding differences between treatment groups.
However, given the life-threatening nature of systemic malignancy, documentation of OS is 
customary in oncology therapeutic clinical trials, including those evaluating subjects with 
recurrent CLL {17680}, {21022}. Evaluation of OS in this study continues the survival 
assessment from the primary study (Study GS-US-312-0116). The study program as a whole 
(considering both the primary randomized trial and secondary extension study) offers the 
potential to better understand OS and causes of death in a frail population of patients with both 
CLL, considering the consequences of the disease and comorbidities.
3.2.2.2.
Health-Related Quality of Life
Direct patient reporting of outcomes using standardized methods has become an increasingly 
important component of therapeutic assessment. Evaluation of patient-reported outcomes (PROs) 
is particularly relevant in patients who cannot be cured of disease {23859}. PRO questionnaires 
have been previously used in CLL to understand how patients differ from the general population 
in terms of health concerns {24669}, {24662}, {24681}, {24664}, to understand differences in 
perceptions of well-being in younger vs older patients {24671}, {24664}, to determine how 
treatment affects HRQL {20164}, {24662}, {24661}, and to assess the pharmacoeconomic cost of 
improvements in HRQL {24683}.
Patients with CLL have overtly impaired well-being relative to comparable controls {24669}, 
{24662}, {24681}, {24664}. Fatigue is cited as a common complaint, being present in the 
substantial majority of patients. Impairment of HRQL prior to any treatment is apparent in those 
with B symptoms or in patients with anemia, supporting the concept of initiating treatment when 
patients experience symptomatic disease. Factors associated with lower overall HRQL have 
included older age, greater fatigue, severity of co-morbid health conditions, advanced stage, and 
ongoing treatment for CLL {24681}. Younger patients appear to have worse emotional and social 
well-being but older patients experience worse physical HRQL {24671}. In comparative 
evaluation of chemotherapy-containing regimens, differences in HRQL between therapies 
(eg, fludarabine vs fludarabine-cyclophosphamide vs chlorambucil) reflected differences in 
toxicity while improved HRQL was associated with greater efficacy {20164}, {24662}.
In this study, it is postulated that idelalisib-mediated tumor control will be correlated with greater 
positive changes in HRQL and that assessments of the drug’s safety profile will be supported by 
HRQL evaluations. The FACT-Leu (Appendix 2) has been selected to evaluate such outcomes 


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for the study. The FACT-Leu comprises a general HRQL measure for patients receiving cancer 
treatment that yields a total score and subscales for physical, functional, social/family and 
emotional well-being {23894} and a diagnosis-specific measure for patients with leukemia 
{24808}. The FACT-Leu was developed to assess symptoms (eg, fevers, chills, night sweats, 
nodal swelling, fatigue) specifically relevant to patients with leukemia. FACT instruments have 
documented psychometric properties {23894}, {24808}, {23848}, {23847}, {23827}.
The FACT-Leu instrument is available in appropriate languages for this study. FACT-Leu data 
will be obtained at baseline and during each investigational clinic visit during treatment. Having 
FACT-Leu data concurrent with tumor response information will allow an evaluation of the 
potential relationship between tumor response and symptomatic changes as reported by patients. 
To avoid biasing HRQL results, the FACT-Leu will be administered at each visit before other 
procedures are performed and before any study information is conveyed to the subject.
3.2.2.3.
Changes in Performance Status
Performance status evaluation provides an integrated assessment of patient well-being before, 
during, and after treatment and, ideally, may indicate how drug efficacy and toxicity affect 
patient functioning. In patients with CLL performance status can be predictive of PFS or OS 
{26559}, {26534}, {26551}.
In this study, it is hypothesized that idelalisib-mediated tumor control will be correlated with 
changes in performance status and that assessments of the drug’s safety profile might be 
supported by performance status evaluations. The well-established, reliable, and validated 
Karnofsky performance score {23840}, {23824}, {22654} (see Appendix 3) will be employed in 
the trial for characterization of the subject population and repeated assessment of performance 
status.
3.2.3.
Pharmacodynamic Markers of Drug Activity and Resistance
In CLL, disease-related perturbations in inflammatory status can be clinically overt; patients 
often develop bothersome B symptoms (fevers, night sweats, and weight loss) that are 
characteristic of excessive systemic inflammation {20168}. Consistent with such disease 
manifestations, the PI3K/AKT/mTOR pathway is constitutively overactive in circulating CLL 
cells {21030}. In addition, chemokines and cytokines that are markers of aberrant B-cell 
trafficking or perturbations in inflammation are overexpressed by CLL tissues or by stromal cells 
and circulate in plasma {23884}, {21030}. In Phase 1 studies of idelalisib it has been confirmed 
that idelalisib largely normalizes AKT phosphorylation and induces dose-dependent reductions 
in plasma concentrations of circulating chemokines and cytokines in patients with CLL {21030}.
In this study, it is hypothesized that incremental changes in these biomarkers provide direct 
evidence of mechanism-specific idelalisib effects on PI3Kδ activity or indirectly document drug 
effects on overall tumor cell volume. In either case, improvements in these pharmacodynamic 
measures provide corroborative evidence in support of idelalisib pharmacological activity; 
conversely, worsening of these biomarkers may indicate acquisition of resistance to idelalisib. In 
addition, it is possible that disease-or inflammation-related biomarkers may provide corollary 


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information relating to the adverse effects of idelalisib on the liver; such data might allow better 
prediction of which subjects might be most susceptible to ALT/AST elevations during idelalisib
treatment. Finally, it can also be postulated that genetic, protein, or metabolic changes in CLL 
cells could provide signatures that would correlate with drug sensitivity and resistance.
Based on these considerations, this study will evaluate PI3K/AKT/mTOR pathway activation 
status in CLL cells. For this purpose, blood will be evaluated by flow cytometry using a 
clinically validated assay {23401}. CLL cells will be identified using anti-CD5 and anti-CD19
antibodies. AKT activation will be determined by quantifying phosphorylation at the Ser473 and 
Thr308 AKT sites using specific anti-pAKT Thr308 and anti-pAKT Ser473 antibodies. 
Additional assessments of PI3K/AKT/mTOR pathway signaling (eg, evaluating phosphorylation 
state for other downstream enzymes) may also be explored.
Plasma will be collected for assessment of circulating concentrations of relevant chemokines and 
cytokines with a particular focus on CCL2, CCL3, CCL4, CXCL12, CXCL13, CCL17, CCL19, 
CCL21, CCL22, sCD40 ligand, tumor necrosis factor-α, and C-reactive protein. In addition 
serum markers of iron metabolism (eg, hepcidin, iron, ferritin, transferrin) that might provide 
markers linking disease-related inflammation with perturbations of liver iron and sensitivity to 
liver injury will be evaluated {23835}, {23843}. Clinically validated assays (eg, enzyme-linked 
immunosorbent assays [ELISAs]) will be used to measure circulating concentrations of 
chemokines and cytokines at baseline and during the course of idelalisib therapy.
CLL cell deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein will be collected at 
baseline and at the conclusion of a subject’s treatment on study. DNA and RNA samples will be 
analyzed using gene array technologies to evaluate for changes in DNA mutations or in RNA 
expression patterns that might be associated with intrinsic or acquired resistance to study 
treatments. Similarly, protein will be evaluated for state-specific changes in protein 
phosphorylation to evaluate for differences in pathway activation at baseline or during therapy 
that might be associated with differences in response or in acquisition of resistance to therapy.
3.2.4.
Assessments of Exposure
3.2.4.1.
Study Drug Administration and Compliance
Evaluation of study drug administration and compliance provides context for assessments of 
safety, pharmacokinetics, and pharmacological activity. Evaluations of treatment administration 
and modifications from planned therapy document the influence of treatment-emergent adverse 
events on prescribing practice. Compliance assessment offers a general indication of patients’ 
acceptance of therapy, integrating factors of tolerability, palatability, and convenience.
In this study, information regarding planned treatment and modification from planned treatment 
(eg, dose reductions and interruptions) will be kept. The compliance of the subject will be 
verified by accounting for used and unused drug.


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3.2.4.2.
Pharmacokinetics
Given the intent of this protocol to assess longer-term dosing, collection of plasma for idelalisib
concentrations is important for evaluating exposure over time. These data may allow correlations 
of exposure with measures of efficacy, toxicity, and resistance. Because the idelalisib
pharmacokinetic profile has been well characterized in Phase 1 studies, limited plasma sampling 
will be performed in this study. Samples will be collected pre-dose and 1.5 hours post-dose 
relative to the morning administration of idelalisib. Based on discussions with investigators, 
collecting more than 2 samples in the morning is not considered reasonable given the need to 
minimize time requirements for study participants and to avoid substantial inconvenience for 
clinic staff.
Evaluation of idelalisib plasma concentrations will be performed using liquid chromatography 
with tandem mass spectrometry. The method has been fully validated in the context of prior 
Phase 1 studies. Plasma samples will be retained for potential later analyses of idelalisib
metabolites.
3.2.5.
Evaluations of Safety
In defining the therapeutic relevance of a drug in a particular clinical setting, it is imperative that 
its safety profile be fully characterized. As is conventional in all clinical studies, proper 
description of each adverse event or laboratory abnormality requires an understanding of the 
type, incidence, timing, severity, and relatedness to study drug. While information on all reported 
adverse events will be collected, listed, and summarized, particular focus will be placed on 
monitoring and reporting adverse events and laboratory abnormalities that were encountered in 
the prior toxicology studies and clinical experience with idelalisib. Safety parameters of specific 
interest in reporting study results will include those relating to bone marrow function, 
dermatological events, gastrointestinal inflammation, infection, pulmonary events 
(eg, pneumonia/pneumonitis), and liver injury. Additional scrutiny will be applied to Grade 3-4 
adverse events, to adverse events causing interruption or discontinuation of idelalisib, and to 
serious adverse events.
In addition, the protocol will evaluate for potential adverse idelalisib effects on laboratory 
parameters of immune function; the absolute number of CD4+, CD5+,CD8+, CD16/CD56+, 
CD19+, and CD20+ cells will be assessed by flow cytometry. Serum concentrations of IgA, IgE, 
IgG, and IgM will be obtained.
For consistency of interpretation, adverse events will be coded using the standard Medical 
Dictionary for Regulatory Activities (MedDRA) [http://www.meddramsso.com]), and the 
severity adverse events and laboratory abnormalities will be graded using the well-defined 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). 
Standard definitions for seriousness will be applied (see Section 8.1.2).


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3.2.6.
Pharmacoeconomic Measures
It is increasingly important to understand the potential cost implications of introducing a new 
medication into patient care for CLL {26545}, {26535}. In order to analyze the 
pharmacoeconomic consequences of idelalisib administration, data will be collected regarding 
the health status of subjects and regarding health care resource utilization.
Heath status information will be obtained with the EQ-5D, which is a self-administered, generic, 
indirect utility measure {24948} (Appendix 4). The EQ-5D consists of a visual analogue scale on 
which subjects are asked to rate their current overall health status and 5 single-item dimensions 
which ask subjects to rate their health in terms of mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. For each of the 5 items, patients must choose between 
3 levels of difficulty in accomplishing tasks in that dimension. The visual analog scale is then 
used in combination with the dimension scores to generate a health utility score that can be 
incorporated into analyses of cost effectiveness. The EQ-5D has been successfully used in the 
evaluation of patients with B-cell and other cancers {26305}, {26277}, {26308}.
The EQ-5D instrument is available in appropriate languages for this study. EQ-5D data will be 
obtained at baseline and during each investigational clinic visit during treatment. The EQ-5D 
will be administered immediately after administration of the FACT-Leu instrument, before other 
procedures are performed and before any study information is conveyed to the subject. The 
EQ-5D instrument takes only 5 minutes to complete.
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach will be to combine the resource utilization data from the trial with data on 
unit prices (collected separately) to estimate total costs. The costs will be described relative to 
the health care findings as measured by duration of tumor control, the symptom-free survival 
period, and/or utility outcomes or some other appropriate measure of clinical benefits.


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4.
SUBJECT POPULATION
Number of Subjects
4.1.
The planned sample size is ~160 subjects but will be bounded by the number of subjects enrolled 
to the primary clinical trial (Study GS-US-312-0116).
Subject Selection Criteria
4.2.
Subjects in the primary Phase 3 study (GS-US-312-0116) who are compliant, are tolerating 
primary study therapy, and 1) have definitive progression of CLL while receiving primary study 
drug therapy (idelalisib /placebo) or 2) are actively participating in Study GS-US-312-0116 at 
the time the study is stopped, including if stopped early due to overwhelming efficacy following 
an interim analysis are eligible to enroll in the extension study. Eligibility criteria may not be 
waived by the investigator and conformance to the eligibility criteria is subject to review in the 
case of a Good Clinical Practice (GCP) or a regulatory authority audit. Any questions regarding a 
subject’s eligibility should be discussed with the study sponsor medical monitor prior to 
enrollment.
4.2.1.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while receiving study drug therapy 
(idelalisib/placebo) in Study GS-US-312-0116. Note: Definitive disease progression is CLL 
progression based on standard criteria and occurring for any reason (ie, increasing 
lymphadenopathy, organomegaly, or bone marrow involvement; decreasing platelet count, 
hemoglobin, or neutrophil count; or worsening of disease-related symptoms) other than 
lymphocytosis. Subjects must have confirmation by the sponsor working in collaboration 
with an independent review committee (IRC) that the disease has progressed on the 
clinical trial (Study GS-US-312-0116) before receiving secondary idelalisib therapy on this 
extension trial (Study GS-US-312-0117).
3) Presence of radiographically measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures 2.0 cm in the longest diameter [LD] and 1.0 cm in the 
longest perpendicular diameter [LPD] as assessed by CT or MRI). 
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab and idelalisib/placebo) 
and no intervening or continuing therapy (including radiotherapy, chemotherapy, 
immunotherapy, or investigational therapy) for the treatment of CLL. Note: Subjects may 
receive corticosteroids to manage CLL manifestations.


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5) The time from permanent cessation of Study GS-US-312-0116 treatment (rituximab and/or 
idelalisib/placebo) and the initiation of Study GS-US-312-0117 therapy is 12 weeks. Note:
Study procedures performed as part of Study GS-US-312-0116 need not be repeated and 
can be used as screening procedures for Study GS-US-312-0117 if performed within 4 
weeks prior to initiation of study drug therapy on Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation of study treatment) as 
shown in the table below. Note: Confirmation should be considered for out-of-range values 
to determine if the abnormality is real or artifactual. Values should be obtained within the 
screening period and should generally be the most recent measurement obtained. Subjects 
with any degree of neutropenia, thrombocytopenia, or anemia due to CLL or prior therapy 
may enroll.
Table 4-1.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCra
>30 ml/min
Pregnancy
-HCGb
Negative 
a
As calculated by the Cockcroft-Gault formula (see Appendix 5) {2202}
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or urine 
dipstick pregnancy test must be negative at start of study treatment (Visit 2)
Abbreviations: -HCG= beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
eCCr=estimated creatinine clearance, ULN=upper limit of normal
8) For female subjects of childbearing potential, willingness to use a protocol-recommended 
method of contraception (as outlined in section 5.6.4) from the screening visit (Visit 1) 
throughout the study and for 30 days following the last dose of study drug. Note: A female 
subject is considered to be of childbearing potential unless she has had a hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian 
failure (with serum estradiol and follicle-stimulating hormone [FSH] levels within the 
institutional postmenopausal range and a negative serum or urine HCG), or is 
menopausal (age >55 with amenorrhea for >12 months or amenorrhea for > 6 months 
with serum estradiol and FSH levels within the institutional postmenopausal range). 


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9) For male subjects of childbearing potential having intercourse with females of childbearing 
potential, willingness to use a protocol-recommended method of contraception (as outlined in 
section 5.6.4) from the start of study drug (Visit 2) throughout the study and for 90 days 
following the last dose of study drug and to refrain from sperm donation from the start of 
study drug (Visit 2) throughout the study and for 90 days following the last dose of study 
drug. Note: A male subject is considered able to father a child unless he has had a bilateral 
vasectomy with documented aspermia or a bilateral orchiectomy, or has ongoing testicular 
suppression with a depot luteinizing hormone- releasing hormone (LH-RH) agonist 
(eg, goserelin acetate [Zoladex®]), leuprolide acetate  [Lupron®]), or triptorelin pamoate 
[Trelstar®]).
10) In the judgment of the investigator, participation in the protocol offers an acceptable benefit-
to-risk ratio when considering current CLL disease status, medical condition, and the 
potential benefits and risks of alternative treatments for CLL. 
11) Willingness and ability to comply with scheduled visits, drug administration plan, imaging 
studies, laboratory tests, other study procedures, and study restrictions. Note: Psychological, 
social, familial, or geographical factors that might preclude adequate study participation 
should be considered.
12) Evidence of a personally signed informed consent indicating that the subject is aware of the 
neoplastic nature of the disease and has been informed of the procedures to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study participation.
4.2.2.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
1) Known histological transformation from CLL to an aggressive lymphoma 
(ie, Richter transformation). Note: Biopsy documentation of the absence or presence of 
transformation is not required.
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of the start of 
study treatment (Visit 2). Note: Subjects with localized fungal infections of skin or nails are 
eligible. Subjects may be receiving prophylactic antiviral or antibacterial therapies at the 
discretion of the investigator; anti-pneumocystis prophylaxis is encouraged. For subjects 
who are at substantial risk of an infection (eg, influenza) that may be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of 
protocol therapy.
3) Pregnancy or breastfeeding. 
4) Intentional breaking of the blind in Study GS-US-312-0116 by the investigator or the study 
subject.


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5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical condition, surgical history, physical 
finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the 
investigator’s opinion, could adversely affect the safety of the subject or impair the 
assessment of study results.
Enrollment Criteria Rationale
4.3.
The eligibility criteria are designed to limit enrollment to subjects who participated in the 
primary clinical trial (Study GS-US-312-0116), are compliant, have been generally able to 
tolerate study therapy and study procedures, and have experienced definitive CLL progression 
while receiving study treatment (rituximab and/or idelalisib/placebo) in the primary study or who 
are actively participating in Study GS-US-312-0116 at the time the study is stopped, including if 
stopped early due to overwhelming efficacy.
The requirement of measurable lymphadenopathy to enter the blinded portion of the study 
ensures that subjects have disease that can adequately be assessed for evidence of drug activity. 
Prior therapy provisions are intended to ensure that subjects are transitioning directly from 
Study GS-US-312-0116 to Study GS-US-312-0117 without receiving intervening treatments. 
The stipulation of 12-week interval from Study GS-US-312-0116 treatment until 
Study GS-US-312-0117 treatment precludes excessively protracted intervals between 
participation in the 2 studies but also permits sufficient time for clinicians and subjects to 
determine whether participation is appropriate. 
In the blinded portion of the study, to ensure that subjects are not so acutely ill from 
life-threatening comorbidities that they require hospitalization and stabilization, subjects with 
Karnofsky performance scores <40 (ie, those who are bed-bound or hospitalized) will not be 
enrolled. Baseline laboratory evaluations are designed to limit participation to subjects who have 
not developed serious organ compromise that would pose a safety risk or confound the 
interpretation of adverse effects. Pregnancy testing and restrictions on eligibility relating to 
reproduction, pregnancy, and nursing are important because idelalisib is a new chemical entity 
with teratogenic effects in rats and it is unknown if it may have adverse effects on conception, on 
fetal development, or on the health of a breast-feeding child. To minimize missing data and 
premature discontinuations, subjects should have sufficient psychological and social resources to 
comply with study procedures and restrictions. Consistent with GCP guidelines, subjects must 
provide informed consent before initiation of any study procedures.


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5.
TREATMENT OF SUBJECTS
Enrollment
5.1.
5.1.1.
Interactive Web Response System
An IWRS will be employed to manage the conduct of the trial. The IWRS will be used to 
maintain a central log documenting enrollment, to manage dose modifications, to assess current 
inventories of study drug, to initiate any necessary resupply of study drug, and to document 
discontinuation of study .
5.1.2.
Treatment Assignment
After a subject has completed the necessary documentation of definitive CLL progression in the 
primary clinical trial (GS-US-312-0116) and has been confirmed to be eligible, the subject can 
be entered into this trial (Study GS-US-312-0117). In order to obtain a treatment arm allocation 
for a subject, a site representative will access the IWRS and supply the system with the required 
information.
Subjects will be assigned to either of the following treatment assignments with allocation based 
on the original primary study randomization:
Treatment Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117)
Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly enrolled subjects will 
receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly enrolled subjects will 
receive 150 mg BID
Note: At the Investigator’s discretion, subjects who were randomized to placebo on 
study GS-US-312-0116 may delay initiation of idelalisib following enrollment on 
Study GS-US-312-0117 until the time of disease progression or until the investigator 
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Treatment Assignment

Assignment to Arm A or Arm B with allocation based on the original primary study 
randomization

Implementation through an interactive web response system (IWRS)
The IWRS will assign blister card, or bottle numbers and instructions for dispensing of blinded 
study drug (high-dose or standard-dose idelalisib). It is anticipated that subjects will usually 
begin study drug immediately at Visit 2 of the study. 
5.1.3.
Blinding
During the blinded portion of the study, the identity of the treatments will be concealed by 
central blinding of study drug assignments. Blinding will be accomplished through use of a 
placebo that is well-matched to the active drug in appearance, packaging, labeling, and schedule 
of administration (see Section 5.2.1). During the study, subjects, caregivers, investigational site 
personnel, Gilead Sciences study team members, and all other study personnel will remain 
blinded to the identity of the treatment assignments; these assignments will be available only to 
the IWRS, the data monitoring committee (DMC) for the study, an independent bioanalytical 
group that supports the DMC, and drug safety personnel who are not part of the study team.
Unblinding an individual subject’s treatment assignment during the study will only occur in the 
case of subject emergencies (see Section 5.5) or in the event the study is discontinued by the
Sponsor, a Regulatory Agency, or an IRB or EC (see Section 5.9). Where required by local 
regulation, expedited reporting of serious adverse events to specific regulatory authorities will 
include information regarding the study drug treatment assignment (high-dose or standard-dose 
idelalisib); this will be done in such a way that subjects, investigational site personnel, 
institutional review board/independent ethics committees (IRB/IEC), and study team members 
remain blinded as to the treatment assignment for the subject described in the adverse event 
report.
The unblinded analysis of the study will be performed when the database is completed and 
locked following unblinding of Study GS-US-312-0116 and Study GS-US-312-0117. The final 
analysis of the open label portion of the study will occur once the open label portion is stopped.
While bioanalytical assays to determine idelalisib concentrations may be performed prior to 
unblinding, pharmacokinetic data that would allow identification of treatment assignments for 
individual subjects will not be available to the study team until after the blind is broken and the 
primary analysis has occurred. Except for emergency unblinding, individual subjects, caregivers, 
and site personnel will not be informed of the treatment assignments until the implications of 
revealing such data for the overall idelalisib study program have been determined by the clinical 
project leader for the idelalisib development program.


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Investigational Study Drug (Idelalisib/Placebo)
5.2.
5.2.1.
Description
Subjects allocated to Arm A in the blinded portion of the study will be provided with 2 tablets of 
active idelalisib for oral administration at each dose. Each tablet contains 150 mg or 100 mg of 
active idelalisib. The 150-mg tablets will be used for initial therapy; the 100-mg tablets are 
provided for use by those subjects who require a dose reduction (see Table 5-1). 
Subjects allocated to Arm B in the blinded portion of the study will be provided with 1 tablet of 
active idelalisib and 1 tablet of placebo for oral administration at each dose. Each active tablet 
contains 150 mg or 100 mg of active idelalisib. The 150-mg tablets (and matching placebo) will 
be used for initial therapy; the 100-mg tablets (and matching placebo) are provided for use by 
those subjects who require a dose reduction. 
In the open-label portion of the study, subjects will be provided with 150 mg tablets of idelalisib.
The 150-mg tablets are pink, film-coated, and include the following inactive excipients: 
microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch 
glycolate, magnesium stearate, red iron oxide, polyethylene glycol, talc, polyvinyl alcohol
(PVA), and titanium dioxide. The 100-mg tablets are orange, film-coated, and include the 
following inactive excipients: microcrystalline cellulose, hydroxypropyl cellulose, 
croscarmellose sodium, sodium starch glycolate, magnesium stearate, yellow iron oxide, 
polyethylene glycol, talc, PVA, and titanium dioxide.
The placebo tablets match the active idelalisib formulations in appearance. The placebo tablets 
matching the 150-mg tablets are pink, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium stearate, 
red iron oxide, polyethylene glycol, talc, PVA, and titanium dioxide. The placebo tablets 
matching the 100-mg tablets are orange, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium stearate, 
yellow iron oxide, polyethylene glycol, talc, PVA and titanium dioxide.
5.2.2.
Source
Both active idelalisib and placebo will be supplied free of charge by Gilead Sciences. 
5.2.3.
Packaging and Labeling
During the blinded portion of the study, study drug (idelalisib or idelalisib/placebo) will be 
provided in blister cards. The blister cards are made of polyvinyl 
chloride/polychlorotrifluoroethylene (PVC/PCTFE) film and have aluminum foil lidding 
materials. Each blister card contains 120 tablets (4-week supply plus a modest overage) of one of 
the relevant dose strengths. The 100-mg or 150-mg and matching placebo tablets will be 
combined in order to obtain the daily doses to be used in this study. Thus, in Arm A, the 300-mg 
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dose will be obtained by administering two 100-mg tablets. In Arm B, the 150-mg idelalisib dose 
will be obtained by administering one 150-mg tablet and one placebo tablet and the 100-mg 
idelalisib dose will be obtained by administering one 100-mg tablet and one placebo tablet. 
Each blister card will have a unique number. Labeling for blister cards dispensed to subjects in 
Arm A will appear identical to blister cards dispensed to subjects in Arm B, and may include 
either idelalisib or placebo. 
When the primary study (GS-US-312-0116) is stopped including if early after an interim 
analysis, GS-US-312-0116 active study subjects will become eligible for participation on 
Study GS-US-312-0117. Active GS-US-312-0117 study subjects will be transitioned to 
open-label idelalisib at this time. Each bottle contains 60 tablets (4 week supply plus a modest 
overage) of one of the relevant dose strengths (150 mg, 100 mg) and a polyester coil. Bottles are 
white and are made of high-density polyethylene. Each bottle is closed with a white, continuous-
thread, child-resistant, polypropylene screw cap fitted with an induction-sealed, aluminum-faced 
liner.
All labels for study drugs to be distributed to centers in the United States, the EU, and other 
countries will meet all applicable requirements of the United States Food and Drug 
Administration (FDA), the EU Annex 13 of Current Good Manufacturing Practice (cGMP) 
(Manufacture of Investigational Medicinal Products, July 2010), and/or other local regulations as 
applicable.
5.2.4.
Storage and Handling
Blister cards or bottles containing tablets of study drug (idelalisib or idelalisib/placebo) should
be stored at controlled room temperature (ie, ~25°C, with a range of 15 to 30°C). While the 
stability of study drug tablets stored at controlled room temperature has been confirmed, brief 
excursions to temperatures as low as -20°C or as high as 40°C (eg, during shipping) will not 
adversely affect the drug. Updated stability data will be provided to the sites, as appropriate.
5.2.5.
Dispensing
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing 
study drug according to the IWRS directions. It is planned that drug will be dispensed at 4-week 
intervals through the first 24 weeks of treatment and at 12-week intervals thereafter. Sufficient 
study drug will be provided for each study period at the beginning of the period. Multiple blister 
cards or bottles may be dispensed at a single visit. Tablets should be kept in the original blister 
cards or bottles provided until they are self-administered by the subject.
At the time of starting study treatment, the IWRS will provide the clinic staff with the blister 
card numbers designating the blister cards to be dispensed, or the quantity of open-label bottles 
to be dispensed. The clinic staff (eg, pharmacist or other qualified person) will write the subject 
number on each blister card or bottle that is dispensed. Immediately before dispensing, the clinic 
staff will write the blister card or bottle number in the study drug administration record 
corresponding to the subject number.


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5.2.6.
Return
The study drug should be retrieved from each subject at the end of each dispensing interval. The 
quantity of study drug and the date returned by the subject should be recorded in the study drug 
accountability records. When possible, all study drug returned by the subject should be retained 
for review by the study site monitor prior to return to Gilead Sciences or destruction.
5.2.7.
Accountability
The disposition of all study drug should be documented from the time of receipt at the site 
through subject dispensing and return.
Study personnel must ensure that all study drug is kept in a secure locked area with access 
limited to authorized personnel. The study drug must not be used outside the context of this 
protocol. Under no circumstances should the investigator or site personnel supply study drug to 
other investigators or clinics, or allow the study drug to be used other than as directed by this 
protocol.
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by Gilead Sciences or its designee, including, but not limited to, 
the date received, lot number, amount received, and the disposition of all study drug. Upon 
receipt of a drug shipment, the shipment must be logged into the IWRS. Study drug 
accountability records must also be maintained that include the subject number to whom the 
study drug was dispensed and the date, quantity and lot number of the study drug dispensed.
Depending upon the decision of Gilead Sciences, remaining unused study drug supply will be 
returned to Gilead Sciences or its designee after the study is completed or will be discarded or 
destroyed at the clinical site. If the study drug is discarded or destroyed at the clinical site, 
standard institutional policy should be followed. Records documenting the date of study drug 
shipping or destruction, relevant lot numbers, and amount shipped or destroyed should be 
maintained.
5.2.8.
Overdose Precautions
In Phase 1 studies, an MTD for idelalisib was not reached when the drug was administered 
continuously at dose levels through 350 mg/dose BID (700 mg per day) {21030}, {21036}. 
However, in this protocol, an overdose is defined as administration of more than the prescribed 
daily dose (ie, >600 mg in a single day). In a subject who experiences an overdose consideration 
should be given as to whether idelalisib administration should be temporarily interrupted. If the 
overdose ingestion is recent and substantial, and if there are no medical contraindications, use of 
gastric lavage or induction of emesis may be considered. Observation for any symptomatic side 
effects should be instituted, and biochemical and hematological parameters should be followed 
closely (consistent with the protocol or more frequently, as needed). Appropriate supportive 
management to mitigate adverse effects should be initiated.


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The Gilead Sciences medical monitor should be contacted if a study drug overdose occurs. Cases 
of study drug overdose will result in specific reporting requirements (see Section 8.8).
5.2.9.
Inadvertent Exposure and Spill Precautions
Based on available data from nonclinical studies, idelalisib does not appear to be acutely toxic, 
genotoxic, or irritative at levels that are likely to result from inadvertent exposure to the contents 
of broken tablets. However, personnel handling the drug should use reasonable precautions to 
avoid eye contact, skin contact, inhalation, or ingestion of the study drug product. For further 
information regarding inadvertent exposure and spill precautions, please consult the idelalisib
investigator brochure.
Study Drug Administration
5.3.
5.3.1.
Premedication
No specific premedications or supporting medications are required in conjunction with study 
drug administration.
5.3.2.
Administration Instructions
The prescribed dose of study drug (idelalisib/placebo) should be taken orally. At each dose 
administration, the tablet number corresponding to the appropriate dose of study drug is to be 
swallowed whole with 100 to 200 mL (~ 4 to 8 ounces) of water. In case of breakage of the 
tablets in the oral cavity, additional water should be taken as a rinse. 
Study drug may be taken with or without food. There are no known dietary restrictions related to 
study drug use.
5.3.3.
Dosing Schedule
Study drug should be taken on a BID schedule at approximately the same times each day. Ideally,
doses should be taken at ~12-hour intervals (eg, at ~7 AM and at ~7 PM). While it is realized 
that variations in dosing schedule may occur in the outpatient setting, the prescribed regimen 
should be followed as closely as possible, especially in the clinic.
At specified clinic visits, the study drug will be administered in the clinic with dosing 
appropriately timed relative to blood sampling for idelalisib pharmacokinetics. As detailed in 
Section 6.2, clinic staff should record idelalisib administration information, including the exact 
clock time of each dose, for doses of study drug administered in the clinic or hospital. Thereafter, 
subjects will be given an adequate supply of tablets to take at home.
5.3.4.
Dose Levels
Study drug dose levels for Arm A and Arm B are described in Table 5-1. The lower dose level
(Dose Level -1) is provided in case a subject requires a study drug dose modification.


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Table 5-1.
Study Drug Dose Levels
Treatment Arm
Starting Dose
Dose Level -1
Arm A
300 mg/dose BID
200 mg/dose BID
Arm B
150 mg/dose BID
100 mg/dose BID
Abbreviation: BID=twice per day
When the primary study (GS-US-312-0116) is stopped, and GS-US-312-0116 active study 
subjects become eligible for participation on Study GS-US-312-0117 subjects will be enrolled 
into Study GS-US-312-0117 at open label 150 mg BID. Subjects already participating in 
Study GS-US-312-0117 will remain on the same dose.
5.3.5.
Dose Schedule Interruptions and Vomited Doses
Subjects who have a delay in administration of a dose of the study drug of <6 hours should take 
the planned dose as soon as possible after the intended time of administration. For subjects who 
have a delay in administration of study drug of 6 hours, the dose should not be taken. Study 
drug administration may continue but the missed dose should not be made up and the planned 
timing of subsequent study drug dosing should not be altered.
Vomited doses may be retaken, but only if the tablet is visible in the vomitus.
5.3.6.
Safety Monitoring and Study Drug Interruption/Dose Modification
Subjects must be monitored closely for adverse events or laboratory abnormalities during the
course of the study. Reference should be made to the CTCAE, Version 4.03 for grading the 
severity of adverse events and laboratory abnormalities.
Based on Phase 1 clinical experience adverse events potentially attributable to idelalisib in 
patients with CLL have included infrequent hepatic events (manifest primarily as asymptomatic 
and isolated elevations in serum ALT/AST).  Other adverse events potentially related to 
idelalisib have included instances of pneumonitis, gastrointestinal inflammation, or rash.
Myelosuppression has not been an overt toxicity of idelalisib in previous experience but 
provisions for intervention in subjects experiencing very protracted treatment-emergent 
neutropenia or thrombocytopenia are provided as a precaution. It is possible that idelalisib is 
responsible for other adverse events for which a causal relationship has not yet been established.
Recommendations for modifications of the dosing regimens based on the drug and the type and 
severity of adverse events or laboratory abnormalities are provided in Table 5-2 below. The dose 
modification instructions focus on the types of events most commonly attributed to each of the 
study agents. The recommendations provided in Table 5-2 comprise only guidelines; variations 
from these recommendations may be warranted based on an investigator’s individual judgment 
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Consistent with Table 5-2, if a subject experiences an adverse event that is suspected to be 
related to study drug and requires a dose modification during the course of study therapy, then 
study drug administration should be held, as necessary, until the adverse event resolves or 
stabilizes to an acceptable degree (generally to Grade 1). Thereafter, study drug may be 
reinstituted, but the dose should be reduced to Dose Level -1 (see Table 5-1). If the adverse event 
occurs again, one further attempt at reinitiation of therapy at Dose Level -1 may be attempted if 
the investigator feels that a second rechallenge is medically appropriate. If the subject cannot 
tolerate idelalisib at Dose Level -1 after 2 rechallenges, then the subject should be discontinued 
from study drug therapy unless continued therapy is permitted by the Gilead Sciences medical 
monitor.
After the study drug dose is reduced, the dose need not be re-escalated, even if there is minimal 
or no toxicity with the reduced dose. However, if the subject tolerates the lower dose level of
study drug for ≥4 weeks then the dose level may be increased to the starting dose level (see 
Table 5-1) at the discretion of the investigator. Such re-escalation may be particularly warranted 
if further evaluation reveals that the adverse event that led to the dose reduction was not study-
drug-related. The starting dose level should not intentionally be exceeded in this study.
Whenever possible, any dose adjustment of study drug should be discussed between the 
investigator and the Gilead Sciences medical monitor prior to implementation. To implement 
either a dose reduction or a dose reescalation, the investigator/study staff member will call the 
IWRS, enter the subject number, and inform the IWRS of the need for dose titration. The IWRS 
will provide details regarding the blister card to be dispensed to the subject. The appropriate 
clinic staff should instruct the subject/caregiver about the change in dose.
Recommendations for dose modification based on the type and severity of adverse events or 
laboratory abnormalities are provided in Table 5-2 below.


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Table 5-2.
Recommendations for Study Drug Dose Modifications Based on Type 
and Severity of Treatment-Related Adverse Events or Laboratory
Abnormalities
NCI CTCAE Grade
Recommendation
Idelalisib
HEMATOLOGICAL ADVERSE EVENTS
Neutropenia
Grade 2 neutropenia
Maintain current dose level and schedule.
Grade 3 neutropenia
During combination or continuing single-agent therapy periods, maintain current idelalisib 
dose level and schedule. Consider G-CSF support.
Grade 4 neutropenia (or 
occurrence of 
neutropenic fever or 
infection)
During combination therapy period, consider G-CSF support and maintain current 
idelalisib dose level and schedule. During continuing single-agent idelalisib therapy 
period, consider G-CSF support and continue idelalisib at initial or lower dose level at 
investigator discretion.
Thrombocytopenia
Grade 3
Maintain current dose level and schedule.
Grade 4
During combination therapy period, maintain current idelalisib dose level and schedule. 
During continuing single-agent idelalisib therapy period, withhold for bruising or bleeding 
until Grade 3. May resume idelalisib at initial or lower dose level at investigator 
discretion.
NON-HEMATOLOGICAL ADVERSE EVENTS
Dermatological
Grade 1
Maintain current dose level and schedule.
Grade 2
Withhold idelalisib until Grade 1. Resume idelalisib at current dose level. If rechallenge 
at current dose level results in recurrence, may resume at same or lower idelalisib dose 
level at investigator discretion.
Grade 3 or 4
Withhold idelalisib until Grade 1. May resume at lower dose level or discontinue 
idelalisib at investigator discretion.
Gastrointestinal Inflammation/Diarrhea
Grade 1
Provide anti-diarrheal (eg, loperamide) and maintain current idelalisib dose level and 
schedule.
Grade 2
Provide anti-diarrheal (eg, loperamide). Withhold idelalisib until Grade 1. Resume 
idelalisib at current dose level. If rechallenge results in recurrence, may resume at initial 
or lower dose level at investigator discretion. Consider addition of anti-inflammatory (eg, 
sulfasalazine, budesonide).
Grade 3
Provide anti-diarrheal (eg, loperamide). Withhold idelalisib until Grade 1. Resume at 
lower dose level. Consider addition of anti-inflammatory (eg, sulfasalazine, budesonide).
Grade 4
Provide anti-diarrheal (eg, loperamide). Withhold idelalisib until Grade 1. May resume 
at lower dose level or discontinue idelalisib at investigator discretion. Consider addition of 
anti-inflammatory (eg, sulfasalazine, budesonide).


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NCI CTCAE Grade
Recommendation
Idelalisib
Hepatic Adverse Events (elevations in ALT, AST, or bilirubin)
Grade 1
(ALT/AST3xULN)
(Bilirubin1.5xULN)
Maintain current dose level and schedule.
Grade 2
(ALT/AST>3-5xULN)
(Bilirubin>1.5-
3xULN)
Maintain current dose level and schedule. Monitor ALT, AST, ALP, and bilirubin at least 
1x per week.
Grade 3
(ALT/AST>5-20xULN)
(Bilirubin>3-10xULN)
Withhold idelalisib. Monitor ALT, AST, ALP, and bilirubin at least 1x per week until all 
abnormalities are Grade 1. If bilirubin abnormality was Grade <3, resume idelalisib at 
same dose level. If bilirubin abnormality was Grade 3, resume at lower dose level.
Grade 4
(ALT/AST>20xULN)
(Bilirubin>10xULN)
Withhold idelalisib. Monitor ALT, AST, ALP, and bilirubin at least 1x per week until all 
abnormalities are Grade 1. If bilirubin abnormality was Grade <4, resume idelalisib at 
lower dose level. If bilirubin abnormality was Grade 4, discontinue idelalisib.
Pneumonitis (dyspnea, cough, hypoxia and/or diffuse interstitial pattern or ground-glass opacities on chest 
CT and no obvious infectious cause)
Grade 1
Maintain current dose level and schedule. Consider pneumocystis prophylaxis.
Grade 2
Withhold idelalisib until Grade 1, consider systemic corticosteroids and 
pneumocystistreatment. May resume at initial or lower dose level at investigator 
discretion.
Grade 3
Withhold idelalisib until Grade 1, consider systemic corticosteroids and consider 
pneumocystis treatment. May resume at lower dose level or discontinue idelalisib at 
investigator discretion.
Other Nonhematological Adverse Events
Grade 2
Maintain current dose level and schedule
Grade 3
Withhold idelalisib until Grade 1. May resume idelalisib at initial or lower dose level or 
discontinue idelalisib at investigator discretion.
Abbreviations:  ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST= aspartate aminotransferase, ANC=absolute 
neutrophil count, CTCAE=Common Terminology Criteria for Adverse Events, G-CSF=granulocyte colony-stimulating factor, 
NCI=National Cancer Institute, ULN=upper limit of normal
Recommendations for Evaluation, Intervention, and Drug Discontinuation
5.4.
for Specific Adverse Events or Conditions
5.4.1.
Dermatological Events
idelalisib administration has occasionally been associated with the occurrence of a 
maculopapular rash affecting the trunk and extremities. Based on skin biopsy data in several 
subjects, the findings have been consistent with a delayed-type hypersensitivity reaction. 
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In subjects who develop a rash while on study drug, causes related to concomitant medications, 
environmental exposures, or infection should be considered and eliminated. Depending upon the 
severity of the initial dermatological event, rechallenge with study drug therapy at the same or a 
lower dose level (see Table 5-2) should be considered if continued drug administration offers the 
potential for clinical benefit.
5.4.2.
Gastrointestinal Events
Inflammation of the tongue has been noted in rats undergoing repeated gavage administration of 
idelalisib; this inflammation may have represented a drug-related exacerbation of 
gavage-mediated irritation. Mild congestion or hemorrhage in the large intestine has been seen in 
dogs receiving high doses of idelalisib. In patients, isolated cases of gastrointestinal 
inflammation (eg, stomatitis, colitis, cecitis) have been noted. While disease-related factors, 
neutropenia, toxicity from prior therapies, effects of ongoing supportive care, or pre-existing 
cholelithiasis may have initiated such events, it is possible that idelalisib played a contributory 
role. In such subjects, rechallenge with idelalisib has been possible and has not been associated 
with other severe adverse events. Patients who have developed evidence of enteritis during 
idelalisib therapy have been successfully treated with antidiarrheals (eg, loperamide) and with 
enteric steroidal (eg, budesonide) or non-steroidal (eg sulfasalazine [Azulfidine®]) anti-
inflammatory agents and have been able to continue or resume idelalisib.
For study subjects who develop severe abdominal pain, particularly if early during therapy, the 
possibility of a bowel obstruction or perforation should be considered. Appropriate clinical and 
radiographic examination should be performed and supportive care and surgical intervention 
should be considered. Upon recovery, study therapy may be continued if appropriate for the 
clinical situation.
For subjects who develop persistent diarrhea, causes related to concomitant medications or 
gastrointestinal infection should be considered and eliminated. Depending upon the clinical 
circumstances, endoscopy and biopsy may be warranted. Providing an antidiarrheal
(eg, loperamide) may lessen symptoms. Consideration should be given to intervention with 
enteric steroidal (eg, budesonide) or non-steroidal (eg, sulfasalazine) anti-inflammatory agents.In 
such subjects, rechallenge with idelalisib at a lower dose level has resulted in recurrence of 
symptoms in some but not all subjects and has not been associated with other severe adverse 
events. One patient who developed evidence of inflammatory bowel disease during idelalisib
therapy has been treated with sulfasalazine (Azulfidine®) and antidiarrheals (eg, loperamide) 
while continuing on idelalisib.
Thus, depending upon the type and severity of the initial gastrointestinal event, rechallenge with 
study drug at a reduced dose level and with and appropriate support care may be warranted if 
continued drug administration offers the potential for clinical benefit.


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5.4.3.
Hepatic Events
In patients with lymphoid malignancies, reversible serum ALT/AST elevations have been 
observed {21030}, {21036}. In these patients, the onset of Grade 3 or 4 transaminase elevations 
has typically occurred within approximately 4 to 8 weeks of starting idelalisib therapy (median 
5.7, Q1-Q3 3.9-8.1). Among patients with Grade 1-2 ALT/AST abnormalities, continued dosing 
has been possible; transaminase values commonly resolve despite continued idelalisib treatment. 
For those with Grade 3-4 ALT/AST elevations, drug interruption has resulted in resolution over 
2 to 6 weeks. Successful rechallenge at lower dose levels of idelalisib has been achieved in the 
majority of patients. Thus, in subjects with uncomplicated hepatic events, the instructions in 
Table 5-2 should be followed in an attempt to maximize the potential that subjects who appear to 
be benefiting can continue with study drug treatment.
In selected subjects who experience more complicated hepatic adverse events, further work-up 
may be warranted, as requested by the Gilead Sciences medical monitor. Such an evaluation may 
be particularly warranted in subjects who first experience a serum ALT/AST elevation 
12 weeks from the start of study drug therapy, who have an elevation in serum bilirubin 
concentration or coagulation parameters, or who have other characteristics that suggest an 
atypical change in transaminase values. Further workup may include: obtaining a history of 
recent symptoms/illnesses and of relevant past history (eg, history of hepatitis or of hepatitis A or 
hepatitis B vaccination); obtaining information regarding concomitant drug use (prescription and 
nonprescription medications, dietary supplements, alcohol, illicit drugs, special diets); 
questioning the subject regarding potential exposure to environmental toxins; ruling out viral 
hepatitis A, B, C, D (if hepatitis B is positive), and E, Epstein-Barr virus, cytomegalovirus, 
autoimmune hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis, hypoxic/ischemic 
hepatopathy, and biliary tract disease; obtaining additional tests to evaluate liver function 
(eg, prothrombin time [PT], activated partial thromboplastin time [aPTT], international 
normalized ratio [INR], albumin); and considering gastroenterology or hepatology consultation 
{15648}.
Of note, HBV reactivation can occur in patients treated with rituximab with a median time to 
diagnosis of hepatitis among patients with hematologic malignancies of 4 months after the 
initiation of rituximab but such events can occur months after completion of rituximab therapy. 
The risk is very low among patients with negative anti-HBc serology {24673} and/or 
undetectable HBV DNA as assessed by quanititative PCR. Because subjects with such evidence 
of persistent HBV infection are excluded from this study, reactivation is not anticipated. 
However, among subjects with evidence of Grade 3 serum ALT/AST abnormalities, evaluation 
for HBV reactivation (manifest as positivity for serum HBsAg) should be considered as a 
precautionary measure. In a subject with active HBV, anti-HBV antiviral agents should be 
initiated. At the discretion of the investigators, study drug may be continued if HBV infection 
can be adequately controlled, particularly if the subject is experiencing clinical benefit from 
study therapy and there are few other options for treating the subject’s CLL.


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5.4.4.
Hematological and Immunological Events
In the Phase 1 experience with idelalisib in CLL, patients with Grade3 neutropenia, anemia, 
and and/or thrombocytopenia were enrolled to clinical trials. Decreased levels of neutrophil 
counts, hemoglobin, or platelet counts during therapy were largely due to minor fluctuations in 
these parameters among patients with pre-existing hematological abnormalities due to disease or 
prior therapy. Thus, idelalisib did not appear to induce overt myelosuppression. Obvious patterns 
of drug-mediated reductions in circulating CD4+ lymphocyte counts or suppression of serum 
IgG levels were also not observed.
Given that patients with CLL commonly have Grade 3 hematological abnormalities due to 
underlying disease or prior therapy and that idelalisib is not associated with substantial 
myelotoxicity or off-target immunosuppression, alterations in study drug dose level for such 
events should only focus on subjects with protracted or symptomatic neutropenia or 
thrombocytopenia, unresponsive to G-CSF supportive care. No modification of idelalisib for 
changes in circulating CD4+ counts or Ig levels is planned.
5.4.5.
Infectious Events
Patients with CLL receiving idelalisib have developed serious bacterial, fungal, and viral 
infections during therapy. Similarly, serious bacterial, fungal, and new or reactivated viral 
infections have also occurred during and for ~1 year following rituximab-based therapy {24667}. 
New or reactivated viral infections in patients receiving rituximab have included 
cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, 
HBV (see Section 5.4.3) and HCV. Because patients with lymphoid malignancies (particularly 
those with CLL) are susceptible to infection due to the underlying disease, neutropenia, and the 
effects of prior therapy, the specific causal role of idelalisib or rituximab in any of these types of 
events is unclear.
Patients with previously treated CLL have developed Pneumocystis (carinii) jiroveci pneumonia 
while receiving idelalisib. While idelalisib has not specifically been implicated in such cases, 
patients with lymphoid malignancies (particularly those with CLL) may be susceptible to 
pneumocystis infections due to the underlying disease and the effects of prior therapy. 
Pre-existing risk factors of specific concern may include previous pneumocystis pneumonia, 
underlying disease (eg, CLL), prior therapy (eg, alemtuzumab, progenitor cell transplantation), 
or immunocompromised status (low CD4+ lymphocyte counts, HIV infection) {17881}.
In a subject with a history of recurrent infections, prophylaxis with intravenous Ig should be 
considered {23885}. Unless there is a contra-indication in a specific study subject, consideration 
should be given to initiation of antibiotic prophylaxis against pneumocystis infection 
(eg, with trimethoprim-sulfamethoxazole, dapsone, aerosolized pentamidine, or atovaquone) 
beginning prior to study drug administration. Such support may also offer the benefit of reducing 
the risk for other bacterial infections {17881}. Local practices or guidelines regarding infection 
prophylaxis may be followed.


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For subjects who develop an infection, appropriate medical therapy (with antibiotics, antifungals, 
or antiviral) or other interventions should be instituted. Whenever appropriate, subjects should 
continue with study drug during treatment for the infection.
5.4.6.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) due to polyomavirus JC has been observed 
in patients who have received rituximab therapy {24656} for hematologic malignancies. The 
specific causal role of rituximab is unknown because many of these patients had other risk 
factors (eg, low CD4+ counts) and the majority had received rituximab in combination with 
chemotherapy or as part of a hematopoietic stem cell transplant. Most cases of PML were 
diagnosed within 12 months of the last infusion of rituximab.
The diagnosis of PML should be considered in any subject presenting with new-onset or 
worsening neurologic manifestations, especially weakness or paralysis, vision loss, impaired 
speech, or cognitive deterioration. Evaluation of PML should include consultation with a 
neurologist, brain MRI, and lumbar puncture. In subjects diagnosed with PML, study drug 
should also be permanently discontinued.
5.4.7.
Pulmonary Events
Documented bacterial, fungal, viral, and pneumocystis pneumonias have been observed in 
patients receiving idelalisib, primarily in patients with CLL. Some patients receiving idelalisib
alone or in combination have developed evidence of pneumonitis without documented lung 
infection. The specific role of idelalisib in these events is unclear; nonclinical evaluations of 
pulmonary function and pathology do not indicate a direct toxic effect of idelalisib on the lungs 
and disease-related factors or toxicity from prior or concomitant therapies may have contributed 
to these clinical events. Rituximab-related noninfectious pneumonitis has been described {24807}
with an incidence of ~4.3% {19677}. In patients developing rituximab-associated pneumonitis, 
the mean time from the first rituximab infusion to the onset of respiratory symptoms was 
3 months, with a peak incidence after administration of a mean cumulative dosage of 
1600 mg/m2 {19670}.
Given the potential for infectious or drug-related adverse events, clinicians should be particularly 
observant for evidence of respiratory events in subjects participating in this trial. Subjects should 
be evaluated who describe pulmonary symptoms (eg, dyspnea on exertion, cough, shortness of 
breath); manifest a decline from baseline of 5% in oxygen saturation, or demonstrate evidence 
of pulmonary inflammation (eg, focal or diffuse interstitial pattern or ground-glass opacities on 
chest CT). Potential bacterial, fungal, or viral etiologies should be assessed. 
Pneumocystis (carinii) jiroveci should be considered, especially if the subject is not receiving 
pneumocystis prophylaxis. Depending upon the changes observed and the response to antibiotic 
intervention, recommended diagnostic work-up may include blood and sputum cultures; 
polymerase chain reaction or antigen testing for pneumocystis and respiratory viruses
(eg, CMV, influenza virus, respiratory syncytial virus, parainfluenza virus, rhinovirus); chest 
X-ray, CT or other imaging methods; pulmonary function testing and diffusing capacity of the 


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lung for carbon monoxide (DLCO); bronchoscopic lavage and/or biopsy; or open-lung biopsy. 
Noninfectious etiologies such as pulmonary edema or thromboembolism should also be 
considered.
As appropriate for the clinical situation and culture results, subjects should be treated empirically 
or given specific antibiotics, antifungals, or antiviral agents for a cultured organism. Supportive 
care, including oxygen or mechanical ventilation, should be provided as necessary. 
For subjects with a symptomatic pneumonitis (eg, onset of cough, dyspnea, hypoxia and/or a 
diffuse interstitial pattern or ground-glass opacities on chest (CT), study drug should be 
interrupted and therapy with systemic corticosteroids (eg, prednisone, 60 mg/day) should be 
instituted rapidly {19670}. Resumption of study drug at Dose Level -1 should only be considered 
if the subject is experiencing evidence of clinical benefit from study drug; reoccurrence of 
drug-related pneumonitis upon rechallenge should result in permanent discontinuation of study 
drug.
5.4.8.
Tumor Lysis Syndrome
Patients with tumor lysis syndrome may experience hyperkalemia, hypocalcemia, hyperuricemia, 
hyperphosphatemia, cardiac dysrhythmias, and acute renal failure.
Tumor lysis syndrome has not been observed with idelalisib monotherapy. However, if tumor 
lysis were to occur in a subject participating in this study, the subject should receive rapid 
reversal of hyperkalemia, intravenous hydration, antihyperuricemic agents, and appropriate 
cardiac and renal support, including dialysis as indicated. Upon recovery to baseline functioning, 
such subjects should continue study therapy to maintain tumor control.
5.4.9.
Pregnancy, Lactation, and Reproduction
Idelalisib has induced embryo lethality and teratogenicity when administered to pregnant female 
rats at maternally toxic doses. However, definitive reproductive toxicology studies in animals 
have not yet been performed and the specific effects of idelalisib on human embryogenesis or 
fetal development are unknown. Whether idelalisib is excreted in human breast milk is unknown. 
General toxicology studies in rats and dogs indicated dose-dependent reductions in testicular 
weights, with persistent minimal to mild degeneration of the seminiferous tubules and decreased 
spermatozoa in rats and hypospermatogenesis in dogs. The implications of these testicular 
changes for animal or human fertility are unknown.
Given the preliminary nature of data regarding the risks to a fetus or infant as a result of 
exposure to idelalisib, women of reproductive potential entering this study must have a negative 
serum pregnancy test at baseline and must not be breastfeeding. Males and females of 
childbearing potential should abstain from sexual intercourse or use an effective form of 
contraception (see Section 5.6.4). If a female study participant becomes pregnant or decides to 
breastfeed during the course of the study, all study therapy must be discontinued. Study 
candidates will be informed of the testicular findings through the informed consent process.


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5.4.10.
Ultraviolet Exposure
In vitro studies indicate enhanced cytotoxicity when embryonic murine fibroblasts treated with 
GS-563117 (the major metabolite of idelalisib) are simultaneously exposed to ultraviolet light.  
While nonclinical findings suggest the hypothetical potential for phototoxicity in humans, 
available clinical data do not reveal a photosafety concern. Although specific clinical correlates 
for these nonclinical data are not available, investigators and study subjects should be observant 
for the possibility that study participants may have exaggerated sunburn reactions (eg, burning, 
erythema, exudation, vesicles, blistering, edema) involving areas of skin exposed to ultraviolet 
light.
Emergency Unblinding
5.5.
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IWRS system 
for that subject.  Gilead recommends but does not require that the investigator contact the Gilead 
medical monitor before breaking the blind. Treatment assignment should remain blinded unless 
that knowledge is necessary to determine subject emergency medical care. The rationale for 
unblinding must be clearly explained in source documentation and on the case report 
form/ electronic case report form (CRF/eCRF), along with the date on which the treatment 
assignment was obtained. The investigator is requested to contact the Gilead medical monitor 
promptly in case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).
Concomitant and Supportive Therapy
5.6.
To the extent possible, administration of any prescription or over-the-counter drug products other 
than study medication should be minimized during the study period. Subjects should be 
discouraged from use of street drugs, herbal remedies, self-prescribed drugs, tobacco products, or 
excessive alcohol at any time during the clinical study.
If considered necessary for the subject’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator. The decision to 
authorize the use of any drug other than study drug should take into account subject safety, the 
medical need, the potential for drug interactions, the possibility for masking symptoms of a more 
significant underlying event, and whether use of the drug will compromise the outcome or 
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Subjects should be instructed about the importance of the need to inform the clinic staff of the 
use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and during 
the course of the study. Any concomitant drugs taken by a subject during the course of the study 
and the reason for use should be recorded on the eCRFs.
Information regarding use or restrictions on specific concomitant medications, dietary measures, 
or other interventions is provided below.
5.6.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments
Except for corticosteroids (See Section 5.6.5), no other anticancer therapies (including 
chemotherapy, radiation, antibody therapy, immunotherapy, or other experimental therapies) of 
any kind are permitted. Subjects are not allowed to participate concurrently in any other 
therapeutic clinical study.
5.6.2.
Antibiotics
Except in a subject who has a contra-indication, investigators should consider initiation of 
antibiotic prophylaxis against pneumocystis infection (eg, with trimethoprim-sulfamethoxazole, 
dapsone, aerosolized pentamidine, or atovaquone) beginning prior to study drug administration. 
Such support may also offer the benefit of reducing the risk for other bacterial infections 
{17881}. Investigator discretion and local practices or guidelines may be followed.
For subjects who develop an infection, appropriate medical therapy (with antibiotics, antifungals, 
or antiviral) or other interventions should be instituted. Whenever appropriate, subjects may 
continue with study drug during treatment for the infection.
5.6.3.
Antiemetics and Antidiarrheals
Drug-related nausea and/or vomiting have not been commonly observed with idelalisib in prior 
studies. However, subjects who experience nausea or vomiting while on study therapy may 
receive antiemetics based on the judgment of the treating physician and local institutional 
practices. At the occurrence of persistent nausea or vomiting of severity Grade 1, it is suggested 
that the subject receive an oral or transdermal serotonin antagonist (eg, dolasetron, granisetron, 
ondansetron, tropisetron, palonosetron). Other classes of antiemetic medications that may be 
employed include dopamine antagonists or benzodiazepines. As needed, subjects may be 
prescribed loperamide (Imodium® or others) or diphenoxylate and atropine (Lomotil®) to control 
diarrheal symptoms.
5.6.4.
Contraception
In the context of this protocol, a female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, a bilateral tubal ligation, or a bilateral oophorectomy; has 
medically documented ovarian failure (with serum estradiol and FSH levels within the 
institutional postmenopausal range and a negative serum or urine HCG); or is menopausal 
(age >55 years with amenorrhea for >12 months or amenorrhea for >6 months with serum 
estradiol and FSH levels within the institutional postmenopausal range).


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Sexually active females of childbearing potential must agree to use a protocol-recommended 
method of contraception during heterosexual intercourse throughout the study treatment period 
and for 30 days following the last dose of the study drug. The investigator should counsel 
subjects on the most effective methods for avoiding pregnancy during the trial. 
Protocol-recommended contraceptive methods are described in Table 5-3.
Table 5-3.
Protocol-Recommended Contraceptive Methods
Individual Methods
Combination Methods
Hormonal Methods
(One method to be used 
with a barrier method)
Barrier Methods
(Both of these methods to be used OR one of these 
methods to be used with a hormonal method)
IUD
Estrogen and progesterone
Diaphragm with spermicidea
Copper T 380A IUD
Oral contraceptives
Male condom (with spermicidea)
LNg 20 IUD
Transdermal patch
Tubal sterilization
Vaginal ring
Hysterectomy
Progesterone
Injection
Implant
a
If available/approved for use in the specific country
Abbreviation: IUD=intrauterine device
In the context of this protocol, a male subject is considered able to father a child unless he has 
had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or is receiving
ongoing testicular suppression with a depot luteinizing hormone-releasing hormone (LH-RH) 
agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or triptorelin pamoate 
[Trelstar®]).
Sexually active male subjects who can father a child must accept continuous heterosexual 
abstinence as a lifestyle choice; limit intercourse to female partners who are surgically sterile, 
post-menopausal, or using effective contraception (as noted in Table 5-3); or agree to use a 
protocol-recommended method of contraception during heterosexual intercourse throughout the 
study treatment period and for 90 days following discontinuation of the study drug (as noted in 
Table 5-3). 
The Gilead Sciences medical monitor should be consulted regarding any questions relating to 
childbearing status or contraception.


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5.6.5.
Corticosteroids
Subjects may receive topical, inhaled, enteric, or systemic corticosteroids while on study. It 
should be realized that the use of systemic corticosteroids in patients with CLL may confound 
interpretation of antitumor effects mediated by study drug therapy. However, subjects who 
develop conditions that may be alleviated by systemic corticosteroid therapy are permitted to 
receive such drugs and are not required to discontinue study participation.
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin
Granulocyte-macrophage colony-stimulating factor (GM-CSF) should not be administered given 
the potential for GM-CSF-related inflammatory symptoms.
G-CSF (filgrastim, PEG-filgrastim, lenograstim) may be administered in response to Grade 4
neutropenia or neutropenic complications; use should be particularly considered if providing 
hematopoietic support might help to maintain study drug treatment (see Table 5-2).
While erythropoietic agents (eg, erythropoietin or darbepoetin) may be administered for Grade 
3 anemia, their use in this study is discouraged given the potential to confound assessments of 
improvements in bone marrow function related to study drug.
Reference may be made to the American Society of Clinical Oncology guidelines {22486}, 
{22483}.
5.6.7.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism
Idelalisib is metabolized primarily via aldehyde oxidase and in part by CYP3A.  A clinical drug-
drug interaction study indicated that administration of a potent CYP3A inhibitor together with 
idelalisib resulted in a ~80% increase in idelalisib plasma exposures (AUC) (see Section 1.3.5.1), 
which is not considered to be clinically relevant and suggesting that idelalisib is a weak CYP3A 
substrate. Preliminary data indicate when coadministered with rifampin, a highly potent inducer 
of CYP3A, idelalisib exposures are ~75% lower. Coadministration of potent inducers of CYP3A 
with idelalisib should be avoided; a list of strong inducers is provided in Table 5-4:
Table 5-4.
Known Strong Inducers of CYP3A
Effect on 
CYP3A 
Drug Class
Medications
Strong CYP3A 
Inducers
Antimycobacterial
Rifampin
Anticonvulsants
carbamazepine, phenytoin
Foods/herbs
St. John’s wort
Abbreviation: CYP=cytochrome P450 enzyme


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5.6.8.
Drugs that undergo CYP3A-Dependent Metabolism
The major metabolite of idelalisib, GS-563117, is a competitive and time dependent inhibitor of 
CYP3A; accordingly coadministration of idelalisib with midazolam, a probe CYP3A substrate, 
resulted in a ~5-fold increase in midazolam systemic exposure (AUC). Coadministration of 
CYP3A substrates with idelalisib may result in an increase in their systemic exposures 
(eg, antiarrhythmics, calcium channel blockers, benzodiazepines, certain HMG-CoA reductase 
inhibitors, phosphodiesterase-5 (PDE5) inhibitors, warfarin). Particular caution is recommended 
during coadministration of drugs that are narrow therapeutic index CYP3A substrates 
(eg, alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, fentanyl, quinidine, 
ergotamine, dihydroergotamine, astemizole, terfenadine) with idelalisib.
5.6.9.
Immunization
Because of its actions to inhibit PI3Kδ-dependent B-cell function, high doses of idelalisib can 
impair primary or secondary responses to immunization in animals.
The specific clinical relevance of these findings with idelalisib is unknown. However, for 
subjects who are at substantial risk of an infection (eg, influenza) that might be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of study 
therapy.
Of note, the safety of immunization with live viral vaccines following idelalisib therapy has not 
been studied and vaccination with live virus vaccines during study treatment is not 
recommended.
5.6.10.
Surgery
There are no known effects of idelalisib on coagulation or wound healing. Pending receipt of 
additional information, study drug may be continued in the peri-procedural period in subjects 
who require surgery or invasive procedures.
5.6.11.
Diet
There are no specific dietary restrictions in the study. Study drug may be taken with or without 
food.
Duration of Study Drug
5.7.
Subjects may continue receiving study drug until the occurrence of any events requiring study 
drug discontinuation as defined in Section 5.8.


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Discontinuation of Study Drug
5.8.
All study participants may receive study drug indefinitely; however:

Any subject has the right to discontinue study drug at any time.

Any subject who has objective evidence based on IRC review of definitive CLL progression
will discontinue study drug.

Any subject unable to tolerate a second rechallenge with protocol-described, dose-modified 
idelalisib at Dose Level –1 (see Section 5.2) should discontinue study drug.

Any subject who becomes pregnant or begins breastfeeding should discontinue study drug.

Any subject who becomes significantly noncompliant with study drug administration, study 
procedures, or study requirements should discontinue study drug.

Any subject for whom the blind is intentionally broken by the subject or the study site should 
discontinue study drug.

The investigator, in consultation with the Gilead Sciences medical monitor, may discontinue
study drug, if, it is not in the subject’s best interest to continue. 

If allowed by local regulations, Gilead Sciences may transition subjects from study drug to 
commercial drug supply when idelalisib becomes commercially available in the country 
where the subject is living.
Subjects who permanently discontinue study drug for a reason other than disease progression 
(as determined by the IRC) shall continue with assessments per the schedule of procedures until 
disease progression or until another anticancer or experimental therapy is initiated. 
Discontinuation from Study
5.9.
Subject study participation will be ended due to any of the following reasons:

Adverse event.

Disease progression.

Withdrawal of consent.

Significant subject noncompliance with study drug administration, study procedures, or study 
requirements.

Initiation of any additional anticancer therapies (other than corticosteroids, see Section 5.6.5) 
including chemotherapy, radiation, antibody therapy, immunotherapy, or other experimental 
treatment.


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
Physician’s decision to remove the subject from the study.

Pregnancy.

The subject is lost to follow-up.

Death.

Discontinuation of study by the Sponsor, a Regulatory Agency, or an IRB or EC.
Study Treatment Rationale
5.10.
Subjects will be assigned to treatment (Arm A or Arm B) in this study based on their 
randomization in the primary study. The 1:1 randomization in the primary trial
(GS-US-312-0116) ensures that sufficient Arm B subjects will cross over from rituximab alone 
to single-agent idelalisib at the 150-mg/dose BID starting dose level in this extension trial
(GS-US-312-0117) to allow an adequate evaluation of efficacy and safety in this trial. The 
randomization and allocation processes will be established and performed through an IWRS; the 
intent is to maximize the integrity and security of the subject disposition and to ensure 
appropriate access and convenience-of-use by the investigational sites.
Double blinding is included to provide protection against biased interpretations of efficacy and 
safety data by subjects, caregivers, investigators, Gilead Sciences personnel, or others involved 
in study conduct. 
Selection of the idelalisib treatment regimen (including starting dose level, dose-modifications 
and supportive care, schedule, duration, and conditions of administration) for this study program 
has been based primarily on safety, exposure, and activity profiles from previous Phase 1 clinical 
studies involving healthy volunteers, patients with allergic rhinitis, and patients with 
refractory/relapsed lymphoid malignancies {20361}, {21030}, {21036}. The following 
information was considered in selecting the study drug dosing regimen for the primary study and 
this companion extension study:

Idelalisib was symptomatically well tolerated in patients with lymphoid malignancies 
receiving dose levels of 50 mg/dose BID through 350 mg/dose BID (the highest dose level 
tested). No specific MTD was apparent over the dose range tested. However, monitorable, 
reversible transaminase elevations were observed in some patients and may have been more 
frequent at higher dose levels (~10% rate among patients with CLL receiving starting doses 
of 150 mg/dose). Thus, while doses through 350 mg/dose BID are tolerable, the starting 
dose of 150 mg/dose BID appears to appropriately balance safety with efficacy in 
idelalisib-naïve subjects. The starting dose of 300 mg/dose BID in this study also appears 
appropriate for evaluation; it is lower than the dose level of 350 mg/dose BID that has been 
tolerable in prior studies and is likely to be suitable in subjects who have already been 
tolerating idelalisib therapy at 100 mg/dose BID. 


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
Upon disease progression, permitting escalation from 150 mg/dose BID to 300 mg/dose BID 
among subjects allocated to Arm A offers a systematic evaluation of higher doses in subjects 
who are tolerating idelalisib treatment and might benefit from increased PI3Kinhibition. 
The pharmacological basis for considering such an intervention is based on the concept that 
some individuals might have lower-than-expected plasma exposures or dose-dependent 
resistance to the compound at 150 mg/dose BID and might benefit from a higher dose. The 
intent is to determine if the higher dose can reestablish disease control or whether absolute 
resistance to PI3Kinhibition has been acquired. The safety data obtained in these subjects 
would add to the overall safety database.

In an allergic rhinitis study, idelalisib induced statistically significant improvements in 
clinical and pharmacodynamic endpoints when administered at 100 mg/dose BID over 
7 days. These data support the pharmacological relevance of idelalisib-mediated PI3Kδ 
inhibition when administered at the dose-levels to be used in this study.

A positive correlation was noted between idelalisib dose and measures of tumor control and 
chemokine normalization in patients with B-cell malignancies. The majority of patients 
appear to have tumor responses and protracted PFS when receiving starting doses of 
100 mg/dose BID. Thus, treatment with a idelalisib at a starting dose of 150 mg/dose BID 
appears to offer most patients the potential to benefit from therapy and the dose level of 
300 mg/dose BID may provide additional benefit in patients with disease resistance as 
systematically evaluated in this trial. 

Increases in idelalisib plasma Cmax, AUC, and Ctrough values were less than dose-proportional 
in subjects with lymphoid malignancies; the dose-exposure evaluation indicated modest 
increases in plasma exposure at dose levels >150 mg BID.  Thus, administration of starting 
doses of idelalisib of 150 mg/dose BID appears appropriate to ensure adequate exposure in 
the majority of patients. 

In Phase 1 studies, the mean plasma t1/2 of idelalisib was ~6.5 to 9.8 hours across all dose 
levels and there was no substantive plasma accumulation over 7 or 28 days.

The changes in exposure observed when administering idelalisib after a high-fat, high-calorie 
meal are modest (~40% increase in mean AUC with no change in mean Cmax). Thus, 
idelalisib can be administered with or without food. 

The idelalisib dose modification provisions described in the protocol are designed to balance 
a primary concern for subject safety with the potential for observing pharmacological and 
antitumor activity in circumstances under which a subject experiencing an adverse event may 
still be able to continue on therapy at a lower idelalisib dose level. The enhanced monitoring 
to be performed and the actions to be taken in response to toxicity are based on experience 
with interruption, dose-modification, rechallenge, and re-escalation already piloted in 
idelalisib Phase 1 trials. In addition, idelalisib antitumor activity has been observed in the 
Phase 1 studies across all dose levels tested, including doses in the range of the modified 
dose levels planned for this protocol. Thus, use of the lower dose level to accommodate 
individual subject tolerability in this protocol is justified because subjects receiving such an
idelalisib dose level still have the potential for benefit.


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
In both the primary and extension studies, study treatment will be continued for each subject
until the occurrence of disease progression. Such a strategy is considered appropriate under 
the assumption that persistent interference with PI3Ksignaling is likely to extend treatment 
effect. In addition, this design permits collection of further single-agent safety information 
and thus is likely to enhance understanding of the overall safety profile of idelalisib. 


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6.
STUDY PROCEDURES
Enrollment and Study Management Procedures
6.1.
6.1.1.
Subject Recruitment
Study candidates are limited to those subjects who participated in the primary clinical trial
(Study GS-US-312-0116) and meet the entry criteria for this trial (Study GS-US-312-0117).
Subjects will be enrolled from investigational sites in the United States and Europe. The site 
principal investigator, designated sub-investigators, or other designees will discuss the possibility 
of participation directly with subjects who participated in the primary study. 
The study sponsor will post a description of the study on the ClinicalTrials.gov website. Any 
promotional information generated by the sponsor or investigational sites will be submitted for 
IRB/IEC review.
6.1.2.
Subject Compensation for Participation
For subjects requesting such assistance, reasonable reimbursements for the costs of travel 
required to participate in this study will be provided by the study sponsor. To receive payment 
for travel, subjects will need to submit the original travel receipts to the research study staff at 
the investigational site.
However, other than medical care that may be provided, subjects will not be paid for 
participation in the study. Payments for such items as lost wages, disability, discomfort due to 
injury, or meals obtained while waiting at the clinical research center will not be provided. 
Through the informed consent process, study candidates will be notified that their insurance 
company could be charged for standard care that is a component of this research study and that 
subjects may be responsible for co-payments and deductible payments that are typical for their 
insurance coverage.
6.1.3.
Screening
The investigator must inform each prospective subject of the nature of the study, explain the 
potential risks, and obtain written informed consent from the subject and/or a legal guardian 
prior to performing any study-related screening procedures. At the time the study candidate signs 
the informed consent, a site representative should access the IWRS to indicate that a study 
candidate is being screened. The user will need to supply the IWRS with required information 
identifying the site and the subject number as already assigned in Study GS-US-312-0116.
Any consented subject who is excluded from the study before initiation of study treatment will 
be considered a screen failure. All screen failures must be documented along with an adequate 
description of the reason the subject was considered a screen failure. If available, information 
should be provided as to why the subject did not meet eligibility criteria, withdrew consent, 
experienced an intercurrent illness, or had other events that precluded treatment on this study.


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Explanation of Study Visits
6.2.
The specific study procedures to be conducted for each subject enrolled in the study are 
presented in tabular form in Appendix 7 and are described in the sections that follow. Additional 
information on the study procedures is provided in the study manual.
For visits at which HRQL and healthy utility data are obtained, it is important that the subject be 
administered the FACT-Leu and the EQ-5D before any other procedures are performed and 
before any study-related information is communicated to the subject; this is necessary to avoid 
biasing the PRO responses provided by the subject. Once the subject has completed the 
FACT-Leu and the EQ-5D assessments, the remaining procedures may be performed.
At visits involving idelalisib administration and pharmacokinetic sampling in the clinic, care 
should be taken to perform procedures with the appropriate timing relative to idelalisib
administration. The actual sample collection times of pharmacokinetic blood specimens should 
be recorded. If a heparinized venous catheter is placed for sample collection in order to avoid 
repeated needle sticks, at least 2 mL of blood should be removed and discarded prior to each 
sample collection in order to avoid heparin contamination of the sample.
At the visit designated as a laboratory-only visit (Visit 7), subjects will have laboratory 
assessments that may be performed at the investigational site or at an accredited local laboratory 
or clinic that is convenient for the subject/caregiver. If blood is collected at a local laboratory, 
samples are not to be analyzed at the local laboratory. For these visits, subjects and/or caregivers 
will be provided with central laboratory kits that will contain materials necessary for the 
collection and shipment of the laboratory samples by the local laboratory clinic to the central 
laboratory.
Local lab results may be requested in the event central laboratory results are not available for 
assessment of disease response, progression, or the evaluation of a significant event. In addition 
to clinical assessments of tumor status, CT or MRI imaging of the neck, chest, abdomen, and 
pelvis will be performed as a component of tumor assessments during the study based on the 
rationale provided in Section 3.2.1.
Following unblinding of the study, subjects who were randomized to idelalisib on 
Study GS-US-312-0116 will not be required to have study visits 3, 5, and 7 performed on 
GS-US-312-0117.
6.2.1.
Visit 1 and Screening Period (Clinic Visit)
The initial screening visit is designated as Visit 1. At Visit 1, the investigator must inform each 
prospective study participant of the nature of the study, explain the potential risks, and obtain 
written informed consent from the study candidate and/or legal guardian prior to performing any 
study-related screening procedures. Once the informed consent document has been signed, the 
subject may undergo the screening procedures.


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In order to optimize scheduling convenience for the subject and for the investigational staff, 
study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be 
used as screening procedures for Study GS-US-312-0117 if performed within 4 weeks prior to 
initiation of study drug therapy on Study GS-US-312-0117. In addition, screening procedures 
may be performed over as many days as necessary provided that screening is completed within 
4 weeks prior to initiation of study drug therapy on Study GS-US-312-0117. 
The tests and evaluations outline in Table 6-1 will be performed at Visit 1 or during the 
screening period prior to initiation of study treatment.


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Table 6-1.
Procedures and Assessments at Visit 1 (During Screening Period)
Assessment 
or Procedure
Explanationa
Informed consent
To be obtained before any screening procedures are initiated
IWRS access
Access IWRS to document that subject is in screening and provide the subject number from 
Study GS-US-312-0116
CIRS assessment
Recording of current comorbid conditions using the CIRS scoring instrument
(see Appendix 6)
Concomitant
medications
Recording of ongoing concomitant medication use
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including height, weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Serum β-HCG
Women of childbearing potential only
CLL peripheral 
blood evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 12 trisomy; 
DNA mutational analysis for p53, IgHV (including IgHV3-21), and other genes of interest in 
CLL (eg, Notch); flow cytometry for CD5, CD10, CD11c, CD19, CD20, CD23, CD38, 
CD45, kappa and lambda light chains, and ZAP-70; cytology for karyotyping.
CLL serology
Serum 2 microglobulin
 
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol,
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis, to be scheduled with 4 weeks prior 
to initiation of study treatment at Visit 2
Bone marrow 
biopsy and aspirate
To be performed at investigator discretion to determine extent of CLL involvement and bone 
marrow cellularity.
a
Study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be used as screening 
procedures for Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117.
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase,
AST=aspartate aminotransferase, CIRS=cumulative illness rating scale, CLL=chronic lymphocytic leukemia, CT=computed 
tomography, DNA=deoxyribonucleic acid, FISH= fluorescence in-situ hybridization, GGT=gamma--glutamyltransferase, 
Ig=immunoglobulin, IgHV=immunoglobulin heavy chain variable region, IWRS=interactive web response system, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging, RNA=ribonucleic acid, ZAP-70=zeta-associated protein 70
PPD


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6.2.2.
Visit 2 (Day 1) (Clinic Visit)
Subjects will be assessed to determine if they still meet eligibility criteria and can initiate study 
treatment. Study drug holds from primary study GS-US-312-0116 may continue as medically 
appropriate. The procedures outlined in Table 6-2 will be performed at Visit 2 (Day 1).
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1)
Assessment or 
Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the 
subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant 
medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly
β-HCG
For women of child-bearing potential only; serum -HCG or urine dipstick pregnancy test must 
be negative prior to initial study treatment
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Idelalisib
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the date 
and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration
Study drug 
administrationa
First dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib
pharmacokineticsa
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after study 
drug administration (with recording of the date and actual clock time of blood collection)
Study drug dispensinga
Dispensing of 4-week supply of study drug to the subject with instructions for self-
administration at home
Instruction regarding 
study drug dosing at 
next full clinic visita
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 3.
a
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll on Study GS-US-312-0117 following 
unblinding may have idelalisib treatment (and associated PK testing) delayed at the Investigator’s discretion until the time of 
disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib treatment
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response 
system, LDH=lactate dehydrogenase, RNA=ribonucleic acid


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6.2.3.
Visit 3 (Day 15) (Clinic Visit)
The procedures outlined in Table 6-3 will be performed at Visit 3 (Day 15 [±2 days]). 
Table 6-3.
Procedures and Assessments at Visit 3 (Day 15)
Assessment or 
Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the 
subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant 
medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib
pharmacokinetics
Recording of the date and actual clock time of the last prior subject self-administration of study 
drug (should be the prior evening dose)Pre-dose collection of plasma sample for idelalisib
pharmacokinetics (with recording of the date and actual clock time of the date and actual clock 
time of blood collection)
IWRS access
Access of IWRS to document subject visit
Study Therapy Administration
Study drug 
administration
Study drug to be administered to the subject (with recording of the date and actual clock time of 
the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after study 
drug administration (with recording of the date and actual clock time of blood collection)
Instruction regarding 
study drug dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 4.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, EQ-5D=EuroQoL 
Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, HRQL=health-related quality of life, 
GGT=gamma-glutamyltransferase, IWRS=interactive web response system, LDH=lactate dehydrogenase


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6.2.4.
Visit 4 (Day 29) (Clinic Visit)
The procedures outlined in Table 6-4 will be performed at Visit 4 (Day 29 [±2 days]).
Table 6-4.
Procedures and Assessments at Visit 4 (Day 29)
Assessment or 
Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated to 
the subject
Adverse events 
Recording of adverse events occurring since Visit 3
Concomitant 
medications
Recording of concomitant medication used since Visit 3
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last prior 
subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration and Dispensing
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration)


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Assessment or 
Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after 
study drug administration (with recording of the date and actual clock time of blood 
collection)
Study drug 
dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for self-
administration at home
Instruction 
regarding dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the day 
of Visit 5.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed 
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging


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6.2.5.
Visit 5 (Day 43) (Clinic Visit)
The procedures outlined in Table 6-5 will be performed at Visit 5 (Day 43 [±2 days]). 
Table 6-5.
Procedures and Assessments at Visit 5 (Day 43)
Assessment or 
Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated 
to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant 
medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
IWRS access
Access of IWRS to document subject visit
Study Therapy Administration
Study drug 
administration
Study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration)
Post-Therapy Procedures and Assessments
Instruction regarding 
study drug dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the day 
of Visit 6.
Scheduling of Visit 6 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 6.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, EQ-5D=EuroQoL 
Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, HRQL=health-related quality of life, 
GGT=gamma-glutamyltransferase, IWRS=interactive web response system, LDH=lactate dehydrogenase


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6.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit)
The procedures outlined in Table 6-6 will be performed at Visit 6 (Day 57 [±2 days]). 
Table 6-6.
Procedures and Assessments at Visit 6 (Day 57)
Assessment or 
Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the 
assessment should be done even if study drug has been interrupted. 
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated 
to the subject
Adverse events 
Recording of adverse events occurring since Visit 5
Concomitant 
medications
Recording of concomitant medication used since Visit 5
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last prior 
subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow 
biopsy and aspirate
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not 
necessary to obtain a follow-up bone marrow biopsy/aspirate to establish CR.


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Assessment or 
Procedure
Explanation
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug bottle number
Study Therapy Administration
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after 
study drug administration (with recording of the date and actual clock time of blood 
collection)
Study drug 
dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for self-
administration at home
Instruction 
regarding dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the day 
of Visit 8.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging
6.2.7.
Visit 7 (Day 71) (Laboratory Visit)
The procedures outlined in Table 6-7 will be performed at Visit 7 (Day 71 [±2 days]).
Table 6-7.
Procedures and Assessments at Visit 7 (Day 71)
Assessment or 
Procedure
Explanation
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including ALT, AST, ALP, GGT, total bilirubin, LDH
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
GGT=gamma-glutamyltransferase, LDH=lactate dehydrogenase


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6.2.8.
Visit 8 (Day 85) (Clinic Visit)
The procedures outlined in Table 6-8 will be performed at Visit 8 (Day 85 [±2 days]).
Table 6-8.
Procedures and Assessments at Visit 8 (Day 85)
Assessment or 
Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated to 
the subject
Adverse events 
Recording of adverse events occurring since Visit 6
Concomitant 
medications
Recording of concomitant medication used since Visit 6
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last prior 
subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration and Dispensing
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration)


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Assessment or 
Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after 
study drug administration (with recording of the date and actual clock time of blood 
collection)
Study drug 
dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for self-
administration at home
Instruction 
regarding dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the day
of Visit 9.
Scheduling of 
Visit 9 radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 9.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed 
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging


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6.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit)
The procedures outlined in Table 6-9 will be performed at Visit 9 (Day 113 [±3 days]).
Table 6-9.
Procedures and Assessments at Visit 9 (Day 113)
Assessment or 
Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit the 
assessment should be done even if study drug has been interrupted.
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated 
to the subject
Adverse events 
Recording of adverse events occurring since Visit 8
Concomitant 
medications
Recording of concomitant medication used since Visit 8
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last prior 
subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow 
biopsy and aspirate
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not 
necessary to obtain a follow-up bone marrow biopsy/aspirate to establish CR.


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Assessment or 
Procedure
Explanation
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after 
study drug administration (with recording of the date and actual clock time of blood 
collection)
Study drug 
dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for self-
administration at home
Instruction 
regarding dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the day 
of Visit 10.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging


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6.2.10.
Visit 10 (Day 141) (Clinic Visit)
The procedures outlined in Table 6-10 will be performed at Visit 10 (Day 141 [±3 days]) 
Table 6-10.
Procedures and Assessments at Visit 10 (Day 141)
Assessment or 
Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated to 
the subject
Adverse events 
Recording of adverse events occurring since Visit 9
Concomitant 
medications
Recording of concomitant medication used since Visit 9
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last prior 
subject self-administration of study drug (should be the prior evening dose)
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug  blister card number
Study Therapy Administration
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after 
study drug administration (with recording of the date and actual clock time of blood 
collection)


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Assessment or 
Procedure
Explanation
Study drug 
dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for self-
administration at home
Instruction 
regarding dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the day 
of Visit 11.
Scheduling of 
Visit 11 radiology
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 11.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed 
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging


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6.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit)
The procedures outlined in Table 6-11 will be performed at Visit 11 (Day 169 [±3 days]). 
Table 6-11.
Procedures and Assessments at Visit 11 (Day 169)
Assessment or 
Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the 
assessment should be done even if study drug has been interrupted. 
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated to 
the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant 
medications
Recording of concomitant medication used since Visit 10
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last prior 
subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow 
biopsy and aspirate
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not 
necessary to obtain a follow-up bone marrow biopsy/aspirate to establish CR.


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Assessment or 
Procedure
Explanation
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study Therapy Administration
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after 
study drug administration (with recording of the date and actual clock time of blood 
collection)
Study drug 
dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for self-
administration at home.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging


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6.2.12.
Visit 12 (Day 211) (Clinic Visit)
The procedures outlined in Table 6-12 will be performed at Visit 12 (Day 211 [±3 days]) 
Table 6-12.
Procedures and Assessments at Visit 12 (Day 211)
Assessment or 
Procedure
Explanation
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated to 
the subject
Adverse events 
Recording of adverse events occurring since Visit 11
Concomitant 
medications
Recording of concomitant medication used since Visit 11
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit
Study drug 
administration
Subject to continue with study drug as prescribed.
Scheduling of 
Visit 13 radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 13.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed 
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging


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6.2.13.
Visit 13 (Day 253) (Clinic and Radiology Visit)
The procedures outlined in Table 6-13 will be performed at Visit 13 (Day 253 [±3 days]). 
Table 6-13.
Procedures and Assessments at Visit 13 (Day 253)
Assessment or 
Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the 
assessment should be done even if study drug has been interrupted. 
During-Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the 
subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant 
medications
Recording of concomitant medication used since Visit 10
Study drug 
return/accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy 
and aspirate
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR.
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study drug 
administration
Subject to continue with study drug as prescribed.
Study drug 
dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for self-
administration at home.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging


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6.2.14.
Visit 14 (Day 295) (Clinic Visit)
The procedures outlined in Table 6-14 will be performed at Visit 14 (Day 295 [±3 days]) 
Table 6-14.
Procedures and Assessments at Visit 14 (Day 295)
Assessment or 
Procedure
Explanation
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated to 
the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant 
medications
Recording of concomitant medication used since Visit 10
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit
Study drug 
administration
Subject to continue with study drug as prescribed.
Scheduling of 
Visit 15 radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 15.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed 
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging


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6.2.15.
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks) (Clinic and 
Radiology Visits)
The procedures outlined in Table 6-15 will be performed at Visit 15 (Day 337 [±3 days]) and 
every 12 weeks thereafter [±7 Days]).
Table 6-15.
Procedures and Assessments at Visit 15 and Subsequent Visits
(Day 337 and Every 12 Weeks)
Assessment or 
Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology 
assessmenta
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the 
assessment should be done even if study drug has been interrupted.
During-Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated to 
the subject
Adverse events 
Recording of adverse events occurring since prior visit
Concomitant 
medications
Recording of concomitant medication used since prior visit
Study drug 
return/accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM


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Assessment or 
Procedure
Explanation
Bone marrow 
biopsy and aspirate
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not 
necessary to obtain a follow-up bone marrow biopsy/aspirate to establish CR.
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study drug 
administration
Subject to continue with study drug as prescribed.
Study drug 
dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for self-
administration at home
Scheduling of next 
visit radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for next clinic visit 
(every 12 weeks).
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging
6.2.16.
End-of-Study Visit (Clinic Visit)
At the time of discontinuation from the study, the subject should have the procedures and 
assessments performed as documented in Table 6-16. An end-of-study CT/MRI tumor 
assessment should be performed unless the subject already has radiographic confirmation of 
definitive disease progression 4 weeks prior to study discontinuation. 


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Table 6-16.
Procedures and Assessments at End-of-Study Visit
Assessment or 
Procedure
Explanation
Radiology 
assessmenta
CT or MRI imaging of neck, chest, abdomen, and pelvis
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are performed
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed
Adverse events 
Recording of adverse events occurring since prior visit; if a clinically significant adverse event or 
abnormal result is observed that is not resolved by the end-of treatment visit, repeat evaluations 
should be performed to document resolution or stabilization of the abnormality
Concomitant 
medications
Recording of concomitant medication used since prior visit
Study drug 
return/accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly
Serum β-HCG
Women of childbearing potential only
CLL peripheral 
blood evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 12 trisomy; DNA 
mutational analysis for p53, IgHV (including IgHV3-21), and other genes of interest in CLL (eg, 
Notch); flow cytometry for CD5, CD10, CD11c, CD19, CD20, CD23, CD38, CD45, kappa and 
lambda light chains, and ZAP-70; cytology for karyotyping
CLL serology
Serum 2 microglobulin
 
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS
Access IWRS to document that subject has permanently discontinued study therapy and to indicate 
whether subject agrees to continue to undergo long-term follow-up
a
An end-of-study CT/MRI tumor assessment should be performed unless the subject has per-protocol CT/MRI assessments 
4 weeks prior to end-of-study discontinuation.
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, CLL=chronic lymphocytic leukemia, CT=computed tomography, FISH= fluorescence in-situ 
hybridization, GGT=gamma-glutamyltransferase, IgHV=immunoglobulin heavy-chain variable-region, IWRS=interactive web 
response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, RNA=ribonucleic acid, 
ZAP-70=zeta-associated protein 70
PPD


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6.2.17.
30 Day and Long-Term Follow-up
A 30 Day follow-up visit will be performed 30 (+ 5) days following the end-of-study visit; 
however, it may be waived for subjects who have permanently discontinued study drug and have 
had a study visit > 30 days after the last dose of study drug.
Long-term, follow-up will be requested of all subjects who withdraw from study for any reason.
The long-term follow-up for survival will be conducted  at ~6-month intervals for 5 years, 
starting at the end-of-study visit. Information may be gathered during a routine clinic visit or 
other contact with the subject, or via telephone. Information gathered will include medical status, 
anti-tumor treatments, secondary malignancies, and survival.
Sample Storage
6.3.
 
 
 
  
 
 
Blood Collection
6.4.
. The maximum amount of blood to be drawn at a visit ~115 mL and the total amount of blood 
to be drawn over the initial 52-week study period (including the 4-week screening period and 
through Week 48 of the study including a possible end-of-therapy visit) is ~560 mL. For a 40-kg 
person (the smallest participant expected to enroll in the study), this equates to maximum blood 
volume per body weight per visit of ~2.8 mL/kg and a total blood volume per body weight per 
average 6-week period of ~1.6 mL/kg. These quantities of blood are within accepted limits of 
3.0 mL/kg of body weight for a single blood draw and 7.0 mL/kg of body weight for a 6-week 
period.
Specific details regarding blood sample collection and processing requirements will be provided 
separately in the study manual.
 
 
PPD
PPD


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Study Procedure Rationale
6.5.
The planned study assessments and timing have been selected as appropriate for screening of 
subjects, for determination of idelalisib-related or disease-related toxicities, for dose 
modification during the study, for characterization of drug exposure and desired pharmacological 
effects, and for evaluation of drug activity. The scheduling of testing is designed to collect a 
complete safety and pharmacology data set while maintaining subject tolerance of study 
procedures. The planned schedule of tumor assessments is consistent with expected rate of 
changes and appropriately balances precise measurement of tumor control with the expense and 
subject inconvenience associated with clinical and radiological procedures. For discussion of the 
rationale for endpoint selection, see Section 3.2.


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7.
EFFICACY ASSESSMENTS
Tumor Status Assessments
7.1.
The determination of CLL response and progression will be based on standardized IWCLL
criteria {12154}, as specifically modified for this study to reflect current recommendations which 
consider the mechanism of action of idelalisib and similar drugs {22541}. Treatment decisions by 
the investigator in this study will be based on these assessments. Radiographic and clinical tumor 
assessments will be subject to independent confirmation by the IRC (see Section 10.4.2).
Method of Assessment
7.2.
In addition to clinical examination, imaging-based evaluation will be used in this study in all 
subjects enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI 
scanning may be used at the investigator’s discretion in subjects for whom this may be a 
preferred alternative to CT scanning; however, if MRI is performed, a non-contrast CT of the 
chest should be performed. Contrast-enhanced scanning is preferred, but iodine-containing or 
gadolinium contrast material may be omitted in subjects for whom use of a contrast agent would 
be medically contraindicated. Chest x-ray, ultrasound, endoscopy, laparoscopy, PET, 
radionuclide scans, or tumor markers will not be considered for response assessment.
For radiographic evaluations, the same method of assessment and the same technique 
(eg, scan type, scanner, subject position, dose of contrast, injection/scan interval) should be used 
to characterize each identified and reported lesion at baseline and during study treatment and 
follow-up. 
All relevant clinical and radiographic information required to make each tumor status assessment 
must be made available for source verification and for submission to the IRC 
(see Section 10.4.2).
Timing of Assessments
7.3.
All baseline clinical and CT/MRI tumor assessments should be performed within 4 weeks prior 
to initiation of study drug therapy. In order to optimize scheduling convenience for the subject 
and for the investigational staff, clinical and CT/MRI tumor assessments performed as part of 
Study GS-US-312-0116 need not be repeated and can be used as baseline tumor assessments for 
Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117. Clinical tumor assessments should be performed at each clinical visit. 
On-study CT/MRI tumor assessments should be performed at ~8- to 12-week intervals as 
dictated by the study protocol. An end-of-study CT/MRI tumor assessment should be performed 
unless the subject has per-protocol CT/MRI assessments 4 weeks prior. If a subject 
permanently discontinues study drug prior to objective documentation of CLL progression, 
investigators should continue further follow-up at ~12-week intervals until CLL progression is 
documented by the central IRC.


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Identification and Measurement of Tumor Lesions and Organomegaly
7.4.
7.4.1.
Index Lesions
At baseline, up to 6 lymph nodes should be selected as index lesions that will be used to 
quantitate the status of the disease during study treatment. Ideally, the index lesions should be 
located in disparate regions of the body. Only peripheral nodes need be selected as index lesions. 
However, it is optimal if mediastinal and retroperitoneal areas of disease are assessed whenever 
these sites are involved.
Index lesions will be measured and recorded at baseline and at the stipulated intervals. The cross-
sectional dimensions (the largest cross-sectional diameter, ie, the LD × LPD) will be recorded 
(in cm) for each index lesion. The product of the perpendicular diameters (PPD) (in cm2) for 
each index lesion and the sum of the products (SPDs) (in cm2) for all index lesions will be 
calculated and recorded. The baseline SPDs will be used as references by which tumor response 
will be characterized during treatment. The nadir LD of individual lesions and the nadir SPD will 
be used as references by which CLL progression will be characterized. All LD and LPD 
diameters will be reported in centimenters and all PPDs and SPDs will be reported in centimeters 
squared.
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable at 
baseline. A lymph node lesion is considered abnormal if it has a single diameter that is 1.5 cm 
and is considered measurable if it has 2 perpendicular diameters that can be accurately measured 
in cross section with the LD being 1.0 cm and the LPD also being 1.0 cm.
At follow-up time points, the LDs for individual lesions and the SPD of all nodal index lesions 
will be considered. Because nodal index lesions that have one or both diameters >0 cm and 
1.0 cm cannot be reliably measured, a default value of 1.0 cm will be assigned for each 
diameter that meets these criteria and the resulting PPD will be used in SPD calculations. Based 
on this convention, a CR may be achieved even if an SPD value is >0 cm2, (ie, if all lymph nodes 
measure <1.0 cm2).
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD will be considered 
progressive disease.
In cases in which a large lymph node mass has split into multiple components, all 
subcomponents regardless of size will be used in calculating the SPD. Progression of the lesion 
will be based on the SPD of sub-components. Lesion sub-components will have the true PPDs 
calculated. Similarly, lesion sub-components that are visible but neither abnormal nor 
measurable will have the default PPD of 1.0 cm2 (1.0 cm 1.0 cm) used in calculating the SPD.
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer 
be separated by this boundary, the newly merged lesion will be measured bi-dimensionally.


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7.4.2.
Spleen and Liver
Both the spleen and liver will be assessed by CT/MRI scan at baseline and at the stipulated 
intervals during treatment. The baseline and nadir values for the longest vertical dimension 
(LVD) of each organ will be used as reference to further characterize the objective tumor 
response of the measurable dimensions of the CLL during treatment. All spleen and liver LVD 
measurements should be recorded in centimeters.
By imaging, the spleen will be considered enlarged if it is >12 cm in LVD {22487}, {22959}.  
For subjects with splenomegaly at baseline or at the splenic LVD nadir, respective response and 
progression evaluations of the spleen will consider only changes relative to the enlargement of 
the spleen at baseline or nadir, not changes relative to the total splenic LVD. 
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen in its LVD or 
decrease to ≤12 cm in the LVD, is required for declaration of a splenomegaly response. 
Conversely, an increase in splenic enlargement by ≥50% from nadir (with a minimum 2 cm 
increase) is required for declaration of splenic progression. 
By imaging, the liver will be considered enlarged if it is >18 cm in LVD {22485}.
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the liver in its LVD or 
decrease to ≤ 18 cm in the LVD is required for declaration of a hepatomegaly response. 
Conversely, an increase in liver enlargement by ≥50% from nadir (with a minimum 2 cm 
increase) is required for declaration of hepatic progression.
7.4.3.
Non-Index Lesions
Any other measurable and abnormal nodal lesions not selected for quantitation as index lesions 
may be considered non-index lesions. In addition, non-measurable evidence of CLL such as 
nodal lesions with both diameters <1.0 cm, extra-nodal lesions, bone lesions, leptomeningeal 
disease, ascites, pleural or pericardial effusions, lymphangitis of the skin or lung, abdominal 
masses that are not confirmed and followed by imaging techniques, cystic lesions, previously 
irradiated lesions, lesions with artifacts, and may be considered as non-index disease.
The presence or absence of non-index disease should be recorded at baseline and at the stipulated 
intervals during treatment. If present at baseline, up to 6 non-index lesions should be recorded. 
The non-index disease at baseline will be used as a general reference to further characterize 
regression or progression of CLL during assessments of the objective tumor response during 
treatment. Measurements are not required and these lesions should be followed as “present” or 
“absent”.


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Definitions of Tumor Response and Progression
7.5.
Responses will be categorized by the IRC as CR, PR, SD, or PD. In addition, a response category 
of not evaluable (NE) is provided for situations in which there is inadequate information to 
otherwise categorize response status. A response category of no disease (ND) is included for 
situations in which there is absence of tumor both at baseline and on treatment.
The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until disease/recurrence progression (taking as a reference 
for disease progression the smallest measurements recorded since treatment started). Subjects 
with a best overall response of NE or ND will be counted in the denominators in calculations of 
tumor response rates.
7.5.1.
Complete Response
To satisfy criteria for a CR, all of the following criteria must be met:

No evidence of new disease

ALC in peripheral blood of <4 x 109/L

Regression of all index nodal masses to normal size (1.5 cm in the LD)

Normal spleen and liver size

Regression to normal of all nodal non-index disease and disappearance of all detectable non-
nodal, non-index disease

Morphologically negative bone marrow defined as <30% of nucleated cells being lymphoid 
cells and no lymphoid nodules in a bone marrow sample that is normocellular for age

Peripheral blood counts meeting all of the following criteria:
— ANC >1.5 x 109/L without need for exogenous growth factors (eg, G-CSF)
— Platelet count 100 x 109/L without need for exogenous growth factors
— Hemoglobin 110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (eg, erythropoietin)
Note: Subjects who fulfill all the criteria for a CR (including bone marrow criteria) but who 
have a persistent anemia, thrombocytopenia, or neutropenia or a hypocellular bone marrow 
that is related to prior or ongoing drug toxicity (and not to CLL) will be considered as a CR 
with incomplete marrow recovery (CRi).


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7.5.2.
Partial Response
To satisfy criteria for a PR, all of the following criteria must be met:

No evidence of new disease

A change in disease status meeting 2 of the following criteria, with 2 exceptions in which 
only 1 criterion is needed: (1) Only lymphadenopathy is present at baseline; (2) Only 
lymphadenopathy and lymphocytosis are present at baseline. In these 2 cases, only 
lymphadenopathy must improve to the extent specified below:
— In a subject with baseline lymphocytosis (ALC4 x 109/L), a decrease in peripheral blood 
ALC by 50% from baseline or a decrease to <4 x 109/L
— A decrease by 50% from the baseline in the SPD of the index nodal lesions
— In a subject with enlargement of the spleen at baseline, a splenomegaly response, defined 
as a ≥ 50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen or 
decrease to ≤12 cm in the LVD by imaging
— In a subject with enlargement of the liver at baseline, a hepatomegaly response, defined 
as a ≥ 50% decrease (minimum 2 cm) from baseline in the enlargement of the liver or 
decrease to ≤18 cm in the LVD by imaging
— A decrease by 50% from baseline in the CLL marrow infiltrate or in B-lymphoid 
nodules

No index, splenic, liver, or non-index disease with worsening that meets the criteria for 
definitive PD

Peripheral blood counts meeting 1 of the following criteria:
— ANC >1.5 x 109/L or 50% increase over baseline without need for exogenous growth 
factors (eg, G-CSF)
— Platelet count 100 x 109/L or 50% increase over baseline without need for exogenous 
growth factors
— Hemoglobin 110 g/L (11.0 g/dL) or 50% increase over baseline without red blood cell 
transfusions or need for exogenous growth factors (eg, erythropoietin)
7.5.3.
Stable Disease
To satisfy criteria for stable disease (SD), the following criteria must be met:

No evidence of new disease

There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD


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7.5.4.
Definitive Progressive Disease
The occurrence of any of the following events indicates definitive PD:

Evidence of any new disease:
— A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD
— New or recurrent splenomegaly, with a minimum LVD of 14 cm
— New or recurrent hepatomegaly, with a minimum LVD of 20 cm
— Unequivocal reappearance of an extra-nodal lesion that had resolved   
— A new unequivocal extra-nodal lesion of any size
— New non-index disease (eg, effusions, ascites, or other organ abnormalities related to 
CLL)
Note: Isolated new effusions, ascites, or other organ abnormalities are not sufficient evidence 
alone of PD unless histologically confirmed. Thus, a declaration of PD should not be made if 
this is the only manifestation of apparently new disease.

Evidence of worsening of index lesions, spleen or liver, or non-index disease:
— Increase by 50% from the nadir in the SPD of index lesions
— Increase from the nadir by 50% in the LD of an individual node or extra-nodal mass that 
now has an LD of >1.5 cm and an LPD of > 1.0 cm
— Splenic progression, defined as an increase in splenic enlargement by 50% from nadir 
(with a minimum 2 cm increase and a minimum LVD of 14 cm)
— Hepatic progression, defined as an increase in hepatic enlargement by 50% from nadir 
(with a minimum 2 cm increase and minimum LVD of 20 cm)
— Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or other 
organ abnormalities related to CLL) 
— Transformation to a more aggressive histology (eg, Richter syndrome) as established by 
biopsy (with the date of the biopsy being considered the date of CLL progression if the 
subject has no earlier objective documentation of CLL progression).


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
Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to an 
autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an infiltrate of 
clonal CLL cells
— The current platelet count is <100 x 109/L and there has been a decrease by >50% from 
the highest on-study platelet count 
— The current hemoglobin is <110 g/L (11.0 g/dL) and there has been a decrease by 
>20 g/L (2 g/dL) from the highest on-study hemoglobin
Note: If there is uncertainty regarding whether there is true progression, the subject should 
continue study treatment and remain under close observation (eg, evaluated at 4-week 
intervals) pending confirmation of progression status by the IRC. In particular, worsening of 
constitutional symptoms in the absence of objective evidence of worsening CLL will not be 
considered definitive disease progression; in such subjects, both CLL-related and 
non-CLL-related causes for the constitutional symptoms should be considered. Worsening of 
disease during temporary interruption of study treatment (eg, for intercurrent illness) is not 
necessarily indicative of resistance to study treatment. In these instances, CT/MRI or other 
relevant evaluations should be considered in order to document whether definitive disease 
progression has occurred. If subsequent evaluations suggest that the subject has experienced 
persistent definitive CLL progression, then the date of progression should be the timepoint at 
which progression was first objectively documented.
7.5.5.
Non-Evaluable
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE: 

There are no images or inadequate or missing images

Images of the liver and spleen are missing at that time point (with the exception that absence 
of splenic images will not result in an NE designation in a subject known to have undergone 
splenectomy).
Note: A time-point will be considered to have a response of NE if any index lesion is missing. 
PD may be assigned at any time point regardless of the extent of missing index or non-index 
lesions. Missing non-index lesions will not impact the ability to assess for response or disease 
progression.
7.5.6.
No Disease
Subjects have a status of ND if all of the following conditions occur:

No index disease noted at baseline or on-treatment 

No non-index disease noted at baseline or on-treatment.


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
No enlargement of the liver or spleen at baseline or on-treatment

No abnormalities of peripheral blood counts (elevated ALC or abnormally low ANC, platelet 
count, or hemoglobin) and no evidence of CLL in bone marrow (if available) at baseline or 
on treatment
7.5.7.
Lymphocytosis During Therapy
Idelalisib can mobilize CLL cells from tissues into the peripheral blood. This characteristic 
pharmacological action can be prominent early in therapy but can persist over time and should 
not be confused with disease progression in subjects who have persistent control of other 
CLL-related signs and symptoms. In the absence of other objective evidence of disease 
progression, lymphocytosis alone will not preclude subjects from meeting the criteria for PR if 
other criteria for PR are met and will not be considered evidence of disease progression if 
occurring in isolation. Subjects with lymphocytosis should be continued on study drug until the 
occurrence of definitive disease progression (ie, disease progression that is manifest by 
worsening CLL-related signs other than lymphocytosis alone), or the occurrence of another 
reason to discontinue study therapy as described in Section 5.8.
7.5.8.
Documentation of Definitive CLL Progression
Of importance, CLL response and progression data collected from the primary study will be 
subjected to IRC review (see Section 10.4.2). Subjects must have confirmation by the sponsor 
working in collaboration with the IRC that the disease has progressed on the primary clinical 
trial (Study GS-US-312-0116) before being permitted to receive secondary idelalisib therapy 
on this extension trial ( GS-US-312-0117). Subjects should continue study drug pending 
confirmation of progression status. CT/MRI should be attempted in order to document definitive 
disease progression by the IRC. The end-of study scan from the primary study can serve as the 
baseline scan for the extension study if obtained within the specific screening period for the 
extension study. If obtained within the specified screening period for the extension study, this 
scan can serve as the baseline scan for the extension study.


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8.
SAFETY ASSESSMENTS
Adverse Event Definitions
8.1.
8.1.1.
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical product which; does not necessarily have a causal relationship 
with study drug administration or usage. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Lymphocytosis

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 5.2.8)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
In this study, any of the following events will be considered an adverse event:

Any complication that occurs as a result of a protocol-mandated procedure (eg, venipuncture, 
biopsy) in the screening, on-treatment, or post-treatment periods.

Any pre-existing condition that increases in severity or changes in nature during or as a 
consequence of study drug administration. Worsening manifestations of the underlying 
cancer (eg, increase in pain, tumor flare reaction, tumor lysis syndrome) may be considered 
adverse events in this study.


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
Any injury or accident occurring during the screening, on-treatment, or post-treatment 
periods. If a medical condition is known to have caused the injury or accident (eg, a fall 
secondary to dizziness), the medical condition (dizziness) and the accident (fall) should be 
reported as 2 separate adverse events. 

Any abnormality in physiological testing or a physical examination finding that requires 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test).

Any laboratory (eg, clinical chemistry, hematology, urinalysis) or investigational  
abnormality (eg, ECG, X-ray) independent of the underlying medical condition that requires
clinical intervention, results in further investigation (beyond ordering a repeat [confirmatory] 
test), or leads to investigational medicinal product interruption or discontinuation unless it is
associated with an already reported clinical event. If the laboratory abnormality is part of a 
syndrome, the syndrome or diagnosis (eg, anemia) not the laboratory result (eg, decreased 
hemoglobin) should be recorded. 

A complication related to pregnancy or termination of a pregnancy (see Section 5.4.9 for 
additional information).
8.1.2.
Serious Adverse Event
A serious adverse event (SAE) is defined as an event that results in any of the following:

Death

Life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe.) 

In-patient hospitalization or prolongation of existing hospitalization.  

Persistent or significant disability/incapacity.

A congenital anomaly/birth defect

A medically important event or reaction. Such events may not be immediately
life-threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the outcomes listed above.Examples of such events 
might include:
— Allergic bronchospasm requiring intensive treatment in an emergency room or at home
— New cancers or blood dyscrasias
— Convulsions that do not result in hospitalization
— Development of drug dependency or drug abuse


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Medical and scientific judgment must be exercised to determine whether such an event is 
reportable under expedited reporting rules. 
Infections resulting from contaminated medicinal product will be considered a medically 
important event and subject to expedited reporting requirements.
Given the endpoints of the study, in order to maintain the integrity of the study the following 
events that are assessed as unrelated to IMP will not be considered SAEs:

Progression of CLL

Death related to progression of CLL
Disease progression and death from disease progression should be reported as SAEs by the 
investigator only if it is assessed that the IMPs caused or contributed to the disease progression 
(i.e., by a means other than lack of effect). Unrelated disease progression and death due to 
disease progression should be captured on the eCRF.
These events will be reported, as appropriate, in the final clinical study report and in any relevant 
aggregate safety reports. The safety information from this study will also be reviewed by an 
independent DMC on an ongoing basis. The DMC can have access to partially blinded or 
unblinded data in order to determine if it is safe to continue the study according to the protocol.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Section 8.5.  If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result (ie, decreased 
hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 5.4.
Assessment of Adverse Events and Serious Adverse Events
8.2.
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.


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8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
Investigator Requirements and Instructions for Reporting Adverse Events 
8.3.
and Serious Adverse Events to Gilead
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed from screening 
onwards.
All AEs, regardless of cause or relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP must be reported to the CRF/eCRF database as 
instructed. 
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported. 
All AEs should be followed up until resolution if possible. If by the last day on study 
(including the off-study medication follow-up period) the AE has not resolved, then the AE will 
be followed up until the investigator and/or Gilead Sciences determine that the subject's 
condition is stable. However, Gilead Sciences may request that certain AEs be followed until 
resolution.


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Investigators are not obligated to actively seek SAEs after the above period. However, if the 
investigator learns of any SAEs that occur after study participation has concluded and the event 
is deemed relevant to the use of IMP, he/she should promptly document and report the event to 
Gilead DSPH.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 

At the time of study start, SAEs will be reported using a paper serious adverse event 
reporting form. During the study conduct, sites may transition to an electronic SAE (eSAE) 
system. Gilead will notify sites in writing and provide training and account information prior 
to implementing an eSAE system.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by faxing 
the report form within 24 hours of the investigator’s knowledge of the event to the attention 
of Gilead DSPH or to the designated CRO.
Gilead Reporting Requirements
8.4.
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the IRB or IEC of SUSAR reports as soon as is practical, where this is 
required by local regulatory agencies, and in accordance with the local institutional policy.
Grading of the Severity of an Adverse Event
8.5.
The severity of adverse events will be graded using the CTCAE, Version 4.03 (provided in study 
manual and available at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). For 
each episode, the highest severity grade attained should be reported.


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If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: Grade 1 
(mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal) to 
describe the maximum intensity of the adverse event. For purposes of consistency with the 
CTCAE, these intensity grades are defined in Table 8-1.
Table 8-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Sign or symptom is present, but it is easily tolerated, is not expected to have a 
clinically significant effect on the subject’s overall health and well-being, does not 
interfere with the subject’s usual function, and is not likely to require medical 
attention.
Grade 2
Moderate
Sign or symptom causes interference with usual activity or affect clinical status, and 
may require medical intervention.
Grade 3
Severe
Sign or symptom is incapacitating or significantly affects clinical status and likely 
requires medical intervention and/or close follow-up.
Grade 4
Life-threatening
Sign or symptom results in a potential threat to life.
Grade 5
Fatal
Sign or symptom results in death.
The distinction between the seriousness and the severity of an adverse event should be noted. 
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For 
example, a headache may be severe in intensity, but would not be classified as serious unless it 
met one of the criteria for serious events listed in Section 8.1.2 above.
Adverse Event Reporting Period
8.6.
The start of the adverse event reporting for a study subject will coincide with signing of the 
informed consent for Study GS-US-312-0117. Any new adverse events occurring thereafter 
should not be reported within Study GS-US-312-0116, but instead should be reported within
Study GS-US-312-0117. The end of the adverse-event-reporting period for 
Study GS-US-312-0117 occurs 30 days after the discontinuation from study drug or when any 
ongoing drug-related adverse events and/or serious adverse events have resolved or become 
stable. A subject withdrawn from the study because of an adverse event must be followed until 
the clinical outcome from the adverse event is determined. The investigator should use 
appropriate judgment in ordering additional tests as necessary to monitor the resolution of events 
ongoing at the completion of study treatment. Gilead Sciences may request that certain adverse 
events be followed longer.
Investigators are not obligated to actively seek information regarding the occurrence of new 
serious adverse events beginning after the 30-day post-study period. However, if the investigator 
learns of such a serious adverse event and that event is deemed relevant to the use of the study 
drug, he/she should promptly document and report the event. A longer reporting period applies in 
the case of pregnancy (see Section 8.9.1)


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Adverse Event Reporting Requirements
8.7.
8.7.1.
Site Reporting Requirements
Classification of an event as serious or nonserious (see Section 8.1.2) determines the reporting 
procedures to be followed by the site. 
Site reporting requirements for adverse events are summarized in Table 8-2, below.
Table 8-2.
Site Reporting Requirements for Adverse Events
Classification
Reporting Time
Reporting Action
Serious
Within 24 hours
Fax report on designated serious adverse event report form to 
PPD Pharmacovigilancea, and to the site IRB/IEC, as per local IRB/IEC 
requirements; include copies of relevant source documentsb (eg, progress 
notes, autopsy reports, laboratory and diagnostic test results, discharge 
summaries) in communication to PPD Pharmacovigilancea
Per eCRF submission 
procedurec
Record and submit information on appropriate eCRFs
Nonserious
Per eCRF submission 
procedure
Record and submit information on appropriate eCRFs
a
See contact information in Table 8-3 below.
b
Subject name, address, and other personal identifiers should be obscured but without losing the traceability of a document to
the study subject identifiers.
c
CLL progression or death due to CLL progression should be reported by the investigator as a serious adverse event only if it 
is assessed that the study drugs caused or contributed to the CLL progression (ie, by a means other than lack of effect). 
Unrelated events of CLL progression should be captured on the appropriate eCRF. 
Abbreviations: CLL = chronic lymphocytic leukemia, eCRF=case report form, IRB/IEC= Institutional Review 
Board/Independent Ethics Committee
For serious adverse events, in addition to completing the adverse event portion of the eCRF, the 
serious adverse event report form must also be completed. The information in the adverse event 
portion of the eCRF page and the serious adverse event report form(s) must match or be 
reconciled. Where the same data are collected, the forms must be completed in a consistent 
manner. For example, the same adverse event term should be used on both forms. Particularly for 
fatal or life-threatening events, copies of progress notes, autopsy reports, laboratory and 
diagnostic test results, discharge summaries, and other relevant documents should be faxed when 
requested and applicable. Follow-up information to the serious adverse event should be clearly 
documented as “follow up” in the serious adverse event report form and must be faxed to these 
same parties. Gilead Sciences may request additional information from the investigator to ensure 
the timely completion of accurate safety reports.
The subject’s name, address, and other personal identity information should be obscured on any 
source documents (eg, progress notes, nurses’ notes, laboratory and diagnostic test results, 
discharge summaries). Only the subject’s study number, initials, or date of birth are to be 
provided.


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The serious adverse event report form must be communicated to PPD Pharmacovigilance and to 
the site IRB/IEC (if required by local regulations) within 24 hours. In the rare event that the 
investigator does not become aware of the occurrence of a serious adverse event immediately 
(for example, if a subject initially seeks treatment elsewhere), the investigator is to report the 
event within 24 hours after learning of it and to document his/her first awareness of the adverse 
event.
Contact details for PPD Pharmacovigilance and for the Gilead study medical monitor are 
provided in Table 8-3:
Table 8-3.
Contact Information for Reporting Serious Adverse Events
Function
Contact Information
PPD Pharmacovigilance
(US)
Facsimile:
 
PPD Pharmacovigilance 
(International)
Facsimile:
Gilead Sciences Medical 
Monitor
Name:
Title:
Associate Director, Clinical Research
Office Telephone:
Mobile Telephone:
Facsimile:
E-mail:
8.7.2.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population
To maintain the integrity of the study, progression of CLL and death related to progression of 
CLL will not be reported to Gilead Sciences as serious adverse events unless it is assessed that 
the study drug caused or contributed to CLL progression or death related to CLL progression 
(ie, by a means other than lack of effect). These events will be exempt from global expedited 
reporting requirements for the duration of the study because they define the primary efficacy 
endpoint for this study. All events of progression of CLL and death related to progression of 
CLL, regardless of relationship to study drug, will be reported in the eCRFs and, as appropriate, 
in the final clinical study report and in any relevant aggregate safety reports.  Disease 
progression information from this study will be reviewed by an independent DMC on an ongoing 
basis. 
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Special Situations Reporting Requirements 
8.8.
8.8.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, lack of 
effect reports and pregnancy reports regardless of an associated AE.  Also includes reports of 
adverse reactions in infants following exposure from breastfeeding, and reports of adverse 
reactions associated with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following possible maternal or paternal 
exposure to the medicinal product.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer. 
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Lack of effect is defined as a situation where there is apparent failure of the medicinal product or 
medical technology to bring about the intended beneficial effect on the individual in a defined 
population with a given medical problem, under ideal conditions of use. 
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
Instructions for Reporting Special Situations
8.9.
8.9.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (ie, signs the informed consent) and throughout the study, including the 
post study drug follow-up period, to the  or Gilead DSPH ] using the pregnancy report form 
within 24 hours of becoming aware of the pregnancy. Refer to the CRF/eCRF completion 
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The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE, and therefore should be reported as 
such. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must be 
reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to or Gilead DSPH using the pregnancy outcome 
report form. If the end of the pregnancy occurs after the study has been completed, the outcome 
should be reported directly to Gilead DSPH. Gilead DSPH contact information is as follows: 
Email: 
 and Fax: 
 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to or Gilead DSPH using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead DSPH, fax number 
 or email 
8.9.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to  or Gilead DSPH  within 24 hours of the investigator becoming aware of the 
situation. These reports must consist of situations that involve study IMP, but do not apply to 
concomitant medications. Except for situations that result in AEs, special situations involving 
concomitant medications will not be reported. Any inappropriate use of medications prohibited 
by this protocol should not be reported as “misuse,” but may be more appropriately documented 
as a protocol deviation.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.
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9.
STATISTICAL CONSIDERATIONS
Analysis Objectives
9.1.
As described in Section 3, the objectives of this clinical trial will focus on determining the effect 
of idelalisib on the onset, magnitude, and duration of tumor control; measures of patient 
well-being (including OS, HRQL; and changes in subject performance status); disease-associated 
biomarkers and potential mechanisms of resistance; treatment administration; safety; and health 
resource utilization. The study will be analyzed when Study GS-US-312-0116 is unblinded.
Analysis Endpoints
9.2.
The endpoints of the study are defined in Section 3.1, grouped in categories relating to tumor 
control, patient well-being, pharmacodynamic markers of drug activity and resistance, exposure, 
safety, and pharmacoeconomics.
Analysis Conventions
9.3.
9.3.1.
Analysis Sets
9.3.1.1.
Intent-to-Treat Analysis Set
The ITT analysis set includes all subjects who receive 1 dose of any study treatment (high-dose 
idelalisib or standard-dose idelalisib). In the ITT analysis set, study drug assignment will be 
designated according to planned allocation in this study, regardless of whether subjects receive a 
different study therapy from that to which they were allocated. 
This analysis set will be used in the analyses of subject characteristics and all the tumor control 
and patient well-being endpoints. Subjects in the ITT analysis set who do not have sufficient 
baseline or on-study tumor status information to be adequately assessed for response status will 
be included in the denominators in the calculation of response rates. 
9.3.1.2.
Per-Protocol Analysis Set
The PP analysis set includes data from subjects in the ITT analysis set who meet the general 
criteria defining the target population for this study, are adherent to the protocol, are compliant 
with study drug treatment, and are evaluable for relevant efficacy endpoints. Treatment 
assignment will be designated according to the actual treatment received. The specific 
classification of subjects to be included in the PP analysis set will be included in the statisticial 
analysis plan which will be finalized prior to the database lock. 
The PP analysis set will be used in sensitivity analyses of these tumor control and patient 
well-being endpoints: PFS, ORR, lymph node response rate, OS and CR rate.


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9.3.1.3.
Safety Analysis Set
A safety analysis set will include subjects in the ITT analysis set grouped for analyses with 
treatment assignments designated according to the actual study drug received. 
This analysis set will be used in the analyses of safety variables as well as study treatment 
administration, and health economic variables.
9.3.1.4.
Pharmacodynamic and/or Pharmacokinetic Analysis Sets
The pharmacodynamic and/or pharmacokinetic analysis sets include data from subjects in the 
safety analysis set who have the necessary baseline and on-study measurements to provide 
interpretable results for the specific parameters of interest. 
These analysis sets will be used in the analyses of AKT phosphorylation, chemokines/cytokines, 
and idelalisib plasma concentrations.
9.3.2.
Data Handling Conventions
9.3.2.1.
General Methods 
By-subject listings will be created for important variables from each eCRF module. Summary 
tables for continuous variables will contain the following statistics: N (number in population), n 
(number with data), mean, standard deviation, 95% confidence intervals (CIs) on the mean, 
median, minimum, and maximum. Summary tables for categorical variables will include: N, n, 
percentage, and 95% CIs on the percentage. Unless otherwise indicated, 95% CIs for binary 
variables will be calculated using the binomial distribution (exact method) and will be 2-sided. 
Data will be described and summarized by relevant treatment arm, analysis set, and timepoint. 
As appropriate, changes from baseline to each subsequent timepoint will be described and 
summarized by treatment arm. Similarly, as appropriate, the best change from baseline during 
the study will also be described and summarized by treatment arm. Graphical techniques 
(eg, waterfall plots, Kaplan-Meier curves, line plots) may be used when such methods are 
appropriate and informative. 
Time-to-event analyses will be performed with reference to the date of first treatment on this 
clinical trial (Study GS-US-312-0117). Similarly, evaluations of on-therapy changes will 
reference the baseline values obtained prior to treatment in this study. The baseline value used in 
each analysis will be the last (most recent) pre-treatment value. Data from all sites will be pooled 
for all analyses. Analyses will be based upon the observed data unless methods for handling 
missing data are specified. If there is a significant degree of non-normality, analyses may be 
performed on log-transformed data or nonparametric tests may be applied, as appropriate. 
Analyses will generally focus on evaluation of outcomes within each treatment arm; formal 
analyses comparing outcomes in Arm A to those in Arm B are not planned. Unless otherwise 
specified, all analyses will be 2-sided at the 0.05 level of significance. 


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9.3.2.2.
Calculation of Tumor Control and Patient Well-Being Variables
Tumor control assessments will be based on standardized IWCLL criteria {12154} {22541}, as 
specifically modified for this study considering the pharmacology of idelalisib. The individual 
and composite endpoints of response and progression (considering changes in lymph node area, 
liver and spleen size, bone marrow, platelet counts, hemoglobin, neutrophil counts, and 
peripheral blood lymphocyte counts) will be determined. Tumor control will be documented at 
each assessment by response category (eg, CR, PR, SD, definitive PD, NE, ND) as defined for 
each response parameter, SPD value, percentage change in SPD values from baseline or nadir, 
date that response is first documented and date of definitive CLL progression. 
The date of definitive CLL progression will be the timepoint at which progression is 
first identified by relevant objective radiographic or laboratory data. Because of the characteristic 
redistribution lymphocytosis that is expected with PI3Kinhibition, lymphocyte count will be 
ignored in the evaluation of progression. Changes in tumor status as provided by the investigator 
and changes in tumor status as adjudicated by the IRC (see Section 10.4.2) will be described. 
The findings of the IRC will be considered primary for analyses of all tumor control endpoints.
The following censoring conventions will be applied:

PFS and DOR: Data from surviving, non-progressing subjects will be censored at the earliest 
of the time of initiation of antitumor treatment other than the study treatment or the last time 
that lack of definitive CLL progression was objectively documented. Data from subjects 
who have CLL progression or die after 2 consecutive missing tumor assessments will be 
censored at the last time prior to the missing assessments that lack of definitive CLL 
progression was objectively documented.

OS: Data from surviving subjects will be censored at the last time that the subject was known 
to be alive. 
Analysis Plan
9.4.
9.4.1.
Subject Disposition and Baseline Characteristics
A listing of all ITT analysis subjects will be generated to describe site, subject number, 
first screening date, first treatment date, allocated study drug assignment, actual study drug 
assignment, the longest duration of study drug treatment, and the reason for discontinuing study 
treatment. Available information on subjects who were screened or registered but not treated will 
be listed separately. A table will be created summarizing these categories in terms of number and 
percent for the ITT analysis set.
Subject baseline characteristics will be listed and summarized by treatment arm for the ITT 
analysis set. As appropriate for the specific variable, subject baseline characteristics acquired in 
Study GS-US-312-0116 will be referenced in Study GS-US-312-0117. Subject characteristics 
between Arm A and Arm B may be compared using the Wilcoxon rank-sum test for continuous 
variables and the Fisher’s exact test for categorical variables. Similarly, within each arm, subject 
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9.4.2.
Efficacy Analyses
9.4.2.1.
Time-to-Event Tumor Control and Survival Endpoints
PFS, DOR and OS will be described in the ITT analysis set using Kaplan-Meier methods by 
treatment group. Medians, ranges, and corresponding 95% CIs will be presented.
The Cox regression approach may be used to explore the influence of the primary study 
stratification factors and other baseline characteristics on PFS and OS. The stratification 
variables from the primary study and additional baseline subject characteristics may be included 
as covariates, focusing on those with expected prognostic significance. 
9.4.2.2.
Categorical Endpoints 
Response rates, lymph node response rate, splenomegaly response rate, hepatomegaly response 
rate, ALC response rate, platelet response rate, hemoglobin response rate, and neutrophil 
response rate will be described. In the calculation of response rates, subjects who do not have 
sufficient baseline or on-study tumor assessment to characterize response will be included in the 
denominator. For all analyses, the corresponding 95% CIs will be presented.
The potential influence of subject baseline characteristics on response rates may be explored
with multiple logistic regression modeling.
9.4.2.3.
Continuous Endpoints
Changes in lymph node area and changes in performance status, PI3K/AKT/mTOR pathway 
activation, and plasma chemokines/cytokines will be assessed by treatment group. Both changes 
from baseline to each subsequent timepoint and best overall on-study changes will be analyzed 
using appropriate methods (eg, analysis of covariance [ANCOVA] or paired t-tests). Means and 
standard errors will be presented.
9.4.2.4.
Health-Related Quality of Life and Performance Status
The FACT-Leu questionnaire data will be scored and processed according to the user manual. 
Missing items in a subscale will be imputed consistent with the user manual instructions. Data 
collected from the FACT-Leu instrument will not be reconciled with adverse event or laboratory 
data or with EQ-D5 findings.
Because a significant portion of the study subjects will have CLL disease progression during the 
course of the study and no HRQL or performance status data will be collected after disease 
progression, the duration of data collection for these variables will vary among the study 
subjects. Hence, at each HRQL or performance status assessment timepoint, changes from 
baseline in HRQL parameters or in performance status in the 2 treatment groups will be 
described by treatment group. considering both: 1) all subjects that have baseline and at least one 
post-baseline assessment for HRQL or performance status with the worst score assigned to those
subjects who have progressed or died at the timepoint, and 2) all subjects that have baseline and 


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at least one post-baseline assessment for HRQL or performance status who have not progressed 
or died at the timepoint. Subjects who are lost-to-follow-up without disease progression will be 
excluded, ie, missing data will not be imputed. 
9.4.3.
Exposure and Safety Analyses
9.4.3.1.
Treatment Administration and Study Drug Compliance
Descriptive information will be provided by treatment arm regarding the number of doses of 
study therapy prescribed, the total number of doses taken, the percent of expected doses taken, 
the number of days of treatment, and the number and timing of prescribed dose reductions and 
interruptions.
Study drug compliance will be described by treatment arm in terms of the proportion of study 
drug actually taken based on returned pill count relative to the amount that was dispensed (taking 
into account physician-prescribed reductions and interruptions).
9.4.3.2.
Idelalisib Plasma Concentrations
Bioanalytical analyses will performed independently so that the study team and investigators will 
not have knowledge of data from individual subjects. Idelalisib plasma concentrations
immediately pre-dose and at 1.5 hours after administration of the dose of study drug at each 
relevant clinic visit will be summarized by treatment and visit using descriptive statistics.
9.4.3.3.
Prior, Concomitant, and Post-Treatment Medication Use
Prior, concomitant, and post-treatment medications will be coded by means of the World Health 
Organization Drug Dictionary (WHODRUG) dictionary into Anatomical-Therapeutic-Chemical 
classification (ATC) codes.
Descriptions of prior medication use will be focused on drugs and regimens used as treatments 
for CLL. Information regarding CLL therapy that was administered prior to 
Study GS-US-312-0116 will be referenced in reporting the results of Study GS-US-312-0117. In 
addition, relevant treatment administration information collected during Study GS-US-312-0116 
will be referenced in reporting the results of this study. As appropriate and if available, 
information on the sequencing, type, dose, schedule, timing, duration of use, and efficacy of 
prior regimens will be provided, focusing particularly on findings observed in 
Study GS-US-312-0116.
The type and timing of use of concomitant medications will be listed and summarized by type 
and treatment arm. Information regarding the type and use of specific supportive medications 
(eg, pneumocystis prophylaxis, hematopoietic growth factors, corticosteroids) during study 
treatment will be described.


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The number, type, and timing of post-study-treatment regimens for CLL will be summarized by 
treatment arm, characterizing the disposition of all subjects who were eligible for post-study 
treatment and also those who were not eligible for post-study treatment (eg, subjects who are 
never treated at all, die while on study treatment, are still on study, are lost to follow-up, etc).
9.4.3.4.
Adverse Events
All adverse events will be listed. The focus of adverse event summarization will be on 
treatment-emergent adverse events. A treatment-emergent adverse event is defined as an adverse 
event that occurs or worsens in the period from the first dose of study treatment to 30 days after 
the last dose of study treatment. 
Adverse events will be classified using MedDRA (http://www.meddramsso.com) with 
descriptions by System Organ Class, High-Level Group Term, High-Level Term, Preferred 
Term, and Lower-Level Term. The severity of adverse events will be graded by the investigator 
according to the CTCAE, Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf), 
whenever possible. If a CTCAE criterion does not exist for a specific type of adverse event, the 
grade corresponding to the appropriate adjective will be used by the investigator to describe the 
maximum intensity of the adverse event: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), 
Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the adverse event to the study 
drug will be categorized as related or unrelated.
Treatment-emergent adverse events will be summarized by treatment arm and by visit. Summary 
tables will be presented to show the number of subjects reporting treatment-emergent adverse 
events by severity grade and corresponding percentages. A subject who reports multiple 
treatment-emergent adverse events within the same Preferred Term (or System Organ Class) is 
counted only once for that Preferred Term (or System Organ Class) using the worst severity 
grade. Adverse event descriptions will be presented by decreasing frequency for a given System 
Organ Class and Preferred Term.
Separate listings and summaries will be prepared for the following types of treatment-emergent 
adverse events:

Study-drug-related adverse events

Adverse events that are Grade 3 in severity

Adverse events leading to study drug interruption and/or dose modification

Adverse events leading to study drug discontinuation

Serious adverse events (with categorization of the primary reason that the adverse event is 
considered serious, eg, death, hospitalization, etc)


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Separate listings and summaries will be prepared for long-term follow-up safety data 
(see Section 6.2.17).
9.4.3.5.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed data. 
The focus of laboratory data summarization will be on treatment-emergent laboratory 
abnormalities. A treatment-emergent laboratory abnormality is defined as an abnormality that, 
compared to baseline, worsens by 1 grade in the period from the first dose of study drug to
30 days after the last dose of study drug. If baseline data are missing, then any graded 
abnormality (ie, an abnormality that is Grade 1 in severity) will be considered treatment 
emergent. Hematological, serum biochemistry, and urine data will be programmatically graded 
according to CTCAE severity grade, when applicable. For parameters for which a CTCAE scale 
does not exist, reference ranges from the central laboratory will be used to determine 
programmatically if a laboratory parameter is below, within, or above the normal range for the 
subject’s age, sex, etc.
Hematological and serum biochemistry and their changes from baseline will be summarized by 
treatment arm and by visit. Summary tables will be presented for each relevant assay to show the 
number of subjects by CTCAE severity grade with corresponding percentages. For parameters 
for which a CTCAE scale does not exist, the frequency of subjects with values below, within, 
and above the normal ranges will be summarized. Subjects will be characterized only once for a 
given assay, based on their worst severity grade observed during a period of interest 
(eg, during the study or from baseline to a particular visit).
Shift tables for hematology and serum biochemistry will also be presented by showing change in 
CTCAE severity grade from baseline to the worst grade post baseline. Separate listings and 
summaries will be prepared for laboratory abnormalities that are Grade 3 in severity.
9.4.3.6.
Oxygen Saturation Values
All oxygen saturation data will be listed. Summaries of oxygen saturation data will be based on 
observed data and will be reported as % saturation. Data and changes from baseline will be 
summarized by treatment arm and by visit. Summary tables will be presented for values below 
92% and for declines from baseline of 5% to show the number of subjects with corresponding 
percentages. Subjects will be characterized only once for each of these categorizations, based on 
their lowest value observed during a period of interest (eg, during the study or from baseline to a 
particular visit).
9.4.4.
Other Analyses
9.4.4.1.
Between-Study Comparisons
It is expected that patients with a progressive malignancy like CLL will normally fare better 
with an earlier therapy than with a later therapy. However, if the converse situation proves true –
eg, if an investigational treatment (idelalisib) administered later shows similar or greater benefit 


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than a standard treatment (rituximab) administered earlier – strong evidence of investigational 
drug effect is demonstrated. Evaluating data derived from the same study subjects during their 
sequential participation in 2 clinical trials offers unique analytical challenges. However, in this 
integrated Phase 3 study program, it is likely that comparing baseline characteristics and 
outcomes among Arm B subjects participating in Study GS-US-312-0116 and 
Study GS-US-312-0117 will be informative. Such an evaluation characterizes how the subjects
and the CLL disease process change with time and treatment. In addition, such an analysis 
provides relevant supporting information documenting the benefits of single-agent idelalisib
relative to single-agent rituximab in the same subjects.
Accordingly, the subject baseline characteristics at the start of Study GS-US-312-0116 relative to 
those at the start of Study GS-US-312-0117 will be evaluated. Subject baseline characteristics 
between the studies may be compared using the Wilcoxon rank-sum test for continuous variables 
and the Fisher’s exact test for categorical variables. 
Time-to-event efficacy variables (eg, PFS, TTR, DOR, time to performance status, or HRQL 
changes) will be evaluated using the paired Prentice-Wilcoxon test, comparing results in 
Study GS-US-312-0116 to those in Study GS-US-312-0117 among subjects who participate in 
Arm B of both studies. Within each study period, medians, ranges, hazard ratios and 
corresponding 95% CIs will be presented using Kaplan Meier methods. As appropriate, Cox 
regression techniques may be used to explore the influence of baseline characteristics on 
treatment differences when comparing these outcomes between the studies. For categorical 
variables (eg, ORR, lymph node response rate, splenomegaly response rate, hepatomegaly 
response rate), the Wilcoxon signed-rank test will be employed to compare outcomes between 
Study GS-US-312-0116 and Study GS-US-312-0117 for Arm B subjects. For all analyses, odds 
ratios and the corresponding 95% CIs will be presented. Differences between studies for Arm B 
subjects relating to continuous variables (eg, percentage changes in lymph node area; changes in 
performance status, PI3K/AKT/mTOR pathway activation and plasma chemokines/cytokines)
will be analyzed using appropriate methods (eg, analysis of covariance [ANCOVA] or paired 
t-tests). Means and standard errors will be presented. As appropriate, the potential influence of 
subject baseline characteristics on treatment effects may be explored with multiple logistic 
regression techniques.
9.4.4.2.
Health Care Resource Utilization
The EQ-D5 questionnaire data will be scored, processed, and standardized according to the user 
manual. As for the FACT-Leu, data will be analyzed using appropriate methods to account for 
incomplete completion of questionnaires. Data collected from the EQ-D5 will not be reconciled 
with adverse event or laboratory data or with FACT-Leu findings.
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.


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The basic approach to the health economic analysis will be to combine the resource utilization 
data from the trial with data on unit prices (collected separately) to estimate total costs. 
The perspective of this analysis will be that of the third-party payer(s) and the hospital over a 
lifetime horizon in the base case. The costs will be described relative to the health care findings 
as measured by duration of tumor control, the symptom-free survival period, life-years, utility 
outcomes, or other measure of appropriate clinical benefits. In order to facilitate the calculation 
of utilities for use in the cost effectiveness analyses, the health status of subjects will be 
evaluated using PFS, Karnofsky performance status, FACT-Leu, and EQ-5D.
9.4.4.3.
Data Explorations
Changes in biomarkers during acquisition of resistance will be evaluated descriptively. Data 
explorations may be performed to evaluate potential associations between subject characteristics 
and outcome measures. Explorations may be performed to assess the potential associations 
between different outcomes measures (eg, relationships between HRQL changes and 
clinical/radiographic endpoints of tumor control).
Sample Size
9.5.
The sample size for this extension study is not based upon a formal statistical hypothesis. The 
upper bound of the sample size in this study is determined by the sample size of the preceding 
primary study (Study GS-US-312-0116) in which ~160 subjects (~80 per arm) are expected to be 
enrolled. It is estimated that this extension study (Study GS-US-312-0117) will have a total 
idelalisib-treated N~130 (assuming a ~10% dropout rate during Study GS-US-312-0116 and a 
further ~10% dropout rate in the transition from the primary study to the extension study).
Timing of Analyses
9.6.
The DMC will have access to serious adverse events requiring expedited reporting and will be 
provided with accumulating safety data on a regular basis. Interim safety reviews will be 
conducted by the DMC in conjunction with safety reviews of the primary clinical trial
(Study GS-US-312-0116). Thus, interim safety reviews will be performed by the DMC at 
intervals of ~6 months; the specific frequency of these reviews will depend upon the rate at 
which the trials are enrolled, the nature of any emerging safety signals, and monitoring 
recommendations from the DMC. At each review, all available safety data will be summarized 
and evaluated.
An interim efficacy analysis of this clinical trial (Study GS-US-312-0117) is planned to take 
place at the time of the final blinded analysis of the primary study (GS-US-312-0116). The intent 
is to provide the data from this extension study in support of regulatory review of data from the 
primary study. An analysis of efficacy and safety may be performed to satisfy regulatory 
requirements and to perform long-term efficacy, safety and OS follow-up. The timing of this 
analysis is expected to occur within 36 months of accrual of the final subject to 
Study GS-US-312-0117.


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10.
RESPONSIBILITIES
Investigator Responsibilities
10.1.
10.1.1.
Compliance with Ethical and Regulatory Guidelines
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), with ICH guidelines, or with the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the study subject. These 
standards are consistent with the European Union Clinical Trials Directive 2001/20/EC and 
Good Clinical Practice Directive 2005/28/EC. The investigator will ensure adherence to the 
basic principles of GCP as outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and 
Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 1993, 
“Retention of Bioavailability and Bioequivalence Testing Samples.”
Because this is a “covered” clinical trial, the investigator will ensure adherence to 21 CFR, 
Part 54, 1998; a covered clinical trial is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.” This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with Gilead Sciences, or proprietary interests in the drug being studied. 
This documentation must be provided before participation of the investigator and any 
subinvestigator in the trial. The investigator or subinvestigator agrees to notify Gilead Sciences 
of any change in reportable financial interests during the study and for 1 year following 
completion of the study. Study completion is defined as the date that the last subject has 
completed the protocol-defined activities.
10.1.2.
Institutional Review Board/Independent Ethics Committee
This protocol and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IRB (for sites enrolling in the United States)
and to an IEC for sites enrolling outside of the United States). Approval from the IRB/IEC must 
be obtained before starting the study and should be documented in a letter to the investigator 
specifying the protocol number, protocol version, protocol date, documents reviewed, and date 
on which the committee met and granted the approval.


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Any modifications or amendments made to the protocol after receipt of the initial 
IRB/IECapproval must also be submitted to the IRB/IEC for approval before implementation.
Only changes necessary to eliminate apparent immediate hazards to the subjects may be initiated 
prior to IRB/IEC approval. In that event, the investigator must notify the IRB/IEC and 
Gilead Sciences in writing within 5 working days after implementation.
The investigator shall submit a progress report, at least once yearly, to the IRB/IEC, and must 
provide a copy to Gilead Sciences. As soon as possible after completion or termination of the 
study, the investigator will submit a final report to the IRB/IEC and to Gilead Sciences. This 
report should include the dates of initiation and completion of the trial, a description of any 
changes in study procedures or amendments to the protocol, any deviations from the protocol, 
the number and type of subjects evaluated, the number of subjects who discontinued (and the 
reasons for discontinuation), the number of subjects who completed the trial, and the results of 
the trial, including a description of any adverse events. Gilead Sciences will assist the 
investigator in the preparation of this report, as needed.
10.1.3.
Informed Consent
After adequately, explaining the aims, methods, objectives, and potential hazards of the study 
and before undertaking any study-related procedures, the investigator is responsible for obtaining 
written informed consent from each individual participating in this study. The investigator must 
utilize an IRB/IEC-approved consent form for documenting written informed consent. Each 
informed consent will be appropriately signed and dated by the subject or the subject’s legally 
authorized representative and the person obtaining consent.
The approved informed consent must not be changed without prior approval by Gilead Sciences
and the IRB/IEC.
10.1.4.
Confidentiality
The investigator must assure that each subject’s anonymity will be strictly maintained and that 
each subject’s identity is protected from unauthorized parties. Only subject initials, date of birth, 
and an identification code (but no subject names) should be recorded on any form or biological 
sample submitted to the Gilead Sciences or designees (eg, laboratories), or to the IRB/IEC.
However, sufficient information must be retained at the site to permit sample data and data in the 
database to be connected with the unique subject number assigned to each study participant.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the idelalisib investigator brochure, this protocol, eCRFs, the investigational new drug, 
and any other study information, remain the sole and exclusive property of Gilead Sciences
during the conduct of the study and thereafter. This information is not to be disclosed to any third 
party (except employees or agents directly involved in the conduct of the study or as required by 
law) without prior written consent from Gilead Sciences. The investigator further agrees to take 
all reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain.


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10.1.5.
Study Files and Retention of Records and Biological Samples
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator’s study file, and (2) subject 
clinical source documents.
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, the 
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data referenced in the monitoring plan for the study, and should include 
sequential notes containing at least the following information for each subject:

Subject identification (name, date of birth, gender)

Documentation that subject meets eligibility criteria, eg, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria)

Participation in trial (including trial number)

Trial discussed and date of informed consent

Dates of all visits

Documentation that protocol-specific procedures were performed

Results of efficacy parameters, as required by the protocol

Start and end date (including dose regimen) of trial medication (including relevant drug 
dispensing and return information)

Record of all adverse events and other safety parameters (including start and end date, 
causality and intensity)

Concomitant medication (including start and end date and dose if relevant dose changes 
occur)

Date of trial completion and reason for discontinuation, if applicable
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (ie, the United States, Europe, or 
Japan) and until there are no pending or contemplated marketing applications in an ICH region; 
or, if no application is filed or if the application is not approved for such indication, until 2 years 
after the investigation is discontinued and regulatory authorities have been notified. Investigators 
may be required to retain documents longer if required by applicable regulatory requirements, by 
local regulations, or by an agreement with Gilead Sciences. The investigator must notify 
Gilead Sciences before destroying any clinical study records. The investigator will promptly 
notify Gilead Sciences in the event of accidental loss or destruction of any study records. 


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Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead Sciences must be notified in advance.
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead Sciences
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site.
Biological samples including tissue and blood samples collected as a study procedure or as 
standard of care during study participation will be stored and maintained by the investigator until 
notification is received from Gilead Sciences that the retained samples and records no longer 
required. The investigator must obtain written permission from Gilead Sciences before disposing 
of any retained samples. The investigator should promptly notify Gilead Sciences in the event of 
accidental loss or destruction of any study samples. With the permission of Gilead Sciences, the 
retained samples may be transferred to an acceptable designee, such as another investigator, 
another institution, a contract storage site, or to Gilead Sciences.
10.1.6.
Case Report Forms
An eCRF is required and must be completed for each enrolled subject, with all required study 
data accurately recorded such that the information matches the data contained in medical records 
(eg, physicians’ notes, nurses’ notes, clinic charts, or other study-specific source documents). As 
required by the protocol, eCRFs should also be completed for those subjects who fail to complete 
the study (even during the screening period). If a subject withdraws from the study, the reason 
must be noted on the eCRF. If a subject is withdrawn from the study because of a 
treatment-limiting adverse event, thorough efforts should be made to clearly document the 
outcome. 
The eCRFs for this study will exist within a Web-based electronic data capture (EDC) system. 
After the investigator or the investigator’s designees (eg, research coordinators) have been 
appropriately trained, they will be given access to the EDC system and will enter the data 
required by the protocol into the EDC system. Any change of data will be made via the EDC 
system, with all changes tracked by the system to provide an audit trail.
The eCRF must be completed and signed by the principal investigator or subinvestigator 
(as appropriate) within a reasonable time period after data collection. This signature serves to 
attest that the information contained in the eCRF is true.
10.1.7.
Drug Accountability 
As described in the relevant section (see Section 5.2.7), the investigator is responsible for 
ensuring adequate accountability of all used and unused investigational medicinal product, 
placebos, and comparators. This responsibility includes acknowledgment of receipt of each 
shipment of study product (quantity and condition), subject dispensing records, and returned or 
destroyed study product. Dispensing records will document quantities received from 


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Gilead Sciences and quantities dispensed to subjects, including lot number, date dispensed, 
subject identifier number, subject initials, and the initials of the person dispensing the 
medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Sciences’ requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRB/IECs, 
and to regulatory authority or health authority inspectors. It is important that the investigator and 
relevant institutional personnel are available during monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
Sponsor Responsibilities
10.2.
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, will be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB/IEC in 
accordance with local requirements. Except as noted in Section 10.1.2, IRB/IEC approval must 
be obtained before changes can be implemented.
10.2.2.
Communications with Regulatory Authorities
Gilead Sciences, working either directly or through designees, will assume responsibility for 
regulatory interactions with relevant regulatory authorities. Gilead Sciences will maintain an 
IND for idelalisib in support of the study in the United States and will maintain similar 
regulatory applications with other regulatory authorities, as required for conduct of the study. In 
fulfilling this responsibility, Gilead Sciences (or a designee) will collect, assemble, and 


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communicate all required regulatory documents (eg, Form FDA 1572, investigator financial 
disclosure forms, protocol and protocol amendments, investigator brochures, informed consent 
documents, annual reports) as required by regulation. Gilead Sciences (or a designee) will also 
assume responsibility for adverse event reporting to regulatory authorities as described in 
Section 8.7.2.
10.2.3.
Data Management
Electronic data capture will be used to enter study data eCRFs and to transfer the data into a 
study-specific electronic database. During the data collection process, automated quality 
assurance programs will be used to identify missing data, selected protocol violations, 
out-of-range data, and other data inconsistencies. Requests for data clarification or correction 
will be forwarded to the investigative site for resolution. As appropriate, eCRFs, listings, tables, 
and SAS datasets will be provided to the investigational sites for review.
Quality assurance and quality control systems will be implemented and maintained according to 
written standard operating procedures to ensure that the data are generated, recorded, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements. Data 
collection and storage systems will provide audit trail, security mechanisms, and electronic 
signature capabilities that meet the requirements of FDA Title 21 of CFR Part 11 regarding 
electronic records and electronic signatures. 
Data security will be controlled through appropriate and specific restriction of access only to data 
and systems required by individual users to accomplish their roles in the data management 
process. Individual login and password protections will be employed at study sites and at 
Gilead Sciences or its designee. The database will exist on physically secured servers. Data 
backups will be done regularly and will be stored in separate facilities. Printed documents 
relating to the study will be secured when not under review. 
10.2.4.
Study Reporting and Publication
Gilead Sciences may make information obtained during this study available in order to further 
the scientific or business needs of the company or as required by law or regulation. In this 
regard, Gilead Sciences may provide study information to private or public organizations 
(eg, business partners, collaborators, consultants, CROs, investors, other physicians who are 
conducting similar studies, funding organizations, regulatory authorities, or other government 
authorities). 
Gilead Sciences will prepare a clinical study report for submission to relevant regulatory 
agencies. Gilead Sciences will ensure that the report meets the standards set out in the ICH 
Guideline for Structure and Content of Clinical Study Reports (ICH E3). An abbreviated report 
may be prepared in certain cases, as appropriate.


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Gilead Sciences intends that the data from this study will be presented and published. 
Gilead Sciences will work in collaboration with the principal investigators in preparing 
presentations and writing manuscripts for publication. 

Investigators may publish or present the results of the study generated by their individual site 
either with the advanced written consent of Gilead or > 2 years after the completion of this 
extension study (GS-US-312-0117) at all participating institutions.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information (see Section 10.1.4).
The investigator will submit to Gilead Sciences any proposed publication or presentation along 
with the respective scientific journal or presentation forum prior to submission of the publication 
(at least 30 days prior to manuscripts and 15 days prior for abstracts and oral presentations). The 
investigator will comply with Gilead Sciences’ request to delete references to its confidential 
information (other than the study results) in any paper or presentation. If deemed necessary by 
Gilead Sciences, the investigator also agrees to withhold publication or presentation for an 
additional 60 days in order to obtain patent protection.
Joint Investigator/Sponsor Responsibilities
10.3.
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the eCRFs for consistency.
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.
10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences may conduct inspections or audits 
of the clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.
10.3.3.
Public Notification of Study Conduct
Consistent with Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and 
with requirements of the International Committee of Medical Journal Editors (ICMJE) as a 
condition of consideration for publication of study results, Gilead Sciences will be responsible 


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for ensuring that this protocol is listed at the ClinicalTrials.gov website (or equivalent) and that 
information at the website relating to study design and conduct is appropriately updated during 
the course of the study. In order to facilitate this process, investigators will need to supply 
Gilead Sciences with appropriate contact information for study site personnel.
10.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authorities and IRB/IECs. In terminating the study, Gilead Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests. 
Study Committees
10.4.
10.4.1.
Data Monitoring Committee
A DMC, operating autonomously from Gilead Sciences, the clinical investigators, and the SSC, 
will be responsible for providing independent recommendations to Gilead Sciences about 
evolving risk-benefit observed in the course of the study and any modifications required during 
the course of the study. The DMC will consist of a biostatistician and 2 physicians experienced 
in treating patients with lymphoid malignancies. The DMC will be chaired by one of these 
individuals. DMC members must not be actively involved in study design, conduct, or subject
accrual and must not have financial, proprietary, professional, or other interests that may affect 
impartial, independent decision-making. Specialists may be invited to participate as non-voting 
members at any time if additional expertise is desired. The DMC will formally interact with the 
external SSC members through the sharing of meeting minutes. Informal interactions between 
the DMC and external SSC members will be limited. The DMC will operate under a charter 
developed as a collaborative document between Gilead Sciences and the DMC. It is expected 
that the members of the DMC will be the same as those for the primary study 
(Study GS-US-312-0116). 
The primary responsibility of the DMC is to protect the safety and welfare of subjects 
participating in this clinical trial and to ensure the integrity of the clinical trial. In general, the 
DMC will be responsible for:

Reviewing the general progress of the study as regards subject accrual, study conduct, and 
protocol violations

Examining accumulated safety, efficacy, and other relevant data at prespecified points during 
the course of the study 

Reviewing major study design modifications prior to implementation of those modifications

Making recommendations concerning continuation, modification, interruption, or termination
of each study


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
Advising the company on changes to informed consent documents

Proposing updates to the DMC monitoring plan, changes in the DMC membership, actions to 
be taken relating to conflict of interest or confidentiality breaches, the need for additional 
expertise during DMC deliberations, revisions to the DMC charter, or alterations in the 
support provided to the DMC

Providing expert advice to the Gilead Science medical monitor on an ad hoc basis regarding 
matters such as safety concerns or diagnostic evaluations in individual subjects
Based on the results of its deliberations during the course of the study, the DMC can recommend 
appropriate actions (eg, continuation of the study unchanged, continuation of the study with 
modifications in design or monitoring plan, interruption of study accrual, study termination).
10.4.2.
Independent Review Committee
An IRC will be established to provide a blinded review of radiographic data and pertinent 
clinical data in order to provide expert interpretation of changes in tumor status. The IRC will 
include 1 independent board-certified radiologist and 1 independent board-certified 
hematologist or oncologist, and will be managed by a CRO selected by Gilead Sciences. The 
review of radiographic and clinical data by the IRC will be performed on an ongoing basis until 
the primary analysis . The specifics of the IRC’s processes and reading methods will be 
described in an independent review charter developed by the contracted imaging facility in 
conjunction with Gilead Sciences. The same organization that is providing IRC services for 
Study GS-US-312-0116 will provide IRC services for this study. 


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11.
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patient norms for the Functional Assessment of Cancer Therapy-General (FACT-G). 
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tomography scans do not improve the predictive power of 1996 national cancer 
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Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative 
patients: a report of 57 cases from the Research on Adverse Drug Events and Reports 
project. Blood 2009;113 (20):4834-40.


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quality of life assessment and reported outcomes in leukaemia randomised controlled 
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treated with fludarabine plus cyclophosphamide or fludarabine alone for first-line 
therapy: a study by the German CLL Study Group. J Clin Oncol 2007;25 (13):1722-
31.
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Eichhorst BF, Fischer K, Fink AM, Elter T, Wendtner CM, Goede V, et al. Limited 
clinical relevance of imaging techniques in the follow-up of patients with advanced 
chronic lymphocytic leukemia: results of a meta-analysis. Blood 2011;117 (6):1817-
21.
24664
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experience of chronic lymphocytic leukaemia: baseline health-related quality of life 
results from the LRF CLL4 trial. Br J Haematol 2008;143 (5):690-7.
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Gea-Banacloche JC. Rituximab-associated infections. Seminars in hematology 
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R. Quality of life of patients with chronic lymphocytic leukemia: results of a 
longitudinal investigation over 1 yr. Eur J Haematol 2004;72 (6):381-9.
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Matsue K, Kimura S, Takanashi Y, Iwama K, Fujiwara H, Yamakura M, et al. 
Reactivation of hepatitis B virus after rituximab-containing treatment in patients with 
CD20-positive B-cell lymphoma. Cancer 2010;116 (20):4769-76.
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scan is of prognostic importance in patients with chronic lymphocytic leukemia. Med 
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in chronic lymphocytic leukemia: an international survey of 1482 patients. Br J 
Haematol 2007;139 (2):255-64.
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elevation in white blood cell count does not predict inferior outcome in chronic 
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Assessment of chronic lymphocytic leukemia and small lymphocytic lymphoma by 
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of life (QOL) among patients with leukemia: The Functional Assessment of Cancer 
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Doorduijn J, Buijt I, Holt B, Steijaert M, Uyl-de Groot C, Sonneveld P. Self-reported 
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12.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
Appendix 3.
Performance Status Scoring System
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D)
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Appendix 6.
Cumulative Illness Rating Scale (CIRS)
Appendix 7.
Schedule of Study Procedures


PPDPPD
PPD
Idelalisib 
Protocol GS-US-312-0117 
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Gilead Sciences, Inc. 
Version 4.0 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
199 EAST BLAINE STREET 
SEATTLE, WA 98102 
STUDY ACKNOWLEDGEMENT 
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and Safety of 
Two Different Dose Levels of Single-Agent Idelalisib (GS-1101) for Previously Treated 
Chronic Lymphocytic Leukemia 
GS-US-312-0117 Version 4.0, 16 December 2013 
This protocol has been approved by Gilead Sciences, Inr-c_ .... Th
.......,e ... fi ... o.-.Ilo ... w......,in .. =--=·• a-.tu 
... r...,e_d-.o...,c-.u.-m-.e-.n-.ts ..... _...., 
this_annroval.. _______ ___, 
Gilead Sciences Medical Monitor 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator 
Printed N arne 
Date 
CONFIDENTIAL 
Page 148 
Signature 
Site Number 
16 December 2013 


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Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
FACT-Leu (Version 4) 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
GPI 
GP2 
GP3 
GP4 
GP> 
GP6 
GP7 
GS I 
GS2 
GS3 
GS4 
GS5 
GS6 
PHYSICAL WELL-BEING 
I have a lack of energy 
I have nausea ... .................... ............................................ . 
Because of my physical condition, l have trouble 
meeting the needs of my family 
I have pain .......................... . 
I am bothered by side effects of treatment .. 
I feel ill ........ .... . 
I am forced to spend time in bed 
SOCIAL/FAMILY WELL-BEING 
I feel close to my friends 
I get emotional support from my family 
I get support from my friends ......... .. 
My family has accepted my illness .................... . 
I am satisfied with family communication about my 
illness.................. 
. ............... . 
I feel close to my partner (or the person who is my main 
support) . 
Ql 
Regardless ofyour current level of sexual aclivily, please 
answer !he following quesrion. If you prefer no/ to answer it, 
please mark this box 0 and go to !he nexl section. 
GS7 
I am satisfied with my sex life ........................ ................. . 
EngliSh (Univcrs.al) 
Ccv>nght 1987. 1997 
Not 
at all 
0 
0 
0 
0 
0 
0 
0 
A little 
Some-
bit 
what 
2 
2 
2 
2 
2 
2 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
Not 
A little 
Some-
Quite 
at all 
bit 
what 
a bit 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
19 November2007 
Page I of3 


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FACT-Leu (Version 4) 
P lease circle or mark one number per line to indicate you r response as it applies to the past 7 
days. 
EMOTIONAL WELL-BEING 
GEl 
I feel sad ...... 
. . .. . ' ...... ' ..... '. . . ..•......•. . ' ... . ............... 
GE2 
I am satisfied with how I am coping with my illness ..... 
G£3 
I am losing hope in the fight against my illness 
G£4 
I feel nervous 
GB 
I worry about dying ...... 
G£6 
I worry that my condition will get worse .... 
FUNCTIONAL WELL-BEING 
GFI 
I am able to work (include work at home) .............. 
GF2 
My work (include work at home) is fulfilling ......... 
GF3 
I am able to enjoy life ..... 
GF4 
1 have accepted my illness 
.. ............. 
GFS 
I am sleeping well ..... ..•. ......... 
. .............. 
GF6 
I am enjoying the things I usually do for fun 
GF7 
lam content with the quality of my life right now 
Engl1sh (Univt:rsa!) 
Cop}right 1987, 1997 
Not 
A little 
Some-
at all 
bit 
what 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Not 
A little 
Some-
at all 
bit 
what 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
19 NoVt"'llbcr 2007 
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FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
ADDITIONAL CONCERNS 
BRMJ 
I am bothered by fevers (episodes of high body 
temperature) 
. . . . . .. . . .. . . . .. .. 
............... 
P2 
I have certain pa11s of my body where I experience pain 
BRMl 
I am bothered by the chi lls . 
............... 
ES3 
I have night sweats ... 
LEU! 
I am bothered by lumps or swelling in certain parts of 
my body (e.g., neck, armpits, or groin) 
.................. 
THI 
I bleed easily ... 
TH2 
l bruise easily .. 
11112 
I feel weak all over ............ 
................... ...................... 
B~IT6 
1 get tired easily .... 
.......... ............................... 
C2 
I am losing weight 
............... 
co 
r have a good appetite .. 
An7 
I am able to do my usual activities ... 
............... 
N3 
1 worry about getting infections ....... 
LEUS 
I feel uncertain about my future health 
LEU6 
I worry that I might get new symptoms of my illness 
BRM9 
I have emotional ups and downs ..... . . . . . . . . . . . . . . . . . . . 
LF.U7 
I feel isolated from others because of my illness or 
treatment . . . . . . .. .. . . . . . . . .. .. . . . . . . . .. .. ...... ... .... . ...... ..... .. ...... .. . .. ... •.. 
Engl1sh (Univt:rsa!) 
Cop}right 1987, 1997 
Not 
A little 
Some-
at all 
bit 
what 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
19 NoVt"'llbcr 2007 
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Appendix 3.
Performance Status Scoring System
Karnofsky Performance Status
General Description
Score
Specific Description
Able to carry on normal 
activity and to work; no 
special care needed.
100
Normal; no complaints; no evidence of disease.
90
Able to carry on normal activity; minor signs or symptoms of 
disease.
80
Normal activity with effort; some signs or symptoms of disease.
Unable to work; able to live at 
home and care for most 
personal needs; varying 
amount of assistance needed.
70
Cares for self; unable to carry on normal activity or to do active 
work.
60
Requires occasional assistance, but is able to care for most of 
personal needs.
50
Requires considerable assistance and frequent medical care.
Unable to care for self; 
requires equivalent of 
institutional or hospital care; 
disease may be progressing 
rapidly.
40
Disabled; requires special care and assistance.
30
Severely disabled; hospital admission is indicated although death 
not imminent.
20
Very sick; hospital admission necessary; active supportive 
treatment necessary.
10
Moribund; fatal processes progressing rapidly.
0
Dead


Idelalisib 
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Version 4.0 
Appendix 4. 
EuroQoL-5 Dimensions (EQ-5D) 
EuroQoL-5 Dimensions (EQ-5D) 
By placing a c.heckmark m one box m each group beloJ;t·. please indicate whtch 
sratcmem~ be3t de'icribe your own beal!h stare 1oday. 
Mobility 
I have no problems in 'llalking about 
I have sCNne problems rn v.<alkir: 9 about 
I am co 5ired to bed 
Self-Care 
I ha\'~ no prolkms wi:h sctf~re 
I have some prob;ems washing o dressJlg myseH 
I am unable to \\'ash or dress mysel' 
Usual Activities (e.g., work, study, housework, family, or leisure activities) 
I hove no problems with pcrormin9 my u~l octvities 
I have some prob.ems ,,;th performirg my usual aciMties 
I am unable to ~erlorm my ~ruJa' actrv'lties 
Pain/Discomfort 
I have no pain or discomfor1 
I have moderate pa11 or disoorrrort 
I have ex1reme pa.:n or cf.scom!ott 
Anxiety/De pression 
I am not anxious or depressed 
I am moderately anxiO\Is or dep:essed 
I am extremely anxious or depressed 
CONFIDENTIAL 
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D 
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D 
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D 
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D 
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16 December 2013 


Idelalisib 
Protocol GS-US-312-0117 
Gilead Sciences, Inc. 
To help people say how good or bad a health state is. 
we have d!amt a scale (rather like a thennometer) on 
which the best stare you can imagine lS marked 100 
and the worst stare you can imagine is marked 0. 
We would like you to 111dicare on this scale how good 
or bad your own health is today. in your opinion. 
Please do this by drawing a line from the box below 
to wluchever pomt on the scale mdicares how good or 
bad your health state is today. 
CONFIDENTIAL 
Yom· own 
hl>altb statl> 
toda~· 
Page 154 
Best 
unap~able 
health mte 
l OO 
I 
Wor..t 
ima:mab!e 
hshh>bE 
Final 
Version4.0 
16 December 2013 


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Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance 
Formulas for calculating the estimated creatinine clearance (eCcr) are provided in the table 
below. The formula appropriate to the units in which serum creatinine was measured and the 
subject’s gender should be used.
Cockcroft-Gault Formulas for Calculating Estimated Creatinine Clearance
Serum 
Creatinine Units
Gender
Formula
mg/dL
Males
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1
72 subject serum creatinine [mg/dl]
Females
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 0.85
72 subject serum creatinine [mg/dl]
M/dL
Males
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.23
Subject serum creatinine [mg/dl]
Females
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.04
Subject serum creatinine [mg/dl]
Abbreviation: eCcr=estimated creatinine clearance


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Appendix 6.
Cumulative Illness Rating Scale (CIRS)
The CIRS used in this protocol is designed to provide an assessment of recurrent or ongoing 
chronic comorbid conditions, classified by 14 organ systems. Using the drop-down lists of 
organ-specific diagnoses, please select any conditions present in the study subject. If the subject
has a recurrent or ongoing chronic conditions that are not described in the list for a given organ 
system, please indicate the name of the conditions under “other chronic condition” for that organ 
system. Please take into account that CLL-induced discomfort, symptoms, or disability should 
not be considered. If additional explanation would be helpful, text comments may be inserted. 
CIRS List of Comorbid Conditions
Organ System
Diagnosis
Comment
Cardiac
Chronic heart failure
Angina pectoris
Medically relevant arrhythmia
Valve dysfunction
Congenital heart disease
Cardiomyopathy
Myocarditis
Chronic pericarditis
Endocarditis
Other chronic cardiac condition:
Other chronic cardiac condition:
Vascular
Hypertension
Thrombosis
Peripheral diabetic microvascular disease
Peripheral artery disease
Aortic aneurysm
Aortitis
Raynaud disease
Vasculitis
Other chronic vascular condition:
Other chronic vascular condition


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Organ System
Diagnosis
Comment
Hematological/
immunological
Sickle cell anemia
Hemoglobinopathy
Polycythemia
Thrombocythemia
Hemophilia
Paroxysmal nocturnal hemoglobinuria
Thrombotic thrombocytopenic purpura
Dysfibrinogenemia
HIV
Other chronic hematological or immunological 
condition:
Other chronic hematological or immunological 
condition
Abbreviation:  CIRS=Cumulative Illness Rating Scale
For each condition selected from the CIRS List of Comorbid Conditions, please rate the severity 
of that condition. For the severity rating, please use the scoring guidelines shown in the table 
below, considering the magnitude of symptoms, how manageable the condition is, and the extent 
of intervention required:
CIRS Rating Scale
Score
Severity
Findings
1
Mild
Mild discomfort, symptoms or disability
Easy to control
Requiring either no therapy/medication or only as needed
2
Moderate
Moderate  discomfort, symptoms or disability
Manageable
Requiring daily treatment or first-line therapy
3
Severe
Severe discomfort, symptoms or disability
Hard to control
Requiring second-line therapy or multiple medications
4
Extremely
severe
Life threatening, permanently disabling disability, causing organ failure
Poorly manageable
Requiring urgent intervention or resistant to therapy
Abbreviation:  CIRS=Cumulative Illness Rating Scale


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Appendix 7.
Schedule of Study Procedures
Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4
5a
6
7a
8
9
10
11
12
13
14
15
16+
End of 
Study
30 
days
Long-
term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12 
Weeks
Study Day
Within 
-28 
Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within 
+30 
days
To  
+5 
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Informed consent
X
CIRS assessment
X
β-HCG (women of childbearing 
potential)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CLL peripheral blood evaluation
X
X
CLL serology
X
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HRQL/healthy utility – FACT-
Leu/EQ-5D
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exam (includes nodes, liver, 
spleen)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Oxygen saturation (by pulse oximetry)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Circulating cells
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biomarkers
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PPD


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Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4
5a
6
7a
8
9
10
11
12
13
14
15
16+
End of 
Study
30 
days
Long-
term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12 
Weeks
Study Day
Within 
-28 
Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within 
+30 
days
To  
+5 
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Serum Igs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug administration in clinic
Xb
X
X
X
X
X
X
X
Idelalisib pharmacokineticsb
X
X
X
X
X
X
X
X
Study drug dispensing/accountingb
X
X
X
X
X
X
X
X
X
X
X
Radiology assessment (CT/MRI)
X
X
X
X
X
X
X
X
Bone marrow biopsy/aspiratec
X
X
X
X
X
X
X
X
Post-treatment CLL therapy
X
Long-term follow-up 
X
a
Following unblinding of the study, visits 3, 5, and 7 will not be applicable for subjects who were randomized to idelalisib on Study GS-US-312-0116
b
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll following unblinding, may have idelalisib treatment (and associated PK testing) delayed at 
the Investigator’s discretion until the time of disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib treatment
c
At screening, to be performed at investigator discretion to determine extent of CLL involvement and bone marrow cellularity. Post-screening, to be performed to confirm CR 
or PD; if the subject does not otherwise meet criteria for CR or if the nature of PD does not require bone marrow confirmations, it is not necessary to obtain a follow-up bone 
marrow biopsy/aspirate
Abbreviations: -HCG=beta human chorionic gonadotropin, CIRS=chronic illness rating scale, CLL=chronic lymphocytic leukemia, CR=complete response, CT=computed
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy- Leukemia, HRQL= health-related quality of life, Ig=immunoglobulin, 
IWRS=interactive web response system, MRI= magnetic resonance imaging.

Prot_005.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy 
and Safety of Two Different Dose Levels of Single-Agent Idelalisib
(GS-1101) for Previously Treated Chronic Lymphocytic Leukemia
A Companion Trial to Study GS-US-312-0116: A Phase 3, 
Randomized, Double-Blind, Placebo-Controlled Study Evaluating the 
Efficacy and Safety of Idelalisib (GS-1101) in Combination with 
Rituximab for Previously Treated Chronic Lymphocytic Leukemia
Sponsor:
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102
USA
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
EudraCT Number:
101254
2011-006293-72
Indication:
Chronic Lymphocytic Leukemia 
Protocol ID:
GS-US-312-0117
Gilead Sciences
Medical Monitor:
Name:
Office Telephone:
Office Fax:
Mobile Telephone:
E-mail:
Protocol Version/Date:
Version 1.0 (Original)
23 January 2012
Version 2.0 (Amendment 1)
23 January 2013
Version 3.0 (Amendment 2)
10 September 2013
Version 4.0 (Amendment 3)
16 December 2013
Version 5.0 (Amendment 4)
27 May 2014
Version 6.0 (Amendment 5)
10 October 2014
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
institutional review board or independent ethics committee. This information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in the 
protocol. You must not disclose any of the information to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................6
LIST OF IN-TEXT FIGURES ......................................................................................................................................6
PROTOCOL SYNOPSIS ..............................................................................................................................................7
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................19
1.
INTRODUCTION ..............................................................................................................................................23
1.1.
Chronic Lymphocytic Leukemia............................................................................................................23
1.2.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies....................................................................24
1.3.
Idelalisib (formerly GS-1101)................................................................................................................24
1.3.1.
General Information .............................................................................................................24
1.3.2.
Safety Pharmacology............................................................................................................25
1.3.3.
Nonclinical Pharmacology and Metabolism.........................................................................25
1.3.4.
Toxicology ...........................................................................................................................27
1.3.5.
Idelalisib Clinical Studies.....................................................................................................27
1.4.
Summary and Justification for the Current Study ..................................................................................31
2.
STUDY DESIGN................................................................................................................................................33
2.1.
Design Overview and Study Schema .....................................................................................................33
2.2.
Design Rationale ....................................................................................................................................34
3.
OBJECTIVES AND ENDPOINTS ....................................................................................................................36
3.1.
Endpoints ...............................................................................................................................................36
3.1.1.
Tumor Control......................................................................................................................36
3.1.2.
Patient Well-Being ...............................................................................................................37
3.1.3.
Pharmacodynamic Markers of Drug Activity and Resistance..............................................38
3.1.4.
Exposure...............................................................................................................................38
3.1.5.
Safety....................................................................................................................................38
3.1.6.
Pharmacoeconomics.............................................................................................................38
3.2.
Endpoint Selection Rationale.................................................................................................................38
3.2.1.
Tumor Control Endpoints.....................................................................................................38
3.2.2.
Measures of Patient Well-Being...........................................................................................41
3.2.3.
Pharmacodynamic Markers of Drug Activity and Resistance..............................................42
3.2.4.
Assessments of Exposure .....................................................................................................43
3.2.5.
Evaluations of Safety............................................................................................................44
3.2.6.
Pharmacoeconomic Measures ..............................................................................................45
4.
SUBJECT POPULATION..................................................................................................................................46
4.1.
Number of Subjects................................................................................................................................46
4.2.
Subject Selection Criteria.......................................................................................................................46
4.2.1.
Inclusion Criteria..................................................................................................................46
4.2.2.
Exclusion Criteria.................................................................................................................48
4.3.
Enrollment Criteria Rationale ................................................................................................................49
5.
TREATMENT OF SUBJECTS ..........................................................................................................................50
5.1.
Enrollment..............................................................................................................................................50
5.1.1.
Interactive Web Response System .......................................................................................50
5.1.2.
Treatment Assignment .........................................................................................................50
5.1.3.
Blinding................................................................................................................................51
5.2.
Investigational Study Drug (Idelalisib/Placebo) ....................................................................................52


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5.2.1.
Description ...........................................................................................................................52
5.2.2.
Source...................................................................................................................................52
5.2.3.
Packaging and Labeling .......................................................................................................52
5.2.4.
Storage and Handling...........................................................................................................53
5.2.5.
Dispensing............................................................................................................................53
5.2.6.
Return...................................................................................................................................54
5.2.7.
Accountability......................................................................................................................54
5.2.8.
Overdose Precautions...........................................................................................................54
5.2.9.
Inadvertent Exposure and Spill Precautions.........................................................................55
5.3.
Study Drug Administration ....................................................................................................................55
5.3.1.
Premedication.......................................................................................................................55
5.3.2.
Administration Instructions..................................................................................................55
5.3.3.
Dosing Schedule...................................................................................................................55
5.3.4.
Dose Levels..........................................................................................................................55
5.3.5.
Dose Schedule Interruptions and Vomited Doses ................................................................56
5.3.6.
Safety Monitoring and Study Drug Interruption/Dose Modification ...................................56
5.4.
Recommendations for Evaluation, Intervention, and Drug Discontinuation for Specific 
Adverse Events or Conditions................................................................................................................59
5.4.1.
Dermatological Events .........................................................................................................59
5.4.2.
Gastrointestinal Events.........................................................................................................60
5.4.3.
Hepatic Events......................................................................................................................60
5.4.4.
Hematological and Immunological Events...........................................................................61
5.4.5.
Infectious Events..................................................................................................................62
5.4.6.
Progressive Multifocal Leukoencephalopathy .....................................................................62
5.4.7.
Pulmonary Events ................................................................................................................63
5.4.8.
Tumor Lysis Syndrome........................................................................................................64
5.4.9.
Pregnancy, Lactation, and Reproduction..............................................................................64
5.4.10.
Ultraviolet Exposure ............................................................................................................64
5.5.
Emergency Unblinding ..........................................................................................................................64
5.6.
Concomitant and Supportive Therapy....................................................................................................65
5.6.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments............................................................................................................................65
5.6.2.
Antibiotics............................................................................................................................66
5.6.3.
Antiemetics and Antidiarrheals............................................................................................66
5.6.4.
Contraception .......................................................................................................................66
5.6.5.
Corticosteroids .....................................................................................................................67
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin..............................................67
5.6.7.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism..................................................68
5.6.8.
Drugs that undergo CYP3A-Dependent Metabolism...........................................................68
5.6.9.
Immunization .......................................................................................................................69
5.6.10.
Surgery .................................................................................................................................69
5.6.11.
Diet.......................................................................................................................................69
5.7.
Duration of Study Drug..........................................................................................................................69
5.8.
Discontinuation of Study Drug ..............................................................................................................69
5.9.
Discontinuation from Study ...................................................................................................................70
5.10.
Study Treatment Rationale.....................................................................................................................70
6.
STUDY PROCEDURES ....................................................................................................................................73
6.1.
Enrollment and Study Management Procedures ....................................................................................73
6.1.1.
Subject Recruitment .............................................................................................................73
6.1.2.
Subject Compensation for Participation...............................................................................73
6.1.3.
Screening..............................................................................................................................73
6.2.
Explanation of Study Visits....................................................................................................................74
6.2.1.
Visit 1 and Screening Period (Clinic Visit)..........................................................................75


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6.2.2.
Visit 2 (Day 1) (Clinic Visit)................................................................................................77
6.2.3.
Visit 3 (Day 15) (Clinic Visit)..............................................................................................78
6.2.4.
Visit 4 (Day 29) (Clinic Visit)..............................................................................................79
6.2.5.
Visit 5 (Day 43) (Clinic Visit)..............................................................................................81
6.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit) .....................................................................82
6.2.7.
Visit 7 (Day 71) (Laboratory Visit)......................................................................................83
6.2.8.
Visit 8 (Day 85) (Clinic Visit)..............................................................................................84
6.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit) ...................................................................86
6.2.10.
Visit 10 (Day 141) (Clinic Visit)..........................................................................................88
6.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit) .................................................................90
6.2.12.
Visit 12 (Day 211) (Clinic Visit)..........................................................................................92
6.2.13.
Visit 13 (Day 253) (Clinic and Radiology Visit) .................................................................93
6.2.14.
Visit 14 (Day 295) (Clinic Visit)..........................................................................................94
6.2.15.
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks) (Clinic 
and Radiology Visits)...........................................................................................................95
6.2.16.
End-of-Study Visit (Clinic Visit) .........................................................................................97
6.2.17.
30 Day and Long-Term Follow-up.......................................................................................98
6.3.
Sample Storage.......................................................................................................................................98
6.4.
Blood Collection ....................................................................................................................................98
6.5.
Study Procedure Rationale.....................................................................................................................99
7.
EFFICACY ASSESSMENTS...........................................................................................................................100
7.1.
Tumor Status Assessments...................................................................................................................100
7.2.
Method of Assessment .........................................................................................................................100
7.3.
Timing of Assessments ........................................................................................................................100
7.4.
Identification and Measurement of Tumor Lesions and Organomegaly ..............................................101
7.4.1.
Index Lesions .....................................................................................................................101
7.4.2.
Spleen and Liver.................................................................................................................102
7.4.3.
Non-Index Lesions .............................................................................................................102
7.5.
Definitions of Tumor Response and Progression.................................................................................102
7.5.1.
Complete Response............................................................................................................103
7.5.2.
Partial Response .................................................................................................................103
7.5.3.
Stable Disease ....................................................................................................................104
7.5.4.
Definitive Progressive Disease...........................................................................................104
7.5.5.
Non-Evaluable....................................................................................................................106
7.5.6.
No Disease .........................................................................................................................106
7.5.7.
Lymphocytosis During Therapy.........................................................................................106
7.5.8.
Documentation of Definitive CLL Progression..................................................................107
8.
SAFETY ASSESSMENTS...............................................................................................................................108
8.1.
Adverse Event Definitions ...................................................................................................................108
8.1.1.
Adverse Event ....................................................................................................................108
8.1.2.
Serious Adverse Event .......................................................................................................109
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .......................................................................110
8.2.
Assessment of Adverse Events and Serious Adverse Events...............................................................110
8.2.1.
Assessment of Causality for Study Drugs and Procedures.................................................111
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.....................................................................................................................111
8.4.
Gilead Reporting Requirements...........................................................................................................112
8.5.
Grading of the Severity of an Adverse Event.......................................................................................112
8.6.
Adverse Event Reporting Period..........................................................................................................113
8.7.
Adverse Event Reporting Requirements ..............................................................................................113
8.7.1.
Site Reporting Requirements..............................................................................................113


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8.7.2.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population.........................................................115
8.8.
Special Situations Reporting Requirements.........................................................................................115
8.8.1.
Definitions of Special Situations........................................................................................115
8.9.
Instructions for Reporting Special Situations.......................................................................................116
8.9.1.
Instructions for Reporting Pregnancies ..............................................................................116
8.9.2.
Reporting Other Special Situations ....................................................................................117
9.
STATISTICAL CONSIDERATIONS..............................................................................................................118
9.1.
Analysis Objectives..............................................................................................................................118
9.2.
Analysis Endpoints...............................................................................................................................118
9.3.
Analysis Conventions...........................................................................................................................118
9.3.1.
Analysis Sets ......................................................................................................................118
9.3.2.
Data Handling Conventions ...............................................................................................119
9.4.
Analysis Plan........................................................................................................................................121
9.4.1.
Subject Disposition and Baseline Characteristics...............................................................121
9.4.2.
Efficacy Analyses...............................................................................................................122
9.4.3.
Exposure and Safety Analyses ...........................................................................................123
9.4.4.
Other Analyses ...................................................................................................................125
9.5.
Sample Size..........................................................................................................................................126
9.6.
Timing of Analyses..............................................................................................................................127
10.
RESPONSIBILITIES........................................................................................................................................128
10.1.
Investigator Responsibilities ................................................................................................................128
10.1.1.
Compliance with Ethical and Regulatory Guidelines.........................................................128
10.1.2.
Institutional Review Board/Independent Ethics Committee ..............................................128
10.1.3.
Informed Consent...............................................................................................................129
10.1.4.
Confidentiality....................................................................................................................129
10.1.5.
Study Files and Retention of Records and Biological Samples..........................................129
10.1.6.
Case Report Forms.............................................................................................................131
10.1.7.
Drug Accountability...........................................................................................................131
10.1.8.
Inspections..........................................................................................................................132
10.1.9.
Protocol Compliance..........................................................................................................132
10.2.
Sponsor Responsibilities ......................................................................................................................132
10.2.1.
Protocol Modifications.......................................................................................................132
10.2.2.
Communications with Regulatory Authorities...................................................................132
10.2.3.
Data Management ..............................................................................................................133
10.2.4.
Study Reporting and Publication........................................................................................133
10.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................134
10.3.1.
Access to Information for Monitoring................................................................................134
10.3.2.
Access to Information for Auditing or Inspections ............................................................134
10.3.3.
Public Notification of Study Conduct ................................................................................134
10.3.4.
Study Discontinuation........................................................................................................134
10.4.
Study Committees ................................................................................................................................135
10.4.1.
Data Monitoring Committee ..............................................................................................135
10.4.2.
Independent Review Committee ........................................................................................136
11.
REFERENCES .................................................................................................................................................137
12.
APPENDICES ..................................................................................................................................................147
Appendix 1.
Investigator Signature Page..................................................................................................148
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) ...................................149
Appendix 3.
Performance Status Scoring System.....................................................................................152


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Appendix 4.
EuroQoL-5 Dimensions (EQ-5D) ........................................................................................153
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance ............................................155
Appendix 6.
Cumulative Illness Rating Scale (CIRS) ..............................................................................156
Appendix 7.
Schedule of Study Procedures..............................................................................................158
LIST OF IN-TEXT TABLES
Table 4-1.
Required Screening Laboratory Values..................................................................................47
Table 5-1.
Study Drug Dose Levels.........................................................................................................55
Table 5-2.
Recommendations for Study Drug Dose Modifications Based on Type and Severity 
of Treatment-Related Adverse Events or Laboratory Abnormalities .....................................58
Table 5-3.
Protocol-Recommended Contraceptive Methods ...................................................................67
Table 5-4.
Known Strong Inducers of CYP3A........................................................................................68
Table 6-1.
Procedures and Assessments at Visit 1 (During Screening Period)........................................76
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1) .....................................................................77
Table 6-3.
Procedures and Assessments at Visit 3 (Day 15) ...................................................................78
Table 6-4.
Procedures and Assessments at Visit 4 (Day 29) ...................................................................79
Table 6-5.
Procedures and Assessments at Visit 5 (Day 43) ...................................................................81
Table 6-6.
Procedures and Assessments at Visit 6 (Day 57) ...................................................................82
Table 6-7.
Procedures and Assessments at Visit 7 (Day 71) ...................................................................83
Table 6-8.
Procedures and Assessments at Visit 8 (Day 85) ...................................................................84
Table 6-9.
Procedures and Assessments at Visit 9 (Day 113) .................................................................86
Table 6-10.
Procedures and Assessments at Visit 10 (Day 141) ...............................................................88
Table 6-11.
Procedures and Assessments at Visit 11 (Day 169) ...............................................................90
Table 6-12.
Procedures and Assessments at Visit 12 (Day 211) ...............................................................92
Table 6-13.
Procedures and Assessments at Visit 13 (Day 253) ...............................................................93
Table 6-14.
Procedures and Assessments at Visit 14 (Day 295) ...............................................................94
Table 6-15.
Procedures and Assessments at Visit 15 and Subsequent Visits (Day 337 and Every 
12 Weeks)...............................................................................................................................95
Table 6-16.
Procedures and Assessments at End-of-Study Visit...............................................................97
Table 8-1.
Grading of Adverse Event Severity......................................................................................113
Table 8-2.
Site Reporting Requirements for Adverse Events ................................................................114
Table 8-3.
Contact Information for Reporting Serious Adverse Events ................................................115
LIST OF IN-TEXT FIGURES
Figure 2-1.
Study Design ..........................................................................................................................33


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102, USA
Study Title:
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and 
Safety of Two Different Dose Levels of Single-Agent Idelalisib
(GS-1101) as Therapy for Patients with Previously Treated Chronic 
Lymphocytic Leukemia
A Companion Study to Study GS-US-312-0116: A Phase 3, Randomized, 
Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of Idelalisib (GS-1101) in Combination with Rituximab as 
Therapy for Patients with Previously Treated Chronic Lymphocytic 
Leukemia
Study Centers 
Planned:
Approximately 90 centers in the United States and in Europe
IND Number:
EudraCT Number:
101254
2011-006293-72
Objectives:

To evaluate the effect of idelalisib (formerly GS-1101) on the onset, 
magnitude, and duration of tumor control

To compare tumor control in subjects receiving rituximab alone in 
Study GS-US-312-0116 to that observed in the same subjects when 
receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject well-being, 
including overall survival (OS), health-related quality of life 
(HRQL), and performance status

To assess the effects of idelalisib on disease-associated biomarkers 
and to evaluate potential mechanisms of resistance to idelalisib

To characterize exposure to idelalisib as determined by treatment 
administration and evaluation of idelalisib plasma concentrations 
over time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with 
administration of idelalisib


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Study Design:
This study is being conducted as part of an overall clinical program 
evaluating the efficacy and safety of idelalisib in the therapy of patients 
with previously treated chronic lymphocytic leukemia (CLL).
Within this program, the primary clinical trial (Study GS-US-312-0116)
is a Phase 3, multicenter, 2-arm, randomized, double-blind, 
placebo-controlled, parallel-group study.
This clinical trial (Study GS-US-312-0117) is a separate, multicenter, 
2-arm, double-blind, parallel-group extension study that is a companion 
trial to Study GS-US-312-0116; in this trial, compliant subjects from 
GS-US-312-0116 who are tolerating primary study therapy but 
experience definitive CLL progression are eligible to receive active 
blinded idelalisib therapy at the standard dose or a higher dose, with 
allocation based on the original primary study randomization. In the 
event GS-US-312-0116 is stopped early due to overwhelming efficacy 
following an interim analysis or at the final analysis, subjects who are on 
Study GS-US-312-0116 at that time may transition to GS-US-312-0117. 
Additionally, GS-US-312-0117 will become an open-label study
offering idelalisib 150 mg BID to GS-US-312-0116 subjects who were
randomized to placebo, and subjects randomized to idelalisib will 
continue idelalisib at 150 mg BID.
Study Schema:
Treatment Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117)


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Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID
Treatment Assignment

Assignment to Arm A or Arm B with allocation based on the 
original primary study randomization

Implementation through an interactive web response system (IWRS)
Stratification
Not applicable for Study GS-US-312-0117
Number of 
Subjects Planned:
Total of up to ~180 subjects (up to ~90 subjects per treatment arm)
Target 
Population:
Subjects in the primary Phase 3 study (GS-US-312-0116) who are 
compliant, are tolerating primary study therapy, and 1) have definitive 
progression of CLL while receiving primary study drug therapy 
(idelalisib/placebo) or 2) are actively participating in 
Study GS-US-312-0116 at the time the study is stopped, including if 
stopped early due to overwhelming efficacy following an interim 
analysis.
Duration of 
Treatment:
Study drug will be taken continuously until the earliest of subject 
withdrawal from study drug, definitive progression of CLL, intolerable 
study drug-related toxicity, pregnancy, substantial noncompliance with 
study procedures, or study discontinuation.
Diagnosis and 
Main Eligibility 
Criteria:
Inclusion Criteria
Subjects must meet all of the following conditions to be eligible for 
enrollment into the study:
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while 
receiving study drug therapy (idelalisib /placebo) in
Study GS-US-312-0116. Note: Definitive disease progression is 
CLL progression based on standard criteria and occurring for any 
reason (ie, increasing lymphadenopathy, organomegaly, or bone 
marrow involvement; decreasing platelet count, hemoglobin, or 
neutrophil count; or worsening of disease-related symptoms) other 
than lymphocytosis. Subjects must have confirmation by the 
sponsor working in collaboration with an independent review 
committee (IRC) that the disease has progressed on the primary 
clinical trial (Study GS-US-312-0116) before receiving secondary 
idelalisib therapy on this extension trial (Study GS-US-312-0117).


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3) Presence of measurable lymphadenopathy (defined as the presence 
of ≥1 nodal lesion that measures 2.0 cm in the longest diameter
[LD] and 1.0 cm in the longest perpendicular diameter [LPD] as 
assessed by computed tomography [CT] or magnetic resonance 
imaging [MRI]).
4) Permanent cessation of Study GS-US-312-0116 treatment 
(rituximab and/or idelalisib/placebo) and no intervening or 
continuing therapy (including radiotherapy, chemotherapy, 
immunotherapy, or investigational therapy) for the treatment of 
CLL. Note: Subjects may receive corticosteroids to manage CLL 
manifestations.
5) The time from permanent cessation of Study GS-US-312-0116 
treatment (rituximab and/or idelalisib/placebo) and the initiation of 
Study GS-US-312-0117 therapy is 12 weeks. Note: Study 
procedures performed as part of Study GS-US-312-0116 need not 
be repeated and can be used as screening procedures for 
Study GS-US-312-0117 if performed within 4 weeks prior to 
initiation of study drug therapy on Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation 
of study treatment) as shown in the table below. Note: Confirmation 
should be considered for out-of-range values to determine if the 
abnormality is real or artifactual. Values should be obtained within 
the screening period and should generally be the most recent 
measurement obtained. Subjects with any degree of neutropenia, 
thrombocytopenia, or anemia due to CLL or prior therapy may 
enroll.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCr
a
>30 ml/min
Pregnancy
-HCGb
Negative
a
As calculated by the Cockcroft-Gault formula {2202}
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or 
urine dipstick pregnancy test must be negative at randomization (Visit 2)
Abbreviations: -HCG=beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
eCCr=estimated creatinine clearance, ULN=upper limit of normal


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8) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening 
visit (Visit 1) throughout the study and for 30 days from the last dose 
of study drug. Note: A female subject is considered to be of 
childbearing potential unless she has had a hysterectomy, bilateral 
tubal ligation, or bilateral oophorectomy; has medically 
documented ovarian failure (with serum estradiol and 
follicle-stimulating hormone [FSH] levels within the institutional 
postmenopausal range and a negative serum or urine -HCG), or 
is menopausal (defined as age ≥54 years with amenorrhea for 
>12 months or amenorrhea for >6 months with serum estradiol 
and FSH levels within the institutional postmenopausal range).
9) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of 
study drug (Visit 2) throughout the study and for 90 days following 
the last dose of study drug and to refrain from sperm donation from 
the start of study drug (Visit 2) throughout the study and for 90 days 
following the last dose of study drug. Note: A male subject is 
considered able to father a child unless he has had a bilateral 
vasectomy with documented aspermia or a bilateral orchiectomy, 
or has ongoing testicular suppression with a depot luteinizing 
hormone- releasing hormone (LH-RH) agonist 
(eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), 
or triptorelin pamoate [Trelstar®]).
10) In the judgment of the investigator, participation in the protocol 
offers an acceptable benefit-to-risk ratio when considering current 
CLL disease status, medical condition, and the potential benefits and 
risks of alternative treatments for CLL.
11) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, 
familial, or geographical factors that might preclude adequate 
study participation should be considered.
12) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study 
participation.


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Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be 
enrolled in this study:
1) Known histological transformation from CLL to an aggressive 
lymphoma (ie, Richter transformation). 
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at 
the time of the start of study treatment (Visit 2). Note: Subjects with 
localized fungal infections of skin or nails are eligible. Subjects 
may be receiving prophylactic antiviral or antibacterial therapies at 
the discretion of the investigator; anti-pneumocystis prophylaxis is 
encouraged. 
3) Pregnancy or breastfeeding.
4) Intentional breaking of the blind in Study GS-US-312-0116 by the 
investigator or the study subject.
5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical condition, 
surgical history, physical finding, electrocardiogram (ECG) finding, 
or laboratory abnormality that, in the investigator’s opinion, could 
adversely affect the safety of the subject or impair the assessment of 
study results.
In the event Study GS-US-312-0116 is stopped early, subjects who are 
actively participating in Study GS-US-312-0116 will become eligible for 
this study, provided the following inclusion are met:
1) Participation in Study GS-US-312-0116 within 12 weeks of 
enrollment onto GS-US-312-0117.
2) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening 
visit (Visit 1) throughout the study and for 30 days from the last dose 
of study drug. 
3) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of 
study drug (Visit 2) throughout the study and for 90 days following 
the last dose of study drug and to refrain from sperm donation from 
the start of study drug (Visit 2) throughout the study and for 90 days 
following the last dose of study drug.
4) In the judgment of the investigator, participation in the protocol 
offers an acceptable benefit-to-risk ratio when considering current 
CLL disease status, medical condition, and the potential benefits and 
risks of alternative treatments for CLL.


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5) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, 
familial, or geographical factors that might preclude adequate 
study participation should be considered.
6) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study 
participation.
Study Procedures/
Frequency:
Clinic/laboratory visits will occur every 2 weeks for the first 12 weeks, 
every 4 weeks between Weeks 12 and 24, and every 6 weeks between 
Weeks 24 and 48. Subjects continuing on study drug past Week 48 will 
have clinic visits every 12 weeks. Subjects will be assessed for safety at 
each visit. Subjects will be assessed for CLL disease status by physical 
and laboratory examinations at each visit and by CT or MRI at 
Weeks 8, 16, 24, 36, and 48 and every 12 weeks thereafter.
Following unblinding of the study:

Subjects who were randomized to idelalisib on 
Study GS-US-312-0116 and who received ≥24 weeks idelalisib will 
complete Visit 16+ twelve weeks from the date of their last 
radiology assessment (CT/MRI) and study visits will continue every 
12 weeks thereafter. Visits 3 through 15 will not be required.

Subjects who have received < 24 weeks idelalisib will have all 
Study GS-US-312-0117 assessments completed per the 
Schedule of Procedures until they have received idelalisib for 
24 weeks cumulative across both studies. After completion of 
24 weeks of cumulative idelalisib treatment, Visit 16+ will be 
conducted 12 weeks from the date of their last radiology assessment 
(CT/MRI), after which time study visits will occur every 12 weeks.
Test Therapy, Dose, 
and Mode of 
Administration:
Blinded Portion

Arm A: Idelalisib, 300 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be provided 
as 2 tablets of active idelalisib for oral administration

Arm B: Idelalisib, 150 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be provided 
as 1 tablet of active idelalisib and 1 tablet of placebo for oral 
administration


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Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID
Note: At the Investigator’s discretion, subjects who were randomized 
to placebo on study GS-US-312-0116 may delay initiation of idelalisib 
following enrollment on Study GS-US-312-0117 until the time of 
disease progression or until the investigator determines that the 
subject would benefit from initiation of idelalisib treatment
Reference Therapy, 
Dose, and Mode of 
Administration:
Not applicable
Criteria for 
Evaluation:
Tumor Control

Progression-free survival (PFS) – defined as the interval from the 
start of study therapy to the earlier of the first documentation of 
definitive disease progression or death from any cause; definitive 
disease progression is CLL progression based on standard criteria 
other than lymphocytosis alone

Overall response rate (ORR) – defined as the proportion of subjects 
who achieve a complete response (CR) or partial response (PR)

Lymph node response rate – defined as the proportion of subjects 
who achieve a 50% decrease from baseline in the sum of the 
products of the greatest perpendicular diameters (SPD) of index 
lesions

CR rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from start of study 
therapy to the first documentation of CR or PR

Duration of response (DOR) – defined as the interval from the 
first documentation of CR or PR to the earlier of the first 
documentation of definitive disease progression or death from any 
cause

Percent change in lymph node area – defined as the percent change 
from baseline in the SPD of index lymph nodes

Splenomegaly response rate – defined as the proportion of subjects 
with baseline splenomegaly who achieve an on-study normalization 
or a 50% decrease (minimum 2 cm) from baseline in the 
enlargement of the splenic LVD (by imaging)


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
Hepatomegaly response rate – defined as the proportion of subjects 
with baseline hepatomegaly who achieve an on-study normalization
or a 50% decrease (minimum 2 cm) from baseline the hepatic 
longest vertical dimension (LVD) (by imaging)

ALC response rate – defined as the proportion of subjects with 
baseline lymphocytosis (ALC4 x 109/L) who achieve an on-study 
ALC <4 x 109/L or demonstrate a 50% decrease in ALC from 
baseline (ALC values within 4 weeks post-baseline will be excluded 
from the ALC response rate evaluation)

Platelet response rate – defined as the proportion of subjects with 
baseline thrombocytopenia (platelet count <100 x 109/L) who 
achieve an on-study platelet count 100 x 109/L or demonstrate a 
50% increase in platelet count from baseline without need for 
exogenous growth factors (Platelet values within 4 weeks 
post-baseline or within 8 days post transfusion will be excluded from 
the platelet response rate evaluation)

Hemoglobin response rate – defined as the proportion of subjects 
with baseline anemia (hemoglobin <110 g/L [11.0 g/dL]) who 
achieve an on-study hemoglobin 110 g/L (11.0 g/dL) or 
demonstrate a 50% increase in hemoglobin from baseline without 
red blood cell transfusions or need for exogenous growth factors 
(eg erythropoietin)

Neutrophil response rate – defined as the proportion of subjects with 
baseline neutropenia (absolute neutrophil count [ANC] ≤1.5 x 109/L) 
who achieve an ANC >1.5 x 109/L or demonstrate a 50% increase 
in ANC from baseline without need for exogenous growth factors 
(eg, G-CSF)
Patient Well-Being

Overall survival (OS) – defined as the interval from start of study 
therapy to death from any cause

Change from baseline in HRQL domain and symptom scores based 
on the Functional Assessment of Cancer Therapy: 
Leukemia (FACT-Leu) (See Appendix 2)

Changes from baseline in Karnofsky performance status
(See Appendix 3)
Pharmacodynamic Markers of Drug Activity and Resistance

Changes from baseline in PI3K/AKT/mTOR pathway activation as a 
measure of PI3Kpathway activity

Changes from baseline in the plasma concentrations of 
disease-associated chemokines and cytokines


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Exposure

Study drug administration as assessed by prescribing records and 
compliance as assessed by quantification of used and unused drug

Trough (pre-dose) and peak (~1.5-hour samples) of idelalisib plasma 
concentrations as assessed by a validated bioanalytical method
Safety

Overall safety profile of each regimen characterized by the type, 
frequency, severity, timing of onset, duration, and relationship to 
study therapy of any adverse events or abnormalities of laboratory 
tests; serious adverse events; or adverse events leading to 
discontinuation of study drug
Pharmacoeconomics

Change in health status – defined as the change from baseline in 
overall health and single-item dimension scores as assessed using the 
EuroQoL Five-Dimension (EQ-5D) utility measure

Health resource measures, including resource utilization, total costs, 
and measures of cost per unit of benefit (eg, cost per additional 
progression-free month, cost per quality-adjusted life-year)
Statistical Methods:
Appropriate data analysis sets will be defined. The intent-to-treat (ITT) 
analysis set will include data from all subjects who receive 1 dose of 
any study therapy on this study; in this data set, study drug assignment 
(high-dose or standard-dose idelalisib) will be designated according to 
the planned allocation to this study. A safety analysis set will comprise 
data from subjects in the ITT analysis set with treatment assignments 
designated according to the actual study drug (high-dose or 
standard-dose idelalisib) received. Other analysis sets [per-protocol (PP) 
and pharmacodynamic/pharmacokinetic analysis sets] will be used for 
certain analyses as well.
Subject characteristics and study results will be described and 
summarized by treatment arm and assessment for the relevant analysis 
sets. Descriptive summaries will be prepared to show sample size, mean, 
standard deviation, 95% confidence intervals (CIs) on the mean, median, 
minimum, and maximum for continuous variables and counts, 
percentages, and 95% CIs on the percentage for categorical variables.
An independent review committee (IRC) will review radiographic data 
and pertinent clinical data in order to provide expert evaluation of tumor 
status. The findings of the IRC will be considered primary for analyses 
of PFS and other tumor control endpoints.


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For endpoints relating to tumor control, patient well-being, and 
biomarkers, analyses will be done based on ITT, PP or 
pharmacodynamic data sets, as appropriate. Blinded portion of the study 
analyses will be presented in the following two groups:

IDELA 300 mg BID: Subjects who have PD per IRC confirmation in 
Arm A of Study GS-US-312-0116 and subsequently enroll into 
Study GS-US-312-0117 to receive IDELA 300 mg BID during the 
double-blind portion of the study

Placebo in GS-US-312-0116 + IDELA 150 mg BID in 
GS-US-312-0117: Subjects who have PD per IRC confirmation in 
Arm B of Study GS-US-312-0116 and subsequently enroll in 
Study GS-US-312-0117 to receive IDELA 150 mg BID during the 
double-blind portion of the study.
After unblinding, open-label extension study analyses will be presented 
in the following 4 groups:

IDELA 150 mg BID: Subjects who are randomized to Arm A in 
Study GS-US-312-0116 and transition to Study GS-US-312-0117 
during the open-label portion of the study to continue IDELA 
150 mg BID

Placebo in GS-US-312-0116 + IDELA 150 mg BID (open-label): 
Subjects who are randomized to Arm B in Study GS-US-312-0116 
and transition to receive IDELA 150 mg BID during the open-label 
portion of the study

IDELA 300 mg BID: Subjects who have PD per IRC confirmation in 
Arm A of Study GS-US-312-0116 and subsequently enroll 
Study GS-US-312-0117 to receive IDELA 300 mg BID during the 
double-blind portion of the study

Placebo in GS-US-312-0116 + IDELA 150 mg BID in 
GS-US-312-0117: Subjects who have PD per IRC confirmation in 
Arm B of Study GS-US-312-0116 and subsequently enroll 
Study GS-US-312-0117 to receive IDELA 150 mg BID during the 
double-blind portion of the study. Analyses will focus on evaluation 
of outcomes within each treatment arm and will be descriptive in 
nature; formal comparisons of outcomes between arms are not 
planned. Time-to-event endpoints will be summarized using 
Kaplan-Meier methods; medians, ranges, and the corresponding 
95% CI will be presented. Continuous and categorical variables will 
also be summarized as appropriate. Changes from baseline in 
categorical variables and changes from baseline in continuous 
endpoints will be analyzed using appropriate methods.


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Efficacy outcomes among subjects receiving rituximab alone in 
Study GS-US-312-0116 will be evaluated relative to those same 
outcomes among the same subjects receiving standard-dose idelalisib 
alone in Study GS-US-312-0117. 
Based on the safety analysis set, information regarding study drug
administration, study drug compliance, safety variables, and post-study 
therapies will be described and summarized. Using data from the 
pharmacokinetic analysis set, idelalisib plasma concentrations will also 
be described and summarized.
Sample Size Calculation
The sample size for this extension study is not based upon a formal 
statistical hypothesis. The upper bound of the sample size in this study is 
determined by the sample size of the preceding primary clinical trial
(Study GS-US-312-0116) in which ~180 subjects (~90 per arm) are 
expected to be enrolled. Assuming a ~10% dropout rate during 
Study GS-US-312-0116 and a further ~10% dropout rate in the 
transition from the primary study to the extension study, ~180 subjects 
are expected to be enrolled into Study GS-US-312-0117.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP), 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
-HCG
Beta human chorionic gonadotropin
ABCG2
adenosine triphosphate-binding cassette sub-family G member 2 (see also BCRP)
AKT
AKT (a serine/threonine protein kinase)
ALC
absolute lymphocyte count
ALL
acute lymphocytic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
ATC
Anatomical-Therapeutic-Chemical classification system for drugs 
BCRP
breast cancer resistance protein (see also ABCG2)
BID
twice per day
BTK
Bruton tyrosine kinase
CAL-101
Former name for GS-1101
CCL
chemokine (C-C motif) ligand
CFR
Code of Federal Regulations
CI
confidence interval
CIRS
Cumulative Illness Rating Scale
CLL
chronic lymphocytic leukemia
cGMP
current Good Manufacturing Practice
Cmax
maximum concentration
CMV
cytomegalovirus
CR
complete response
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough concentration
CXCL
chemokine (C-X-C motif) ligand
CYP
cytochrome P450 enzyme
DLCO
diffusing capacity of the lung for carbon monoxide
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DOR
duration of response
DSPH
Gilead Sciences Department of Safety and Public Health
ECG
electrocardiogram


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
eCCr
estimated creatinine clearance
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EQ-5D
EuroQoL Five-Dimension utility measure
FACT-Leu
Functional Assessment of Cancer Therapy: Leukemia questionnaire
FCεRI
high-affinity IgE receptor
FDA
United States Food and Drug Administration
FDAMA
Food and Drug Modernization Act
FDG
fluorodeoxyglucose (18F)
FISH
fluorescence in-situ hybridization,
FSH
follicle-stimulating hormone
G-CSF
granulocyte colony-stimulating factor
GGT
gamma-glutamyltransferase
GLP
Good Laboratory Practice
GM-CSF
granulocyte-macrophage colony-stimulating factor
HBc antibody
anti-hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
hERG
human ether-à-go-go-related gene
HL
Hodgkin lymphoma
HIV
human immunodeficiency virus
HRQL
health-related quality of life
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
idelalisib
formerly CAL-101 and GS-1101
IEC
independent ethics committee
Ig
immunoglobulin (including subtypes A, E, G, and M)
IgHV
immunoglobulin heavy chain variable region
IND
Investigational New Drug (application)
iNHL
indolent non-Hodgkin lymphoma
INR
international normalized ratio
IRB
institutional review board
IRC
independent review committee
ITT
intention to treat
IUD
intrauterine device
IWCLL
International Workshop on CLL


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
IWRS
interactive web response system
JAK
Janus kinase
K2-EDTA
potassium-ethylenediaminetetraacetic acid
LD
longest diameter
LDH
lactate dehydrogenase
LH-RH
luteinizing hormone-releasing hormone
LLN
lower limit of normal
LPD
longest perpendicular diameter
LVD
longest vertical dimension
MTD
maximum tolerated dose
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mTOR
mammalian target of rapamycin
ND
no disease
NHL
non-Hodgkin lymphoma
NOAEL
no-observed-adverse effect level
NOEL
no-observed-effect level
OCT
organic cation transporter
ORR
overall response rate
OS
overall survival
pAKT
phosphorylated AKT
PCR
polymerase chain reaction
PD
progressive disease
PET
positron-emission tomography
PI3K
phosphatidylinositol 3-kinase
PI3K
phosphatidylinositol 3-kinase p110isoform
PFS
progression-free survival
PML
progressive multifocal leukoencephalopathy
PP
per-protocol
PPD
product of the perpendicular diameters
PRO
patient-reported outcome
PR
partial response
PT
prothrombin time
PVA
polyvinyl alcohol
PVC/PCTFE
polyvinyl chloride/polychlorotrifluoroethylene
QD
once per day
QT (interval)
measure of time between start of Q wave and end of T wave in electrical cycle of heart


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
RNA
ribonucleic acid
SADR
serious adverse drug reaction
SD
stable disease
SPD
sum of the products of the perpendicular diameters of measured lymph nodes
SSC
study steering committee
SUSAR
suspected, unexpected, serious adverse reaction
SYK
spleen tyrosine kinase
t1/2
half-life
Tmax
time of maximum concentration
TTR
time to response
UGT
uridine 5'-diphospho-glucuronosyltransferase
ULN
upper limit of normal
WHODRUG
World Health Organization Drug Dictionary
ZAP-70
zeta-associated protein 70


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1.
INTRODUCTION
1.1.
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is a neoplasia resulting from the progressive accumulation 
of functionally incompetent monoclonal B lymphocytes in blood, bone marrow, lymph nodes, 
spleen, and liver {19448}. CLL constitutes the most commonly occurring leukemia in Europe and 
the United States {20169}, {17688}. While some patients never require treatment, many will need 
therapy for disfiguring or obstructing lymphadenopathy, debilitating constitutional B symptoms 
(fevers, night sweats, fatigue, weight loss) {20168}, or recurrent cytopenias and infections
{17828}, {19449}. CLL is largely a disease of the elderly; at diagnosis, 70% of patients are 
65 years of age and the median age is 72 years {17688}.
In younger and relatively healthy patients with CLL, chemoimmunotherapy regimens that 
include the anti-CD20 monoclonal antibody, rituximab, are commonly employed to control 
disease manifestations {17676}. Such combination therapies are effective in providing durable 
remissions {20163}, {20165}, {17687}, {20360}, {20359}. However, while rituximab is usually
well tolerated {19036}, the chemotherapeutic agents (typically fludarabine, cyclophosphamide, 
or bendamustine) in such regimens are acutely cytotoxic, induce permanent bone marrow 
compromise, and can cause secondary malignancies {26356}, {18997}, {17717}. Furthermore, in 
elderly patients or in those with comorbid conditions, such regimens are associated with less 
efficacy and greater toxicity {18997}, {19032}, {17674}.
Increasing attention has been paid to the problem of treating patients with CLL who have 
comorbidities. Because of the relatively late age of diagnosis, a large proportion (~90%) of 
patients with CLL have co-morbidities and a substantial proportion (~45%) have major chronic 
conditions such as coronary artery disease, diabetes, or chronic obstructive pulmonary disease 
{20525}. At the time the disease is first identified, ~25% of patients with CLL do not meet 
conventional criteria for participation in clinical studies containing cytotoxic agents {20525}. By 
the time treatment is necessary or during treatment for CLL, patients continue to advance in age 
and have new or worsening chronic conditions; as a result, the proportion of patients with 
comorbidities increases during the course of the illness. Such patients have been substantially 
underrepresented in clinical trials due to concerns regarding the ability of such patients to 
tolerate intensive chemoimmunotherapy {20525}, {20558}. Instruments such as the 
Cumulative Illness Rating Scale (CIRS) {21025} are now being applied in order to categorize
patient populations as fit or relatively unfit and to evaluate regimens tailored to these groups of
patients {20558}, {20165}, {21059}.
Health constraints in older or compromised patients have prompted noncytotoxic approaches to 
therapy. Alternative immunotherapeutics, such as the monoclonal antibodies, alemtuzumab
{17680} or ofatumumab {21022}, have been developed. However the therapeutic utility of these 
drugs is modest; median progression-free survival (PFS) values in patients with recurrent CLL 
have been 4.7 months and 5.8 months, respectively. Moreover, these treatments can have clinical 
liabilities. Alemtuzumab causes extreme immunosuppression that leads to frequent opportunistic 
infection. Administration of the large amounts of protein recommended in ofatumumab product 
labeling results in frequent infusion reactions and cumbersome infusion schedules.


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In view of these issues, repeated use of rituximab monotherapy or rituximab-corticosteroid 
combinations have been advocated in treatment guidelines for older or frail patients with 
recurrent CLL {17670}, {19042}. While single-agent rituximab use can offer palliative benefit 
with good tolerability in some patients with previously treated CLL, tumor control is not lasting, 
especially in patients with bulky adenopathy {19036}. Addition of high-dose corticosteroids to 
rituximab can extend median PFS up to 12 months, but this combination is commonly associated 
with severe hyperglycemia and frequent life-threatening or fatal infections {19037}, {19035}. 
New, noncytotoxic, well-tolerated, and convenient therapies that can successfully be combined 
with rituximab or given as single-agent therapy are needed in order to enhance and prolong 
tumor control in patients with comorbid conditions.
1.2.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies
Phosphatidylinositol 3-kinases (PI3Ks) are enzymes that regulate several cellular functions 
including motility, proliferation, and survival {23618}. PI3K activation recruits and activates 
numerous intracellular signaling enzymes. The most important of these is the 
serine/threonine kinase, AKT, which mediates a positive pleiotropic effect on cell survival, 
proliferation, growth, and metabolism {17720} acting by signaling through mammalian target of 
rapamycin (mTOR) {17678}, {17686}.
PI3K signaling is mediated by 4 catalytic isoforms of the p110 subunit of the enzyme - , , , 
and . While potentially important in multiple cell types, PI3K p110(PI3K) shows an 
expression pattern that is particularly prominent in cells of hematopoietic origin {17690}. Mice 
deficient in PI3Khave no gross abnormalities, are fertile, fecund, and live a normal life span 
without an increased susceptibility to infections {23619}. However, the B-lymphocyte population 
in these animals shows a decrease in maturation, diminished receptor-induced proliferation, and 
increased susceptibility to apoptotic cell death. Conversely, mice with aberrantly elevated 
PI3K signaling develop lymphadenopathy and have an increased incidence of lymphoma 
{17719}. In CLL, sustained activation of the PI3K/AKT/mTOR pathway has been shown to 
promote malignant B-cell survival through mechanisms that are dependent on the PI3Kisoform 
{24339}, {23399}, {19034}.
Knowledge of the critical importance of PI3Kδ in B-cell biology and neoplasia has encouraged a 
search for inhibitors of this enzyme that could provide new options in the therapy of lymphoid 
malignancies, including CLL.
1.3.
Idelalisib (formerly GS-1101)
1.3.1.
General Information
Idelalisib was approved in the US on July 23, 2014 and in the European Union on 
September 18, 2014. Refer to local labeling for the approved indication statements and dosing 
recommendations.
Gilead Sciences, Inc has developed novel drugs that can suppress tumor growth through 
targeting of PI3Kδ activity. High-throughput screening was the basis for the discovery of novel 
agents that selectively inhibit PI3Kfunction but spare other PI3K isoforms and other kinases. 


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Chemical optimization, pharmacological characterization, and toxicological evaluation have led 
to identification of idelalisib (also known as GS-1101), a 415-dalton, orally bioavailable, 
new chemical entity with potential clinical utility in the treatment of cancers.
In primary tumor samples and in cell lines derived from patients with CLL, indolent 
non-Hodgkin lymphoma (iNHL), mantle cell lymphoma (MCL), B-cell acute lymphocytic 
leukemia (ALL), or Hodgkin lymphoma (HL), idelalisib induces dose-dependent reductions in 
AKT phosphorylation {23399}, {20167}, {19034}. In addition, idelalisib disrupts the 
PI3Kactivation and supportive intercellular signaling observed when CLL or HL cells are 
cocultured with stromal cells {20167}, {23401}. These effects have therapeutic consequences. In 
multiple lymphoid primary tumors and malignant cell lines, idelalisib enhances apoptosis and 
concentration-dependent cell killing when applied as a single agent and increases the therapeutic 
efficacy of other antineoplastic agents when given in combination {23401}, {20902}. In 
preclinical systems, coadministration of idelalisib with rituximab has not impaired 
rituximab-mediated activity {23399}.
1.3.2.
Safety Pharmacology
In vitro and in vivo safety pharmacology studies with idelalisib have demonstrated a favorable 
non-clinical safety profile. These studies indicate that the drug may minimally slow bone marrow 
progenitor proliferation and differentiation and that it has expected inhibitory effects on 
B-cell response to antigen challenge. However, the data indicate that idelalisib is unlikely to 
cause serious off-target effects or adverse effects on critical organ systems. Idelalisib has no 
meaningful effect on the human ether-à-go-go-related gene (hERG) channel, indicating that 
idelalisib would not be expected to induce clinical QT prolongation.
The drug has also proved well tolerated in standard in vivo Good Laboratory Practice (GLP) 
studies of pharmacological safety. A functional observation battery in rats revealed no adverse 
effects on behavior or on autonomic, neuromuscular, or sensorimotor function. In a 
cardiopulmonary function study in awake, telemeterized male beagle dogs, single doses of 
idelalisib induced no meaningful abnormalities in pulmonary, cardiovascular, arterial blood gas, 
or electrocardiographic (ECG) (including QT interval) parameters. In an assessment of bacterial 
challenge in rats, idelalisib enhanced, rather than impaired, the phagocytic host clearance of 
staphylococcal bacteria.
1.3.3.
Nonclinical Pharmacology and Metabolism
Consistent with the moderate to high bioavailability seen in nonclinical species, idelalisib shows 
high permeability across human Caco-2 cell monolayers.  At lower concentrations, the reverse 
permeability at low concentration exceeds forward permeability, indicating efflux driven by 
transporters (eg, human P-glycoprotein (MDR1) and breast cancer resistance protein [BCRP]); 
idelalisib is a substrate for the efflux transporters MDR1 and BCRP; however, the permeability 
increases in a concentration-dependent manner, resulting in a lower efflux ratio at higher, 
clinically relevant concentrations of idelalisib.


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Idelalisib exhibits moderately high plasma protein binding in mouse, rat, dog, and human. In dog 
and human plasma, the protein binding is concentration-independent between 1 and 20 µM. 
Protein binding in human plasma is slightly higher than in mouse, rat, and dog plasma, which 
have comparable free fractions.  In human plasma, idelalisib and GS-563117 
(the major metabolite of idelalisib) have an average free fraction of ~16% and ~12%, 
respectively.
After oral administration of 14C-idelalisib to rats and dogs, radioactivity is widely distributed, but 
relatively excluded from bone, brain, spinal cord, and eye lens in rats and from brain and eyes in 
dogs. In rats, the radioactivity declines steadily and most tissues have undetectable levels by 
72 hours post dose.  In bile duct-cannulated rats and dogs, ≥69% of radioactivity is recovered in 
bile and urine, indicating high absorption of idelalisib in vivo.
In hepatic tissues from nonclinical species, idelalisib is primarily metabolized by 
aldehyde oxidase, CYP3A, and UGT1A4.  In vitro metabolism in dog and human yields 
3 primary oxidative metabolites and 5 primary glucuronides. Of these, the oxidative product 
GS-563117 is the predominant metabolite in vitro and in vivo. In preclinical species, plasma 
levels of GS-563117 are below those of idelalisib. In humans, GS-563117 
(only circulating metabolite and formed via aldehyde oxidase) plasma levels significantly exceed 
those of idelalisib. After oral administration of 14C-idelalisib to rats and dogs, biliary excretion 
appears to be the major route of elimination of idelalisib and its metabolites as the majority of 
radioactivity is found in feces or bile and little in urine.
Idelalisib is not a substrate for the renal transporters OCT2, OAT1, and OAT3 or the 
hepatic uptake transporters OATP1B1 and OATP1B3.  GS-563117 is not a substrate for 
OATP1B1 and OATP1B3.
Idelalisib is not an inhibitor of CYP1A, CYP2B6, CYP2C9, and CYP2D6, and at concentrations 
above those observed clinically, is an inhibitor of CYP2C8 (IC50 = 13 µM), CYP2C19 
(IC50 = 76 µM), and CYP3A (IC50 = 44 µM). GS-563117 is not an inhibitor of CYP1A, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and a competitive and time dependent 
inhibitor of CYP3A (IC50 = 3.1 µM), (KI = 0.18 µM, kinact = 0.033 min-1 with midazolam as 
the probe substrate).
In vitro, idelalisib is not an inhibitor of the transporters BCRP, OCT2, OAT1, and OAT3, and is 
an inhibitor of MDR1 (IC50 = 7.7 µM), OATP1B1 (IC50 = 10.1 µM), OATP1B3 (IC50 = 7.0 µM), 
and, at concentrations above those observed clinically, of glucuronosyltransferase UGT1A1 
(IC50 = 42.0 µM). GS-563117 is not an inhibitor of MDR1, BCRP, OATP1B1, OATP1B3, 
OAT1, OAT3, and OCT2, and at concentrations above those observed clinically, an inhibitor of 
UGT1A1 (IC50 = 16.8 µM).
Any potential clinical implications of these metabolism studies were evaluated in a formal 
drug-drug interaction study (GS-US-313-0130) which evaluated the effect of idelalisib on 
cytochrome P450 3A and the drug transporters P-gp, OATP1B1, and OATP1B3. 
Study GS-US-313-0130 also evaluated the impact of an inducer of metabolizing enzymes and 
transporters (rifampin) on the PK of idelalisib in healthy human subjects. Findings from this 
study are presented in Section 1.3.5.1.


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1.3.4.
Toxicology
The toxicological profile of idelalisib was well characterized through the conduct of single dose, 
repeat dose, developmental and reproductive, and genetic toxicology and local tolerance studies. 
The primary target organ toxicities following repeated dosing include the lymphoid, hepatic, 
male reproductive systems in rats and dogs, and gastrointestinal system in dogs. Adverse effects 
in the lymphoid system were primarily the result of on target pharmacology resulting in 
decreased lymphocytes in multiple lymphoid organs, primarily involving B-cell regions. Liver 
effects were transient and reversible with continued dosing and did not result in chronic liver 
injury. Reduction in sperm numbers in males were reversible and did not impact fertility or 
reproductive performance.  Gastrointestinal effects in dogs were minor, superficial, and 
considered secondary to effects on lymphocytes in Peyer’s Patches. Idelalisib was shown to be 
teratogenic and associated with embryo-fetal lethality. Effects on the reproductive system have 
been reported for inhibitors which target other isoforms of PI3K. The dose-dependence and 
potential of idelalisib to selectively inhibit additional PI3K isoforms may be responsible for the 
off-target toxicity. Additionally, the drug may have the potential to produce phototoxic reactions 
in humans. These findings represent toxicities that can be monitored, are considered clinically 
manageable, or are considered acceptable risks in the intended patient population.
Further details on the toxicology of idelalisib can be found in the Idelalisib 
Investigator’s Brochure (IB).
1.3.5.
Idelalisib Clinical Studies
1.3.5.1.
Phase 1 Studies in Healthy Subjects and in Patients with Allergic Rhinitis
Various studies in healthy subjectshave evaluatedsafety, pharmacokinetics, food effect, and the 
potential for drug interactions of idelalisib with CYP3A4 inhibitors {20361}.
Safety results from these studies indicated that idelalisib was well tolerated when administered to 
healthy subjects at single doses through 400 mg (the highest dose level tested) and was also 
generally well tolerated when administered to healthy subjects over 7 days at dose levels through 
200 mg/dose BID (the highest dose level tested). Dosing with 200 mg/dose BID for 7 days 
resulted in a skin rash in 3 out of 6 subjects; histological findings were consistent with a 
delayed-type hypersensitivity maculopapular exanthema. Rashes have sometimes occurred in 
patients with hematological malignancies receiving idelalisib, but have not typically proved 
dose- or treatment-limiting. In placebo-controlled single-dose and multiple-dose trials, repeated 
ECG evaluations performed in tandem with pharmacokinetic monitoring showed no evidence of 
drug-, dose-, or exposure-dependent effects on cardiac rhythm or cardiac intervals 
(eg, QT interval). Pharmacokinetic results indicated that idelalisib appeared rapidly in plasma 
with a median Tmax of 1 to 1.5 hours. Cmax and AUC increased in a less-than-dose-proportional 
manner and mean t1/2 values were across the dose range were 6.5 to 9.8 hours.
Idelalisib dosing after a high-fat, high-calorie meal delayed median time of 
maximum concentration (Tmax) from 0.75 hours to 3 hours; mean Cmax was unaffected and 
mean AUC was ~40% higher. These changes in idelalisib exposures are considered 
modest/clinically non-relevant; thus, idelalisib may be given with or without food.


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Idelalisib is metabolized in humans primarily by aldehyde oxidase, with some involvement of 
CYP3A4 and UGT1A4. Accordingly, when idelalisib was administered following 4 days of daily 
dosing with ketoconazole (a potent inhibitor of CYP3A4), modest/moderate increases in mean 
idelalisib Cmax and AUC values of ~30% and ~80% higher, respectively, which is not considered 
to be clinically relevant and suggesting that idelalisib is a weak CYP3A substrate. GS-563117 is 
formed from idelalisib primarily via aldehyde oxidase.
The 14C-labeled idelalisib human mass balance results showed that the drug has moderate to high 
oral bioavailability. Idelalisib is eliminated mainly via hepatic metabolism and biliary excretion 
in the feces (~78% of dose); recovery in urine was < 15%. GS-563117, the only circulating 
metabolite observed in human plasma, was also observed in urine and feces.
Results from the drug interaction/probe Study GS-US-313-0130 indicate that idelalisib does not 
affect the pharmacokinetics of substrates of Pgp, BCRP, OATP1B1 or OATP1B3 transporters. 
Idelalisib is not expected to affect the exposures of coadministered agents via transporter 
mediated interactions.
The exposures (AUC) of probe CYP3A substrate, midazolam, increased ~5-fold upon 
coadministration with idelalisib, driven by competitive and time-dependent CYP3A inhibition by
GS-563117, the only circulating metabolite of idelalisib. Coadministration of the highly potent 
CYP3A inducer rifampin resulted in a ~75% reduction in idelalisib systemic exposures, likely 
driven by a higher relative contribution of CYP3A to overall idelalisib clearance under the 
induced state.
Pharmacodynamic results showed that a idelalisib dose of 200 mg inhibited ex vivo basophil 
activation via the PI3K-specific, high-affinity immunoglobulin (Ig)E receptor (anti-FCR1) in 
basophils collected from healthy volunteers. The findings were confirmed when the drug was 
assessed over 7 days in a Phase 1b study in subjects with allergic rhinitis. In this study, idelalisib
at a dose level of 100 mg/dose BID showed clinical and pharmacodynamic activity 
(attenuating adverse responses to allergenic challenge and decreasing markers of inflammation) 
and was well tolerated.
1.3.5.2.
Phase 1 Studies in Patients with Hematological Malignancies
1.3.5.2.1.
Phase 1 Monotherapy Study in Patients with Hematological Malignancies
A Phase 1 dose-ranging study (Study 101-02) of single-agent idelalisib extended safety and 
pharmacokinetic observations; documented the clinical and pharmacodynamic activity of 
idelalisib in subjects with iNHL, MCL, and CLL; and provided dosing information in support of 
further development {20397}, {21030}, {21036}. In this study, idelalisib was administered in 
cohorts of subjects across a range of dose levels from 50 mg/dose BID to 350 mg/dose BID. 
Idelalisib administration was continued as long as individual subjects were safely benefitting 
from therapy. Subjects were evaluated in 4-week cycles; response and progression assessments 
were based on standard criteria {12154}.


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A total of 191 subjects were enrolled to the study at dose levels of 50 mg BID (n=17), 
150 mg QD (n=16), 100 mg BID (n=25), 150 mg BID (n=45), 200 mg BID (n=35), 
350 mg BID (n=17), and 300 mg QD (n=19). An additional cohort was also enrolled to receive 
idelalisib 150 mg BID in 28 day cycles (21 days on idelalisib/7 days off [n=17]). Subject
characteristics were as follows: males/females n=139 (73%)/52 (27%) with median age of 
64.5 (range 32-91) years. Diagnoses included: CLL, n=54 (28%); iNHL, n=64 (34%); aggressive 
NHL (MCL and DLBCL), n=49 (26%); AML, n=12 (6%); and MM, n=12 (6%). Categorization 
of disease by response to the last prior therapy included: refractory, n=111 (58%); 
relapsed, n=79 (42%); and unknown, n=1 (1%).  The median (range) number of prior therapies 
was 5 (1-14). Among subjects with iNHL and CLL, the majority had received prior rituximab 
and prior alkylating agent therapy.
Adverse events were usually mild to moderate and not clearly idelalisib-related. Among 
Grade ≥3 adverse events, pneumonias and diarrhea were notable. Pneumonia was observed in 
23 (12%) subjects, primarily in subjects with CLL. In most instances, these findings were 
considered bacterial in origin, based either on culture results or on response to conventional 
antibiotics. Grade ≥3 adverse events of diarrhea were seen in 11 subjects (5.8%). Other 
Grade ≥3 events included rash in 3 (1.6%) subjects. The relative contributions of disease-related 
factors, toxicity from prior therapies or ongoing supportive care, and idelalisib to these events 
was not clear.
Grade ≥3 hematological laboratory abnormalities have included neutropenia, n=46 (24%); 
thrombocytopenia, n=27 (14%), anemia, n=14 (7.3%), and lymphopenia 13 (6.8%); with 
12 subjects (6.3%) having febrile neutropenia.  The occurrence of these events was greater in 
subjects with leukemia, particularly in those with pre-existing hematological abnormalities due 
to disease or prior therapy, commonly making attribution of these events to idelalisib uncertain.
Consistent with the observations in the 28-day dog toxicology study, reversible Grade ≥3 
ALT/AST elevations occurred in 28 (15%) subjects and have been attributed to idelalisib. Onset 
generally occurred between 2 to 16 weeks after idelalisib initiation and resolution was usually 
seen 2 to 6 weeks after idelalisib interruption.  After resolution of ALT/AST increases, 
14 subjects were rechallenged at the same or a reduced dose of idelalisib and 9 (64%) of these 
subjects were able to resume treatment without recurrence of transaminase elevations.
Two (1.0%) subjects had ≥ 2 x ULN elevations in bilirubin in the context of Grade ≥3 
elevated AST/ALT, both of whom had confounding factors (recent history of biliary obstruction 
or concomitant use of potentially hepatotoxic medications) so that a definitive causal relationship 
to idelalisib could not be established.
Pharmacokinetic analyses indicated that the increase in Cmax and AUC0-6h with dose was less 
than dose-proportional, with modest increases above the dose level of 150 mg BID.
Pharmacodynamic data supported drug activity.  In subjects with NHL, plasma concentrations of 
chemokines CCL22 and CCL17 were elevated at baseline and showed significant decreases 
within 1 cycle of idelalisib treatment (p<0.001 for both comparisons). Flow cytometry of CLL 
cells from subjects showed that idelalisib reduced constitutive expression of phosphorylated 
AKT to background levels when measured after 1 week of treatment (p<0.0001), demonstrating 


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pharmacodynamic inhibition of activated PI3K signaling.  Plasma concentrations of 
chemokines CCL3, CCL4, and CXCL13 were elevated in CLL subjects at baseline and 
decreased significantly within 1 cycle of idelalisib administration (p<0.001 for all comparisons).
Tumor reductions meeting antitumor response criteria were not observed in subjects with AML 
or MM. One of 11 subjects with DLBCL achieved a PR.  In 104 subjects with iNHL and MCL, 
idelalisib induced PRs at all dose levels, with respective ORRs in enrolled subjects of 
29/64 (45%) for iNHL and 16/40 (40%) for MCL. The median DOR has not been reached in 
subjects with iNHL; 19 subjects continued to receive idelalisib in a long-term extension study. 
The median [range] DOR was 2.7 months [1 month to 8 months] in subjects with MCL; 
6 MCL subjects continued to receive idelalisib in a long-term extension study.
In subjects with CLL, idelalisib reduced lymphadenopathy in almost all subjects; 
44/54 (81.5%) achieved a lymph node response (≥50% reduction in target nodal lesions). An 
initial increase in peripheral absolute lymphocyte counts of >50% from baseline was observed in 
some subjects; increases were maximal during the first 2 cycles and decreased thereafter; the 
pattern suggested drug-mediated lymphocyte redistribution.  In 54 subjects with CLL, 
39/54 (72%) achieved a PR (includes PR with lymphocytosis).  The median DOR was not 
reached; 23 subjects continued to receive idelalisib in a long-term extension study.
1.3.5.2.2.
Phase 1 Combination Study in Patients with Hematological Malignancies
A separate Phase 1 trial (Study 101-07) has evaluated the safety and preliminary activity of 
idelalisib given in combination with rituximab to subjects with recurrent iNHL or CLL {20397}, 
{19528}.
In this study, rituximab was administered at a standard dose of 375 mg/m2 per infusion weekly 
for 8 weeks in all subjects. Idelalisib was started simultaneously with the rituximab, first at a 
dose level of 100 mg/dose BID (n=13) and then at a dose level of 150 mg/dose BID (n=12) and 
was administered continuously to both subjects with CLL (n=13) and subjects with iNHL (n=12)
for as long as individual subjects were safely benefiting from therapy. Subjects were evaluated in 
4-week cycles; response and progression assessments were based on standard criteria {12154}.
Among the subjects with CLL, the median age was 63 and ranged to 85 years. Bulky tumors 
(1 lymph node 5 cm in diameter) were present in 63% of the subjects. The median number of 
prior therapies by disease was 2 and ranged up to 8 prior treatments. All had received prior 
rituximab and the majority had received prior fludarabine or alkylating agents. Approximately 
one-third of subjects had CLL that was refractory to the last prior therapy. At the time of data 
cut-off, therapy had been administered for a median of 5 cycles, ranging up to 12 cycles 
(ie, 48 weeks).
No idelalisib-related dose-limiting toxicities were observed within the tested subject cohorts. 
Grade 3-4 adverse events largely comprised background events resulting from pre-existing 
disease- or treatment-related conditions or from intercurrent illness. Among subjects with CLL, 
2 (15%) developed pneumonia. For subjects receiving idelalisib together with rituximab, 
Grade 3-4 elevations in ALT/AST were not observed in those with CLL, although 
3 subjects (25%) of those with iNHL had such events.


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The idelalisib plus rituximab combination showed a high level of antitumor activity in both 
subjects with CLL and those with iNHL. Altogether 92% of subjects with CLL receiving the 
combination of idelalisib and rituximab had reductions in nodal size and 77% showed a 
lymph node response (50% reduction in index nodal lesions). Although concomitant 
administration of rituximab did not eliminate the redistribution lymphocytosis that is associated 
with idelalisib, it blunted the magnitude of the change. As a result, the overall response rate 
(ORR) was also 77% among subjects participating in this study. At the time of last data analysis, 
PFS through 48 weeks was 70% and a median PFS had not yet been observed.
Collectively, the emerging data from this study support further evaluation of idelalisib together 
with rituximab in subjects with CLL and indicate that co-administration of idelalisib with 
rituximab is tolerable when using idelalisib at full dose, ie, at a starting dose level of 
150 mg/dose BID.
For additional or updated information, please refer to the current version of the IB.
1.4.
Summary and Justification for the Current Study
Gilead Sciences is conducting this Phase 3 study program to evaluate the efficacy and safety of 
idelalisib in patients with previously treated, recurrent CLL. Collectively the data derived from 
the primary clinical trial (Study GS-US-312-0116) and from this extension trial 
(Study GS-US-312-0117) address the activity of idelalisib together with rituximab, the activity 
of idelalisib when given alone, and the potential for dose-dependent restoration of drug activity 
in subjects who have disease that appears to be drug resistant.
The design and conduct of this clinical trial program is supported by knowledge of the 
demographics of patients with CLL, the natural history and current therapies for the disease, and 
the nonclinical and clinical information regarding idelalisib. The collective data support the 
following conclusions:

CLL is a serious, disabling, and potentially life-threatening disorder of older patients that 
requires sequential treatment with agents that provide alternative mechanisms of tumor 
control. Existing cytotoxic agents have serious acute and chronic toxicities, making them less 
suitable for frail or unfit patients. Single-agent rituximab can offer disease palliation with 
good tolerability in some patients with relapsed CLL but tumor control is not lasting, 
especially in patients with bulky adenopathy. Development of a non-cytotoxic combination 
therapy of idelalisib with rituximab or a monotherapy regimen of idelalisib that can address 
disease pathogenesis with a new mechanism of action and might offer complementary 
nodal and peripheral blood activity would address an unmet medical need, particularly when 
applied in patients with substantial comorbidities or myelosuppression from prior 
chemotherapies.

PI3Kδ over-expression plays an important role in CLL biology. Further evaluation of 
idelalisib as a potential treatment for CLL has sound scientific rationale founded on 
knowledge of the actions of the drug to selectively abrogate PI3Kδ activity and to inhibit 
malignant cell growth and stromal cell signaling in nonclinical models of CLL. These data 
are supported by clinical documentation of idelalisib inhibition of PI3Kδ signaling in patients 
with CLL.


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
The potential for clinical efficacy of idelalisib monotherapy or of idelalisib plus rituximab in 
patients with relapsed or refractory CLL is supported by the observed antitumor activity of 
idelalisib - given alone or in combination with rituximab - in patients with heavily pretreated 
CLL and iNHL.

The safety of advancing development of the idelalisib monotherapy and of a regimen of 
idelalisib plus rituximab in this Phase 3 clinical trial program is well supported by safety 
pharmacology and toxicology studies and by Phase 1 single-agent and combination safety 
data obtained in healthy volunteers and in subjects with lymphoid cancers.

Dose-safety, dose-exposure, and dose-activity relationships identified in Phase 1 studies
support the dosing regimen and dose modification provisions in this study.

Observations relating to patterns of CLL response among subjects receiving idelalisib alone 
or in combination with rituximab in Phase 1 trials provide the foundation for efficacy
monitoring in this trial. Of particular note is that idelalisib mobilizes CLL cells from tissues 
into the peripheral blood. This characteristic pharmacological action is prominent early in 
therapy but can persist over time and should not be confused with disease progression in 
patients who have persistent control of other CLL-related signs and symptoms. For this 
reason, in this Phase 3 study program, subjects will be continued on therapy until the 
occurrence of definitive disease progression, ie, disease progression that is manifest by 
worsening CLL-related signs or symptoms other than lymphocytosis alone. 

Thorough nonclinical and clinical characterization of the type, severity, manifestations, and 
expected timing of adverse events establish the safety monitoring plan in this trial program.

The scientific correlative work performed in prior preclinical and clinical studies provides 
strong scientific underpinnings for the companion laboratory studies to be performed as a 
component of this clinical trial program.

Given the seriousness of previously treated CLL in patients with substantial comorbidity, and 
the aggregate potential benefits considered in the context of potential risks, further 
development of idelalisib in this Phase 3 clinical trial program is justified.
The rationale for specific design features is provided in relevant sections of the protocol, 
including Section 3.2 (Endpoint Selection Rationale), Section 2.2 (Design Rationale), 
Section 4.3 (Enrollment Criteria Rationale), Section 5.10 (Study Treatment Rationale), and 
Section 6.5 (Study Procedure Rationale).


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2.
STUDY DESIGN
2.1.
Design Overview and Study Schema
This study is being conducted as part of an overall clinical program that is evaluating the efficacy 
and safety of idelalisib in the therapy of patients with previously treated CLL (see Figure 2-1). 
Within this program, the primary clinical trial (Study GS-US-312-0116) is a Phase 3, 
multicenter, 2-arm, randomized, double-blind, placebo-controlled, parallel-group study. This 
clinical trial (Study GS-US-312-0117) is a separate, multicenter, 2-arm, double-blind, 
parallel-group extension study that is a companion study to the primary study.
Figure 2-1.
Study Design
Candidates for the primary study will be adults with previously treated recurrent CLL who have 
measurable lymphadenopathy, require therapy for CLL, have experienced CLL progression 
<24 months since the completion of the last prior therapy, and are currently not sufficiently fit to 
receive cytotoxic therapy because of chemotherapy-induced bone marrow damage or 
comorbidities.
Primary study subjects will be stratified based on 17p deletion and/or a p53 mutation status 
(either vs neither), immunoglobulin heavy chain variable region (IgHV) mutation status 
(unmutated vs mutated), and any prior therapy with an anti-CD20 therapeutic monoclonal 
antibody (yes vs no) and randomized in a 1:1 ratio to receive 1 of the 2 treatment arms.
In the primary study, subjects will be administered rituximab intravenously in the clinic starting 
at a dose of 375 mg/m2 on Day 1 (Week 0) and will continue with a dose of 500 mg/m2 on 
Day 15 (Week 2), Day 29 (Week 4), Day 43 (Week 6), Day 57 (Week 8), Day 85 (Week 12), 
Day 113 (Week 16), Day 141 (Week 20) (for a total of 8 infusions). Rituximab will be
administered until the earliest of subject withdrawal from study, definitive progression of CLL, 
intolerable rituximab-related toxicity, pregnancy, substantial noncompliance with study 
procedures, study discontinuation, or a maximum of 8 infusions.


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Idelalisib or placebo will be taken orally, BID continuously. Subjects will continue whichever 
study drug (idelalisib/placebo or rituximab) continues to be tolerated, even if the other drug has 
been discontinued due to toxicity.
If permanent discontinuation of study drug, occurs prior to definitive progression of CLL, 
subjects shall remain on study until definitive progression of CLL or withdrawal from the study 
for reasons specified in Section 5.7.
Compliant subjects who are tolerating therapy but who develop definitive disease progression in 
the primary clinical trial (Study GS-US-312-0116) can consider enrollment in this separate 
companion extension trial (Study GS-US-312-0117). In the extension trial, subjects will take 
active blinded idelalisib therapy, either at a higher starting dose or at the standard starting dose, 
with allocation based on the original primary study randomization. Following unblinding of 
Study GS-US-312-0116, subjects will be allowed to enter Study GS-US-312-0117 in the absence 
of evidence of disease progression and will take 150 mg BID idelalisib regardless of treatment 
assignment in Study GS-US-312-0116.
The primary objective of Study GS-US-312-0116 will be to evaluate the effect of the addition of 
idelalisib to rituximab on PFS. Secondary and tertiary objectives will focus on determining the 
effect of the addition of idelalisib to rituximab on the onset, magnitude, and duration of tumor 
control; overall survival (OS); health-related quality of life (HRQL); changes in subject 
performance status; disease-associated biomarkers and potential mechanisms of resistance; 
treatment administration; safety; and health resource utilization. In Study GS-US-312-0117, the 
same endpoints will be assessed as in Study GS-US-312-0116; the focus of the analysis will be 
largely descriptive except for the within-subject assessment of treatment effects among subjects 
receiving first rituximab alone and then idelalisib alone on Arm B of each trial. No formal 
comparisons of outcomes in Arm A vs Arm B are planned within Study GS-US-312-0117.
2.2.
Design Rationale
The randomized, add-on design for the primary trial (Study GS-US-312-0116) is customary in 
the comparative evaluation of new therapies for cancer. While this design provides idelalisib
efficacy and safety information only in the context of administration of a companion 
antineoplastic agent, it is appropriate because it documents the incremental benefit and toxicity 
of the investigational therapy in the context of a controlled clinical trial while ensuring that all 
participants receive potentially active treatment.
This separate extension trial (Study GS-US-312-0117) enhances subject acceptance of 
randomization in the primary study and provides further information regarding idelalisib
efficacy, resistance, and safety. Among subjects in Arm A, escalation to a higher dose level 
allows evaluation of dose-dependent resistance and a determination if a higher dose can 
reestablish disease control. The safety data obtained in these subjects will add to the overall 
safety database. Among subjects randomized to Arm B in the primary study, evaluation of 
idelalisib at a starting dose of 150 mg/dose BID in the extension study may permit a 
within-subject assessment of the treatment effects with single-agent idelalisib relative to the 
effects previously observed with rituximab alone. Of importance, the extension study maintains 


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the partial blinding of the primary study, thus minimizing the bias that might occur if the overall 
design entailed only a 1-way crossover to open-label idelalisib among subjects who had received 
placebo on Arm B of the primary study. To ensure confirmation of disease progression, tumor 
size data collected from the primary study will be subjected to independent review by an 
independent review committee (IRC) (see Section 10.4.2); subjects will continue with study 
therapy pending confirmation of progression status by the sponsor working in collaboration with 
the IRC. Subjects must have confirmation that the disease has progressed on the primary study 
before being permitted to receive secondary idelalisib therapy on the extension study, or in the 
event the primary study is stopped, subjects who have not yet progressed may enroll on the 
extension study to receive 150 mg BID idelalisib.


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3.
OBJECTIVES AND ENDPOINTS

To evaluate the effect of idelalisib on the onset, magnitude, and duration of tumor control

To compare tumor control in subjects receiving rituximab alone in Study GS-US-312-0116 to 
that observed in the same subjects when receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject well-being, including overall survival 
(OS), health-related quality of life (HRQL), and performance status

To assess the effects of idelalisib on disease-associated biomarkers and to evaluate potential 
mechanisms of resistance to idelalisib

To characterize exposure to idelalisib as determined by treatment administration and 
evaluation of idelalisib plasma concentrations over time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with administration of idelalisib
3.1.
Endpoints
3.1.1.
Tumor Control

Progression-free survival (PFS) – defined as the interval from the start of study therapy to the 
earlier of the first documentation of definitive disease progression or death from any cause; 
definitive disease progression is CLL progression based on standard criteria other than 
lymphocytosis alone

ORR – defined as the proportion of subjects who achieve a CR or partial response (PR) 

Lymph node response rate – defined as the proportion of subjects who achieve a 
50% decrease from baseline in the SPD of index lymph nodes

CR rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from start of study therapy to the first 
documentation of CR or PR

Duration of response (DOR) – defined as the interval from the first documentation of 
CR or PR to the earlier of the first documentation of definitive disease progression or death 
from any cause


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
Percent change in lymph node area – defined as the percent change from baseline in the sum 
of the products of the greatest perpendicular diameters (SPD) of index lymph nodes

Splenomegaly response rate – defined as the proportion of subjects with baseline 
splenomegaly who achieve an on-study normalization or a 50% decrease (minimum 2 cm) 
from baseline in the enlargement of the splenic LVD (by imaging)

Hepatomegaly response rate – defined as the proportion of subjects with baseline 
hepatomegaly who achieve an on-study normalization or a 50% decrease (minimum 2 cm) 
from baseline in the hepatic longest vertical dimension (LVD) (by imaging)

ALC response rate – defined as the proportion of subjects with baseline lymphocytosis 
(ALC4 x 109/L) who achieve an on-study ALC <4 x 109/L or demonstrate a 50% decrease 
in ALC from baseline; ALC values within 4 weeks post-baseline will be excluded from the 
ALC response raete evaluation

Platelet response rate – defined as the proportion of subjects with baseline thrombocytopenia 
(platelet count <100 x 109/L) who achieve an on-study platelet count 100 x 109/L or 
demonstrate a 50% increase in platelet count from baseline; platelet values within 4 weeks 
post-baseline or after 8 days post transfusion will be excluded from the platelet response rate 
evaluation

Hemoglobin response rate – defined as the proportion of subjects with baseline anemia 
(hemoglobin <110 g/L [11.0 g/dL]) who achieve an on-study hemoglobin 110 g/L 
(11.0 g/dL) or demonstrate a 50% increase in hemoglobin from baseline; hemoglobin 
values within 4 weeks post-baseline or after 4 weeks of receiving packed cell/whole blood 
transfusion or after 6 weeks of receiving exogenous growth factors (e.g., Darbepoetin alfa) 
will be excluded for the hemoglobin response evaluation

Neutrophil response rate – defined as the proportion of subjects with baseline neutropenia 
(absolute neutrophil count [ANC] ≤1.5 x 109/L) who achieve an ANC >1.5 x 109/L or 
demonstrate a 50% increase in ANC from baseline; ANC values within 4 weeks of 
post-baseline or after 2 weeks of receiving exogenous growth factors 
(e.g., Filgrastim, G-CSF, Lenograstim) or after 4 weeks of receiving Neulasta were excluded 
for response evaluation
3.1.2.
Patient Well-Being

Overall survival (OS) – defined as the interval from start of study therapy to death from any 
cause

Change from baseline in HRQL domain and symptom scores based on the 
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) (see Appendix 2)

Changes from baseline in Karnofsky performance status – defined as the change from 
baseline in the performance status (see Appendix 3)


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3.1.3.
Pharmacodynamic Markers of Drug Activity and Resistance

Changes from baseline in PI3K/AKT/mTOR pathway activation as a measure of PI3K
pathway activity

Changes from baseline in the plasma concentrations of disease-associated chemokines and 
cytokines
3.1.4.
Exposure

Study drug administration as assessed by prescribing records and compliance as assessed by 
quantification of used and unused drug

Trough (pre-dose) and peak (1.5-hour samples) of idelalisib plasma concentrations as 
assessed by a validated bioanalytical method
3.1.5.
Safety

Overall safety profile of each study treatment regimen characterized by the type, frequency, 
severity, timing of onset, duration, and relationship to study therapy of any adverse events or 
abnormalities of laboratory tests; serious adverse events; or adverse events leading to 
discontinuation of study drug
3.1.6.
Pharmacoeconomics

Change in health status – defined as the change from baseline in overall health and 
single-item dimension scores as assessed using the EuroQoL Five-Dimension (EQ-5D) utility 
measure (Appendix 4)

Health resource measures, including resource utilization, total costs, and measures of 
cost per unit of benefit (eg, cost per additional progression-free month, 
cost per quality-adjusted life-year)
3.2.
Endpoint Selection Rationale
The proposed endpoints have been chosen based on relevance to the pathophysiology and 
clinical manifestations of CLL, the known pharmacology of idelalisib, and the goals of the study 
in documenting idelalisib benefit-to-risk ratio. These types of endpoints have been employed in 
prior studies in CLL and can be evaluated with acceptable reliability and accuracy.
3.2.1.
Tumor Control Endpoints
Assessments of the magnitude and duration of changes in tumor size are routinely employed in 
registration-directed oncology clinical studies to determine therapeutic effect. Unlike OS, these 
endpoints directly assess the ability of the drug to control the malignancy. Such assessments are 
also integral to treatment decisions; because subjects are being treated until disease progression, 


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repeated tumor assessment must be performed in order to define the proper duration of treatment 
for each study participant. Standard response and progression criteria have been established by 
the International Workshop on CLL (IWCLL) {12154}; the assessments of treatment effects in 
this study will be based on these criteria, taking into account the specific pharmacology of 
idelalisib.
In CLL, disease-related nodal enlargement is a major cause of patient discomfort and can cause 
organ dysfunction {19448}. Extensive lymphadenopathy constitutes a reason to treat CLL and 
controlling the size of pathologically enlarged lymph nodes is an important therapeutic goal for 
improving patient well-being and relieving obstructive symptoms {12154}. Given that the natural 
history of recurrent CLL is inexorable nodal growth, enhancing tumor shrinkage and prolonging 
tumor control provides strong evidence of pharmacological activity.
Endpoints of overall tumor control as evaluated in this trial are customarily assessed and reported 
in studies of new therapies in patients with cancer. PFS offers a well established outcome 
measure that directly measures treatment effect, conveys important longitudinal information 
regarding tumor control, can be characterized in all subjects using intention-to-treat (ITT) 
principles, and is readily analyzed using statistical methods such as Kaplan-Meier techniques. 
ORR provides an integrated assessment of the magnitude and extent of changes in 
lymphadenopathy, organomegaly, bone marrow infiltration, and bone marrow function that 
conveniently categorizes and describes treatment effects. TTR and DOR are important in 
characterizing the rapidity of achieving tumor shrinkage and the duration of tumor control. 
Beyond providing descriptions on overall response assessment using ORR, this protocol will also 
seek to characterize the individual components of response that are important in assessment of 
CLL {12154}. Thus, changes in lymph node area and in the proportion of subjects having a 
lymph node response will be analyzed. In addition, among subjects who enter the study with 
splenomegaly or hepatomegaly, the proportion of subjects who achieve substantial (50%) 
reductions in spleen or liver size will be assessed. Similarly, the proportions of subjects who 
experience improvements in ALC, platelets, hemoglobin, and neutrophil counts will be 
characterized in order to provide specific insight into the degree to which therapy alters these 
individual parameters.
Because idelalisib mobilizes CLL cells from tissues into the peripheral blood as part of its 
pharmacological effect, there is a risk of falsely declaring a subject to have experienced disease 
progression if lymphocyte count is considered as the sole basis for potential CLL worsening. To 
account for this potential problem, changes in lymphocyte count will not be considered in 
determining whether a subject has progressive disease, ie, subjects will only be declared to have 
progressive CLL if they meet any of the IWCLL criteria for progressive disease other than 
lymphocytosis alone. Thus, subjects with worsening lymphadenopathy, organomegaly, bone 
marrow involvement, progressive cytopenias, appearance of new disease, or transformation to an 
aggressive lymphoid malignancy histology (eg, Richter syndrome) will be considered to have 
progressed. Subjects with lymphocytosis without any of these other events will not be considered 
to have progressed. Given that lymphocytosis has no prognostic significance in patients with 
relapsed/refractory disease {24682}, {24684} and is not generally considered a reason to treat in 
patients with CLL {12154}, {17670}, {19042}, this approach does not jeopardize subject safety or


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subsequent therapy. Furthermore, it will allow complete collection of all response and 
progression data (both considering lymphocytosis and ignoring lymphocytosis) with the intent of 
providing complete information for regulatory authority review.
The current IWCLL guidelines indicate that physical examination is generally sufficient to 
evaluate nodal response and progression in patients with CLL {12154} but that radiographic 
assessments may be appropriate in clinical trials. Computed tomography (CT) is considered the 
preferred imaging method unless patients have contraindications that require use of 
magnetic resonance imaging (MRI). Given the low fluorodeoxyglucose (FDG) avidity of CLL, 
positron- emission tomography (PET) does not have a role in evaluation of this disease. The 
incremental benefits of using radiographic imaging are limited in patients undergoing long-term
follow-up following first-line therapy {24654}, {24663}. However, in the patients with advanced 
CLL and bulky adenopathy such as those who will be enrolled to this trial, it is known that 
CT scans commonly detect bulky intra-abdominal lymphadenopathy and splenomegaly that 
would be missed by palpation alone and that the presence of large-volume, intra-abdominal 
disease of the nodes and spleen is associated with a poor prognosis {24677}. Thus, while use of 
CT confers greater radiation exposure, subjects have the chance to benefit from radiographic 
imaging because it will offer more accurate information regarding their response to protocol 
therapy and the appropriate duration of protocol treatment. Having this information is 
particularly important in this trial because PI3Kinhibition precludes use of lymphocyte counts 
as evidence for disease progression. In addition, the risk is offset by the fact that the trial subjects 
will primarily be patients who have already received more potent mutagens (eg, purine analogs, 
alkylating agents), and all of whom have advanced cancer and limited treatment options at study 
entry. Based on published data {17680} {21022}, median OS for patients with comparably 
advanced CLL is <18 months, so the long-term secondary malignancy risk from CT-related 
radiation exposure is very low. Finally, in the context of a registration-directed pivotal trial of a 
new drug with a new mechanism of action, radiographic imaging is critically important to 
provide reassurance regarding subject safety and trial validity. In this regard, CT evaluations of 
the lung can be used retrospectively to assess for radiographic evidence of drug-induced 
lung changes {19673}, {19671}. Furthermore, CT measurements have greater accuracy and 
reproducibility than palpation, are subject to independent expert review, and can be audited 
against electronic case report form (eCRF) information.
The timing of radiographic tumor assessments has been carefully considered. To avoid 
duplication, the CT scan documenting CLL progression in Study GS-US-312-0116 will serve as 
the baseline CT scan for Study GS-US-312-0117. Among patients receiving idelalisib in 
Phase 1b/2 studies who experienced a nodal response (50% regression in tumor area), such
responses were observed with the first 16 week of therapy {21030}, {19528}; the planned timing 
of tumor assessments (at Weeks 8, 16, 24, 36, 48 and then every 12 weeks thereafter) in this 
study fits with this known timing of changes in lymph node size during idelalisib therapy. Scans 
at 8-week intervals during the first 24 weeks allow efficient documentation of response. During 
this period, early documentation of disease progression allows subjects who are not benefiting 
from study therapy to move rapidly to alternative treatments. After 24 weeks on study or after 
24 weeks cumulative treatment with idelalisib across Study GS-US-312-0116 and 
Study GS-US-312-0117, the reduction in the frequency of CT scans (to 12-week intervals) 


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reduces the overall protocol burden for subjects while still allowing characterization of the 
expected median PFS in this trial. As outlined in Section 7.3, iodine-containing or 
gadolinium contrast material may be omitted in subjects for whom use of a contrast agent would 
be medically contraindicated.
3.2.2.
Measures of Patient Well-Being
3.2.2.1.
Overall Survival
While OS provides an ultimate measure of patient well-being, it has not routinely been used as 
the primary endpoint in CLL clinical trials. Unlike PFS, it does not specifically measure 
drug-mediated tumor control, and thus provides only an indirect assessment of treatment effect. 
Depending upon the treatment setting, long OS times in patients with CLL can preclude use of 
this endpoint as an efficient method for understanding drug benefits. In both the front-line and 
recurrent disease settings, post-study treatments can influence OS in unpredictable ways, 
potentially confounding differences between treatment groups.
However, given the life-threatening nature of systemic malignancy, documentation of OS is 
customary in oncology therapeutic clinical trials, including those evaluating subjects with 
recurrent CLL {17680}, {21022}. Evaluation of OS in this study continues the survival 
assessment from the primary study (Study GS-US-312-0116). The study program as a whole 
(considering both the primary randomized trial and secondary extension study) offers the 
potential to better understand OS and causes of death in a frail population of patients with both 
CLL, considering the consequences of the disease and comorbidities.
3.2.2.2.
Health-Related Quality of Life
Direct patient reporting of outcomes using standardized methods has become an increasingly 
important component of therapeutic assessment. Evaluation of patient-reported outcomes (PROs) 
is particularly relevant in patients who cannot be cured of disease {23859}. PRO questionnaires 
have been previously used in CLL to understand how patients differ from the general population 
in terms of health concerns {24669}, {24662}, {24681}, {24664}, to understand differences in 
perceptions of well-being in younger vs older patients {24671}, {24664}, to determine how 
treatment affects HRQL {20164}, {24662}, {24661}, and to assess the pharmacoeconomic cost of 
improvements in HRQL {24683}.
Patients with CLL have overtly impaired well-being relative to comparable controls {24669}, 
{24662}, {24681}, {24664}. Fatigue is cited as a common complaint, being present in the 
substantial majority of patients. Impairment of HRQL prior to any treatment is apparent in those 
with B symptoms or in patients with anemia, supporting the concept of initiating treatment when 
patients experience symptomatic disease. Factors associated with lower overall HRQL have 
included older age, greater fatigue, severity of co-morbid health conditions, advanced stage, and 
ongoing treatment for CLL {24681}. Younger patients appear to have worse emotional and social 
well-being but older patients experience worse physical HRQL {24671}. In comparative 
evaluation of chemotherapy-containing regimens, differences in HRQL between therapies 
(eg, fludarabine vs fludarabine-cyclophosphamide vs chlorambucil) reflected differences in 
toxicity while improved HRQL was associated with greater efficacy {20164}, {24662}.


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In this study, it is postulated that idelalisib-mediated tumor control will be correlated with greater 
positive changes in HRQL and that assessments of the drug’s safety profile will be supported by 
HRQL evaluations. The FACT-Leu (Appendix 2) has been selected to evaluate such outcomes 
for the study. The FACT-Leu comprises a general HRQL measure for patients receiving cancer 
treatment that yields a total score and subscales for physical, functional, social/family and 
emotional well-being {23894} and a diagnosis-specific measure for patients with leukemia 
{24808}. The FACT-Leu was developed to assess symptoms (eg, fevers, chills, night sweats, 
nodal swelling, fatigue) specifically relevant to patients with leukemia. FACT instruments have 
documented psychometric properties {23894}, {24808}, {23848}, {23847}, {23827}.
The FACT-Leu instrument is available in appropriate languages for this study. FACT-Leu data 
will be obtained at baseline and during each investigational clinic visit during treatment. Having 
FACT-Leu data concurrent with tumor response information will allow an evaluation of the 
potential relationship between tumor response and symptomatic changes as reported by patients. 
To avoid biasing HRQL results, the FACT-Leu will be administered at each visit before other 
procedures are performed and before any study information is conveyed to the subject.
3.2.2.3.
Changes in Performance Status
Performance status evaluation provides an integrated assessment of patient well-being before, 
during, and after treatment and, ideally, may indicate how drug efficacy and toxicity affect 
patient functioning. In patients with CLL performance status can be predictive of PFS or OS 
{26559}, {26534}, {26551}.
In this study, it is hypothesized that idelalisib-mediated tumor control will be correlated with 
changes in performance status and that assessments of the drug’s safety profile might be 
supported by performance status evaluations. The well-established, reliable, and validated 
Karnofsky performance score {23840}, {23824}, {22654} (see Appendix 3) will be employed in 
the trial for characterization of the subject population and repeated assessment of performance 
status.
3.2.3.
Pharmacodynamic Markers of Drug Activity and Resistance
In CLL, disease-related perturbations in inflammatory status can be clinically overt; patients 
often develop bothersome B symptoms (fevers, night sweats, and weight loss) that are 
characteristic of excessive systemic inflammation {20168}. Consistent with such disease 
manifestations, the PI3K/AKT/mTOR pathway is constitutively overactive in circulating CLL 
cells {21030}. In addition, chemokines and cytokines that are markers of aberrant B-cell 
trafficking or perturbations in inflammation are overexpressed by CLL tissues or by stromal cells 
and circulate in plasma {23884}, {21030}. In Phase 1 studies of idelalisib it has been confirmed 
that idelalisib largely normalizes AKT phosphorylation and induces dose-dependent reductions 
in plasma concentrations of circulating chemokines and cytokines in patients with CLL {21030}.
In this study, it is hypothesized that incremental changes in these biomarkers provide direct 
evidence of mechanism-specific idelalisib effects on PI3Kδ activity or indirectly document drug 
effects on overall tumor cell volume. In either case, improvements in these pharmacodynamic 


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measures provide corroborative evidence in support of idelalisib pharmacological activity; 
conversely, worsening of these biomarkers may indicate acquisition of resistance to idelalisib. In 
addition, it is possible that disease-or inflammation-related biomarkers may provide corollary 
information relating to the adverse effects of idelalisib on the liver; such data might allow better 
prediction of which subjects might be most susceptible to ALT/AST elevations during idelalisib
treatment. Finally, it can also be postulated that genetic, protein, or metabolic changes in CLL 
cells could provide signatures that would correlate with drug sensitivity and resistance.
Based on these considerations, this study will evaluate PI3K/AKT/mTOR pathway activation 
status in CLL cells. For this purpose, blood will be evaluated by flow cytometry using a 
clinically validated assay {23401}. CLL cells will be identified using anti-CD5 and 
anti-CD19 antibodies. AKT activation will be determined by quantifying phosphorylation at the 
Ser473 and Thr308 AKT sites using specific anti-pAKT Thr308 and anti-pAKT
Ser473 antibodies. Additional assessments of PI3K/AKT/mTOR pathway signaling 
(eg, evaluating phosphorylation state for other downstream enzymes) may also be explored.
Plasma will be collected for assessment of circulating concentrations of relevant chemokines and 
cytokines with a particular focus on CCL2, CCL3, CCL4, CXCL12, CXCL13, CCL17, CCL19, 
CCL21, CCL22, sCD40 ligand, tumor necrosis factor-α, and C-reactive protein. In addition 
serum markers of iron metabolism (eg, hepcidin, iron, ferritin, transferrin) that might provide 
markers linking disease-related inflammation with perturbations of liver iron and sensitivity to 
liver injury will be evaluated {23835}, {23843}. Clinically validated assays 
(eg, enzyme-linked immunosorbent assays [ELISAs]) will be used to measure circulating 
concentrations of chemokines and cytokines at baseline and during the course of idelalisib
therapy.
CLL cell deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein will be collected at 
baseline and at the conclusion of a subject’s treatment on study. DNA and RNA samples will be 
analyzed using gene array technologies to evaluate for changes in DNA mutations or in 
RNA expression patterns that might be associated with intrinsic or acquired resistance to study 
treatments. Similarly, protein will be evaluated for state-specific changes in protein 
phosphorylation to evaluate for differences in pathway activation at baseline or during therapy 
that might be associated with differences in response or in acquisition of resistance to therapy.
3.2.4.
Assessments of Exposure
3.2.4.1.
Study Drug Administration and Compliance
Evaluation of study drug administration and compliance provides context for assessments of 
safety, pharmacokinetics, and pharmacological activity. Evaluations of treatment administration 
and modifications from planned therapy document the influence of treatment-emergent adverse 
events on prescribing practice. Compliance assessment offers a general indication of patients’ 
acceptance of therapy, integrating factors of tolerability, palatability, and convenience.
In this study, information regarding planned treatment and modification from planned treatment 
(eg, dose reductions and interruptions) will be kept. The compliance of the subject will be 
verified by accounting for used and unused drug.


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3.2.4.2.
Pharmacokinetics
Given the intent of this protocol to assess longer-term dosing, collection of plasma for idelalisib
concentrations is important for evaluating exposure over time. These data may allow correlations 
of exposure with measures of efficacy, toxicity, and resistance. Because the idelalisib
pharmacokinetic profile has been well characterized in Phase 1 studies, limited plasma sampling 
will be performed in this study. Samples will be collected pre-dose and 1.5 hours post-dose 
relative to the morning administration of idelalisib. Based on discussions with investigators, 
collecting more than 2 samples in the morning is not considered reasonable given the need to 
minimize time requirements for study participants and to avoid substantial inconvenience for 
clinic staff.
Evaluation of idelalisib plasma concentrations will be performed using liquid chromatography 
with tandem mass spectrometry. The method has been fully validated in the context of prior 
Phase 1 studies. Plasma samples will be retained for potential later analyses of idelalisib
metabolites.
3.2.5.
Evaluations of Safety
In defining the therapeutic relevance of a drug in a particular clinical setting, it is imperative that 
its safety profile be fully characterized. As is conventional in all clinical studies, proper 
description of each adverse event or laboratory abnormality requires an understanding of the 
type, incidence, timing, severity, and relatedness to study drug. While information on all reported 
adverse events will be collected, listed, and summarized, particular focus will be placed on 
monitoring and reporting adverse events and laboratory abnormalities that were encountered in 
the prior toxicology studies and clinical experience with idelalisib. Safety parameters of specific 
interest in reporting study results will include those relating to bone marrow function, 
dermatological events, gastrointestinal inflammation, infection, pulmonary events 
(eg, pneumonia/pneumonitis), and liver injury. Additional scrutiny will be applied to 
Grade 3-4 adverse events, to adverse events causing interruption or discontinuation of idelalisib, 
and to serious adverse events.
In addition, the protocol will evaluate for potential adverse idelalisib effects on laboratory 
parameters of immune function; the absolute number of CD4+, CD5+,CD8+, CD16/CD56+, 
CD19+, and CD20+ cells will be assessed by flow cytometry. Serum concentrations of IgA, IgE, 
IgG, and IgM will be obtained.
For consistency of interpretation, adverse events will be coded using the standard 
Medical Dictionary for Regulatory Activities (MedDRA) [http://www.meddramsso.com]), and 
the severity adverse events and laboratory abnormalities will be graded using the well-defined 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). 
Standard definitions for seriousness will be applied (see Section 8.1.2).


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3.2.6.
Pharmacoeconomic Measures
It is increasingly important to understand the potential cost implications of introducing a new 
medication into patient care for CLL {26545}, {26535}. In order to analyze the 
pharmacoeconomic consequences of idelalisib administration, data will be collected regarding 
the health status of subjects and regarding health care resource utilization.
Heath status information will be obtained with the EQ-5D, which is a self-administered, generic, 
indirect utility measure {24948} (Appendix 4). The EQ-5D consists of a visual analogue scale on 
which subjects are asked to rate their current overall health status and 5 single-item dimensions 
which ask subjects to rate their health in terms of mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. For each of the 5 items, patients must choose between 
3 levels of difficulty in accomplishing tasks in that dimension. The visual analog scale is then 
used in combination with the dimension scores to generate a health utility score that can be 
incorporated into analyses of cost effectiveness. The EQ-5D has been successfully used in the 
evaluation of patients with B-cell and other cancers {26305}, {26277}, {26308}.
The EQ-5D instrument is available in appropriate languages for this study. EQ-5D data will be 
obtained at baseline and during each investigational clinic visit during treatment. The EQ-5D 
will be administered immediately after administration of the FACT-Leu instrument, before other 
procedures are performed and before any study information is conveyed to the subject. The 
EQ-5D instrument takes only 5 minutes to complete.
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach will be to combine the resource utilization data from the trial with data on 
unit prices (collected separately) to estimate total costs. The costs will be described relative to 
the health care findings as measured by duration of tumor control, the symptom-free survival 
period, and/or utility outcomes or some other appropriate measure of clinical benefits.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects
The planned sample size is ~160 subjects but will be bounded by the number of subjects enrolled 
to the primary clinical trial (Study GS-US-312-0116).
4.2.
Subject Selection Criteria
Subjects in the primary Phase 3 study (GS-US-312-0116) who are compliant, are tolerating 
primary study therapy, and 1) have definitive progression of CLL while receiving primary study 
drug therapy (idelalisib /placebo) or 2) are actively participating in Study GS-US-312-0116 at 
the time the study is stopped, including if stopped early due to overwhelming efficacy following 
an interim analysis are eligible to enroll in the extension study. Eligibility criteria may not be 
waived by the investigator and conformance to the eligibility criteria is subject to review in the 
case of a Good Clinical Practice (GCP) or a regulatory authority audit. Any questions regarding a 
subject’s eligibility should be discussed with the study sponsor medical monitor prior to 
enrollment.
4.2.1.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while receiving study drug therapy 
(idelalisib/placebo) in Study GS-US-312-0116. Note: Definitive disease progression is CLL 
progression based on standard criteria and occurring for any reason 
(ie, increasing lymphadenopathy, organomegaly, or bone marrow involvement; 
decreasing platelet count, hemoglobin, or neutrophil count; or worsening of 
disease-related symptoms) other than lymphocytosis. Subjects must have confirmation by 
the sponsor working in collaboration with an independent review committee (IRC) that the 
disease has progressed on the clinical trial (Study GS-US-312-0116) before receiving
secondary idelalisib therapy on this extension trial (Study GS-US-312-0117).
3) Presence of radiographically measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures 2.0 cm in the longest diameter [LD] and 1.0 cm in the 
longest perpendicular diameter [LPD] as assessed by CT or MRI).
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab and idelalisib/placebo) 
and no intervening or continuing therapy (including radiotherapy, chemotherapy, 
immunotherapy, or investigational therapy) for the treatment of CLL. Note: Subjects may 
receive corticosteroids to manage CLL manifestations.


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5) The time from permanent cessation of Study GS-US-312-0116 treatment 
(rituximab and/or idelalisib/placebo) and the initiation of Study GS-US-312-0117 therapy is 
12 weeks. Note: Study procedures performed as part of Study GS-US-312-0116 need not 
be repeated and can be used as screening procedures for Study GS-US-312-0117 if 
performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation of study treatment) as 
shown in the table below. Note: Confirmation should be considered for out-of-range values 
to determine if the abnormality is real or artifactual. Values should be obtained within the 
screening period and should generally be the most recent measurement obtained. Subjects 
with any degree of neutropenia, thrombocytopenia, or anemia due to CLL or prior therapy 
may enroll.
Table 4-1.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCra
>30 ml/min
Pregnancy
-HCGb
Negative
a
As calculated by the Cockcroft-Gault formula (see Appendix 5) {2202}
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or 
urine dipstick pregnancy test must be negative at start of study treatment (Visit 2)
Abbreviations: -HCG= beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
eCCr=estimated creatinine clearance, ULN=upper limit of normal
8) For female subjects of childbearing potential, willingness to use a protocol-recommended 
method of contraception (as outlined in Section 5.6.4) from the screening visit (Visit 1) 
throughout the study and for 30 days following the last dose of study drug.
Note: A female subject is considered to be of childbearing potential unless she has had a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically 
documented ovarian failure (with serum estradiol and follicle-stimulating hormone [FSH] 
levels within the institutional postmenopausal range and a negative serum or 
urine HCG), or is menopausal (age ≥54 with amenorrhea for >12 months or 
amenorrhea for >6 months with serum estradiol and FSH levels within the institutional 
postmenopausal range).


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9) For male subjects of childbearing potential having intercourse with females of childbearing 
potential, willingness to use a protocol-recommended method of contraception 
(as outlined in Section 5.6.4) from the start of study drug (Visit 2) throughout the study and 
for 90 days following the last dose of study drug and to refrain from sperm donation from the 
start of study drug (Visit 2) throughout the study and for 90 days following the last dose of 
study drug. Note: A male subject is considered able to father a child unless he has had a 
bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or has ongoing 
testicular suppression with a depot luteinizing hormone- releasing hormone (LH-RH) 
agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate  [Lupron®]), or 
triptorelin pamoate [Trelstar®]).
10) In the judgment of the investigator, participation in the protocol offers an acceptable 
benefit-to-risk ratio when considering current CLL disease status, medical condition, and the 
potential benefits and risks of alternative treatments for CLL. 
11) Willingness and ability to comply with scheduled visits, drug administration plan, imaging 
studies, laboratory tests, other study procedures, and study restrictions. 
Note: Psychological, social, familial, or geographical factors that might preclude adequate 
study participation should be considered.
12) Evidence of a personally signed informed consent indicating that the subject is aware of the 
neoplastic nature of the disease and has been informed of the procedures to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study participation.
4.2.2.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
1) Known histological transformation from CLL to an aggressive lymphoma 
(ie, Richter transformation). Note: Biopsy documentation of the absence or presence of 
transformation is not required.
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of the start of 
study treatment (Visit 2). Note: Subjects with localized fungal infections of skin or nails are 
eligible. Subjects may be receiving prophylactic antiviral or antibacterial therapies at the 
discretion of the investigator; anti-pneumocystis prophylaxis is encouraged. For subjects 
who are at substantial risk of an infection (eg, influenza) that may be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of 
protocol therapy.
3) Pregnancy or breastfeeding. 
4) Intentional breaking of the blind in Study GS-US-312-0116 by the investigator or the study 
subject.


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5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical condition, surgical history, physical 
finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the 
investigator’s opinion, could adversely affect the safety of the subject or impair the 
assessment of study results.
4.3.
Enrollment Criteria Rationale
The eligibility criteria are designed to limit enrollment to subjects who participated in the 
primary clinical trial (Study GS-US-312-0116), are compliant, have been generally able to 
tolerate study therapy and study procedures, and have experienced definitive CLL progression 
while receiving study treatment (rituximab and/or idelalisib/placebo) in the primary study or who 
are actively participating in Study GS-US-312-0116 at the time the study is stopped, including if 
stopped early due to overwhelming efficacy.
The requirement of measurable lymphadenopathy to enter the blinded portion of the study 
ensures that subjects have disease that can adequately be assessed for evidence of drug activity. 
Prior therapy provisions are intended to ensure that subjects are transitioning directly from 
Study GS-US-312-0116 to Study GS-US-312-0117 without receiving intervening treatments. 
The stipulation of 12-week interval from Study GS-US-312-0116 treatment until 
Study GS-US-312-0117 treatment precludes excessively protracted intervals between 
participation in the 2 studies but also permits sufficient time for clinicians and subjects to 
determine whether participation is appropriate. 
In the blinded portion of the study, to ensure that subjects are not so acutely ill from 
life-threatening comorbidities that they require hospitalization and stabilization, subjects with 
Karnofsky performance scores <40 (ie, those who are bed-bound or hospitalized) will not be 
enrolled. Baseline laboratory evaluations are designed to limit participation to subjects who have 
not developed serious organ compromise that would pose a safety risk or confound the 
interpretation of adverse effects. Pregnancy testing and restrictions on eligibility relating to 
reproduction, pregnancy, and nursing are important because idelalisib is a new chemical entity 
with teratogenic effects in rats and it is unknown if it may have adverse effects on conception, on 
fetal development, or on the health of a breast-feeding child. To minimize missing data and 
premature discontinuations, subjects should have sufficient psychological and social resources to 
comply with study procedures and restrictions. Consistent with GCP guidelines, subjects must 
provide informed consent before initiation of any study procedures.


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5.
TREATMENT OF SUBJECTS
5.1.
Enrollment
5.1.1.
Interactive Web Response System
An IWRS will be employed to manage the conduct of the trial. The IWRS will be used to 
maintain a central log documenting enrollment, to manage dose modifications, to assess current 
inventories of study drug, to initiate any necessary resupply of study drug, and to document 
discontinuation of study.
5.1.2.
Treatment Assignment
After a subject has completed the necessary documentation of definitive CLL progression in the 
primary clinical trial (GS-US-312-0116) and has been confirmed to be eligible, the subject can 
be entered into this trial (Study GS-US-312-0117). In order to obtain a treatment arm allocation 
for a subject, a site representative will access the IWRS and supply the system with the required 
information.
Subjects will be assigned to either of the following treatment assignments with allocation based 
on the original primary study randomization:
Treatment Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117)
Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly enrolled subjects will 
receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly enrolled subjects will 
receive 150 mg BID
Note: At the Investigator’s discretion, subjects who were randomized to placebo on 
Study GS-US-312-0116 may delay initiation of idelalisib following enrollment on 
Study GS-US-312-0117 until the time of disease progression or until the investigator 
determines that the subject would benefit from initiation of idelalisib treatment.


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Treatment Assignment

Assignment to Arm A or Arm B with allocation based on the original primary study 
randomization

Implementation through an interactive web response system (IWRS)
The IWRS will assign blister card, or bottle numbers and instructions for dispensing of blinded 
study drug (high-dose or standard-dose idelalisib). It is anticipated that subjects will usually 
begin study drug immediately at Visit 2 of the study.
5.1.3.
Blinding
During the blinded portion of the study, the identity of the treatments will be concealed by 
central blinding of study drug assignments. Blinding will be accomplished through use of a 
placebo that is well-matched to the active drug in appearance, packaging, labeling, and schedule 
of administration (see Section 5.2.1). During the study, subjects, caregivers, investigational site 
personnel, Gilead Sciences study team members, and all other study personnel will remain 
blinded to the identity of the treatment assignments; these assignments will be available only to 
the IWRS, the data monitoring committee (DMC) for the study, an independent bioanalytical 
group that supports the DMC, and drug safety personnel who are not part of the study team.
Unblinding an individual subject’s treatment assignment during the study will only occur in the 
case of subject emergencies (see Section 5.5) or in the event the study is discontinued by the
Sponsor, a Regulatory Agency, or an IRB or EC (see Section 5.9). Where required by local 
regulation, expedited reporting of serious adverse events to specific regulatory authorities will 
include information regarding the study drug treatment assignment 
(high-dose or standard-dose idelalisib); this will be done in such a way that subjects, 
investigational site personnel, institutional review board/independent ethics committees 
(IRB/IEC), and study team members remain blinded as to the treatment assignment for the 
subject described in the adverse event report.
The unblinded analysis of the study will be performed when the database is completed and 
locked following unblinding of Study GS-US-312-0116 and Study GS-US-312-0117. The final 
analysis of the open label portion of the study will occur once the open label portion is stopped.
While bioanalytical assays to determine idelalisib concentrations may be performed prior to 
unblinding, pharmacokinetic data that would allow identification of treatment assignments for 
individual subjects will not be available to the study team until after the blind is broken and the 
primary analysis has occurred. Except for emergency unblinding, individual subjects, caregivers, 
and site personnel will not be informed of the treatment assignments until the implications of 
revealing such data for the overall idelalisib study program have been determined by the clinical 
project leader for the idelalisib development program.


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5.2.
Investigational Study Drug (Idelalisib/Placebo)
5.2.1.
Description
Subjects allocated to Arm A in the blinded portion of the study will be provided with 2 tablets of 
active idelalisib for oral administration at each dose. Each tablet contains 150 mg or 100 mg of 
active idelalisib. The 150-mg tablets will be used for initial therapy; the 100-mg tablets are 
provided for use by those subjects who require a dose reduction (see Table 5-1).
Subjects allocated to Arm B in the blinded portion of the study will be provided with 1 tablet of 
active idelalisib and 1 tablet of placebo for oral administration at each dose. Each active tablet 
contains 150 mg or 100 mg of active idelalisib. The 150-mg tablets (and matching placebo) will 
be used for initial therapy; the 100-mg tablets (and matching placebo) are provided for use by 
those subjects who require a dose reduction.
In the open-label portion of the study, subjects will be provided with 150 mg tablets of idelalisib.
The 150-mg tablets are pink, film-coated, and include the following inactive excipients: 
microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, 
sodium starch glycolate, magnesium stearate, red iron oxide, polyethylene glycol, talc, 
polyvinyl alcohol (PVA), and titanium dioxide. The 100-mg tablets are orange, film-coated, and 
include the following inactive excipients: microcrystalline cellulose, hydroxypropyl cellulose, 
croscarmellose sodium, sodium starch glycolate, magnesium stearate, yellow iron oxide, 
polyethylene glycol, talc, PVA, and titanium dioxide.
The placebo tablets match the active idelalisib formulations in appearance. The placebo tablets 
matching the 150-mg tablets are pink, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium stearate, 
red iron oxide, polyethylene glycol, talc, PVA, and titanium dioxide. The placebo tablets 
matching the 100-mg tablets are orange, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium stearate, 
yellow iron oxide, polyethylene glycol, talc, PVA and titanium dioxide.
5.2.2.
Source
Both active idelalisib and placebo will be supplied free of charge by Gilead Sciences.
5.2.3.
Packaging and Labeling
During the blinded portion of the study, study drug (idelalisib or idelalisib/placebo) will be 
provided in blister cards. The blister cards are made of polyvinyl chloride/
polychlorotrifluoroethylene (PVC/PCTFE) film and have aluminum foil lidding materials. Each 
blister card contains 120 tablets (4-week supply plus a modest overage) of one of the relevant 
dose strengths. The 100-mg or 150-mg and matching placebo tablets will be combined in order 
to obtain the daily doses to be used in this study. Thus, in Arm A, the 300-mg idelalisib dose will 
be obtained by administering two 150-mg tablets and the 200-mg idelalisib dose will be obtained 


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by administering two 100-mg tablets. In Arm B, the 150-mg idelalisib dose will be obtained by 
administering one 150-mg tablet and one placebo tablet and the 100-mg idelalisib dose will be 
obtained by administering one 100-mg tablet and one placebo tablet.
Each blister card will have a unique number. Labeling for blister cards dispensed to subjects in 
Arm A will appear identical to blister cards dispensed to subjects in Arm B, and may include 
either idelalisib or placebo.
When the primary study (GS-US-312-0116) is stopped including if early after an 
interim analysis, GS-US-312-0116 active study subjects will become eligible for participation on 
Study GS-US-312-0117. Active GS-US-312-0117 study subjects will be transitioned to 
open-label idelalisib at this time. Each bottle contains 60 tablets 
(4 week supply plus a modest overage) of one of the relevant dose strengths (150 mg, 100 mg) 
and a polyester coil. Bottles are white and are made of high-density polyethylene. Each bottle is 
closed with a white, continuous-thread, child-resistant, polypropylene screw cap fitted with an 
induction-sealed, aluminum-faced liner.
All labels for study drugs to be distributed to centers in the United States, the EU, and other 
countries will meet all applicable requirements of the United States Food and Drug 
Administration (FDA), the EU Annex 13 of Current Good Manufacturing Practice (cGMP) 
(Manufacture of Investigational Medicinal Products, July 2010), and/or other local regulations as 
applicable.
5.2.4.
Storage and Handling
Blister cards or bottles containing tablets of study drug (idelalisib or idelalisib/placebo) should
be stored at controlled room temperature (ie, ~25 °C, with a range of 15 to 30 °C). While the 
stability of study drug tablets stored at controlled room temperature has been confirmed, brief 
excursions to temperatures as low as -20 °C or as high as 40 °C (eg, during shipping) will not 
adversely affect the drug. Updated stability data will be provided to the sites, as appropriate.
5.2.5.
Dispensing
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing 
study drug according to the IWRS directions. It is planned that drug will be dispensed at 4-week 
intervals through the first 24 weeks of treatment and at 12-week intervals thereafter, or on a 
frequency consistent with the subject’s visit schedule. Sufficient study drug will be provided for 
each study period at the beginning of the period. Multiple blister cards or bottles may be 
dispensed at a single visit. Tablets should be kept in the original blister cards or bottles provided
until they are self-administered by the subject.
At the time of starting study treatment, the IWRS will provide the clinic staff with the blister 
card numbers designating the blister cards to be dispensed, or the quantity of open-label bottles 
to be dispensed. The clinic staff (eg, pharmacist or other qualified person) will write the subject 
number on each blister card or bottle that is dispensed. Immediately before dispensing, the clinic 
staff will write the blister card or bottle number in the study drug administration record 
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5.2.6.
Return
The study drug should be retrieved from each subject at the end of each dispensing interval. The 
quantity of study drug and the date returned by the subject should be recorded in the study drug 
accountability records. When possible, all study drug returned by the subject should be retained 
for review by the study site monitor prior to return to Gilead Sciences or destruction.
5.2.7.
Accountability
The disposition of all study drug should be documented from the time of receipt at the site 
through subject dispensing and return.
Study personnel must ensure that all study drug is kept in a secure locked area with access 
limited to authorized personnel. The study drug must not be used outside the context of this 
protocol. Under no circumstances should the investigator or site personnel supply study drug to 
other investigators or clinics, or allow the study drug to be used other than as directed by this 
protocol.
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by Gilead Sciences or its designee, including, but not limited to, 
the date received, lot number, amount received, and the disposition of all study drug. Upon 
receipt of a drug shipment, the shipment must be logged into the IWRS. Study drug 
accountability records must also be maintained that include the subject number to whom the 
study drug was dispensed and the date, quantity and lot number of the study drug dispensed.
Depending upon the decision of Gilead Sciences, remaining unused study drug supply will be 
returned to Gilead Sciences or its designee after the study is completed or will be discarded or 
destroyed at the clinical site. If the study drug is discarded or destroyed at the clinical site, 
standard institutional policy should be followed. Records documenting the date of study drug 
shipping or destruction, relevant lot numbers, and amount shipped or destroyed should be 
maintained.
5.2.8.
Overdose Precautions
In Phase 1 studies, an MTD for idelalisib was not reached when the drug was administered 
continuously at dose levels through 350 mg/dose BID (700 mg per day) {21030}, {21036}. 
However, in this protocol, an overdose is defined as administration of more than the prescribed 
daily dose (ie, >600 mg in a single day). In a subject who experiences an overdose consideration 
should be given as to whether idelalisib administration should be temporarily interrupted. If the 
overdose ingestion is recent and substantial, and if there are no medical contraindications, use of 
gastric lavage or induction of emesis may be considered. Observation for any symptomatic side 
effects should be instituted, and biochemical and hematological parameters should be followed 
closely (consistent with the protocol or more frequently, as needed). Appropriate supportive 
management to mitigate adverse effects should be initiated.
The Gilead Sciences medical monitor should be contacted if a study drug overdose occurs. Cases 
of study drug overdose will result in specific reporting requirements (see Section 8.8).


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5.2.9.
Inadvertent Exposure and Spill Precautions
Based on available data from nonclinical studies, idelalisib does not appear to be acutely toxic, 
genotoxic, or irritative at levels that are likely to result from inadvertent exposure to the contents 
of broken tablets. However, personnel handling the drug should use reasonable precautions to 
avoid eye contact, skin contact, inhalation, or ingestion of the study drug product. For further 
information regarding inadvertent exposure and spill precautions, please consult the idelalisib
investigator brochure.
5.3.
Study Drug Administration
5.3.1.
Premedication
No specific premedications or supporting medications are required in conjunction with study 
drug administration.
5.3.2.
Administration Instructions
The prescribed dose of study drug (idelalisib/placebo) should be taken orally. At each dose 
administration, the tablet number corresponding to the appropriate dose of study drug is to be 
swallowed whole with 100 to 200 mL (~ 4 to 8 ounces) of water. In case of breakage of the 
tablets in the oral cavity, additional water should be taken as a rinse. 
Study drug may be taken with or without food. There are no known dietary restrictions related to 
study drug use.
5.3.3.
Dosing Schedule
Study drug should be taken on a BID schedule at approximately the same times each day. Ideally,
doses should be taken at ~12-hour intervals (eg, at ~7 AM and at ~7 PM). While it is realized 
that variations in dosing schedule may occur in the outpatient setting, the prescribed regimen 
should be followed as closely as possible, especially in the clinic.
At specified clinic visits, the study drug will be administered in the clinic with dosing 
appropriately timed relative to blood sampling for idelalisib pharmacokinetics. As detailed in 
Section 6.2, clinic staff should record idelalisib administration information, including the exact 
clock time of each dose, for doses of study drug administered in the clinic or hospital. Thereafter, 
subjects will be given an adequate supply of tablets to take at home.
5.3.4.
Dose Levels
Study drug dose levels for Arm A and Arm B are described in Table 5-1. The lower dose level
(Dose Level -1) is provided in case a subject requires a study drug dose modification.
Table 5-1.
Study Drug Dose Levels
Treatment Arm
Starting Dose
Dose Level -1
Arm A
300 mg/dose BID
200 mg/dose BID
Arm B
150 mg/dose BID
100 mg/dose BID
Abbreviation: BID=twice per day


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When the primary study (GS-US-312-0116) is stopped, and GS-US-312-0116 active study 
subjects become eligible for participation on Study GS-US-312-0117 subjects will be enrolled 
into Study GS-US-312-0117 at open label 150 mg BID. Subjects already participating in 
Study GS-US-312-0117 will remain on the same dose.
5.3.5.
Dose Schedule Interruptions and Vomited Doses
Subjects who have a delay in administration of a dose of the study drug of <6 hours should take 
the planned dose as soon as possible after the intended time of administration. For subjects who 
have a delay in administration of study drug of 6 hours, the dose should not be taken. Study 
drug administration may continue but the missed dose should not be made up and the planned 
timing of subsequent study drug dosing should not be altered.
Vomited doses may be retaken, but only if the tablet is visible in the vomitus.
5.3.6.
Safety Monitoring and Study Drug Interruption/Dose Modification
Subjects must be monitored closely for adverse events or laboratory abnormalities during the
course of the study. Reference should be made to the CTCAE, Version 4.03 for grading the 
severity of adverse events and laboratory abnormalities.
Based on Phase 1 clinical experience adverse events potentially attributable to idelalisib in 
patients with CLL have included infrequent hepatic events (manifest primarily as asymptomatic
and isolated elevations in serum ALT/AST). Other adverse events potentially related to idelalisib 
have included instances of pneumonitis, gastrointestinal inflammation, or rash.
Myelosuppression has not been an overt toxicity of idelalisib in previous experience but 
provisions for intervention in subjects experiencing very protracted treatment-emergent 
neutropenia or thrombocytopenia are provided as a precaution. It is possible that idelalisib is 
responsible for other adverse events for which a causal relationship has not yet been established.
Recommendations for modifications of the dosing regimens based on the drug and the type and 
severity of adverse events or laboratory abnormalities are provided in Table 5-2 below. The dose 
modification instructions focus on the types of events most commonly attributed to each of the 
study agents. The recommendations provided in Table 5-2 comprise only guidelines; variations 
from these recommendations may be warranted based on an investigator’s individual judgment 
in considering potential risks, benefits, and therapeutic alternatives available to each subject.
Consistent with Table 5-2, if a subject experiences an adverse event that is suspected to be 
related to study drug and requires a dose modification during the course of study therapy, then 
study drug administration should be held, as necessary, until the adverse event resolves or 
stabilizes to an acceptable degree (generally to Grade 1). Thereafter, study drug may be 
reinstituted, but the dose should be reduced to Dose Level -1 (see Table 5-1). If the adverse event 
occurs again, one further attempt at reinitiation of therapy at Dose Level -1 may be attempted if 
the investigator feels that a second rechallenge is medically appropriate. If the subject cannot 
tolerate idelalisib at Dose Level -1 after 2 rechallenges, then the subject should be discontinued 
from study drug therapy unless continued therapy is permitted by the Gilead Sciences 
medical monitor.


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After the study drug dose is reduced, the dose need not be re-escalated, even if there is minimal 
or no toxicity with the reduced dose. However, if the subject tolerates the lower dose level of 
study drug for ≥4 weeks then the dose level may be increased to the starting dose level 
(see Table 5-1) at the discretion of the investigator. Such re-escalation may be particularly 
warranted if further evaluation reveals that the adverse event that led to the dose reduction was 
not study-drug-related. The starting dose level should not intentionally be exceeded in this study.
Whenever possible, any dose adjustment of study drug should be discussed between the 
investigator and the Gilead Sciences medical monitor prior to implementation. To implement 
either a dose reduction or a dose reescalation, the investigator/study staff member will call the 
IWRS, enter the subject number, and inform the IWRS of the need for dose titration. The IWRS 
will provide details regarding the blister card to be dispensed to the subject. The appropriate 
clinic staff should instruct the subject/caregiver about the change in dose.
Recommendations for dose modification based on the type and severity of adverse events or 
laboratory abnormalities are provided in Table 5-2 below.


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Table 5-2.
Recommendations for Study Drug Dose Modifications Based on Type 
and Severity of Treatment-Related Adverse Events or Laboratory 
Abnormalities
NCI CTCAE Grade
Recommendation
Idelalisib
HEMATOLOGICAL ADVERSE EVENTS
Neutropenia
Grade 2 neutropenia
Maintain current dose level and schedule.
Grade 3 neutropenia
Maintain current idelalisib dose level and schedule.
Grade 4 neutropenia
(or occurrence of 
neutropenic fever 
or infection)
Consider G-CSF support and continue idelalisib at initial or lower dose level at 
investigator discretion.
Thrombocytopenia
Grade 3
Maintain current dose level and schedule.
Grade 4
Withhold for bruising or bleeding until Grade 3. May resume idelalisib at initial or 
lower dose level at investigator discretion.
NON-HEMATOLOGICAL ADVERSE EVENTS
Dermatological
Grade 1
Maintain current dose level and schedule.
Grade 2
Maintain current dose level and schedule.
Grade ≥3 
Withhold idelalisib until Grade 1. May resume at lower dose level or discontinue 
idelalisib at investigator discretion.
Gastrointestinal Inflammation/Diarrhea
Grade 1
Provide anti-diarrheal (eg, loperamide) and maintain current idelalisib dose level and 
schedule.
Grade 2
Provide anti-diarrheal (eg, loperamide). Consider addition of anti-inflammatory agent 
(eg, sulfasalazine, budesonide). Maintain current study drug dose and schedule.
Grade 3
Provide anti-diarrheal (eg, loperamide). Withhold idelalisib until Grade 1. Resume at 
lower dose level. Consider addition of anti-inflammatory agent 
(eg, sulfasalazine, budesonide).
Grade 4
Provide anti-diarrheal (eg, loperamide). Withhold idelalisib until Grade 1. May resume 
at lower dose level or discontinue idelalisib at investigator discretion. Consider addition 
of anti-inflammatory agent (eg, sulfasalazine, budesonide).


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NCI CTCAE Grade
Recommendation
Idelalisib
Hepatic Adverse Events (elevations in ALT, AST, or bilirubin)
Grade 1
(ALT/AST3xULN)
(Bilirubin1.5xULN)
Maintain current dose level and schedule.
Grade 2
(ALT/AST>3-5xULN)
(Bilirubin>1.5-3xULN)
Maintain current dose level and schedule. Monitor ALT, AST, ALP, and bilirubin at 
least 1x per week.
Grade 3
(ALT/AST>5-20xULN)
(Bilirubin>3-10xULN)
Withhold idelalisib. Monitor ALT, AST, ALP, and bilirubin at least 1x per week until 
all abnormalities are Grade 1. If bilirubin abnormality was Grade <3, resume idelalisib 
at same dose level. If bilirubin abnormality was Grade 3, resume at lower dose level.
Grade 4
(ALT/AST>20xULN)
(Bilirubin>10xULN)
Withhold idelalisib. Monitor ALT, AST, ALP, and bilirubin at least 1x per week until 
all abnormalities are Grade 1. If bilirubin abnormality was Grade <4, resume idelalisib 
at lower dose level. If bilirubin abnormality was Grade 4, discontinue idelalisib.
Pneumonitis (dyspnea, cough, hypoxia and/or diffuse interstitial pattern or ground-glass opacities on chest 
CT and no obvious infectious cause)
Grade 1
Maintain current dose level and schedule. Consider pneumocystis prophylaxis.
Grade 2
Withhold idelalisib until Grade 1, institute systemic corticosteroids, and pneumocystis
treatment. May resume at lower dose level.
Grade 3
Withhold idelalisib until Grade 1, institute systemic corticosteroids and consider 
pneumocystis treatment. May resume at lower dose level or discontinue idelalisib at 
investigator discretion.
Other Nonhematological Adverse Events
Grade 2
Maintain current dose level and schedule.
Grade 3
Withhold idelalisib until Grade 1. May resume idelalisib at initial or lower dose level 
or discontinue idelalisib at investigator discretion.
Abbreviations:  ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST= aspartate aminotransferase, 
CTCAE=Common Terminology Criteria for Adverse Events, G-CSF=granulocyte colony-stimulating factor, 
NCI=National Cancer Institute, ULN=upper limit of normal
5.4.
Recommendations for Evaluation, Intervention, and Drug Discontinuation
for Specific Adverse Events or Conditions
5.4.1.
Dermatological Events
Idelalisib administration has occasionally been associated with the occurrence of a 
maculopapular rash affecting the trunk and extremities. Based on skin biopsy data in several 
subjects, the findings have been consistent with a delayed-type hypersensitivity reaction. 
Rechallenge with idelalisib has resulted in recurrence of rash in some but not all subjects.
In subjects who develop a rash while on study drug, causes related to concomitant medications, 
environmental exposures, or infection should be considered and eliminated. Depending upon the 
severity of the initial dermatological event, rechallenge with study drug therapy at the same or a 


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lower dose level (see Table 5-2) should be considered if continued drug administration offers the 
potential for clinical benefit. Subjects should be monitored for the development of a severe 
cutaneous reaction and should be discontinued from study drug in the event of a severe reaction.
5.4.2.
Gastrointestinal Events
Inflammation of the tongue has been noted in rats undergoing repeated gavage administration of 
idelalisib; this inflammation may have represented a drug-related exacerbation of 
gavage-mediated irritation. Mild congestion or hemorrhage in the large intestine has been seen in 
dogs receiving high doses of idelalisib. In patients, isolated cases of gastrointestinal 
inflammation (eg, stomatitis, colitis, cecitis) have been noted. While disease-related factors, 
neutropenia, toxicity from prior therapies, effects of ongoing supportive care, or pre-existing 
cholelithiasis may have initiated such events, it is possible that idelalisib played a contributory 
role. In such subjects, rechallenge with idelalisib has been possible and has not been associated 
with other severe adverse events. Patients who have developed evidence of enteritis during 
idelalisib therapy have been successfully treated with antidiarrheals (eg, loperamide) and with 
enteric steroidal (eg, budesonide) or non-steroidal (eg sulfasalazine [Azulfidine®]) 
anti-inflammatory agents and have been able to continue or resume idelalisib.
For study subjects who develop severe abdominal pain, the possibility of a bowel obstruction or 
perforation should be considered. Appropriate clinical and radiographic examination should be 
performed and supportive care or surgical intervention should be considered. Upon recovery, 
study therapy may be resumed following resolution of a bowel obstruction, if appropriate for the 
clinical situation. Study treatment should be discontinued in subjects who experience bowel 
perforation.
For subjects who develop persistent diarrhea, causes related to concomitant medications or 
gastrointestinal infection should be considered and eliminated. Depending upon the clinical 
circumstances, endoscopy and biopsy may be warranted. Providing an antidiarrheal
(eg, loperamide) may lessen symptoms. Consideration should be given to intervention with 
enteric steroidal (eg, budesonide) or non-steroidal (eg, sulfasalazine) anti-inflammatory agents.In 
such subjects, rechallenge with idelalisib at a lower dose level has resulted in recurrence of 
symptoms in some but not all subjects and has not been associated with other severe adverse 
events. One patient who developed evidence of inflammatory bowel disease during idelalisib
therapy has been treated with sulfasalazine (Azulfidine®) and antidiarrheals (eg, loperamide) 
while continuing on idelalisib.
Thus, depending upon the type and severity of the initial gastrointestinal event, rechallenge with 
study drug at a reduced dose level and with and appropriate support care may be warranted if 
continued drug administration offers the potential for clinical benefit.
5.4.3.
Hepatic Events
In patients with lymphoid malignancies, reversible serum ALT/AST elevations have been 
observed {21030}, {21036}. In these patients, the onset of Grade 3 or 4 transaminase elevations 
has typically occurred within approximately 4 to 8 weeks of starting idelalisib therapy


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(median 5.7, Q1-Q3 3.9-8.1). Among patients with Grade 1-2 ALT/AST abnormalities, 
continued dosing has been possible; transaminase values commonly resolve despite continued 
idelalisib treatment. For those with Grade 3-4 ALT/AST elevations, drug interruption has 
resulted in resolution over 2 to 6 weeks. Successful rechallenge at lower dose levels of idelalisib
has been achieved in the majority of patients. Thus, in subjects with uncomplicated hepatic 
events, the instructions in Table 5-2 should be followed in an attempt to maximize the potential 
that subjects who appear to be benefiting can continue with study drug treatment.
In selected subjects who experience more complicated hepatic adverse events, further work-up 
may be warranted, as requested by the Gilead Sciences medical monitor. Such an evaluation may 
be particularly warranted in subjects who first experience a serum ALT/AST elevation 
12 weeks from the start of study drug therapy, who have an elevation in serum bilirubin 
concentration or coagulation parameters, or who have other characteristics that suggest an 
atypical change in transaminase values. Further workup may include: obtaining a history of 
recent symptoms/illnesses and of relevant past history (eg, history of hepatitis or of 
hepatitis A or hepatitis B vaccination); obtaining information regarding concomitant drug use 
(prescription and nonprescription medications, dietary supplements, alcohol, illicit drugs, special 
diets); questioning the subject regarding potential exposure to environmental toxins; ruling out 
viral hepatitis A, B, C, D (if hepatitis B is positive), and E, Epstein-Barr virus, cytomegalovirus, 
autoimmune hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis, 
hypoxic/ischemic hepatopathy, and biliary tract disease; obtaining additional tests to evaluate 
liver function (eg, prothrombin time [PT], activated partial thromboplastin time [aPTT], 
international normalized ratio [INR], albumin); and considering gastroenterology or hepatology 
consultation {15648}.
Of note, HBV reactivation can occur in patients treated with rituximab with a median time to 
diagnosis of hepatitis among patients with hematologic malignancies of 4 months after the 
initiation of rituximab but such events can occur months after completion of rituximab therapy. 
The risk is very low among patients with negative anti-HBc serology {24673} and/or 
undetectable HBV DNA as assessed by quanititative PCR. Because subjects with such evidence 
of persistent HBV infection are excluded from this study, reactivation is not anticipated. 
However, among subjects with evidence of Grade 3 serum ALT/AST abnormalities, evaluation 
for HBV reactivation (manifest as positivity for serum HBsAg) should be considered as a 
precautionary measure. In a subject with active HBV, anti-HBV antiviral agents should be 
initiated. At the discretion of the investigators, study drug may be continued if HBV infection 
can be adequately controlled, particularly if the subject is experiencing clinical benefit from 
study therapy and there are few other options for treating the subject’s CLL.
5.4.4.
Hematological and Immunological Events
In the Phase 1 experience with idelalisib in CLL, patients with Grade3 neutropenia, anemia, 
and and/or thrombocytopenia were enrolled to clinical trials. Decreased levels of neutrophil 
counts, hemoglobin, or platelet counts during therapy were largely due to minor fluctuations in 
these parameters among patients with pre-existing hematological abnormalities due to disease or 
prior therapy. Thus, idelalisib did not appear to induce overt myelosuppression. Obvious patterns 
of drug-mediated reductions in circulating CD4+ lymphocyte counts or suppression of serum 
IgG levels were also not observed.


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Given that patients with CLL commonly have Grade 3 hematological abnormalities due to 
underlying disease or prior therapy and that idelalisib is not associated with substantial 
myelotoxicity or off-target immunosuppression, alterations in study drug dose level for such 
events should only focus on subjects with protracted or symptomatic neutropenia or 
thrombocytopenia, unresponsive to G-CSF supportive care. No modification of idelalisib for 
changes in circulating CD4+ counts or Ig levels is planned.
5.4.5.
Infectious Events
Patients with CLL receiving idelalisib have developed serious bacterial, fungal, and viral 
infections during therapy. Similarly, serious bacterial, fungal, and new or reactivated viral 
infections have also occurred during and for ~1 year following rituximab-based therapy {24667}. 
New or reactivated viral infections in patients receiving rituximab have included 
cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, 
HBV (see Section 5.4.3) and HCV. Because patients with lymphoid malignancies 
(particularly those with CLL) are susceptible to infection due to the underlying disease, 
neutropenia, and the effects of prior therapy, the specific causal role of idelalisib or rituximab in 
any of these types of events is unclear.
Patients with previously treated CLL have developed Pneumocystis (carinii) jiroveci pneumonia 
while receiving idelalisib. While idelalisib has not specifically been implicated in such cases, 
patients with lymphoid malignancies (particularly those with CLL) may be susceptible to 
pneumocystis infections due to the underlying disease and the effects of prior therapy. 
Pre-existing risk factors of specific concern may include previous pneumocystis pneumonia, 
underlying disease (eg, CLL), prior therapy (eg, alemtuzumab, progenitor cell transplantation), 
or immunocompromised status (low CD4+ lymphocyte counts, HIV infection) {17881}.
In a subject with a history of recurrent infections, prophylaxis with intravenous Ig should be 
considered {23885}. Unless there is a contra-indication in a specific study subject, consideration 
should be given to initiation of antibiotic prophylaxis against pneumocystis infection 
(eg, with trimethoprim-sulfamethoxazole, dapsone, aerosolized pentamidine, or atovaquone) 
beginning prior to study drug administration. Such support may also offer the benefit of reducing 
the risk for other bacterial infections {17881}. Local practices or guidelines regarding infection 
prophylaxis may be followed.
For subjects who develop an infection, appropriate medical therapy (with antibiotics, antifungals, 
or antiviral) or other interventions should be instituted. Whenever appropriate, subjects should 
continue with study drug during treatment for the infection.
5.4.6.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) due to polyomavirus JC has been observed 
in patients who have received rituximab therapy {24656} for hematologic malignancies. The 
specific causal role of rituximab is unknown because many of these patients had other risk 
factors (eg, low CD4+ counts) and the majority had received rituximab in combination with 
chemotherapy or as part of a hematopoietic stem cell transplant. Most cases of PML were 
diagnosed within 12 months of the last infusion of rituximab.


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The diagnosis of PML should be considered in any subject presenting with new-onset or 
worsening neurologic manifestations, especially weakness or paralysis, vision loss, impaired 
speech, or cognitive deterioration. Evaluation of PML should include consultation with a 
neurologist, brain MRI, and lumbar puncture. In subjects diagnosed with PML, study drug 
should also be permanently discontinued.
5.4.7.
Pulmonary Events
Documented bacterial, fungal, viral, and pneumocystis pneumonias have been observed in 
patients receiving idelalisib, primarily in patients with CLL. Some patients receiving idelalisib
alone or in combination have developed evidence of pneumonitis without documented lung 
infection. Nonclinical evaluations of pulmonary function and pathology do not indicate a direct 
toxic effect of idelalisib on the lungs and disease-related factors or toxicity from prior or 
concomitant therapies may have contributed to these clinical events. Rituximab-related 
noninfectious pneumonitis has been described {24807} with an incidence of ~4.3% {19677}. In 
patients developing rituximab-associated pneumonitis, the mean time from the first rituximab 
infusion to the onset of respiratory symptoms was 3 months, with a peak incidence after 
administration of a mean cumulative dosage of 1600 mg/m2 {19670}.
Given the potential for infectious or drug-related adverse events, clinicians should be particularly 
observant for evidence of respiratory events in subjects participating in this trial. Subjects should 
be evaluated who describe pulmonary symptoms (eg, dyspnea on exertion, cough, 
shortness of breath); manifest a decline from baseline of 5% in oxygen saturation, or 
demonstrate evidence of pulmonary inflammation (eg, focal or diffuse interstitial pattern or 
ground-glass opacities on chest CT). Potential bacterial, fungal, or viral etiologies should be 
assessed. Pneumocystis (carinii) jiroveci should be considered, especially if the subject is not 
receiving pneumocystis prophylaxis. Depending upon the changes observed and the response to 
antibiotic intervention, recommended diagnostic work-up may include blood and sputum 
cultures; polymerase chain reaction or antigen testing for pneumocystis and respiratory viruses
(eg, CMV, influenza virus, respiratory syncytial virus, parainfluenza virus, rhinovirus); 
chest X-ray, CT or other imaging methods; pulmonary function testing and diffusing capacity of 
the lung for carbon monoxide (DLCO); bronchoscopic lavage and/or biopsy; or open-lung 
biopsy. Noninfectious etiologies such as pulmonary edema or thromboembolism should also be 
considered.
As appropriate for the clinical situation and culture results, subjects should be treated empirically 
or given specific antibiotics, antifungals, or antiviral agents for a cultured organism. Supportive 
care, including oxygen or mechanical ventilation, should be provided as necessary.
For subjects with suspected pneumonitis (eg, onset of cough, dyspnea, hypoxia and/or a diffuse 
interstitial pattern or ground-glass opacities on chest imaging without obvious infectious 
etiology), study drug should be interrupted and therapy with systemic corticosteroids
(eg, prednisone, 60 mg/day) should be instituted rapidly {19670}. Supportive care, including 
oxygen or mechanical ventilation, should be provided as necessary. Resumption of study drug at 
Dose Level -1 could be considered if the symptoms resolve and if the subject is appropriate for 
re-treatment; reoccurrence of drug-related pneumonitis upon rechallenge should result in 
permanent discontinuation of study drug.


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5.4.8.
Tumor Lysis Syndrome
Patients with tumor lysis syndrome may experience hyperkalemia, hypocalcemia, hyperuricemia, 
hyperphosphatemia, cardiac dysrhythmias, and acute renal failure.
Tumor lysis syndrome has not been observed with idelalisib monotherapy. However, if tumor 
lysis were to occur in a subject participating in this study, the subject should receive rapid 
reversal of hyperkalemia, intravenous hydration, antihyperuricemic agents, and appropriate 
cardiac and renal support, including dialysis as indicated. Upon recovery to baseline functioning, 
such subjects should continue study therapy to maintain tumor control.
5.4.9.
Pregnancy, Lactation, and Reproduction
Idelalisib has induced embryo lethality and teratogenicity when administered to pregnant female 
rats at maternally toxic doses. However, definitive reproductive toxicology studies in animals 
have not yet been performed and the specific effects of idelalisib on human embryogenesis or 
fetal development are unknown. Whether idelalisib is excreted in human breast milk is unknown. 
General toxicology studies in rats and dogs indicated dose-dependent reductions in testicular 
weights, with persistent minimal to mild degeneration of the seminiferous tubules and decreased 
spermatozoa in rats and hypospermatogenesis in dogs. The implications of these testicular 
changes for animal or human fertility are unknown.
Given the preliminary nature of data regarding the risks to a fetus or infant as a result of 
exposure to idelalisib, women of reproductive potential entering this study must have a negative 
serum pregnancy test at baseline and must not be breastfeeding. Males and females of 
childbearing potential should abstain from sexual intercourse or use an effective form of 
contraception (see Section 5.6.4). If a female study participant becomes pregnant or decides to 
breastfeed during the course of the study, all study therapy must be discontinued. Study 
candidates will be informed of the testicular findings through the informed consent process.
5.4.10.
Ultraviolet Exposure
In vitro studies indicate enhanced cytotoxicity when embryonic murine fibroblasts treated with 
GS-563117 (the major metabolite of idelalisib) are simultaneously exposed to ultraviolet light. 
While nonclinical findings suggest the hypothetical potential for phototoxicity in humans, 
available clinical data do not reveal a photosafety concern. Although specific clinical correlates 
for these nonclinical data are not available, investigators and study subjects should be observant 
for the possibility that study participants may have exaggerated sunburn reactions 
(eg, burning, erythema, exudation, vesicles, blistering, edema) involving areas of skin exposed to 
ultraviolet light.
5.5.
Emergency Unblinding
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IWRS system 
for that subject. Gilead recommends but does not require that the investigator contact the 


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Gilead medical monitor before breaking the blind. Treatment assignment should remain blinded 
unless that knowledge is necessary to determine subject emergency medical care. The rationale 
for unblinding must be clearly explained in source documentation and on the case report 
form/ electronic case report form (CRF/eCRF), along with the date on which the treatment 
assignment was obtained. The investigator is requested to contact the Gilead medical monitor 
promptly in case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).
5.6.
Concomitant and Supportive Therapy
To the extent possible, administration of any prescription or over-the-counter drug products other 
than study medication should be minimized during the study period. Subjects should be 
discouraged from use of street drugs, herbal remedies, self-prescribed drugs, tobacco products, or 
excessive alcohol at any time during the clinical study.
If considered necessary for the subject’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator. The decision to 
authorize the use of any drug other than study drug should take into account subject safety, the 
medical need, the potential for drug interactions, the possibility for masking symptoms of a more 
significant underlying event, and whether use of the drug will compromise the outcome or 
integrity of the study
Subjects should be instructed about the importance of the need to inform the clinic staff of the 
use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and during 
the course of the study. Any concomitant drugs taken by a subject during the course of the study 
and the reason for use should be recorded on the eCRFs.
Information regarding use or restrictions on specific concomitant medications, dietary measures, 
or other interventions is provided below.
5.6.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments
Except for corticosteroids (see Section 5.6.5), no other anticancer therapies (including 
chemotherapy, radiation, antibody therapy, immunotherapy, or other experimental therapies) of 
any kind are permitted. Subjects are not allowed to participate concurrently in any other 
therapeutic clinical study.


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5.6.2.
Antibiotics
Except in a subject who has a contra-indication, investigators should consider initiation of 
antibiotic prophylaxis against pneumocystis infection (eg, with trimethoprim-sulfamethoxazole, 
dapsone, aerosolized pentamidine, or atovaquone) beginning prior to study drug administration. 
Such support may also offer the benefit of reducing the risk for other bacterial infections 
{17881}. Investigator discretion and local practices or guidelines may be followed.
For subjects who develop an infection, appropriate medical therapy (with antibiotics, antifungals, 
or antiviral) or other interventions should be instituted. Whenever appropriate, subjects may 
continue with study drug during treatment for the infection.
5.6.3.
Antiemetics and Antidiarrheals
Drug-related nausea and/or vomiting have not been commonly observed with idelalisib in prior 
studies. However, subjects who experience nausea or vomiting while on study therapy may 
receive antiemetics based on the judgment of the treating physician and local institutional 
practices. At the occurrence of persistent nausea or vomiting of severity Grade 1, it is suggested 
that the subject receive an oral or transdermal serotonin antagonist (eg, dolasetron, granisetron, 
ondansetron, tropisetron, palonosetron). Other classes of antiemetic medications that may be 
employed include dopamine antagonists or benzodiazepines. As needed, subjects may be 
prescribed loperamide (Imodium® or others) or diphenoxylate and atropine (Lomotil®) to control 
diarrheal symptoms.
5.6.4.
Contraception
In the context of this protocol, a female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, a bilateral tubal ligation, or a bilateral oophorectomy; has 
medically documented ovarian failure (with serum estradiol and FSH levels within the 
institutional postmenopausal range and a negative serum or urine HCG); or is menopausal 
(age ≥54 years with amenorrhea for >12 months or amenorrhea for >6 months with serum 
estradiol and FSH levels within the institutional postmenopausal range).
Sexually active females of childbearing potential must agree to use a protocol-recommended 
method of contraception during heterosexual intercourse throughout the study treatment period 
and for 30 days following the last dose of the study drug. The investigator should counsel 
subjects on the most effective methods for avoiding pregnancy during the trial. 
Protocol-recommended contraceptive methods are described in Table 5-3.


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Table 5-3.
Protocol-Recommended Contraceptive Methods
Individual Methods
Combination Methods
Hormonal Methods
(One method to be used
with a barrier method)
Barrier Methods
(Both of these methods to be used OR
one of these methods to be used
with a hormonal method)
IUD

Copper T 380A IUD

LNg 20 IUD
Tubal sterilization
Hysterectomy
Estrogen and progesterone

Oral contraceptives

Transdermal patch

Vaginal ring
Progesterone

Injection

Implant

Diaphragm with spermicidea

Male condom
(with spermicidea)
a
If available/approved for use in the specific country
Abbreviation: IUD=intrauterine device
In the context of this protocol, a male subject is considered able to father a child unless he has 
had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or is receiving
ongoing testicular suppression with a depot luteinizing hormone-releasing hormone (LH-RH) 
agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or 
triptorelin pamoate [Trelstar®]).
Sexually active male subjects who can father a child must accept continuous heterosexual 
abstinence as a lifestyle choice; limit intercourse to female partners who are surgically sterile, 
post-menopausal, or using effective contraception (as noted in Table 5-3); or agree to use a 
protocol-recommended method of contraception during heterosexual intercourse throughout the 
study treatment period and for 90 days following discontinuation of the study drug
(as noted in Table 5-3). 
The Gilead Sciences medical monitor should be consulted regarding any questions relating to 
childbearing status or contraception.
5.6.5.
Corticosteroids
Subjects may receive topical, inhaled, enteric, or systemic corticosteroids while on study. It 
should be realized that the use of systemic corticosteroids in patients with CLL may confound 
interpretation of antitumor effects mediated by study drug therapy. However, subjects who 
develop conditions that may be alleviated by systemic corticosteroid therapy are permitted to 
receive such drugs and are not required to discontinue study participation.
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin
Granulocyte-macrophage colony-stimulating factor (GM-CSF) should not be administered given 
the potential for GM-CSF-related inflammatory symptoms.


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G-CSF (filgrastim, PEG-filgrastim, lenograstim) may be administered in response to 
Grade 4 neutropenia or neutropenic complications; use should be particularly considered if 
providing hematopoietic support might help to maintain study drug treatment (see Table 5-2).
While erythropoietic agents (eg, erythropoietin or darbepoetin) may be administered for 
Grade 3 anemia, their use in this study is discouraged given the potential to confound 
assessments of improvements in bone marrow function related to study drug.
Reference may be made to the American Society of Clinical Oncology guidelines {22486}, 
{22483}.
5.6.7.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism
Idelalisib is metabolized primarily via aldehyde oxidase and in part by CYP3A. A clinical 
drug-drug interaction study indicated that administration of a potent CYP3A inhibitor together 
with idelalisib resulted in a ~80% increase in idelalisib plasma exposures (AUC) 
(see Section 1.3.5.1), which is not considered to be clinically relevant and suggesting that 
idelalisib is a weak CYP3A substrate. Preliminary data indicate when coadministered with 
rifampin, a highly potent inducer of CYP3A, idelalisib exposures are ~75% lower. 
Coadministration of potent inducers of CYP3A with idelalisib should be avoided; a list of strong 
inducers is provided in Table 5-4:
Table 5-4.
Known Strong Inducers of CYP3A
Effect on CYP3A
Drug Class
Medications
Strong CYP3A Inducers
Antimycobacterial
Rifampin
Anticonvulsants
carbamazepine, phenytoin
Foods/herbs
St. John’s wort
Abbreviation: CYP=cytochrome P450 enzyme
5.6.8.
Drugs that undergo CYP3A-Dependent Metabolism
The major metabolite of idelalisib, GS-563117, is a reversible and time dependent inhibitor of 
CYP3A; accordingly coadministration of idelalisib with midazolam, a probe CYP3A substrate, 
resulted in a ~5-fold increase in midazolam systemic exposure (AUC), indicating that idelalisib 
is a strong inhibitor of CYP3A. Coadministration of CYP3A substrates with idelalisib may result 
in an increase in their systemic exposures (eg, antiarrhythmics, calcium channel blockers, 
benzodiazepines, certain HMG-CoA reductase inhibitors, phosphodiesterase-5 (PDE5) 
inhibitors, warfarin). Avoid coadministration of drugs that are narrow therapeutic index CYP3A 
substrates (eg, alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, fentanyl, 
quinidine, ergotamine, dihydroergotamine, astemizole, terfenadine) with idelalisib.


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5.6.9.
Immunization
Because of its actions to inhibit PI3Kδ-dependent B-cell function, high doses of idelalisib can 
impair primary or secondary responses to immunization in animals.
The specific clinical relevance of these findings with idelalisib is unknown. However, for 
subjects who are at substantial risk of an infection (eg, influenza) that might be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of study 
therapy.
Of note, the safety of immunization with live viral vaccines following idelalisib therapy has not 
been studied and vaccination with live virus vaccines during study treatment is not 
recommended.
5.6.10.
Surgery
There are no known effects of idelalisib on coagulation or wound healing. Pending receipt of 
additional information, study drug may be continued in the peri-procedural period in subjects 
who require surgery or invasive procedures.
5.6.11.
Diet
There are no specific dietary restrictions in the study. Study drug may be taken with or without 
food.
5.7.
Duration of Study Drug
Subjects may continue receiving study drug until the occurrence of any events requiring study 
drug discontinuation as defined in Section 5.8.
5.8.
Discontinuation of Study Drug
All study participants may receive study drug indefinitely; however:

Any subject has the right to discontinue study drug at any time.

Any subject who has objective evidence based on IRC review of definitive CLL progression
will discontinue study drug.

Any subject unable to tolerate a second rechallenge with protocol-described, dose-modified 
idelalisib at Dose Level –1 (see Section 5.2) should discontinue study drug.

Any subject who becomes pregnant or begins breastfeeding should discontinue study drug.

Any subject who becomes significantly noncompliant with study drug administration, study 
procedures, or study requirements should discontinue study drug.


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
Any subject for whom the blind is intentionally broken by the subject or the study site should 
discontinue study drug (only applicable to the blinded portion of the study).

The investigator, in consultation with the Gilead Sciences medical monitor, may discontinue
study drug, if, it is not in the subject’s best interest to continue.

If allowed by local regulations, Gilead Sciences may transition subjects from study drug to 
commercial drug supply when idelalisib becomes commercially available in the country 
where the subject is living.
Subjects who permanently discontinue study drug for a reason other than disease progression 
(as determined by the IRC) shall continue with assessments per the schedule of procedures until 
disease progression or until another anticancer or experimental therapy is initiated.
5.9.
Discontinuation from Study
Subject study participation will be ended due to any of the following reasons:

Adverse event.

Disease progression.

Withdrawal of consent.

Significant subject noncompliance with study drug administration, study procedures, or study 
requirements.

Initiation of any additional anticancer therapies (other than corticosteroids, see Section 5.6.5) 
including chemotherapy, radiation, antibody therapy, immunotherapy, or other experimental 
treatment.

Physician’s decision to remove the subject from the study.

Pregnancy.

The subject is lost to follow-up.

Death.

Discontinuation of study by the Sponsor, a Regulatory Agency, or an IRB or EC.
5.10.
Study Treatment Rationale
Subjects will be assigned to treatment (Arm A or Arm B) in this study based on their 
randomization in the primary study. The 1:1 randomization in the primary trial
(GS-US-312-0116) ensures that sufficient Arm B subjects will cross over from 


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rituximab alone to single-agent idelalisib at the 150-mg/dose BID starting dose level in this 
extension trial (GS-US-312-0117) to allow an adequate evaluation of efficacy and safety in this 
trial. The randomization and allocation processes will be established and performed through an 
IWRS; the intent is to maximize the integrity and security of the subject disposition and to ensure 
appropriate access and convenience-of-use by the investigational sites.
Double blinding is included to provide protection against biased interpretations of efficacy and 
safety data by subjects, caregivers, investigators, Gilead Sciences personnel, or others involved 
in study conduct.
Selection of the idelalisib treatment regimen (including starting dose level, dose-modifications 
and supportive care, schedule, duration, and conditions of administration) for this study program 
has been based primarily on safety, exposure, and activity profiles from previous Phase 1 clinical 
studies involving healthy volunteers, patients with allergic rhinitis, and patients with 
refractory/relapsed lymphoid malignancies {20361}, {21030}, {21036}. The following 
information was considered in selecting the study drug dosing regimen for the primary study and 
this companion extension study:

Idelalisib was symptomatically well tolerated in patients with lymphoid malignancies 
receiving dose levels of 50 mg/dose BID through 350 mg/dose BID 
(the highest dose level tested). No specific MTD was apparent over the dose range tested. 
However, monitorable, reversible transaminase elevations were observed in some patients 
and may have been more frequent at higher dose levels (~10% rate among patients with CLL 
receiving starting doses of 150 mg/dose). Thus, while doses through 350 mg/dose BID are
tolerable, the starting dose of 150 mg/dose BID appears to appropriately balance safety with 
efficacy in idelalisib-naïve subjects. The starting dose of 300 mg/dose BID in this study also 
appears appropriate for evaluation; it is lower than the dose level of 350 mg/dose BID that 
has been tolerable in prior studies and is likely to be suitable in subjects who have already 
been tolerating idelalisib therapy at 100 mg/dose BID. 

Upon disease progression, permitting escalation from 150 mg/dose BID to 300 mg/dose BID 
among subjects allocated to Arm A offers a systematic evaluation of higher doses in subjects 
who are tolerating idelalisib treatment and might benefit from increased PI3Kinhibition. 
The pharmacological basis for considering such an intervention is based on the concept that 
some individuals might have lower-than-expected plasma exposures or dose-dependent 
resistance to the compound at 150 mg/dose BID and might benefit from a higher dose. The 
intent is to determine if the higher dose can reestablish disease control or whether absolute 
resistance to PI3Kinhibition has been acquired. The safety data obtained in these subjects 
would add to the overall safety database.

In an allergic rhinitis study, idelalisib induced statistically significant improvements in 
clinical and pharmacodynamic endpoints when administered at 100 mg/dose BID over 
7 days. These data support the pharmacological relevance of idelalisib-mediated 
PI3Kδ inhibition when administered at the dose-levels to be used in this study.


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
A positive correlation was noted between idelalisib dose and measures of tumor control and 
chemokine normalization in patients with B-cell malignancies. The majority of patients 
appear to have tumor responses and protracted PFS when receiving starting doses of 
100 mg/dose BID. Thus, treatment with a idelalisib at a starting dose of 150 mg/dose BID 
appears to offer most patients the potential to benefit from therapy and the dose level of 
300 mg/dose BID may provide additional benefit in patients with disease resistance as 
systematically evaluated in this trial. 

Increases in idelalisib plasma Cmax, AUC, and Ctrough values were less than dose-proportional 
in subjects with lymphoid malignancies; the dose-exposure evaluation indicated modest 
increases in plasma exposure at dose levels >150 mg BID.  Thus, administration of starting 
doses of idelalisib of 150 mg/dose BID appears appropriate to ensure adequate exposure in 
the majority of patients. 

In Phase 1 studies, the mean plasma t1/2 of idelalisib was ~6.5 to 9.8 hours across all dose 
levels and there was no substantive plasma accumulation over 7 or 28 days.

The changes in exposure observed when administering idelalisib after a high-fat, high-calorie 
meal are modest (~40% increase in mean AUC with no change in mean Cmax). 
Thus, idelalisib can be administered with or without food. 

The idelalisib dose modification provisions described in the protocol are designed to balance 
a primary concern for subject safety with the potential for observing pharmacological and 
antitumor activity in circumstances under which a subject experiencing an adverse event may 
still be able to continue on therapy at a lower idelalisib dose level. The enhanced monitoring 
to be performed and the actions to be taken in response to toxicity are based on experience 
with interruption, dose-modification, rechallenge, and re-escalation already piloted in 
idelalisib Phase 1 trials. In addition, idelalisib antitumor activity has been observed in the 
Phase 1 studies across all dose levels tested, including doses in the range of the modified 
dose levels planned for this protocol. Thus, use of the lower dose level to accommodate 
individual subject tolerability in this protocol is justified because subjects receiving such an
idelalisib dose level still have the potential for benefit.

In both the primary and extension studies, study treatment will be continued for each subject
until the occurrence of disease progression. Such a strategy is considered appropriate under 
the assumption that persistent interference with PI3Ksignaling is likely to extend treatment 
effect. In addition, this design permits collection of further single-agent safety information 
and thus is likely to enhance understanding of the overall safety profile of idelalisib. 


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6.
STUDY PROCEDURES
6.1.
Enrollment and Study Management Procedures
6.1.1.
Subject Recruitment
Study candidates are limited to those subjects who participated in the primary clinical trial
(Study GS-US-312-0116) and meet the entry criteria for this trial (Study GS-US-312-0117).
Subjects will be enrolled from investigational sites in the United States and Europe. The site 
principal investigator, designated sub-investigators, or other designees will discuss the possibility 
of participation directly with subjects who participated in the primary study.
The study sponsor will post a description of the study on the ClinicalTrials.gov website. Any 
promotional information generated by the sponsor or investigational sites will be submitted for 
IRB/IEC review.
6.1.2.
Subject Compensation for Participation
For subjects requesting such assistance, reasonable reimbursements for the costs of travel 
required to participate in this study will be provided by the study sponsor. To receive payment 
for travel, subjects will need to submit the original travel receipts to the research study staff at 
the investigational site.
However, other than medical care that may be provided, subjects will not be paid for 
participation in the study. Payments for such items as lost wages, disability, discomfort due to 
injury, or meals obtained while waiting at the clinical research center will not be provided. 
Through the informed consent process, study candidates will be notified that their insurance 
company could be charged for standard care that is a component of this research study and that 
subjects may be responsible for co-payments and deductible payments that are typical for their 
insurance coverage.
6.1.3.
Screening
The investigator must inform each prospective subject of the nature of the study, explain the 
potential risks, and obtain written informed consent from the subject and/or a legal guardian 
prior to performing any study-related screening procedures. At the time the study candidate signs 
the informed consent, a site representative should access the IWRS to indicate that a study 
candidate is being screened. The user will need to supply the IWRS with required information 
identifying the site and the subject number as already assigned in Study GS-US-312-0116.
Any consented subject who is excluded from the study before initiation of study treatment will 
be considered a screen failure. All screen failures must be documented along with an adequate 
description of the reason the subject was considered a screen failure. If available, information 
should be provided as to why the subject did not meet eligibility criteria, withdrew consent, 
experienced an intercurrent illness, or had other events that precluded treatment on this study.


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6.2.
Explanation of Study Visits
The specific study procedures to be conducted for each subject enrolled in the study are 
presented in tabular form in Appendix 7 and are described in the sections that follow. Additional 
information on the study procedures is provided in the study manual.
For visits at which HRQL and healthy utility data are obtained, it is important that the subject be 
administered the FACT-Leu and the EQ-5D before any other procedures are performed and 
before any study-related information is communicated to the subject; this is necessary to avoid 
biasing the PRO responses provided by the subject. Once the subject has completed the 
FACT-Leu and the EQ-5D assessments, the remaining procedures may be performed.
At visits involving idelalisib administration and pharmacokinetic sampling in the clinic, care 
should be taken to perform procedures with the appropriate timing relative to idelalisib
administration. The actual sample collection times of pharmacokinetic blood specimens should 
be recorded. If a heparinized venous catheter is placed for sample collection in order to avoid 
repeated needle sticks, at least 2 mL of blood should be removed and discarded prior to each 
sample collection in order to avoid heparin contamination of the sample.
At the visit designated as a laboratory-only visit (Visit 7), subjects will have laboratory 
assessments that may be performed at the investigational site or at an accredited local laboratory 
or clinic that is convenient for the subject/caregiver. If blood is collected at a local laboratory, 
samples are not to be analyzed at the local laboratory. For these visits, subjects and/or caregivers 
will be provided with central laboratory kits that will contain materials necessary for the 
collection and shipment of the laboratory samples by the local laboratory clinic to the central 
laboratory.
Local lab results may be requested in the event central laboratory results are not available for 
assessment of disease response, progression, or the evaluation of a significant event. In addition 
to clinical assessments of tumor status, CT or MRI imaging of the neck, chest, abdomen, and 
pelvis will be performed as a component of tumor assessments during the study based on the 
rationale provided in Section 3.2.1.
Following unblinding of the study:

Subjects who were randomized to idelalisib on Study GS-US-312-0116 and who received 
≥24 weeks idelalisib will complete Visit 16+ twelve weeks from the date of their last 
radiology assessment (CT/MRI) and study visits will continue every 12 weeks thereafter.
Visits 3 through 15 will not be required.

Subjects who have received < 24 weeks of idelalisib will have all Study GS-US-312-0117 
assessments completed per the Schedule of Procedures until they have received idelalisib for 
24 weeks cumulative across both studies. After completion of 24 weeks of cumulative 
idelalisib treatment, Visit 16+ will be conducted 12 weeks from the date of their last 
radiology assessment (CT/MRI), after which time study visits will occur every 12 weeks.


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6.2.1.
Visit 1 and Screening Period (Clinic Visit)
The initial screening visit is designated as Visit 1. At Visit 1, the investigator must inform each 
prospective study participant of the nature of the study, explain the potential risks, and obtain 
written informed consent from the study candidate and/or legal guardian prior to performing any 
study-related screening procedures. Once the informed consent document has been signed, the 
subject may undergo the screening procedures.
In order to optimize scheduling convenience for the subject and for the investigational staff, 
study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be 
used as screening procedures for Study GS-US-312-0117 if performed within 4 weeks prior to 
initiation of study drug therapy on Study GS-US-312-0117. In addition, screening procedures 
may be performed over as many days as necessary provided that screening is completed within 
4 weeks prior to initiation of study drug therapy on Study GS-US-312-0117.
The tests and evaluations outline in Table 6-1 will be performed at Visit 1 or during the 
screening period prior to initiation of study treatment.


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Table 6-1.
Procedures and Assessments at Visit 1 (During Screening Period)
Assessment or Procedure
Explanationa
Informed consent
To be obtained before any screening procedures are initiated
IWRS access
Access IWRS to document that subject is in screening and provide the subject number
from Study GS-US-312-0116
CIRS assessment
Recording of current comorbid conditions using the CIRS scoring instrument
(see Appendix 6)
Concomitant medications
Recording of ongoing concomitant medication use
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including height, weight, evidence of palpable lymphadenopathy, hepatomegaly, 
and/or splenomegaly
Serum β-HCG
Women of childbearing potential only
CLL peripheral blood 
evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 
12 trisomy; DNA mutational analysis for p53, IgHV (including IgHV3-21), and other 
genes of interest in CLL (eg, Notch); flow cytometry for CD5, CD10, CD11c, CD19, 
CD20, CD23, CD38, CD45, kappa and lambda light chains, and ZAP-70; 
cytology for karyotyping.
CLL serology
Serum 2 microglobulin
 
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis, to be scheduled with 
4 weeks prior to initiation of study treatment at Visit 2
Bone marrow biopsy and 
aspirate
To be performed at investigator discretion to determine extent of CLL involvement 
and bone marrow cellularity.
a
Study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be used as screening 
procedures for Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117.
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase,
AST=aspartate aminotransferase, CIRS=cumulative illness rating scale, CLL=chronic lymphocytic leukemia, CT=computed 
tomography, DNA=deoxyribonucleic acid, FISH= fluorescence in-situ hybridization, GGT=gamma--glutamyltransferase, 
Ig=immunoglobulin, IgHV=immunoglobulin heavy chain variable region, IWRS=interactive web response system, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, RNA=ribonucleic acid, ZAP-70=zeta-associated protein 70
PPD


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6.2.2.
Visit 2 (Day 1) (Clinic Visit)
Subjects will be assessed to determine if they still meet eligibility criteria and can initiate study 
treatment. Study drug holds from primary study GS-US-312-0116 may continue as medically 
appropriate. The procedures outlined in Table 6-2 will be performed at Visit 2 (Day 1).
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
β-HCG
For women of child-bearing potential only; serum -HCG or urine dipstick pregnancy 
test must be negative prior to initial study treatment
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics
(with recording of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration
Study drug administrationa
First dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib
pharmacokineticsa
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensinga
Dispensing of 4-week supply of study drug to the subject with instructions for
self-administration at home
Instruction regarding study 
drug dosing at next full 
clinic visita
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 3.
a
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll on Study GS-US-312-0117 following 
unblinding may have idelalisib treatment (and associated PK testing) delayed at the Investigator’s discretion until the time of 
disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib treatment
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response 
system, LDH=lactate dehydrogenase, RNA=ribonucleic acid


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6.2.3.
Visit 3 (Day 15) (Clinic Visit)
The procedures outlined in Table 6-3 will be performed at Visit 3 (Day 15 [±2 days]).
Table 6-3.
Procedures and Assessments at Visit 3 (Day 15)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib pharmacokinetics
Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose). Pre-dose 
collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to document subject visit
Study Therapy Administration
Study drug administration
Study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Instruction regarding study 
drug dosing at next full 
clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 4.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase,
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, HRQL=health-related 
quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, LDH=lactate dehydrogenase


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6.2.4.
Visit 4 (Day 29) (Clinic Visit)
The procedures outlined in Table 6-4 will be performed at Visit 4 (Day 29 [±2 days]).
Table 6-4.
Procedures and Assessments at Visit 4 (Day 29)
Assessment or Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 3
Concomitant medications
Recording of concomitant medication used since Visit 3
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics
(with recording of the date and actual clock time of the date and actual clock time of 
blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration and Dispensing
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)


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Assessment or Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 5.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.5.
Visit 5 (Day 43) (Clinic Visit)
The procedures outlined in Table 6-5 will be performed at Visit 5 (Day 43 [±2 days]).
Table 6-5.
Procedures and Assessments at Visit 5 (Day 43)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
IWRS access
Access of IWRS to document subject visit
Post-Therapy Procedures and Assessments
Instruction regarding study 
drug dosing at next full 
clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 6.
Scheduling of Visit 6 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 6.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, 
LDH=lactate dehydrogenase


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6.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit)
The procedures outlined in Table 6-6 will be performed at Visit 6 (Day 57 [±2 days]).
Table 6-6.
Procedures and Assessments at Visit 6 (Day 57)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted.
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 5
Concomitant medications
Recording of concomitant medication used since Visit 5
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and 
CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug bottle number


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Assessment or Procedure
Explanation
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 8.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging
6.2.7.
Visit 7 (Day 71) (Laboratory Visit)
The procedures outlined in Table 6-7 will be performed at Visit 7 (Day 71 [±2 days]).
Table 6-7.
Procedures and Assessments at Visit 7 (Day 71)
Assessment or Procedure
Explanation
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including ALT, AST, ALP, GGT, total bilirubin, LDH
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
GGT=gamma-glutamyltransferase, LDH=lactate dehydrogenase


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6.2.8.
Visit 8 (Day 85) (Clinic Visit)
The procedures outlined in Table 6-8 will be performed at Visit 8 (Day 85 [±2 days]).
Table 6-8.
Procedures and Assessments at Visit 8 (Day 85)
Assessment or Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 6
Concomitant medications
Recording of concomitant medication used since Visit 6
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration and Dispensing
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)


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Assessment or Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 9.
Scheduling of Visit 9 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 9.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit)
The procedures outlined in Table 6-9 will be performed at Visit 9 (Day 113 [±3 days]).
Table 6-9.
Procedures and Assessments at Visit 9 (Day 113)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit the assessment should be done even if study drug has been interrupted.
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 8
Concomitant medications
Recording of concomitant medication used since Visit 8
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and 
CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number


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Assessment or Procedure
Explanation
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 10.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.10.
Visit 10 (Day 141) (Clinic Visit)
The procedures outlined in Table 6-10 will be performed at Visit 10 (Day 141 [±3 days]).
Table 6-10.
Procedures and Assessments at Visit 10 (Day 141)
Assessment or Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 9
Concomitant medications
Recording of concomitant medication used since Visit 9
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug  blister card number
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)


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Assessment or Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 11.
Scheduling of Visit 11 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 11.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit)
The procedures outlined in Table 6-11 will be performed at Visit 11 (Day 169 [±3 days]). 
Table 6-11.
Procedures and Assessments at Visit 11 (Day 169)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted. 
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant medications
Recording of concomitant medication used since Visit 10
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card numbers


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Assessment or Procedure
Explanation
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for 
self-administration at home.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.12.
Visit 12 (Day 211) (Clinic Visit)
The procedures outlined in Table 6-12 will be performed at Visit 12 (Day 211 [±3 days]).
Table 6-12.
Procedures and Assessments at Visit 12 (Day 211)
Assessment or Procedure
Explanation
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 11
Concomitant medications
Recording of concomitant medication used since Visit 11
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit
Study drug administration
Subject to continue with study drug as prescribed.
Scheduling of Visit 13 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 13.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.13.
Visit 13 (Day 253) (Clinic and Radiology Visit)
The procedures outlined in Table 6-13 will be performed at Visit 13 (Day 253 [±3 days]).
Table 6-13.
Procedures and Assessments at Visit 13 (Day 253)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted.
During-Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant medications
Recording of concomitant medication used since Visit 10
Study drug return/
accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study drug administration
Subject to continue with study drug as prescribed.
Study drug dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for 
self-administration at home.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.14.
Visit 14 (Day 295) (Clinic Visit)
The procedures outlined in Table 6-14 will be performed at Visit 14 (Day 295 [±3 days]).
Table 6-14.
Procedures and Assessments at Visit 14 (Day 295)
Assessment or Procedure
Explanation
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant medications
Recording of concomitant medication used since Visit 10
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit
Study drug administration
Subject to continue with study drug as prescribed.
Scheduling of Visit 15 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 15.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.15.
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks)
(Clinic and Radiology Visits)
The procedures outlined in Table 6-15 will be performed at Visit 15 (Day 337 [±3 days]) and 
every 12 weeks thereafter [±7 Days]).
Table 6-15.
Procedures and Assessments at Visit 15 and Subsequent Visits
(Day 337 and Every 12 Weeks)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted.
During-Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since prior visit
Concomitant medications
Recording of concomitant medication used since prior visit
Study drug return/
accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM


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Assessment or Procedure
Explanation
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study drug administration
Subject to continue with study drug as prescribed.
Study drug dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for 
self-administration at home
Scheduling of next visit 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for next 
clinic visit (every 12 weeks).
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.16.
End-of-Study Visit (Clinic Visit)
At the time of discontinuation from the study, the subject should have the procedures and 
assessments performed as documented in Table 6-16. An end-of-study CT/MRI tumor 
assessment should be performed unless the subject already has radiographic confirmation of 
definitive disease progression or a CT/MRI has been performed within 4 weeks prior to the 
end-of-study visit.
Table 6-16.
Procedures and Assessments at End-of-Study Visit
Assessment or Procedure
Explanation
Radiology assessmenta
CT or MRI imaging of neck, chest, abdomen, and pelvis
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed
Adverse events 
Recording of adverse events occurring since prior visit; if a clinically significant 
adverse event or abnormal result is observed that is not resolved by the 
end-of-treatment visit, repeat evaluations should be performed to document resolution 
or stabilization of the abnormality
Concomitant medications
Recording of concomitant medication used since prior visit
Study drug return/
accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Serum β-HCG
Women of childbearing potential only
CLL peripheral blood 
evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 
12 trisomy; DNA mutational analysis for p53, IgHV (including IgHV3-21), and other 
genes of interest in CLL (eg, Notch); flow cytometry for CD5, CD10, CD11c, CD19, 
CD20, CD23, CD38, CD45, kappa and lambda light chains, and ZAP-70; 
cytology for karyotyping
CLL serology
Serum 2 microglobulin
 
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
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Assessment or Procedure
Explanation
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS
Access IWRS to document that subject has permanently discontinued study therapy
and to indicate whether subject agrees to continue to undergo long-term follow-up
a
An end-of-study CT/MRI tumor assessment should be performed unless the subject has per-protocol CT/MRI assessments 
4 weeks prior to end-of-study discontinuation.
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, CLL=chronic lymphocytic leukemia, CT=computed tomography, FISH= fluorescence in-situ 
hybridization, GGT=gamma-glutamyltransferase, IgHV=immunoglobulin heavy-chain variable-region, IWRS=interactive web 
response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, RNA=ribonucleic acid, 
ZAP-70=zeta-associated protein 70
6.2.17.
30 Day and Long-Term Follow-up
A 30 Day follow-up visit will be performed 30 (+ 5) days following the end-of-study visit; 
however, it may be waived for subjects who have permanently discontinued study drug and have 
had a study visit >30 days after the last dose of study drug.
Long-term, follow-up will be requested of all subjects who withdraw from study for any reason.
The long-term follow-up for survival will be conducted at ~6-month intervals for 5 years, 
starting at the end-of-study visit. Information may be gathered during a routine clinic visit or 
other contact with the subject, or via telephone. Information gathered will include medical status, 
anti-tumor treatments, secondary malignancies, and survival.
6.3.
Sample Storage
 
 
 
 
 
6.4.
Blood Collection
The maximum amount of blood to be drawn at a visit ~115 mL and the total amount of blood to 
be drawn over the initial 52-week study period (including the 4-week screening period and 
through Week 48 of the study including a possible end-of-therapy visit) is ~560 mL. For a 
40-kg person (the smallest participant expected to enroll in the study), this equates to 
maximum blood volume per body weight per visit of ~2.8 mL/kg and a total blood volume 
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per body weight per average 6-week period of ~1.6 mL/kg. These quantities of blood are within 
accepted limits of 3.0 mL/kg of body weight for a single blood draw and 7.0 mL/kg of 
body weight for a 6-week period.
Specific details regarding blood sample collection and processing requirements will be provided 
separately in the study manual.
 
 
 
6.5.
Study Procedure Rationale
The planned study assessments and timing have been selected as appropriate for screening of 
subjects, for determination of idelalisib-related or disease-related toxicities, for dose 
modification during the study, for characterization of drug exposure and desired pharmacological 
effects, and for evaluation of drug activity. The scheduling of testing is designed to collect a 
complete safety and pharmacology data set while maintaining subject tolerance of study 
procedures. The planned schedule of tumor assessments is consistent with expected rate of 
changes and appropriately balances precise measurement of tumor control with the expense and 
subject inconvenience associated with clinical and radiological procedures. For discussion of the 
rationale for endpoint selection, see Section 3.2.
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7.
EFFICACY ASSESSMENTS
7.1.
Tumor Status Assessments
The determination of CLL response and progression will be based on standardized IWCLL
criteria {12154}, as specifically modified for this study to reflect current recommendations which 
consider the mechanism of action of idelalisib and similar drugs {22541}. Treatment decisions by 
the investigator in this study will be based on these assessments. Radiographic and clinical tumor 
assessments will be subject to independent confirmation by the IRC (see Section 10.4.2).
7.2.
Method of Assessment
In addition to clinical examination, imaging-based evaluation will be used in this study in all 
subjects enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI 
scanning may be used at the investigator’s discretion in subjects for whom this may be a 
preferred alternative to CT scanning; however, if MRI is performed, a non-contrast CT of the 
chest should be performed. Contrast-enhanced scanning is preferred, but iodine-containing or 
gadolinium contrast material may be omitted in subjects for whom use of a contrast agent would 
be medically contraindicated. Chest x-ray, ultrasound, endoscopy, laparoscopy, PET, 
radionuclide scans, or tumor markers will not be considered for response assessment.
For radiographic evaluations, the same method of assessment and the same technique 
(eg, scan type, scanner, subject position, dose of contrast, injection/scan interval) should be used 
to characterize each identified and reported lesion at baseline and during study treatment and 
follow-up.
All relevant clinical and radiographic information required to make each tumor status assessment 
must be made available for source verification and for submission to the IRC 
(see Section 10.4.2).
7.3.
Timing of Assessments
All baseline clinical and CT/MRI tumor assessments should be performed within 4 weeks prior 
to initiation of study drug therapy. In order to optimize scheduling convenience for the subject 
and for the investigational staff, clinical and CT/MRI tumor assessments performed as part of 
Study GS-US-312-0116 need not be repeated and can be used as baseline tumor assessments for 
Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117. Clinical tumor assessments should be performed at each clinical visit. 
On-study CT/MRI tumor assessments should be performed at ~8- to 12-week intervals as 
dictated by the study protocol. An end-of-study CT/MRI tumor assessment should be performed 
unless the subject has per-protocol CT/MRI assessments 4 weeks prior. If a subject 
permanently discontinues study drug prior to objective documentation of CLL progression, 
investigators should continue further follow-up at ~12-week intervals until CLL progression is 
documented by the central IRC.


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7.4.
Identification and Measurement of Tumor Lesions and Organomegaly
7.4.1.
Index Lesions
At baseline, up to 6 lymph nodes should be selected as index lesions that will be used to 
quantitate the status of the disease during study treatment. Ideally, the index lesions should be 
located in disparate regions of the body. Only peripheral nodes need be selected as index lesions. 
However, it is optimal if mediastinal and retroperitoneal areas of disease are assessed whenever 
these sites are involved.
Index lesions will be measured and recorded at baseline and at the stipulated intervals. The 
cross-sectional dimensions (the largest cross-sectional diameter, ie, the LD × LPD) will be 
recorded (in cm) for each index lesion. The product of the perpendicular diameters (PPD) 
(in cm2) for each index lesion and the sum of the products (SPDs) (in cm2) for all index lesions 
will be calculated and recorded. The baseline SPDs will be used as references by which tumor 
response will be characterized during treatment. The nadir LD of individual lesions and the nadir 
SPD will be used as references by which CLL progression will be characterized. All LD and 
LPD diameters will be reported in centimenters and all PPDs and SPDs will be reported in 
centimeters squared.
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable at 
baseline. A lymph node lesion is considered abnormal if it has a single diameter that is 1.5 cm 
and is considered measurable if it has 2 perpendicular diameters that can be accurately measured 
in cross section with the LD being 1.0 cm and the LPD also being 1.0 cm.
At follow-up time points, the LDs for individual lesions and the SPD of all nodal index lesions 
will be considered. Because nodal index lesions that have one or both diameters 
>0 cm and 1.0 cm cannot be reliably measured, a default value of 1.0 cm will be assigned for 
each diameter that meets these criteria and the resulting PPD will be used in SPD calculations. 
Based on this convention, a CR may be achieved even if an SPD value is >0 cm2, 
(ie, if all lymph nodes measure <1.0 cm2).
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD will be considered 
progressive disease.
In cases in which a large lymph node mass has split into multiple components, all 
subcomponents regardless of size will be used in calculating the SPD. Progression of the lesion 
will be based on the SPD of sub-components. Lesion sub-components will have the true PPDs 
calculated. Similarly, lesion sub-components that are visible but neither abnormal nor 
measurable will have the default PPD of 1.0 cm2 (1.0 cm 1.0 cm) used in calculating the SPD.
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer 
be separated by this boundary, the newly merged lesion will be measured bi-dimensionally.


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7.4.2.
Spleen and Liver
Both the spleen and liver will be assessed by CT/MRI scan at baseline and at the stipulated 
intervals during treatment. The baseline and nadir values for the longest vertical dimension 
(LVD) of each organ will be used as reference to further characterize the objective tumor 
response of the measurable dimensions of the CLL during treatment. All spleen and liver LVD 
measurements should be recorded in centimeters.
By imaging, the spleen will be considered enlarged if it is >12 cm in LVD {22487}, {22959}.
For subjects with splenomegaly at baseline or at the splenic LVD nadir, respective response and 
progression evaluations of the spleen will consider only changes relative to the enlargement of 
the spleen at baseline or nadir, not changes relative to the total splenic LVD.
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen in its LVD or 
decrease to ≤12 cm in the LVD, is required for declaration of a splenomegaly response. 
Conversely, an increase in splenic enlargement by ≥50% from nadir 
(with a minimum 2 cm increase) is required for declaration of splenic progression.
By imaging, the liver will be considered enlarged if it is >18 cm in LVD {22485}.
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the liver in its LVD or 
decrease to ≤ 18 cm in the LVD is required for declaration of a hepatomegaly response. 
Conversely, an increase in liver enlargement by ≥50% from nadir 
(with a minimum 2 cm increase) is required for declaration of hepatic progression.
7.4.3.
Non-Index Lesions
Any other measurable and abnormal nodal lesions not selected for quantitation as index lesions 
may be considered non-index lesions. In addition, non-measurable evidence of CLL such as 
nodal lesions with both diameters <1.0 cm, extra-nodal lesions, bone lesions, leptomeningeal 
disease, ascites, pleural or pericardial effusions, lymphangitis of the skin or lung, abdominal 
masses that are not confirmed and followed by imaging techniques, cystic lesions, previously 
irradiated lesions, lesions with artifacts, and may be considered as non-index disease.
The presence or absence of non-index disease should be recorded at baseline and at the stipulated 
intervals during treatment. If present at baseline, up to 6 non-index lesions should be recorded. 
The non-index disease at baseline will be used as a general reference to further characterize 
regression or progression of CLL during assessments of the objective tumor response during 
treatment. Measurements are not required and these lesions should be followed as 
“present” or “absent”.
7.5.
Definitions of Tumor Response and Progression
Responses will be categorized by the IRC as CR, PR, SD, or PD. In addition, a response category 
of not evaluable (NE) is provided for situations in which there is inadequate information to 
otherwise categorize response status. A response category of no disease (ND) is included for 
situations in which there is absence of tumor both at baseline and on treatment.


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The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until disease/recurrence progression (taking as a reference 
for disease progression the smallest measurements recorded since treatment started). Subjects 
with a best overall response of NE or ND will be counted in the denominators in calculations of 
tumor response rates.
7.5.1.
Complete Response
To satisfy criteria for a CR, all of the following criteria must be met:

No evidence of new disease

ALC in peripheral blood of <4 x 109/L

Regression of all index nodal masses to normal size (1.5 cm in the LD)

Normal spleen and liver size

Regression to normal of all nodal non-index disease and disappearance of all detectable 
non-nodal, non-index disease

Morphologically negative bone marrow defined as <30% of nucleated cells being lymphoid 
cells and no lymphoid nodules in a bone marrow sample that is normocellular for age

Peripheral blood counts meeting all of the following criteria:
ANC >1.5 x 109/L without need for exogenous growth factors (eg, G-CSF)
Platelet count 100 x 109/L without need for exogenous growth factors or transfusions
Hemoglobin 110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (eg, erythropoietin)
Note: Subjects who fulfill all the criteria for a CR (including bone marrow criteria) but who 
have a persistent anemia, thrombocytopenia, or neutropenia or a hypocellular bone marrow 
that is related to prior or ongoing drug toxicity (and not to CLL) will be considered as a CR 
with incomplete marrow recovery (CRi).
7.5.2.
Partial Response
To satisfy criteria for a PR, all of the following criteria must be met:

No evidence of new disease

A change in disease status meeting 2 of the following criteria, with 2 exceptions in which 
only 1 criterion is needed: (1) Only lymphadenopathy is present at baseline; 
(2) Only lymphadenopathy and lymphocytosis are present at baseline. In these 2 cases, only 
lymphadenopathy must improve to the extent specified below:


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In a subject with baseline lymphocytosis (ALC4 x 109/L), a decrease in 
peripheral blood ALC by 50% from baseline or a decrease to <4 x 109/L
A decrease by 50% from the baseline in the SPD of the index nodal lesions
In a subject with enlargement of the spleen at baseline, a splenomegaly response, defined 
as a ≥50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen or 
decrease to ≤12 cm in the LVD by imaging
In a subject with enlargement of the liver at baseline, a hepatomegaly response, defined 
as a ≥50% decrease (minimum 2 cm) from baseline in the enlargement of the liver or 
decrease to ≤18 cm in the LVD by imaging
A decrease by 50% from baseline in the CLL marrow infiltrate or in 
B-lymphoid nodules

No index, splenic, liver, or non-index disease with worsening that meets the criteria for 
definitive PD

Peripheral blood counts meeting 1 of the following criteria:
ANC >1.5 x 109/L or 50% increase over baseline without need for exogenous growth 
factors (eg, G-CSF)
Platelet count 100 x 109/L or 50% increase over baseline without need for 
exogenous growth factors or transfusions
Hemoglobin 110 g/L (11.0 g/dL) or 50% increase over baseline without red blood cell 
transfusions or need for exogenous growth factors (eg, erythropoietin)
7.5.3.
Stable Disease
To satisfy criteria for stable disease (SD), the following criteria must be met:

No evidence of new disease

There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD
7.5.4.
Definitive Progressive Disease
The occurrence of any of the following events indicates definitive PD:

Evidence of any new disease:
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD
New or recurrent splenomegaly, with a minimum LVD of 14 cm


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New or recurrent hepatomegaly, with a minimum LVD of 20 cm
Unequivocal reappearance of an extra-nodal lesion that had resolved
A new unequivocal extra-nodal lesion of any size
New non-index disease (eg, effusions, ascites, or other organ abnormalities 
related to CLL)
Note: Isolated new effusions, ascites, or other organ abnormalities are not sufficient evidence 
alone of PD unless histologically confirmed. Thus, a declaration of PD should not be made if 
this is the only manifestation of apparently new disease.

Evidence of worsening of index lesions, spleen or liver, or non-index disease:
Increase by 50% from the nadir in the SPD of index lesions
Increase from the nadir by 50% in the LD of an individual node or extra-nodal mass that 
now has an LD of >1.5 cm and an LPD of > 1.0 cm
Splenic progression, defined as an increase in splenic enlargement by 50% from nadir 
(with a minimum 2 cm increase and a minimum LVD of 14 cm)
Hepatic progression, defined as an increase in hepatic enlargement by 50% from nadir 
(with a minimum 2 cm increase and minimum LVD of 20 cm)
Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or other 
organ abnormalities related to CLL) 
Transformation to a more aggressive histology (eg, Richter syndrome) as established by 
lymph node or other tissue biopsy, or fluid cytology (with the biopsy or fluid cytology 
date being considered the date of CLL progression if the subject has no earlier objective 
documentation of CLL progression).

Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to an 
autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an infiltrate of 
clonal CLL cells
The current platelet count is <100 x 109/L and there has been a decrease by >50% from 
the highest on-study platelet count
The current hemoglobin is <110 g/L (11.0 g/dL) and there has been a 
decrease by >20 g/L (2 g/dL) from the highest on-study hemoglobin
Note: If there is uncertainty regarding whether there is true progression, the subject should 
continue study treatment and remain under close observation 
(eg, evaluated at 4-week intervals) pending confirmation of progression status by the IRC. In 
particular, worsening of constitutional symptoms in the absence of objective evidence of 


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worsening CLL will not be considered definitive disease progression; in such subjects, both 
CLL-related and non-CLL-related causes for the constitutional symptoms should be 
considered. Worsening of disease during temporary interruption of study treatment 
(eg, for intercurrent illness) is not necessarily indicative of resistance to study treatment. In 
these instances, CT/MRI or other relevant evaluations should be considered in order to 
document whether definitive disease progression has occurred. If subsequent evaluations 
suggest that the subject has experienced persistent definitive CLL progression, then the date of 
progression should be the timepoint at which progression was first objectively documented.
7.5.5.
Non-Evaluable
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE:

There are no images or inadequate or missing images

Images of the liver and spleen are missing at that time point (with the exception that absence 
of splenic images will not result in an NE designation in a subject known to have 
undergone splenectomy).
Note: A time-point will be considered to have a response of NE if any index lesion is missing. 
PD may be assigned at any time point regardless of the extent of missing index or 
non-index lesions. Missing non-index lesions will not impact the ability to assess for response 
or disease progression.
7.5.6.
No Disease
Subjects have a status of ND if all of the following conditions occur:

No index disease noted at baseline or on-treatment 

No non-index disease noted at baseline or on-treatment.

No enlargement of the liver or spleen at baseline or on-treatment

No abnormalities of peripheral blood counts (elevated ALC or abnormally low ANC, 
platelet count, or hemoglobin) and no evidence of CLL in bone marrow (if available) at 
baseline or on treatment
7.5.7.
Lymphocytosis During Therapy
Idelalisib can mobilize CLL cells from tissues into the peripheral blood. This characteristic 
pharmacological action can be prominent early in therapy but can persist over time and should 
not be confused with disease progression in subjects who have persistent control of other 
CLL-related signs and symptoms. In the absence of other objective evidence of disease 
progression, lymphocytosis alone will not preclude subjects from meeting the criteria for PR if 
other criteria for PR are met and will not be considered evidence of disease progression if 
occurring in isolation. Subjects with lymphocytosis should be continued on study drug until the 


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occurrence of definitive disease progression (ie, disease progression that is manifest by 
worsening CLL-related signs other than lymphocytosis alone), or the occurrence of another 
reason to discontinue study therapy as described in Section 5.8.
7.5.8.
Documentation of Definitive CLL Progression
Of importance, CLL response and progression data collected from the primary study will be 
subjected to IRC review (see Section 10.4.2). Subjects must have confirmation by the sponsor 
working in collaboration with the IRC that the disease has progressed on the primary clinical 
trial (Study GS-US-312-0116) before being permitted to receive secondary idelalisib therapy 
on this extension trial (GS-US-312-0117). Subjects should continue study drug pending 
confirmation of progression status. CT/MRI should be attempted in order to document definitive 
disease progression by the IRC. The end-of study scan from the primary study can serve as the 
baseline scan for the extension study if obtained within the specific screening period for the 
extension study. If obtained within the specified screening period for the extension study, this 
scan can serve as the baseline scan for the extension study.


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8.
SAFETY ASSESSMENTS
8.1.
Adverse Event Definitions
8.1.1.
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical product which; does not necessarily have a causal relationship 
with study drug administration or usage. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Lymphocytosis

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 5.2.8)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
In this study, any of the following events will be considered an adverse event:

Any complication that occurs as a result of a protocol-mandated procedure 
(eg, venipuncture, biopsy) in the screening, on-treatment, or post-treatment periods.

Any pre-existing condition that increases in severity or changes in nature during or as a 
consequence of study drug administration. Worsening manifestations of the underlying 
cancer (eg, increase in pain, tumor flare reaction, tumor lysis syndrome) may be considered 
adverse events in this study.


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
Any injury or accident occurring during the screening, on-treatment, or post-treatment 
periods. If a medical condition is known to have caused the injury or accident 
(eg, a fall secondary to dizziness), the medical condition (dizziness) and the accident (fall) 
should be reported as 2 separate adverse events. 

Any abnormality in physiological testing or a physical examination finding that requires 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test).

Any laboratory (eg, clinical chemistry, hematology, urinalysis) or investigational abnormality 
(eg, ECG, X-ray) independent of the underlying medical condition that requires clinical
intervention, results in further investigation (beyond ordering a repeat [confirmatory] test), or 
leads to investigational medicinal product interruption or discontinuation unless it is
associated with an already reported clinical event. If the laboratory abnormality is part of a 
syndrome, the syndrome or diagnosis (eg, anemia) not the laboratory result 
(eg, decreased hemoglobin) should be recorded. 

A complication related to pregnancy or termination of a pregnancy (see Section 5.4.9 for 
additional information).
8.1.2.
Serious Adverse Event
A serious adverse event (SAE) is defined as an event that results in any of the following:

Death

Life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization.

Persistent or significant disability/incapacity.

A congenital anomaly/birth defect

A medically important event or reaction. Such events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the outcomes listed above. Examples of such events 
might include:
Allergic bronchospasm requiring intensive treatment in an emergency room or at home
New cancers or blood dyscrasias
Convulsions that do not result in hospitalization
Development of drug dependency or drug abuse


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Medical and scientific judgment must be exercised to determine whether such an event is 
reportable under expedited reporting rules.
Infections resulting from contaminated medicinal product will be considered a medically 
important event and subject to expedited reporting requirements.
Given the endpoints of the study, in order to maintain the integrity of the study the following 
events that are assessed as unrelated to IMP will not be considered SAEs:

Progression of CLL

Death related to progression of CLL
Disease progression and death from disease progression should be reported as SAEs by the 
investigator only if it is assessed that the IMPs caused or contributed to the disease progression 
(i.e., by a means other than lack of effect). Unrelated disease progression and death due to 
disease progression should be captured on the eCRF.
These events will be reported, as appropriate, in the final clinical study report and in any relevant 
aggregate safety reports. The safety information from this study will also be reviewed by an 
independent DMC on an ongoing basis. The DMC can have access to partially blinded or 
unblinded data in order to determine if it is safe to continue the study according to the protocol.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Section 8.5. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result 
(ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 5.4.
8.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.


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8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting.
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed from screening 
onwards.
All AEs, regardless of cause or relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP must be reported to the CRF/eCRF database as 
instructed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported.
All AEs should be followed up until resolution if possible. If by the last day on study 
(including the off-study medication follow-up period) the AE has not resolved, then the AE will 
be followed up until the investigator and/or Gilead Sciences determine that the subject's 
condition is stable. However, Gilead Sciences may request that certain AEs be followed until 
resolution.


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Investigators are not obligated to actively seek SAEs after the above period. However, if the 
investigator learns of any SAEs that occur after study participation has concluded and the event 
is deemed relevant to the use of IMP, he/she should promptly document and report the event to 
Gilead DSPH.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.

At the time of study start, SAEs will be reported using a paper serious adverse event 
reporting form. During the study conduct, sites may transition to an electronic SAE (eSAE) 
system. Gilead will notify sites in writing and provide training and account information prior 
to implementing an eSAE system.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by faxing 
the report form within 24 hours of the investigator’s knowledge of the event to the attention 
of Gilead DSPH or to the designated CRO.
8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to expedite 
to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the 
EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide 
regulatory agencies and the relevant IEC in concerned Member States of applicable SUSARs as 
outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the IRB or IEC of SUSAR reports as soon as is practical, where this is 
required by local regulatory agencies, and in accordance with the local institutional policy.
8.5.
Grading of the Severity of an Adverse Event
The severity of adverse events will be graded using the CTCAE, Version 4.03 (provided in 
study manual and available at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). For 
each episode, the highest severity grade attained should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or 
Grade 5 (fatal) to describe the maximum intensity of the adverse event. For purposes of 
consistency with the CTCAE, these intensity grades are defined in Table 8-1.


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Table 8-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Sign or symptom is present, but it is easily tolerated, is not expected to have a 
clinically significant effect on the subject’s overall health and well-being, does not 
interfere with the subject’s usual function, and is not likely to require medical 
attention.
Grade 2
Moderate
Sign or symptom causes interference with usual activity or affect clinical status, and 
may require medical intervention.
Grade 3
Severe
Sign or symptom is incapacitating or significantly affects clinical status and likely 
requires medical intervention and/or close follow-up.
Grade 4
Life-threatening
Sign or symptom results in a potential threat to life.
Grade 5
Fatal
Sign or symptom results in death.
The distinction between the seriousness and the severity of an adverse event should be noted. 
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For 
example, a headache may be severe in intensity, but would not be classified as serious unless it 
met one of the criteria for serious events listed in Section 8.1.2 above.
8.6.
Adverse Event Reporting Period
The start of the adverse event reporting for a study subject will coincide with signing of the 
informed consent for Study GS-US-312-0117. Any new adverse events occurring thereafter 
should not be reported within Study GS-US-312-0116, but instead should be reported within
Study GS-US-312-0117. The end of the adverse-event-reporting period for 
Study GS-US-312-0117 occurs 30 days after the discontinuation from study drug or when any 
ongoing drug-related adverse events and/or serious adverse events have resolved or become 
stable. A subject withdrawn from the study because of an adverse event must be followed until 
the clinical outcome from the adverse event is determined. The investigator should use 
appropriate judgment in ordering additional tests as necessary to monitor the resolution of events 
ongoing at the completion of study treatment. Gilead Sciences may request that certain adverse 
events be followed longer.
Investigators are not obligated to actively seek information regarding the occurrence of new 
serious adverse events beginning after the 30-day post-study period. However, if the investigator 
learns of such a serious adverse event and that event is deemed relevant to the use of the study 
drug, he/she should promptly document and report the event. A longer reporting period applies in 
the case of pregnancy (see Section 8.9.1)
8.7.
Adverse Event Reporting Requirements
8.7.1.
Site Reporting Requirements
Classification of an event as serious or nonserious (see Section 8.1.2) determines the reporting 
procedures to be followed by the site.


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Site reporting requirements for adverse events are summarized in Table 8-2, below.
Table 8-2.
Site Reporting Requirements for Adverse Events
Classification
Reporting Time
Reporting Action
Serious
Within 24 hours
Fax report on designated serious adverse event report form 
to PPD Pharmacovigilancea, and to the site IRB/IEC, 
as per local IRB/IEC requirements; include copies of 
relevant source documentsb (eg, progress notes, 
autopsy reports, laboratory and diagnostic test results, 
discharge summaries) in communication to 
PPD Pharmacovigilancea
Per eCRF submission procedurec
Record and submit information on appropriate eCRFs
Nonserious
Per eCRF submission procedure
Record and submit information on appropriate eCRFs
a
See contact information in Table 8-3 below.
b
Subject name, address, and other personal identifiers should be obscured but without losing the traceability of a document to
the study subject identifiers.
c
CLL progression or death due to CLL progression should be reported by the investigator as a serious adverse event only if it 
is assessed that the study drugs caused or contributed to the CLL progression (ie, by a means other than lack of effect). 
Unrelated events of CLL progression should be captured on the appropriate eCRF. 
Abbreviations: CLL = chronic lymphocytic leukemia, eCRF=case report form, IRB/IEC= Institutional Review Board/
Independent Ethics Committee
For serious adverse events, in addition to completing the adverse event portion of the eCRF, the 
serious adverse event report form must also be completed. The information in the adverse event 
portion of the eCRF page and the serious adverse event report form(s) must match or be 
reconciled. Where the same data are collected, the forms must be completed in a consistent 
manner. For example, the same adverse event term should be used on both forms. Particularly for 
fatal or life-threatening events, copies of progress notes, autopsy reports, laboratory and 
diagnostic test results, discharge summaries, and other relevant documents should be faxed when 
requested and applicable. Follow-up information to the serious adverse event should be clearly 
documented as “follow up” in the serious adverse event report form and must be faxed to these 
same parties. Gilead Sciences may request additional information from the investigator to ensure 
the timely completion of accurate safety reports.
The subject’s name, address, and other personal identity information should be obscured on any 
source documents (eg, progress notes, nurses’ notes, laboratory and diagnostic test results, 
discharge summaries). Only the subject’s study number, initials, or date of birth are to be 
provided.
The serious adverse event report form must be communicated to PPD Pharmacovigilance and to 
the site IRB/IEC (if required by local regulations) within 24 hours. In the rare event that the 
investigator does not become aware of the occurrence of a serious adverse event immediately 
(for example, if a subject initially seeks treatment elsewhere), the investigator is to report the 
event within 24 hours after learning of it and to document his/her first awareness of the adverse 
event.


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Contact details for PPD Pharmacovigilance and for the Gilead study medical monitor are 
provided in Table 8-3:
Table 8-3.
Contact Information for Reporting Serious Adverse Events
Function
Contact Information
PPD Pharmacovigilance
(US)
Facsimile:
PPD Pharmacovigilance
(International)
Facsimile:
Gilead Sciences
Medical Monitor
Name:
Title:
Associate Director, Clinical Research
Office Telephone:
Mobile Telephone:
Facsimile:
E-mail:
8.7.2.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population
To maintain the integrity of the study, progression of CLL and death related to progression of 
CLL will not be reported to Gilead Sciences as serious adverse events unless it is assessed that 
the study drug caused or contributed to CLL progression or death related to CLL progression 
(ie, by a means other than lack of effect). These events will be exempt from global expedited 
reporting requirements for the duration of the study because they define the primary efficacy 
endpoint for this study. All events of progression of CLL and death related to progression of 
CLL, regardless of relationship to study drug, will be reported in the eCRFs and, as appropriate, 
in the final clinical study report and in any relevant aggregate safety reports. Disease progression
information from this study will be reviewed by an independent DMC on an ongoing basis.
8.8.
Special Situations Reporting Requirements
8.8.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, lack of 
effect reports and pregnancy reports regardless of an associated AE. Also includes reports of 
adverse reactions in infants following exposure from breastfeeding, and reports of adverse 
reactions associated with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following possible maternal or paternal 
exposure to the medicinal product.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Lack of effect is defined as a situation where there is apparent failure of the medicinal product or 
medical technology to bring about the intended beneficial effect on the individual in a defined 
population with a given medical problem, under ideal conditions of use.
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
8.9.
Instructions for Reporting Special Situations
8.9.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (ie, signs the informed consent) and throughout the study, including the 
post study drug follow-up period, to the  or Gilead DSPH ] using the pregnancy report form 
within 24 hours of becoming aware of the pregnancy. Refer to the CRF/eCRF completion 
guidelines for full instructions on the mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE, and therefore should be reported as 
such. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must be 
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The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to PPD Pharmacovigilance or Gilead DSPH using 
the pregnancy outcome report form. If the end of the pregnancy occurs after the study has been 
completed, the outcome should be reported directly to Gilead DSPH. Gilead DSPH 
contact information is as follows: Email:
 and Fax:
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to PPD Pharmacovigilance 
or Gilead DSPH using the pregnancy and pregnancy outcome forms within 24 hours. Monitoring 
of the subject should continue until the conclusion of the pregnancy. If the end of the pregnancy 
occurs after the study has been completed, the outcome should be reported directly to 
Gilead DSPH, fax number
 or email 
8.9.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to PPD Pharmacovigilance or Gilead DSPH within 24 hours of the investigator 
becoming aware of the situation. These reports must consist of situations that involve study IMP, 
but do not apply to concomitant medications. Except for situations that result in AEs, special 
situations involving concomitant medications will not be reported. Any inappropriate use of 
medications prohibited by this protocol should not be reported as “misuse,” but may be more 
appropriately documented as a protocol deviation.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.
PPD
PPD
PPD
PPD


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9.
STATISTICAL CONSIDERATIONS
9.1.
Analysis Objectives
As described in Section 3, the objectives of this clinical trial will focus on determining the effect 
of idelalisib on the onset, magnitude, and duration of tumor control; measures of patient 
well-being (including OS, HRQL; and changes in subject performance status); disease-associated
biomarkers and potential mechanisms of resistance; treatment administration; safety; and health 
resource utilization.
9.2.
Analysis Endpoints
The endpoints of the study are defined in Section 3.1, grouped in categories relating to tumor 
control, patient well-being, pharmacodynamic markers of drug activity and resistance, exposure, 
safety, and pharmacoeconomics.
9.3.
Analysis Conventions
9.3.1.
Analysis Sets
9.3.1.1.
Intent-to-Treat Analysis Set
The ITT analysis set includes all subjects who receive 1 dose of any study treatment 
(high-dose idelalisib or standard-dose idelalisib). In the ITT analysis set, study drug assignment 
will be designated according to planned allocation in this study, regardless of whether subjects 
receive a different study therapy from that to which they were allocated.
This analysis set will be used in the analyses of subject characteristics and all the tumor control 
and patient well-being endpoints. Subjects in the ITT analysis set who do not have sufficient 
baseline or on-study tumor status information to be adequately assessed for response status will 
be included in the denominators in the calculation of response rates.
9.3.1.2.
Per-Protocol Analysis Set
The PP analysis set includes data from subjects in the ITT analysis set who meet the general 
criteria defining the target population for this study, are adherent to the protocol, are compliant 
with study drug treatment, and are evaluable for relevant efficacy endpoints. Treatment 
assignment will be designated according to the actual treatment received. The specific 
classification of subjects to be included in the PP analysis set will be included in the statisticial 
analysis plan which will be finalized prior to the database lock.
The PP analysis set will be used in sensitivity analyses of these tumor control and patient 
well-being endpoints: PFS, ORR, lymph node response rate, OS and CR rate.


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9.3.1.3.
Safety Analysis Set
A safety analysis set will include subjects in the ITT analysis set grouped for analyses with 
treatment assignments designated according to the actual study drug received.
This analysis set will be used in the analyses of safety variables as well as study treatment 
administration, and health economic variables.
9.3.1.4.
Pharmacodynamic and/or Pharmacokinetic Analysis Sets
The pharmacodynamic and/or pharmacokinetic analysis sets include data from subjects in the 
safety analysis set who have the necessary baseline and on-study measurements to provide 
interpretable results for the specific parameters of interest. 
These analysis sets will be used in the analyses of AKT phosphorylation, chemokines/cytokines, 
and idelalisib plasma concentrations.
9.3.2.
Data Handling Conventions
9.3.2.1.
General Methods 
By-subject listings will be created for important variables from each eCRF module. 
Summary tables for continuous variables will contain the following statistics: 
N (number in population), n (number with data), mean, standard deviation, 
95% confidence intervals (CIs) on the mean, median, minimum, and maximum. Summary tables 
for categorical variables will include: N, n, percentage, and 95% CIs on the percentage. Unless 
otherwise indicated, 95% CIs for binary variables will be calculated using the binomial 
distribution (exact method) and will be 2-sided. Data will be described and summarized by 
relevant treatment arm, analysis set, and timepoint. As appropriate, changes from baseline to 
each subsequent timepoint will be described and summarized by treatment arm. Similarly, as 
appropriate, the best change from baseline during the study will also be described and 
summarized by treatment arm. Graphical techniques (eg, waterfall plots, 
Kaplan-Meier curves, line plots) may be used when such methods are appropriate and 
informative.
Data from all sites will be pooled for all analyses. Analyses will be based upon the observed data 
unless methods for handling missing data are specified. If there is a significant degree of 
non-normality, analyses may be performed on log-transformed data or nonparametric tests may 
be applied, as appropriate.


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9.3.2.2.
Double-Blinded Portion of the Study Analyses
Efficacy and safety data collected during the blinded portion of Study GS-US-312-0117 will be 
presented in the following 2 groups:

•IDELA 300 mg BID: Subjects who have PD per IRC confirmation in Arm A of 
Study GS-US-312-0116 and subsequently enroll into Study GS-US-312-0117 to receive 
IDELA 300 mg BID during the double-blind portion of the study

•Placebo in Study GS-US-312-0116 + IDELA 150 mg BID in Study GS-US-312-0117: 
Subjects who have PD per IRC confirmation in Arm B of Study GS-US-312-0116 and 
subsequently enroll Study GS-US-312-0117 to receive IDELA 150 mg BID during the 
double-blind portion of the study
All analyses will be performed based on the data collected during the blinded-portion of the 
extension study. Time-to-event analyses will reference to the date of first treatment on this 
clinical trial (Study GS-US-312-0117). Similarly, evaluations of on-therapy changes will 
reference the baseline values obtained prior to treatment in this study. The baseline value used in 
each analysis will be the last (most recent) pre-treatment value. Analyses will be descriptive in 
nature and formal comparisons of outcomes in the 2 groups are not planned.
9.3.2.3.
Open-Label Extension Study Analyses
GS-US-312-0117 will become an open-label study offering idelalisib 150 mg BID to 
GS-US-312-0116 subjects who were randomized to Arm B. Subjects randomized to Arm A will 
continue idelalisib at 150 mg BID. Efficacy and safety data collected during the primary and 
open-label extension studies will be presented in the following 4 groups:

IDELA 150 mg BID: Subjects who are randomized to Arm A in Study GS-US-312-0116 and 
transition to Study GS-US-312-0117 during the open-label portion of the study to continue 
IDELA 150 mg BID

Placebo in GS-US-312-0116 + IDELA 150 mg BID (open-label): Subjects who are 
randomized to Arm B in Study GS-US-312-0116 and transition to receive 
IDELA 150 mg BID during the open-label portion of the study

IDELA 300 mg BID: Subjects who have PD per IRC confirmation in Arm A of 
Study GS-US-312-0116 and subsequently enroll Study GSUS-312-0117 to receive 
IDELA 300 mg BID during double-blind portion of the study

Placebo in GS-US-312-0116 + IDELA 150 mg BID in GS-US-312-0117: Subjects who have 
PD per IRC confirmation in Arm B of Study GS-US-312-0116 and subsequently enroll 
Study GS-US-312-0117 to receive IDELA 150 mg BID during double-blind portion of the 
study.


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Depending on the endpoints, analyses may be based on the combined data from both primary and 
extension studies or data from the extension study alone. Analyses will be descriptive in nature 
and formal comparisons of outcomes in the 4 groups are not planned. A separate statistical 
analysis plan will be created for the open-label portion of the study.
9.3.2.4.
Calculation of Tumor Control and Patient Well-Being Variables
Tumor control assessments will be based on standardized IWCLL criteria {12154} {22541}, as 
specifically modified for this study considering the pharmacology of idelalisib. The individual 
and composite endpoints of response and progression (considering changes in lymph node area, 
liver and spleen size, bone marrow, platelet counts, hemoglobin, neutrophil counts, and 
peripheral blood lymphocyte counts) will be determined. Tumor control will be documented at 
each assessment by response category (eg, CR, PR, SD, definitive PD, NE, ND) as defined for 
each response parameter, SPD value, percentage change in SPD values from baseline or nadir, 
date that response is first documented and date of definitive CLL progression.
The date of definitive CLL progression will be the timepoint at which progression is 
first identified by relevant objective radiographic or laboratory data. Because of the characteristic 
redistribution lymphocytosis that is expected with PI3Kinhibition, lymphocyte count will be 
ignored in the evaluation of progression. Changes in tumor status as provided by the investigator 
and changes in tumor status as adjudicated by the IRC (see Section 10.4.2) will be described. 
The findings of the IRC will be considered primary for analyses of all tumor control endpoints.
The following censoring conventions will be applied:

PFS and DOR: Data from surviving, non-progressing subjects will be censored at the earliest 
of the time of initiation of antitumor treatment other than the study treatment or the last time 
that lack of definitive CLL progression was objectively documented. Data from subjects who 
have CLL progression or die after 2 consecutive missing tumor assessments will be 
censored at the last time prior to the missing assessments that lack of definitive CLL 
progression was objectively documented.

OS: Data from surviving subjects will be censored at the last time that the subject was known 
to be alive.
9.4.
Analysis Plan
9.4.1.
Subject Disposition and Baseline Characteristics
A listing of all ITT analysis subjects will be generated to describe site, subject number, 
first screening date, first treatment date, allocated study drug assignment, actual study drug 
assignment, the longest duration of study drug treatment, and the reason for discontinuing study 
treatment. Available information on subjects who were screened or registered but not treated will 
be listed separately. A table will be created summarizing these categories in terms of number and 
percent for the ITT analysis set.


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Subject baseline characteristics will be listed and summarized by treatment arm for the 
ITT analysis set. As appropriate for the specific variable, subject baseline characteristics
acquired in Study GS-US-312-0116 will be referenced in Study GS-US-312-0117.
9.4.2.
Efficacy Analyses
9.4.2.1.
Time-to-Event Tumor Control and Survival Endpoints
PFS, DOR and OS will be described in the ITT analysis set using Kaplan-Meier methods by 
treatment group. Medians, ranges, and corresponding 95% CIs will be presented.
The Cox regression approach may be used to explore the influence of the primary study 
stratification factors and other baseline characteristics on PFS and OS. The stratification 
variables from the primary study and additional baseline subject characteristics may be included 
as covariates, focusing on those with expected prognostic significance.
9.4.2.2.
Categorical Endpoints
Response rates, lymph node response rate, splenomegaly response rate, 
hepatomegaly response rate, ALC response rate, platelet response rate, hemoglobin response 
rate, and neutrophil response rate will be described. In the calculation of response rates, subjects 
who do not have sufficient baseline or on-study tumor assessment to characterize response will 
be included in the denominator. For all analyses, the corresponding 95% CIs will be presented.
The potential influence of subject baseline characteristics on response rates may be explored
with multiple logistic regression modeling.
9.4.2.3.
Continuous Endpoints
Changes in lymph node area and changes in performance status, PI3K/AKT/mTOR pathway 
activation, and plasma chemokines/cytokines will be assessed by treatment group. Both changes 
from baseline to each subsequent timepoint and best overall on-study changes will be analyzed 
using appropriate methods (eg, analysis of covariance [ANCOVA] or paired t-tests). Means and 
standard errors will be presented.
9.4.2.4.
Health-Related Quality of Life and Performance Status
The FACT-Leu questionnaire data will be scored and processed according to the user manual. 
Missing items in a subscale will be imputed consistent with the user manual instructions. Data 
collected from the FACT-Leu instrument will not be reconciled with adverse event or laboratory 
data or with EQ-D5 findings.
As a baseline, the last value obtained prior to receiving the first idelalisib dose of 
150 mg and 300 mg will be used, depending on the treatment group assigned.
The mean and change from baseline in mean scores to each subsequent assessment will be 
summarized for the FACT-Lym subscale and composite scores. The best change from baseline 
during the study, defined as the highest positive value among all post-baseline visits minus 
the baseline value, will also be summarized.


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9.4.3.
Exposure and Safety Analyses
9.4.3.1.
Treatment Administration and Study Drug Compliance
Descriptive information will be provided by treatment arm regarding the number of doses of 
study therapy prescribed, the total number of doses taken, the percent of expected doses taken, 
the number of days of treatment, and the number and timing of prescribed dose reductions and 
interruptions.
Study drug compliance will be described by treatment arm in terms of the proportion of study 
drug actually taken based on returned pill count relative to the amount that was dispensed 
(taking into account physician-prescribed reductions and interruptions).
9.4.3.2.
Idelalisib Plasma Concentrations
Bioanalytical analyses will performed independently so that the study team and investigators will 
not have knowledge of data from individual subjects. Idelalisib plasma concentrations
immediately pre-dose and at 1.5 hours after administration of the dose of study drug at each 
relevant clinic visit will be summarized by treatment and visit using descriptive statistics.
9.4.3.3.
Prior, Concomitant, and Post-Treatment Medication Use
Prior, concomitant, and post-treatment medications will be coded by means of the 
World Health Organization Drug Dictionary (WHODRUG) dictionary into 
Anatomical-Therapeutic-Chemical classification (ATC) codes.
Descriptions of prior medication use will be focused on drugs and regimens used as treatments 
for CLL. Information regarding CLL therapy that was administered prior to 
Study GS-US-312-0116 will be referenced in reporting the results of Study GS-US-312-0117. In 
addition, relevant treatment administration information collected during Study GS-US-312-0116 
will be referenced in reporting the results of this study. As appropriate and if available, 
information on the sequencing, type, dose, schedule, timing, duration of use, and efficacy of 
prior regimens will be provided, focusing particularly on findings observed in 
Study GS-US-312-0116.
The type and timing of use of concomitant medications will be listed and summarized by type 
and treatment arm. Information regarding the type and use of specific supportive medications 
(eg, pneumocystis prophylaxis, hematopoietic growth factors, corticosteroids) during study 
treatment will be described.
The number, type, and timing of post-study-treatment regimens for CLL will be summarized by 
treatment arm, characterizing the disposition of all subjects who were eligible for post-study 
treatment and also those who were not eligible for post-study treatment (eg, subjects who are 
never treated at all, die while on study treatment, are still on study, are lost to follow-up, etc).


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9.4.3.4.
Adverse Events
All adverse events will be listed. The focus of adverse event summarization will be on 
treatment-emergent adverse events. A treatment-emergent adverse event is defined as an adverse 
event that occurs or worsens in the period from the first dose of study treatment to 30 days after 
the last dose of study treatment.
Adverse events will be classified using MedDRA (http://www.meddramsso.com) with 
descriptions by System Organ Class, High-Level Group Term, High-Level Term, 
Preferred Term, and Lower-Level Term. The severity of adverse events will be graded by the 
investigator according to the CTCAE, Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf), 
whenever possible. If a CTCAE criterion does not exist for a specific type of adverse event, the 
grade corresponding to the appropriate adjective will be used by the investigator to describe the 
maximum intensity of the adverse event: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), 
Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the adverse event to the study 
drug will be categorized as related or unrelated.
Treatment-emergent adverse events will be summarized by treatment arm and by visit. 
Summary tables will be presented to show the number of subjects reporting treatment-emergent 
adverse events by severity grade and corresponding percentages. A subject who reports multiple 
treatment-emergent adverse events within the same Preferred Term (or System Organ Class) is 
counted only once for that Preferred Term (or System Organ Class) using the worst severity 
grade. Adverse event descriptions will be presented by decreasing frequency for a given 
System Organ Class and Preferred Term.
Separate listings and summaries will be prepared for the following types of treatment-emergent 
adverse events:

Study-drug-related adverse events

Adverse events that are Grade 3 in severity

Adverse events leading to study drug interruption and/or dose modification

Adverse events leading to study drug discontinuation

Serious adverse events (with categorization of the primary reason that the adverse event is 
considered serious, eg, death, hospitalization, etc)
Separate listings and summaries will be prepared for long-term follow-up safety data 
(see Section 6.2.17).
9.4.3.5.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed data. 
The focus of laboratory data summarization will be on treatment-emergent laboratory 
abnormalities. A treatment-emergent laboratory abnormality is defined as an abnormality that, 


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compared to baseline, worsens by 1 grade in the period from the first dose of study drug to
30 days after the last dose of study drug. If baseline data are missing, then any graded 
abnormality (ie, an abnormality that is Grade 1 in severity) will be considered treatment 
emergent. Hematological, serum biochemistry, and urine data will be programmatically graded 
according to CTCAE severity grade, when applicable. For parameters for which a CTCAE scale 
does not exist, reference ranges from the central laboratory will be used to determine 
programmatically if a laboratory parameter is below, within, or above the normal range for the 
subject’s age, sex, etc.
Hematological and serum biochemistry and their changes from baseline will be summarized by 
treatment arm and by visit. Summary tables will be presented for each relevant assay to show the 
number of subjects by CTCAE severity grade with corresponding percentages. For parameters 
for which a CTCAE scale does not exist, the frequency of subjects with values below, within, 
and above the normal ranges will be summarized. Subjects will be characterized only once for a 
given assay, based on their worst severity grade observed during a period of interest 
(eg, during the study or from baseline to a particular visit).
Shift tables for hematology and serum biochemistry will also be presented by showing change in 
CTCAE severity grade from baseline to the worst grade post baseline. Separate listings and 
summaries will be prepared for laboratory abnormalities that are Grade 3 in severity.
9.4.3.6.
Oxygen Saturation Values
All oxygen saturation data will be listed. Summaries of oxygen saturation data will be based on 
observed data and will be reported as % saturation. Data and changes from baseline will be 
summarized by treatment arm and by visit. Summary tables will be presented for values 
below 92% and for declines from baseline of 5% to show the number of subjects with 
corresponding percentages. Subjects will be characterized only once for each of these 
categorizations, based on their lowest value observed during a period of interest 
(eg, during the study or from baseline to a particular visit).
9.4.4.
Other Analyses
9.4.4.1.
Between-Study Comparisons
It is expected that patients with a progressive malignancy like CLL will normally fare better with 
an earlier therapy than with a later therapy. However, if the converse situation proves true –
eg, if an investigational treatment (idelalisib) administered later shows similar or greater benefit 
than a standard treatment (rituximab) administered earlier – strong evidence of investigational 
drug effect is demonstrated. Evaluating data derived from the same study subjects during their 
sequential participation in 2 clinical trials offers unique analytical challenges. However, in this 
integrated Phase 3 study program, it is likely that comparing baseline characteristics and 
outcomes among Arm B subjects participating in Study GS-US-312-0116 and 
Study GS-US-312-0117 will be informative. Such an evaluation characterizes how the subjects
and the CLL disease process change with time and treatment. In addition, such an analysis 
provides relevant supporting information documenting the benefits of single-agent idelalisib
relative to single-agent rituximab in the same subjects.


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Accordingly, baseline characteristics, time-to-event efficacy variables (eg, PFS, TTR, DOR), 
categorical variables (eg, ORR, lymph node response rate, splenomegaly response rate, 
hepatomegaly response rate), and continuous variables (eg, percentage changes in 
lymph node area; changes in performance status, PI3K/AKT/mTOR pathway activation and 
plasma chemokines/cytokines)  may be evaluated between Study GS-US-312-0116 and 
Study GS-US-312-0117 for Arm B subjects.
9.4.4.2.
Health Care Resource Utilization
The EQ-D5 questionnaire data will be scored, processed, and standardized according to the user 
manual. Change from baseline in EQ-5D visual analogue scale and EQ-5D index will be 
summarized. As for the FACT-Leu, data will be analyzed using appropriate methods to account 
for incomplete completion of questionnaires. Data collected from the EQ-D5 will not be 
reconciled with adverse event or laboratory data or with FACT-Leu findings.
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach to the health economic analysis will be to combine the resource utilization 
data from the trial with data on unit prices (collected separately) to estimate total costs.
The perspective of this analysis will be that of the third-party payer(s) and the hospital over a 
lifetime horizon in the base case. The costs will be described relative to the health care findings 
as measured by duration of tumor control, the symptom-free survival period, life-years, utility 
outcomes, or other measure of appropriate clinical benefits. In order to facilitate the calculation 
of utilities for use in the cost effectiveness analyses, the health status of subjects will be 
evaluated using PFS, Karnofsky performance status, FACT-Leu, and EQ-5D.
9.4.4.3.
Data Explorations
Changes in biomarkers during acquisition of resistance will be evaluated descriptively. Data 
explorations may be performed to evaluate potential associations between subject characteristics 
and outcome measures. Explorations may be performed to assess the potential associations 
between different outcomes measures (eg, relationships between HRQL changes and 
clinical/radiographic endpoints of tumor control).
9.5.
Sample Size
The sample size for this extension study is not based upon a formal statistical hypothesis. The 
upper bound of the sample size in this study is determined by the sample size of the preceding 
primary study (Study GS-US-312-0116) in which ~220 subjects (~110 per arm) are expected to 
be enrolled. It is estimated that this extension study (Study GS-US-312-0117) will have a total 
idelalisib-treated N~180 (assuming a ~10% dropout rate during Study GS-US-312-0116 and a 
further ~10% dropout rate in the transition from the primary study to the extension study).


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9.6.
Timing of Analyses
The DMC will have access to serious adverse events requiring expedited reporting and will be 
provided with accumulating safety data on a regular basis. Interim safety reviews will be 
conducted by the DMC in conjunction with safety reviews of the primary clinical trial
(Study GS-US-312-0116) if applicable. Thus, interim safety reviews will be performed by the 
DMC at intervals of ~6 months; the specific frequency of these reviews will depend upon the 
rate at which the trials are enrolled, the nature of any emerging safety signals, and monitoring 
recommendations from the DMC. At each review, all available safety data will be summarized 
and evaluated.
An interim efficacy analysis of this clinical trial (Study GS-US-312-0117) is planned to take 
place at the time of the final blinded analysis of the primary study (GS-US-312-0116). The intent 
is to provide the data from this extension study in support of regulatory review of data from the 
primary study. An analysis of efficacy and safety may be performed to satisfy regulatory 
requirements and to perform long-term efficacy, safety and OS follow-up. The timing of the final
analysis is expected to occur within 48 months of accrual of the final subject to 
Study GS-US-312-0117.


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
Compliance with Ethical and Regulatory Guidelines
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), with ICH guidelines, or with the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the study subject. These 
standards are consistent with the European Union Clinical Trials Directive 2001/20/EC and 
Good Clinical Practice Directive 2005/28/EC. The investigator will ensure adherence to the 
basic principles of GCP as outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and 
Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 1993, 
“Retention of Bioavailability and Bioequivalence Testing Samples.”
Because this is a “covered” clinical trial, the investigator will ensure adherence to 
21 CFR, Part 54, 1998; a covered clinical trial is any “study of a drug or device in humans 
submitted in a marketing application or reclassification petition subject to this part that the 
applicant or FDA relies on to establish that the product is effective (including studies that show 
equivalence to an effective product) or that make a significant contribution to the demonstration 
of safety.” This requires that investigators and all sub-investigators must provide documentation 
of their financial interest or arrangements with Gilead Sciences, or proprietary interests in the 
drug being studied. This documentation must be provided before participation of the investigator 
and any subinvestigator in the trial. The investigator or subinvestigator agrees to notify 
Gilead Sciences of any change in reportable financial interests during the study and for 1 year 
following completion of the study. Study completion is defined as the date that the last subject 
has completed the protocol-defined activities.
10.1.2.
Institutional Review Board/Independent Ethics Committee
This protocol and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) will be submitted by the investigator to an IRB (for sites enrolling in 
the United States) and to an IEC for sites enrolling outside of the United States). Approval from 
the IRB/IEC must be obtained before starting the study and should be documented in a letter to 
the investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.
Any modifications or amendments made to the protocol after receipt of the initial 
IRB/IECapproval must also be submitted to the IRB/IEC for approval before implementation.
Only changes necessary to eliminate apparent immediate hazards to the subjects may be initiated 
prior to IRB/IEC approval. In that event, the investigator must notify the IRB/IEC and 
Gilead Sciences in writing within 5 working days after implementation.


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The investigator shall submit a progress report, at least once yearly, to the IRB/IEC, and must 
provide a copy to Gilead Sciences. As soon as possible after completion or termination of the 
study, the investigator will submit a final report to the IRB/IEC and to Gilead Sciences. This 
report should include the dates of initiation and completion of the trial, a description of any 
changes in study procedures or amendments to the protocol, any deviations from the protocol, 
the number and type of subjects evaluated, the number of subjects who discontinued 
(and the reasons for discontinuation), the number of subjects who completed the trial, and the 
results of the trial, including a description of any adverse events. Gilead Sciences will assist the 
investigator in the preparation of this report, as needed.
10.1.3.
Informed Consent
After adequately, explaining the aims, methods, objectives, and potential hazards of the study 
and before undertaking any study-related procedures, the investigator is responsible for obtaining 
written informed consent from each individual participating in this study. The investigator must 
utilize an IRB/IEC-approved consent form for documenting written informed consent. Each 
informed consent will be appropriately signed and dated by the subject or the subject’s legally 
authorized representative and the person obtaining consent.
The approved informed consent must not be changed without prior approval by Gilead Sciences
and the IRB/IEC.
10.1.4.
Confidentiality
The investigator must assure that each subject’s anonymity will be strictly maintained and that 
each subject’s identity is protected from unauthorized parties. Only subject initials, date of birth, 
and an identification code (but no subject names) should be recorded on any form or biological 
sample submitted to the Gilead Sciences or designees (eg, laboratories), or to the IRB/IEC.
However, sufficient information must be retained at the site to permit sample data and data in the 
database to be connected with the unique subject number assigned to each study participant.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the idelalisib investigator brochure, this protocol, eCRFs, the investigational new drug, 
and any other study information, remain the sole and exclusive property of Gilead Sciences
during the conduct of the study and thereafter. This information is not to be disclosed to any 
third party (except employees or agents directly involved in the conduct of the study or 
as required by law) without prior written consent from Gilead Sciences. The investigator further 
agrees to take all reasonable precautions to prevent the disclosure by any employee or agent of 
the study site to any third party or otherwise into the public domain.
10.1.5.
Study Files and Retention of Records and Biological Samples
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator’s study file, and 
(2) subject clinical source documents.


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The investigator’s study file will contain the protocol/amendments, eCRF and query forms, the 
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data referenced in the monitoring plan for the study, and should include 
sequential notes containing at least the following information for each subject:

Subject identification (name, date of birth, gender)

Documentation that subject meets eligibility criteria, eg, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria)

Participation in trial (including trial number)

Trial discussed and date of informed consent

Dates of all visits

Documentation that protocol-specific procedures were performed

Results of efficacy parameters, as required by the protocol

Start and end date (including dose regimen) of trial medication (including relevant drug 
dispensing and return information)

Record of all adverse events and other safety parameters (including start and end date, 
causality and intensity)

Concomitant medication (including start and end date and dose if relevant dose changes 
occur)

Date of trial completion and reason for discontinuation, if applicable
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (ie, the United States, Europe, 
or Japan) and until there are no pending or contemplated marketing applications in an 
ICH region; or, if no application is filed or if the application is not approved for such indication, 
until 2 years after the investigation is discontinued and regulatory authorities have been notified. 
Investigators may be required to retain documents longer if required by applicable regulatory 
requirements, by local regulations, or by an agreement with Gilead Sciences. The investigator 
must notify Gilead Sciences before destroying any clinical study records. The investigator will 
promptly notify Gilead Sciences in the event of accidental loss or destruction of any study 
records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead Sciences must be notified in advance.


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If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead Sciences
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site.
Biological samples including tissue and blood samples collected as a study procedure or as 
standard of care during study participation will be stored and maintained by the investigator until 
notification is received from Gilead Sciences that the retained samples and records no longer 
required. The investigator must obtain written permission from Gilead Sciences before disposing 
of any retained samples. The investigator should promptly notify Gilead Sciences in the event of 
accidental loss or destruction of any study samples. With the permission of Gilead Sciences, the 
retained samples may be transferred to an acceptable designee, such as another investigator, 
another institution, a contract storage site, or to Gilead Sciences.
10.1.6.
Case Report Forms
An eCRF is required and must be completed for each enrolled subject, with all required study 
data accurately recorded such that the information matches the data contained in medical records 
(eg, physicians’ notes, nurses’ notes, clinic charts, or other study-specific source documents). As 
required by the protocol, eCRFs should also be completed for those subjects who fail to complete 
the study (even during the screening period). If a subject withdraws from the study, the reason 
must be noted on the eCRF. If a subject is withdrawn from the study because of a 
treatment-limiting adverse event, thorough efforts should be made to clearly document the 
outcome.
The eCRFs for this study will exist within a Web-based electronic data capture (EDC) system. 
After the investigator or the investigator’s designees (eg, research coordinators) have been 
appropriately trained, they will be given access to the EDC system and will enter the data 
required by the protocol into the EDC system. Any change of data will be made via the 
EDC system, with all changes tracked by the system to provide an audit trail.
The eCRF must be completed and signed by the principal investigator or subinvestigator 
(as appropriate) within a reasonable time period after data collection. This signature serves to
attest that the information contained in the eCRF is true.
10.1.7.
Drug Accountability
As described in the relevant section (see Section 5.2.7), the investigator is responsible for 
ensuring adequate accountability of all used and unused investigational medicinal product, 
placebos, and comparators. This responsibility includes acknowledgment of receipt of each 
shipment of study product (quantity and condition), subject dispensing records, and returned or 
destroyed study product. Dispensing records will document quantities received from 
Gilead Sciences and quantities dispensed to subjects, including lot number, date dispensed, 
subject identifier number, subject initials, and the initials of the person dispensing the 
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At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Sciences’ requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRB/IECs, 
and to regulatory authority or health authority inspectors. It is important that the investigator and 
relevant institutional personnel are available during monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, will be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB/IEC in 
accordance with local requirements. Except as noted in Section 10.1.2, IRB/IEC approval must 
be obtained before changes can be implemented.
10.2.2.
Communications with Regulatory Authorities
Gilead Sciences, working either directly or through designees, will assume responsibility for 
regulatory interactions with relevant regulatory authorities. Gilead Sciences will maintain an 
IND for idelalisib in support of the study in the United States and will maintain similar 
regulatory applications with other regulatory authorities, as required for conduct of the study. In 
fulfilling this responsibility, Gilead Sciences (or a designee) will collect, assemble, and 
communicate all required regulatory documents (eg, Form FDA 1572, investigator financial 
disclosure forms, protocol and protocol amendments, investigator brochures, informed consent 
documents, annual reports) as required by regulation. Gilead Sciences (or a designee) will also 
assume responsibility for adverse event reporting to regulatory authorities as described in 
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10.2.3.
Data Management
Electronic data capture will be used to enter study data eCRFs and to transfer the data into a 
study-specific electronic database. During the data collection process, automated quality 
assurance programs will be used to identify missing data, selected protocol violations, 
out-of-range data, and other data inconsistencies. Requests for data clarification or correction 
will be forwarded to the investigative site for resolution. As appropriate, eCRFs, listings, tables, 
and SAS datasets will be provided to the investigational sites for review.
Quality assurance and quality control systems will be implemented and maintained according to 
written standard operating procedures to ensure that the data are generated, recorded, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements. Data 
collection and storage systems will provide audit trail, security mechanisms, and electronic 
signature capabilities that meet the requirements of FDA Title 21 of CFR Part 11 regarding 
electronic records and electronic signatures.
Data security will be controlled through appropriate and specific restriction of access only to data 
and systems required by individual users to accomplish their roles in the data management 
process. Individual login and password protections will be employed at study sites and at 
Gilead Sciences or its designee. The database will exist on physically secured servers. Data 
backups will be done regularly and will be stored in separate facilities. Printed documents 
relating to the study will be secured when not under review.
10.2.4.
Study Reporting and Publication
Gilead Sciences may make information obtained during this study available in order to further 
the scientific or business needs of the company or as required by law or regulation. In this 
regard, Gilead Sciences may provide study information to private or public organizations 
(eg, business partners, collaborators, consultants, CROs, investors, other physicians who are 
conducting similar studies, funding organizations, regulatory authorities, or other 
government authorities).
Gilead Sciences will prepare a clinical study report for submission to relevant regulatory 
agencies. Gilead Sciences will ensure that the report meets the standards set out in the 
ICH Guideline for Structure and Content of Clinical Study Reports (ICH E3). An abbreviated 
report may be prepared in certain cases, as appropriate.
Gilead Sciences intends that the data from this study will be presented and published. 
Gilead Sciences will work in collaboration with the principal investigators in preparing 
presentations and writing manuscripts for publication.

Investigators may publish or present the results of the study generated by their individual site 
either with the advanced written consent of Gilead or > 2 years after the completion of this 
extension study (GS-US-312-0117) at all participating institutions.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information (see Section 10.1.4).


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The investigator will submit to Gilead Sciences any proposed publication or presentation along 
with the respective scientific journal or presentation forum prior to submission of the publication 
(at least 30 days prior to manuscripts and 15 days prior for abstracts and oral presentations). The 
investigator will comply with Gilead Sciences’ request to delete references to its confidential 
information (other than the study results) in any paper or presentation. If deemed necessary by 
Gilead Sciences, the investigator also agrees to withhold publication or presentation for an 
additional 60 days in order to obtain patent protection.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the eCRFs for consistency.
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.
10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences may conduct inspections or audits 
of the clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.
10.3.3.
Public Notification of Study Conduct
Consistent with Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and 
with requirements of the International Committee of Medical Journal Editors (ICMJE) as a 
condition of consideration for publication of study results, Gilead Sciences will be responsible 
for ensuring that this protocol is listed at the ClinicalTrials.gov website (or equivalent) and that 
information at the website relating to study design and conduct is appropriately updated during 
the course of the study. In order to facilitate this process, investigators will need to supply 
Gilead Sciences with appropriate contact information for study site personnel.
10.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authorities and IRB/IECs. In terminating the study, Gilead Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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10.4.
Study Committees
10.4.1.
Data Monitoring Committee
A DMC, operating autonomously from Gilead Sciences, the clinical investigators, and the SSC, 
will be responsible for providing independent recommendations to Gilead Sciences about 
evolving risk-benefit observed in the course of the study and any modifications required during 
the course of the study. The DMC will consist of a biostatistician and 2 physicians experienced 
in treating patients with lymphoid malignancies. The DMC will be chaired by one of these 
individuals. DMC members must not be actively involved in study design, conduct, or subject
accrual and must not have financial, proprietary, professional, or other interests that may affect 
impartial, independent decision-making. Specialists may be invited to participate as non-voting 
members at any time if additional expertise is desired. The DMC will formally interact with the 
external SSC members through the sharing of meeting minutes. Informal interactions between 
the DMC and external SSC members will be limited. The DMC will operate under a charter 
developed as a collaborative document between Gilead Sciences and the DMC. It is expected 
that the members of the DMC will be the same as those for the primary study 
(Study GS-US-312-0116). 
The primary responsibility of the DMC is to protect the safety and welfare of subjects 
participating in this clinical trial and to ensure the integrity of the clinical trial. In general, the 
DMC will be responsible for:

Reviewing the general progress of the study as regards subject accrual, study conduct, and 
protocol violations

Examining accumulated safety, efficacy, and other relevant data at prespecified points during 
the course of the study 

Reviewing major study design modifications prior to implementation of those modifications

Making recommendations concerning continuation, modification, interruption, or termination
of each study

Advising the company on changes to informed consent documents

Proposing updates to the DMC monitoring plan, changes in the DMC membership, actions to 
be taken relating to conflict of interest or confidentiality breaches, the need for additional 
expertise during DMC deliberations, revisions to the DMC charter, or alterations in the 
support provided to the DMC

Providing expert advice to the Gilead Science medical monitor on an ad hoc basis regarding 
matters such as safety concerns or diagnostic evaluations in individual subjects
Based on the results of its deliberations during the course of the study, the DMC can recommend 
appropriate actions (eg, continuation of the study unchanged, continuation of the study with 
modifications in design or monitoring plan, interruption of study accrual, study termination).


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10.4.2.
Independent Review Committee
An IRC will be established to provide a blinded review of radiographic data and pertinent 
clinical data in order to provide expert interpretation of changes in tumor status. The IRC will 
include 1 independent board-certified radiologist and 1 independent board-certified 
hematologist or oncologist, and will be managed by a CRO selected by Gilead Sciences. The 
review of radiographic and clinical data by the IRC will be performed on an ongoing basis until 
the primary analysis . The specifics of the IRC’s processes and reading methods will be 
described in an independent review charter developed by the contracted imaging facility in 
conjunction with Gilead Sciences. The same organization that is providing IRC services for 
Study GS-US-312-0116 will provide IRC services for this study.


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11.
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12.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
Appendix 3.
Performance Status Scoring System
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D)
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Appendix 6.
Cumulative Illness Rating Scale (CIRS)
Appendix 7.
Schedule of Study Procedures


PPDPPD
PPD
ldelalisib 
l'rotocol GS-US-312·0117 
l'inal 
Gilead Sciences, lnc. 
Version 6.0 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
199 EAST BLAINE STREET 
SEATTLE, WA 98102 
STUDY ACKNOWLEDGEMENT 
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and Safety of 
Two Different Dose Levels of Single-Agent Idelalisib (GS-1 1 0 I) for Previously Treated 
Chronic Lymphocytic leukemia 
GS-US-312-0l 17, Version 6.0 (Amendment 5), 10 October 201.4 
This protocol has been approved by Gilead Sciences, Inc. The followin~gnature documents 
this a l roval. 
uilead :>ctences 
edical Monitor 
v 
(o(ro( ry 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the sntdy within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator 
Printed Name 
• 
Date 
CONFIDENTIAL 
Signature 
Site Number 
Page 148 
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Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
fACT-Leu (Version 4) 
13elow is a list o( StaiCIUCriiS that Other people with yOu!' illness have s.aid are irnporlanr. Ple:lSC eirde 
or mark one number per line to indicate your response as it applies 10 the nast 7 dnvs. 
PIIYSICAL Wf:l,lr OEING 
Not 
at all 
... 
I have a lac:k of energy .. ................................................... 
0 
... 
I have nausea ................. . ................... ........ .... 
0 
.., 
Because of my physical condition. I have trouble 
meeting the needs of my family ...... ..................... 
0 
... 
I have pain .......................................................................... 
0 
"" 
I am bothered by side enects of treatment 
....... ......... 0 
... 
1 r<e~ ill .............................................................................. 
0 
"" 
I am forced 10 spend time in bed ... .......... 
·· ··· - · · ·· · ···· ~ ··· · 
0 
SOCIAUF'AMILY WELL-BEING 
Not 
at all 
I feel close1omy friends ................................ ,................... 
0 
I get cmo1ional support from my family ....................... 
0 
... 
I gel suppOrt from my friends ....................................... . 
"" 
My family has accepted my illness ........ , 
... 
I am satisfied with famiJy communication about my 
illness ........ ................................................................. . 
-
I ft."CI close 10 my panner (or 1hc person who is my main 
suppon) ....... .............. ...................... ... ..... . ................ . 
Ql 
&-.,;ardles.s Q/,mttr CJtrrtmlcw/ ()j :ltXua/ Mrlwty, plfosc 
l11U'we,.J/h: fl)//(m lng quetri()lr. /f)t.m twefi•r nm 10 OtU'M'('r It, 
plt•f1.n• ln<lrk lh/1 bw,· 0 (IJt(/ /:(' {(IJ/N• n<'A'I :Sf:f:ll(}n 
0 
0 
0 
0 
.... 
lam satisfied wi1h my $C:X life....................... ................... 
0 
--
G..,... rM'.t;¥' 
A liul<e 
Some-
bi1 
what 
2 
2 
2 
2 
2 
2 
2 
A littl~ Some-
bit 
Whllt 
2 
2 
2 
2 
2 
2 
Quite 
II bit 
3 
3 
3 
3 
3 
3 
3 
Quite-
a bit 
3 
3 
3 
3 
3 
3 
Vuy 
mu ~h 
4 
4 
4 
4 
4 
4 
4 
Vtr)' 
In 11t h 
4 
4 
4 
4 
4 
4 


Idelalisib
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Final
Gilead Sciences, Inc.
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FACT-teu (Ve,..ion 4) 
l,lense circle or mark one number per line ro indicate your response as it 3J)J)Iies to lhe 1!!!.lll 
da\'S. 
EMOTIONAl. WELL-BEING 
Not 
i\ liule Some--
Quilt 
Vtry 
at all 
bit 
what 
a bit 
mue;h 
"' 
I feeiS>d .............................................................................. 
0 
2 
J 
~ 
.., 
I am satisfied with how 1 am coping with my illness ......... 
0 
2 
3 
~ 
"" 
I am losing. hope in the fight against my illness .......... 
0 
2 
3 
4 
... 
I feel nervous ....................................... . ............ ........... 
0 
2 
J 
4 
"" 
I " 'Orl)' about dying ........................................................... 
0 
2 
3 
4 
... 
I worry that my condition will get worse . ........•................ 
0 
2 
3 
4 
FUNCTIONAL WELI~BE ING 
Noo 
A little 
Som~ Q uilt: 
Very 
a1 all 
bil 
whal 
a bit 
mueh 
... 
I am able to work (include \VQI't ftl hom~) ......................... 
0 
2 
J 
4 
.., 
My worl:" (include work at home) i.s f\1llilling .................... 
0 
2 
3 
4 
-
I am able m enjoy life ............ ................................... 
0 
2 
3 
4 
~· 
I h8\'e accepted my illness ...... ············-·· ... ···· .... ·-·-.. 
0 
2 
J 
4 
"" 
I am slcx-ping well ......... .............................. 
0 
2 
3 
4 
... 
I am enjoying the things ] usually do for fun ........... 
0 
2 
3 
4 
"" 
I am eontent with the quality of my life right now ............. 
0 
2 
3 
4 


Idelalisib
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FACT-teu (Ve,..ion 4) 
Please circle or mnrk one number per line 10 indicate your response as it Df)pljes to the mast 7 
dl\v~. 
t\OOITIONt\L CONCERNS 
Not 
A litllt' 
Sonuo.. 
Quit'<' 
Vt'ry 
al all 
hi I 
what 
a bit 
murh 
"'" 
I am bothered by fever's (episodes of high body 
temperature) ..... ..................................... ............... 
0 
2 
3 
4 
" 
I have cenain parts of my body where I experience pain .. 
0 
2 
3 
4 
-
lam bothered by the chills ........... ......•.. ............. ,_ 
0 
2 
3 
4 
0) 
I have night $\\'(':alS ..................................................... 
0 
2 
J 
4 
""' 
I am bolhcrcd by lumps or- swclling in cenain pans of 
.ny body (e.g,. neck. ann pits,. or gl'oin) ... ................ 
0 
2 
3 
4 
... 
I blccd easily 
. ............................................ 
0 
2 
J 
4 
"" 
I bruise easily ............................................... ··············· 0 
2 
J 
4 
.... 
I feel weak all over .. 
. .................................. 
0 
2 
3 
4 
.... 
I get tired easily .. . ................. ................................... 
0 
2 
J 
4 
<> 
lam losing weight,. ..................... ,, 
................................ 
0 
2 
3 
4 
a 
I have a good appetite ............................. ......................... 
l) 
2 
3 
• 
.... 
I am able 10 do my us-ual activicies ........... . .................. ,,.,, _ 
0 
2 
J 
4 
" 
I worry about getting. infections ....... ............................... 
0 
2 
J 
4 
""' 
I feel uncenain about my fuiUre h-ealth .............................. 
0 
2 
3 
4 
""' 
I \\lOfT)' that l rnig.ht get ne\li symptoms of my illness ........ 
0 
2 
J 
4 
..... 
I have cmodooal ups and downs ..................................... 
0 
2 
3 
4 
""' 
I feel isolatc.xl from others because of my illness or 
treatnlent ............................................................................. 
0 
2 
J 
4 


Idelalisib
Protocol GS-US-312-0117
Final
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Page 152
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Appendix 3.
Performance Status Scoring System
Karnofsky Performance Status
General Description
Score
Specific Description
Able to carry on normal activity and 
to work; no special care needed.
100
Normal; no complaints;
no evidence of disease.
90
Able to carry on normal activity;
minor signs or symptoms of disease.
80
Normal activity with effort;
some signs or symptoms of disease.
Unable to work; able to live at home 
and care for most personal needs; 
varying amount of assistance 
needed.
70
Cares for self;
unable to carry on normal activity or to do active work.
60
Requires occasional assistance,
but is able to care for most of personal needs.
50
Requires considerable assistance and frequent medical care.
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly.
40
Disabled; requires special care and assistance.
30
Severely disabled;
hospital admission is indicated although death not imminent.
20
Very sick; hospital admission necessary;
active supportive treatment necessary.
10
Moribund; fatal processes progressing rapidly.
0
Dead


Idelalisib 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Version 6.0 
Appendix 4. 
EuroQoL-5 Dimensions (EQ-SD) 
By placmg a c:h~kma.rk m one box m each group below. pltase mdtcJte wblc:h 
sratementiJ bes: de~ be your own ilealth state roday. 
Mobility 
I have no pro~ms in w;.afking abo .. t 
I have some problems 
wal\irrg about 
I am co ·iJted to bed 
Self-Care 
UsuaJ Aetivi :es (e g., work study, housework. famjly, or leisure activities} 
I have some- pro~ 'K.th perfonn.ng my U:SUaJ aoiMtes 
I a:n ISI1ilb e to oerfonn my lli\la ~ 
Pain!D' scomfort 
I h3•1.e no pain o· diseomfon: 
I h!•Je moderate !')a or d1$COrrfOtt 
AnxietyiDepresslon 
I a.., not anxiOI:lS or cteptessed 
I am moderately al'\xrous or depressed 
I a.~ extrerrely atlXlOC.lS cr depressed 
CONFIDENTIAL 
Page 153 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
D 
D 
0 
0 
D 
10 October 2014 


Idelalisib 
Protocol GS-US-312-0117 
Gilead Sciences, Inc. 
To help people say how good or bad a health srate lS. 
we ba\'e dr.l\\ll a sct~ Jc (rather like a thermometer) on 
whldl ihe ~r state you can 1Jll3gme ts mark~ 100 
and the wont sta~ you C3D imagme lS nwked 0. 
We would til--e you to 111dlcate on this scale bow good 
or bad your 0\'<'0 health ts today. in your opinion. 
Please do this l>y dr.m'll\g a we tiom the boll below 
10 wluchcvc:r powl ou the scale wdical~ how good or 
bad yoll! health state i~ today 
CONFIDENTIAL 
Yonr own 
hraltb statE' 
totby 
Page 154 
lw.t 
~It 
bullh 5bw 
10 0 
T 
• 0 
l ,t 
-r 
:r 
:z 0 
"'T ,io 
l 
t 
..L 
0 
\\'CI&l 
im.Jl""~b'• 
~ ~tall! 
Final 
Version 6.0 
10 October 2014 


Idelalisib
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10 October 2014
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Formulas for calculating the estimated creatinine clearance (eCcr) are provided in the table 
below. The formula appropriate to the units in which serum creatinine was measured and the 
subject’s gender should be used.
Cockcroft-Gault Formulas for Calculating Estimated Creatinine Clearance
Serum
Creatinine Units
Gender
Formula
mg/dL
Males
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1
72 subject serum creatinine [mg/dl]
Females
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 0.85
72 subject serum creatinine [mg/dl]
M/dL
Males
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.23
Subject serum creatinine [mg/dl]
Females
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.04
Subject serum creatinine [mg/dl]
Abbreviation: eCcr=estimated creatinine clearance


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10 October 2014
Appendix 6.
Cumulative Illness Rating Scale (CIRS)
The CIRS used in this protocol is designed to provide an assessment of recurrent or ongoing 
chronic comorbid conditions, classified by 14 organ systems. Using the drop-down lists of 
organ-specific diagnoses, please select any conditions present in the study subject. If the subject
has a recurrent or ongoing chronic conditions that are not described in the list for a given organ 
system, please indicate the name of the conditions under “other chronic condition” for that organ 
system. Please take into account that CLL-induced discomfort, symptoms, or disability should 
not be considered. If additional explanation would be helpful, text comments may be inserted.
CIRS List of Comorbid Conditions
Organ System
Diagnosis
Comment
Cardiac
Chronic heart failure
Angina pectoris
Medically relevant arrhythmia
Valve dysfunction
Congenital heart disease
Cardiomyopathy
Myocarditis
Chronic pericarditis
Endocarditis
Other chronic cardiac condition:
Other chronic cardiac condition:
Vascular
Hypertension
Thrombosis
Peripheral diabetic microvascular disease
Peripheral artery disease
Aortic aneurysm
Aortitis
Raynaud disease
Vasculitis
Other chronic vascular condition:
Other chronic vascular condition


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Organ System
Diagnosis
Comment
Hematological/
immunological
Sickle cell anemia
Hemoglobinopathy
Polycythemia
Thrombocythemia
Hemophilia
Paroxysmal nocturnal hemoglobinuria
Thrombotic thrombocytopenic purpura
Dysfibrinogenemia
HIV
Other chronic hematological or 
immunological condition:
Other chronic hematological or 
immunological condition
Abbreviation: CIRS=Cumulative Illness Rating Scale
For each condition selected from the CIRS List of Comorbid Conditions, please rate the severity 
of that condition. For the severity rating, please use the scoring guidelines shown in the table 
below, considering the magnitude of symptoms, how manageable the condition is, and the extent 
of intervention required:
CIRS Rating Scale
Score
Severity
Findings
1
Mild
Mild discomfort, symptoms or disability
Easy to control
Requiring either no therapy/medication or only as needed
2
Moderate
Moderate  discomfort, symptoms or disability
Manageable
Requiring daily treatment or first-line therapy
3
Severe
Severe discomfort, symptoms or disability
Hard to control
Requiring second-line therapy or multiple medications
4
Extremely severe
Life threatening, permanently disabling disability, causing organ failure
Poorly manageable
Requiring urgent intervention or resistant to therapy
Abbreviation: CIRS=Cumulative Illness Rating Scale


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Appendix 7.
Schedule of Study Procedures
Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4 a
5a
6 a
7a
8 a
9 a
10 a
11 a
12 a
13 a
14 a
15 a
16+d
End
of
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28 Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30 days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Informed consent
X
CIRS assessment
X
β-HCG
(women of childbearing 
potential)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CLL peripheral blood 
evaluation
X
X
CLL serology
X
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HRQL/healthy utility –
FACT-Leu/EQ-5D
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PPD


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Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4 a
5a
6 a
7a
8 a
9 a
10 a
11 a
12 a
13 a
14 a
15 a
16+d
End
of
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28 Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30 days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Physical exam
(includes nodes, liver, 
spleen)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Oxygen saturation
(by pulse oximetry)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Circulating cells
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biomarkers
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Igs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug
administration in clinic
Xb
X
X
X
X
X
X
X
Idelalisib
pharmacokinetics b
X
X
X
X
X
X
X
X
Study drug dispensing/
accounting b
X
X
X
X
X
X
X
X
X
X
X
Radiology assessment 
(CT/MRI)
X
Xe
Xe
Xe
Xe
Xe
Xe
Xe, f


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Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4 a
5a
6 a
7a
8 a
9 a
10 a
11 a
12 a
13 a
14 a
15 a
16+d
End
of
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28 Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30 days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Bone marrow biopsy/
aspirate c
X
X
X
X
X
X
X
X
Post-treatment CLL 
therapy
X
Long-term follow-up 
X
a
Following unblinding of the study, the visit schedule will be modified per Section 6.2 and Visits 3 – 15 may not be applicable for subjects who were randomized to idelalisib 
on Study GS-US-312-0116 or who were randomized to placebo on GS-US-312-0116 and have received 24 weeks cumulative treatment with idelalisib
b
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll following unblinding, may have idelalisib treatment (and associated PK testing) delayed at 
the Investigator’s discretion until the time of disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib treatment
c
At screening, to be performed at investigator discretion to determine extent of CLL involvement and bone marrow cellularity. Post-screening, to be performed to confirm 
response category in subjects with potential CR or to confirm a hematologically-based disease progression; if the subject does not otherwise meet criteria for CR or if the 
nature of PD does not require bone marrow confirmations, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate
d
Following unblinding, Visit 16+ may be completed prior to 48 weeks as subjects transition to a Q12 week visit schedule 
e
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the assessment should be done even if study drug has been interrupted
f
An end-of-study CT/MRI tumor assessment should be performed unless the subject already has radiographic confirmation of definitive disease progression < 4 weeks prior to 
study discontinuation
Abbreviations: -HCG=beta human chorionic gonadotropin, CIRS=chronic illness rating scale, CLL=chronic lymphocytic leukemia, CR=complete response, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy- Leukemia, HRQL= health-related quality of life, 
Ig=immunoglobulin, IWRS=interactive web response system, MRI= magnetic resonance imaging.

Prot_002.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Double-Blind Extension Study Evaluating the 
Efficacy and Safety of Two Different Dose Levels of 
Single-Agent Idelalisib (GS-1101) for Previously Treated 
Chronic Lymphocytic Leukemia
A Companion Trial to Study GS-US-312-0116: A Phase 3, 
Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Efficacy and Safety of Idelalisib (GS-1101) 
in Combination with Rituximab for Previously Treated 
Chronic Lymphocytic Leukemia
Sponsor:
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102
USA
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
101254
EudraCT Number:
2011-006293-72
Indication:
Chronic Lymphocytic Leukemia 
Protocol ID:
GS-US-312-0117
Gilead Sciences Medical 
Monitor:
Name:
Office Telephone:
Office Fax:
Mobile Telephone:
E-mail:
Protocol Version/Date:
Version 1.0 (Original)
23 January 2012
Version 2.0 (Amendment 1)
23 January 2013 
Version 3.0 (Amendment 2)
10 September 2013
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable institutional review board or independent ethics committee. This information is 
only to be used by you in connection with authorized clinical studies of the investigational 
drug described in the protocol. You must not disclose any of the information to others 
without written authorization from Gilead Sciences, Inc., except to the extent necessary to 
obtain informed consent from those persons to whom the drug may be administered.
PPD
PPD
PPD
PPD
PPD
PPD


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 3.0
CONFIDENTIAL
Page 2
10 September 2013
TABLE OF CONTENTS
TABLE OF CONTENTS .......................................................................................................................................2
LIST OF IN-TEXT TABLES.................................................................................................................................6
LIST OF IN-TEXT FIGURES ...............................................................................................................................6
PROTOCOL SYNOPSIS.......................................................................................................................................7
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................18
1.
INTRODUCTION .......................................................................................................................................22
Chronic Lymphocytic Leukemia.....................................................................................................22
1.1.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies ............................................................23
1.2.
Idelalisib (formerly GS-1101).........................................................................................................24
1.3.
1.3.1.
Discovery and Efficacy Pharmacology.........................................................................24
1.3.2.
Safety Pharmacology ....................................................................................................24
1.3.3.
Nonclinical Pharmacology and Metabolism .................................................................25
1.3.4.
Toxicology ....................................................................................................................26
1.3.5.
Idelalisib Clinical Studies..............................................................................................27
Summary and Justification for the Current Study...........................................................................32
1.4.
2.
STUDY DESIGN ........................................................................................................................................34
Design Overview and Study Schema..............................................................................................34
2.1.
Design Rationale.............................................................................................................................35
2.2.
3.
OBJECTIVES AND ENDPOINTS.............................................................................................................37
Endpoints ........................................................................................................................................37
3.1.
3.1.1.
Tumor Control...............................................................................................................37
3.1.2.
Patient Well-Being........................................................................................................38
3.1.3.
Pharmacodynamic Markers of Drug Activity and Resistance.......................................38
3.1.4.
Exposure........................................................................................................................39
3.1.5.
Safety ............................................................................................................................39
3.1.6.
Pharmacoeconomics......................................................................................................39
Endpoint Selection Rationale..........................................................................................................39
3.2.
3.2.1.
Tumor Control Endpoints..............................................................................................39
3.2.2.
Measures of Patient Well-Being....................................................................................42
3.2.3.
Pharmacodynamic Markers of Drug Activity and Resistance.......................................43
3.2.4.
Assessments of Exposure..............................................................................................45
3.2.5.
Evaluations of Safety ....................................................................................................45
3.2.6.
Pharmacoeconomic Measures.......................................................................................46
4.
SUBJECT POPULATION...........................................................................................................................47
Number of Subjects.........................................................................................................................47
4.1.
Subject Selection Criteria................................................................................................................47
4.2.
4.2.1.
Inclusion Criteria...........................................................................................................47
4.2.2.
Exclusion Criteria..........................................................................................................49
Enrollment Criteria Rationale .........................................................................................................50
4.3.
5.
TREATMENT OF SUBJECTS ...................................................................................................................51
Enrollment.......................................................................................................................................51
5.1.
5.1.1.
Interactive Web Response System................................................................................51
5.1.2.
Treatment Assignment ..................................................................................................51
5.1.3.
Blinding.........................................................................................................................52


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Investigational Study Drug (Idelalisib/Placebo) .............................................................................53
5.2.
5.2.1.
Description....................................................................................................................53
5.2.2.
Source............................................................................................................................53
5.2.3.
Packaging and Labeling ................................................................................................53
5.2.4.
Storage and Handling....................................................................................................54
5.2.5.
Dispensing.....................................................................................................................54
5.2.6.
Return............................................................................................................................55
5.2.7.
Accountability...............................................................................................................55
5.2.8.
Overdose Precautions....................................................................................................55
5.2.9.
Inadvertent Exposure and Spill Precautions..................................................................56
Study Drug Administration.............................................................................................................56
5.3.
5.3.1.
Premedication................................................................................................................56
5.3.2.
Administration Instructions...........................................................................................56
5.3.3.
Dosing Schedule............................................................................................................56
5.3.4.
Dose Levels...................................................................................................................57
5.3.5.
Dose Schedule Interruptions and Vomited Doses.........................................................57
5.3.6.
Safety Monitoring and Study Drug Interruption/Dose Modification............................57
Recommendations for Evaluation, Intervention, and Drug Discontinuation for Specific 
5.4.
Adverse Events or Conditions.........................................................................................................61
5.4.1.
Dermatological Events..................................................................................................61
5.4.2.
Gastrointestinal Events..................................................................................................61
5.4.3.
Hepatic Events ..............................................................................................................62
5.4.4.
Hematological and Immunological Events ...................................................................63
5.4.5.
Infectious Events...........................................................................................................63
5.4.6.
Progressive Multifocal Leukoencephalopathy ..............................................................64
5.4.7.
Pulmonary Events .........................................................................................................64
5.4.8.
Tumor Lysis Syndrome.................................................................................................65
5.4.9.
Pregnancy, Lactation, and Reproduction ......................................................................65
5.4.10.
Ultraviolet Exposure .....................................................................................................66
Emergency Unblinding ...................................................................................................................66
5.5.
Concomitant and Supportive Therapy.............................................................................................67
5.6.
5.6.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments.....................................................................................................................67
5.6.2.
Antibiotics.....................................................................................................................67
5.6.3.
Antiemetics and Antidiarrheals.....................................................................................68
5.6.4.
Contraception................................................................................................................68
5.6.5.
Corticosteroids ..............................................................................................................69
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin.......................................69
5.6.7.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism ..........................................69
5.6.8.
Drugs that undergo CYP3A-Dependent Metabolism....................................................70
5.6.9.
Immunization ................................................................................................................70
5.6.10.
Surgery..........................................................................................................................71
5.6.11.
Diet................................................................................................................................71
Duration of Study Drug...................................................................................................................71
5.7.
Discontinuation of Study Drug .......................................................................................................71
5.8.
Discontinuation from Study............................................................................................................72
5.9.
Study Treatment Rationale..............................................................................................................72
5.10.
6.
STUDY PROCEDURES .............................................................................................................................75
Enrollment and Study Management Procedures.............................................................................75
6.1.
6.1.1.
Subject Recruitment......................................................................................................75
6.1.2.
Subject Compensation for Participation........................................................................75
6.1.3.
Screening.......................................................................................................................75
Explanation of Study Visits ............................................................................................................76
6.2.


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6.2.1.
Visit 1 and Screening Period (Clinic Visit)...................................................................77
6.2.2.
Visit 2 (Day 1) (Clinic Visit).........................................................................................79
6.2.3.
Visit 3 (Day 15) (Clinic Visit).......................................................................................80
6.2.4.
Visit 4 (Day 29) (Clinic Visit).......................................................................................81
6.2.5.
Visit 5 (Day 43) (Clinic Visit).......................................................................................82
6.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit) ..............................................................83
6.2.7.
Visit 7 (Day 71) (Laboratory Visit)...............................................................................84
6.2.8.
Visit 8 (Day 85) (Clinic Visit).......................................................................................84
6.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit) ............................................................87
6.2.10.
Visit 10 (Day 141) (Clinic Visit)...................................................................................89
6.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit) ..........................................................90
6.2.12.
Visit 12 (Day 211) (Clinic Visit)...................................................................................92
6.2.13.
Visit 13 (Day 253) (Clinic and Radiology Visit) ..........................................................93
6.2.14.
Visit 14 (Day 295) (Clinic Visit)...................................................................................94
6.2.15.
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks) 
(Clinic and Radiology Visits)........................................................................................95
6.2.16.
End-of-Study Visit (Clinic Visit) ..................................................................................96
6.2.17.
30 Day and Long-Term Follow-up ...............................................................................98
Sample Storage ...............................................................................................................................98
6.3.
Blood Collection.............................................................................................................................98
6.4.
Study Procedure Rationale..............................................................................................................99
6.5.
7.
EFFICACY ASSESSMENTS ...................................................................................................................100
Tumor Status Assessments............................................................................................................100
7.1.
Method of Assessment..................................................................................................................100
7.2.
Timing of Assessments .................................................................................................................100
7.3.
Identification and Measurement of Tumor Lesions and Organomegaly.......................................101
7.4.
7.4.1.
Index Lesions ..............................................................................................................101
7.4.2.
Spleen and Liver .........................................................................................................102
7.4.3.
Non-Index Lesions......................................................................................................102
Definitions of Tumor Response and Progression..........................................................................103
7.5.
7.5.1.
Complete Response.....................................................................................................103
7.5.2.
Partial Response..........................................................................................................104
7.5.3.
Stable Disease .............................................................................................................104
7.5.4.
Definitive Progressive Disease....................................................................................105
7.5.5.
Non-Evaluable.............................................................................................................106
7.5.6.
No Disease ..................................................................................................................106
7.5.7.
Lymphocytosis During Therapy..................................................................................107
7.5.8.
Documentation of Definitive CLL Progression ..........................................................107
8.
SAFETY ASSESSMENTS........................................................................................................................108
Adverse Event Definitions............................................................................................................108
8.1.
8.1.1.
Adverse Event.............................................................................................................108
8.1.2.
Serious Adverse Event ................................................................................................109
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events............................................................110
Assessment of Adverse Events and Serious Adverse Events........................................................111
8.2.
8.2.1.
Assessment of Causality for Study Drugs and Procedures..........................................111
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
8.3.
Adverse Events to Gilead..............................................................................................................111
Gilead Reporting Requirements....................................................................................................112
8.4.
Grading of the Severity of an Adverse Event................................................................................113
8.5.
Adverse Event Reporting Period...................................................................................................113
8.6.
Adverse Event Reporting Requirements.......................................................................................114
8.7.


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8.7.1.
Site Reporting Requirements ......................................................................................114
8.7.2.
Reporting of Adverse Events Relating to the Primary Endpoint and 
Other Anticipated Medical Events in the Study Population........................................115
Special Situations Reporting Requirements..................................................................................116
8.8.
8.8.1.
Definitions of Special Situations.................................................................................116
Instructions for Reporting Special Situations................................................................................116
8.9.
8.9.1.
Instructions for Reporting Pregnancies.......................................................................116
8.9.2.
Reporting Other Special Situations.............................................................................117
9.
STATISTICAL CONSIDERATIONS.......................................................................................................118
Analysis Objectives.......................................................................................................................118
9.1.
Analysis Endpoints .......................................................................................................................118
9.2.
Analysis Conventions ...................................................................................................................118
9.3.
9.3.1.
Analysis Sets...............................................................................................................118
9.3.2.
Data Handling Conventions ........................................................................................119
Analysis Plan ................................................................................................................................120
9.4.
9.4.1.
Subject Disposition and Baseline Characteristics .......................................................120
9.4.2.
Efficacy Analyses........................................................................................................121
9.4.3.
Exposure and Safety Analyses....................................................................................122
9.4.4.
Other Analyses............................................................................................................125
Sample Size...................................................................................................................................126
9.5.
Timing of Analyses.......................................................................................................................126
9.6.
9.6.1.
Interim Analysis..........................................................................................................126
9.6.2.
Final Analysis .............................................................................................................127
10.
RESPONSIBILITIES ................................................................................................................................128
Investigator Responsibilities.........................................................................................................128
10.1.
10.1.1.
Compliance with Ethical and Regulatory Guidelines..................................................128
10.1.2.
Institutional Review Board/Independent Ethics Committee .......................................128
10.1.3.
Informed Consent........................................................................................................129
10.1.4.
Confidentiality ............................................................................................................129
10.1.5.
Study Files and Retention of Records and Biological Samples ..................................130
10.1.6.
Case Report Forms......................................................................................................131
10.1.7.
Drug Accountability....................................................................................................132
10.1.8.
Inspections ..................................................................................................................132
10.1.9.
Protocol Compliance...................................................................................................132
Sponsor Responsibilities...............................................................................................................132
10.2.
10.2.1.
Protocol Modifications................................................................................................132
10.2.2.
Communications with Regulatory Authorities............................................................133
10.2.3.
Data Management .......................................................................................................133
10.2.4.
Study Reporting and Publication.................................................................................133
Joint Investigator/Sponsor Responsibilities ..................................................................................134
10.3.
10.3.1.
Access to Information for Monitoring.........................................................................134
10.3.2.
Access to Information for Auditing or Inspections.....................................................134
10.3.3.
Public Notification of Study Conduct .........................................................................135
10.3.4.
Study Discontinuation.................................................................................................135
Study Committees.........................................................................................................................135
10.4.
10.4.1.
Study Steering Committee ..........................................................................................135
10.4.2.
Data Monitoring Committee .......................................................................................135
10.4.3.
Independent Review Committee.................................................................................136


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11.
REFERENCES ..........................................................................................................................................137
12.
APPENDICES ...........................................................................................................................................151
Appendix 1.
Investigator Signature Page.........................................................................................152
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia 
(FACT-Leu) ................................................................................................................153
Appendix 3.
Performance Status Scoring System............................................................................156
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D) ...............................................................................157
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance...................................159
Appendix 6.
Cumulative Illness Rating Scale (CIRS).....................................................................160
Appendix 7.
Schedule of Study Procedures.....................................................................................162
LIST OF IN-TEXT TABLES
Table 4-1.
Required Screening Laboratory Values ........................................................................48
Table 5-1.
Study Drug Dose Levels ...............................................................................................57
Table 5-2.
Recommendations for Study Drug Dose Modifications Based on 
Type and Severity of Treatment-Related Adverse Events or 
Laboratory Abnormalities .............................................................................................59
Table 5-3.
Protocol-Recommended Contraceptive Methods..........................................................68
Table 5-4.
Known Strong Inducers of CYP3A...............................................................................70
Table 6-1.
Procedures and Assessments at Visit 1 (During Screening 
Period)...........................................................................................................................78
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1) ............................................................79
Table 6-3.
Procedures and Assessments at Visit 3 (Day 15) ..........................................................80
Table 6-4.
Procedures and Assessments at Visit 4 (Day 29) ..........................................................81
Table 6-5.
Procedures and Assessments at Visit 5 (Day 43) ..........................................................82
Table 6-6.
Procedures and Assessments at Visit 6 (Day 57) ..........................................................83
Table 6-7.
Procedures and Assessments at Visit 7 (Day 71) ..........................................................84
Table 6-8.
Procedures and Assessments at Visit 8 (Day 85) ..........................................................85
Table 6-9.
Procedures and Assessments at Visit 9 (Day 113) ........................................................87
Table 6-10.
Procedures and Assessments at Visit 10 (Day 141) ......................................................89
Table 6-11.
Procedures and Assessments at Visit 11 (Day 169) ......................................................90
Table 6-12.
Procedures and Assessments at Visit 12 (Day 211) ......................................................92
Table 6-13.
Procedures and Assessments at Visit 13 (Day 253) ......................................................93
Table 6-14.
Procedures and Assessments at Visit 14 (Day 295) ......................................................94
Table 6-15.
Procedures and Assessments at Visit 15 and Subsequent Visits 
(Day 337 and Every 12 Weeks) ....................................................................................95
Table 6-16.
Procedures and Assessments at End-of-Study Visit......................................................97
Table 8-1.
Grading of Adverse Event Severity.............................................................................113
Table 8-2.
Site Reporting Requirements for Adverse Events.......................................................114
Table 8-3.
Contact Information for Reporting Serious Adverse Events.......................................115
LIST OF IN-TEXT FIGURES
Figure 2-1.
Study Design.................................................................................................................34


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc
199 East Blaine Street
Seattle, WA 98102, USA
Study Title: 
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and 
Safety of Two Different Dose Levels of Single-Agent Idelalisib
(GS-1101) as Therapy for Patients with Previously Treated Chronic 
Lymphocytic Leukemia
A Companion Study to Study GS-US-312-0116: A Phase 3, Randomized, 
Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of Idelalisib (GS-1101) in Combination with Rituximab as Therapy 
for Patients with Previously Treated Chronic Lymphocytic Leukemia
Study Centers 
Planned:
Approximately 90 centers in the United States and in Europe
IND Number:
101254
EudraCT 
Number:
2011-006293-72
Objectives:

To evaluate the effect of idelalisib (formerly GS-1101) on the onset, 
magnitude, and duration of tumor control 

To compare tumor control in subjects receiving rituximab alone in 
Study GS-US-312-0116 to that observed in the same subjects when 
receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject well-being, 
including overall survival (OS), health-related quality of life 
(HRQL), and performance status

To assess the effects of idelalisib on disease-associated biomarkers 
and to evaluate potential mechanisms of resistance to idelalisib

To characterize exposure to idelalisib as determined by treatment 
administration and evaluation of idelalisib plasma concentrations 
over time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with 
administration of idelalisib


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Study Design:
This study is being conducted as part of an overall clinical program 
evaluating the efficacy and safety of idelalisib in the therapy of patients 
with previously treated chronic lymphocytic leukemia (CLL). 
Within this program, the primary clinical trial (Study GS-US-312-0116)
is a Phase 3, multicenter, 2-arm, randomized, double-blind, 
placebo-controlled, parallel-group study.
This clinical trial (Study GS-US-312-0117) is a separate, multicenter, 
2-arm, double-blind, parallel-group extension study that is a companion 
trial to Study GS-US-312-0116; in this trial, compliant subjects from 
GS-US-312-0116 who are tolerating primary study therapy but 
experience definitive CLL progression are eligible to receive active 
blinded idelalisib therapy at the standard dose or a higher dose, with 
allocation based on the original primary study randomization. In the event 
GS-US-312-0116 is stopped early due to overwhelming efficacy 
following an interim analysis or at the final analysis, subjects who are on 
Study GS-US-312-0116 at that time may transition to GS-US-312-0117.  
Additionally, GS-US-312-0117 will become an open-label study offering 
idelalisib 150mg BID to GS-US-312-0116 subjects who were randomized 
to placebo, and subjects randomized to idelalisib will continue idelalisib 
at 150mg BID .
Study Schema:
Treatment Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117)


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Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID
Treatment Assignment

Assignment to Arm A or Arm B with allocation based on the 
original primary study randomization

Implementation through an interactive web response system 
(IWRS)
Stratification
Not applicable for Study GS-US-312-0117
Number of 
Subjects 
Planned:
Total of up to ~160 subjects (up to ~80 subjects per treatment arm)
Target 
Population
Subjects in the primary Phase 3 study (GS-US-312-0116) who are 
compliant, are tolerating primary study therapy, and 1) have definitive 
progression of CLL while receiving primary study drug therapy 
(idelalisib /placebo)  or 2) are actively participating in 
Study= GS-US-312-0116 at the time the study is stopped, including if 
stopped early due to overwhelming efficacy following an interim 
analysis.
Diagnosis and 
Main Eligibility 
Criteria:
Inclusion Criteria
Subjects must meet all of the following conditions to be eligible for 
enrollment into the study:
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while receiving 
study drug therapy (idelalisib /placebo) in Study GS-US-312-0116. 
Note: Definitive disease progression is CLL progression based on 
standard criteria and occurring for any reason (ie, increasing 
lymphadenopathy, organomegaly, or bone marrow involvement; 
decreasing platelet count, hemoglobin, or neutrophil count; or 
worsening of disease-related symptoms) other than lymphocytosis. 
Subjects must have confirmation by the sponsor working in 
collaboration with an independent review committee (IRC) that the 
disease has progressed on the primary clinical trial
(Study GS-US-312-0116) before receiving secondary idelalisib
therapy on this extension trial (Study GS-US-312-0117).


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3) Presence of measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures 2.0 cm in the longest diameter [LD] 
and 1.0 cm in the longest perpendicular diameter [LPD] as assessed 
by computed tomography [CT] or magnetic resonance imaging 
[MRI]).
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab 
and/or idelalisib/placebo) and no intervening or continuing therapy 
(including radiotherapy, chemotherapy, immunotherapy, or 
investigational therapy) for the treatment of CLL. Note: Subjects may 
receive corticosteroids to manage CLL manifestations.
5) The time from permanent cessation of Study GS-US-312-0116 
treatment (rituximab and/or idelalisib/placebo) and the initiation of 
Study GS-US-312-0117 therapy is 12 weeks. Note: Study 
procedures performed as part of Study GS-US-312-0116 need not be 
repeated and can be used as screening procedures for 
Study GS-US-312-0117 if performed within 4 weeks prior to 
initiation of study drug therapy on Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation 
of study treatment) as shown in the table below. Note: Confirmation 
should be considered for out-of-range values to determine if the 
abnormality is real or artifactual. Values should be obtained within 
the screening period and should generally be the most recent 
measurement obtained. Subjects with any degree of neutropenia, 
thrombocytopenia, or anemia due to CLL or prior therapy may 
enroll.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCr
a
>30 ml/min
Pregnancy
-HCGb
Negative 
a
As calculated by the Cockcroft-Gault formula
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or 
urine dipstick pregnancy test must be negative at randomization (Visit 2)
Abbreviations: -HCG=beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate 
aminotransferase, eCCr=estimated creatinine clearance, ULN=upper limit of normal


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8) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening 
visit (Visit 1) throughout the study and for 30 days from the last dose 
of study drug. Note: A female subject is considered to be of 
childbearing potential unless she has had a hysterectomy, bilateral 
tubal ligation, or bilateral oophorectomy; has medically documented 
ovarian failure (with serum estradiol and follicle-stimulating 
hormone [FSH] levels within the institutional postmenopausal 
range and a negative serum or urine HCG), or is menopausal 
(defined as age >55 years with amenorrhea for >12 months or 
amenorrhea for >6 months with serum estradiol and FSH levels 
within the institutional postmenopausal range). 
9) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of 
study drug (Visit 2) throughout the study and for 90 days following 
the last dose of study drug and to refrain from sperm donation from 
the start of study drug (Visit 2) throughout the study and for 90 days 
following the last dose of study drug. Note: A male subject is 
considered able to father a child unless he has had a bilateral 
vasectomy with documented aspermia or a bilateral orchiectomy, or 
has ongoing testicular suppression with a depot luteinizing 
hormone- releasing hormone (LH-RH) agonist (eg, goserelin 
acetate [Zoladex®]), leuprolide acetate [Lupron®]), or triptorelin 
pamoate [Trelstar®]).
10) In the judgment of the investigator, participation in the protocol offers 
an acceptable benefit-to-risk ratio when considering current CLL 
disease status, medical condition, and the potential benefits and risks 
of alternative treatments for CLL. 
11) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, 
familial, or geographical factors that might preclude adequate study 
participation should be considered.
12) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature of 
the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study 
participation.


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Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be 
enrolled in this study:
1) Known histological transformation from CLL to an aggressive 
lymphoma (ie, Richter transformation). 
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at 
the time of the start of study treatment (Visit 2). Note: Subjects with 
localized fungal infections of skin or nails are eligible. Subjects may 
be receiving prophylactic antiviral or antibacterial therapies at the 
discretion of the investigator; anti-pneumocystis prophylaxis is 
encouraged. 
3) Pregnancy or breastfeeding. 
4) Intentional breaking of the blind in Study GS-US-312-0116 by the 
investigator or the study subject.
5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical condition, 
surgical history, physical finding, electrocardiogram (ECG) finding, 
or laboratory abnormality that, in the investigator’s opinion, could 
adversely affect the safety of the subject or impair the assessment of 
study results.
In the event Study GS-US-312-0116 is stopped early, subjects who are 
actively participating in Study GS-US-312-0116 will become eligible for 
this study, provided the following inclusion are met: Participation in 
Study GS-US-312-0116 within 12 weeks of enrollment onto 
GS-US-312-0117.
1) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening 
visit (Visit 1) throughout the study and for 30 days from the last dose 
of study drug. 
2) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of 
study drug (Visit 2) throughout the study and for 90 days following 
the last dose of study drug and to refrain from sperm donation from 
the start of study drug (Visit 2) throughout the study and for 90 days 
following the last dose of study drug. 
3) In the judgment of the investigator, participation in the protocol offers 
an acceptable benefit-to-risk ratio when considering current CLL 
disease status, medical condition, and the potential benefits and risks 
of alternative treatments for CLL. 


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4) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, 
familial, or geographical factors that might preclude adequate study 
participation should be considered.
5) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature of 
the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study 
participation.
Study 
Procedures/
Frequency:
Clinic/laboratory visits will occur every 2 weeks for the first 12 weeks, 
every 4 weeks between Weeks 12 and 24, and every 6 weeks between 
Weeks 24 and 48. Subjects continuing on study drug past Week 48 will 
have clinic visits every 12 weeks. Subjects will be assessed for safety at 
each visit. Subjects will be assessed for CLL disease status by physical 
and laboratory examinations at each visit and by CT or MRI at Weeks 8, 
16, 24, 36, and 48 and every 12 weeks thereafter.
Following unblinding of the study, subjects who were randomized to 
idelalisib on Study GS-US-312-0116 will not be required to have study 
visits 3, 5, and 7 performed and will follow local standard of care for 
follow-up imaging.
Test Therapy, 
Dose, and 
Mode of 
Administration:
Blinded Portion

Arm A: Idelalisib, 300 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be 
provided as 2 tablets of active idelalisib for oral administration

Arm B: Idelalisib, 150 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be 
provided as 1 tablet of active idelalisib and 1 tablet of placebo for 
oral administration
Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID
Note: At the Investigator’s discretion, subjects who were randomized 
to placebo on study GS-US-312-0116 may delay initiation of idelalisib 
following enrollment on Study GS-US-312-0117 until the time of 
disease progression or until the investigator determines that the 
subject would benefit from initiation of idelalisib treatment


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Reference 
Therapy, Dose, 
and Mode of 
Administration:
Not applicable
Duration of 
Treatment:
Study drug will be taken continuously until the earliest of subject 
withdrawal from study drug, definitive progression of CLL, intolerable 
study drug-related toxicity, pregnancy, substantial noncompliance with 
study procedures, or study discontinuation.
Criteria for 
Evaluation:
Tumor Control

Progression-free survival (PFS) – defined as the interval from the 
start of study therapy to the earlier of the first documentation of 
definitive disease progression or death from any cause; definitive 
disease progression is CLL progression based on standard criteria 
other than lymphocytosis alone

Overall response rate (ORR) – defined as the proportion of subjects 
who achieve a complete response (CR) or partial response (PR)

Lymph node response rate – defined as the proportion of subjects 
who achieve a 50% decrease from baseline in the sum of the 
products of the greatest perpendicular diameters (SPD) of index 
lesions

CR rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from start of study 
therapy to the first documentation of CR or PR

Duration of response (DOR) – defined as the interval from the 
first documentation of CR or PR to the earlier of the first 
documentation of definitive disease progression or death from any 
cause

Percent change in lymph node area – defined as the percent change 
from baseline in the SPD of index lymph nodes

Splenomegaly response rate – defined as the proportion of subjects 
with a 50% decrease (minimum 2 cm) from baseline in the 
enlargement of the spleen in its LVD or to <12 cm 

Hepatomegaly response rate – defined as the proportion of subjects 
with a 50% decrease (minimum 2 cm) from baseline in the 
enlargement of the liver in its LVD or <18 cm 

ALC response rate – defined as the proportion of subjects with 
baseline lymphocytosis (ALC4 x 109/L) who achieve an on-study 
ALC <4 x 109/L or demonstrate a 50% decrease in ALC from 
baseline


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
Platelet response rate – defined as the proportion of subjects with 
baseline thrombocytopenia (platelet count <100 x 109/L) who 
achieve an on-study platelet count 100 x 109/L or demonstrate a 
50% increase in platelet count from baseline

Hemoglobin response rate – defined as the proportion of subjects 
with baseline anemia (hemoglobin <110 g/L [11.0 g/dL]) who 
achieve an on-study hemoglobin 110 g/L (11.0 g/dL) or 
demonstrate a 50% increase in hemoglobin from baseline

Neutrophil response rate – defined as the proportion of subjects with 
baseline neutropenia (absolute neutrophil count [ANC] 
≤1.5 x 109/L) who achieve an ANC >1.5 x 109/L or demonstrate a 
50% increase in ANC from baseline
Patient Well-Being

Overall survival (OS) – defined as the interval from start of study 
therapy to death from any cause

Change from baseline in HRQL domain and symptom scores based 
on the Functional Assessment of Cancer Therapy: Leukemia 
(FACT-Leu) (See Appendix 2)

Changes from baseline in Karnofsky performance status
(See Appendix 3)
Pharmacodynamic Markers of Drug Activity and Resistance

Changes from baseline in PI3K/AKT/mTOR pathway activation as 
a measure of PI3Kpathway activity 

Changes from baseline in the plasma concentrations of 
disease-associated chemokines and cytokines
Exposure

Study drug administration as assessed by prescribing records and 
compliance as assessed by quantification of used and unused drug

Trough (pre-dose) and peak (1.5-hour samples) of idelalisib plasma 
concentrations as assessed by a validated bioanalytical method
Safety

Overall safety profile of each regimen characterized by the type, 
frequency, severity, timing of onset, duration, and relationship to 
study therapy of any adverse events or abnormalities of laboratory 
tests; serious adverse events; or adverse events leading to 
discontinuation of study drug


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Pharmacoeconomics

Change in health status – defined as the change from baseline in 
overall health and single-item dimension scores as assessed using 
the EuroQoL Five-Dimension (EQ-5D) utility measure 

Health resource measures, including resource utilization, total costs, 
and measures of cost per unit of benefit (eg, cost per additional
progression-free month, cost per quality-adjusted life-year)
Statistical 
Methods:
Appropriate data analysis sets will be defined. The intent-to-treat (ITT) 
analysis set will include data from all subjects who receive 1 dose of any 
study therapy on this study; in this data set, study drug assignment 
(high-dose or standard-dose idelalisib) will be designated according to the 
planned allocation to this study. A safety analysis set will comprise data 
from subjects in the ITT analysis set with treatment assignments designated 
according to the actual study drug (high-dose or standard-dose idelalisib) 
received. Other analysis sets [per-protocol (PP) and 
pharmacodynamic/pharmacokinetic analysis sets] will be used for certain 
analyses as well.
Subject characteristics and study results will be described and 
summarized by treatment arm and assessment for the relevant analysis 
sets. Descriptive summaries will be prepared to show sample size, mean, 
standard deviation, 95% confidence intervals (CIs) on the mean, median, 
minimum, and maximum for continuous variables and counts, 
percentages, and 95% CIs on the percentage for categorical variables.
An independent review committee (IRC) will review radiographic data 
and pertinent clinical data in order to provide expert evaluation of tumor 
status. The findings of the IRC will be considered primary for analyses of 
PFS and other tumor control endpoints.
For endpoints relating to tumor control, patient well-being, and 
biomarkers, analyses will be done based on ITT, PP or pharmacodynamic 
data sets, as appropriate. Time-to-event analyses will be performed with 
reference to the date of first treatment on this study 
(Study GS-US-312-0117). Similarly, evaluations of on-therapy changes 
will reference the baseline values obtained prior to treatment in this study. 
Analyses will focus on evaluation of outcomes within each treatment arm 
and will be largely descriptive in nature; formal comparisons of outcomes 
in Arm A vs Arm B are not planned. Time-to-event endpoints will be 
summarized using Kaplan-Meier methods; medians, ranges, and the 
corresponding 95% CI will be presented. Continuous and categorical 
variables will also be summarized as appropriate. Changes from baseline 
in categorical variables and changes from baseline in continuous 
endpoints will be analyzed using appropriate methods.


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Efficacy outcomes among subjects receiving rituximab alone in 
Study GS-US-312-0116 will be evaluated relative to those same 
outcomes among the same subjects receiving standard-dose idelalisib
alone in Study GS-US-312-0117. More specifically, time-to-event 
endpoints will be compared using the paired Prentice-Wilcoxon test; 
continuous endpoints will be compared using the paired t-test; and 
categorical or non-normal data will be compared using the Wilcoxon 
signed-rank test.
Based on the safety analysis set, information regarding study drug
administration, study drug compliance, safety variables, and post-study 
therapies will be described and summarized. Using data from the
pharmacokinetic analysis set, idelalisib plasma concentrations will also be 
described and summarized.
Sample Size Calculation
The sample size for this extension study is not based upon a formal 
statistical hypothesis. The upper bound of the sample size in this study is 
determined by the sample size of the preceding primary clinical trial
(Study GS-US-312-0116) in which ~160 subjects (~80 per arm) are 
expected to be enrolled. Assuming a ~10% dropout rate during 
Study GS-US-312-0116 and a further ~10% dropout rate in the transition 
from the primary study to the extension study, ~130 subjects are expected 
to be enrolled into Study GS-US-312-0117.
This study will be conducted in accordance with the guidelines of Good Clinical Practice 
(GCP), including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
-HCG
Beta human chorionic gonadotropin
ABCG2
adenosine triphosphate-binding cassette sub-family G member 2 (see also BCRP)
AKT
AKT (a serine/threonine protein kinase)
ALC
absolute lymphocyte count
ALL
acute lymphocytic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
ATC
Anatomical-Therapeutic-Chemical classification system for drugs 
BCRP
breast cancer resistance protein (see also ABCG2)
BID
twice per day
BTK
Bruton tyrosine kinase
CAL-101
Former name for GS-1101
CCL
chemokine (C-C motif) ligand
CFR
Code of Federal Regulations
CI
confidence interval
CIRS
Cumulative Illness Rating Scale
CLL
chronic lymphocytic leukemia
cGMP
current Good Manufacturing Practice
Cmax
maximum concentration
CMV
cytomegalovirus
CR
complete response
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough concentration
CXCL
chemokine (C-X-C motif) ligand
CYP
cytochrome P450 enzyme
DLCO
diffusing capacity of the lung for carbon monoxide
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DOR
duration of response
DSPH
Gilead Sciences Department of Safety and Public Health
ECG
electrocardiogram


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
eCCr
estimated creatinine clearance
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EQ-5D
EuroQoL Five-Dimension utility measure
FACT-Leu
Functional Assessment of Cancer Therapy: Leukemia questionnaire
FCεRI
high-affinity IgE receptor
FDA
United States Food and Drug Administration
FDAMA
Food and Drug Modernization Act
FDG
fluorodeoxyglucose (18F)
FISH
fluorescence in-situ hybridization,
FSH
follicle-stimulating hormone
G-CSF
granulocyte colony-stimulating factor
GGT
gamma-glutamyltransferase
GLP
Good Laboratory Practice
GM-CSF
granulocyte-macrophage colony-stimulating factor
HBc antibody
anti-hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
hERG
human ether-à-go-go-related gene
HL
Hodgkin lymphoma
HIV
human immunodeficiency virus
HRQL
health-related quality of life
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
idelalisib
formerly CAL-101 and GS-1101
IEC
independent ethics committee
Ig
immunoglobulin (including subtypes A, E, G, and M)
IgHV
immunoglobulin heavy chain variable region
IND
Investigational New Drug (application)
iNHL
indolent non-Hodgkin lymphoma
INR
international normalized ratio
IRB
institutional review board
IRC
independent review committee
ITT
intention to treat
IUD
intrauterine device
IWCLL
International Workshop on CLL


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
IWRS
interactive web response system
JAK
Janus kinase
K2-EDTA
potassium-ethylenediaminetetraacetic acid
LD
longest diameter
LDH
lactate dehydrogenase
LH-RH
luteinizing hormone-releasing hormone
LLN
lower limit of normal
LPD
longest perpendicular diameter
LVD
longest vertical dimension
MTD
maximum tolerated dose
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mTOR
mammalian target of rapamycin
ND
no disease
NHL
non-Hodgkin lymphoma
NOAEL
no-observed-adverse effect level
NOEL
no-observed-effect level
OCT
organic cation transporter
ORR
overall response rate
OS
overall survival
pAKT
phosphorylated AKT
PCR
polymerase chain reaction
PD
progressive disease
PET
positron-emission tomography
PI3K
phosphatidylinositol 3-kinase
PI3K
phosphatidylinositol 3-kinase p110isoform
PFS
progression-free survival
PML
progressive multifocal leukoencephalopathy
PP
per-protocol
PPD
product of the perpendicular diameters
PRO
patient-reported outcome
PR
partial response
PT
prothrombin time
PVA
polyvinyl alcohol
PVC/PCTFE
polyvinyl chloride/polychlorotrifluoroethylene
QD
once per day
QT (interval)
measure of time between start of Q wave and end of T wave in electrical cycle of heart


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
RNA
ribonucleic acid
SADR
serious adverse drug reaction
SD
stable disease
SPD
sum of the products of the perpendicular diameters of measured lymph nodes
SSC
study steering committee
SUSAR
suspected, unexpected, serious adverse reaction
SYK
spleen tyrosine kinase
t1/2
half-life
Tmax
time of maximum concentration
TTR
time to response
UGT
uridine 5'-diphospho-glucuronosyltransferase
ULN
upper limit of normal
WHODRUG
World Health Organization Drug Dictionary
ZAP-70
zeta-associated protein 70


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1.
INTRODUCTION
Chronic Lymphocytic Leukemia
1.1.
Chronic lymphocytic leukemia (CLL) is a neoplasia resulting from the progressive 
accumulation of functionally incompetent monoclonal B lymphocytes in blood, bone 
marrow, lymph nodes, spleen, and liver [Dighiero 2008]. CLL constitutes the most 
commonly occurring leukemia in Europe and the United States [Sant 2010, SEER 2011]. 
While some patients never require treatment, many will need therapy for disfiguring or 
obstructing lymphadenopathy, debilitating constitutional B symptoms (fevers, night sweats, 
fatigue, weight loss) [Redaelli 2004], or recurrent cytopenias and infections [Perkins 2002, 
Keating 2002a]. CLL is largely a disease of the elderly; at diagnosis, 70% of patients are 
65 years of age and the median age is 72 years [SEER 2011].
In younger and relatively healthy patients with CLL, chemoimmunotherapy regimens that 
include the anti-CD20 monoclonal antibody, rituximab, are commonly employed to control 
disease manifestations [Gribben 2011]. Such combination therapies are effective in providing 
durable remissions [Byrd 2005, Hallek 2010, Robak 2010, Fischer 2011, and Iannitto 2011]. 
However, while rituximab is usually well tolerated [Gentile 2010], the chemotherapeutic 
agents (typically fludarabine, cyclophosphamide, or bendamustine) in such regimens are 
acutely cytotoxic, induce permanent bone marrow compromise, and can cause secondary 
malignancies [Kyasa 2004, Tam 2008, Carney 2010]. Furthermore, in elderly patients or in 
those with comorbid conditions, such regimens are associated with less efficacy and greater 
toxicity [Tam 2008, Eichhorst 2009b, Goede 2011].
Increasing attention has been paid to the problem of treating patients with CLL who have 
comorbidities. Because of the relatively late age of diagnosis, a large proportion (~90%) of 
patients with CLL have co-morbidities and a substantial proportion (~45%) have major 
chronic conditions such as coronary artery disease, diabetes, or chronic obstructive 
pulmonary disease [Thurmes 2008]. At the time the disease is first identified, ~25% of 
patients with CLL do not meet conventional criteria for participation in clinical studies 
containing cytotoxic agents [Thurmes 2008]. By the time treatment is necessary or during 
treatment for CLL, patients continue to advance in age and have new or worsening chronic 
conditions; as a result, the proportion of patients with comorbidities increases during the 
course of the illness. Such patients have been substantially underrepresented in clinical trials 
due to concerns regarding the ability of such patients to tolerate intensive 
chemoimmunotherapy [Thurmes 2008, Eichhorst 2009a]. Instruments such as the 
Cumulative Illness Rating Scale (CIRS) [Linn 1968] are now being applied in order to 
categorize patient populations as fit or relatively unfit and to evaluate regimens tailored to 
these groups of patients [Eichhorst 2009a, Hallek 2010, Giudice 2011].


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Health constraints in older or compromised patients have prompted noncytotoxic approaches
to therapy. Alternative immunotherapeutics, such as the monoclonal antibodies, 
alemtuzumab [Keating 2002b] or ofatumumab [Wierda 2010], have been developed. 
However the therapeutic utility of these drugs is modest; median progression-free survival 
(PFS) values in patients with recurrent CLL have been 4.7 months and 5.8 months, 
respectively. Moreover, these treatments can have clinical liabilities. Alemtuzumab causes 
extreme immunosuppression that leads to frequent opportunistic infection. Administration of 
the large amounts of protein recommended in ofatumumab product labeling results in 
frequent infusion reactions and cumbersome infusion schedules.
In view of these issues, repeated use of rituximab monotherapy or rituximab-corticosteroid 
combinations have been advocated in treatment guidelines for older or frail patients with 
recurrent CLL [Eichhorst 2010, Zelenetz 2011]. While single-agent rituximab use can offer 
palliative benefit with good tolerability in some patients with previously treated CLL, tumor 
control is not lasting, especially in patients with bulky adenopathy [Gentile 2010]. Addition 
of high-dose corticosteroids to rituximab can extend median PFS up to 12 months, but this 
combination is commonly associated with severe hyperglycemia and frequent 
life-threatening or fatal infections [Bowen 2007, Dungarwalla 2008]. New, noncytotoxic, 
well-tolerated, and convenient therapies that can successfully be combined with rituximab or 
given as single-agent therapy are needed in order to enhance and prolong tumor control in 
patients with comorbid conditions.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies
1.2.
Phosphatidylinositol 3-kinases (PI3Ks) are enzymes that regulate several cellular functions 
including motility, proliferation, and survival [Okkenhaug 2003a]. PI3K activation recruits 
and activates numerous intracellular signaling enzymes. The most important of these is the 
serine/threonine kinase, AKT, which mediates a positive pleiotropic effect on cell survival, 
proliferation, growth, and metabolism [Engelman 2006] acting by signaling through 
mammalian target of rapamycin (mTOR) [Hay 2005, Osaki 2004].
PI3K signaling is mediated by 4 catalytic isoforms of the p110 subunit of the enzyme - , , 
, and . While potentially important in multiple cell types, PI3K p110(PI3K) shows an 
expression pattern that is particularly prominent in cells of hematopoietic origin 
[Vanhaesebroeck 2005]. Mice deficient in PI3Khave no gross abnormalities, are fertile, 
fecund, and live a normal life span without an increased susceptibility to infections 
[Okkenhaug 2003b]. However, the B-lymphocyte population in these animals shows a 
decrease in maturation, diminished receptor-induced proliferation, and increased 
susceptibility to apoptotic cell death. Conversely, mice with aberrantly elevated PI3K 
signaling develop lymphadenopathy and have an increased incidence of lymphoma 
[Donahue 2004]. In CLL, sustained activation of the PI3K/AKT/mTOR pathway has been 
shown to promote malignant B-cell survival through mechanisms that are dependent on the 
PI3Kisoform [Cuni 2004, Herman 2010, Lannutti 2011].


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Knowledge of the critical importance of PI3Kδ in B-cell biology and neoplasia has 
encouraged a search for inhibitors of this enzyme that could provide new options in the 
therapy of lymphoid malignancies, including CLL.
Idelalisib (formerly GS-1101)
1.3.
1.3.1.
Discovery and Efficacy Pharmacology
Gilead Sciences, Inc has developed novel drugs that can suppress tumor growth through 
targeting of PI3Kδ activity. High-throughput screening was the basis for the discovery of 
novel agents that selectively inhibit PI3Kfunction but spare other PI3K isoforms and other 
kinases. Chemical optimization, pharmacological characterization, and toxicological 
evaluation have led to identification of idelalisib (also known as GS-1101), a 415-dalton, 
orally bioavailable, new chemical entity with potential clinical utility in the treatment of 
cancers [Gilead Sciences 2011].
In primary tumor samples and in cell lines derived from patients with CLL, indolent 
non-Hodgkin lymphoma (iNHL), mantle cell lymphoma (MCL), B-cell acute lymphocytic 
leukemia (ALL), or Hodgkin lymphoma (HL), idelalisib induces dose-dependent reductions
in AKT phosphorylation [Herman 2010, Meadows 2010, Lannutti 2011]. In addition, 
idelalisib disrupts the PI3Kactivation and supportive intercellular signaling observed when 
CLL or HL cells are cocultured with stromal cells [Meadows 2010, Hoellenriegel 2011].
These effects have therapeutic consequences. In multiple lymphoid primary tumors and 
malignant cell lines, idelalisib enhances apoptosis and concentration-dependent cell killing 
when applied as a single agent and increases the therapeutic efficacy of other antineoplastic 
agents when given in combination [Hoellenriegel 2011, Meadows 2011]. In preclinical 
systems, coadministration of idelalisib with rituximab has not impaired rituximab-mediated 
activity [Herman 2010].
1.3.2.
Safety Pharmacology
In vitro and in vivo safety pharmacology studies with idelalisib have demonstrated a 
favorable non-clinical safety profile [Gilead Sciences 2011]. These studies indicate that the 
drug may minimally slow bone marrow progenitor proliferation and differentiation and that it 
has expected inhibitory effects on B-cell response to antigen challenge. However, the data 
indicate that idelalisib is unlikely to cause serious off-target effects or adverse effects on 
critical organ systems. idelalisib has no meaningful effect on the human ether-à-go-go-related 
gene (hERG) channel, indicating that idelalisib would not be expected to induce clinical QT 
prolongation.


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The drug has also proved well tolerated in standard in vivo Good Laboratory Practice (GLP) 
studies of pharmacological safety. A functional observation battery in rats revealed no 
adverse effects on behavior or on autonomic, neuromuscular, or sensorimotor function. In a 
cardiopulmonary function study in awake, telemeterized male beagle dogs, single doses of 
idelalisib induced no meaningful abnormalities in pulmonary, cardiovascular, arterial blood 
gas, or electrocardiographic (ECG) (including QT interval) parameters. In an assessment of 
bacterial challenge in rats, idelalisib enhanced, rather than impaired, the phagocytic host 
clearance of staphylococcal bacteria.
1.3.3.
Nonclinical Pharmacology and Metabolism
Consistent with the moderate to high bioavailability seen in nonclinical species, idelalisib 
shows high permeability across human Caco-2 cell monolayers.  At lower concentrations, the 
reverse permeability at low concentration exceeds forward permeability, indicating efflux 
driven by transporters (eg, human P-glycoprotein (MDR1) and breast cancer resistance 
protein [BCRP]); idelalisib is a substrate for the efflux transporters MDR1 and BCRP; 
however, the permeability increases in a concentration-dependent manner, resulting in a 
lower efflux ratio at higher, clinically relevant concentrations of idelalisib. 
Idelalisib exhibits moderately high plasma protein binding in mouse, rat, dog, and human.  In 
dog and human plasma, the protein binding is concentration-independent between 1 and 
20 µM.  Protein binding in human plasma is slightly higher than in mouse, rat, and dog 
plasma, which have comparable free fractions.  In human plasma, idelalisib and GS-563117 
(the major metabolite of idelalisib) have an average free fraction of ~16% and ~12%, 
respectively.
After oral administration of 14C-idelalisib to rats and dogs, radioactivity is widely distributed, 
but relatively excluded from bone, brain, spinal cord, and eye lens in rats and from brain and 
eyes in dogs.  In rats, the radioactivity declines steadily and most tissues have undetectable 
levels by 72 hours post dose.  In bile duct-cannulated rats and dogs, ≥ 69% of radioactivity is 
recovered in bile and urine, indicating high absorption of idelalisib in vivo.
In hepatic tissues from nonclinical species, idelalisib is primarily metabolized by aldehyde 
oxidase, CYP3A, and UGT1A4.  In vitro metabolism in dog and human yields 3 primary 
oxidative metabolites and 5 primary glucuronides.  Of these, the oxidative product 
GS-563117 is the predominant metabolite in vitro and in vivo.  In preclinical species, plasma 
levels of GS-563117 are below those of idelalisib.  In humans, GS-563117 (only circulating 
metabolite and formed via aldehyde oxidase) plasma levels significantly exceed those of 
idelalisib.  After oral administration of 14C-idelalisib to rats and dogs, biliary excretion 
appears to be the major route of elimination of idelalisib and its metabolites as the majority 
of radioactivity is found in feces or bile and little in urine.
Idelalisib is not a substrate for the renal transporters OCT2, OAT1, and OAT3 or the hepatic 
uptake transporters OATP1B1 and OATP1B3.  GS-563117 is not a substrate for OATP1B1 
and OATP1B3.  


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Idelalisib is not an inhibitor of CYP1A, CYP2B6, CYP2C9, and CYP2D6, and at 
concentrations above those observed clinically, is an inhibitor of CYP2C8 (IC50 = 13 µM), 
CYP2C19 (IC50 = 76 µM), and CYP3A (IC50 = 44 µM). GS-563117 is not an inhibitor of 
CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and a competitive and time 
dependent inhibitor of CYP3A (IC50 = 3.1 µM), (KI = 0.18 µM, kinact = 0.033 min-1 with 
midazolam as the probe substrate). 
In vitro, idelalisib is not an inhibitor of the transporters BCRP, OCT2, OAT1, and OAT3, 
and is an inhibitor of MDR1 (IC50 = 7.7 µM), OATP1B1 (IC50 = 10.1 µM), OATP1B3 (IC50
= 7.0 µM), and, at concentrations above those observed clinically, of glucuronosyltransferase 
UGT1A1 (IC50 = 42.0 µM).  GS-563117 is not an inhibitor of MDR1, BCRP, OATP1B1, 
OATP1B3, OAT1, OAT3, and OCT2, and at concentrations above those observed clinically, 
an inhibitor of UGT1A1 (IC50 = 16.8 µM).
Any potential clinical implications of these metabolism studies were evaluated in a formal 
drug-drug interaction study (GS-US-313-0130) which evaluated the effect of idelalisib on 
cytochrome P450 3A and the drug transporters P-gp, OATP1B1, and OATP1B3.  
Study GS-US-313-0130 also evaluated the impact of an inducer of metabolizing enzymes 
and transporters (rifampin) on the PK of idelalisib in healthy human subjects. Findings from 
this study are presented in Section 1.3.5.1.
1.3.4.
Toxicology
A comprehensive package of nonclinical studies has been conducted and provides a 
toxicological profile of idelalisib in support of the treatment of adults with advanced cancer. 
The following toxicology studies have been conducted to assess the safety of idelalisib: 
single-dose (in rats and dogs) and repeat-dose oral toxicity studies (up to 26 weeks in rats and 
up to 39 weeks in dogs), in vitro and in vivo genotoxicity studies, and developmental and 
reproductive toxicity studies (fertility and embryo-fetal development in rats).
Once daily administration of idelalisib was associated with B-cell depletion in numerous 
lymphoid organs in rats and dogs, consistent with the known pharmacology of PI3Kδ 
inhibition [So 2012]. All changes were partially or completely reversible following a 4-week 
recovery period. Serum transaminase elevations were noted in the dog in both the 28-day and 
13-week studies at doses ≥7.5 mg/kg/day. Peak elevations occurred approximately 4 weeks 
following initiation of dosing and resolved completely with continued dosing. No evidence 
of chronic hepatic injury was noted in either the 13- or 39-week studies at dose levels up to 
7.5 mg/kg/day (Day 272 AUC0-t 17.1 µg∙hr/mL). In an investigative pharmacology study, a 
further characterization of the pattern of serum transaminase changes associated with 
administration of 15 mg/kg/day of idelalisib to dogs confirmed hepatic adaptation to the 
effect. In this study, mean serum ALT/AST values peaked at approximately Day 24 to 
Day 27 and resolved spontaneously as the dogs continued on idelalisib through the end of the 
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Decreased testes weights were observed in GLP repeat dose studies in rats and dogs. 
Decreased testicular weights were noted in all studies. A male fertility in rats study indicated 
that there was no impact on fertiliy or reproductive potential following daily dosing for 
10 weeks up to 100 mg/kg/day. Spermatogenic assessment of idelalisib-treated animals was 
similar to controls.  Changes in testicular weight in repeat-dose studies is suspected to be 
associated with fluid production and/or tubular contraction and not a degenerative effect.
Pregnant female rats were administered idelalisib in a standard embryo-fetal development 
toxicity study at oral doses of up to 150 mg/kg/day.  Idelalisib was shown to be embryo lethal 
and teratogenic in rats at ≥ 75 mg/kg/day (Gestation Day 17 AUC0-t 251 µg hr/mL). 
Dose-dependent developmental findings included decreased fetal viability, increased early 
and late resorptions, and decreased mean fetal body weights. Dose-dependent external 
malformations included short tails and complete tail loss. Additional external malformations 
were single instances of hydrocephaly and microphthalmia, occurring in separate fetuses 
from different litters.
Idelalisib was negative for mutagenic potential in a bacterial reverse-mutation test and 
negative for inducing chromosomal aberrations in cultured human peripheral blood 
lymphocytes. Idelalisib has shown some evidence of inducing micronuclei in this in vivo test 
system when tested at high dose levels, up to the standard limit of 2000 mg/kg. However, 
based on the mechanism of action of PI3Ks and their role as intracellular signaling proteins 
essential to migratory, proliferative, survival, and differentiation pathways, idelalisib may 
cause a small increase in micronucleated erythrocytes by mechanisms unrelated to the 
inherent genotoxicity of the compound [Tweats 2007]. These data suggest that idelalisib is 
not genotoxic.
Coadministration of cyclophosphamide with idelalisib did not appear to exacerbate the 
myelosuppressive effects of cyclophosphamide. Idelalisib did not impair bacterial clearance 
in a rat S. aureus abscess model.
A phototoxicity study yielded inconclusive results for the assessment of idelalisib due to 
cytotoxicity observed in the assay. However, the predominant oxidative metabolite, 
GS-563117, was determined to be toxic only in the presence of ultraviolet A (UVA) light
1.3.5.
Idelalisib Clinical Studies
1.3.5.1.
Phase 1 Studies in Healthy Subjects and in Patients with Allergic Rhinitis
Various studies in healthy subjectshave evaluatedsafety, pharmacokinetics, food effect, and 
the potential for drug interactions of idelalisib with CYP3A4 inhibitors [Webb 2010, 
Gilead Sciences 2011]. 


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Safety results from these studies indicated that idelalisib was well tolerated when 
administered to healthy subjects at single doses through 400 mg (the highest dose level 
tested) and was also generally well tolerated when administered to healthy subjects over 
7 days at dose levels through 200 mg/dose BID (the highest dose level tested). Dosing with 
200 mg/dose BID for 7 days resulted in a skin rash in 3 out of 6 subjects; histological 
findings were consistent with a delayed-type hypersensitivity maculopapular exanthema. 
Rashes have sometimes occurred in patients with hematological malignancies receiving 
idelalisib, but have not typically proved dose- or treatment-limiting. In placebo-controlled 
single-dose and multiple-dose trials, repeated ECG evaluations performed in tandem with 
pharmacokinetic monitoring showed no evidence of drug-, dose-, or exposure-dependent 
effects on cardiac rhythm or cardiac intervals (eg, QT interval). Pharmacokinetic results 
indicated that idelalisib appeared rapidly in plasma with a median Tmax of 1 to 1.5 hours.  
Cmax and AUC increased in a less-than-dose-proportional manner and mean t1/2 values were 
across the dose range were 6.5 to 9.8 hours.
Idelalisib dosing after a high-fat, high-calorie meal delayed median time of maximum 
concentration (Tmax) from 0.75 hours to 3 hours; mean Cmax was unaffected and mean AUC 
was ~40% higher. These changes in idelalisib exposures are considered modest/clinically 
non-relevant; thus, idelalisib may be given with or without food.
Idelalisib is metabolized in humans primarily by aldehyde oxidase, with some involvement 
of CYP3A4 and UGT1A4. Accordingly, when idelalisib was administered following 4 days 
of daily dosing with ketoconazole (a potent inhibitor of CYP3A4), modest/moderate 
increases in mean idelalisib Cmax and AUC values of ~30% and ~80% higher, respectively, 
which is not considered to be clinically relevant and suggesting that idelalisib is a weak 
CYP3A substrate. GS-563117 is formed from idelalisib primarily via aldehyde oxidase.
The 14C-labeled idelalisib human mass balance results showed that the drug has moderate to 
high oral bioavailability. Idelalisib is eliminated mainly via hepatic metabolism and biliary 
excretion in the feces (~78% of dose); recovery in urine was < 15%. GS-563117, the only 
circulating metabolite observed in human plasma, was also observed in urine and feces. 
Results from the drug interaction/probe Study GS-US-313-0130 indicate that idelalisib does 
not affect the pharmacokinetics of substrates of Pgp, BCRP, OATP1B1 or OATP1B3 
transporters. Idelalisib is not expected to affect the exposures of coadministered agents via 
transporter mediated interactions. 
The exposures (AUC) of probe CYP3A substrate, midazolam, increased ~5-fold upon 
coadministration with idelalisib, driven by competitive and time-dependent CYP3A 
inhibition by GS-563117, the only circulating metabolite of idelalisib. Coadministration of 
the highly potent CYP3A inducer rifampin resulted in a ~75% reduction in idelalisib 
systemic exposures, likely driven by a higher relative contribution of CYP3A to overall 
idelalisib clearance under the induced state.


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Pharmacodynamic results showed that a idelalisib dose of 200 mg inhibited ex vivo basophil 
activation via the PI3K-specific, high-affinity immunoglobulin (Ig)E receptor (anti-FCR1) 
in basophils collected from healthy volunteers. The findings were confirmed when the drug 
was assessed over 7 days in a Phase 1b study in subjects with allergic rhinitis. In this study, 
idelalisib at a dose level of 100 mg/dose BID showed clinical and pharmacodynamic activity 
(attenuating adverse responses to allergenic challenge and decreasing markers of 
inflammation) and was well tolerated.
1.3.5.2.
Phase 1 Studies in Patients with Hematological Malignancies
1.3.5.2.1.
Phase 1 Monotherapy Study in Patients with Hematological Malignancies
A Phase 1 dose-ranging study (Study 101-02) of single-agent idelalisib extended safety and 
pharmacokinetic observations; documented the clinical and pharmacodynamic activity of 
idelalisib in subjects with iNHL, MCL, and CLL; and provided dosing information in support 
of further development [Brown 2011, Coutre 2011, Gilead 2011, Kahl 2011]. In this study, 
idelalisib was administered in cohorts of subjects across a range of dose levels from 
50 mg/dose BID to 350 mg/dose BID. Idelalisib administration was continued as long as 
individual subjects were safely benefitting from therapy. Subjects were evaluated in 4-week 
cycles; response and progression assessments were based on standard criteria [Hallek 2008].
A total of 191 subjects were enrolled to the study at dose levels of 50 mg BID (n=17), 
150 mg QD (n=16), 100 mg BID (n=25), 150 mg BID (n=45), 200 mg BID (n=35), 350 mg 
BID (n=17), and 300 mg QD (n=19). An additional cohort was also enrolled to receive 
idelalisib 150 mg BID in 28 day cycles (21 days on idelalisib/7 days off [n=17]). Subject
characteristics were as follows: males/females n=139 (73%)/52 (27%) with median age of 
64.5 (range 32-91) years.  Diagnoses included: CLL, n=54 (28%); iNHL, n=64 (34%); 
aggressive NHL (MCL and DLBCL), n=49 (26%); AML, n=12 (6%); and MM, n=12 (6%).  
Categorization of disease by response to the last prior therapy included: 
refractory, n=111 (58%); relapsed, n=79 (42%); and unknown, n=1 (1%).  The median 
(range) number of prior therapies was 5 (1-14). Among subjects with iNHL and CLL, the 
majority had received prior rituximab and prior alkylating agent therapy. 
Adverse events were usually mild to moderate and not clearly idelalisib-related.  Among 
Grade ≥3 adverse events, pneumonias and diarrhea were notable.  Pneumonia was observed 
in 23 (12%) subjects, primarily in subjects with CLL.  In most instances, these findings were 
considered bacterial in origin, based either on culture results or on response to conventional 
antibiotics.  Grade ≥3 adverse events of diarrhea were seen in 11 subjects (5.8%).  Other 
Grade ≥3 events included rash in 3 (1.6%) subjects.  The relative contributions of 
disease-related factors, toxicity from prior therapies or ongoing supportive care, and 
idelalisib to these events was not clear.


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Grade ≥3 hematological laboratory abnormalities have included neutropenia, n=46 (24%); 
thrombocytopenia, n=27 (14%), anemia, n=14 (7.3%), and lymphopenia 13 (6.8%); with 
12 subjects (6.3%) having febrile neutropenia. The occurrence of these events was greater in 
subjects with leukemia, particularly in those with pre-existing hematological abnormalities 
due to disease or prior therapy, commonly making attribution of these events to idelalisib 
uncertain.
Consistent with the observations in the 28-day dog toxicology study, reversible Grade ≥3 
ALT/AST elevations occurred in 28 (15%) subjects and have been attributed to idelalisib.  
Onset generally occurred between 2 to 16 weeks after idelalisib initiation and resolution was 
usually seen 2 to 6 weeks after idelalisib interruption.  After resolution of ALT/AST 
increases, 14 subjects were rechallenged at the same or a reduced dose of idelalisib and 
9 (64%) of these subjects were able to resume treatment without recurrence of transaminase 
elevations.  Two (1.0%) subjects had ≥ 2 x ULN elevations in bilirubin in the context of 
Grade ≥ 3 elevated AST / ALT, both of whom had confounding factors (recent history of 
biliary obstruction or concomitant use of potentially hepatotoxic medications) so that a 
definitive causal relationship to idelalisib could not be established. 
Pharmacokinetic analyses indicated that the increase in Cmax and AUC0-6h with dose was less 
than dose-proportional, with modest increases above the dose level of 150 mg BID.  
Pharmacodynamic data supported drug activity.  In subjects with NHL, plasma 
concentrations of chemokines CCL22 and CCL17 were elevated at baseline and showed 
significant decreases within 1 cycle of idelalisib treatment (p<0.001 for both comparisons).  
Flow cytometry of CLL cells from subjects showed that idelalisib reduced constitutive 
expression of phosphorylated AKT to background levels when measured after 1 week of 
treatment (p<0.0001), demonstrating pharmacodynamic inhibition of activated PI3K 
signaling.  Plasma concentrations of chemokines CCL3, CCL4, and CXCL13 were elevated 
in CLL subjects at baseline and decreased significantly within 1 cycle of idelalisib 
administration (p<0.001 for all comparisons).
Tumor reductions meeting antitumor response criteria were not observed in subjects with 
AML or MM.  One of 11 subjects with DLBCL achieved a PR.  In 104 subjects with iNHL 
and MCL, idelalisib induced PRs at all dose levels, with respective ORRs in enrolled subjects 
of 29/64 (45%) for iNHL and 16/40 (40%) for MCL. The median DOR has not been reached 
in subjects with iNHL; 19 subjects continued to receive idelalisib in a long-term extension 
study.   The median [range] DOR was 2.7 months [1 month to 8 months] in subjects with 
MCL; 6 MCL subjects continued to receive idelalisib in a long-term extension study. 
In subjects with CLL, idelalisib reduced lymphadenopathy in almost all subjects; 
44/54 (81.5%) achieved a lymph node response (≥50% reduction in target nodal lesions).  An 
initial increase in peripheral absolute lymphocyte counts of >50% from baseline was 
observed in some subjects; increases were maximal during the first 2 cycles and decreased 
thereafter; the pattern suggested drug-mediated lymphocyte redistribution.  In 54 subjects 
with CLL, 39/54 (72%) achieved a PR (includes PR with lymphocytosis).  The median DOR 
was not reached; 23 subjects continued to receive idelalisib in a long-term extension study.  


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1.3.5.2.2.
Phase 1 Combination Study in Patients with Hematological Malignancies
A separate Phase 1 trial (Study 101-07) has evaluated the safety and preliminary activity of 
idelalisib given in combination with rituximab to subjects with recurrent iNHL or CLL 
[Brown 2011, Leonard 2011].
In this study, rituximab was administered at a standard dose of 375 mg/m2 per infusion 
weekly for 8 weeks in all subjects. Idelalisib was started simultaneously with the rituximab, 
first at a dose level of 100 mg/dose BID (n=13) and then at a dose level of 150 mg/dose BID 
(n=12) and was administered continuously to both subjects with CLL (n=13) and subjects 
with iNHL (n=12) for as long as individual subjects were safely benefiting from therapy. 
Subjects were evaluated in 4-week cycles; response and progression assessments were based 
on standard criteria [Hallek 2008].
Among the subjects with CLL, the median age was 63 and ranged to 85 years. Bulky tumors 
(1 lymph node 5 cm in diameter) were present in 63% of the subjects. The median number 
of prior therapies by disease was 2 and ranged up to 8 prior treatments. All had received prior 
rituximab and the majority had received prior fludarabine or alkylating agents.
Approximately one-third of subjects had CLL that was refractory to the last prior therapy. At 
the time of data cut-off, therapy had been administered for a median of 5 cycles, ranging up 
to 12 cycles (ie, 48 weeks).
No idelalisib-related dose-limiting toxicities were observed within the tested subject cohorts. 
Grade 3-4 adverse events largely comprised background events resulting from pre-existing 
disease- or treatment-related conditions or from intercurrent illness. Among subjects with 
CLL, 2 (15%) developed pneumonia. For subjects receiving idelalisib together with 
rituximab, Grade 3-4 elevations in ALT/AST were not observed in those with CLL, although 
3 subjects (25%) of those with iNHL had such events.
The idelalisib plus rituximab combination showed a high level of antitumor activity in both 
subjects with CLL and those with iNHL. Altogether 92% of subjects with CLL receiving the 
combination of idelalisib and rituximab had reductions in nodal size and 77% showed a 
lymph node response (50% reduction in index nodal lesions). Although concomitant 
administration of rituximab did not eliminate the redistribution lymphocytosis that is 
associated with idelalisib, it blunted the magnitude of the change. As a result, the overall 
response rate (ORR) was also 77% among subjects participating in this study. At the time of 
last data analysis, PFS through 48 weeks was 70% and a median PFS had not yet been 
observed.
Collectively, the emerging data from this study support further evaluation of idelalisib
together with rituximab in subjects with CLL and indicate that co-administration of idelalisib
with rituximab is tolerable when using idelalisib at full dose, ie, at a starting dose level of 
150 mg/dose BID.


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Summary and Justification for the Current Study
1.4.
Gilead Sciences is conducting this Phase 3 study program to evaluate the efficacy and safety 
of idelalisib in patients with previously treated, recurrent CLL. Collectively the data derived 
from the primary clinical trial (Study GS-US-312-0116) and from this extension trial 
(Study GS-US-312-0117) address the activity of idelalisib together with rituximab, the 
activity of idelalisib when given alone, and the potential for dose-dependent restoration of 
drug activity in subjects who have disease that appears to be drug resistant.
The design and conduct of this clinical trial program is supported by knowledge of the 
demographics of patients with CLL, the natural history and current therapies for the disease, 
and the nonclinical and clinical information regarding idelalisib. The collective data support 
the following conclusions:

CLL is a serious, disabling, and potentially life-threatening disorder of older patients that 
requires sequential treatment with agents that provide alternative mechanisms of tumor 
control. Existing cytotoxic agents have serious acute and chronic toxicities, making them 
less suitable for frail or unfit patients. Single-agent rituximab can offer disease palliation 
with good tolerability in some patients with relapsed CLL but tumor control is not 
lasting, especially in patients with bulky adenopathy. Development of a non-cytotoxic 
combination therapy of idelalisib with rituximab or a monotherapy regimen of idelalisib
that can address disease pathogenesis with a new mechanism of action and might offer 
complementary nodal and peripheral blood activity would address an unmet medical 
need, particularly when applied in patients with substantial comorbidities or 
myelosuppression from prior chemotherapies.

PI3Kδ over-expression plays an important role in CLL biology. Further evaluation of 
idelalisib as a potential treatment for CLL has sound scientific rationale founded on 
knowledge of the actions of the drug to selectively abrogate PI3Kδ activity and to inhibit 
malignant cell growth and stromal cell signaling in nonclinical models of CLL. These 
data are supported by clinical documentation of idelalisib inhibition of PI3Kδ signaling in 
patients with CLL.

The potential for clinical efficacy of idelalisib monotherapy or of idelalisib plus 
rituximab in patients with relapsed or refractory CLL is supported by the observed 
antitumor activity of idelalisib – given alone or in combination with rituximab - in 
patients with heavily pretreated CLL and iNHL.

The safety of advancing development of the idelalisib monotherapy and of a regimen of 
idelalisib plus rituximab in this Phase 3 clinical trial program is well supported by safety 
pharmacology and toxicology studies and by Phase 1 single-agent and combination safety 
data obtained in healthy volunteers and in subjects with lymphoid cancers. 

Dose-safety, dose-exposure, and dose-activity relationships identified in Phase 1 studies
support the dosing regimen and dose modification provisions in this study.


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
Observations relating to patterns of CLL response among subjects receiving idelalisib
alone or in combination with rituximab in Phase 1 trials provide the foundation for 
efficacy monitoring in this trial. Of particular note is that idelalisib mobilizes CLL cells 
from tissues into the peripheral blood. This characteristic pharmacological action is 
prominent early in therapy but can persist over time and should not be confused with 
disease progression in patients who have persistent control of other CLL-related signs 
and symptoms. For this reason, in this Phase 3 study program, subjects will be continued 
on therapy until the occurrence of definitive disease progression, ie, disease progression 
that is manifest by worsening CLL-related signs or symptoms other than lymphocytosis 
alone. 

Thorough nonclinical and clinical characterization of the type, severity, manifestations, 
and expected timing of adverse events establish the safety monitoring plan in this trial
program.

The scientific correlative work performed in prior preclinical and clinical studies
provides strong scientific underpinnings for the companion laboratory studies to be 
performed as a component of this clinical trial program.

Given the seriousness of previously treated CLL in patients with substantial comorbidity, 
and the aggregate potential benefits considered in the context of potential risks, further 
development of idelalisib in this Phase 3 clinical trial program is justified.
The rationale for specific design features is provided in relevant sections of the protocol, 
including Section 3.2 (Endpoint Selection Rationale), Section 2.2 (Design Rationale), 
Section 4.3 (Enrollment Criteria Rationale), Section 5.10 (Study Treatment Rationale), and 
Section 6.5 (Study Procedure Rationale).


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2.
STUDY DESIGN
Design Overview and Study Schema
2.1.
This study is being conducted as part of an overall clinical program that is evaluating the 
efficacy and safety of idelalisib in the therapy of patients with previously treated CLL
(see Figure 2-1). Within this program, the primary clinical trial (Study GS-US-312-0116) is a 
Phase 3, multicenter, 2-arm, randomized, double-blind, placebo-controlled, parallel-group 
study. This clinical trial (Study GS-US-312-0117) is a separate, multicenter, 2-arm, 
double-blind, parallel-group extension study that is a companion study to the primary study.
Figure 2-1.
Study Design
Candidates for the primary study will be adults with previously treated recurrent CLL who 
have measurable lymphadenopathy, require therapy for CLL, have experienced CLL 
progression <24 months since the completion of the last prior therapy, and are currently not 
sufficiently fit to receive cytotoxic therapy because of chemotherapy-induced bone marrow 
damage or comorbidities.
Primary study subjects will be stratified based on 17p deletion and/or a p53 mutation status 
(either vs neither), immunoglobulin heavy chain variable region (IgHV) mutation status 
(unmutated vs mutated), and any prior therapy with an anti-CD20 therapeutic monoclonal 
antibody (yes vs no) and randomized in a 1:1 ratio to receive 1 of the 2 treatment arms. 
In the primary study, subjects will be administered rituximab intravenously in the clinic 
starting at a dose of 375 mg/m2 on Day 1 (Week 0) and will continue with a dose of 
500 mg/m2 on Day 15 (Week 2), Day 29 (Week 4), Day 43 (Week 6), Day 57 (Week 8), 
Day 85 (Week 12), Day 113 (Week 16), Day 141 (Week 20) (for a total of 8 infusions). 
Rituximab will be administered until the earliest of subject withdrawal from study, definitive 
progression of CLL, intolerable rituximab-related toxicity, pregnancy, substantial 
noncompliance with study procedures, study discontinuation, or a maximum of 8 infusions.


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Idelalisib or placebo will be taken orally, BID continuously. Subjects will continue 
whichever study drug (idelalisib/placebo or rituximab) continues to be tolerated, even if the 
other drug has been discontinued due to toxicity.
If permanent discontinuation of study drug, occurs prior to definitive progression of CLL, 
subjects shall remain on study until definitive progression of CLL or withdrawal from the 
study for reasons specified in Section 5.7
Compliant subjects who are tolerating therapy but who develop definitive disease 
progression in the primary clinical trial (Study GS-US-312-0116) can consider enrollment in 
this separate companion extension trial (Study GS-US-312-0117). In the extension trial, 
subjects will take active blinded idelalisib therapy, either at a higher starting dose or at the 
standard starting dose, with allocation based on the original primary study randomization.
The primary objective of Study GS-US-312-0116 will be to evaluate the effect of the 
addition of idelalisib to rituximab on PFS. Secondary and tertiary objectives will focus on 
determining the effect of the addition of idelalisib to rituximab on the onset, magnitude, and 
duration of tumor control; overall survival (OS); health-related quality of life (HRQL); 
changes in subject performance status; disease-associated biomarkers and potential 
mechanisms of resistance; treatment administration; safety; and health resource utilization. In 
Study GS-US-312-0117, the same endpoints will be assessed as in Study GS-US-312-0116; 
the focus of the analysis will be largely descriptive except for the within-subject assessment
of treatment effects among subjects receiving first rituximab alone and then idelalisib alone 
on Arm B of each trial. No formal comparisons of outcomes in Arm A vs Arm B are planned 
within Study GS-US-312-0117.
Design Rationale
2.2.
The randomized, add-on design for the primary trial (Study GS-US-312-0116) is customary 
in the comparative evaluation of new therapies for cancer. While this design provides 
idelalisib efficacy and safety information only in the context of administration of a 
companion antineoplastic agent, it is appropriate because it documents the incremental 
benefit and toxicity of the investigational therapy in the context of a controlled clinical trial 
while ensuring that all participants receive potentially active treatment.
This separate extension trial (Study GS-US-312-0117) enhances subject acceptance of 
randomization in the primary study and provides further information regarding idelalisib
efficacy, resistance, and safety. Among subjects in Arm A, escalation to a higher dose level 
allows evaluation of dose-dependent resistance and a determination if a higher dose can 
reestablish disease control. The safety data obtained in these subjects will add to the overall 
safety database. Among subjects randomized to Arm B in the primary study, evaluation of 
idelalisib at a starting dose of 150 mg/dose BID in the extension study may permit a 
within-subject assessment of the treatment effects with single-agent idelalisib relative to the 
effects previously observed with rituximab alone. Of importance, the extension study 
maintains the partial blinding of the primary study, thus minimizing the bias that might occur 
if the overall design entailed only a 1-way crossover to open-label idelalisib among subjects 


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who had received placebo on Arm B of the primary study. To ensure confirmation of disease 
progression, tumor size data collected from the primary study will be subjected to 
independent review by an independent review committee (IRC) (see Section 10.4.3); subjects 
will continue with study therapy pending confirmation of progression status by the sponsor 
working in collaboration with the IRC. Subjects must have confirmation that the disease has 
progressed on the primary study before being permitted to receive secondary idelalisib
therapy on the extension study, or in the event the primary study is stopped, subjects who 
have not yet progressed may enroll on the extension study to receive 150 mg BID idelalisib.


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3.
OBJECTIVES AND ENDPOINTS

To evaluate the effect of idelalisib on the onset, magnitude, and duration of tumor control

To compare tumor control in subjects receiving rituximab alone in 
Study GS-US-312-0116 to that observed in the same subjects when receiving the 
standard dose of idelalisib alone in Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject well-being, including overall 
survival (OS), health-related quality of life (HRQL), and performance status

To assess the effects of idelalisib on disease-associated biomarkers and to evaluate 
potential mechanisms of resistance to idelalisib

To characterize exposure to idelalisib as determined by treatment administration and 
evaluation of idelalisib plasma concentrations over time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with administration of idelalisib
Endpoints
3.1.
3.1.1.
Tumor Control

Progression-free survival (PFS) – defined as the interval from the start of study therapy to 
the earlier of the first documentation of definitive disease progression or death from any 
cause; definitive disease progression is CLL progression based on standard criteria other 
than lymphocytosis alone

ORR – defined as the proportion of subjects who achieve a CR or partial response (PR) 

Lymph node response rate – defined as the proportion of subjects who achieve a 
50% decrease from baseline in the SPD of index lymph nodes

CR rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from start of study therapy to the first 
documentation of CR or PR

Duration of response (DOR) – defined as the interval from the first documentation of CR 
or PR to the earlier of the first documentation of definitive disease progression or death 
from any cause

Percent change in lymph node area – defined as the percent change from baseline in the 
sum of the products of the greatest perpendicular diameters (SPD) of index lymph nodes


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
Splenomegaly response rate – defined as the proportion of subjects with a 50% decrease
(minimum 2 cm) from baseline in the enlargement of the spleen in its LVD or to 12 cm
by imaging

Hepatomegaly response rate – defined as the proportion of subjects with a 50% decrease
(minimum 2 cm) from baseline in the enlargement of the liver in its LVD or to 18 cm by 
imaging

ALC response rate – defined as the proportion of subjects with baseline lymphocytosis 
(ALC4 x 109/L) who achieve an on-study ALC <4 x 109/L or demonstrate a 
50% decrease in ALC from baseline

Platelet response rate – defined as the proportion of subjects with baseline 
thrombocytopenia (platelet count <100 x 109/L) who achieve an on-study platelet count 
100 x 109/L or demonstrate a 50% increase in platelet count from baseline

Hemoglobin response rate – defined as the proportion of subjects with baseline anemia 
(hemoglobin <110 g/L [11.0 g/dL]) who achieve an on-study hemoglobin 110 g/L 
(11.0 g/dL) or demonstrate a 50% increase in hemoglobin from baseline

Neutrophil response rate – defined as the proportion of subjects with baseline neutropenia 
(absolute neutrophil count [ANC] ≤1.5 x 109/L) who achieve an ANC >1.5 x 109/L or 
demonstrate a 50% increase in ANC from baseline
3.1.2.
Patient Well-Being

Overall survival (OS) – defined as the interval from start of study therapy to death from 
any cause

Change from baseline in HRQL domain and symptom scores based on  the Functional 
Assessment of Cancer Therapy: Leukemia (FACT-Leu) (see Appendix 2) 

Changes from baseline in Karnofsky performance status – defined as the change from 
baseline in the performance status (see Appendix 3) 
3.1.3.
Pharmacodynamic Markers of Drug Activity and Resistance

Changes from baseline in PI3K/AKT/mTOR pathway activation as a measure of PI3K
pathway activity

Changes from baseline in the plasma concentrations of disease-associated chemokines 
and cytokines


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3.1.4.
Exposure

Study drug administration as assessed by prescribing records and compliance as assessed 
by quantification of used and unused drug

Trough (pre-dose) and peak (1.5-hour samples) of idelalisib plasma concentrations as 
assessed by a validated bioanalytical method
3.1.5.
Safety

Overall safety profile of each study treatment regimen characterized by the type, 
frequency, severity, timing of onset, duration, and relationship to study therapy of any 
adverse events or abnormalities of laboratory tests; serious adverse events; or adverse 
events leading to discontinuation of study drug
3.1.6.
Pharmacoeconomics

Change in health status – defined as the change from baseline in overall health and 
single-item dimension scores as assessed using the EuroQoL Five-Dimension (EQ-5D) 
utility measure (Appendix 4)

Health resource measures, including resource utilization, total costs, and measures of cost 
per unit of benefit (eg, cost per additional progression-free month, cost per 
quality-adjusted life-year)
Endpoint Selection Rationale
3.2.
The proposed endpoints have been chosen based on relevance to the pathophysiology and 
clinical manifestations of CLL, the known pharmacology of idelalisib, and the goals of the 
study in documenting idelalisib benefit-to-risk ratio. These types of endpoints have been 
employed in prior studies in CLL and can be evaluated with acceptable reliability and 
accuracy.
3.2.1.
Tumor Control Endpoints
Assessments of the magnitude and duration of changes in tumor size are routinely employed 
in registration-directed oncology clinical studies to determine therapeutic effect. Unlike OS, 
these endpoints directly assess the ability of the drug to control the malignancy. Such 
assessments are also integral to treatment decisions; because subjects are being treated until 
disease progression, repeated tumor assessment must be performed in order to define the 
proper duration of treatment for each study participant. Standard response and progression 
criteria have been established by the International Workshop on CLL (IWCLL) 
[Hallek 2008]; the assessments of treatment effects in this study will be based on these 
criteria, taking into account the specific pharmacology of idelalisib.


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In CLL, disease-related nodal enlargement is a major cause of patient discomfort and can 
cause organ dysfunction [Dighiero 2008]. Extensive lymphadenopathy constitutes a reason to 
treat CLL and controlling the size of pathologically enlarged lymph nodes is an important 
therapeutic goal for improving patient well-being and relieving obstructive symptoms 
[Hallek 2008]. Given that the natural history of recurrent CLL is inexorable nodal growth, 
enhancing tumor shrinkage and prolonging tumor control provides strong evidence of 
pharmacological activity. 
Endpoints of overall tumor control as evaluated in this trial are customarily assessed and 
reported in studies of new therapies in patients with cancer. PFS offers a well established 
outcome measure that directly measures treatment effect, conveys important longitudinal 
information regarding tumor control, can be characterized in all subjects using 
intention-to-treat (ITT) principles, and is readily analyzed using statistical methods such as 
Kaplan-Meier techniques. ORR provides an integrated assessment of the magnitude and 
extent of changes in lymphadenopathy, organomegaly, bone marrow infiltration, and bone 
marrow function that conveniently categorizes and describes treatment effects. TTR and 
DOR are important in characterizing the rapidity of achieving tumor shrinkage and the 
duration of tumor control. Beyond providing descriptions on overall response assessment 
using ORR, this protocol will also seek to characterize the individual components of response 
that are important in assessment of CLL [Hallek 2008]. Thus, changes in lymph node area 
and in the proportion of subjects having a lymph node response will be analyzed. In addition, 
among subjects who enter the study with splenomegaly or hepatomegaly, the proportion of 
subjects who achieve substantial (50%) reductions in spleen or liver size will be assessed. 
Similarly, the proportions of subjects who experience improvements in ALC, platelets,
hemoglobin, and neutrophil counts will be characterized in order to provide specific insight 
into the degree to which therapy alters these individual parameters. 
Because idelalisib mobilizes CLL cells from tissues into the peripheral blood as part of its 
pharmacological effect, there is a risk of falsely declaring a subject to have experienced 
disease progression if lymphocyte count is considered as the sole basis for potential CLL 
worsening. To account for this potential problem, changes in lymphocyte count will not be 
considered in determining whether a subject has progressive disease, ie, subjects will only be 
declared to have progressive CLL if they meet any of the IWCLL criteria for progressive 
disease other than lymphocytosis alone. Thus, subjects with worsening lymphadenopathy, 
organomegaly, bone marrow involvement, progressive cytopenias, appearance of new 
disease, or transformation to an aggressive lymphoid malignancy histology 
(eg, Richter syndrome) will be considered to have progressed. Subjects with lymphocytosis 
without any of these other events will not be considered to have progressed. Given that 
lymphocytosis has no prognostic significance in patients with relapsed/refractory disease 
[Silverman 2002, Tsimberidou 2007] and is not generally considered a reason to treat in 
patients with CLL [Hallek 2008, Eichhorst 2010, Zelenetz 2011], this approach does not 
jeopardize subject safety or subsequent therapy. Furthermore, it will allow complete 
collection of all response and progression data (both considering lymphocytosis and ignoring 
lymphocytosis) with the intent of providing complete information for regulatory authority 
review.


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The current IWCLL guidelines indicate that physical examination is generally sufficient to 
evaluate nodal response and progression in patients with CLL [Hallek 2008] but that 
radiographic assessments may be appropriate in clinical trials. Computed tomography (CT) is 
considered the preferred imaging method unless patients have contraindications that require 
use of magnetic resonance imaging (MRI). Given the low fluorodeoxyglucose (FDG) avidity 
of CLL, positron- emission tomography (PET) does not have a role in evaluation of this 
disease. The incremental benefits of using radiographic imaging are limited in patients 
undergoing long-term follow-up following first-line therapy [Blum 2007, Eichhorst 2011]. 
However, in the patients with advanced CLL and bulky adenopathy such as those who will 
be enrolled to this trial, it is known that CT scans commonly detect bulky intra-abdominal 
lymphadenopathy and splenomegaly that would be missed by palpation alone and that the 
presence of large-volume, intra-abdominal disease of the nodes and spleen is associated with 
a poor prognosis [Norin 2010]. Thus, while use of CT confers greater radiation exposure, 
subjects have the chance to benefit from radiographic imaging because it will offer more 
accurate information regarding their response to protocol therapy and the appropriate 
duration of protocol treatment. Having this information is particularly important in this trial 
because PI3Kinhibition precludes use of lymphocyte counts as evidence for disease 
progression. In addition, the risk is offset by the fact that the trial subjects will primarily be 
patients who have already received more potent mutagens (eg, purine analogs, alkylating 
agents), and all of whom have advanced cancer and limited treatment options at study entry. 
Based on published data [Keating 2002, Wierda 2010], median OS for patients with 
comparably advanced CLL is <18 months, so the long-term secondary malignancy risk from 
CT-related radiation exposure is very low. Finally, in the context of a registration-directed 
pivotal trial of a new drug with a new mechanism of action, radiographic imaging is critically 
important to provide reassurance regarding subject safety and trial validity. In this regard, CT 
evaluations of the lung can be used retrospectively to assess for radiographic evidence of 
drug-induced lung changes [White 2010, Maroto 2011]. Furthermore, CT measurements 
have greater accuracy and reproducibility than palpation, are subject to independent expert 
review, and can be audited against electronic case report form (eCRF) information.
The timing of radiographic tumor assessments has been carefully considered. To avoid 
duplication, the CT scan documenting CLL progression in Study GS-US-312-0116 will serve 
as the baseline CT scan for Study GS-US-312-0117. Among patients receiving idelalisib in 
Phase 1b/2 studies who experienced a nodal response (50% regression in tumor area), such 
responses were observed with the first 16 week of therapy [Coutre 2011, Leonard 2011]; the 
planned timing of tumor assessments (at Weeks 8, 16, 24, 36, 48 and then every 12 weeks on 
thereafter) in this study fits with this known timing of changes in lymph node size during 
idelalisib therapy. Scans at 8-week intervals during the first 24 weeks allow efficient 
documentation of response. During this period, early documentation of disease progression 
allows subjects who are not benefiting from study therapy to move rapidly to alternative 
treatments. After 24 weeks on study, the reduction in the frequency of CT scans 
(to 12-week intervals) reduces the overall protocol burden for subjects while still allowing 
characterization of the expected median PFS in this trial. As outlined in Section 7.3, 
iodine-containing or gadolinium contrast material may be omitted in subjects for whom use 
of a contrast agent would be medically contraindicated.


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3.2.2.
Measures of Patient Well-Being
3.2.2.1.
Overall Survival
While OS provides an ultimate measure of patient well-being, it has not routinely been used 
as the primary endpoint in CLL clinical trials. Unlike PFS, it does not specifically measure 
drug-mediated tumor control, and thus provides only an indirect assessment of treatment 
effect. Depending upon the treatment setting, long OS times in patients with CLL can 
preclude use of this endpoint as an efficient method for understanding drug benefits. In both 
the front-line and recurrent disease settings, post-study treatments can influence OS in 
unpredictable ways, potentially confounding differences between treatment groups.
However, given the life-threatening nature of systemic malignancy, documentation of OS is 
customary in oncology therapeutic clinical trials, including those evaluating subjects with 
recurrent CLL [Keating 2002, Wierda 2010]. Evaluation of OS in this study continues the 
survival assessment from the primary study (Study GS-US-312-0116). The study program as 
a whole (considering both the primary randomized trial and secondary extension study) 
offers the potential to better understand OS and causes of death in a frail population of 
patients with both CLL, considering the consequences of the disease and comorbidities.
3.2.2.2.
Health-Related Quality of Life
Direct patient reporting of outcomes using standardized methods has become an increasingly 
important component of therapeutic assessment. Evaluation of patient-reported outcomes 
(PROs) is particularly relevant in patients who cannot be cured of disease [Fairclough 2002]. 
PRO questionnaires have been previously used in CLL to understand how patients differ 
from the general population in terms of health concerns [Holzner 2004, Eichhorst 2007, 
Shanafelt 2007, Else 2008], to understand differences in perceptions of well-being in younger 
vs older patients [Levin 2007, Else 2008], to determine how treatment affects HRQL 
[Catovksy 2007, Eichhorst 2007, Efficace 2008], and to assess the pharmacoeconomic cost 
of improvements in HRQL [Stephens 2005].
Patients with CLL have overtly impaired well-being relative to comparable controls 
[Holzner 2004, Eichhorst 2007, Shanafelt 2007, Else 2008]. Fatigue is cited as a common 
complaint, being present in the substantial majority of patients. Impairment of HRQL prior to 
any treatment is apparent in those with B symptoms or in patients with anemia, supporting 
the concept of initiating treatment when patients experience symptomatic disease. Factors 
associated with lower overall HRQL have included older age, greater fatigue, severity of 
co-morbid health conditions, advanced stage, and ongoing treatment for CLL 
[Shanafelt 2007]. Younger patients appear to have worse emotional and social well-being but 
older patients experience worse physical HRQL [Levin 2007]. In comparative evaluation of 
chemotherapy-containing regimens, differences in HRQL between therapies (eg, fludarabine 
vs fludarabine-cyclophosphamide vs chlorambucil) reflected differences in toxicity while 
improved HRQL was associated with greater efficacy [Catovksy 2007, Eichhorst 2007].


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In this study, it is postulated that idelalisib-mediated tumor control will be correlated with 
greater positive changes in HRQL and that assessments of the drug’s safety profile will be 
supported by HRQL evaluations. The FACT-Leu (Appendix 2) has been selected to evaluate 
such outcomes for the study. The FACT-Leu comprises a general HRQL measure for patients 
receiving cancer treatment that yields a total score and subscales for physical, functional, 
social/family and emotional well-being [Cella 1993] and a diagnosis-specific measure for 
patients with leukemia [Webster 2002]. The FACT-Leu was developed to assess symptoms 
(eg, fevers, chills, night sweats, nodal swelling, fatigue) specifically relevant to patients with 
leukemia. FACT instruments have documented psychometric properties [Cella 1993, 
Webster 2002, Brucker 2005, Cella 2005, Victorson 2008].
The FACT-Leu instrument is available in appropriate languages for this study. FACT-Leu 
data will be obtained at baseline and during each investigational clinic visit during treatment. 
Having FACT-Leu data concurrent with tumor response information will allow an evaluation 
of the potential relationship between tumor response and symptomatic changes as reported by 
patients. To avoid biasing HRQL results, the FACT-Leu will be administered at each visit 
before other procedures are performed and before any study information is conveyed to the 
subject.
3.2.2.3.
Changes in Performance Status
Performance status evaluation provides an integrated assessment of patient well-being 
before, during, and after treatment and, ideally, may indicate how drug efficacy and toxicity 
affect patient functioning. In patients with CLL performance status can be predictive of PFS 
or OS [Sorensen 1997, Hallek 1996, Youngson 1995].
In this study, it is hypothesized that idelalisib-mediated tumor control will be correlated with 
changes in performance status and that assessments of the drug’s safety profile might be 
supported by performance status evaluations. The well-established, reliable, and validated 
Karnofsky performance score [Karnofsky 1949, Yates 1980, Schag 1984] (see Appendix 3) 
will be employed in the trial for characterization of the subject population and repeated 
assessment of performance status.
3.2.3.
Pharmacodynamic Markers of Drug Activity and Resistance
In CLL, disease-related perturbations in inflammatory status can be clinically overt; patients
often develop bothersome B symptoms (fevers, night sweats, and weight loss) that are 
characteristic of excessive systemic inflammation [Redaelli 2004]. Consistent with such 
disease manifestations, the PI3K/AKT/mTOR pathway is constitutively overactive in
circulating CLL cells [Coutre 2011]. In addition, chemokines and cytokines that are markers 
of aberrant B-cell trafficking or perturbations in inflammation are overexpressed by CLL 
tissues or by stromal cells and circulate in plasma [Burger 2010b, Coutre 2011]. In Phase 1 
studies of idelalisib it has been confirmed that idelalisib largely normalizes AKT
phosphorylation and induces dose-dependent reductions in plasma concentrations of 
circulating chemokines and cytokines in patients with CLL [Coutre 2011].


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In this study, it is hypothesized that incremental changes in these biomarkers provide direct 
evidence of mechanism-specific idelalisib effects on PI3Kδ activity or indirectly document 
drug effects on overall tumor cell volume. In either case, improvements in these 
pharmacodynamic measures provide corroborative evidence in support of idelalisib
pharmacological activity; conversely, worsening of these biomarkers may indicate 
acquisition of resistance to idelalisib. In addition, it is possible that disease-or
inflammation-related biomarkers may provide corollary information relating to the adverse 
effects of idelalisib on the liver; such data might allow better prediction of which subjects 
might be most susceptible to ALT/AST elevations during idelalisib treatment. Finally, it can 
also be postulated that genetic, protein, or metabolic changes in CLL cells could provide 
signatures that would correlate with drug sensitivity and resistance.
Based on these considerations, this study will evaluate PI3K/AKT/mTOR pathway activation 
status in CLL cells. For this purpose, blood will be evaluated by flow cytometry using a 
clinically validated assay [Hoellenriegel 2011]. CLL cells will be identified using anti-CD5 
and anti-CD19 antibodies. AKT activation will be determined by quantifying 
phosphorylation at the Ser473 and Thr308 AKT sites using specific anti-pAKT Thr308 and 
anti-pAKT Ser473 antibodies. Additional assessments of PI3K/AKT/mTOR pathway 
signaling (eg, evaluating phosphorylation state for other downstream enzymes) may also be 
explored.
Plasma will be collected for assessment of circulating concentrations of relevant chemokines 
and cytokines with a particular focus on CCL2, CCL3, CCL4, CXCL12, CXCL13, CCL17, 
CCL19, CCL21, CCL22, sCD40 ligand, tumor necrosis factor-α, and C-reactive protein. In 
addition serum markers of iron metabolism (eg, hepcidin, iron, ferritin, transferrin) that might 
provide markers linking disease-related inflammation with perturbations of liver iron and 
sensitivity to liver injury will be evaluated [Nemeth 2003, Ferrucci 2010]. Clinically 
validated assays (eg, enzyme-linked immunosorbent assays [ELISAs]) will be used to 
measure circulating concentrations of chemokines and cytokines at baseline and during the 
course of idelalisib therapy.
CLL cell deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein will be 
collected at baseline and at the conclusion of a subject’s treatment on study. DNA and RNA 
samples will be analyzed using gene array technologies to evaluate for changes in DNA 
mutations or in RNA expression patterns that might be associated with intrinsic or acquired 
resistance to study treatments. Similarly, protein will be evaluated for state-specific changes 
in protein phosphorylation to evaluate for differences in pathway activation at baseline or 
during therapy that might be associated with differences in response or in acquisition of 
resistance to therapy.


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3.2.4.
Assessments of Exposure
3.2.4.1.
Study Drug Administration and Compliance
Evaluation of study drug administration and compliance provides context for assessments of 
safety, pharmacokinetics, and pharmacological activity. Evaluations of treatment 
administration and modifications from planned therapy document the influence of 
treatment-emergent adverse events on prescribing practice. Compliance assessment offers a 
general indication of patients’ acceptance of therapy, integrating factors of tolerability, 
palatability, and convenience.
In this study, information regarding planned treatment and modification from planned 
treatment (eg, dose reductions and interruptions) will be kept. The compliance of the subject 
will be verified by accounting for used and unused drug.
3.2.4.2.
Pharmacokinetics
Given the intent of this protocol to assess longer-term dosing, collection of plasma for 
idelalisib concentrations is important for evaluating exposure over time. These data may 
allow correlations of exposure with measures of efficacy, toxicity, and resistance. Because 
the idelalisib pharmacokinetic profile has been well characterized in Phase 1 studies, limited 
plasma sampling will be performed in this study. Samples will be collected pre-dose and 
1.5 hours post-dose relative to the morning administration of idelalisib. Based on discussions 
with investigators, collecting more than 2 samples in the morning is not considered 
reasonable given the need to minimize time requirements for study participants and to avoid 
substantial inconvenience for clinic staff.
Evaluation of idelalisib plasma concentrations will be performed using liquid 
chromatography with tandem mass spectrometry. The method has been fully validated in the 
context of prior Phase 1 studies. Plasma samples will be retained for potential later analyses 
of idelalisib metabolites.
3.2.5.
Evaluations of Safety
In defining the therapeutic relevance of a drug in a particular clinical setting, it is imperative 
that its safety profile be fully characterized. As is conventional in all clinical studies, proper 
description of each adverse event or laboratory abnormality requires an understanding of the 
type, incidence, timing, severity, and relatedness to study drug. While information on all 
reported adverse events will be collected, listed, and summarized, particular focus will be 
placed on monitoring and reporting adverse events and laboratory abnormalities that were 
encountered in the prior toxicology studies and clinical experience with idelalisib. Safety 
parameters of specific interest in reporting study results will include those relating to bone 
marrow function, dermatological events, gastrointestinal inflammation, infection, pulmonary 
events (eg, pneumonia/pneumonitis), and liver injury. Additional scrutiny will be applied to 
Grade 3-4 adverse events, to adverse events causing interruption or discontinuation of 
idelalisib, and to serious adverse events.


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In addition, the protocol will evaluate for potential adverse idelalisib effects on laboratory 
parameters of immune function; the absolute number of CD4+, CD5+,CD8+, CD16/CD56+, 
CD19+, and CD20+ cells will be assessed by flow cytometry. Serum concentrations of IgA, 
IgE, IgG, and IgM will be obtained.
For consistency of interpretation, adverse events will be coded using the standard Medical 
Dictionary for Regulatory Activities (MedDRA) [http://www.meddramsso.com]), and the 
severity adverse events and laboratory abnormalities will be graded using the well-defined 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). 
Standard definitions for seriousness will be applied (see Section 8.1.2).
3.2.6.
Pharmacoeconomic Measures
It is increasingly important to understand the potential cost implications of introducing a new 
medication into patient care for CLL [Main 2010, Hornberger 2011]. In order to analyze the 
pharmacoeconomic consequences of idelalisib administration, data will be collected 
regarding the health status of subjects and regarding health care resource utilization.
Heath status information will be obtained with the EQ-5D, which is a self-administered, 
generic, indirect utility measure [EuroQoL Group 1990] (Appendix 4). The EQ-5D consists 
of a visual analogue scale on which subjects are asked to rate their current overall health 
status and 5 single-item dimensions which ask subjects to rate their health in terms of 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. For each of the 
5 items, patients must choose between 3 levels of difficulty in accomplishing tasks in that 
dimension. The visual analog scale is then used in combination with the dimension scores to 
generate a health utility score that can be incorporated into analyses of cost effectiveness. 
The EQ-5D has been successfully used in the evaluation of patients with B-cell and other 
cancers [Doorduijn 2005, Witzens-Harig 2009, Yang 2010].
The EQ-5D instrument is available in appropriate languages for this study. EQ-5D data will 
be obtained at baseline and during each investigational clinic visit during treatment. The 
EQ-5D will be administered immediately after administration of the FACT-Leu instrument, 
before other procedures are performed and before any study information is conveyed to the 
subject. The EQ-5D instrument takes only 5 minutes to complete.
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach will be to combine the resource utilization data from the trial with data 
on unit prices (collected separately) to estimate total costs. The costs will be described 
relative to the health care findings as measured by duration of tumor control, the 
symptom-free survival period, and/or utility outcomes or some other appropriate measure of 
clinical benefits.


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4.
SUBJECT POPULATION
Number of Subjects
4.1.
The planned sample size is ~160 subjects but will be bounded by the number of subjects 
enrolled to the primary clinical trial (Study GS-US-312-0116).
Subject Selection Criteria
4.2.
Subjects in the primary Phase 3 study (GS-US-312-0116) who are compliant, are tolerating 
primary study therapy, and 1) have definitive progression of CLL while receiving primary 
study drug therapy (idelalisib /placebo) or 2) are actively participating in Study 
GS-US-312-0116 at the time the study is stopped, including if stopped early due to 
overwhelming efficacy following an interim analysis are eligible to enroll in the extension 
study. Eligibility criteria may not be waived by the investigator and conformance to the 
eligibility criteria is subject to review in the case of a Good Clinical Practice (GCP) or a 
regulatory authority audit. Any questions regarding a subject’s eligibility should be discussed 
with the study sponsor medical monitor prior to enrollment.
4.2.1.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in 
this study:
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while receiving study drug therapy 
(idelalisib/placebo) in Study GS-US-312-0116. Note: Definitive disease progression is 
CLL progression based on standard criteria and occurring for any reason 
(ie, increasing lymphadenopathy, organomegaly, or bone marrow involvement; 
decreasing platelet count, hemoglobin, or neutrophil count; or worsening of 
disease-related symptoms) other than lymphocytosis. Subjects must have confirmation 
by the sponsor working in collaboration with an independent review committee (IRC) 
that the disease has progressed on the clinical trial (Study GS-US-312-0116) before 
receiving secondary idelalisib therapy on this extension trial (Study GS-US-312-0117).
3) Presence of radiographically measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures 2.0 cm in the longest diameter [LD] and 1.0 cm in the 
longest perpendicular diameter [LPD] as assessed by CT or MRI). 
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab and 
idelalisib/placebo) and no intervening or continuing therapy (including radiotherapy, 
chemotherapy, immunotherapy, or investigational therapy) for the treatment of CLL.
Note: Subjects may receive corticosteroids to manage CLL manifestations.


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5) The time from permanent cessation of Study GS-US-312-0116 treatment (rituximab 
and/or idelalisib/placebo) and the initiation of Study GS-US-312-0117 therapy is 
12 weeks. Note: Study procedures performed as part of Study GS-US-312-0116 need 
not be repeated and can be used as screening procedures for Study GS-US-312-0117 if 
performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation of study treatment) 
as shown in the table below. Note: Confirmation should be considered for out-of-range 
values to determine if the abnormality is real or artifactual. Values should be obtained 
within the screening period and should generally be the most recent measurement 
obtained. Subjects with any degree of neutropenia, thrombocytopenia, or anemia due 
to CLL or prior therapy may enroll.
Table 4-1.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCra
>30 ml/min
Pregnancy
-HCGb
Negative 
a
As calculated by the Cockcroft-Gault formula (see Appendix 5)
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or 
urine dipstick pregnancy test must be negative at start of study treatment (Visit 2)
Abbreviations: -HCG= beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate 
aminotransferase, eCCr=estimated creatinine clearance, ULN=upper limit of normal
8) For female subjects of childbearing potential, willingness to use a protocol-recommended 
method of contraception (as outlined in section 5.6.4) from the screening visit (Visit 1) 
throughout the study and for 30 days following the last dose of study drug. Note: A 
female subject is considered to be of childbearing potential unless she has had a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically 
documented ovarian failure (with serum estradiol and follicle-stimulating hormone 
[FSH] levels within the institutional postmenopausal range and a negative serum or
urine HCG), or is menopausal (age >55 with amenorrhea for >12 months or 
amenorrhea for > 6 months with serum estradiol and FSH levels within the 
institutional postmenopausal range). 


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9) For male subjects of childbearing potential having intercourse with females of 
childbearing potential, willingness to use a protocol-recommended method of 
contraception (as outlined in section 5.6.4) from the start of study drug (Visit 2) 
throughout the study and for 90 days following the last dose of study drug and to refrain 
from sperm donation from the start of study drug (Visit 2) throughout the study and for 
90 days following the last dose of study drug. Note: A male subject is considered able to 
father a child unless he has had a bilateral vasectomy with documented aspermia or a 
bilateral orchiectomy, or has ongoing testicular suppression with a depot luteinizing 
hormone- releasing hormone (LH-RH) agonist (eg, goserelin acetate [Zoladex®]), 
leuprolide acetate  [Lupron®]), or triptorelin pamoate [Trelstar®]).
10) In the judgment of the investigator, participation in the protocol offers an acceptable 
benefit-to-risk ratio when considering current CLL disease status, medical condition, and 
the potential benefits and risks of alternative treatments for CLL. 
11) Willingness and ability to comply with scheduled visits, drug administration plan, 
imaging studies, laboratory tests, other study procedures, and study restrictions. 
Note: Psychological, social, familial, or geographical factors that might preclude 
adequate study participation should be considered.
12) Evidence of a personally signed informed consent indicating that the subject is aware of 
the neoplastic nature of the disease and has been informed of the procedures to be 
followed, the experimental nature of the therapy, alternatives, potential benefits, possible 
side effects, potential risks and discomforts, and other pertinent aspects of study 
participation.
4.2.2.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
1) Known histological transformation from CLL to an aggressive lymphoma 
(ie, Richter transformation). Note: Biopsy documentation of the absence or presence of 
transformation is not required.
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of the start 
of study treatment (Visit 2). Note: Subjects with localized fungal infections of skin or 
nails are eligible. Subjects may be receiving prophylactic antiviral or antibacterial 
therapies at the discretion of the investigator; anti-pneumocystis prophylaxis is 
encouraged. For subjects who are at substantial risk of an infection (eg, influenza) that 
may be prevented by immunization, consideration should be given to providing the 
vaccine prior to initiation of protocol therapy.
3) Pregnancy or breastfeeding. 
4) Intentional breaking of the blind in Study GS-US-312-0116 by the investigator or the 
study subject.


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5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical condition, surgical history, 
physical finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the 
investigator’s opinion, could adversely affect the safety of the subject or impair the 
assessment of study results.
Enrollment Criteria Rationale
4.3.
The eligibility criteria are designed to limit enrollment to subjects who participated in the 
primary clinical trial (Study GS-US-312-0116), are compliant, have been generally able to 
tolerate study therapy and study procedures, and have experienced definitive CLL 
progression while receiving study treatment (rituximab and/or idelalisib/placebo) in the 
primary study or who are actively participating in Study GS-US-312-0116 at the time the 
study is stopped, including if stopped early due to overwhelming efficacy .
The requirement of measurable lymphadenopathy to enter the blinded portion of the study 
ensures that subjects have disease that can adequately be assessed for evidence of drug 
activity. Prior therapy provisions are intended to ensure that subjects are transitioning 
directly from Study GS-US-312-0116 to Study GS-US-312-0117 without receiving 
intervening treatments. The stipulation of 12-week interval from Study GS-US-312-0116 
treatment until Study GS-US-312-0117 treatment precludes excessively protracted intervals 
between participation in the 2 studies but also permits sufficient time for clinicians and 
subjects to determine whether participation is appropriate. 
In the blinded portion of the study, to ensure that subjects are not so acutely ill from 
life-threatening comorbidities that they require hospitalization and stabilization, subjects with 
Karnofsky performance scores <40 (ie, those who are bed-bound or hospitalized) will not be 
enrolled. Baseline laboratory evaluations are designed to limit participation to subjects who 
have not developed serious organ compromise that would pose a safety risk or confound the 
interpretation of adverse effects. Pregnancy testing and restrictions on eligibility relating to 
reproduction, pregnancy, and nursing are important because idelalisib is a new chemical 
entity with teratogenic effects in rats and it is unknown if it may have adverse effects on 
conception, on fetal development, or on the health of a breast-feeding child. To minimize 
missing data and premature discontinuations, subjects should have sufficient psychological 
and social resources to comply with study procedures and restrictions. Consistent with GCP 
guidelines, subjects must provide informed consent before initiation of any study procedures.


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5.
TREATMENT OF SUBJECTS
Enrollment
5.1.
5.1.1.
Interactive Web Response System
An IWRS will be employed to manage the conduct of the trial. The IWRS will be used to 
maintain a central log documenting enrollment, to manage dose modifications, to assess 
current inventories of study drug, to initiate any necessary resupply of study drug, and to 
document discontinuation of study .
5.1.2.
Treatment Assignment
After a subject has completed the necessary documentation of definitive CLL progression in 
the primary clinical trial (GS-US-312-0116) and has been confirmed to be eligible, the 
subject can be entered into this trial (Study GS-US-312-0117). In order to obtain a treatment 
arm allocation for a subject, a site representative will access the IWRS and supply the system 
with the required information.
Subjects will be assigned to either of the following treatment assignments with allocation 
based on the original primary study randomization:
Treatment Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117)
Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly enrolled subjects will 
receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly enrolled subjects will 
receive 150 mg BID
Note: At the Investigator’s discretion, subjects who were randomized to placebo on study 
GS-US-312-0116 may delay initiation of idelalisib following enrollment on 
Study GS-US-312-0117 until the time of disease progression or until the investigator 
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Treatment Assignment

Assignment to Arm A or Arm B with allocation based on the original primary study 
randomization

Implementation through an interactive web response system (IWRS)
The IWRS will assign blister card, or bottle numbers and instructions for dispensing of 
blinded study drug (high-dose or standard-dose idelalisib). It is anticipated that subjects will 
usually begin study drug immediately at Visit 2 of the study. 
5.1.3.
Blinding
During the blinded portion of the study, the identity of the treatments will be concealed by 
central blinding of study drug assignments. Blinding will be accomplished through use of a 
placebo that is well-matched to the active drug in appearance, packaging, labeling, and 
schedule of administration (see Section 5.2.1). During the study, subjects, caregivers, 
investigational site personnel, Gilead Sciences study team members, and all other study 
personnel will remain blinded to the identity of the treatment assignments; these assignments 
will be available only to the IWRS, the data monitoring committee (DMC) for the study, an 
independent bioanalytical group that supports the DMC, and drug safety personnel who are 
not part of the study team. Unblinding an individual subject’s treatment assignment during 
the study will only occur in the case of subject emergencies (see Section 5.5) or in the event 
the study is discontinued by the Sponsor, a Regulatory Agency, or an IRB or EC 
(see Section 5.9). Where required by local regulation, expedited reporting of serious adverse 
events to specific regulatory authorities will include information regarding the study drug 
treatment assignment (high-dose or standard-dose idelalisib); this will be done in such a way 
that subjects, investigational site personnel, institutional review board/independent ethics 
committees (IRB/IEC), and study team members remain blinded as to the treatment 
assignment for the subject described in the adverse event report.
The unblinded analysis of the study will be performed when the database is completed and 
locked following unblinding of Study GS-US-312-0116 and Study GS-US-312-0117. The 
final analysis of the open label portion of the study will occur once the open label portion is 
stopped. While bioanalytical assays to determine idelalisib concentrations may be performed 
prior to unblinding, pharmacokinetic data that would allow identification of treatment 
assignments for individual subjects will not be available to the study team until after the 
blind is broken and the primary analysis has occurred. Except for emergency unblinding, 
individual subjects, caregivers, and site personnel will not be informed of the treatment 
assignments until the implications of revealing such data for the overall idelalisib study 
program have been determined by the clinical project leader for the idelalisib development 
program.


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Investigational Study Drug (Idelalisib/Placebo)
5.2.
5.2.1.
Description
Subjects allocated to Arm A in the blinded portion of the study will be provided with 
2 tablets of active idelalisib for oral administration at each dose. Each tablet contains 150 mg 
or 100 mg of active idelalisib. The 150-mg tablets will be used for initial therapy; the 100-mg 
tablets are provided for use by those subjects who require a dose reduction (see Table 5-1). 
Subjects allocated to Arm B in the blinded portion of the study will be provided with 1 tablet 
of active idelalisib and 1 tablet of placebo for oral administration at each dose. Each active 
tablet contains 150 mg or 100 mg of active idelalisib. The 150-mg tablets (and matching 
placebo) will be used for initial therapy; the 100-mg tablets (and matching placebo) are 
provided for use by those subjects who require a dose reduction. 
In the open-label portion of the study, subjects will be provided with 150 mg tablets of 
idelalisib.
The 150-mg tablets are pink, film-coated, and include the following inactive excipients: 
microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch 
glycolate, magnesium stearate, red iron oxide, polyethylene glycol, talc, polyvinyl alcohol
(PVA), and titanium dioxide. The 100-mg tablets are orange, film-coated, and include the 
following inactive excipients: microcrystalline cellulose, hydroxypropyl cellulose, 
croscarmellose sodium, sodium starch glycolate, magnesium stearate, yellow iron oxide, 
polyethylene glycol, talc, PVA, and titanium dioxide.
The placebo tablets match the active idelalisib formulations in appearance. The placebo 
tablets matching the 150-mg tablets are pink, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium 
stearate, red iron oxide, polyethylene glycol, talc, PVA, and titanium dioxide. The placebo 
tablets matching the 100-mg tablets are orange, film-coated, and include the following
inactive ingredients: silicified microcrystalline cellulose, sodium starch glycolate, 
magnesium stearate, yellow iron oxide, polyethylene glycol, talc, PVA and titanium dioxide.
5.2.2.
Source
Both active idelalisib and placebo will be supplied free of charge by Gilead Sciences. 
5.2.3.
Packaging and Labeling
During the blinded portion of the study, study drug (idelalisib or idelalisib/placebo) will be 
provided in blister cards. The blister cards are made of polyvinyl 
chloride/polychlorotrifluoroethylene (PVC/PCTFE) film and have aluminum foil lidding 
materials. Each blister card contains 120 tablets (4-week supply plus a modest overage) of 
one of the relevant dose strengths. The 100-mg or 150-mg and matching placebo tablets will 
be combined in order to obtain the daily doses to be used in this study. Thus, in Arm A, the 


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300-mg idelalisib dose will be obtained by administering two 150-mg tablets and the 200-mg 
idelalisib dose will be obtained by administering two 100-mg tablets. In Arm B, the 150-mg 
idelalisib dose will be obtained by administering one 150-mg tablet and one placebo tablet 
and the 100-mg idelalisib dose will be obtained by administering one 100-mg tablet and one 
placebo tablet. 
Each blister card will have a unique number. Labeling for blister cards dispensed to subjects 
in Arm A will appear identical to blister cards dispensed to subjects in Arm B, and may 
include either idelalisib or placebo. 
When the primary study (GS-US-312-0116) is stopped including if early after an interim 
analysis, GS-US-312-0116 active study subjects will become eligible for participation on 
Study GS-US-312-0117. Active GS-US-312-0117 study subjects will be transitioned to 
open-label idelalisib at this time. Each bottle contains 60 tablets (4 week supply plus a 
modest overage) of one of the relevant dose strengths (150 mg, 100 mg) and a polyester coil. 
Bottles are white and are made of high-density polyethylene. Each bottle is closed with a 
white, continuous-thread, child-resistant, polypropylene screw cap fitted with an induction-
sealed, aluminum-faced liner.
All labels for study drugs to be distributed to centers in the United States, the EU, and other 
countries will meet all applicable requirements of the United States Food and Drug 
Administration (FDA), the EU Annex 13 of Current Good Manufacturing Practice (cGMP) 
(Manufacture of Investigational Medicinal Products, July 2010), and/or other local 
regulations as applicable.
5.2.4.
Storage and Handling
Blister cards or bottles containing tablets of study drug (idelalisib or idelalisib/placebo)
should be stored at controlled room temperature (ie, ~25°C, with a range of 15 to 30°C). 
While the stability of study drug tablets stored at controlled room temperature has been 
confirmed, brief excursions to temperatures as low as -20°C or as high as 40°C 
(eg, during shipping) will not adversely affect the drug. Updated stability data will be 
provided to the sites, as appropriate.
5.2.5.
Dispensing
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing 
study drug according to the IWRS directions. It is planned that drug will be dispensed at 
4-week intervals through the first 24 weeks of treatment and at 12-week intervals thereafter. 
Sufficient study drug will be provided for each study period at the beginning of the period.
Multiple blister cards or bottles may be dispensed at a single visit. Tablets should be kept in 
the original blister cards or bottles provided until they are self-administered by the subject.


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At the time of starting study treatment, the IWRS will provide the clinic staff with the blister 
card numbers designating the blister cards to be dispensed, or the quantity of open-label 
bottles to be dispensed. The clinic staff (eg, pharmacist or other qualified person) will write 
the subject number on each blister card or bottle that is dispensed. Immediately before 
dispensing, the clinic staff will write the blister card or bottle number in the study drug 
administration record corresponding to the subject number.
5.2.6.
Return
The study drug should be retrieved from each subject at the end of each dispensing interval. 
The quantity of study drug and the date returned by the subject should be recorded in the 
study drug accountability records. When possible, all study drug returned by the subject 
should be retained for review by the study site monitor prior to return to Gilead Sciences or 
destruction.
5.2.7.
Accountability
The disposition of all study drug should be documented from the time of receipt at the site 
through subject dispensing and return.
Study personnel must ensure that all study drug is kept in a secure locked area with access 
limited to authorized personnel. The study drug must not be used outside the context of this 
protocol. Under no circumstances should the investigator or site personnel supply study drug 
to other investigators or clinics, or allow the study drug to be used other than as directed by 
this protocol.
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by Gilead Sciences or its designee, including, but not 
limited to, the date received, lot number, amount received, and the disposition of all study 
drug. Upon receipt of a drug shipment, the shipment must be logged into the IWRS. Study 
drug accountability records must also be maintained that include the subject number to whom 
the study drug was dispensed and the date, quantity and lot number of the study drug 
dispensed.
Depending upon the decision of Gilead Sciences, remaining unused study drug supply will be 
returned to Gilead Sciences or its designee after the study is completed or will be discarded 
or destroyed at the clinical site. If the study drug is discarded or destroyed at the clinical site, 
standard institutional policy should be followed. Records documenting the date of study drug 
shipping or destruction, relevant lot numbers, and amount shipped or destroyed should be 
maintained.
5.2.8.
Overdose Precautions
In Phase 1 studies, an MTD for idelalisib was not reached when the drug was administered 
continuously at dose levels through 350 mg/dose BID (700 mg per day) [Coutre 2011, 
Kahl 2011]. However, in this protocol, an overdose is defined as administration of more than 


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the prescribed daily dose (ie, >600 mg in a single day). In a subject who experiences an 
overdose consideration should be given as to whether idelalisib administration should be 
temporarily interrupted. If the overdose ingestion is recent and substantial, and if there are no 
medical contraindications, use of gastric lavage or induction of emesis may be considered. 
Observation for any symptomatic side effects should be instituted, and biochemical and 
hematological parameters should be followed closely (consistent with the protocol or more 
frequently, as needed). Appropriate supportive management to mitigate adverse effects 
should be initiated.
The Gilead Sciences medical monitor should be contacted if a study drug overdose occurs. 
Cases of study drug overdose will result in specific reporting requirements (see Section 8.8).
5.2.9.
Inadvertent Exposure and Spill Precautions
Based on available data from nonclinical studies, idelalisib does not appear to be acutely 
toxic, genotoxic, or irritative at levels that are likely to result from inadvertent exposure to 
the contents of broken tablets. However, personnel handling the drug should use reasonable 
precautions to avoid eye contact, skin contact, inhalation, or ingestion of the study drug 
product. For further information regarding inadvertent exposure and spill precautions, please 
consult the idelalisib investigator brochure.
Study Drug Administration
5.3.
5.3.1.
Premedication
No specific premedications or supporting medications are required in conjunction with study 
drug administration.
5.3.2.
Administration Instructions
The prescribed dose of study drug (idelalisib/placebo) should be taken orally. At each dose 
administration, the tablet number corresponding to the appropriate dose of study drug is to be 
swallowed whole with 100 to 200 mL (~ 4 to 8 ounces) of water. In case of breakage of the 
tablets in the oral cavity, additional water should be taken as a rinse. 
Study drug may be taken with or without food. There are no known dietary restrictions 
related to study drug use.
5.3.3.
Dosing Schedule
Study drug should be taken on a BID schedule at approximately the same times each day.
Ideally, doses should be taken at ~12-hour intervals (eg, at ~7 AM and at ~7 PM). While it is 
realized that variations in dosing schedule may occur in the outpatient setting, the prescribed 
regimen should be followed as closely as possible, especially in the clinic.


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At specified clinic visits, the study drug will be administered in the clinic with dosing 
appropriately timed relative to blood sampling for idelalisib pharmacokinetics. As detailed in 
Section 6.2, clinic staff should record idelalisib administration information, including the 
exact clock time of each dose, for doses of study drug administered in the clinic or hospital. 
Thereafter, subjects will be given an adequate supply of tablets to take at home.
5.3.4.
Dose Levels
Study drug dose levels for Arm A and Arm B are described in Table 5-1. The lower dose 
level (Dose Level -1) is provided in case a subject requires a study drug dose modification.
Table 5-1.
Study Drug Dose Levels
Treatment Arm
Starting Dose
Dose Level -1
Arm A
300 mg/dose BID
200 mg/dose BID
Arm B
150 mg/dose BID
100 mg/dose BID
Abbreviation: BID=twice per day
When the primary study (GS-US-312-0116) is stopped, and GS-US-312-0116 active study 
subjects become eligible for participation on Study GS-US-312-0117 subjects will be 
enrolled into Study GS-US-312-0117 at open label 150mg BID. Subjects already 
participating in Study GS-US-312-0117 will remain on the same dose.
5.3.5.
Dose Schedule Interruptions and Vomited Doses
Subjects who have a delay in administration of a dose of the study drug of <6 hours should 
take the planned dose as soon as possible after the intended time of administration. For 
subjects who have a delay in administration of study drug of 6 hours, the dose should not be 
taken. Study drug administration may continue but the missed dose should not be made up 
and the planned timing of subsequent study drug dosing should not be altered.
Vomited doses may be retaken, but only if the tablet is visible in the vomitus.
5.3.6.
Safety Monitoring and Study Drug Interruption/Dose Modification
Subjects must be monitored closely for adverse events or laboratory abnormalities during the
course of the study. Reference should be made to the CTCAE, Version 4.03 for grading the 
severity of adverse events and laboratory abnormalities.
Based on Phase 1 clinical experience adverse events potentially attributable to idelalisib in 
patients with CLL have included infrequent hepatic events (manifest primarily as 
asymptomatic and isolated elevations in serum ALT/AST).  Other adverse events potentially 
related to idelalisib have included instances of pneumonitis, gastrointestinal inflammation, 
or rash. Myelosuppression has not been an overt toxicity of idelalisib in previous experience


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but provisions for intervention in subjects experiencing very protracted treatment-emergent 
neutropenia or thrombocytopenia are provided as a precaution. It is possible that idelalisib is 
responsible for other adverse events for which a causal relationship has not yet been 
established.
Recommendations for modifications of the dosing regimens based on the drug and the type 
and severity of adverse events or laboratory abnormalities are provided in Table 5-2 below. 
The dose modification instructions focus on the types of events most commonly attributed to 
each of the study agents. The recommendations provided in Table 5-2 comprise only 
guidelines; variations from these recommendations may be warranted based on an 
investigator’s individual judgment in considering potential risks, benefits, and therapeutic 
alternatives available to each subject.
Consistent with Table 5-2, if a subject experiences an adverse event that is suspected to be 
related to study drug and requires a dose modification during the course of study therapy, 
then study drug administration should be held, as necessary, until the adverse event resolves 
or stabilizes to an acceptable degree (generally to Grade 1). Thereafter, study drug may be 
reinstituted, but the dose should be reduced to Dose Level -1 (see Table 5-1). If the adverse 
event occurs again, one further attempt at reinitiation of therapy at Dose Level -1 may be 
attempted if the investigator feels that a second rechallenge is medically appropriate. If the 
subject cannot tolerate idelalisib at Dose Level -1 after 2 rechallenges, then the subject 
should be discontinued from study drug therapy unless continued therapy is permitted by the 
Gilead Sciences medical monitor.
After the study drug dose is reduced, the dose need not be re-escalated, even if there is 
minimal or no toxicity with the reduced dose. However, if the subject tolerates the lower 
dose level of study drug for ≥4 weeks then the dose level may be increased to the starting 
dose level (see Table 5-1) at the discretion of the investigator. Such re-escalation may be 
particularly warranted if further evaluation reveals that the adverse event that led to the dose 
reduction was not study-drug-related. The starting dose level should not intentionally be 
exceeded in this study.
Whenever possible, any dose adjustment of study drug should be discussed between the 
investigator and the Gilead Sciences medical monitor prior to implementation. To implement 
either a dose reduction or a dose reescalation, the investigator/study staff member will call 
the IWRS, enter the subject number, and inform the IWRS of the need for dose titration. The 
IWRS will provide details regarding the blister card to be dispensed to the subject. The 
appropriate clinic staff should instruct the subject/caregiver about the change in dose.
Recommendations for dose modification based on the type and severity of adverse events or 
laboratory abnormalities are provided in Table 5-2 below.


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Table 5-2.
Recommendations for Study Drug Dose Modifications Based on 
Type and Severity of Treatment-Related Adverse Events or 
Laboratory Abnormalities
NCI CTCAE Grade
Recommendation
Idelalisib
HEMATOLOGICAL ADVERSE EVENTS
Neutropenia
Grade 2 neutropenia
Maintain current dose level and schedule.
Grade 3 neutropenia
During combination or continuing single-agent therapy periods, maintain current 
idelalisib dose level and schedule. Consider G-CSF support.
Grade 4 neutropenia 
(or occurrence of 
neutropenic fever or 
infection)
During combination therapy period, consider G-CSF support and maintain current 
idelalisib dose level and schedule. During continuing single-agent idelalisib therapy 
period, consider G-CSF support and continue idelalisib at initial or lower dose level at 
investigator discretion.
Thrombocytopenia
Grade 3
Maintain current dose level and schedule.
Grade 4
During combination therapy period, maintain current idelalisib dose level and 
schedule. During continuing single-agent idelalisib therapy period, withhold for 
bruising or bleeding until Grade 3. May resume idelalisib at initial or lower dose 
level at investigator discretion.
NON-HEMATOLOGICAL ADVERSE EVENTS
Dermatological
Grade 1
Maintain current dose level and schedule.
Grade 2
Withhold idelalisib until Grade 1. Resume idelalisib at current dose level. If 
rechallenge at current dose level results in recurrence, may resume at same or lower 
idelalisib dose level at investigator discretion.
Grade 3 or 4
Withhold idelalisib until Grade 1. May resume at lower dose level or discontinue 
idelalisib at investigator discretion.
Gastrointestinal Inflammation/Diarrhea
Grade 1
Provide anti-diarrheal (eg, loperamide) and maintain current idelalisib dose level and 
schedule
Grade 2
Provide anti-diarrheal (eg, loperamide). Withhold idelalisib until Grade 1. Resume 
idelalisib at current dose level. If rechallenge results in recurrence, may resume at 
initial or lower dose level at investigator discretion. Consider addition of 
anti-inflammatory (eg, sulfasalazine, budesonide).
Grade 3
Provide anti-diarrheal (eg, loperamide). Withhold idelalisib until Grade 1. Resume at 
lower dose level. Consider addition of anti-inflammatory (eg, sulfasalazine, 
budesonide).
Grade 4
Provide anti-diarrheal (eg, loperamide). Withhold idelalisib until Grade 1. May 
resume at lower dose level or discontinue idelalisib at investigator discretion. Consider 
addition of anti-inflammatory (eg, sulfasalazine, budesonide).


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NCI CTCAE Grade
Recommendation
Idelalisib
Hepatic Adverse Events (elevations in ALT, AST, or bilirubin)
Grade 1
(ALT/AST3xULN)
(Bilirubin1.5xULN)
Maintain current dose level and schedule.
Grade 2
(ALT/AST>3-5xULN)
(Bilirubin>1.5-
3xULN)
Maintain current dose level and schedule. Monitor ALT, AST, ALP, and bilirubin at 
least 1x per week.
Grade 3
(ALT/AST>5-20xUL
N)
(Bilirubin>3-10xULN)
Withhold idelalisib. Monitor ALT, AST, ALP, and bilirubin at least 1x per week until 
all abnormalities are Grade 1. If bilirubin abnormality was Grade <3, resume 
idelalisib at same dose level. If bilirubin abnormality was Grade 3, resume at lower 
dose level.
Grade 4
(ALT/AST>20xULN)
(Bilirubin>10xULN)
Withhold idelalisib. Monitor ALT, AST, ALP, and bilirubin at least 1x per week until 
all abnormalities are Grade 1. If bilirubin abnormality was Grade <4, resume 
idelalisib at lower dose level. If bilirubin abnormality was Grade 4, discontinue 
idelalisib.
Pneumonitis (dyspnea, cough, hypoxia and/or diffuse interstitial pattern or ground-glass opacities on 
chest CT and no obvious infectious cause)
Grade 1
Maintain current dose level and schedule. Consider pneumocystis prophylaxis.
Grade 2
Withhold idelalisib until Grade 1, consider systemic corticosteroids and 
pneumocystistreatment. May resume at initial or lower dose level at investigator 
discretion.
Grade 3
Withhold idelalisib until Grade 1, consider systemic corticosteroids and consider 
pneumocystis treatment. May resume at lower dose level or discontinue idelalisib at 
investigator discretion.
Other Nonhematological Adverse Events
Grade 2
Maintain current dose level and schedule
Grade 3
Withhold idelalisib until Grade 1. May resume idelalisib at initial or lower dose level 
or discontinue idelalisib at investigator discretion.
Abbreviations:  ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST= aspartate aminotransferase, 
ANC=absolute neutrophil count, CTCAE=Common Terminology Criteria for Adverse Events, G-CSF=granulocyte 
colony-stimulating factor, NCI=National Cancer Institute, ULN=upper limit of normal


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Recommendations for Evaluation, Intervention, and Drug 
5.4.
Discontinuation for Specific Adverse Events or Conditions
5.4.1.
Dermatological Events
idelalisib administration has occasionally been associated with the occurrence of a 
maculopapular rash affecting the trunk and extremities [Gilead Sciences 2011]. Based on 
skin biopsy data in several subjects, the findings have been consistent with a delayed-type 
hypersensitivity reaction. Rechallenge with idelalisib has resulted in recurrence of rash in
some but not all subjects.
In subjects who develop a rash while on study drug, causes related to concomitant 
medications, environmental exposures, or infection should be considered and eliminated. 
Depending upon the severity of the initial dermatological event, rechallenge with study drug 
therapy at the same or a lower dose level (see Table 5-2) should be considered if continued 
drug administration offers the potential for clinical benefit.
5.4.2.
Gastrointestinal Events
Inflammation of the tongue has been noted in rats undergoing repeated gavage administration 
of idelalisib; this inflammation may have represented a drug-related exacerbation of 
gavage-mediated irritation. Mild congestion or hemorrhage in the large intestine has been 
seen in dogs receiving high doses of idelalisib. In patients, isolated cases of gastrointestinal 
inflammation (eg, stomatitis, colitis, cecitis) have been noted. While disease-related factors, 
neutropenia, toxicity from prior therapies, effects of ongoing supportive care, or pre-existing 
cholelithiasis may have initiated such events, it is possible that idelalisib played a 
contributory role [Gilead Sciences 2011]. In such subjects, rechallenge with idelalisib has 
been possible and has not been associated with other severe adverse events. Patients who 
have developed evidence of enteritis during idelalisib therapy have been successfully treated 
with antidiarrheals (eg, loperamide) and with enteric steroidal (eg, budesonide) or 
non-steroidal (eg sulfasalazine [Azulfidine®]) anti-inflammatory agents and have been able to 
continue or resume idelalisib.
For study subjects who develop severe abdominal pain, particularly if early during therapy, 
the possibility of a bowel obstruction or perforation should be considered. Appropriate 
clinical and radiographic examination should be performed and supportive care and surgical 
intervention should be considered. Upon recovery, study therapy may be continued if 
appropriate for the clinical situation.
For subjects who develop persistent diarrhea, causes related to concomitant medications or 
gastrointestinal infection should be considered and eliminated. Depending upon the clinical 
circumstances, endoscopy and biopsy may be warranted. Providing an antidiarrheal
(eg, loperamide) may lessen symptoms. Consideration should be given to intervention with 
enteric steroidal (eg, budesonide) or non-steroidal (eg, sulfasalazine) anti-inflammatory 
agents.In such subjects, rechallenge with idelalisib at a lower dose level has resulted in 
recurrence of symptoms in some but not all subjects and has not been associated with other 


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severe adverse events. One patient who developed evidence of inflammatory bowel disease 
during idelalisib therapy has been treated with sulfasalazine (Azulfidine®) and antidiarrheals 
(eg, loperamide) while continuing on idelalisib.
Thus, depending upon the type and severity of the initial gastrointestinal event, rechallenge 
with study drug at a reduced dose level and with and appropriate support care may be 
warranted if continued drug administration offers the potential for clinical benefit.
5.4.3.
Hepatic Events
. In patients with lymphoid malignancies, reversible serum ALT/AST elevations have been 
observed [Coutre 2011, Kahl 2011]. In these patients, the onset of Grade 3 or 4 transaminase 
elevations has typically occurred within approximately 4 to 8 weeks of starting idelalisib
therapy (median 5.7, Q1-Q3 3.9-8.1). Among patients with Grade 1-2 ALT/AST 
abnormalities, continued dosing has been possible; transaminase values commonly resolve 
despite continued idelalisib treatment. For those with Grade 3-4 ALT/AST elevations, drug 
interruption has resulted in resolution over 2 to 6 weeks. Successful rechallenge at lower 
dose levels of idelalisib has been achieved in the majority of patients. Thus, in subjects with 
uncomplicated hepatic events, the instructions in Table 5-2 should be followed in an attempt 
to maximize the potential that subjects who appear to be benefiting can continue with study 
drug treatment.
In selected subjects who experience more complicated hepatic adverse events, further 
work-up may be warranted, as requested by the Gilead Sciences medical monitor. Such an 
evaluation may be particularly warranted in subjects who first experience a serum ALT/AST 
elevation 12 weeks from the start of study drug therapy, who have an elevation in serum 
bilirubin concentration or coagulation parameters, or who have other characteristics that 
suggest an atypical change in transaminase values. Further workup may include: obtaining a 
history of recent symptoms/illnesses and of relevant past history (eg, history of hepatitis or of 
hepatitis A or hepatitis B vaccination); obtaining information regarding concomitant drug use 
(prescription and nonprescription medications, dietary supplements, alcohol, illicit drugs, 
special diets); questioning the subject regarding potential exposure to environmental toxins; 
ruling out viral hepatitis A, B, C, D (if hepatitis B is positive), and E, Epstein-Barr virus,
cytomegalovirus, autoimmune hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis, 
hypoxic/ischemic hepatopathy, and biliary tract disease; obtaining additional tests to evaluate 
liver function (eg, prothrombin time [PT], activated partial thromboplastin time [aPTT], 
international normalized ratio [INR], albumin); and considering gastroenterology or 
hepatology consultation [FDA 2009].
Of note, HBV reactivation can occur in patients treated with rituximab with a median time to 
diagnosis of hepatitis among patients with hematologic malignancies of 4 months after the 
initiation of rituximab but such events can occur months after completion of rituximab 
therapy. The risk is very low among patients with negative anti-HBc serology [Matsue 2010]
and/or undetectable HBV DNA as assessed by quanititative PCR. Because subjects with such 
evidence of persistent HBV infection are excluded from this study, reactivation is not 


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anticipated. However, among subjects with evidence of Grade 3 serum ALT/AST 
abnormalities, evaluation for HBV reactivation (manifest as positivity for serum HBsAg)
should be considered as a precautionary measure. In a subject with active HBV, anti-HBV 
antiviral agents should be initiated. At the discretion of the investigators, study drug may be 
continued if HBV infection can be adequately controlled, particularly if the subject is 
experiencing clinical benefit from study therapy and there are few other options for treating 
the subject’s CLL.
5.4.4.
Hematological and Immunological Events
In the Phase 1 experience with idelalisib in CLL, patients with Grade3 neutropenia, anemia, 
and and/or thrombocytopenia were enrolled to clinical trials. Decreased levels of neutrophil 
counts, hemoglobin, or platelet counts during therapy were largely due to minor fluctuations 
in these parameters among patients with pre-existing hematological abnormalities due to 
disease or prior therapy. Thus, idelalisib did not appear to induce overt myelosuppression. 
Obvious patterns of drug-mediated reductions in circulating CD4+ lymphocyte counts or 
suppression of serum IgG levels were also not observed.
Given that patients with CLL commonly have Grade 3 hematological abnormalities due to 
underlying disease or prior therapy and that idelalisib is not associated with substantial 
myelotoxicity or off-target immunosuppression, alterations in study drug dose level for such 
events should only focus on subjects with protracted or symptomatic neutropenia or 
thrombocytopenia, unresponsive to G-CSF supportive care. No modification of idelalisib for 
changes in circulating CD4+ counts or Ig levels is planned.
5.4.5.
Infectious Events
Patients with CLL receiving idelalisib have developed serious bacterial, fungal, and viral 
infections during therapy [Gilead Sciences 2011]. Similarly, serious bacterial, fungal, and 
new or reactivated viral infections have also occurred during and for ~1 year following 
rituximab-based therapy [Gea-Banacloche 2010]. New or reactivated viral infections in 
patients receiving rituximab have included cytomegalovirus, herpes simplex virus, 
parvovirus B19, varicella zoster virus, West Nile virus, HBV (see Section 5.4.3) and HCV. 
Because patients with lymphoid malignancies (particularly those with CLL) are susceptible 
to infection due to the underlying disease, neutropenia, and the effects of prior therapy, the 
specific causal role of idelalisib or rituximab in any of these types of events is unclear.
Patients with previously treated CLL have developed Pneumocystis (carinii) jiroveci
pneumonia while receiving idelalisib. While idelalisib has not specifically been implicated in 
such cases, patients with lymphoid malignancies (particularly those with CLL) may be 
susceptible to pneumocystis infections due to the underlying disease and the effects of prior 
therapy. Pre-existing risk factors of specific concern may include previous pneumocystis 
pneumonia, underlying disease (eg, CLL), prior therapy (eg, alemtuzumab, progenitor cell 
transplantation), or immunocompromised status (low CD4+ lymphocyte counts, HIV
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In a subject with a history of recurrent infections, prophylaxis with intravenous Ig should be 
considered [Raanani 2009]. Unless there is a contra-indication in a specific study subject, 
consideration should be given to initiation of antibiotic prophylaxis against pneumocystis 
infection (eg, with trimethoprim-sulfamethoxazole, dapsone, aerosolized pentamidine, or 
atovaquone) beginning prior to study drug administration. Such support may also offer the 
benefit of reducing the risk for other bacterial infections [Green 2007]. Local practices or 
guidelines regarding infection prophylaxis may be followed.
For subjects who develop an infection, appropriate medical therapy (with antibiotics, 
antifungals, or antiviral) or other interventions should be instituted. Whenever appropriate, 
subjects should continue with study drug during treatment for the infection.
5.4.6.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) due to polyomavirus JC has been 
observed in patients who have received rituximab therapy [Carson 2009] for hematologic 
malignancies. The specific causal role of rituximab is unknown because many of these 
patients had other risk factors (eg, low CD4+ counts) and the majority had received 
rituximab in combination with chemotherapy or as part of a hematopoietic stem cell 
transplant. Most cases of PML were diagnosed within 12 months of the last infusion of 
rituximab.
The diagnosis of PML should be considered in any subject presenting with new-onset or 
worsening neurologic manifestations, especially weakness or paralysis, vision loss, impaired 
speech, or cognitive deterioration. Evaluation of PML should include consultation with a 
neurologist, brain MRI, and lumbar puncture. In subjects diagnosed with PML, study drug 
should also be permanently discontinued.
5.4.7.
Pulmonary Events
Documented bacterial, fungal, viral, and pneumocystis pneumonias have been observed in 
patients receiving idelalisib, primarily in patients with CLL. Some patients receiving 
idelalisib alone or in combination have developed evidence of pneumonitis without 
documented lung infection. The specific role of idelalisib in these events is unclear; 
nonclinical evaluations of pulmonary function and pathology do not indicate a direct toxic 
effect of idelalisib on the lungs [Gilead Sciences 2011] and disease-related factors or toxicity 
from prior or concomitant therapies may have contributed to these clinical events. 
Rituximab-related noninfectious pneumonitis has been described [Subramanian 2010] with 
an incidence of ~4.3% [Salmasi 2010]. In patients developing rituximab-associated 
pneumonitis, the mean time from the first rituximab infusion to the onset of respiratory 
symptoms was 3 months, with a peak incidence after administration of a mean cumulative 
dosage of 1600 mg/m2 [Lioté 2010].


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Given the potential for infectious or drug-related adverse events, clinicians should be 
particularly observant for evidence of respiratory events in subjects participating in this trial. 
Subjects should be evaluated who describe pulmonary symptoms (eg, dyspnea on exertion, 
cough, shortness of breath); manifest a decline from baseline of 5% in oxygen saturation, or 
demonstrate evidence of pulmonary inflammation (eg, focal or diffuse interstitial pattern or 
ground-glass opacities on chest CT). Potential bacterial, fungal, or viral etiologies should be 
assessed. Pneumocystis (carinii) jiroveci should be considered, especially if the subject is not 
receiving pneumocystis prophylaxis. Depending upon the changes observed and the response 
to antibiotic intervention, recommended diagnostic work-up may include blood and sputum 
cultures; polymerase chain reaction or antigen testing for pneumocystis and respiratory 
viruses (eg, CMV, influenza virus, respiratory syncytial virus, parainfluenza virus, 
rhinovirus); chest X-ray, CT or other imaging methods; pulmonary function testing and 
diffusing capacity of the lung for carbon monoxide (DLCO); bronchoscopic lavage and/or 
biopsy; or open-lung biopsy. Noninfectious etiologies such as pulmonary edema or 
thromboembolism should also be considered.
As appropriate for the clinical situation and culture results, subjects should be treated 
empirically or given specific antibiotics, antifungals, or antiviral agents for a cultured 
organism. Supportive care, including oxygen or mechanical ventilation, should be provided 
as necessary. 
For subjects with a symptomatic pneumonitis (eg, onset of cough, dyspnea, hypoxia and/or a 
diffuse interstitial pattern or ground-glass opacities on chest (CT), study drug should be 
interrupted and therapy with systemic corticosteroids (eg, prednisone, 60 mg/day) should be 
instituted rapidly [Lioté 2010]. Resumption of study drug at Dose Level -1 should only be 
considered if the subject is experiencing evidence of clinical benefit from study drug; 
reoccurrence of drug-related pneumonitis upon rechallenge should result in permanent 
discontinuation of study drug.
5.4.8.
Tumor Lysis Syndrome
Patients with tumor lysis syndrome may experience hyperkalemia, hypocalcemia, 
hyperuricemia, hyperphosphatemia, cardiac dysrhythmias, and acute renal failure.
Tumor lysis syndrome has not been observed with idelalisib monotherapy. However, if tumor 
lysis were to occur in a subject participating in this study, the subject should receive rapid 
reversal of hyperkalemia, intravenous hydration, antihyperuricemic agents, and appropriate 
cardiac and renal support, including dialysis as indicated. Upon recovery to baseline 
functioning, such subjects should continue study therapy to maintain tumor control.
5.4.9.
Pregnancy, Lactation, and Reproduction
Idelalisib has induced embryo lethality and teratogenicity when administered to pregnant 
female rats at maternally toxic doses [Gilead Sciences 2012]. However, definitive 
reproductive toxicology studies in animals have not yet been performed and the specific 
effects of idelalisib on human embryogenesis or fetal development are unknown. Whether 


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idelalisib is excreted in human breast milk is unknown. General toxicology studies in rats and 
dogs indicated dose-dependent reductions in testicular weights, with persistent minimal to 
mild degeneration of the seminiferous tubules and decreased spermatozoa in rats and 
hypospermatogenesis in dogs. The implications of these testicular changes for animal or 
human fertility are unknown.
Given the preliminary nature of data regarding the risks to a fetus or infant as a result of 
exposure to idelalisib, women of reproductive potential entering this study must have a 
negative serum pregnancy test at baseline and must not be breastfeeding. Males and females 
of childbearing potential should abstain from sexual intercourse or use an effective form of 
contraception (see Section 5.6.4). If a female study participant becomes pregnant or decides 
to breastfeed during the course of the study, all study therapy must be discontinued. Study 
candidates will be informed of the testicular findings through the informed consent process.
5.4.10.
Ultraviolet Exposure
In vitro studies indicate enhanced cytotoxicity when embryonic murine fibroblasts treated 
with GS-563117 (the major metabolite of idelalisib) are simultaneously exposed to 
ultraviolet light.  While nonclinical findings suggest the hypothetical potential for 
phototoxicity in humans, available clinical data do not reveal a photosafety concern 
[Gilead Sciences 2012]. Although specific clinical correlates for these nonclinical data are 
not available, investigators and study subjects should be observant for the possibility that 
study participants may have exaggerated sunburn reactions (eg, burning, erythema, 
exudation, vesicles, blistering, edema) involving areas of skin exposed to ultraviolet light.
Emergency Unblinding
5.5.
In the event of a medical emergency where breaking the blind is required to provide medical 
care to the subject, the investigator may obtain treatment assignment directly from the IWRS 
system for that subject.  Gilead recommends but does not require that the investigator contact 
the Gilead medical monitor before breaking the blind. Treatment assignment should remain 
blinded unless that knowledge is necessary to determine subject emergency medical care. 
The rationale for unblinding must be clearly explained in source documentation and on the 
case report form/ electronic case report form (CRF/eCRF), along with the date on which the 
treatment assignment was obtained. The investigator is requested to contact the Gilead 
medical monitor promptly in case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent 
to do so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for 
expedited reporting of suspected unexpected serious adverse reactions (SUSARs).


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Concomitant and Supportive Therapy
5.6.
To the extent possible, administration of any prescription or over-the-counter drug products 
other than study medication should be minimized during the study period. Subjects should be 
discouraged from use of street drugs, herbal remedies, self-prescribed drugs, tobacco 
products, or excessive alcohol at any time during the clinical study.
If considered necessary for the subject’s well-being, drugs for concomitant medical 
conditions or for symptom management may be given at the discretion of the investigator. 
The decision to authorize the use of any drug other than study drug should take into account 
subject safety, the medical need, the potential for drug interactions, the possibility for 
masking symptoms of a more significant underlying event, and whether use of the drug will 
compromise the outcome or integrity of the study
Subjects should be instructed about the importance of the need to inform the clinic staff of 
the use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and 
during the course of the study. Any concomitant drugs taken by a subject during the course 
of the study and the reason for use should be recorded on the eCRFs.
Information regarding use or restrictions on specific concomitant medications, dietary 
measures, or other interventions is provided below.
5.6.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments
Except for corticosteroids (See Section 5.6.5), no other anticancer therapies (including 
chemotherapy, radiation, antibody therapy, immunotherapy, or other experimental therapies) 
of any kind are permitted. Subjects are not allowed to participate concurrently in any other 
therapeutic clinical study.
5.6.2.
Antibiotics
Except in a subject who has a contra-indication, investigators should consider initiation of 
antibiotic prophylaxis against pneumocystis infection (eg, with trimethoprim-
sulfamethoxazole, dapsone, aerosolized pentamidine, or atovaquone) beginning prior to study 
drug administration. Such support may also offer the benefit of reducing the risk for other 
bacterial infections [Green 2007]. Investigator discretion and local practices or guidelines 
may be followed.
For subjects who develop an infection, appropriate medical therapy (with antibiotics, 
antifungals, or antiviral) or other interventions should be instituted. Whenever appropriate, 
subjects may continue with study drug during treatment for the infection.


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5.6.3.
Antiemetics and Antidiarrheals
Drug-related nausea and/or vomiting have not been commonly observed with idelalisib in 
prior studies. However, subjects who experience nausea or vomiting while on study therapy 
may receive antiemetics based on the judgment of the treating physician and local 
institutional practices. At the occurrence of persistent nausea or vomiting of severity 
Grade 1, it is suggested that the subject receive an oral or transdermal serotonin antagonist 
(eg, dolasetron, granisetron, ondansetron, tropisetron, palonosetron). Other classes of 
antiemetic medications that may be employed include dopamine antagonists or 
benzodiazepines. As needed, subjects may be prescribed loperamide (Imodium® or others) or 
diphenoxylate and atropine (Lomotil®) to control diarrheal symptoms.
5.6.4.
Contraception
In the context of this protocol, a female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, a bilateral tubal ligation, or a bilateral oophorectomy; has 
medically documented ovarian failure (with serum estradiol and FSH levels within the 
institutional postmenopausal range and a negative serum or urine HCG); or is menopausal 
(age >55 years with amenorrhea for >12 months or amenorrhea for >6 months with serum 
estradiol and FSH levels within the institutional postmenopausal range).
Sexually active females of childbearing potential must agree to use a protocol-recommended 
method of contraception during heterosexual intercourse throughout the study treatment 
period and for 30 days following the last dose of the study drug. The investigator should 
counsel subjects on the most effective methods for avoiding pregnancy during the trial. 
Protocol-recommended contraceptive methods are described in Table 5-3.
Table 5-3.
Protocol-Recommended Contraceptive Methods
Individual Methods
Combination Methods
Hormonal Methods
(One method to be used 
with a barrier method)
Barrier Methods
(Both of these methods to be used OR one of these 
methods to be used with a hormonal method)
IUD
Estrogen and progesterone
Diaphragm with spermicidea
Copper T 380A IUD
Oral contraceptives
Male condom (with spermicidea)
LNg 20 IUD
Transdermal patch
Tubal sterilization
Vaginal ring
Hysterectomy
Progesterone
Injection
Implant
a
If available/approved for use in the specific country
Abbreviation: IUD=intrauterine device


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In the context of this protocol, a male subject is considered able to father a child unless he 
has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or is 
receiving ongoing testicular suppression with a depot luteinizing hormone-releasing hormone 
(LH-RH) agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or 
triptorelin pamoate [Trelstar®]).
Sexually active male subjects who can father a child must accept continuous heterosexual 
abstinence as a lifestyle choice; limit intercourse to female partners who are surgically sterile, 
post-menopausal, or using effective contraception (as noted in Table 5-3); or agree to use a 
protocol-recommended method of contraception during heterosexual intercourse throughout 
the study treatment period and for 90 days following discontinuation of the study drug
(as noted in Table 5-3). 
The Gilead Sciences medical monitor should be consulted regarding any questions relating to 
childbearing status or contraception.
5.6.5.
Corticosteroids
Subjects may receive topical, inhaled, enteric, or systemic corticosteroids while on study. It 
should be realized that the use of systemic corticosteroids in patients with CLL may 
confound interpretation of antitumor effects mediated by study drug therapy. However,
subjects who develop conditions that may be alleviated by systemic corticosteroid therapy 
are permitted to receive such drugs and are not required to discontinue study participation.
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin
Granulocyte-macrophage colony-stimulating factor (GM-CSF) should not be administered 
given the potential for GM-CSF-related inflammatory symptoms.
G-CSF (filgrastim, PEG-filgrastim, lenograstim) may be administered in response to Grade 4
neutropenia or neutropenic complications; use should be particularly considered if providing 
hematopoietic support might help to maintain study drug treatment (see Table 5-2).
While erythropoietic agents (eg, erythropoietin or darbepoetin) may be administered for 
Grade 3 anemia, their use in this study is discouraged given the potential to confound 
assessments of improvements in bone marrow function related to study drug.
Reference may be made to the American Society of Clinical Oncology guidelines 
[Rizzo 2008, Smith 2006].
5.6.7.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism
Idelalisib is metabolized primarily via aldehyde oxidase and in part by CYP3A.  A clinical 
drug-drug interaction study indicated that administration of a potent CYP3A inhibitor 
together with idelalisib resulted in a ~80% increase in idelalisib plasma exposures (AUC) 
(see Section 1.3.5.1), which is not considered to be clinically relevant and suggesting that 


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idelalisib is a weak CYP3A substrate. Preliminary data indicate when coadministered with 
rifampin, a highly potent inducer of CYP3A, idelalisib exposures are ~75% lower. 
Coadministration of potent inducers of CYP3A with idelalisib should be avoided; a list of 
strong inducers is provided in Table 5-4:
Table 5-4.
Known Strong Inducers of CYP3A
Effect on 
CYP3A 
Drug Class
Medications
Strong CYP3A 
Inducers
Antimycobacterial
Rifampin
Anticonvulsants
carbamazepine, phenytoin
Foods/herbs
St. John’s wort
Abbreviation: CYP=cytochrome P450 enzyme
5.6.8.
Drugs that undergo CYP3A-Dependent Metabolism
The major metabolite of idelalisib, GS-563117, is a competitive and time dependent inhibitor 
of CYP3A; accordingly coadministration of idelalisib with midazolam, a probe CYP3A 
substrate, resulted in a ~5-fold increase in midazolam systemic exposure (AUC). 
Coadministration of CYP3A substrates with idelalisib may result in an increase in their 
systemic exposures (eg, antiarrhythmics, calcium channel blockers, benzodiazepines, certain 
HMG-CoA reductase inhibitors, phosphodiesterase-5 (PDE5) inhibitors, warfarin). Particular 
caution is recommended during coadministration of drugs that are narrow therapeutic index 
CYP3A substrates (eg, alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, 
fentanyl, quinidine, ergotamine, dihydroergotamine, astemizole, terfenadine) with idelalisib.
5.6.9.
Immunization
Because of its actions to inhibit PI3Kδ-dependent B-cell function, high doses of idelalisib
can impair primary or secondary responses to immunization in animals
[Gilead Sciences 2011].
The specific clinical relevance of these findings with idelalisib is unknown. However, for 
subjects who are at substantial risk of an infection (eg, influenza) that might be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of 
study therapy.
Of note, the safety of immunization with live viral vaccines following idelalisib therapy has 
not been studied and vaccination with live virus vaccines during study treatment is not 
recommended.


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5.6.10.
Surgery
There are no known effects of idelalisib on coagulation or wound healing. Pending receipt of 
additional information, study drug may be continued in the peri-procedural period in subjects 
who require surgery or invasive procedures.
5.6.11.
Diet
There are no specific dietary restrictions in the study. Study drug may be taken with or 
without food.
Duration of Study Drug
5.7.
Subjects may continue receiving study drug until the occurrence of any events requiring 
study drug discontinuation as defined in Section 5.8.
Discontinuation of Study Drug
5.8.
All study participants may receive study drug indefinitely; however:

Any subject has the right to discontinue study drug at any time.

Any subject who has objective evidence based on IRC review of definitive CLL 
progression will discontinue study drug.

Any subject unable to tolerate a second rechallenge with protocol-described, 
dose-modified idelalisib at Dose Level –1 (see Section 5.2) should discontinue study 
drug.

Any subject who becomes pregnant or begins breastfeeding should discontinue study 
drug.

Any subject who becomes significantly noncompliant with study drug administration, 
study procedures, or study requirements should discontinue study drug.

Any subject for whom the blind is intentionally broken by the subject or the study site 
should discontinue study drug.

The investigator, in consultation with the Gilead Sciences medical monitor, may 
discontinue study drug, if, it is not in the subject’s best interest to continue. 

If allowed by local regulations, Gilead Sciences may transition subjects from study drug 
to commercial drug supply when idelalisib becomes commercially available in the 
country where the subject is living.


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Subjects who permanently discontinue study drug for a reason other than disease progression 
(as determined by the IRC) shall continue with assessments per the schedule of procedures 
until disease progression or until another anticancer or experimental therapy is initiated. 
Discontinuation from Study
5.9.
Subject study participation will be ended due to any of the following reasons:

Adverse event;

Disease progression;

Withdrawal of consent;

Significant subject noncompliance with study drug administration, study procedures, or 
study requirements;

Initiation of any additional anticancer therapies (other than corticosteroids, see 
Section 5.6.5) including chemotherapy, radiation, antibody therapy, immunotherapy, or 
other experimental treatment; 

Physician’s decision to remove the subject from the study;

Pregnancy;

The subject is lost to follow-up; 

Death;

Discontinuation of study by the Sponsor, a Regulatory Agency, or an IRB or EC.
Study Treatment Rationale
5.10.
Subjects will be assigned to treatment (Arm A or Arm B) in this study based on their 
randomization in the primary study. The 1:1 randomization in the primary trial
(GS-US-312-0116) ensures that sufficient Arm B subjects will cross over from rituximab 
alone to single-agent idelalisib at the 150-mg/dose BID starting dose level in this extension 
trial (GS-US-312-0117) to allow an adequate evaluation of efficacy and safety in this trial.
The randomization and allocation processes will be established and performed through an 
IWRS; the intent is to maximize the integrity and security of the subject disposition and to 
ensure appropriate access and convenience-of-use by the investigational sites.
Double blinding is included to provide protection against biased interpretations of efficacy 
and safety data by subjects, caregivers, investigators, Gilead Sciences personnel, or others 
involved in study conduct. 


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Selection of the idelalisib treatment regimen (including starting dose level, 
dose-modifications and supportive care, schedule, duration, and conditions of administration) 
for this study program has been based primarily on safety, exposure, and activity profiles 
from previous Phase 1 clinical studies involving healthy volunteers, patients with allergic 
rhinitis, and patients with refractory/relapsed lymphoid malignancies [Webb 2010, 
Coutre 2011, Kahl 2011]. The following information was considered in selecting the study 
drug dosing regimen for the primary study and this companion extension study:

Idelalisib was symptomatically well tolerated in patients with lymphoid malignancies 
receiving dose levels of 50 mg/dose BID through 350 mg/dose BID (the highest dose 
level tested). No specific MTD was apparent over the dose range tested. However, 
monitorable, reversible transaminase elevations were observed in some patients and may 
have been more frequent at higher dose levels (~10% rate among patients with CLL 
receiving starting doses of 150 mg/dose). Thus, while doses through 350 mg/dose BID 
are tolerable, the starting dose of 150 mg/dose BID appears to appropriately balance 
safety with efficacy in idelalisib-naïve subjects. The starting dose of 300 mg/dose BID in 
this study also appears appropriate for evaluation; it is lower than the dose level of 
350 mg/dose BID that has been tolerable in prior studies and is likely to be suitable in 
subjects who have already been tolerating idelalisib therapy at 100 mg/dose BID. 

Upon disease progression, permitting escalation from 150 mg/dose BID to 
300 mg/dose BID among subjects allocated to Arm A offers a systematic evaluation of 
higher doses in subjects who are tolerating idelalisib treatment and might benefit from 
increased PI3Kinhibition. The pharmacological basis for considering such an 
intervention is based on the concept that some individuals might have 
lower-than-expected plasma exposures or dose-dependent resistance to the compound at 
150 mg/dose BID and might benefit from a higher dose. The intent is to determine if the 
higher dose can reestablish disease control or whether absolute resistance to PI3K
inhibition has been acquired. The safety data obtained in these subjects would add to the 
overall safety database.

In an allergic rhinitis study, idelalisib induced statistically significant improvements in 
clinical and pharmacodynamic endpoints when administered at 100 mg/dose BID over 
7 days. These data support the pharmacological relevance of idelalisib-mediated PI3Kδ 
inhibition when administered at the dose-levels to be used in this study.

A positive correlation was noted between idelalisib dose and measures of tumor control 
and chemokine normalization in patients with B-cell malignancies. The majority of 
patients appear to have tumor responses and protracted PFS when receiving starting doses 
of 100 mg/dose BID. Thus, treatment with a idelalisib at a starting dose of 150 mg/dose 
BID appears to offer most patients the potential to benefit from therapy and the dose level 
of 300 mg/dose BID may provide additional benefit in patients with disease resistance as 
systematically evaluated in this trial. 


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
Increases in idelalisib plasma Cmax, AUC, and Ctrough values were less than dose-
proportional in subjects with lymphoid malignancies; the dose-exposure evaluation 
indicated modest increases in plasma exposure at dose levels >150 mg BID.  Thus,
administration of starting doses of idelalisib of 150 mg/dose BID appears appropriate to 
ensure adequate exposure in the majority of patients. 

In Phase 1 studies, the mean plasma t1/2 of idelalisib was ~6.5 to 9.8 hours across all dose 
levels and there was no substantive plasma accumulation over 7 or 28 days.

The changes in exposure observed when administering idelalisib after a high-fat, 
high-calorie meal are modest (~40% increase in mean AUC with no change in mean 
Cmax). Thus, idelalisib can be administered with or without food. 

The idelalisib dose modification provisions described in the protocol are designed to 
balance a primary concern for subject safety with the potential for observing 
pharmacological and antitumor activity in circumstances under which a subject
experiencing an adverse event may still be able to continue on therapy at a lower 
idelalisib dose level. The enhanced monitoring to be performed and the actions to be 
taken in response to toxicity are based on experience with interruption, 
dose-modification, rechallenge, and re-escalation already piloted in idelalisib Phase 1 
trials. In addition, idelalisib antitumor activity has been observed in the Phase 1 studies 
across all dose levels tested, including doses in the range of the modified dose levels
planned for this protocol. Thus, use of the lower dose level to accommodate individual 
subject tolerability in this protocol is justified because subjects receiving such an
idelalisib dose level still have the potential for benefit.

In both the primary and extension studies, study treatment will be continued for each 
subject until the occurrence of disease progression. Such a strategy is considered 
appropriate under the assumption that persistent interference with PI3Ksignaling is 
likely to extend treatment effect. In addition, this design permits collection of further 
single-agent safety information and thus is likely to enhance understanding of the overall 
safety profile of idelalisib. 


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6.
STUDY PROCEDURES
Enrollment and Study Management Procedures
6.1.
6.1.1.
Subject Recruitment
Study candidates are limited to those subjects who participated in the primary clinical trial
(Study GS-US-312-0116) and meet the entry criteria for this trial (Study GS-US-312-0117).
Subjects will be enrolled from investigational sites in the United States and Europe. The site 
principal investigator, designated sub-investigators, or other designees will discuss the 
possibility of participation directly with subjects who participated in the primary study. 
The study sponsor will post a description of the study on the ClinicalTrials.gov website. Any 
promotional information generated by the sponsor or investigational sites will be submitted 
for IRB/IEC review.
6.1.2.
Subject Compensation for Participation
For subjects requesting such assistance, reasonable reimbursements for the costs of travel 
required to participate in this study will be provided by the study sponsor. To receive 
payment for travel, subjects will need to submit the original travel receipts to the research 
study staff at the investigational site.
However, other than medical care that may be provided, subjects will not be paid for 
participation in the study. Payments for such items as lost wages, disability, discomfort due 
to injury, or meals obtained while waiting at the clinical research center will not be provided. 
Through the informed consent process, study candidates will be notified that their insurance 
company could be charged for standard care that is a component of this research study and 
that subjects may be responsible for co-payments and deductible payments that are typical 
for their insurance coverage.
6.1.3.
Screening
The investigator must inform each prospective subject of the nature of the study, explain the 
potential risks, and obtain written informed consent from the subject and/or a legal guardian 
prior to performing any study-related screening procedures. At the time the study candidate 
signs the informed consent, a site representative should access the IWRS to indicate that a 
study candidate is being screened. The user will need to supply the IWRS with required 
information identifying the site and the subject number as already assigned in 
Study GS-US-312-0116.
Any consented subject who is excluded from the study before initiation of study treatment
will be considered a screen failure. All screen failures must be documented along with an 
adequate description of the reason the subject was considered a screen failure. If available, 
information should be provided as to why the subject did not meet eligibility criteria, 
withdrew consent, experienced an intercurrent illness, or had other events that precluded 
treatment on this study.


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Explanation of Study Visits
6.2.
The specific study procedures to be conducted for each subject enrolled in the study are 
presented in tabular form in Appendix 7 and are described in the sections that follow.
Additional information on the study procedures is provided in the study manual.
For visits at which HRQL and healthy utility data are obtained, it is important that the subject
be administered the FACT-Leu and the EQ-5D before any other procedures are performed 
and before any study-related information is communicated to the subject; this is necessary to 
avoid biasing the PRO responses provided by the subject. Once the subject has completed the 
FACT-Leu and the EQ-5D assessments, the remaining procedures may be performed.
At visits involving idelalisib administration and pharmacokinetic sampling in the clinic, care 
should be taken to perform procedures with the appropriate timing relative to idelalisib
administration. The actual sample collection times of pharmacokinetic blood specimens 
should be recorded. If a heparinized venous catheter is placed for sample collection in order 
to avoid repeated needle sticks, at least 2 mL of blood should be removed and discarded prior 
to each sample collection in order to avoid heparin contamination of the sample.
At the visit designated as a laboratory-only visit (Visit 7), subjects will have laboratory 
assessments that may be performed at the investigational site or at an accredited local 
laboratory or clinic that is convenient for the subject/caregiver. If blood is collected at a local 
laboratory, samples are not to be analyzed at the local laboratory. For these visits, subjects 
and/or caregivers will be provided with central laboratory kits that will contain materials 
necessary for the collection and shipment of the laboratory samples by the local laboratory 
clinic to the central laboratory.
Local lab results may be requested in the event central laboratory results are not available for 
assessment of disease response, progression, or the evaluation of a significant event.
In addition to clinical assessments of tumor status, CT or MRI imaging of the neck, chest, 
abdomen, and pelvis will be performed as a component of tumor assessments during the 
study based on the rationale provided in Section 3.2.1.
Following unblinding of the study, subjects who were randomized to idelalisib on 
Study GS-US-312-0116 will not be required to have study visits 3, 5, and 7 performed and 
will follow local standard of care for follow-up imaging. Subjects who were randomized to 
placebo on Study GS-US-312-0116, enroll on GS-US-312-0117 and delay initiation of 
idelalisib will follow local standard of care for follow-up imaging until initiation of idelalisib, 
at which time the per-protocol schedule will be followed.


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6.2.1.
Visit 1 and Screening Period (Clinic Visit)
The initial screening visit is designated as Visit 1. At Visit 1, the investigator must inform 
each prospective study participant of the nature of the study, explain the potential risks, and 
obtain written informed consent from the study candidate and/or legal guardian prior to 
performing any study-related screening procedures. Once the informed consent document has 
been signed, the subject may undergo the screening procedures.
In order to optimize scheduling convenience for the subject and for the investigational staff, 
study procedures performed as part of Study GS-US-312-0116 need not be repeated and can 
be used as screening procedures for Study GS-US-312-0117 if performed within 4 weeks 
prior to initiation of study drug therapy on Study GS-US-312-0117. In addition, screening 
procedures may be performed over as many days as necessary provided that screening is 
completed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117. 
The tests and evaluations outline in Table 6-1 will be performed at Visit 1 or during the 
screening period prior to initiation of study treatment.


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Table 6-1.
Procedures and Assessments at Visit 1 (During Screening Period)
Assessment 
or Procedure
Explanationa
Informed consent
To be obtained before any screening procedures are initiated
IWRS access
Access IWRS to document that subject is in screening and provide the subject number
from Study GS-US-312-0116
CIRS assessment
Recording of current comorbid conditions using the CIRS scoring instrument
(see Appendix 6)
Concomitant
medications
Recording of ongoing concomitant medication use
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including height, weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Serum β-HCG
Women of childbearing potential only
CLL peripheral 
blood evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 12 trisomy; 
DNA mutational analysis for p53, IgHV (including IgHV3-21), and other genes of 
interest in CLL (eg, Notch); flow cytometry for CD5, CD10, CD11c, CD19, CD20, 
CD23, CD38, CD45, kappa and lambda light chains, and ZAP-70; cytology for 
karyotyping.
CLL serology
Serum 2 microglobulin
 
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, 
total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, 
cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by 
flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis, to be scheduled with 4 weeks 
prior to initiation of study treatment at Visit 2
Bone marrow 
biopsy and aspirate
To be performed at investigator discretion to determine extent of CLL involvement and 
bone marrow cellularity.
a
Study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be used as screening 
procedures for Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117.
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase,
AST=aspartate aminotransferase, CIRS=cumulative illness rating scale, CLL=chronic lymphocytic leukemia, CT=computed 
tomography, DNA=deoxyribonucleic acid, FISH= fluorescence in-situ hybridization, GGT=gamma--glutamyltransferase, 
Ig=immunoglobulin, IgHV=immunoglobulin heavy chain variable region, IWRS=interactive web response system, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, RNA=ribonucleic acid, ZAP-70=zeta-associated 
protein 70
PPD


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6.2.2.
Visit 2 (Day 1) (Clinic Visit)
Subjects will be assessed to determine if they still meet eligibility criteria and can initiate 
study treatment. Study drug holds from primary study GS-US-312-0116 may continue as 
medically appropriate. The procedures outlined in Table 6-2 will be performed at 
Visit 2 (Day 1).
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1)
Assessment or 
Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the 
subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant 
medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly
β-HCG
For women of child-bearing potential only; serum -HCG or urine dipstick pregnancy test must 
be negative prior to initial study treatment
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides
Idelalisib
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the date 
and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration
Study drug 
administrationa
First dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib
pharmacokineticsa
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after study 
drug administration (with recording of the date and actual clock time of blood collection)
Study drug dispensinga
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration
at home
Instruction regarding 
study drug dosing at 
next full clinic visita
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 3.
a
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll on Study GS-US-312-0117 following 
unblinding may have idelalisib treatment (and associated PK testing) delayed at the Investigator’s discretion until the 
time of disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib 
treatment
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web 
response system, LDH=lactate dehydrogenase, RNA=ribonucleic acid


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6.2.3.
Visit 3 (Day 15) (Clinic Visit)
The procedures outlined in Table 6-3 will be performed at Visit 3 (Day 15 [±2 days]). 
Table 6-3.
Procedures and Assessments at Visit 3 (Day 15)
Assessment or 
Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the 
subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant 
medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib
pharmacokinetics
Recording of the date and actual clock time of the last prior subject self-administration of study 
drug (should be the prior evening dose)Pre-dose collection of plasma sample for idelalisib
pharmacokinetics (with recording of the date and actual clock time of the date and actual clock 
time of blood collection)
IWRS access
Access of IWRS to document subject visit
Study Therapy Administration
Study drug 
administration
Study drug to be administered to the subject (with recording of the date and actual clock time of 
the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after study 
drug administration (with recording of the date and actual clock time of blood collection)
Instruction regarding 
study drug dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 4.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase,
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, 
LDH=lactate dehydrogenase


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6.2.4.
Visit 4 (Day 29) (Clinic Visit)
The procedures outlined in Table 6-4 will be performed at Visit 4 (Day 29 [±2 days]).
Table 6-4.
Procedures and Assessments at Visit 4 (Day 29)
Assessment or 
Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 3
Concomitant 
medications
Recording of concomitant medication used since Visit 3
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration and Dispensing
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection)
Study drug 
dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home
Instruction regarding 
dosing at next full 
clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 5.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed 
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging


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6.2.5.
Visit 5 (Day 43) (Clinic Visit)
The procedures outlined in Table 6-5 will be performed at Visit 5 (Day 43 [±2 days]). 
Table 6-5.
Procedures and Assessments at Visit 5 (Day 43)
Assessment or 
Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant 
medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, 
total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, 
cholesterol, triglycerides
IWRS access
Access of IWRS to document subject visit
Study Therapy Administration
Study drug 
administration
Study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration)
Post-Therapy Procedures and Assessments
Instruction 
regarding study drug 
dosing at next full 
clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the 
day of Visit 6.
Scheduling of 
Visit 6 radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 6.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, HRQL=health-
related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, LDH=lactate 
dehydrogenase


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6.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit)
The procedures outlined in Table 6-6 will be performed at Visit 6 (Day 57 [±2 days]). 
Table 6-6.
Procedures and Assessments at Visit 6 (Day 57)
Assessment or 
Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; 
the assessment should be done even if study drug has been interrupted. 
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 5
Concomitant 
medications
Recording of concomitant medication used since Visit 5
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, 
total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, 
cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and CD+20 
cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow 
biopsy and aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for CR, it 
is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish CR.


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Assessment or 
Procedure
Explanation
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of 
the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug bottle number
Study Therapy Administration
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and 
actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after 
study drug administration (with recording of the date and actual clock time of blood 
collection)
Study drug 
dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for self-
administration at home
Instruction 
regarding dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the 
day of Visit 8.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging
6.2.7.
Visit 7 (Day 71) (Laboratory Visit)
The procedures outlined in Table 6-7 will be performed at Visit 7 (Day 71 [±2 days]).
Table 6-7.
Procedures and Assessments at Visit 7 (Day 71)
Assessment or 
Procedure
Explanation
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including ALT, AST, ALP, GGT, total bilirubin, LDH
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
GGT=gamma-glutamyltransferase, LDH=lactate dehydrogenase
6.2.8.
Visit 8 (Day 85) (Clinic Visit)
The procedures outlined in Table 6-8 will be performed at Visit 8 (Day 85 [±2 days]).


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Gilead Sciences, Inc.
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Table 6-8.
Procedures and Assessments at Visit 8 (Day 85)
Assessment or 
Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 6
Concomitant 
medications
Recording of concomitant medication used since Visit 6
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, 
total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, 
cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by 
flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of 
the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration and Dispensing
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and 
actual clock time of the study drug administration)


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 3.0
CONFIDENTIAL
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10 September 2013
Assessment or 
Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after 
study drug administration (with recording of the date and actual clock time of blood 
collection)
Study drug 
dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for self-
administration at home
Instruction 
regarding dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the 
day of Visit 9.
Scheduling of 
Visit 9 radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 9.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed 
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging


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6.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit)
The procedures outlined in Table 6-9 will be performed at Visit 9 (Day 113 [±3 days]).
Table 6-9.
Procedures and Assessments at Visit 9 (Day 113)
Assessment or 
Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit 
the assessment should be done even if study drug has been interrupted.
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 8
Concomitant 
medications
Recording of concomitant medication used since Visit 8
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, 
total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, 
cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and CD+20 
cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow 
biopsy and aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for CR, it 
is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish CR.


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 3.0
CONFIDENTIAL
Page 88
10 September 2013
Assessment or 
Procedure
Explanation
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of 
the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and 
actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after 
study drug administration (with recording of the date and actual clock time of blood 
collection)
Study drug 
dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for self-
administration at home
Instruction 
regarding dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the 
day of Visit 10.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


Idelalisib
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Gilead Sciences, Inc.
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6.2.10.
Visit 10 (Day 141) (Clinic Visit)
The procedures outlined in Table 6-10 will be performed at Visit 10 (Day 141 [±3 days]) 
Table 6-10.
Procedures and Assessments at Visit 10 (Day 141)
Assessment or 
Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 9
Concomitant 
medications
Recording of concomitant medication used since Visit 9
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last prior subject
self-administration of study drug (should be the prior evening dose)
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug  blister card number
Study Therapy Administration
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection)
Study drug 
dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home
Instruction regarding 
dosing at next full 
clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 11.
Scheduling of 
Visit 11 radiology
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 11.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed 
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging


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Version 3.0
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10 September 2013
6.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit)
The procedures outlined in Table 6-11 will be performed at Visit 11 (Day 169 [±3 days]). 
Table 6-11.
Procedures and Assessments at Visit 11 (Day 169)
Assessment or 
Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; 
the assessment should be done even if study drug has been interrupted. 
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant 
medications
Recording of concomitant medication used since Visit 10
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, 
total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, 
cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by 
flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow 
biopsy and aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for CR, it 
is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish CR.


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 3.0
CONFIDENTIAL
Page 91
10 September 2013
Assessment or 
Procedure
Explanation
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of 
the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study Therapy Administration
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and 
actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after 
study drug administration (with recording of the date and actual clock time of blood 
collection)
Study drug 
dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for self-
administration at home.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment 
of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 3.0
CONFIDENTIAL
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10 September 2013
6.2.12.
Visit 12 (Day 211) (Clinic Visit)
The procedures outlined in Table 6-12 will be performed at Visit 12 (Day 211 [±3 days]) 
Table 6-12.
Procedures and Assessments at Visit 12 (Day 211)
Assessment or 
Procedure
Explanation
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 11
Concomitant 
medications
Recording of concomitant medication used since Visit 11
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, 
total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, 
cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by 
flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit
Study drug 
administration
Subject to continue with study drug as prescribed.
Scheduling of 
Visit 13 radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 13.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed 
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 3.0
CONFIDENTIAL
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10 September 2013
6.2.13.
Visit 13 (Day 253) (Clinic and Radiology Visit)
The procedures outlined in Table 6-13 will be performed at Visit 13 (Day 253 [±3 days]). 
Table 6-13.
Procedures and Assessments at Visit 13 (Day 253)
Assessment or 
Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the 
assessment should be done even if study drug has been interrupted. 
During-Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant 
medications
Recording of concomitant medication used since Visit 10
Study drug 
return/accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy 
and aspirate
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR.
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study drug 
administration
Subject to continue with study drug as prescribed.
Study drug 
dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for self-administration 
at home.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 3.0
CONFIDENTIAL
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10 September 2013
6.2.14.
Visit 14 (Day 295) (Clinic Visit)
The procedures outlined in Table 6-14 will be performed at Visit 14 (Day 295 [±3 days]) 
Table 6-14.
Procedures and Assessments at Visit 14 (Day 295)
Assessment or 
Procedure
Explanation
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant 
medications
Recording of concomitant medication used since Visit 10
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, 
total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, 
cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by 
flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit
Study drug 
administration
Subject to continue with study drug as prescribed.
Scheduling of 
Visit 15 radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 15.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed 
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 3.0
CONFIDENTIAL
Page 95
10 September 2013
6.2.15.
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks) (Clinic and 
Radiology Visits)
The procedures outlined in Table 6-15 will be performed at Visit 15 (Day 337 [±3 days]) and 
every 12 weeks thereafter [±7 Days]).
Table 6-15.
Procedures and Assessments at Visit 15 and Subsequent Visits
(Day 337 and Every 12 Weeks)
Assessment or 
Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology 
assessmenta
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; 
the assessment should be done even if study drug has been interrupted.
During-Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since prior visit
Concomitant 
medications
Recording of concomitant medication used since prior visit
Study drug 
return/accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, 
total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, 
cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by 
flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM


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Assessment or 
Procedure
Explanation
Bone marrow 
biopsy and aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for CR, it 
is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish CR.
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study drug 
administration
Subject to continue with study drug as prescribed.
Study drug 
dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for self-
administration at home
Scheduling of next 
visit radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for next clinic 
visit (every 12 weeks).
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging
6.2.16.
End-of-Study Visit (Clinic Visit)
At the time of discontinuation from the study, the subject should have the procedures and 
assessments performed as documented in Table 6-16. An end-of-study CT/MRI tumor 
assessment should be performed unless the subject already has radiographic confirmation of 
definitive disease progression 4 weeks prior to study discontinuation. 


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Table 6-16.
Procedures and Assessments at End-of-Study Visit
Assessment or 
Procedure
Explanation
Radiology 
assessmenta
CT or MRI imaging of neck, chest, abdomen, and pelvis
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are performed
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed
Adverse events 
Recording of adverse events occurring since prior visit; if a clinically significant adverse event 
or abnormal result is observed that is not resolved by the end-of treatment visit, repeat 
evaluations should be performed to document resolution or stabilization of the abnormality
Concomitant 
medications
Recording of concomitant medication used since prior visit
Study drug 
return/accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly
Serum β-HCG
Women of childbearing potential only
CLL peripheral 
blood evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 12 trisomy; DNA 
mutational analysis for p53, IgHV (including IgHV3-21), and other genes of interest in CLL 
(eg, Notch); flow cytometry for CD5, CD10, CD11c, CD19, CD20, CD23, CD38, CD45, 
kappa and lambda light chains, and ZAP-70; cytology for karyotyping
CLL serology
Serum 2 microglobulin
 
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS
Access IWRS to document that subject has permanently discontinued study therapy and to 
indicate whether subject agrees to continue to undergo long-term follow-up
a
An end-of-study CT/MRI tumor assessment should be performed unless the subject has per-protocol CT/MRI 
assessments 4 weeks prior to end-of-study discontinuation.
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, CLL=chronic lymphocytic leukemia, CT=computed tomography, FISH= fluorescence 
in-situ hybridization, GGT=gamma-glutamyltransferase, IgHV=immunoglobulin heavy-chain variable-region, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, 
RNA=ribonucleic acid, ZAP-70=zeta-associated protein 70
PPD


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6.2.17.
30 Day and Long-Term Follow-up
A 30 Day follow-up visit will be performed 30 (+ 5) days following the end-of-study visit; 
however, it may be waived for subjects who have permanently discontinued study drug and 
have had a study visit > 30 days after the last dose of study drug.
Long-term, follow-up will be requested of all subjects who withdraw from study for any 
reason.
The long-term follow-up for survival will be conducted  at ~6-month intervals for 5 years, 
starting at the end-of-study visit. Information may be gathered during a routine clinic visit or 
other contact with the subject, or via telephone.
Sample Storage
6.3.
 
 
 
 
 
  
Blood Collection
6.4.
. The maximum amount of blood to be drawn at a visit ~115 mL and the total amount of 
blood to be drawn over the initial 52-week study period (including the 4-week screening 
period and through Week 48 of the study including a possible end-of-therapy visit) is 
~560 mL. For a 40-kg person (the smallest participant expected to enroll in the study), this 
equates to maximum blood volume per body weight per visit of ~2.8 mL/kg and a total blood 
volume per body weight per average 6-week period of ~1.6 mL/kg. These quantities of blood 
are within accepted limits of 3.0 mL/kg of body weight for a single blood draw and 
7.0 mL/kg of body weight for a 6-week period [National Institutes of Health 2003].
Specific details regarding blood sample collection and processing requirements will be 
provided separately in the study manual.
 
 
PPD
PPD


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Study Procedure Rationale
6.5.
The planned study assessments and timing have been selected as appropriate for screening of 
subjects, for determination of idelalisib-related or disease-related toxicities, for dose 
modification during the study, for characterization of drug exposure and desired 
pharmacological effects, and for evaluation of drug activity. The scheduling of testing is 
designed to collect a complete safety and pharmacology data set while maintaining subject
tolerance of study procedures. The planned schedule of tumor assessments is consistent with 
expected rate of changes and appropriately balances precise measurement of tumor control 
with the expense and subject inconvenience associated with clinical and radiological 
procedures. For discussion of the rationale for endpoint selection, see Section 3.2.


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7.
EFFICACY ASSESSMENTS
Tumor Status Assessments
7.1.
The determination of CLL response and progression will be based on standardized IWCLL
criteria [Hallek 2008], as specifically modified for this study to reflect current 
recommendations which consider the mechanism of action of idelalisib and similar drugs 
[Cheson 2012]. Treatment decisions by the investigator in this study will be based on these 
assessments. Radiographic and clinical tumor assessments will be subject to independent 
confirmation by the IRC (see Section 10.4.3).
Method of Assessment
7.2.
In addition to clinical examination, imaging-based evaluation will be used in this study in all 
subjects enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI 
scanning may be used at the investigator’s discretion in subjects for whom this may be a 
preferred alternative to CT scanning; however, if MRI is performed, a non-contrast CT of the 
chest should be performed. Contrast-enhanced scanning is preferred, but iodine-containing or 
gadolinium contrast material may be omitted in subjects for whom use of a contrast agent 
would be medically contraindicated. Chest x-ray, ultrasound, endoscopy, laparoscopy, PET, 
radionuclide scans, or tumor markers will not be considered for response assessment.
For radiographic evaluations, the same method of assessment and the same technique 
(eg, scan type, scanner, subject position, dose of contrast, injection/scan interval) should be 
used to characterize each identified and reported lesion at baseline and during study 
treatment and follow-up. However, if a subject is imaged without contrast at baseline, 
subsequent assessments should be performed with contrast, unless the subject cannot tolerate 
the contrast.
All relevant clinical and radiographic information required to make each tumor status 
assessment must be made available for source verification and for submission to the IRC 
(see Section 10.4.3).
Timing of Assessments
7.3.
All baseline clinical and CT/MRI tumor assessments should be performed within 4 weeks
prior to initiation of study drug therapy. In order to optimize scheduling convenience for the 
subject and for the investigational staff, clinical and CT/MRI tumor assessments performed 
as part of Study GS-US-312-0116 need not be repeated and can be used as baseline tumor 
assessments for Study GS-US-312-0117 if performed within 4 weeks prior to initiation of 
study drug therapy on Study GS-US-312-0117. Clinical tumor assessments should be 
performed at each clinical visit. On-study CT/MRI tumor assessments should be performed 
at ~8- to 12-week intervals as dictated by the study protocol. An end-of-study CT/MRI tumor 
assessment should be performed unless the subject has per-protocol CT/MRI assessments 
4 weeks prior. If a subject permanently discontinues study drug prior to objective 
documentation of CLL progression, investigators should continue further follow-up at 
~12-week intervals until CLL progression is documented by the central IRC.


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Identification and Measurement of Tumor Lesions and Organomegaly
7.4.
7.4.1.
Index Lesions
At baseline, up to 6 lymph nodes should be selected as index lesions that will be used to 
quantitate the status of the disease during study treatment. Ideally, the index lesions should 
be located in disparate regions of the body. Only peripheral nodes need be selected as index 
lesions. However, it is optimal if mediastinal and retroperitoneal areas of disease are assessed 
whenever these sites are involved.
Index lesions will be measured and recorded at baseline and at the stipulated intervals. The 
cross-sectional dimensions (the largest cross-sectional diameter, ie, the LD × LPD) will be 
recorded (in cm) for each index lesion. The product of the perpendicular diameters (PPD) 
(in cm2) for each index lesion and the sum of the products (SPDs) (in cm2) for all index 
lesions will be calculated and recorded. The baseline SPDs will be used as references by 
which tumor response will be characterized during treatment. The nadir LD of individual 
lesions and the nadir SPD will be used as references by which CLL progression will be 
characterized. All LD and LPD diameters will be reported in centimenters and all PPDs and 
SPDs will be reported in centimeters squared.
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable 
at baseline. A lymph node lesion is considered abnormal if it has a single diameter that is 
1.5 cm and is considered measurable if it has 2 perpendicular diameters that can be 
accurately measured in cross section with the LD being 1.0 cm and the LPD also being 
1.0 cm.
At follow-up time points, the LDs for individual lesions and the SPD of all nodal index 
lesions will be considered. Because nodal index lesions that have one or both diameters 
>0 cm and 1.0 cm cannot be reliably measured, a default value of 1.0 cm will be assigned 
for each diameter that meets these criteria and the resulting PPD will be used in SPD 
calculations. Based on this convention, a CR may be achieved even if an SPD value is 
>0 cm2, (ie, if all lymph nodes measure <1.0 cm2).
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD will be considered 
progressive disease.
In cases in which a large lymph node mass has split into multiple components, all 
subcomponents regardless of size will be used in calculating the SPD. Progression of the 
lesion will be based on the SPD of sub-components. Lesion sub-components will have the 
true PPDs calculated. Similarly, lesion sub-components that are visible but neither abnormal 
nor measurable will have the default PPD of 1.0 cm2 (1.0 cm 1.0 cm) used in calculating 
the SPD.
If lesions merge, a boundary between the lesions will be established so the LD of each 
individual lesion can continue to be measured. If the lesions have merged in a way that they 
can no longer be separated by this boundary, the newly merged lesion will be measured 
bi-dimensionally.


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7.4.2.
Spleen and Liver
Both the spleen and liver will be assessed by CT/MRI scan at baseline and at the stipulated 
intervals during treatment. The baseline and nadir values for the longest vertical dimension 
(LVD) of each organ will be used as reference to further characterize the objective tumor 
response of the measurable dimensions of the CLL during treatment. All spleen and liver 
LVD measurements should be recorded in centimeters.
By imaging, the spleen will be considered enlarged if it is >12 cm in LVD [Bezerra 2005, 
Asghar 2011].  
For subjects with splenomegaly at baseline or at the splenic LVD nadir, respective response 
and progression evaluations of the spleen will consider only changes relative to the 
enlargement of the spleen at baseline or nadir, not changes relative to the total splenic LVD. 
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen in its LVD 
or decrease to ≤12 cm in the LVD, is required for declaration of a splenomegaly response. 
Conversely, an increase in splenic enlargement by ≥50% from nadir (with a minimum 2 cm 
increase) is required for declaration of splenic progression. 
By imaging, the liver will be considered enlarged if it is >18 cm in LVD [Erturk 2006].
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the liver in its LVD or 
decrease to ≤ 18 cm in the LVD is required for declaration of a hepatomegaly response. 
Conversely, an increase in liver enlargement by ≥50% from nadir (with a minimum 2 cm 
increase) is required for declaration of hepatic progression.
7.4.3.
Non-Index Lesions
Any other measurable and abnormal nodal lesions not selected for quantitation as index 
lesions may be considered non-index lesions. In addition, non-measurable evidence of CLL 
such as nodal lesions with both diameters <1.0 cm, extra-nodal lesions, bone lesions, 
leptomeningeal disease, ascites, pleural or pericardial effusions, lymphangitis of the skin or 
lung, abdominal masses that are not confirmed and followed by imaging techniques, cystic 
lesions, previously irradiated lesions, lesions with artifacts, and may be considered as 
non-index disease.
The presence or absence of non-index disease should be recorded at baseline and at the 
stipulated intervals during treatment. If present at baseline, up to 6 non-index lesions should 
be recorded. The non-index disease at baseline will be used as a general reference to further 
characterize regression or progression of CLL during assessments of the objective tumor 
response during treatment. Measurements are not required and these lesions should be 
followed as “present” or “absent”.


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Definitions of Tumor Response and Progression
7.5.
Responses will be categorized by the IRC as CR, PR, SD, or PD. In addition, a response 
category of not evaluable (NE) is provided for situations in which there is inadequate 
information to otherwise categorize response status. A response category of no disease (ND) 
is included for situations in which there is absence of tumor both at baseline and on 
treatment.
The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until disease/recurrence progression (taking as a 
reference for disease progression the smallest measurements recorded since treatment 
started). Subjects with a best overall response of NE or ND will be counted in the 
denominators in calculations of tumor response rates.
7.5.1.
Complete Response
To satisfy criteria for a CR, all of the following criteria must be met:

No evidence of new disease

ALC in peripheral blood of <4 x 109/L

Regression of all index nodal masses to normal size (1.5 cm in the LD)

Normal spleen and liver size

Regression to normal of all nodal non-index disease and disappearance of all detectable 
non-nodal, non-index disease

Morphologically negative bone marrow defined as <30% of nucleated cells being 
lymphoid cells and no lymphoid nodules in a bone marrow sample that is normocellular 
for age

Peripheral blood counts meeting all of the following criteria:
— ANC >1.5 x 109/L without need for exogenous growth factors (eg, G-CSF)
— Platelet count 100 x 109/L without need for exogenous growth factors
— Hemoglobin 110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (eg, erythropoietin)
Note: Subjects who fulfill all the criteria for a CR (including bone marrow criteria) but 
who have a persistent anemia, thrombocytopenia, or neutropenia or a hypocellular bone 
marrow that is related to prior or ongoing drug toxicity (and not to CLL) will be 
considered as a CR with incomplete marrow recovery (CRi).


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7.5.2.
Partial Response
To satisfy criteria for a PR, all of the following criteria must be met:

No evidence of new disease

A change in disease status meeting 2 of the following criteria, with 2 exceptions in 
which only 1 criterion is needed: (1) Only lymphadenopathy is present at baseline; 
(2) Only lymphadenopathy and lymphocytosis are present at baseline. In these 2 cases, 
only lymphadenopathy must improve to the extent specified below:
— In a subject with baseline lymphocytosis (ALC4 x 109/L), a decrease in peripheral 
blood ALC by 50% from baseline or a decrease to <4 x 109/L
— A decrease by 50% from the baseline in the SPD of the index nodal lesions
— In a subject with enlargement of the spleen at baseline, a splenomegaly response, 
defined as a ≥ 50% decrease (minimum 2 cm) from baseline in the enlargement of the 
spleen or decrease to ≤12 cm in the LVD by imaging
— In a subject with enlargement of the liver at baseline, a hepatomegaly response, 
defined as a ≥ 50% decrease (minimum 2 cm) from baseline in the enlargement of the 
liver or decrease to ≤18 cm in the LVD by imaging
— A decrease by 50% from baseline in the CLL marrow infiltrate or in B-lymphoid 
nodules

No index, splenic, liver, or non-index disease with worsening that meets the criteria for 
definitive PD

Peripheral blood counts meeting 1 of the following criteria:
— ANC >1.5 x 109/L or 50% increase over baseline without need for exogenous 
growth factors (eg, G-CSF)
— Platelet count 100 x 109/L or 50% increase over baseline without need for 
exogenous growth factors
— Hemoglobin 110 g/L (11.0 g/dL) or 50% increase over baseline without red blood 
cell transfusions or need for exogenous growth factors (eg, erythropoietin)
7.5.3.
Stable Disease
To satisfy criteria for stable disease (SD), the following criteria must be met:

No evidence of new disease

There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD


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7.5.4.
Definitive Progressive Disease
The occurrence of any of the following events indicates definitive PD:

Evidence of any new disease:
— A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD
— New or recurrent splenomegaly, with a minimum LVD of 14 cm
— New or recurrent hepatomegaly, with a minimum LVD of 20 cm
— Unequivocal reappearance of an extra-nodal lesion that had resolved   
— A new unequivocal extra-nodal lesion of any size
— New non-index disease (eg, effusions, ascites, or other organ abnormalities related to 
CLL)
Note: Isolated new effusions, ascites, or other organ abnormalities are not sufficient 
evidence alone of PD unless histologically confirmed. Thus, a declaration of PD should 
not be made if this is the only manifestation of apparently new disease.

Evidence of worsening of index lesions, spleen or liver, or non-index disease:
— Increase by 50% from the nadir in the SPD of index lesions
— Increase from the nadir by 50% in the LD of an individual node or extra-nodal mass 
that now has an LD of >1.5 cm and an LPD of > 1.0 cm
— Splenic progression, defined as an increase in splenic enlargement by 50% from 
nadir (with a minimum 2 cm increase and a minimum LVD of 14 cm)
— Hepatic progression, defined as an increase in hepatic enlargement by 50% from 
nadir (with a minimum 2 cm increase and minimum LVD of 20 cm)
— Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or other 
organ abnormalities related to CLL) 
— Transformation to a more aggressive histology (eg, Richter syndrome) as established 
by biopsy (with the date of the biopsy being considered the date of CLL progression 
if the subject has no earlier objective documentation of CLL progression).


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
Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to 
an autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an 
infiltrate of clonal CLL cells
— The current platelet count is <100 x 109/L and there has been a decrease by 
>50% from the highest on-study platelet count 
— The current hemoglobin is <110 g/L (11.0 g/dL) and there has been a decrease by 
>20 g/L (2 g/dL) from the highest on-study hemoglobin
Note: If there is uncertainty regarding whether there is true progression, the subject 
should continue study treatment and remain under close observation (eg, evaluated at 
4-week intervals) pending confirmation of progression status by the IRC. In particular, 
worsening of constitutional symptoms in the absence of objective evidence of worsening 
CLL will not be considered definitive disease progression; in such subjects, both 
CLL-related and non-CLL-related causes for the constitutional symptoms should be 
considered. Worsening of disease during temporary interruption of study treatment 
(eg, for intercurrent illness) is not necessarily indicative of resistance to study treatment. 
In these instances, CT/MRI or other relevant evaluations should be considered in order to 
document whether definitive disease progression has occurred. If subsequent evaluations 
suggest that the subject has experienced persistent definitive CLL progression, then the 
date of progression should be the timepoint at which progression was first objectively 
documented.
7.5.5.
Non-Evaluable
In a subject who does not have evidence of PD, the occurrence of any of the following 
conditions indicates a response status of NE: 

There are no images or inadequate or missing images

Images of the liver and spleen are missing at that time point (with the exception that 
absence of splenic images will not result in an NE designation in a subject known to have 
undergone splenectomy).
Note: A time-point will be considered to have a response of NE if any index lesion is 
missing. PD may be assigned at any time point regardless of the extent of missing index or 
non-index lesions. Missing non-index lesions will not impact the ability to assess for 
response or disease progression.
7.5.6.
No Disease
Subjects have a status of ND if all of the following conditions occur:

No index disease noted at baseline or on-treatment 

No non-index disease noted at baseline or on-treatment.


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
No enlargement of the liver or spleen at baseline or on-treatment

No abnormalities of peripheral blood counts (elevated ALC or abnormally low ANC, 
platelet count, or hemoglobin) and no evidence of CLL in bone marrow (if available) at 
baseline or on treatment
7.5.7.
Lymphocytosis During Therapy
Idelalisib can mobilize CLL cells from tissues into the peripheral blood. This characteristic 
pharmacological action can be prominent early in therapy but can persist over time and 
should not be confused with disease progression in subjects who have persistent control of 
other CLL-related signs and symptoms. In the absence of other objective evidence of 
disease progression, lymphocytosis alone will not preclude subjects from meeting the 
criteria for PR if other criteria for PR are met and will not be considered evidence of 
disease progression if occurring in isolation. Subjects with lymphocytosis should be 
continued on study drug until the occurrence of definitive disease progression
(ie, disease progression that is manifest by worsening CLL-related signs other than 
lymphocytosis alone), or the occurrence of another reason to discontinue study therapy as 
described in Section 5.8.
7.5.8.
Documentation of Definitive CLL Progression
Of importance, CLL response and progression data collected from the primary study will be 
subjected to IRC review (see Section 10.4.3). Subjects must have confirmation by the 
sponsor working in collaboration with the IRC that the disease has progressed on the 
primary clinical trial (Study GS-US-312-0116) before being permitted to receive secondary 
idelalisib therapy on this extension trial ( GS-US-312-0117). Subjects should continue study 
drug pending confirmation of progression status. CT/MRI should be attempted in order to 
document definitive disease progression by the IRC. The end-of study scan from the primary 
study can serve as the baseline scan for the extension study if obtained within the specific 
screening period for the extension study. If obtained within the specified screening period for
the extension study, this scan can serve as the baseline scan for the extension study.


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8.
SAFETY ASSESSMENTS
Adverse Event Definitions
8.1.
8.1.1.
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical product which; does not necessarily have a causal relationship 
with study drug administration or usage. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product. AEs may also include pre- or post-treatment complications that 
occur as a result of protocol specified procedures, lack of efficacy, overdose, drug 
abuse/misuse reports, or occupational exposure. Preexisting events that increase in severity 
or change in nature during or as a consequence of participation in the clinical study will also 
be considered AEs.
An AE does not include the following:

Lymphocytosis

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and 
transfusion. The condition that led to the procedure may be an adverse event and must be 
reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before 
the screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization 
for elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 5.2.8)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not 
an AE. It is considered to be pre-existing and should be documented on the medical 
history CRF.
In this study, any of the following events will be considered an adverse event:

Any complication that occurs as a result of a protocol-mandated procedure 
(eg, venipuncture, biopsy) in the screening, on-treatment, or post-treatment periods.


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
Any pre-existing condition that increases in severity or changes in nature during or as a 
consequence of study drug administration. Worsening manifestations of the underlying 
cancer (eg, increase in pain, tumor flare reaction, tumor lysis syndrome) may be 
considered adverse events in this study.

Any injury or accident occurring during the screening, on-treatment, or post-treatment 
periods. If a medical condition is known to have caused the injury or accident (eg, a fall 
secondary to dizziness), the medical condition (dizziness) and the accident (fall) should 
be reported as 2 separate adverse events. 

Any abnormality in physiological testing or a physical examination finding that requires 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test).

Any laboratory (eg, clinical chemistry, hematology, urinalysis) or investigational  
abnormality (eg, ECG, X-ray) independent of the underlying medical condition that 
requires clinical intervention, results in further investigation (beyond ordering a repeat 
[confirmatory] test), or leads to investigational medicinal product interruption or 
discontinuation unless it is associated with an already reported clinical event. If the 
laboratory abnormality is part of a syndrome, the syndrome or diagnosis (eg, anemia) not 
the laboratory result (eg, decreased hemoglobin) should be recorded. 

A complication related to pregnancy or termination of a pregnancy (see Section 5.4.9 for 
additional information).
8.1.2.
Serious Adverse Event
A serious adverse event (SAE) is defined as an event that results in any of the following:

Death

Life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the subject was at risk of death at the time of the event; it does 
not refer to an event that hypothetically might have caused death if it were more severe.) 

In-patient hospitalization or prolongation of existing hospitalization.  

Persistent or significant disability/incapacity.

A congenital anomaly/birth defect
— A medically important event or reaction. Such events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or 
may require intervention to prevent one of the outcomes listed above.Examples of 
such events might include:Allergic bronchospasm requiring intensive treatment in an 
emergency room or at home


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— New cancers or blood dyscrasias
— Convulsions that do not result in hospitalization
— Development of drug dependency or drug abuse
Medical and scientific judgment must be exercised to determine whether such an event is 
reportable under expedited reporting rules. 
Infections resulting from contaminated medicinal product will be considered a medically 
important event and subject to expedited reporting requirements.
Given the endpoints of the study, in order to maintain the integrity of the study the following 
events that are assessed as unrelated to IMP will not be considered SAEs:

Progression of CLL

Death related to progression of CLL
Disease progression and death from disease progression should be reported as SAEs by the 
investigator only if it is assessed that the IMPs caused or contributed to the disease 
progression (i.e., by a means other than lack of effect). Unrelated disease progression and 
death due to disease progression should be captured on the eCRF.
These events will be reported, as appropriate, in the final clinical study report and in any 
relevant aggregate safety reports. The safety information from this study will also be 
reviewed by an independent DMC on an ongoing basis. The DMC can have access to 
partially blinded or unblinded data in order to determine if it is safe to continue the study 
according to the protocol.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Section 8.5.  If the laboratory abnormality is part 
of a syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result 
(ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 5.4.


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Assessment of Adverse Events and Serious Adverse Events
8.2.
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event 
information and assessments.
8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to 
IMP therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, 
an alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally 
related in the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or 
biopsy) should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
Investigator Requirements and Instructions for Reporting Adverse 
8.3.
Events and Serious Adverse Events to Gilead
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to 
the CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. 
This also includes any SAEs resulting from protocol-associated procedures performed from 
screening onwards.
All AEs, regardless of cause or relationship, that occur from initiation of study medication 
until 4 weeks after last administration of study IMP must be reported to the CRF/eCRF 
database as instructed. 
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of 
the last dose of study IMP, regardless of causality, should also be reported. 


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All AEs should be followed up until resolution if possible. If by the last day on study 
(including the off-study medication follow-up period) the AE has not resolved, then the AE 
will be followed up until the investigator and/or Gilead Sciences determine that the subject's 
condition is stable. However, Gilead Sciences may request that certain AEs be followed until 
resolution.
Investigators are not obligated to actively seek SAEs after the above period. However, if the 
investigator learns of any SAEs that occur after study participation has concluded and the 
event is deemed relevant to the use of IMP, he/she should promptly document and report the 
event to Gilead DSPH.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines 
outlined in the CRF/eCRF completion guideline. 

At the time of study start, SAEs will be reported using a paper serious adverse event 
reporting form. During the study conduct, sites may transition to an electronic SAE 
(eSAE) system. Gilead will notify sites in writing and provide training and account 
information prior to implementing an eSAE system.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by 
faxing the report form within 24 hours of the investigator’s knowledge of the event to the 
attention of Gilead DSPH or to the designated CRO.
Gilead Reporting Requirements
8.4.
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to 
expedite to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions 
(SADRs), or suspected unexpected serious adverse reactions (SUSARs). In accordance with 
the EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify 
worldwide regulatory agencies and the relevant IEC in concerned Member States of 
applicable SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the IRB or IEC of SUSAR reports as soon as is practical, where 
this is required by local regulatory agencies, and in accordance with the local institutional 
policy.


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Grading of the Severity of an Adverse Event
8.5.
The severity of adverse events will be graded using the CTCAE, Version 4.03 (provided in 
study manual and available at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). 
For each episode, the highest severity grade attained should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 
(fatal) to describe the maximum intensity of the adverse event. For purposes of consistency 
with the CTCAE, these intensity grades are defined in Table 8-1.
Table 8-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Sign or symptom is present, but it is easily tolerated, is not expected to have a 
clinically significant effect on the subject’s overall health and well-being, does not 
interfere with the subject’s usual function, and is not likely to require medical 
attention.
Grade 2
Moderate
Sign or symptom causes interference with usual activity or affect clinical status, 
and may require medical intervention.
Grade 3
Severe
Sign or symptom is incapacitating or significantly affects clinical status and likely 
requires medical intervention and/or close follow-up.
Grade 4
Life-threatening
Sign or symptom results in a potential threat to life.
Grade 5
Fatal
Sign or symptom results in death.
The distinction between the seriousness and the severity of an adverse event should be noted. 
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. 
For example, a headache may be severe in intensity, but would not be classified as serious 
unless it met one of the criteria for serious events listed in Section 8.1.2 above.
Adverse Event Reporting Period
8.6.
The start of the adverse event reporting for a study subject will coincide with signing of the 
informed consent for Study GS-US-312-0117. Any new adverse events occurring thereafter 
should not be reported within Study GS-US-312-0116, but instead should be reported within
Study GS-US-312-0117. The end of the adverse-event-reporting period for 
Study GS-US-312-0117 occurs 30 days after the discontinuation from study drug or when 
any ongoing drug-related adverse events and/or serious adverse events have resolved or 
become stable. A subject withdrawn from the study because of an adverse event must be 
followed until the clinical outcome from the adverse event is determined. The investigator 
should use appropriate judgment in ordering additional tests as necessary to monitor the 
resolution of events ongoing at the completion of study treatment. Gilead Sciences may 
request that certain adverse events be followed longer.


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Investigators are not obligated to actively seek information regarding the occurrence of new 
serious adverse events beginning after the 30-day post-study period. However, if the 
investigator learns of such a serious adverse event and that event is deemed relevant to the 
use of the study drug, he/she should promptly document and report the event. A longer 
reporting period applies in the case of pregnancy (see Section 8.9.1)
Adverse Event Reporting Requirements
8.7.
8.7.1.
Site Reporting Requirements
Classification of an event as serious or nonserious (see Section 8.1.2) determines the 
reporting procedures to be followed by the site. 
Site reporting requirements for adverse events are summarized in Table 8-2, below.
Table 8-2.
Site Reporting Requirements for Adverse Events
Classification
Reporting Time
Reporting Action
Serious
Within 24 hours
Fax report on designated serious adverse event report form to 
PPD Pharmacovigilancea, and to the site IRB/IEC, as per local IRB/IEC 
requirements; include copies of relevant source documentsb (eg, progress 
notes, autopsy reports, laboratory and diagnostic test results, discharge 
summaries) in communication to PPD Pharmacovigilancea
Per eCRF submission 
procedurec
Record and submit information on appropriate eCRFs
Nonserious
Per eCRF submission 
procedure
Record and submit information on appropriate eCRFs
a
See contact information in Table 8-3 below.
b
Subject name, address, and other personal identifiers should be obscured but without losing the traceability of a 
document to the study subject identifiers.
c
CLL progression or death due to CLL progression should be reported by the investigator as a serious adverse event 
only if it is assessed that the study drugs caused or contributed to the CLL progression (ie, by a means other than lack 
of effect). Unrelated events of CLL progression should be captured on the appropriate eCRF. 
Abbreviations: CLL = chronic lymphocytic leukemia, eCRF=case report form, IRB/IEC= Institutional Review 
Board/Independent Ethics Committee
For serious adverse events, in addition to completing the adverse event portion of the eCRF, 
the serious adverse event report form must also be completed. The information in the adverse 
event portion of the eCRF page and the serious adverse event report form(s) must match or 
be reconciled. Where the same data are collected, the forms must be completed in a 
consistent manner. For example, the same adverse event term should be used on both forms.
Particularly for fatal or life-threatening events, copies of progress notes, autopsy reports, 
laboratory and diagnostic test results, discharge summaries, and other relevant documents 
should be faxed when requested and applicable. Follow-up information to the serious adverse 
event should be clearly documented as “follow up” in the serious adverse event report form 
and must be faxed to these same parties. Gilead Sciences may request additional information 
from the investigator to ensure the timely completion of accurate safety reports.


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The subject’s name, address, and other personal identity information should be obscured on 
any source documents (eg, progress notes, nurses’ notes, laboratory and diagnostic test 
results, discharge summaries). Only the subject’s study number, initials, or date of birth are 
to be provided.
The serious adverse event report form must be communicated to PPD Pharmacovigilance and 
to the site IRB/IEC (if required by local regulations) within 24 hours. In the rare event that 
the investigator does not become aware of the occurrence of a serious adverse event 
immediately (for example, if a subject initially seeks treatment elsewhere), the investigator is 
to report the event within 24 hours after learning of it and to document his/her first awareness 
of the adverse event.
Contact details for PPD Pharmacovigilance and for the Gilead study medical monitor are 
provided in Table 8-3:
Table 8-3.
Contact Information for Reporting Serious Adverse Events
Function
Contact Information
PPD Pharmacovigilance
(US)
Facsimile:
 
PPD Pharmacovigilance 
(International)
Facsimile:
Gilead Sciences Medical 
Monitor
Name:
 
Title:
Associate Director, Clinical Research
Office Telephone:
Mobile Telephone:
Facsimile:
E-mail:
8.7.2.
Reporting of Adverse Events Relating to the Primary Endpoint and 
Other Anticipated Medical Events in the Study Population
To maintain the integrity of the study, progression of CLL and death related to progression of 
CLL will not be reported to Gilead Sciences as serious adverse events unless it is assessed 
that the study drug caused or contributed to CLL progression or death related to CLL 
progression (ie, by a means other than lack of effect). These events will be exempt from 
global expedited reporting requirements for the duration of the study because they define the 
primary efficacy endpoint for this study. All events of progression of CLL and death related 
to progression of CLL, regardless of relationship to study drug, will be reported in the eCRFs 
and, as appropriate, in the final clinical study report and in any relevant aggregate safety 
reports.  Disease progression information from this study will be reviewed by an independent 
DMC on an ongoing basis. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Special Situations Reporting Requirements 
8.8.
8.8.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, lack 
of effect reports and pregnancy reports regardless of an associated AE.  Also includes reports 
of adverse reactions in infants following exposure from breastfeeding, and reports of adverse 
reactions associated with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following possible maternal or paternal 
exposure to the medicinal product.
Medication error is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product while in the control of the health care provider, subject, or consumer. 
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by 
a subject.
Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a 
medicinal product given per administration or cumulatively which is above the maximum 
recommended dose as per protocol or in the product labelling (as it applies to the daily dose 
of the subject in question). In cases of a discrepancy in drug accountability, overdose will be 
established only when it is clear that the subject has taken the excess dose(s). Overdose 
cannot be established when the subject cannot account for the discrepancy except in cases in 
which the investigator has reason to suspect that the subject has taken the additional dose(s).
Lack of effect is defined as a situation where there is apparent failure of the medicinal 
product or medical technology to bring about the intended beneficial effect on the individual 
in a defined population with a given medical problem, under ideal conditions of use. 
Product complaint is defined as complaints arising from potential deviations in the 
manufacture, packaging, or distribution of the medicinal product.  
Instructions for Reporting Special Situations
8.9.
8.9.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first 
consents to participate in the study (ie, signs the informed consent) and throughout the study, 
including the post study drug follow-up period, to the  or Gilead DSPH ] using the pregnancy 
report form within 24 hours of becoming aware of the pregnancy. Refer to the CRF/eCRF 
completion guidelines for full instructions on the mechanism of pregnancy reporting.


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The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate 
a pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as 
an SAE. The underlying medical reason for this procedure should be recorded as the AE 
term.
A spontaneous abortion is always considered to be an SAE, and therefore should be reported 
as such. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must 
be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to or Gilead DSPH using the pregnancy outcome 
report form. If the end of the pregnancy occurs after the study has been completed, the 
outcome should be reported directly to Gilead DSPH. Gilead DSPH contact information is as 
follows: Email: 
 and Fax: 
 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to or Gilead DSPH using 
the pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject 
should continue until the conclusion of the pregnancy. If the end of the pregnancy occurs 
after the study has been completed, the outcome should be reported directly to Gilead DSPH, 
fax number 
 or email 
8.9.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to  or Gilead DSPH  within 24 hours of the investigator becoming aware of the 
situation. These reports must consist of situations that involve study IMP, but do not apply to 
concomitant medications. Except for situations that result in AEs, special situations involving 
concomitant medications will not be reported. Any inappropriate use of medications 
prohibited by this protocol should not be reported as “misuse,” but may be more 
appropriately documented as a protocol deviation.
All clinical sequelae in relation to these special situation reports will be reported as AEs or 
SAEs at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the 
symptoms and signs, clinical management, and outcome will be reported, when available.
PPD
PPD
PPD
PPD


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9.
STATISTICAL CONSIDERATIONS
Analysis Objectives
9.1.
As described in Section 3, the objectives of this clinical trial will focus on determining the 
effect of idelalisib on the onset, magnitude, and duration of tumor control; measures of 
patient well-being (including OS, HRQL; and changes in subject performance status); 
disease-associated biomarkers and potential mechanisms of resistance; treatment 
administration; safety; and health resource utilization. The study will be analyzed when 
Study GS-US-312-0116 is unblinded.
Analysis Endpoints
9.2.
The endpoints of the study are defined in Section 3.1, grouped in categories relating to tumor 
control, patient well-being, pharmacodynamic markers of drug activity and resistance, 
exposure, safety, and pharmacoeconomics.
Analysis Conventions
9.3.
9.3.1.
Analysis Sets
9.3.1.1.
Intent-to-Treat Analysis Set
The ITT analysis set includes all subjects who receive 1 dose of any study treatment 
(high-dose idelalisib or standard-dose idelalisib). In the ITT analysis set, study drug 
assignment will be designated according to planned allocation in this study, regardless of 
whether subjects receive a different study therapy from that to which they were allocated. 
This analysis set will be used in the analyses of subject characteristics and all the tumor 
control and patient well-being endpoints. Subjects in the ITT analysis set who do not have 
sufficient baseline or on-study tumor status information to be adequately assessed for 
response status will be included in the denominators in the calculation of response rates. 
9.3.1.2.
Per-Protocol Analysis Set
The PP analysis set includes data from subjects in the ITT analysis set who meet the general 
criteria defining the target population for this study, are adherent to the protocol, are 
compliant with study drug treatment, and are evaluable for relevant efficacy endpoints. 
Treatment assignment will be designated according to the actual treatment received. The 
specific classification of subjects to be included in the PP analysis set will be included in the 
statisticial analysis plan which will be finalized prior to the database lock. 
The PP analysis set will be used in sensitivity analyses of these tumor control and patient 
well-being endpoints: PFS, ORR, lymph node response rate, OS and CR rate.


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9.3.1.3.
Safety Analysis Set
A safety analysis set will include subjects in the ITT analysis set grouped for analyses with 
treatment assignments designated according to the actual study drug received. 
This analysis set will be used in the analyses of safety variables as well as study treatment 
administration, and health economic variables.
9.3.1.4.
Pharmacodynamic and/or Pharmacokinetic Analysis Sets
The pharmacodynamic and/or pharmacokinetic analysis sets include data from subjects in the 
safety analysis set who have the necessary baseline and on-study measurements to provide 
interpretable results for the specific parameters of interest. 
These analysis sets will be used in the analyses of AKT phosphorylation, 
chemokines/cytokines, and idelalisib plasma concentrations.
9.3.2.
Data Handling Conventions
9.3.2.1.
General Methods 
By-subject listings will be created for important variables from each eCRF module. 
Summary tables for continuous variables will contain the following statistics: N (number in 
population), n (number with data), mean, standard deviation, 95% confidence intervals (CIs)
on the mean, median, minimum, and maximum. Summary tables for categorical variables 
will include: N, n, percentage, and 95% CIs on the percentage. Unless otherwise indicated, 
95% CIs for binary variables will be calculated using the binomial distribution 
(exact method) and will be 2-sided. Data will be described and summarized by relevant 
treatment arm, analysis set, and timepoint. As appropriate, changes from baseline to each 
subsequent timepoint will be described and summarized by treatment arm. Similarly, as 
appropriate, the best change from baseline during the study will also be described and 
summarized by treatment arm. Graphical techniques (eg, waterfall plots, Kaplan-Meier 
curves, line plots) may be used when such methods are appropriate and informative. 
Time-to-event analyses will be performed with reference to the date of first treatment on this 
clinical trial (Study GS-US-312-0117). Similarly, evaluations of on-therapy changes will 
reference the baseline values obtained prior to treatment in this study. The baseline value 
used in each analysis will be the last (most recent) pre-treatment value. Data from all sites 
will be pooled for all analyses. Analyses will be based upon the observed data unless 
methods for handling missing data are specified. If there is a significant degree of 
non-normality, analyses may be performed on log-transformed data or nonparametric tests 
may be applied, as appropriate. 
Analyses will generally focus on evaluation of outcomes within each treatment arm; formal 
analyses comparing outcomes in Arm A to those in Arm B are not planned. Unless otherwise 
specified, all analyses will be 2-sided at the 0.05 level of significance. 


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9.3.2.2.
Calculation of Tumor Control and Patient Well-Being Variables
Tumor control assessments will be based on standardized IWCLL criteria [Hallek 2008]
[Cheson 2012], as specifically modified for this study considering the pharmacology of 
idelalisib. The individual and composite endpoints of response and progression 
(considering changes in lymph node area, liver and spleen size, bone marrow, platelet counts, 
hemoglobin, neutrophil counts, and peripheral blood lymphocyte counts) will be determined.
Tumor control will be documented at each assessment by response category (eg, CR, PR, SD, 
definitive PD, NE, ND) as defined for each response parameter, SPD value, percentage 
change in SPD values from baseline or nadir, date that response is first documented and date
of definitive CLL progression. 
The date of definitive CLL progression will be the timepoint at which progression is first 
identified by relevant objective radiographic or laboratory data. Because of the characteristic 
redistribution lymphocytosis that is expected with PI3Kinhibition, lymphocyte count will 
be ignored in the evaluation of progression. Changes in tumor status as provided by the 
investigator and changes in tumor status as adjudicated by the IRC (see Section 10.4.3) will 
be described. The findings of the IRC will be considered primary for analyses of all tumor 
control endpoints.
The following censoring conventions will be applied:

PFS and DOR: Data from surviving, non-progressing subjects will be censored at the 
earliest of the time of initiation of antitumor treatment other than the study treatment or 
the last time that lack of definitive CLL progression was objectively documented. Data 
from subjects who have CLL progression or die after 2 consecutive missing tumor 
assessments will be censored at the last time prior to the missing assessments that lack of 
definitive CLL progression was objectively documented.

OS: Data from surviving subjects will be censored at the last time that the subject was 
known to be alive. 
Analysis Plan
9.4.
9.4.1.
Subject Disposition and Baseline Characteristics
A listing of all ITT analysis subjects will be generated to describe site, subject number, 
first screening date, first treatment date, allocated study drug assignment, actual study drug 
assignment, the longest duration of study drug treatment, and the reason for discontinuing 
study treatment. Available information on subjects who were screened or registered but not 
treated will be listed separately. A table will be created summarizing these categories in 
terms of number and percent for the ITT analysis set.


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Subject baseline characteristics will be listed and summarized by treatment arm for the ITT 
analysis set. As appropriate for the specific variable, subject baseline characteristics acquired 
in Study GS-US-312-0116 will be referenced in Study GS-US-312-0117. Subject 
characteristics between Arm A and Arm B may be compared using the Wilcoxon rank-sum 
test for continuous variables and the Fisher’s exact test for categorical variables. Similarly, 
within each arm, subject characteristics between GS-US-312-0116 and GS-US-312-0117 
may also be compared.
9.4.2.
Efficacy Analyses
9.4.2.1.
Time-to-Event Tumor Control and Survival Endpoints
PFS, DOR and OS will be described in the ITT analysis set using Kaplan-Meier methods by 
treatment group. Medians, ranges, and corresponding 95% CIs will be presented.
The Cox regression approach may be used to explore the influence of the primary study 
stratification factors and other baseline characteristics on PFS and OS. The stratification 
variables from the primary study and additional baseline subject characteristics may be 
included as covariates, focusing on those with expected prognostic significance. 
9.4.2.2.
Categorical Endpoints 
Response rates, lymph node response rate, splenomegaly response rate, hepatomegaly
response rate, ALC response rate, platelet response rate, hemoglobin response rate, and 
neutrophil response rate will be described. In the calculation of response rates, subjects who 
do not have sufficient baseline or on-study tumor assessment to characterize response will be 
included in the denominator. For all analyses, the corresponding 95% CIs will be presented.
The potential influence of subject baseline characteristics on response rates may be explored
with multiple logistic regression modeling.
9.4.2.3.
Continuous Endpoints
Changes in lymph node area and changes in performance status, PI3K/AKT/mTOR pathway 
activation, and plasma chemokines/cytokines will be assessed by treatment group. Both 
changes from baseline to each subsequent timepoint and best overall on-study changes will 
be analyzed using appropriate methods (eg, analysis of covariance [ANCOVA] or paired 
t-tests). Means and standard errors will be presented.
9.4.2.4.
Health-Related Quality of Life and Performance Status
The FACT-Leu questionnaire data will be scored and processed according to the user 
manual. Missing items in a subscale will be imputed consistent with the user manual 
instructions. Data collected from the FACT-Leu instrument will not be reconciled with 
adverse event or laboratory data or with EQ-D5 findings.


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Because a significant portion of the study subjects will have CLL disease progression during 
the course of the study and no HRQL or performance status data will be collected after 
disease progression, the duration of data collection for these variables will vary among the 
study subjects. Hence, at each HRQL or performance status assessment timepoint, changes 
from baseline in HRQL parameters or in performance status in the 2 treatment groups will be 
described by treatment group. considering both: 1) all subjects that have baseline and at least 
one post-baseline assessment for HRQL or performance status with the worst score assigned 
to those subjects who have progressed or died at the timepoint, and 2) all subjects that have 
baseline and at least one post-baseline assessment for HRQL or performance status who have 
not progressed or died at the timepoint. Subjects who are lost-to-follow-up without disease 
progression will be excluded, ie, missing data will not be imputed. 
9.4.3.
Exposure and Safety Analyses
9.4.3.1.
Treatment Administration and Study Drug Compliance
Descriptive information will be provided by treatment arm regarding the number of doses of 
study therapy prescribed, the total number of doses taken, the percent of expected doses 
taken, the number of days of treatment, and the number and timing of prescribed dose
reductions and interruptions.
Study drug compliance will be described by treatment arm in terms of the proportion of study 
drug actually taken based on returned pill count relative to the amount that was dispensed 
(taking into account physician-prescribed reductions and interruptions).
9.4.3.2.
Idelalisib Plasma Concentrations
Bioanalytical analyses will performed independently so that the study team and investigators 
will not have knowledge of data from individual subjects. Idelalisib plasma concentrations 
immediately pre-dose and at 1.5 hours after administration of the dose of study drug at each 
relevant clinic visit will be summarized by treatment and visit using descriptive statistics.
9.4.3.3.
Prior, Concomitant, and Post-Treatment Medication Use
Prior, concomitant, and post-treatment medications will be coded by means of the World 
Health Organization Drug Dictionary (WHODRUG) dictionary into 
Anatomical-Therapeutic-Chemical classification (ATC) codes.
Descriptions of prior medication use will be focused on drugs and regimens used as 
treatments for CLL. Information regarding CLL therapy that was administered prior to 
Study GS-US-312-0116 will be referenced in reporting the results of Study
GS-US-312-0117. In addition, relevant treatment administration information collected during 
Study GS-US-312-0116 will be referenced in reporting the results of this study. As 
appropriate and if available, information on the sequencing, type, dose, schedule, timing, 
duration of use, and efficacy of prior regimens will be provided, focusing particularly on 
findings observed in Study GS-US-312-0116.


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The type and timing of use of concomitant medications will be listed and summarized by 
type and treatment arm. Information regarding the type and use of specific supportive 
medications (eg, pneumocystis prophylaxis, hematopoietic growth factors, corticosteroids) 
during study treatment will be described.
The number, type, and timing of post-study-treatment regimens for CLL will be summarized 
by treatment arm, characterizing the disposition of all subjects who were eligible for 
post-study treatment and also those who were not eligible for post-study treatment 
(eg, subjects who are never treated at all, die while on study treatment, are still on study, are 
lost to follow-up, etc).
9.4.3.4.
Adverse Events
All adverse events will be listed. The focus of adverse event summarization will be on 
treatment-emergent adverse events. A treatment-emergent adverse event is defined as an 
adverse event that occurs or worsens in the period from the first dose of study treatment to 
30 days after the last dose of study treatment. 
Adverse events will be classified using MedDRA (http://www.meddramsso.com) with 
descriptions by System Organ Class, High-Level Group Term, High-Level Term, Preferred 
Term, and Lower-Level Term. The severity of adverse events will be graded by the 
investigator according to the CTCAE, Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf), 
whenever possible. If a CTCAE criterion does not exist for a specific type of adverse event, 
the grade corresponding to the appropriate adjective will be used by the investigator to 
describe the maximum intensity of the adverse event: Grade 1 (mild), Grade 2 (moderate), 
Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the 
adverse event to the study drug will be categorized as related or unrelated.
Treatment-emergent adverse events will be summarized by treatment arm and by visit. 
Summary tables will be presented to show the number of subjects reporting 
treatment-emergent adverse events by severity grade and corresponding percentages. A 
subject who reports multiple treatment-emergent adverse events within the same Preferred 
Term (or System Organ Class) is counted only once for that Preferred Term (or System 
Organ Class) using the worst severity grade. Adverse event descriptions will be presented by
decreasing frequency for a given System Organ Class and Preferred Term.
Separate listings and summaries will be prepared for the following types of 
treatment-emergent adverse events:

Study-drug-related adverse events

Adverse events that are Grade 3 in severity

Adverse events leading to study drug interruption and/or dose modification


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
Adverse events leading to study drug discontinuation

Serious adverse events (with categorization of the primary reason that the adverse event
is considered serious, eg, death, hospitalization, etc)
Separate listings and summaries will be prepared for long-term follow-up safety data 
(see Section 6.2.17).
9.4.3.5.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed 
data. The focus of laboratory data summarization will be on treatment-emergent laboratory 
abnormalities. A treatment-emergent laboratory abnormality is defined as an abnormality 
that, compared to baseline, worsens by 1 grade in the period from the first dose of study 
drug to 30 days after the last dose of study drug. If baseline data are missing, then any graded 
abnormality (ie, an abnormality that is Grade 1 in severity) will be considered treatment 
emergent. Hematological, serum biochemistry, and urine data will be programmatically 
graded according to CTCAE severity grade, when applicable. For parameters for which a 
CTCAE scale does not exist, reference ranges from the central laboratory will be used to 
determine programmatically if a laboratory parameter is below, within, or above the normal 
range for the subject’s age, sex, etc.
Hematological and serum biochemistry and their changes from baseline will be summarized 
by treatment arm and by visit. Summary tables will be presented for each relevant assay to 
show the number of subjects by CTCAE severity grade with corresponding percentages. For 
parameters for which a CTCAE scale does not exist, the frequency of subjects with values 
below, within, and above the normal ranges will be summarized. Subjects will be 
characterized only once for a given assay, based on their worst severity grade observed 
during a period of interest (eg, during the study or from baseline to a particular visit).
Shift tables for hematology and serum biochemistry will also be presented by showing 
change in CTCAE severity grade from baseline to the worst grade post baseline. Separate 
listings and summaries will be prepared for laboratory abnormalities that are Grade 3 in 
severity.
9.4.3.6.
Oxygen Saturation Values
All oxygen saturation data will be listed. Summaries of oxygen saturation data will be based 
on observed data and will be reported as % saturation. Data and changes from baseline will 
be summarized by treatment arm and by visit. Summary tables will be presented for values 
below 92% and for declines from baseline of 5% to show the number of subjects with 
corresponding percentages. Subjects will be characterized only once for each of these 
categorizations, based on their lowest value observed during a period of interest 
(eg, during the study or from baseline to a particular visit).


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9.4.4.
Other Analyses
9.4.4.1.
Between-Study Comparisons
It is expected that patients with a progressive malignancy like CLL will normally fare better 
with an earlier therapy than with a later therapy. However, if the converse situation proves 
true – eg, if an investigational treatment (idelalisib) administered later shows similar or 
greater benefit than a standard treatment (rituximab) administered earlier – strong evidence 
of investigational drug effect is demonstrated. Evaluating data derived from the same study 
subjects during their sequential participation in 2 clinical trials offers unique analytical 
challenges. However, in this integrated Phase 3 study program, it is likely that comparing 
baseline characteristics and outcomes among Arm B subjects participating in Study 
GS-US-312-0116 and Study GS-US-312-0117 will be informative. Such an evaluation
characterizes how the subjects and the CLL disease process change with time and treatment. 
In addition, such an analysis provides relevant supporting information documenting the 
benefits of single-agent idelalisib relative to single-agent rituximab in the same subjects.
Accordingly, the subject baseline characteristics at the start of Study GS-US-312-0116 
relative to those at the start of Study GS-US-312-0117 will be evaluated. Subject baseline 
characteristics between the studies may be compared using the Wilcoxon rank-sum test for 
continuous variables and the Fisher’s exact test for categorical variables. 
Time-to-event efficacy variables (eg, PFS, TTR, DOR, time to performance status, or HRQL 
changes) will be evaluated using the paired Prentice-Wilcoxon test, comparing results in 
Study GS-US-312-0116 to those in Study GS-US-312-0117 among subjects who participate 
in Arm B of both studies. Within each study period, medians, ranges, hazard ratios and 
corresponding 95% CIs will be presented using Kaplan Meier methods. As appropriate, Cox 
regression techniques may be used to explore the influence of baseline characteristics on 
treatment differences when comparing these outcomes between the studies. For categorical 
variables (eg, ORR, lymph node response rate, splenomegaly response rate, hepatomegaly 
response rate), the Wilcoxon signed-rank test will be employed to compare outcomes 
between Study GS-US-312-0116 and Study GS-US-312-0117 for Arm B subjects. For all 
analyses, odds ratios and the corresponding 95% CIs will be presented. Differences between 
studies for Arm B subjects relating to continuous variables (eg, percentage changes in lymph 
node area; changes in performance status, PI3K/AKT/mTOR pathway activation and plasma 
chemokines/cytokines) will be analyzed using appropriate methods (eg, analysis of 
covariance [ANCOVA] or paired t-tests). Means and standard errors will be presented. As 
appropriate, the potential influence of subject baseline characteristics on treatment effects 
may be explored with multiple logistic regression techniques.
9.4.4.2.
Health Care Resource Utilization
The EQ-D5 questionnaire data will be scored, processed, and standardized according to the 
user manual. As for the FACT-Leu, data will be analyzed using appropriate methods to 
account for incomplete completion of questionnaires. Data collected from the EQ-D5 will not 
be reconciled with adverse event or laboratory data or with FACT-Leu findings.


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Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach to the health economic analysis will be to combine the resource 
utilization data from the trial with data on unit prices (collected separately) to estimate total 
costs. 
The perspective of this analysis will be that of the third-party payer(s) and the hospital over a 
lifetime horizon in the base case. The costs will be described relative to the health care 
findings as measured by duration of tumor control, the symptom-free survival period, 
life-years, utility outcomes, or other measure of appropriate clinical benefits. In order to 
facilitate the calculation of utilities for use in the cost effectiveness analyses, the health status 
of subjects will be evaluated using PFS, Karnofsky performance status, FACT-Leu, and 
EQ-5D.
9.4.4.3.
Data Explorations
Changes in biomarkers during acquisition of resistance will be evaluated descriptively. Data 
explorations may be performed to evaluate potential associations between subject
characteristics and outcome measures. Explorations may be performed to assess the potential 
associations between different outcomes measures (eg, relationships between HRQL changes 
and clinical/radiographic endpoints of tumor control).
Sample Size
9.5.
The sample size for this extension study is not based upon a formal statistical hypothesis. The 
upper bound of the sample size in this study is determined by the sample size of the 
preceding primary study (Study GS-US-312-0116) in which ~160 subjects (~80 per arm) are 
expected to be enrolled. It is estimated that this extension study (Study GS-US-312-0117) 
will have a total idelalisib-treated N~130 (assuming a ~10% dropout rate during 
Study GS-US-312-0116 and a further ~10% dropout rate in the transition from the primary 
study to the extension study).
Timing of Analyses
9.6.
9.6.1.
Interim Analysis
The DMC will have access to serious adverse events requiring expedited reporting and will 
be provided with accumulating safety data on a regular basis. Interim safety reviews will be 
conducted by the DMC in conjunction with safety reviews of the primary clinical trial
(Study GS-US-312-0116). Thus, interim safety reviews will be performed by the DMC at 
intervals of ~6 months; the specific frequency of these reviews will depend upon the rate at 
which the trials are enrolled, the nature of any emerging safety signals, and monitoring 
recommendations from the DMC. At each review, all available safety data will be 
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An interim efficacy analysis of this clinical trial (Study GS-US-312-0117) is planned to take 
place at the time of the final analysis of the primary study (GS-US-312-0116). The intent is 
to provide the data from this extension study in support of regulatory review of data from the 
primary study. The blind will be broken to the study team at Gilead Sciences for analysis 
purposes. However, the study will be continued to obtain further follow-up efficacy and 
safety information; individual subjects, caregivers, and site personnel will not be informed of 
the treatment assignments until the implications of revealing such data for the overall 
idelalisib study program have been determined.
9.6.2.
Final Analysis
An additional, final analysis of efficacy and safety may be performed to satisfy regulatory 
requirements and to perform long-term efficacy, safety and OS follow-up. The timing of this 
analysis is expected to occur within 36 months of accrual of the final subject to 
Study GS-US-312-0117.


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10.
RESPONSIBILITIES
Investigator Responsibilities
10.1.
10.1.1.
Compliance with Ethical and Regulatory Guidelines
The investigator will ensure that this study is conducted in accordance with the principles of 
the “Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), with ICH guidelines, or with the laws and regulations of the country in which 
the research is conducted, whichever affords the greater protection to the study subject.
These standards are consistent with the European Union Clinical Trials Directive 
2001/20/EC and Good Clinical Practice Directive 2005/28/EC. The investigator will ensure 
adherence to the basic principles of GCP as outlined in 21 CFR 312, subpart D, 
“Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, 
part 56, 1998.
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 
1993, “Retention of Bioavailability and Bioequivalence Testing Samples.”
Because this is a “covered” clinical trial, the investigator will ensure adherence to 21 CFR, 
Part 54, 1998; a covered clinical trial is any “study of a drug or device in humans submitted 
in a marketing application or reclassification petition subject to this part that the applicant or 
FDA relies on to establish that the product is effective (including studies that show 
equivalence to an effective product) or that make a significant contribution to the 
demonstration of safety.” This requires that investigators and all sub-investigators must 
provide documentation of their financial interest or arrangements with Gilead Sciences, or 
proprietary interests in the drug being studied. This documentation must be provided before 
participation of the investigator and any subinvestigator in the trial. The investigator or 
subinvestigator agrees to notify Gilead Sciences of any change in reportable financial 
interests during the study and for 1 year following completion of the study. Study completion 
is defined as the date that the last subject has completed the protocol-defined activities.
10.1.2.
Institutional Review Board/Independent Ethics Committee
This protocol and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) will be submitted by the investigator to an IRB (for sites enrolling in the 
United States) and to an IEC for sites enrolling outside of the United States). Approval from 
the IRB/IEC must be obtained before starting the study and should be documented in a letter 
to the investigator specifying the protocol number, protocol version, protocol date, 
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Any modifications or amendments made to the protocol after receipt of the initial 
IRB/IECapproval must also be submitted to the IRB/IEC for approval before 
implementation. Only changes necessary to eliminate apparent immediate hazards to the 
subjects may be initiated prior to IRB/IEC approval. In that event, the investigator must 
notify the IRB/IEC and Gilead Sciences in writing within 5 working days after 
implementation.
The investigator shall submit a progress report, at least once yearly, to the IRB/IEC, and must 
provide a copy to Gilead Sciences. As soon as possible after completion or termination of the 
study, the investigator will submit a final report to the IRB/IEC and to Gilead Sciences. This 
report should include the dates of initiation and completion of the trial, a description of any 
changes in study procedures or amendments to the protocol, any deviations from the 
protocol, the number and type of subjects evaluated, the number of subjects who 
discontinued (and the reasons for discontinuation), the number of subjects who completed the 
trial, and the results of the trial, including a description of any adverse events. 
Gilead Sciences will assist the investigator in the preparation of this report, as needed.
10.1.3.
Informed Consent
After adequately, explaining the aims, methods, objectives, and potential hazards of the study 
and before undertaking any study-related procedures, the investigator is responsible for 
obtaining written informed consent from each individual participating in this study. The 
investigator must utilize an IRB/IEC-approved consent form for documenting written 
informed consent. Each informed consent will be appropriately signed and dated by the 
subject or the subject’s legally authorized representative and the person obtaining consent.
The approved informed consent must not be changed without prior approval by 
Gilead Sciences and the IRB/IEC.
10.1.4.
Confidentiality
The investigator must assure that each subject’s anonymity will be strictly maintained and 
that each subject’s identity is protected from unauthorized parties. Only subject initials, date 
of birth, and an identification code (but no subject names) should be recorded on any form or 
biological sample submitted to the Gilead Sciences or designees (eg, laboratories), or to the 
IRB/IEC. However, sufficient information must be retained at the site to permit sample data 
and data in the database to be connected with the unique subject number assigned to each 
study participant.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the idelalisib investigator brochure, this protocol, eCRFs, the investigational new 
drug, and any other study information, remain the sole and exclusive property of 
Gilead Sciences during the conduct of the study and thereafter. This information is not to be 
disclosed to any third party (except employees or agents directly involved in the conduct of 
the study or as required by law) without prior written consent from Gilead Sciences. The 
investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain.


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10.1.5.
Study Files and Retention of Records and Biological Samples
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into at least the following 2 categories: (1) investigator’s 
study file, and (2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
the IRB/IEC and governmental approval with correspondence, informed consent, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence.
The required source data referenced in the monitoring plan for the study, and should include 
sequential notes containing at least the following information for each subject:

Subject identification (name, date of birth, gender)

Documentation that subject meets eligibility criteria, eg, history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria)

Participation in trial (including trial number)

Trial discussed and date of informed consent

Dates of all visits

Documentation that protocol-specific procedures were performed

Results of efficacy parameters, as required by the protocol

Start and end date (including dose regimen) of trial medication (including relevant drug 
dispensing and return information)

Record of all adverse events and other safety parameters (including start and end date, 
causality and intensity)

Concomitant medication (including start and end date and dose if relevant dose changes 
occur)

Date of trial completion and reason for discontinuation, if applicable
All clinical study documents must be retained by the investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (ie, the United States, Europe, 
or Japan) and until there are no pending or contemplated marketing applications in an ICH 
region; or, if no application is filed or if the application is not approved for such indication, 
until 2 years after the investigation is discontinued and regulatory authorities have been 
notified. Investigators may be required to retain documents longer if required by applicable 


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regulatory requirements, by local regulations, or by an agreement with Gilead Sciences. The 
investigator must notify Gilead Sciences before destroying any clinical study records. The 
investigator will promptly notify Gilead Sciences in the event of accidental loss or 
destruction of any study records. 
Should the investigator wish to assign the study records to another party or move them to 
another location, Gilead Sciences must be notified in advance.
If the investigator cannot guarantee this archiving requirement at the study site for any or all 
of the documents, special arrangements must be made between the investigator and 
Gilead Sciences to store these in sealed containers outside of the site so that they can be 
returned sealed to the investigator in case of a regulatory audit. When source documents are 
required for the continued care of the subject, appropriate copies should be made for storage 
outside of the site.
Biological samples including tissue and blood samples collected as a study procedure or as 
standard of care during study participation will be stored and maintained by the investigator 
until notification is received from Gilead Sciences that the retained samples and records no 
longer required. The investigator must obtain written permission from Gilead Sciences before 
disposing of any retained samples. The investigator should promptly notify Gilead Sciences
in the event of accidental loss or destruction of any study samples. With the permission of 
Gilead Sciences, the retained samples may be transferred to an acceptable designee, such as 
another investigator, another institution, a contract storage site, or to Gilead Sciences.
10.1.6.
Case Report Forms
An eCRF is required and must be completed for each enrolled subject, with all required study 
data accurately recorded such that the information matches the data contained in medical 
records (eg, physicians’ notes, nurses’ notes, clinic charts, or other study-specific source 
documents). As required by the protocol, eCRFs should also be completed for those subjects 
who fail to complete the study (even during the screening period). If a subject withdraws 
from the study, the reason must be noted on the eCRF. If a subject is withdrawn from the 
study because of a treatment-limiting adverse event, thorough efforts should be made to 
clearly document the outcome. 
The eCRFs for this study will exist within a Web-based electronic data capture (EDC) 
system. After the investigator or the investigator’s designees (eg, research coordinators) have 
been appropriately trained, they will be given access to the EDC system and will enter the 
data required by the protocol into the EDC system. Any change of data will be made via the 
EDC system, with all changes tracked by the system to provide an audit trail.
The eCRF must be completed and signed by the principal investigator or subinvestigator 
(as appropriate) within a reasonable time period after data collection. This signature serves to 
attest that the information contained in the eCRF is true.


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10.1.7.
Drug Accountability 
As described in the relevant section (see Section 5.2.7), the investigator is responsible for 
ensuring adequate accountability of all used and unused investigational medicinal product, 
placebos, and comparators. This responsibility includes acknowledgment of receipt of each 
shipment of study product (quantity and condition), subject dispensing records, and returned 
or destroyed study product. Dispensing records will document quantities received from 
Gilead Sciences and quantities dispensed to subjects, including lot number, date dispensed, 
subject identifier number, subject initials, and the initials of the person dispensing the 
medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during 
the study if appropriate. At the end of the study, following final drug inventory reconciliation 
by the monitor, the study site will dispose of and/or destroy all unused investigational 
medicinal product supplies, including empty containers, according to these procedures. If the 
site cannot meet Gilead Sciences’ requirements for disposal, arrangements will be made 
between the site and Gilead Sciences or its representative for destruction or return of unused 
investigational medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by 
the study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from Gilead Sciences or its representatives, to 
IRB/IECs, and to regulatory authority or health authority inspectors. It is important that the 
investigator and relevant institutional personnel are available during monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
Sponsor Responsibilities
10.2.
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, will 
be made only by Gilead Sciences. All protocol modifications must be submitted to the 
IRB/IEC in accordance with local requirements. Except as noted in Section 10.1.2, IRB/IEC 
approval must be obtained before changes can be implemented.


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10.2.2.
Communications with Regulatory Authorities
Gilead Sciences, working either directly or through designees, will assume responsibility for 
regulatory interactions with relevant regulatory authorities. Gilead Sciences will maintain an 
IND for idelalisib in support of the study in the United States and will maintain similar 
regulatory applications with other regulatory authorities, as required for conduct of the study. 
In fulfilling this responsibility, Gilead Sciences (or a designee) will collect, assemble, and 
communicate all required regulatory documents (eg, Form FDA 1572, investigator financial 
disclosure forms, protocol and protocol amendments, investigator brochures, informed 
consent documents, annual reports) as required by regulation. Gilead Sciences (or a designee) 
will also assume responsibility for adverse event reporting to regulatory authorities as 
described in Section 8.7.2.
10.2.3.
Data Management
Electronic data capture will be used to enter study data eCRFs and to transfer the data into a 
study-specific electronic database. During the data collection process, automated quality 
assurance programs will be used to identify missing data, selected protocol violations, out-of-
range data, and other data inconsistencies. Requests for data clarification or correction will 
be forwarded to the investigative site for resolution. As appropriate, eCRFs, listings, tables, 
and SAS datasets will be provided to the investigational sites for review.
Quality assurance and quality control systems will be implemented and maintained according 
to written standard operating procedures to ensure that the data are generated, recorded, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements. Data 
collection and storage systems will provide audit trail, security mechanisms, and electronic 
signature capabilities that meet the requirements of FDA Title 21 of CFR Part 11 regarding 
electronic records and electronic signatures. 
Data security will be controlled through appropriate and specific restriction of access only to 
data and systems required by individual users to accomplish their roles in the data 
management process. Individual login and password protections will be employed at study 
sites and at Gilead Sciences or its designee. The database will exist on physically secured 
servers. Data backups will be done regularly and will be stored in separate facilities. Printed 
documents relating to the study will be secured when not under review. 
10.2.4.
Study Reporting and Publication
Gilead Sciences may make information obtained during this study available in order to 
further the scientific or business needs of the company or as required by law or regulation. In 
this regard, Gilead Sciences may provide study information to private or public organizations 
(eg, business partners, collaborators, consultants, CROs, investors, other physicians who are 
conducting similar studies, funding organizations, regulatory authorities, or other government 
authorities). 


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Gilead Sciences will prepare a clinical study report for submission to relevant regulatory 
agencies. Gilead Sciences will ensure that the report meets the standards set out in the ICH 
Guideline for Structure and Content of Clinical Study Reports (ICH E3). An abbreviated 
report may be prepared in certain cases, as appropriate.
Gilead Sciences intends that the data from this study will be presented and published. 
Gilead Sciences will work in collaboration with the principal investigators in preparing 
presentations and writing manuscripts for publication. 

Investigators may publish or present the results of the study generated by their individual 
site either with the advanced written consent of Gilead or > 2 years after the completion 
of this extension study (GS-US-312-0117) at all participating institutions.
No such communication, presentation, or publication will include Gilead Sciences’ 
confidential information (see Section 10.1.4).
The investigator will submit to Gilead Sciences any proposed publication or presentation 
along with the respective scientific journal or presentation forum prior to submission of the 
publication (at least 30 days prior to manuscripts and 15 days prior for abstracts and oral 
presentations). The investigator will comply with Gilead Sciences’ request to delete 
references to its confidential information (other than the study results) in any paper or 
presentation. If deemed necessary by Gilead Sciences, the investigator also agrees to 
withhold publication or presentation for an additional 60 days in order to obtain patent 
protection.
Joint Investigator/Sponsor Responsibilities
10.3.
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor 
must have direct access to the investigator’s source documentation in order to verify the data 
recorded in the eCRFs for consistency.
The monitor is responsible for routine review of the eCRFs at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy 
of the data being entered on them. The monitor should have access to any subject records 
needed to verify the entries on the eCRFs. The investigator agrees to cooperate with the 
monitor to ensure that any problems detected in the course of these monitoring visits are 
resolved.
10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences may conduct inspections or 
audits of the clinical study. If the investigator is notified of an inspection by a regulatory 
authority the investigator agrees to notify the Gilead Sciences medical monitor immediately. 
The investigator agrees to provide to representatives of a regulatory agency or 
Gilead Sciences access to records, facilities, and personnel for the effective conduct of any 
inspection or audit.


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10.3.3.
Public Notification of Study Conduct
Consistent with Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and 
with requirements of the International Committee of Medical Journal Editors (ICMJE) as a
condition of consideration for publication of study results, Gilead Sciences will be 
responsible for ensuring that this protocol is listed at the ClinicalTrials.gov website 
(or equivalent) and that information at the website relating to study design and conduct is 
appropriately updated during the course of the study. In order to facilitate this process, 
investigators will need to supply Gilead Sciences with appropriate contact information for 
study site personnel.
10.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. 
Should this be necessary, both parties will arrange discontinuation procedures and notify the 
appropriate regulatory authorities and IRB/IECs. In terminating the study, Gilead Sciences
and the investigator will assure that adequate consideration is given to the protection of the 
subjects’ interests. 
Study Committees
10.4.
10.4.1.
Study Steering Committee
A study steering committee (SSC) will be responsible for assisting Gilead Sciences with 
protocol development, review of any study amendments, coordination of study conduct, 
interpretation of data, and presentation and publication of study results. The SSC comprises 
the Gilead Sciences medical monitor for the study, the Gilead Sciences study director, and 
several clinicians with expertise in the care of subjects with CLL. Other specialists may be 
invited to participate as members of the SSC at any time if additional expertise is desired. 
Academic SSC members may be involved in accruing subjects to the study. The 
Gilead Sciences study director serves as the chair of the SSC. It is expected that the members 
of the SSC will be the same as those for the SSC of the primary clinical trial
(Study GS-US-312-0116). 
10.4.2.
Data Monitoring Committee
A DMC, operating autonomously from Gilead Sciences, the clinical investigators, and the 
SSC, will be responsible for providing independent recommendations to Gilead Sciences
about evolving risk-benefit observed in the course of the study and any modifications 
required during the course of the study. The DMC will consist of a biostatistician and 
2 physicians experienced in treating patients with lymphoid malignancies. The DMC will 
be chaired by one of these individuals. DMC members must not be actively involved in study 
design, conduct, or subject accrual and must not have financial, proprietary, professional, or 
other interests that may affect impartial, independent decision-making. Specialists may be 
invited to participate as non-voting members at any time if additional expertise is desired. 
The DMC will formally interact with the external SSC members through the sharing of 


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meeting minutes. Informal interactions between the DMC and external SSC members will be 
limited. The DMC will operate under a charter developed as a collaborative document 
between Gilead Sciences and the DMC. It is expected that the members of the DMC will be 
the same as those for the primary study (Study GS-US-312-0116). 
The primary responsibility of the DMC is to protect the safety and welfare of subjects 
participating in this clinical trial and to ensure the integrity of the clinical trial. In general, the 
DMC will be responsible for:

Reviewing the general progress of the study as regards subject accrual, study conduct, 
and protocol violations

Examining accumulated safety, efficacy, and other relevant data at prespecified points 
during the course of the study 

Reviewing major study design modifications prior to implementation of those 
modifications

Making recommendations concerning continuation, modification, interruption, or 
termination of each study

Advising the company on changes to informed consent documents

Proposing updates to the DMC monitoring plan, changes in the DMC membership, 
actions to be taken relating to conflict of interest or confidentiality breaches, the need for 
additional expertise during DMC deliberations, revisions to the DMC charter, or
alterations in the support provided to the DMC

Providing expert advice to the Gilead Science medical monitor on an ad hoc basis 
regarding matters such as safety concerns or diagnostic evaluations in individual subjects
Based on the results of its deliberations during the course of the study, the DMC can 
recommend appropriate actions (eg, continuation of the study unchanged, continuation of the 
study with modifications in design or monitoring plan, interruption of study accrual, study 
termination).
10.4.3.
Independent Review Committee
An IRC will be established to provide a blinded review of radiographic data and pertinent 
clinical data in order to provide expert interpretation of changes in tumor status. The IRC will 
include 1 independent board-certified radiologist and 1 independent board-certified 
hematologist or oncologist, and will be managed by a CRO selected by Gilead Sciences. The 
review of radiographic and clinical data by the IRC will be performed on an ongoing basis
until the primary analysis . The specifics of the IRC’s processes and reading methods will be 
described in an independent review charter developed by the contracted imaging facility in 
conjunction with Gilead Sciences. The same organization that is providing IRC services for 
Study GS-US-312-0116 will provide IRC services for this study. 


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11.
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12.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia 
(FACT-Leu)
Appendix 3.
Performance Status Scoring System
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D)
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Appendix 6.
Cumulative Illness Rating Scale (CIRS)
Appendix 7.
Schedule of Study Procedures


PPD
PPD
Jdelalisib 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Version 3.0 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
199 EAST BLAINE STREET 
SEATTLE, WA 98102 
STUDY ACKNOWLEDGEMENT 
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and Safety of 
Two Different Dose Levels of Single-Agent ldelalisib (GS-1101) for Previously Treated 
Chronic Lymphocytic Leukemia 
GS-US-312-0117 Version 3.0, 10 September 2013 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Gilead Sciences .MedlcaJ. 
omtor 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to 
all information provided by Gilead Sciences, Inc. I will discuss this material with them to 
ensure that they are fully informed about the drugs and the study. 
Principal Investigator 
Printed N arne 
Date 
CONFIDENTIAL 
Page 152 
Signature 
Site Number 
10 September 2013 


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Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia 
(FACT-Leu)
FACT-Leu (Version 4) 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
GPI 
GP2 
GP3 
GP4 
GP5 
GP6 
GP7 
GSI 
GS2 
GS3 
GS4 
GS> 
GS6 
PHYSICAL WELL-BEING 
I have a lack of energy 
I have nausea ............................................................... . 
Because of my physical condition, I have trouble 
meeting the needs of my family .............................. . 
I have pain ...... ............... . 
I am bothered by side effects of treatment 
I feel ill ................ .................................... .. 
J am forced to spend time in bed 
SOCIAL/FAMILY WELL-BEING 
I feel close to my friends ... 
I get emotional support from my family 
I get support from my friends ............ . 
My family has accepted my illness .. 
I am satisfied with family communication about my 
illness ................. . 
I feel close to my partner (or the person who is my main 
support) 
Ql 
Regardless of your current/eve/ ofsexual activity. please 
answer the following question. If you prefer not to answer it. 
please mark this box 0 and go to the next section. 
GS7 
I am satisfied with my sex life 
English (Uruvcrsal) 
~)righ11987, 1997 
Not 
at all 
0 
0 
0 
0 
0 
0 
0 
Not 
at all 
0 
0 
0 
0 
0 
0 
0 
A little 
Some-
bit 
what 
2 
2 
2 
2 
2 
2 
2 
A little 
Some· 
bit 
what 
2 
2 
2 
2 
2 
2 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
19 Novembcr2007 
Page I of3 


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FACT-Leu (Version 4) 
Please circle or ma rk one number per line to indicate your response as it applies to the past 7 
days. 
EMOTIONAL WELL-BEING 
GEl 
I feel sad 
. ..............•..•.....• ..• 
mJ 
I am satisfied with how I am coping with my illness 
OE3 
I am losing hope in the fight against my illness 
GE4 
I feel nervous ... 
................... 
GES 
I worry about dying 
.. ' .. ' .... ..... .... 
. .................... 
GE6 
I worry that my condition will get worse ................ 
FUNCTIONAL WELL-BEING 
GFI 
Tam able to work (include work at home) .............. 
GF2 
My work (include work at home) is fulfilling ........... 
GF3 
I am able to enjoy life ....... 
GF4 
1 have accepted my illness 
GF5 
l am sleeping well .............. 
................ 
GF6 
1 am enjoying the things I usually do for fun 
GF7 
I am content with the quality of my life right now 
Enghsh (Universal) 
Cop)Tight 1987, 1997 
Not 
at all 
0 
0 
0 
0 
0 
0 
Not 
at all 
0 
0 
0 
0 
0 
0 
0 
A little 
Some-
Quite 
bit 
what 
a bit 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
A little 
Some-
Quite 
bit 
what 
a bit 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
Ve1-y 
much 
4 
4 
4 
4 
4 
4 
4 
19No\'embcr2007 
Page2 of3 


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FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
ADDITIONAL CONCERNS 
Not 
A little 
Some-
Quite 
Very 
at all 
bit 
what 
a bit 
much 
BRM3 
I am bothered by fevers (episodes of high body 
temperature) 
0 
2 
3 
4 
P2 
I have certain parts of my body where I experience pain.... 
0 
BRM2 
I am bothered by the chills .. 
ESJ 
I have night sweats .... 
LEU! 
I am bothered by lumps or swelling in certain parts of 
my body (e.g., neck, armpits, or groin) ..................... . 
THI 
I bleed easily . 
Tlll 
l bruise easily .... 
Hll2 
I feel weak all over . ................ ..... . 
BMT6 
r get tired easily ..... . 
C2 
Tam losing weight ..... . 
co 
I have a good appetite 
An7 
I am able to do my usual activities .................. . 
NJ 
I worry about getting infections .................. . 
LEUS 
I feel uncertain about my future health 
LEU6 
l worry that 1 might get new symptoms of my illness 
BRM9 
I have emotional ups and downs ... 
LEu? 
I feel isolated from others because of my illness or 
treatment ............................................................... ............ . 
Enghsh (Universal) 
Cop)Tight 1987, 1997 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
19No\'embcr2007 
Page 3 of3 


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Appendix 3.
Performance Status Scoring System
Karnofsky Performance Status
General Description
Score
Specific Description
Able to carry on normal 
activity and to work; no 
special care needed.
100
Normal; no complaints; no evidence of disease.
90
Able to carry on normal activity; minor signs or symptoms of 
disease.
80
Normal activity with effort; some signs or symptoms of 
disease.
Unable to work; able to live 
at home and care for most 
personal needs; varying 
amount of assistance needed.
70
Cares for self; unable to carry on normal activity or to do 
active work.
60
Requires occasional assistance, but is able to care for most of 
personal needs.
50
Requires considerable assistance and frequent medical care.
Unable to care for self; 
requires equivalent of 
institutional or hospital care; 
disease may be progressing 
rapidly.
40
Disabled; requires special care and assistance.
30
Severely disabled; hospital admission is indicated although 
death not imminent.
20
Very sick; hospital admission necessary; active supportive 
treatment necessary.
10
Moribund; fatal processes progressing rapidly.
0
Dead


Idelalisib 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Version 3.0 
Appendix 4. 
EuroQoL-5 Dimensions (EQ-5D) 
EuroQoL-5 Dimensions (EQ-5D) 
By placing a checkmark m one box m each group belon·, please indicate whtch 
stacemems be;l deRn"be your own beahh smte today. 
Mobility 
I have no prob:ems in walking about 
I have some problems in v.•alkif'g aboot 
I am co 5ned to bed 
Self-Care 
I have no problems wiili self-care 
I ha .. ·e some prob1ems washing o dteSSJ~g myself 
I am unable to wash or dress mysel 
Usual Activities (e.g., work, study, housework, family. or leisure activities) 
I have no problems with perZotming my usual aciMties 
I have some pro ems ,,·th periormir'lg my usual actMtres 
I am unable to perform my U'Sual activifes 
PainJDiscomfort 
I ha .. ·e no pain ()t discomfon 
I have moderate pan or disoom:()tt 
I ha•.·e ex1reme pa11 or cfscom:ott 
Anxiety/Depression 
I am nOi anxious ot cfep.ressed 
I am moderately ar.xioos or ctep essed 
I am extremely anxious or depressed 
CONFIDENTIAL 
Page 157 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
10 September 2013 


Idelalisib 
Protocol GS-US-312-0117 
Gilead Sciences, Inc. 
To help people say how good or bad a ltealth state is, 
we have dr.m11 a scale (rather like a thennometer) on 
which the best stare you can imagine ts marked 100 
and the worst stare you can imagine is marked 0. 
We would like you to mdicate on this scale bO\\" good 
or bad your own health is today. in your opinion. 
Please do this by drawing a line from the box below 
to wlucllever pomt on the scale mdicates how good or 
bad your health state is today. 
CONFIDENTIAL 
Your own 
hl'altb statl' 
toda~· 
Page 158 
l OO 
I 0 
1 
0 
Wor.:t 
~b!e 
hu!Usa~ 
Final 
Version 3.0 
10 September 2013 


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Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance 
Formulas for calculating the estimated creatinine clearance (eCcr) are provided in the table 
below. The formula appropriate to the units in which serum creatinine was measured and the 
subject’s gender should be used.
Cockcroft-Gault Formulas for Calculating Estimated Creatinine Clearance
Serum 
Creatinine Units
Gender
Formula
mg/dL
Males
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1
72 subject serum creatinine [mg/dl]
Females eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 
0.85
72 subject serum creatinine [mg/dl]
M/dL
Males
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 
1.23
Subject serum creatinine [mg/dl]
Females eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 
1.04
Subject serum creatinine [mg/dl]
Abbreviation: eCcr=estimated creatinine clearance


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Appendix 6.
Cumulative Illness Rating Scale (CIRS)
The CIRS used in this protocol is designed to provide an assessment of recurrent or ongoing 
chronic comorbid conditions, classified by 14 organ systems. Using the drop-down lists of 
organ-specific diagnoses, please select any conditions present in the study subject. If the 
subject has a recurrent or ongoing chronic conditions that are not described in the list for a 
given organ system, please indicate the name of the conditions under “other chronic 
condition” for that organ system. Please take into account that CLL-induced discomfort, 
symptoms, or disability should not be considered. If additional explanation would be helpful, 
text comments may be inserted. 
CIRS List of Comorbid Conditions
Organ System
Diagnosis
Comment
Cardiac
Chronic heart failure
Angina pectoris
Medically relevant arrhythmia
Valve dysfunction
Congenital heart disease
Cardiomyopathy
Myocarditis
Chronic pericarditis
Endocarditis
Other chronic cardiac condition:
Other chronic cardiac condition:
Vascular
Hypertension
Thrombosis
Peripheral diabetic microvascular disease
Peripheral artery disease
Aortic aneurysm
Aortitis
Raynaud disease
Vasculitis
Other chronic vascular condition:
Other chronic vascular condition


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Organ System
Diagnosis
Comment
Hematological/
immunological
Sickle cell anemia
Hemoglobinopathy
Polycythemia
Thrombocythemia
Hemophilia
Paroxysmal nocturnal hemoglobinuria
Thrombotic thrombocytopenic purpura
Dysfibrinogenemia
HIV
Other chronic hematological or immunological 
condition:
Other chronic hematological or immunological 
condition
Abbreviation:  CIRS=Cumulative Illness Rating Scale
For each condition selected from the CIRS List of Comorbid Conditions, please rate the 
severity of that condition. For the severity rating, please use the scoring guidelines shown in 
the table below, considering the magnitude of symptoms, how manageable the condition is, 
and the extent of intervention required:
CIRS Rating Scale
Score
Severity
Findings
1
Mild
Mild discomfort, symptoms or disability
Easy to control
Requiring either no therapy/medication or only as needed
2
Moderate
Moderate  discomfort, symptoms or disability
Manageable
Requiring daily treatment or first-line therapy
3
Severe
Severe discomfort, symptoms or disability
Hard to control
Requiring second-line therapy or multiple medications
4
Extremely
severe
Life threatening, permanently disabling disability, causing organ failure
Poorly manageable
Requiring urgent intervention or resistant to therapy
Abbreviation:  CIRS=Cumulative Illness Rating Scale


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Appendix 7.
Schedule of Study Procedures
Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4
5a
6
7a
8
9
10
11
12
13
14
15
16+
End of 
Study
30 
days
Long-
term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12 
Weeks
Study Day
Within 
-28 
Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within 
+30 
days
To  
+5 
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Informed consent
X
CIRS assessment
X
β-HCG (women of childbearing 
potential)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CLL peripheral blood evaluation
X
X
CLL serology
X
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HRQL/healthy utility – FACT-
Leu/EQ-5D
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exam (includes nodes, liver, 
spleen)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Oxygen saturation (by pulse 
oximetry)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PPD


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Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4
5a
6
7a
8
9
10
11
12
13
14
15
16+
End of 
Study
30 
days
Long-
term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12 
Weeks
Study Day
Within 
-28 
Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within 
+30 
days
To  
+5 
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Circulating cells
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biomarkers
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Igs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug administration in clinic
Xb
X
X
X
X
X
X
X
Idelalisib pharmacokineticsb
X
X
X
X
X
X
X
X
Study drug dispensing/accountingb
X
X
X
X
X
X
X
X
X
X
X
Radiology assessment (CT/MRI)d
X
X
X
X
X
X
X
X
Bone marrow biopsy/aspiratec
X
X
X
X
X
X
X
X
Post-treatment CLL therapy
X
Long-term follow-up 
X
a
Following unblinding of the study, visits 3, 5, and 7 will not be applicable for subjects who were randomized to idelalisib on Study GS-US-312-0116
b
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll following unblinding, may have idelalisib treatment (and associated PK testing) delayed 
at the Investigator’s discretion until the time of disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib treatment
c
At screening, to be performed at investigator discretion to determine extent of CLL involvement and bone marrow cellularity. Post-screening, to be performed to confirm 
CR or PD; if the subject does not otherwise meet criteria for CR or if the nature of PD does not require bone marrow confirmations, it is not necessary to obtain a 
follow-up bone marrow biopsy/aspirate
d
Following unblinding of the study, the imaging schedule will follow standard of care for subjects who were randomized to idelalisib on Study GS-US-312-0116 and 
subjects who were randomized to placebo on Study GS-US-312-0116 and enroll on Study GS-US-312-0117 will follow local standard of care for follow-up imaging 
until initiation of idelalisib, at which time the per-protocol schedule will be followed
Abbreviations: -HCG=beta human chorionic gonadotropin, CIRS=chronic illness rating scale, CLL=chronic lymphocytic leukemia, CR=complete response, CT=computed
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy- Leukemia, HRQL= health-related quality of life, 
Ig=immunoglobulin, IWRS=interactive web response system, MRI= magnetic resonance imaging.

Prot_004.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy 
and Safety of Two Different Dose Levels of Single-Agent 
Idelalisib (GS-1101) for Previously Treated Chronic Lymphocytic 
Leukemia
A Companion Trial to Study GS-US-312-0116: A Phase 3, 
Randomized, Double-Blind, Placebo-Controlled Study Evaluating 
the Efficacy and Safety of Idelalisib (GS-1101) in Combination 
with Rituximab for Previously Treated Chronic Lymphocytic 
Leukemia
Sponsor:
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102
USA
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
101254
EudraCT Number:
2011-006293-72
Indication:
Chronic Lymphocytic Leukemia 
Protocol ID:
GS-US-312-0117
Gilead Sciences Medical 
Monitor:
Name:
Office Telephone:
Office Fax:
Mobile Telephone:
E-mail:
Protocol Version/Date:
Version 1.0 (Original)
23 January 2012
Version 2.0 (Amendment 1)
23 January 2013 
Version 3.0 (Amendment 2)
10 September 2013
Version 4.0 (Amendment 3)
16 December 2013
Version 5.0 (Amendment 4)
27 May 2014
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable institutional 
review board or independent ethics committee. This information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You must not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
PPD
PPD
PPD
PPD


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Final
Gilead Sciences, Inc.
Version 5.0
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27 May 2014
TABLE OF CONTENTS
TABLE OF CONTENTS .......................................................................................................................................2
LIST OF IN-TEXT TABLES.................................................................................................................................6
LIST OF IN-TEXT FIGURES ...............................................................................................................................6
PROTOCOL SYNOPSIS .......................................................................................................................................7
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................................19
1.
INTRODUCTION .......................................................................................................................................23
Chronic Lymphocytic Leukemia.....................................................................................................23
1.1.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies.............................................................24
1.2.
Idelalisib (formerly GS-1101).........................................................................................................25
1.3.
1.3.1.
Discovery and Efficacy Pharmacology .........................................................................25
1.3.2.
Safety Pharmacology.....................................................................................................25
1.3.3.
Nonclinical Pharmacology and Metabolism..................................................................26
1.3.4.
Toxicology ....................................................................................................................27
1.3.5.
Idelalisib Clinical Studies..............................................................................................27
Summary and Justification for the Current Study...........................................................................32
1.4.
2.
STUDY DESIGN.........................................................................................................................................34
Design Overview and Study Schema ..............................................................................................34
2.1.
Design Rationale.............................................................................................................................35
2.2.
3.
OBJECTIVES AND ENDPOINTS .............................................................................................................37
Endpoints ........................................................................................................................................37
3.1.
3.1.1.
Tumor Control...............................................................................................................37
3.1.2.
Patient Well-Being ........................................................................................................38
3.1.3.
Pharmacodynamic Markers of Drug Activity and Resistance.......................................39
3.1.4.
Exposure........................................................................................................................39
3.1.5.
Safety.............................................................................................................................39
3.1.6.
Pharmacoeconomics......................................................................................................39
Endpoint Selection Rationale..........................................................................................................39
3.2.
3.2.1.
Tumor Control Endpoints..............................................................................................40
3.2.2.
Measures of Patient Well-Being....................................................................................42
3.2.3.
Pharmacodynamic Markers of Drug Activity and Resistance.......................................43
3.2.4.
Assessments of Exposure..............................................................................................44
3.2.5.
Evaluations of Safety.....................................................................................................45
3.2.6.
Pharmacoeconomic Measures .......................................................................................46
4.
SUBJECT POPULATION...........................................................................................................................47
Number of Subjects.........................................................................................................................47
4.1.
Subject Selection Criteria................................................................................................................47
4.2.
4.2.1.
Inclusion Criteria...........................................................................................................47
4.2.2.
Exclusion Criteria..........................................................................................................49
Enrollment Criteria Rationale .........................................................................................................50
4.3.
5.
TREATMENT OF SUBJECTS ...................................................................................................................51
Enrollment.......................................................................................................................................51
5.1.
5.1.1.
Interactive Web Response System ................................................................................51
5.1.2.
Treatment Assignment ..................................................................................................51
5.1.3.
Blinding.........................................................................................................................52


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Investigational Study Drug (Idelalisib/Placebo) .............................................................................53
5.2.
5.2.1.
Description ....................................................................................................................53
5.2.2.
Source............................................................................................................................53
5.2.3.
Packaging and Labeling ................................................................................................53
5.2.4.
Storage and Handling....................................................................................................54
5.2.5.
Dispensing.....................................................................................................................54
5.2.6.
Return............................................................................................................................55
5.2.7.
Accountability...............................................................................................................55
5.2.8.
Overdose Precautions....................................................................................................55
5.2.9.
Inadvertent Exposure and Spill Precautions..................................................................56
Study Drug Administration.............................................................................................................56
5.3.
5.3.1.
Premedication................................................................................................................56
5.3.2.
Administration Instructions...........................................................................................56
5.3.3.
Dosing Schedule............................................................................................................56
5.3.4.
Dose Levels...................................................................................................................57
5.3.5.
Dose Schedule Interruptions and Vomited Doses.........................................................57
5.3.6.
Safety Monitoring and Study Drug Interruption/Dose Modification ............................57
Recommendations for Evaluation, Intervention, and Drug Discontinuation for Specific 
5.4.
Adverse Events or Conditions.........................................................................................................60
5.4.1.
Dermatological Events ..................................................................................................60
5.4.2.
Gastrointestinal Events..................................................................................................61
5.4.3.
Hepatic Events...............................................................................................................62
5.4.4.
Hematological and Immunological Events....................................................................63
5.4.5.
Infectious Events...........................................................................................................63
5.4.6.
Progressive Multifocal Leukoencephalopathy ..............................................................64
5.4.7.
Pulmonary Events .........................................................................................................64
5.4.8.
Tumor Lysis Syndrome.................................................................................................65
5.4.9.
Pregnancy, Lactation, and Reproduction.......................................................................65
5.4.10.
Ultraviolet Exposure .....................................................................................................66
Emergency Unblinding ...................................................................................................................66
5.5.
Concomitant and Supportive Therapy.............................................................................................66
5.6.
5.6.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments.....................................................................................................................67
5.6.2.
Antibiotics.....................................................................................................................67
5.6.3.
Antiemetics and Antidiarrheals.....................................................................................67
5.6.4.
Contraception ................................................................................................................67
5.6.5.
Corticosteroids ..............................................................................................................69
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin.......................................69
5.6.7.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism...........................................69
5.6.8.
Drugs that undergo CYP3A-Dependent Metabolism....................................................70
5.6.9.
Immunization ................................................................................................................70
5.6.10.
Surgery..........................................................................................................................70
5.6.11.
Diet................................................................................................................................70
Duration of Study Drug...................................................................................................................70
5.7.
Discontinuation of Study Drug .......................................................................................................71
5.8.
Discontinuation from Study ............................................................................................................71
5.9.
Study Treatment Rationale..............................................................................................................72
5.10.
6.
STUDY PROCEDURES .............................................................................................................................75
Enrollment and Study Management Procedures .............................................................................75
6.1.
6.1.1.
Subject Recruitment ......................................................................................................75
6.1.2.
Subject Compensation for Participation........................................................................75
6.1.3.
Screening.......................................................................................................................75
Explanation of Study Visits.............................................................................................................76
6.2.


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6.2.1.
Visit 1 and Screening Period (Clinic Visit)...................................................................77
6.2.2.
Visit 2 (Day 1) (Clinic Visit).........................................................................................79
6.2.3.
Visit 3 (Day 15) (Clinic Visit).......................................................................................80
6.2.4.
Visit 4 (Day 29) (Clinic Visit).......................................................................................81
6.2.5.
Visit 5 (Day 43) (Clinic Visit).......................................................................................83
6.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit) ..............................................................84
6.2.7.
Visit 7 (Day 71) (Laboratory Visit)...............................................................................85
6.2.8.
Visit 8 (Day 85) (Clinic Visit).......................................................................................86
6.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit) ............................................................88
6.2.10.
Visit 10 (Day 141) (Clinic Visit)...................................................................................90
6.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit) ..........................................................92
6.2.12.
Visit 12 (Day 211) (Clinic Visit)...................................................................................94
6.2.13.
Visit 13 (Day 253) (Clinic and Radiology Visit) ..........................................................95
6.2.14.
Visit 14 (Day 295) (Clinic Visit)...................................................................................96
6.2.15.
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks) (Clinic 
and Radiology Visits)....................................................................................................97
6.2.16.
End-of-Study Visit (Clinic Visit) ..................................................................................98
6.2.17.
30 Day and Long-Term Follow-up..............................................................................100
Sample Storage..............................................................................................................................100
6.3.
Blood Collection ...........................................................................................................................100
6.4.
Study Procedure Rationale............................................................................................................101
6.5.
7.
EFFICACY ASSESSMENTS....................................................................................................................102
Tumor Status Assessments............................................................................................................102
7.1.
Method of Assessment ..................................................................................................................102
7.2.
Timing of Assessments .................................................................................................................102
7.3.
Identification and Measurement of Tumor Lesions and Organomegaly.......................................103
7.4.
7.4.1.
Index Lesions ..............................................................................................................103
7.4.2.
Spleen and Liver..........................................................................................................104
7.4.3.
Non-Index Lesions ......................................................................................................104
Definitions of Tumor Response and Progression..........................................................................105
7.5.
7.5.1.
Complete Response.....................................................................................................105
7.5.2.
Partial Response..........................................................................................................106
7.5.3.
Stable Disease .............................................................................................................106
7.5.4.
Definitive Progressive Disease....................................................................................107
7.5.5.
Non-Evaluable.............................................................................................................108
7.5.6.
No Disease ..................................................................................................................108
7.5.7.
Lymphocytosis During Therapy..................................................................................109
7.5.8.
Documentation of Definitive CLL Progression...........................................................109
8.
SAFETY ASSESSMENTS........................................................................................................................110
Adverse Event Definitions ............................................................................................................110
8.1.
8.1.1.
Adverse Event .............................................................................................................110
8.1.2.
Serious Adverse Event ................................................................................................111
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events ................................................................112
Assessment of Adverse Events and Serious Adverse Events........................................................112
8.2.
8.2.1.
Assessment of Causality for Study Drugs and Procedures..........................................113
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
8.3.
Adverse Events to Gilead..............................................................................................................113
Gilead Reporting Requirements....................................................................................................114
8.4.
Grading of the Severity of an Adverse Event................................................................................114
8.5.
Adverse Event Reporting Period...................................................................................................115
8.6.
Adverse Event Reporting Requirements.......................................................................................116
8.7.


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8.7.1.
Site Reporting Requirements.......................................................................................116
8.7.2.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population..................................................117
Special Situations Reporting Requirements..................................................................................118
8.8.
8.8.1.
Definitions of Special Situations.................................................................................118
Instructions for Reporting Special Situations................................................................................118
8.9.
8.9.1.
Instructions for Reporting Pregnancies .......................................................................118
8.9.2.
Reporting Other Special Situations .............................................................................119
9.
STATISTICAL CONSIDERATIONS.......................................................................................................120
Analysis Objectives.......................................................................................................................120
9.1.
Analysis Endpoints........................................................................................................................120
9.2.
Analysis Conventions....................................................................................................................120
9.3.
9.3.1.
Analysis Sets ...............................................................................................................120
9.3.2.
Data Handling Conventions ........................................................................................121
Analysis Plan.................................................................................................................................123
9.4.
9.4.1.
Subject Disposition and Baseline Characteristics........................................................123
9.4.2.
Efficacy Analyses........................................................................................................124
9.4.3.
Exposure and Safety Analyses ....................................................................................125
9.4.4.
Other Analyses............................................................................................................127
Sample Size...................................................................................................................................129
9.5.
Timing of Analyses.......................................................................................................................129
9.6.
10.
RESPONSIBILITIES.................................................................................................................................130
Investigator Responsibilities .........................................................................................................130
10.1.
10.1.1.
Compliance with Ethical and Regulatory Guidelines..................................................130
10.1.2.
Institutional Review Board/Independent Ethics Committee .......................................130
10.1.3.
Informed Consent........................................................................................................131
10.1.4.
Confidentiality.............................................................................................................131
10.1.5.
Study Files and Retention of Records and Biological Samples...................................132
10.1.6.
Case Report Forms......................................................................................................133
10.1.7.
Drug Accountability....................................................................................................133
10.1.8.
Inspections...................................................................................................................134
10.1.9.
Protocol Compliance...................................................................................................134
Sponsor Responsibilities...............................................................................................................134
10.2.
10.2.1.
Protocol Modifications................................................................................................134
10.2.2.
Communications with Regulatory Authorities............................................................134
10.2.3.
Data Management .......................................................................................................135
10.2.4.
Study Reporting and Publication.................................................................................135
Joint Investigator/Sponsor Responsibilities ..................................................................................136
10.3.
10.3.1.
Access to Information for Monitoring.........................................................................136
10.3.2.
Access to Information for Auditing or Inspections .....................................................136
10.3.3.
Public Notification of Study Conduct .........................................................................136
10.3.4.
Study Discontinuation.................................................................................................137
Study Committees.........................................................................................................................137
10.4.
10.4.1.
Data Monitoring Committee .......................................................................................137
10.4.2.
Independent Review Committee .................................................................................138
11.
REFERENCES ..........................................................................................................................................139
12.
APPENDICES ...........................................................................................................................................149
Appendix 1.
Investigator Signature Page.........................................................................................150
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)..........................151


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Appendix 3.
Performance Status Scoring System............................................................................154
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D) ...............................................................................155
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance ...................................157
Appendix 6.
Cumulative Illness Rating Scale (CIRS) .....................................................................158
Appendix 7.
Schedule of Study Procedures.....................................................................................160
LIST OF IN-TEXT TABLES
Table 4-1.
Required Screening Laboratory Values.........................................................................48
Table 5-1.
Study Drug Dose Levels................................................................................................57
Table 5-2.
Recommendations for Study Drug Dose Modifications Based on 
Type and Severity of Treatment-Related Adverse Events or 
Laboratory Abnormalities .............................................................................................59
Table 5-3.
Protocol-Recommended Contraceptive Methods..........................................................68
Table 5-4.
Known Strong Inducers of CYP3A...............................................................................69
Table 6-1.
Procedures and Assessments at Visit 1 (During Screening Period) ..............................78
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1) ............................................................79
Table 6-3.
Procedures and Assessments at Visit 3 (Day 15) ..........................................................80
Table 6-4.
Procedures and Assessments at Visit 4 (Day 29) ..........................................................81
Table 6-5.
Procedures and Assessments at Visit 5 (Day 43) ..........................................................83
Table 6-6.
Procedures and Assessments at Visit 6 (Day 57) ..........................................................84
Table 6-7.
Procedures and Assessments at Visit 7 (Day 71) ..........................................................85
Table 6-8.
Procedures and Assessments at Visit 8 (Day 85) ..........................................................86
Table 6-9.
Procedures and Assessments at Visit 9 (Day 113) ........................................................88
Table 6-10.
Procedures and Assessments at Visit 10 (Day 141) ......................................................90
Table 6-11.
Procedures and Assessments at Visit 11 (Day 169) ......................................................92
Table 6-12.
Procedures and Assessments at Visit 12 (Day 211) ......................................................94
Table 6-13.
Procedures and Assessments at Visit 13 (Day 253) ......................................................95
Table 6-14.
Procedures and Assessments at Visit 14 (Day 295) ......................................................96
Table 6-15.
Procedures and Assessments at Visit 15 and Subsequent Visits (Day 
337 and Every 12 Weeks) .............................................................................................97
Table 6-16.
Procedures and Assessments at End-of-Study Visit......................................................99
Table 8-1.
Grading of Adverse Event Severity.............................................................................115
Table 8-2.
Site Reporting Requirements for Adverse Events.......................................................116
Table 8-3.
Contact Information for Reporting Serious Adverse Events.......................................117
LIST OF IN-TEXT FIGURES
Figure 2-1.
Study Design .................................................................................................................34


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc
199 East Blaine Street
Seattle, WA 98102, USA
Study Title: 
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and 
Safety of Two Different Dose Levels of Single-Agent Idelalisib (GS-1101) 
as Therapy for Patients with Previously Treated Chronic Lymphocytic 
Leukemia
A Companion Study to Study GS-US-312-0116: A Phase 3, Randomized, 
Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety 
of Idelalisib (GS-1101) in Combination with Rituximab as Therapy for 
Patients with Previously Treated Chronic Lymphocytic Leukemia
Study Centers 
Planned:
Approximately 90 centers in the United States and in Europe
IND Number:
101254
EudraCT 
Number:
2011-006293-72
Objectives:

To evaluate the effect of idelalisib (formerly GS-1101) on the onset, 
magnitude, and duration of tumor control 

To compare tumor control in subjects receiving rituximab alone in 
Study GS-US-312-0116 to that observed in the same subjects when 
receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject well-being, 
including overall survival (OS), health-related quality of life (HRQL),
and performance status

To assess the effects of idelalisib on disease-associated biomarkers and 
to evaluate potential mechanisms of resistance to idelalisib

To characterize exposure to idelalisib as determined by treatment 
administration and evaluation of idelalisib plasma concentrations over 
time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with administration 
of idelalisib


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Study Design:
This study is being conducted as part of an overall clinical program 
evaluating the efficacy and safety of idelalisib in the therapy of patients with 
previously treated chronic lymphocytic leukemia (CLL). 
Within this program, the primary clinical trial (Study GS-US-312-0116) is a 
Phase 3, multicenter, 2-arm, randomized, double-blind, placebo-controlled, 
parallel-group study.
This clinical trial (Study GS-US-312-0117) is a separate, multicenter, 2-arm, 
double-blind, parallel-group extension study that is a companion trial to 
Study GS-US-312-0116; in this trial, compliant subjects from 
GS-US-312-0116 who are tolerating primary study therapy but experience 
definitive CLL progression are eligible to receive active blinded idelalisib
therapy at the standard dose or a higher dose, with allocation based on the 
original primary study randomization. In the event GS-US-312-0116 is 
stopped early due to overwhelming efficacy following an interim analysis or 
at the final analysis, subjects who are on Study GS-US-312-0116 at that time 
may transition to GS-US-312-0117.  Additionally, GS-US-312-0117 will 
become an open-label study offering idelalisib 150 mg BID to 
GS-US-312-0116 subjects who were randomized to placebo, and subjects 
randomized to idelalisib will continue idelalisib at 150 mg BID.
Study Schema:
Treatment Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117)


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Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID
Treatment Assignment

Assignment to Arm A or Arm B with allocation based on the original 
primary study randomization

Implementation through an interactive web response system (IWRS)
Stratification
Not applicable for Study GS-US-312-0117
Number of 
Subjects 
Planned:
Total of up to ~180 subjects (up to ~90 subjects per treatment arm)
Target 
Population:
Subjects in the primary Phase 3 study (GS-US-312-0116) who are 
compliant, are tolerating primary study therapy, and 1) have definitive 
progression of CLL while receiving primary study drug therapy 
(idelalisib/placebo) or 2) are actively participating in 
Study GS-US-312-0116 at the time the study is stopped, including if stopped 
early due to overwhelming efficacy following an interim analysis.
Diagnosis 
and Main 
Eligibility 
Criteria:
Inclusion Criteria
Subjects must meet all of the following conditions to be eligible for 
enrollment into the study:
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while receiving 
study drug therapy (idelalisib /placebo) in Study GS-US-312-0116. 
Note: Definitive disease progression is CLL progression based on 
standard criteria and occurring for any reason (ie, increasing 
lymphadenopathy, organomegaly, or bone marrow involvement; 
decreasing platelet count, hemoglobin, or neutrophil count; or 
worsening of disease-related symptoms) other than lymphocytosis. 
Subjects must have confirmation by the sponsor working in 
collaboration with an independent review committee (IRC) that the 
disease has progressed on the primary clinical trial
(Study GS-US-312-0116) before receiving secondary idelalisib therapy 
on this extension trial (Study GS-US-312-0117).


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3) Presence of measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures 2.0 cm in the longest diameter [LD] and 
1.0 cm in the longest perpendicular diameter [LPD] as assessed by 
computed tomography [CT] or magnetic resonance imaging [MRI]).
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab 
and/or idelalisib/placebo) and no intervening or continuing therapy 
(including radiotherapy, chemotherapy, immunotherapy, or 
investigational therapy) for the treatment of CLL. Note: Subjects may 
receive corticosteroids to manage CLL manifestations.
5) The time from permanent cessation of Study GS-US-312-0116 treatment 
(rituximab and/or idelalisib/placebo) and the initiation of Study 
GS-US-312-0117 therapy is 12 weeks. Note: Study procedures 
performed as part of Study GS-US-312-0116 need not be repeated and 
can be used as screening procedures for Study GS-US-312-0117 if 
performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation of 
study treatment) as shown in the table below. Note: Confirmation 
should be considered for out-of-range values to determine if the 
abnormality is real or artifactual. Values should be obtained within the 
screening period and should generally be the most recent measurement 
obtained. Subjects with any degree of neutropenia, thrombocytopenia, 
or anemia due to CLL or prior therapy may enroll.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCr
a
>30 ml/min
Pregnancy
-HCGb
Negative 
a
As calculated by the Cockcroft-Gault formula {2202}
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or urine 
dipstick pregnancy test must be negative at randomization (Visit 2)
Abbreviations: -HCG=beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
eCCr=estimated creatinine clearance, ULN=upper limit of normal


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8) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening visit 
(Visit 1) throughout the study and for 30 days from the last dose of study 
drug. Note: A female subject is considered to be of childbearing 
potential unless she has had a hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy; has medically documented ovarian failure 
(with serum estradiol and follicle-stimulating hormone [FSH] levels 
within the institutional postmenopausal range and a negative serum or 
urine HCG), or is menopausal (defined as age >55 years with 
amenorrhea for >12 months or amenorrhea for >6 months with serum 
estradiol and FSH levels within the institutional postmenopausal 
range). 
9) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of study 
drug (Visit 2) throughout the study and for 90 days following the last 
dose of study drug and to refrain from sperm donation from the start of 
study drug (Visit 2) throughout the study and for 90 days following the 
last dose of study drug. Note: A male subject is considered able to 
father a child unless he has had a bilateral vasectomy with documented 
aspermia or a bilateral orchiectomy, or has ongoing testicular 
suppression with a depot luteinizing hormone- releasing hormone 
(LH-RH) agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate 
[Lupron®]), or triptorelin pamoate [Trelstar®]).
10) In the judgment of the investigator, participation in the protocol offers an 
acceptable benefit-to-risk ratio when considering current CLL disease 
status, medical condition, and the potential benefits and risks of 
alternative treatments for CLL. 
11) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, familial, 
or geographical factors that might preclude adequate study 
participation should be considered.
12) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature of the 
therapy, alternatives, potential benefits, possible side effects, potential 
risks and discomforts, and other pertinent aspects of study participation.


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Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be 
enrolled in this study:
1) Known histological transformation from CLL to an aggressive 
lymphoma (ie, Richter transformation). 
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at the 
time of the start of study treatment (Visit 2). Note: Subjects with 
localized fungal infections of skin or nails are eligible. Subjects may be 
receiving prophylactic antiviral or antibacterial therapies at the 
discretion of the investigator; anti-pneumocystis prophylaxis is 
encouraged. 
3) Pregnancy or breastfeeding. 
4) Intentional breaking of the blind in Study GS-US-312-0116 by the 
investigator or the study subject.
5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical condition, surgical 
history, physical finding, electrocardiogram (ECG) finding, or laboratory 
abnormality that, in the investigator’s opinion, could adversely affect the 
safety of the subject or impair the assessment of study results.
In the event Study GS-US-312-0116 is stopped early, subjects who are 
actively participating in Study GS-US-312-0116 will become eligible for this 
study, provided the following inclusion are met: Participation in Study 
GS-US-312-0116 within 12 weeks of enrollment onto GS-US-312-0117.
1) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening visit 
(Visit 1) throughout the study and for 30 days from the last dose of study 
drug. 
2) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of study 
drug (Visit 2) throughout the study and for 90 days following the last 
dose of study drug and to refrain from sperm donation from the start of 
study drug (Visit 2) throughout the study and for 90 days following the 
last dose of study drug. 
3) In the judgment of the investigator, participation in the protocol offers an 
acceptable benefit-to-risk ratio when considering current CLL disease 
status, medical condition, and the potential benefits and risks of 
alternative treatments for CLL. 


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4) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, familial, 
or geographical factors that might preclude adequate study participation 
should be considered.
5) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature of the 
therapy, alternatives, potential benefits, possible side effects, potential 
risks and discomforts, and other pertinent aspects of study participation.
Study 
Procedures/
Frequency:
Clinic/laboratory visits will occur every 2 weeks for the first 12 weeks, every 
4 weeks between Weeks 12 and 24, and every 6 weeks between Weeks 24 
and 48. Subjects continuing on study drug past Week 48 will have clinic 
visits every 12 weeks. Subjects will be assessed for safety at each visit. 
Subjects will be assessed for CLL disease status by physical and laboratory 
examinations at each visit and by CT or MRI at Weeks 8, 16, 24, 36, and 
48 and every 12 weeks thereafter.
Following unblinding of the study:

Subjects who were randomized to idelalisib on Study GS-US-312-
0116 and who received ≥ 24 weeks idelalisib will complete Visit 16+
twelve weeks from the date of their last radiology assessment 
(CT/MRI) and study visits will continue every 12 weeks thereafter..
Visits 3 through 15 will not be required.

Subjects who have received < 24 weeks idelalisib will have all Study 
GS-US-312-0117 assessments completed per the Schedule of 
Procedures until they have received idelalisib for 24 weeks 
cumulative across both studies. After completion of 24 weeks of 
cumulative idelalisib treatment, Visit 16+ will be conducted 12 
weeks from the date of their last radiology assessment (CT/MRI), 
after which time study visits will occur every 12 weeks.
Test Therapy, 
Dose, and 
Mode of 
Administration:
Blinded Portion

Arm A: Idelalisib, 300 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be provided 
as 2 tablets of active idelalisib for oral administration

Arm B: Idelalisib, 150 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be provided 
as 1 tablet of active idelalisib and 1 tablet of placebo for oral 
administration


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Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID
Note: At the Investigator’s discretion, subjects who were randomized to 
placebo on study GS-US-312-0116 may delay initiation of idelalisib 
following enrollment on Study GS-US-312-0117 until the time of disease 
progression or until the investigator determines that the subject would 
benefit from initiation of idelalisib treatment
Reference 
Therapy, Dose, 
and Mode of 
Administration:
Not applicable
Duration of 
Treatment:
Study drug will be taken continuously until the earliest of subject withdrawal 
from study drug, definitive progression of CLL, intolerable study 
drug-related toxicity, pregnancy, substantial noncompliance with study 
procedures, or study discontinuation.
Criteria for 
Evaluation:
Tumor Control

Progression-free survival (PFS) – defined as the interval from the start 
of study therapy to the earlier of the first documentation of definitive 
disease progression or death from any cause; definitive disease 
progression is CLL progression based on standard criteria other than 
lymphocytosis alone

Overall response rate (ORR) – defined as the proportion of subjects 
who achieve a complete response (CR) or partial response (PR)

Lymph node response rate – defined as the proportion of subjects who 
achieve a 50% decrease from baseline in the sum of the products of 
the greatest perpendicular diameters (SPD) of index lesions

CR rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from start of study 
therapy to the first documentation of CR or PR

Duration of response (DOR) – defined as the interval from the 
first documentation of CR or PR to the earlier of the first 
documentation of definitive disease progression or death from any 
cause

Percent change in lymph node area – defined as the percent change 
from baseline in the SPD of index lymph nodes


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
Splenomegaly response rate – defined as the proportion of subjects 
with baseline splenomegaly who achieve an on-study normalization or
a 50% decrease (minimum 2 cm) from baseline in the enlargement of 
the splenic LVD (by imaging)

Hepatomegaly response rate – defined as the proportion of subjects 
with baseline hepatomegaly who achieve an on-study normalization or
a 50% decrease (minimum 2 cm) from baseline the hepatic longest 
vertical dimension (LVD) (by imaging)

ALC response rate – defined as the proportion of subjects with baseline 
lymphocytosis (ALC4 x 109/L) who achieve an on-study ALC 
<4 x 109/L or demonstrate a 50% decrease in ALC from baseline

Platelet response rate – defined as the proportion of subjects with 
baseline thrombocytopenia (platelet count <100 x 109/L) who achieve 
an on-study platelet count 100 x 109/L or demonstrate a 
50% increase in platelet count from baseline without need for 
exogenous growth factors

Hemoglobin response rate – defined as the proportion of subjects with 
baseline anemia (hemoglobin <110 g/L [11.0 g/dL]) who achieve an 
on-study hemoglobin 110 g/L (11.0 g/dL) or demonstrate a 
50% increase in hemoglobin from baseline without red blood cell 
transfusions or need for exogenous growth factors (eg, erythropoietin)

Neutrophil response rate – defined as the proportion of subjects with 
baseline neutropenia (absolute neutrophil count [ANC] ≤1.5 x 109/L) 
who achieve an ANC >1.5 x 109/L or demonstrate a 50% increase in 
ANC from baseline without need for exogenous growth factors (eg, G-
CSF)
Patient Well-Being

Overall survival (OS) – defined as the interval from start of study 
therapy to death from any cause

Change from baseline in HRQL domain and symptom scores based on
the Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
(See Appendix 2)

Changes from baseline in Karnofsky performance status
(See Appendix 3)
Pharmacodynamic Markers of Drug Activity and Resistance

Changes from baseline in PI3K/AKT/mTOR pathway activation as a 
measure of PI3Kpathway activity 

Changes from baseline in the plasma concentrations of 
disease-associated chemokines and cytokines


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Exposure

Study drug administration as assessed by prescribing records and 
compliance as assessed by quantification of used and unused drug

Trough (pre-dose) and peak (~1.5-hour samples) of idelalisib plasma 
concentrations as assessed by a validated bioanalytical method
Safety

Overall safety profile of each regimen characterized by the type, 
frequency, severity, timing of onset, duration, and relationship to study 
therapy of any adverse events or abnormalities of laboratory tests; 
serious adverse events; or adverse events leading to discontinuation of 
study drug
Pharmacoeconomics

Change in health status – defined as the change from baseline in 
overall health and single-item dimension scores as assessed using the 
EuroQoL Five-Dimension (EQ-5D) utility measure 

Health resource measures, including resource utilization, total costs, 
and measures of cost per unit of benefit (eg, cost per additional 
progression-free month, cost per quality-adjusted life-year)
Statistical 
Methods:
Appropriate data analysis sets will be defined. The intent-to-treat (ITT) 
analysis set will include data from all subjects who receive 1 dose of any 
study therapy on this study; in this data set, study drug assignment 
(high-dose or standard-dose idelalisib) will be designated according to the 
planned allocation to this study. A safety analysis set will comprise data from 
subjects in the ITT analysis set with treatment assignments designated 
according to the actual study drug (high-dose or standard-dose idelalisib) 
received. Other analysis sets [per-protocol (PP) and 
pharmacodynamic/pharmacokinetic analysis sets] will be used for certain 
analyses as well.
Subject characteristics and study results will be described and summarized 
by treatment arm and assessment for the relevant analysis sets. Descriptive 
summaries will be prepared to show sample size, mean, standard deviation, 
95% confidence intervals (CIs) on the mean, median, minimum, and 
maximum for continuous variables and counts, percentages, and 95% CIs on 
the percentage for categorical variables.
An independent review committee (IRC) will review radiographic data and 
pertinent clinical data in order to provide expert evaluation of tumor status. 
The findings of the IRC will be considered primary for analyses of PFS and 
other tumor control endpoints.


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For endpoints relating to tumor control, patient well-being, and biomarkers, 
analyses will be done based on ITT, PP or pharmacodynamic data sets, as 
appropriate. Blinded portion of the study analyses will be presented in the 
following two groups:
•IDELA 300 mg BID: Subjects who have PD per IRC confirmation in Arm 
A of Study GS-US-312-0116 and subsequently enroll into Study GS-US-
312-0117 to receive IDELA 300 mg BID during the double-blind portion of 
the study
•Placebo in GS-US-312-0116 + IDELA 150 mg BID in GS US-312-0117: 
Subjects who have PD per IRC confirmation in Arm B of Study GS-US-312-
0116 and subsequently enroll in Study GS-US-312-0117 to receive IDELA 
150 mg BID during the double-blind portion of the study.
After unblinding, open-label extension study analyses will be presented in 
the following 4 groups:
•IDELA 150 mg BID: Subjects who are randomized to Arm A in Study GS-
US-312-0116 and transition to Study GS- US-312-0117 during the open-
label portion of the study to continue IDELA 150 mg BID
•Placebo in GS-US-312-0116 + IDELA 150 mg BID (open-label): Subjects 
who are randomized to Arm B in Study GS-US-312-0116 and transition to 
receive IDELA 150 mg BID during the open-label portion of the study
•IDELA 300 mg BID: Subjects who have PD per IRC confirmation in Arm 
A of Study GS-US-312-0116 and subsequently enroll Study GS-US-312-
0117 to receive IDELA 300 mg BID during the double-blind portion of the 
study
•Placebo in GS-US-312-0116 + IDELA 150 mg BID in GS-US-312-0117: 
Subjects who have PD per IRC confirmation in Arm B of Study GS-US-312-
0116 and subsequently enroll Study GS-US-312-0117 to receive IDELA 150
mg BID during the double-blind portion of the study. Analyses will focus on
evaluation of outcomes within each treatment arm and will be descriptive in 
nature; formal comparisons of outcomes between arms are not planned. 
Time-to-event endpoints will be summarized using Kaplan-Meier methods; 
medians, ranges, and the corresponding 95% CI will be presented. 
Continuous and categorical variables will also be summarized as appropriate. 
Changes from baseline in categorical variables and changes from baseline in 
continuous endpoints will be analyzed using appropriate methods.
Efficacy outcomes among subjects receiving rituximab alone in 
Study GS-US-312-0116 will be evaluated relative to those same outcomes 
among the same subjects receiving standard-dose idelalisib alone in 
Study GS-US-312-0117. 


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Based on the safety analysis set, information regarding study drug
administration, study drug compliance, safety variables, and post-study 
therapies will be described and summarized. Using data from the 
pharmacokinetic analysis set, idelalisib plasma concentrations will also be 
described and summarized.
Sample Size Calculation
The sample size for this extension study is not based upon a formal statistical 
hypothesis. The upper bound of the sample size in this study is determined 
by the sample size of the preceding primary clinical trial (Study GS-
US-312-0116) in which ~180 subjects (~90 per arm) are expected to be 
enrolled. Assuming a ~10% dropout rate during Study GS-US-312-0116 and 
a further ~10% dropout rate in the transition from the primary study to the 
extension study, ~180 subjects are expected to be enrolled into 
Study GS-US-312-0117.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP), 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
-HCG
Beta human chorionic gonadotropin
ABCG2
adenosine triphosphate-binding cassette sub-family G member 2 (see also BCRP)
AKT
AKT (a serine/threonine protein kinase)
ALC
absolute lymphocyte count
ALL
acute lymphocytic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
ATC
Anatomical-Therapeutic-Chemical classification system for drugs 
BCRP
breast cancer resistance protein (see also ABCG2)
BID
twice per day
BTK
Bruton tyrosine kinase
CAL-101
Former name for GS-1101
CCL
chemokine (C-C motif) ligand
CFR
Code of Federal Regulations
CI
confidence interval
CIRS
Cumulative Illness Rating Scale
CLL
chronic lymphocytic leukemia
cGMP
current Good Manufacturing Practice
Cmax
maximum concentration
CMV
cytomegalovirus
CR
complete response
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough concentration
CXCL
chemokine (C-X-C motif) ligand
CYP
cytochrome P450 enzyme
DLCO
diffusing capacity of the lung for carbon monoxide
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DOR
duration of response
DSPH
Gilead Sciences Department of Safety and Public Health
ECG
electrocardiogram


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
eCCr
estimated creatinine clearance
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EQ-5D
EuroQoL Five-Dimension utility measure
FACT-Leu
Functional Assessment of Cancer Therapy: Leukemia questionnaire
FCεRI
high-affinity IgE receptor
FDA
United States Food and Drug Administration
FDAMA
Food and Drug Modernization Act
FDG
fluorodeoxyglucose (18F)
FISH
fluorescence in-situ hybridization,
FSH
follicle-stimulating hormone
G-CSF
granulocyte colony-stimulating factor
GGT
gamma-glutamyltransferase
GLP
Good Laboratory Practice
GM-CSF
granulocyte-macrophage colony-stimulating factor
HBc antibody
anti-hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
hERG
human ether-à-go-go-related gene
HL
Hodgkin lymphoma
HIV
human immunodeficiency virus
HRQL
health-related quality of life
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
idelalisib
formerly CAL-101 and GS-1101
IEC
independent ethics committee
Ig
immunoglobulin (including subtypes A, E, G, and M)
IgHV
immunoglobulin heavy chain variable region
IND
Investigational New Drug (application)
iNHL
indolent non-Hodgkin lymphoma
INR
international normalized ratio
IRB
institutional review board
IRC
independent review committee
ITT
intention to treat
IUD
intrauterine device
IWCLL
International Workshop on CLL


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
IWRS
interactive web response system
JAK
Janus kinase
K2-EDTA
potassium-ethylenediaminetetraacetic acid
LD
longest diameter
LDH
lactate dehydrogenase
LH-RH
luteinizing hormone-releasing hormone
LLN
lower limit of normal
LPD
longest perpendicular diameter
LVD
longest vertical dimension
MTD
maximum tolerated dose
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mTOR
mammalian target of rapamycin
ND
no disease
NHL
non-Hodgkin lymphoma
NOAEL
no-observed-adverse effect level
NOEL
no-observed-effect level
OCT
organic cation transporter
ORR
overall response rate
OS
overall survival
pAKT
phosphorylated AKT
PCR
polymerase chain reaction
PD
progressive disease
PET
positron-emission tomography
PI3K
phosphatidylinositol 3-kinase
PI3K
phosphatidylinositol 3-kinase p110isoform
PFS
progression-free survival
PML
progressive multifocal leukoencephalopathy
PP
per-protocol
PPD
product of the perpendicular diameters
PRO
patient-reported outcome
PR
partial response
PT
prothrombin time
PVA
polyvinyl alcohol
PVC/PCTFE
polyvinyl chloride/polychlorotrifluoroethylene
QD
once per day
QT (interval)
measure of time between start of Q wave and end of T wave in electrical cycle of heart


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED)
RNA
ribonucleic acid
SADR
serious adverse drug reaction
SD
stable disease
SPD
sum of the products of the perpendicular diameters of measured lymph nodes
SSC
study steering committee
SUSAR
suspected, unexpected, serious adverse reaction
SYK
spleen tyrosine kinase
t1/2
half-life
Tmax
time of maximum concentration
TTR
time to response
UGT
uridine 5'-diphospho-glucuronosyltransferase
ULN
upper limit of normal
WHODRUG
World Health Organization Drug Dictionary
ZAP-70
zeta-associated protein 70


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1.
INTRODUCTION
Chronic Lymphocytic Leukemia
1.1.
Chronic lymphocytic leukemia (CLL) is a neoplasia resulting from the progressive accumulation 
of functionally incompetent monoclonal B lymphocytes in blood, bone marrow, lymph nodes, 
spleen, and liver {19448}. CLL constitutes the most commonly occurring leukemia in Europe and 
the United States {20169}, {17688}. While some patients never require treatment, many will need 
therapy for disfiguring or obstructing lymphadenopathy, debilitating constitutional B symptoms 
(fevers, night sweats, fatigue, weight loss) {20168}, or recurrent cytopenias and infections
{17828}, {19449}. CLL is largely a disease of the elderly; at diagnosis, 70% of patients are 
65 years of age and the median age is 72 years {17688}.
In younger and relatively healthy patients with CLL, chemoimmunotherapy regimens that 
include the anti-CD20 monoclonal antibody, rituximab, are commonly employed to control 
disease manifestations {17676}. Such combination therapies are effective in providing durable 
remissions {20163}, {20165}, {17687}, {20360}, {20359}. However, while rituximab is usually
well tolerated {19036}, the chemotherapeutic agents (typically fludarabine, cyclophosphamide, or 
bendamustine) in such regimens are acutely cytotoxic, induce permanent bone marrow 
compromise, and can cause secondary malignancies {26356}, {18997}, {17717}. Furthermore, in 
elderly patients or in those with comorbid conditions, such regimens are associated with less 
efficacy and greater toxicity {18997}, {19032}, {17674}.
Increasing attention has been paid to the problem of treating patients with CLL who have 
comorbidities. Because of the relatively late age of diagnosis, a large proportion (~90%) of 
patients with CLL have co-morbidities and a substantial proportion (~45%) have major chronic 
conditions such as coronary artery disease, diabetes, or chronic obstructive pulmonary disease 
{20525}. At the time the disease is first identified, ~25% of patients with CLL do not meet 
conventional criteria for participation in clinical studies containing cytotoxic agents {20525}. By 
the time treatment is necessary or during treatment for CLL, patients continue to advance in age 
and have new or worsening chronic conditions; as a result, the proportion of patients with 
comorbidities increases during the course of the illness. Such patients have been substantially 
underrepresented in clinical trials due to concerns regarding the ability of such patients to 
tolerate intensive chemoimmunotherapy {20525}, {20558}. Instruments such as the Cumulative 
Illness Rating Scale (CIRS) {21025} are now being applied in order to categorize patient 
populations as fit or relatively unfit and to evaluate regimens tailored to these groups of patients 
{20558}, {20165}, {21059}.


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Health constraints in older or compromised patients have prompted noncytotoxic approaches to 
therapy. Alternative immunotherapeutics, such as the monoclonal antibodies, alemtuzumab
{17680} or ofatumumab {21022}, have been developed. However the therapeutic utility of these 
drugs is modest; median progression-free survival (PFS) values in patients with recurrent CLL 
have been 4.7 months and 5.8 months, respectively. Moreover, these treatments can have clinical 
liabilities. Alemtuzumab causes extreme immunosuppression that leads to frequent opportunistic 
infection. Administration of the large amounts of protein recommended in ofatumumab product 
labeling results in frequent infusion reactions and cumbersome infusion schedules.
In view of these issues, repeated use of rituximab monotherapy or rituximab-corticosteroid 
combinations have been advocated in treatment guidelines for older or frail patients with 
recurrent CLL {17670}, {19042}. While single-agent rituximab use can offer palliative benefit 
with good tolerability in some patients with previously treated CLL, tumor control is not lasting, 
especially in patients with bulky adenopathy {19036}. Addition of high-dose corticosteroids to 
rituximab can extend median PFS up to 12 months, but this combination is commonly associated 
with severe hyperglycemia and frequent life-threatening or fatal infections {19037}, {19035}. 
New, noncytotoxic, well-tolerated, and convenient therapies that can successfully be combined 
with rituximab or given as single-agent therapy are needed in order to enhance and prolong 
tumor control in patients with comorbid conditions.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies
1.2.
Phosphatidylinositol 3-kinases (PI3Ks) are enzymes that regulate several cellular functions 
including motility, proliferation, and survival {23618}. PI3K activation recruits and activates 
numerous intracellular signaling enzymes. The most important of these is the serine/threonine 
kinase, AKT, which mediates a positive pleiotropic effect on cell survival, proliferation, growth, 
and metabolism {17720} acting by signaling through mammalian target of rapamycin (mTOR) 
{17678}, {17686}.
PI3K signaling is mediated by 4 catalytic isoforms of the p110 subunit of the enzyme - , , , 
and . While potentially important in multiple cell types, PI3K p110(PI3K) shows an 
expression pattern that is particularly prominent in cells of hematopoietic origin {17690}. Mice 
deficient in PI3Khave no gross abnormalities, are fertile, fecund, and live a normal life span 
without an increased susceptibility to infections {23619}. However, the B-lymphocyte population 
in these animals shows a decrease in maturation, diminished receptor-induced proliferation, and 
increased susceptibility to apoptotic cell death. Conversely, mice with aberrantly elevated PI3K 
signaling develop lymphadenopathy and have an increased incidence of lymphoma {17719}. In 
CLL, sustained activation of the PI3K/AKT/mTOR pathway has been shown to promote 
malignant B-cell survival through mechanisms that are dependent on the PI3Kisoform {24339}, 
{23399}, {19034}.
Knowledge of the critical importance of PI3Kδ in B-cell biology and neoplasia has encouraged a 
search for inhibitors of this enzyme that could provide new options in the therapy of lymphoid 
malignancies, including CLL.


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Idelalisib (formerly GS-1101)
1.3.
1.3.1.
Discovery and Efficacy Pharmacology
Gilead Sciences, Inc has developed novel drugs that can suppress tumor growth through 
targeting of PI3Kδ activity. High-throughput screening was the basis for the discovery of novel 
agents that selectively inhibit PI3Kfunction but spare other PI3K isoforms and other kinases. 
Chemical optimization, pharmacological characterization, and toxicological evaluation have led 
to identification of idelalisib (also known as GS-1101), a 415-dalton, orally bioavailable, new 
chemical entity with potential clinical utility in the treatment of cancers.
In primary tumor samples and in cell lines derived from patients with CLL, indolent 
non-Hodgkin lymphoma (iNHL), mantle cell lymphoma (MCL), B-cell acute lymphocytic 
leukemia (ALL), or Hodgkin lymphoma (HL), idelalisib induces dose-dependent reductions in 
AKT phosphorylation {23399}, {20167}, {19034}. In addition, idelalisib disrupts the PI3K
activation and supportive intercellular signaling observed when CLL or HL cells are cocultured 
with stromal cells {20167}, {23401}. These effects have therapeutic consequences. In multiple 
lymphoid primary tumors and malignant cell lines, idelalisib enhances apoptosis and 
concentration-dependent cell killing when applied as a single agent and increases the therapeutic 
efficacy of other antineoplastic agents when given in combination {23401}, {20902}. In 
preclinical systems, coadministration of idelalisib with rituximab has not impaired 
rituximab-mediated activity {23399}.
1.3.2.
Safety Pharmacology
In vitro and in vivo safety pharmacology studies with idelalisib have demonstrated a favorable 
non-clinical safety profile. These studies indicate that the drug may minimally slow bone marrow 
progenitor proliferation and differentiation and that it has expected inhibitory effects on B-cell
response to antigen challenge. However, the data indicate that idelalisib is unlikely to cause 
serious off-target effects or adverse effects on critical organ systems. idelalisib has no 
meaningful effect on the human ether-à-go-go-related gene (hERG) channel, indicating that 
idelalisib would not be expected to induce clinical QT prolongation.
The drug has also proved well tolerated in standard in vivo Good Laboratory Practice (GLP) 
studies of pharmacological safety. A functional observation battery in rats revealed no adverse 
effects on behavior or on autonomic, neuromuscular, or sensorimotor function. In a 
cardiopulmonary function study in awake, telemeterized male beagle dogs, single doses of 
idelalisib induced no meaningful abnormalities in pulmonary, cardiovascular, arterial blood gas, 
or electrocardiographic (ECG) (including QT interval) parameters. In an assessment of bacterial 
challenge in rats, idelalisib enhanced, rather than impaired, the phagocytic host clearance of 
staphylococcal bacteria.


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1.3.3.
Nonclinical Pharmacology and Metabolism
Consistent with the moderate to high bioavailability seen in nonclinical species, idelalisib shows 
high permeability across human Caco-2 cell monolayers.  At lower concentrations, the reverse 
permeability at low concentration exceeds forward permeability, indicating efflux driven by 
transporters (eg, human P-glycoprotein (MDR1) and breast cancer resistance protein [BCRP]); 
idelalisib is a substrate for the efflux transporters MDR1 and BCRP; however, the permeability 
increases in a concentration-dependent manner, resulting in a lower efflux ratio at higher, 
clinically relevant concentrations of idelalisib. 
Idelalisib exhibits moderately high plasma protein binding in mouse, rat, dog, and human.  In 
dog and human plasma, the protein binding is concentration-independent between 1 and 20 µM.  
Protein binding in human plasma is slightly higher than in mouse, rat, and dog plasma, which 
have comparable free fractions.  In human plasma, idelalisib and GS-563117 (the major
metabolite of idelalisib) have an average free fraction of ~16% and ~12%, respectively.
After oral administration of 14C-idelalisib to rats and dogs, radioactivity is widely distributed, but 
relatively excluded from bone, brain, spinal cord, and eye lens in rats and from brain and eyes in 
dogs.  In rats, the radioactivity declines steadily and most tissues have undetectable levels by 
72 hours post dose.  In bile duct-cannulated rats and dogs, ≥ 69% of radioactivity is recovered in 
bile and urine, indicating high absorption of idelalisib in vivo.
In hepatic tissues from nonclinical species, idelalisib is primarily metabolized by aldehyde 
oxidase, CYP3A, and UGT1A4.  In vitro metabolism in dog and human yields 3 primary 
oxidative metabolites and 5 primary glucuronides.  Of these, the oxidative product GS-563117 is 
the predominant metabolite in vitro and in vivo.  In preclinical species, plasma levels of 
GS-563117 are below those of idelalisib.  In humans, GS-563117 (only circulating metabolite 
and formed via aldehyde oxidase) plasma levels significantly exceed those of idelalisib.  After 
oral administration of 14C-idelalisib to rats and dogs, biliary excretion appears to be the major 
route of elimination of idelalisib and its metabolites as the majority of radioactivity is found in 
feces or bile and little in urine.
Idelalisib is not a substrate for the renal transporters OCT2, OAT1, and OAT3 or the hepatic 
uptake transporters OATP1B1 and OATP1B3.  GS-563117 is not a substrate for OATP1B1 and 
OATP1B3.  
Idelalisib is not an inhibitor of CYP1A, CYP2B6, CYP2C9, and CYP2D6, and at concentrations 
above those observed clinically, is an inhibitor of CYP2C8 (IC50 = 13 µM), CYP2C19 
(IC50 = 76 µM), and CYP3A (IC50 = 44 µM). GS-563117 is not an inhibitor of CYP1A, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and a competitive and time dependent 
inhibitor of CYP3A (IC50 = 3.1 µM), (KI = 0.18 µM, kinact = 0.033 min-1 with midazolam as 
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In vitro, idelalisib is not an inhibitor of the transporters BCRP, OCT2, OAT1, and OAT3, and is 
an inhibitor of MDR1 (IC50 = 7.7 µM), OATP1B1 (IC50 = 10.1 µM), OATP1B3 (IC50 = 7.0 µM), 
and, at concentrations above those observed clinically, of glucuronosyltransferase UGT1A1 
(IC50 = 42.0 µM).  GS-563117 is not an inhibitor of MDR1, BCRP, OATP1B1, OATP1B3, 
OAT1, OAT3, and OCT2, and at concentrations above those observed clinically, an inhibitor of 
UGT1A1 (IC50 = 16.8 µM).
Any potential clinical implications of these metabolism studies were evaluated in a formal drug-
drug interaction study (GS-US-313-0130) which evaluated the effect of idelalisib on cytochrome 
P450 3A and the drug transporters P-gp, OATP1B1, and OATP1B3.  Study GS-US-313-0130 
also evaluated the impact of an inducer of metabolizing enzymes and transporters (rifampin) on 
the PK of idelalisib in healthy human subjects. Findings from this study are presented in 
Section 1.3.5.1.
1.3.4.
Toxicology
The toxicological profile of idelalisib was well characterized through the conduct of single dose, 
repeat dose, developmental and reproductive, and genetic toxicology and local tolerance studies.  
The primary target organ toxicities following repeated dosing include the lymphoid, hepatic, 
male reproductive systems in rats and dogs, and gastrointestinal system in dogs.  Adverse effects 
in the lymphoid system were primarily the result of on target pharmacology resulting in 
decreased lymphocytes in multiple lymphoid organs, primarily involving B-cell regions.  Liver 
effects were transient and reversible with continued dosing and did not result in chronic liver 
injury.  Reduction in sperm numbers in males were reversible and did not impact fertility or 
reproductive performance.  Gastrointestinal effects in dogs were minor, superficial, and 
considered secondary to effects on lymphocytes in Peyer’s Patches.  Idelalisib was shown to be 
teratogenic and associated with embryo-fetal lethality.  Effects on the reproductive system have 
been reported for inhibitors which target other isoforms of PI3K.  The dose-dependence and 
potential of idelalisib to selectively inhibit additional PI3K isoforms may be responsible for the 
off-target toxicity.  Additionally, the drug may have the potential to produce phototoxic reactions 
in humans.  These findings represent toxicities that can be monitored, are considered clinically 
manageable, or are considered acceptable risks in the intended patient population.
Further details on the toxicology of idelalisib can be found in the Idelalisib Investigator’s 
Brochure (IB).
1.3.5.
Idelalisib Clinical Studies
1.3.5.1.
Phase 1 Studies in Healthy Subjects and in Patients with Allergic Rhinitis
Various studies in healthy subjectshave evaluatedsafety, pharmacokinetics, food effect, and the 
potential for drug interactions of idelalisib with CYP3A4 inhibitors {20361}. 


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Safety results from these studies indicated that idelalisib was well tolerated when administered to 
healthy subjects at single doses through 400 mg (the highest dose level tested) and was also 
generally well tolerated when administered to healthy subjects over 7 days at dose levels through 
200 mg/dose BID (the highest dose level tested). Dosing with 200 mg/dose BID for 7 days 
resulted in a skin rash in 3 out of 6 subjects; histological findings were consistent with a 
delayed-type hypersensitivity maculopapular exanthema. Rashes have sometimes occurred in 
patients with hematological malignancies receiving idelalisib, but have not typically proved 
dose- or treatment-limiting. In placebo-controlled single-dose and multiple-dose trials, repeated 
ECG evaluations performed in tandem with pharmacokinetic monitoring showed no evidence of 
drug-, dose-, or exposure-dependent effects on cardiac rhythm or cardiac intervals 
(eg, QT interval). Pharmacokinetic results indicated that idelalisib appeared rapidly in plasma 
with a median Tmax of 1 to 1.5 hours.  Cmax and AUC increased in a less-than-dose-proportional 
manner and mean t1/2 values were across the dose range were 6.5 to 9.8 hours.
Idelalisib dosing after a high-fat, high-calorie meal delayed median time of maximum 
concentration (Tmax) from 0.75 hours to 3 hours; mean Cmax was unaffected and mean AUC was 
~40% higher. These changes in idelalisib exposures are considered modest/clinically 
non-relevant; thus, idelalisib may be given with or without food.
Idelalisib is metabolized in humans primarily by aldehyde oxidase, with some involvement of 
CYP3A4 and UGT1A4. Accordingly, when idelalisib was administered following 4 days of daily 
dosing with ketoconazole (a potent inhibitor of CYP3A4), modest/moderate increases in mean 
idelalisib Cmax and AUC values of ~30% and ~80% higher, respectively, which is not considered 
to be clinically relevant and suggesting that idelalisib is a weak CYP3A substrate. GS-563117 is 
formed from idelalisib primarily via aldehyde oxidase.
The 14C-labeled idelalisib human mass balance results showed that the drug has moderate to high 
oral bioavailability. Idelalisib is eliminated mainly via hepatic metabolism and biliary excretion 
in the feces (~78% of dose); recovery in urine was < 15%. GS-563117, the only circulating 
metabolite observed in human plasma, was also observed in urine and feces. 
Results from the drug interaction/probe Study GS-US-313-0130 indicate that idelalisib does not 
affect the pharmacokinetics of substrates of Pgp, BCRP, OATP1B1 or OATP1B3 transporters. 
Idelalisib is not expected to affect the exposures of coadministered agents via transporter 
mediated interactions. 
The exposures (AUC) of probe CYP3A substrate, midazolam, increased ~5-fold upon 
coadministration with idelalisib, driven by competitive and time-dependent CYP3A inhibition by 
GS-563117, the only circulating metabolite of idelalisib. Coadministration of the highly potent 
CYP3A inducer rifampin resulted in a ~75% reduction in idelalisib systemic exposures, likely 
driven by a higher relative contribution of CYP3A to overall idelalisib clearance under the 
induced state.


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Pharmacodynamic results showed that a idelalisib dose of 200 mg inhibited ex vivo basophil 
activation via the PI3K-specific, high-affinity immunoglobulin (Ig)E receptor (anti-FCR1) in 
basophils collected from healthy volunteers. The findings were confirmed when the drug was 
assessed over 7 days in a Phase 1b study in subjects with allergic rhinitis. In this study, idelalisib
at a dose level of 100 mg/dose BID showed clinical and pharmacodynamic activity 
(attenuating adverse responses to allergenic challenge and decreasing markers of inflammation) 
and was well tolerated.
1.3.5.2.
Phase 1 Studies in Patients with Hematological Malignancies
1.3.5.2.1.
Phase 1 Monotherapy Study in Patients with Hematological Malignancies
A Phase 1 dose-ranging study (Study 101-02) of single-agent idelalisib extended safety and 
pharmacokinetic observations; documented the clinical and pharmacodynamic activity of 
idelalisib in subjects with iNHL, MCL, and CLL; and provided dosing information in support of 
further development {20397}, {21030}, {21036}. In this study, idelalisib was administered in 
cohorts of subjects across a range of dose levels from 50 mg/dose BID to 350 mg/dose BID. 
Idelalisib administration was continued as long as individual subjects were safely benefitting 
from therapy. Subjects were evaluated in 4-week cycles; response and progression assessments 
were based on standard criteria {12154}.
A total of 191 subjects were enrolled to the study at dose levels of 50 mg BID (n=17), 150 mg 
QD (n=16), 100 mg BID (n=25), 150 mg BID (n=45), 200 mg BID (n=35), 350 mg BID (n=17), 
and 300 mg QD (n=19). An additional cohort was also enrolled to receive idelalisib 150 mg BID 
in 28 day cycles (21 days on idelalisib/7 days off [n=17]). Subject characteristics were as 
follows: males/females n=139 (73%)/52 (27%) with median age of 64.5 (range 32-91) years.  
Diagnoses included: CLL, n=54 (28%); iNHL, n=64 (34%); aggressive NHL (MCL and 
DLBCL), n=49 (26%); AML, n=12 (6%); and MM, n=12 (6%).  Categorization of disease by 
response to the last prior therapy included: refractory, n=111 (58%); relapsed, n=79 (42%); and 
unknown, n=1 (1%).  The median (range) number of prior therapies was 5 (1-14). Among 
subjects with iNHL and CLL, the majority had received prior rituximab and prior alkylating 
agent therapy. 
Adverse events were usually mild to moderate and not clearly idelalisib-related.  Among 
Grade ≥3 adverse events, pneumonias and diarrhea were notable.  Pneumonia was observed in 
23 (12%) subjects, primarily in subjects with CLL.  In most instances, these findings were 
considered bacterial in origin, based either on culture results or on response to conventional 
antibiotics.  Grade ≥3 adverse events of diarrhea were seen in 11 subjects (5.8%).  Other 
Grade ≥3 events included rash in 3 (1.6%) subjects.  The relative contributions of disease-related 
factors, toxicity from prior therapies or ongoing supportive care, and idelalisib to these events 
was not clear.


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Grade ≥3 hematological laboratory abnormalities have included neutropenia, n=46 (24%); 
thrombocytopenia, n=27 (14%), anemia, n=14 (7.3%), and lymphopenia 13 (6.8%); with 
12 subjects (6.3%) having febrile neutropenia.  The occurrence of these events was greater in 
subjects with leukemia, particularly in those with pre-existing hematological abnormalities due 
to disease or prior therapy, commonly making attribution of these events to idelalisib uncertain.
Consistent with the observations in the 28-day dog toxicology study, reversible Grade ≥3 
ALT/AST elevations occurred in 28 (15%) subjects and have been attributed to idelalisib.  Onset 
generally occurred between 2 to 16 weeks after idelalisib initiation and resolution was usually 
seen 2 to 6 weeks after idelalisib interruption.  After resolution of ALT/AST increases, 
14 subjects were rechallenged at the same or a reduced dose of idelalisib and 9 (64%) of these 
subjects were able to resume treatment without recurrence of transaminase elevations.  
Two (1.0%) subjects had ≥ 2 x ULN elevations in bilirubin in the context of Grade ≥3 elevated 
AST / ALT, both of whom had confounding factors (recent history of biliary obstruction or 
concomitant use of potentially hepatotoxic medications) so that a definitive causal relationship to 
idelalisib could not be established. 
Pharmacokinetic analyses indicated that the increase in Cmax and AUC0-6h with dose was less 
than dose-proportional, with modest increases above the dose level of 150 mg BID.  
Pharmacodynamic data supported drug activity.  In subjects with NHL, plasma concentrations of 
chemokines CCL22 and CCL17 were elevated at baseline and showed significant decreases 
within 1 cycle of idelalisib treatment (p<0.001 for both comparisons).  Flow cytometry of CLL 
cells from subjects showed that idelalisib reduced constitutive expression of phosphorylated 
AKT to background levels when measured after 1 week of treatment (p<0.0001), demonstrating 
pharmacodynamic inhibition of activated PI3K signaling.  Plasma concentrations of chemokines 
CCL3, CCL4, and CXCL13 were elevated in CLL subjects at baseline and decreased 
significantly within 1 cycle of idelalisib administration (p<0.001 for all comparisons).
Tumor reductions meeting antitumor response criteria were not observed in subjects with AML 
or MM.  One of 11 subjects with DLBCL achieved a PR.  In 104 subjects with iNHL and MCL, 
idelalisib induced PRs at all dose levels, with respective ORRs in enrolled subjects of 
29/64 (45%) for iNHL and 16/40 (40%) for MCL. The median DOR has not been reached in 
subjects with iNHL; 19 subjects continued to receive idelalisib in a long-term extension study.   
The median [range] DOR was 2.7 months [1 month to 8 months] in subjects with MCL; 6 MCL 
subjects continued to receive idelalisib in a long-term extension study. 
In subjects with CLL, idelalisib reduced lymphadenopathy in almost all subjects; 44/54 (81.5%) 
achieved a lymph node response (≥50% reduction in target nodal lesions).  An initial increase in 
peripheral absolute lymphocyte counts of >50% from baseline was observed in some subjects; 
increases were maximal during the first 2 cycles and decreased thereafter; the pattern suggested 
drug-mediated lymphocyte redistribution.  In 54 subjects with CLL, 39/54 (72%) achieved a PR 
(includes PR with lymphocytosis).  The median DOR was not reached; 23 subjects continued to 
receive idelalisib in a long-term extension study.  


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1.3.5.2.2.
Phase 1 Combination Study in Patients with Hematological Malignancies
A separate Phase 1 trial (Study 101-07) has evaluated the safety and preliminary activity of 
idelalisib given in combination with rituximab to subjects with recurrent iNHL or CLL {20397}, 
{19528}.
In this study, rituximab was administered at a standard dose of 375 mg/m2 per infusion weekly 
for 8 weeks in all subjects. Idelalisib was started simultaneously with the rituximab, first at a 
dose level of 100 mg/dose BID (n=13) and then at a dose level of 150 mg/dose BID (n=12) and 
was administered continuously to both subjects with CLL (n=13) and subjects with iNHL (n=12)
for as long as individual subjects were safely benefiting from therapy. Subjects were evaluated in 
4-week cycles; response and progression assessments were based on standard criteria {12154}.
Among the subjects with CLL, the median age was 63 and ranged to 85 years. Bulky tumors 
(1 lymph node 5 cm in diameter) were present in 63% of the subjects. The median number of 
prior therapies by disease was 2 and ranged up to 8 prior treatments. All had received prior 
rituximab and the majority had received prior fludarabine or alkylating agents. Approximately 
one-third of subjects had CLL that was refractory to the last prior therapy. At the time of data 
cut-off, therapy had been administered for a median of 5 cycles, ranging up to 12 cycles 
(ie, 48 weeks).
No idelalisib-related dose-limiting toxicities were observed within the tested subject cohorts. 
Grade 3-4 adverse events largely comprised background events resulting from pre-existing 
disease- or treatment-related conditions or from intercurrent illness. Among subjects with CLL, 
2 (15%) developed pneumonia. For subjects receiving idelalisib together with rituximab, 
Grade 3-4 elevations in ALT/AST were not observed in those with CLL, although 3 subjects 
(25%) of those with iNHL had such events.
The idelalisib plus rituximab combination showed a high level of antitumor activity in both 
subjects with CLL and those with iNHL. Altogether 92% of subjects with CLL receiving the 
combination of idelalisib and rituximab had reductions in nodal size and 77% showed a lymph 
node response (50% reduction in index nodal lesions). Although concomitant administration of 
rituximab did not eliminate the redistribution lymphocytosis that is associated with idelalisib, it 
blunted the magnitude of the change. As a result, the overall response rate (ORR) was also 
77% among subjects participating in this study. At the time of last data analysis, PFS through 
48 weeks was 70% and a median PFS had not yet been observed.
Collectively, the emerging data from this study support further evaluation of idelalisib together 
with rituximab in subjects with CLL and indicate that co-administration of idelalisib with 
rituximab is tolerable when using idelalisib at full dose, ie, at a starting dose level of 
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Summary and Justification for the Current Study
1.4.
Gilead Sciences is conducting this Phase 3 study program to evaluate the efficacy and safety of 
idelalisib in patients with previously treated, recurrent CLL. Collectively the data derived from 
the primary clinical trial (Study GS-US-312-0116) and from this extension trial 
(Study GS-US-312-0117) address the activity of idelalisib together with rituximab, the activity 
of idelalisib when given alone, and the potential for dose-dependent restoration of drug activity 
in subjects who have disease that appears to be drug resistant.
The design and conduct of this clinical trial program is supported by knowledge of the 
demographics of patients with CLL, the natural history and current therapies for the disease, and 
the nonclinical and clinical information regarding idelalisib. The collective data support the 
following conclusions:

CLL is a serious, disabling, and potentially life-threatening disorder of older patients that 
requires sequential treatment with agents that provide alternative mechanisms of tumor 
control. Existing cytotoxic agents have serious acute and chronic toxicities, making them less 
suitable for frail or unfit patients. Single-agent rituximab can offer disease palliation with 
good tolerability in some patients with relapsed CLL but tumor control is not lasting, 
especially in patients with bulky adenopathy. Development of a non-cytotoxic combination 
therapy of idelalisib with rituximab or a monotherapy regimen of idelalisib that can address 
disease pathogenesis with a new mechanism of action and might offer complementary nodal 
and peripheral blood activity would address an unmet medical need, particularly when 
applied in patients with substantial comorbidities or myelosuppression from prior 
chemotherapies.

PI3Kδ over-expression plays an important role in CLL biology. Further evaluation of 
idelalisib as a potential treatment for CLL has sound scientific rationale founded on 
knowledge of the actions of the drug to selectively abrogate PI3Kδ activity and to inhibit 
malignant cell growth and stromal cell signaling in nonclinical models of CLL. These data 
are supported by clinical documentation of idelalisib inhibition of PI3Kδ signaling in patients 
with CLL.

The potential for clinical efficacy of idelalisib monotherapy or of idelalisib plus rituximab in 
patients with relapsed or refractory CLL is supported by the observed antitumor activity of 
idelalisib – given alone or in combination with rituximab - in patients with heavily pretreated 
CLL and iNHL.

The safety of advancing development of the idelalisib monotherapy and of a regimen of 
idelalisib plus rituximab in this Phase 3 clinical trial program is well supported by safety 
pharmacology and toxicology studies and by Phase 1 single-agent and combination safety 
data obtained in healthy volunteers and in subjects with lymphoid cancers. 

Dose-safety, dose-exposure, and dose-activity relationships identified in Phase 1 studies
support the dosing regimen and dose modification provisions in this study.


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
Observations relating to patterns of CLL response among subjects receiving idelalisib alone 
or in combination with rituximab in Phase 1 trials provide the foundation for efficacy
monitoring in this trial. Of particular note is that idelalisib mobilizes CLL cells from tissues 
into the peripheral blood. This characteristic pharmacological action is prominent early in 
therapy but can persist over time and should not be confused with disease progression in 
patients who have persistent control of other CLL-related signs and symptoms. For this 
reason, in this Phase 3 study program, subjects will be continued on therapy until the 
occurrence of definitive disease progression, ie, disease progression that is manifest by 
worsening CLL-related signs or symptoms other than lymphocytosis alone. 

Thorough nonclinical and clinical characterization of the type, severity, manifestations, and 
expected timing of adverse events establish the safety monitoring plan in this trial program.

The scientific correlative work performed in prior preclinical and clinical studies provides 
strong scientific underpinnings for the companion laboratory studies to be performed as a 
component of this clinical trial program.

Given the seriousness of previously treated CLL in patients with substantial comorbidity, and 
the aggregate potential benefits considered in the context of potential risks, further 
development of idelalisib in this Phase 3 clinical trial program is justified.
The rationale for specific design features is provided in relevant sections of the protocol, 
including Section 3.2 (Endpoint Selection Rationale), Section 2.2 (Design Rationale), Section 4.3
(Enrollment Criteria Rationale), Section 5.10 (Study Treatment Rationale), and Section 6.5
(Study Procedure Rationale).


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2.
STUDY DESIGN
Design Overview and Study Schema
2.1.
This study is being conducted as part of an overall clinical program that is evaluating the efficacy 
and safety of idelalisib in the therapy of patients with previously treated CLL (see Figure 2-1). 
Within this program, the primary clinical trial (Study GS-US-312-0116) is a Phase 3, 
multicenter, 2-arm, randomized, double-blind, placebo-controlled, parallel-group study. This 
clinical trial (Study GS-US-312-0117) is a separate, multicenter, 2-arm, double-blind, 
parallel-group extension study that is a companion study to the primary study.
Figure 2-1.
Study Design
Candidates for the primary study will be adults with previously treated recurrent CLL who have 
measurable lymphadenopathy, require therapy for CLL, have experienced CLL progression 
<24 months since the completion of the last prior therapy, and are currently not sufficiently fit to 
receive cytotoxic therapy because of chemotherapy-induced bone marrow damage or 
comorbidities.
Primary study subjects will be stratified based on 17p deletion and/or a p53 mutation status 
(either vs neither), immunoglobulin heavy chain variable region (IgHV) mutation status 
(unmutated vs mutated), and any prior therapy with an anti-CD20 therapeutic monoclonal 
antibody (yes vs no) and randomized in a 1:1 ratio to receive 1 of the 2 treatment arms. 
In the primary study, subjects will be administered rituximab intravenously in the clinic starting 
at a dose of 375 mg/m2 on Day 1 (Week 0) and will continue with a dose of 500 mg/m2 on 
Day 15 (Week 2), Day 29 (Week 4), Day 43 (Week 6), Day 57 (Week 8), Day 85 (Week 12), 
Day 113 (Week 16), Day 141 (Week 20) (for a total of 8 infusions). Rituximab will be
administered until the earliest of subject withdrawal from study, definitive progression of CLL, 
intolerable rituximab-related toxicity, pregnancy, substantial noncompliance with study 
procedures, study discontinuation, or a maximum of 8 infusions.


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Idelalisib or placebo will be taken orally, BID continuously. Subjects will continue whichever 
study drug (idelalisib/placebo or rituximab) continues to be tolerated, even if the other drug has 
been discontinued due to toxicity.
If permanent discontinuation of study drug, occurs prior to definitive progression of CLL, 
subjects shall remain on study until definitive progression of CLL or withdrawal from the study 
for reasons specified in Section 5.7.
Compliant subjects who are tolerating therapy but who develop definitive disease progression in 
the primary clinical trial (Study GS-US-312-0116) can consider enrollment in this separate 
companion extension trial (Study GS-US-312-0117). In the extension trial, subjects will take 
active blinded idelalisib therapy, either at a higher starting dose or at the standard starting dose, 
with allocation based on the original primary study randomization. Following unblinding of 
Study GS-US-312-0116, subjects will be allowed to enter Study GS-US-312-0117 in the absence 
of evidence of disease progression and will take 150 mg BID idelalisib regardless of treatment 
assignment in Study GS-US-312-0116.
The primary objective of Study GS-US-312-0116 will be to evaluate the effect of the addition of 
idelalisib to rituximab on PFS. Secondary and tertiary objectives will focus on determining the 
effect of the addition of idelalisib to rituximab on the onset, magnitude, and duration of tumor 
control; overall survival (OS); health-related quality of life (HRQL); changes in subject 
performance status; disease-associated biomarkers and potential mechanisms of resistance; 
treatment administration; safety; and health resource utilization. In Study GS-US-312-0117, the 
same endpoints will be assessed as in Study GS-US-312-0116; the focus of the analysis will be 
largely descriptive except for the within-subject assessment of treatment effects among subjects 
receiving first rituximab alone and then idelalisib alone on Arm B of each trial. No formal 
comparisons of outcomes in Arm A vs Arm B are planned within Study GS-US-312-0117.
Design Rationale
2.2.
The randomized, add-on design for the primary trial (Study GS-US-312-0116) is customary in 
the comparative evaluation of new therapies for cancer. While this design provides idelalisib
efficacy and safety information only in the context of administration of a companion 
antineoplastic agent, it is appropriate because it documents the incremental benefit and toxicity 
of the investigational therapy in the context of a controlled clinical trial while ensuring that all 
participants receive potentially active treatment.
This separate extension trial (Study GS-US-312-0117) enhances subject acceptance of 
randomization in the primary study and provides further information regarding idelalisib
efficacy, resistance, and safety. Among subjects in Arm A, escalation to a higher dose level 
allows evaluation of dose-dependent resistance and a determination if a higher dose can 
reestablish disease control. The safety data obtained in these subjects will add to the overall 
safety database. Among subjects randomized to Arm B in the primary study, evaluation of 
idelalisib at a starting dose of 150 mg/dose BID in the extension study may permit a 
within-subject assessment of the treatment effects with single-agent idelalisib relative to the 
effects previously observed with rituximab alone. Of importance, the extension study maintains 


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the partial blinding of the primary study, thus minimizing the bias that might occur if the overall 
design entailed only a 1-way crossover to open-label idelalisib among subjects who had received 
placebo on Arm B of the primary study. To ensure confirmation of disease progression, tumor 
size data collected from the primary study will be subjected to independent review by an 
independent review committee (IRC) (see Section 10.4.2); subjects will continue with study 
therapy pending confirmation of progression status by the sponsor working in collaboration with 
the IRC. Subjects must have confirmation that the disease has progressed on the primary study 
before being permitted to receive secondary idelalisib therapy on the extension study, or in the 
event the primary study is stopped, subjects who have not yet progressed may enroll on the 
extension study to receive 150 mg BID idelalisib.


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3.
OBJECTIVES AND ENDPOINTS

To evaluate the effect of idelalisib on the onset, magnitude, and duration of tumor control

To compare tumor control in subjects receiving rituximab alone in Study GS-US-312-0116 to 
that observed in the same subjects when receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject well-being, including overall survival 
(OS), health-related quality of life (HRQL), and performance status

To assess the effects of idelalisib on disease-associated biomarkers and to evaluate potential 
mechanisms of resistance to idelalisib

To characterize exposure to idelalisib as determined by treatment administration and 
evaluation of idelalisib plasma concentrations over time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with administration of idelalisib
Endpoints
3.1.
3.1.1.
Tumor Control

Progression-free survival (PFS) – defined as the interval from the start of study therapy to the 
earlier of the first documentation of definitive disease progression or death from any cause; 
definitive disease progression is CLL progression based on standard criteria other than 
lymphocytosis alone

ORR – defined as the proportion of subjects who achieve a CR or partial response (PR) 

Lymph node response rate – defined as the proportion of subjects who achieve a 
50% decrease from baseline in the SPD of index lymph nodes

CR rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from start of study therapy to the first 
documentation of CR or PR

Duration of response (DOR) – defined as the interval from the first documentation of CR or 
PR to the earlier of the first documentation of definitive disease progression or death from 
any cause


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
Percent change in lymph node area – defined as the percent change from baseline in the sum 
of the products of the greatest perpendicular diameters (SPD) of index lymph nodes

Splenomegaly response rate – defined as the proportion of subjects with baseline 
splenomegaly who achieve an on-study normalization or a 50% decrease (minimum 2 cm) 
from baseline in the enlargement of the splenic LVD (by imaging)

Hepatomegaly response rate – defined as the proportion of subjects with baseline 
hepatomegaly who achieve an on-study normalization or a 50% decrease (minimum 2 cm) 
from baseline in the hepatic longest vertical dimension (LVD) (by imaging)

ALC response rate – defined as the proportion of subjects with baseline lymphocytosis 
(ALC4 x 109/L) who achieve an on-study ALC <4 x 109/L or demonstrate a 50% decrease 
in ALC from baseline; ALC values within 4 weeks post-baseline will be excluded from the 
ALC response raete evaluation

Platelet response rate – defined as the proportion of subjects with baseline thrombocytopenia 
(platelet count <100 x 109/L) who achieve an on-study platelet count 100 x 109/L or 
demonstrate a 50% increase in platelet count from baseline; platelet values within 4 weeks 
post-baseline or after 8 days post transfusion will be excluded from the platelet response rate 
evaluation

Hemoglobin response rate – defined as the proportion of subjects with baseline anemia 
(hemoglobin <110 g/L [11.0 g/dL]) who achieve an on-study hemoglobin 110 g/L
(11.0 g/dL) or demonstrate a 50% increase in hemoglobin from baseline; hemoglobin 
values within 4 weeks post-baseline or after 4 weeks of receiving packed cell/whole blood 
transfusion or after 6 weeks of receiving exogenous growth factors (e.g., Darbepoetin alfa) 
will be excluded for the hemoglobin response evaluation

Neutrophil response rate – defined as the proportion of subjects with baseline neutropenia 
(absolute neutrophil count [ANC] ≤1.5 x 109/L) who achieve an ANC >1.5 x 109/L or 
demonstrate a 50% increase in ANC from baseline; ANC values within 4 weeks of 
post-baseline or after 2 weeks of receiving exogenous growth factors (e.g., Filgrastim, 
G-CSF, Lenograstim) or after 4 weeks of receiving Neulasta were excluded for response 
evaluation
3.1.2.
Patient Well-Being

Overall survival (OS) – defined as the interval from start of study therapy to death from any 
cause

Change from baseline in HRQL domain and symptom scores based on  the Functional 
Assessment of Cancer Therapy: Leukemia (FACT-Leu) (see Appendix 2) 


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
Changes from baseline in Karnofsky performance status – defined as the change from 
baseline in the performance status (see Appendix 3) 
3.1.3.
Pharmacodynamic Markers of Drug Activity and Resistance

Changes from baseline in PI3K/AKT/mTOR pathway activation as a measure of PI3K
pathway activity

Changes from baseline in the plasma concentrations of disease-associated chemokines and 
cytokines
3.1.4.
Exposure

Study drug administration as assessed by prescribing records and compliance as assessed by 
quantification of used and unused drug

Trough (pre-dose) and peak (1.5-hour samples) of idelalisib plasma concentrations as 
assessed by a validated bioanalytical method
3.1.5.
Safety

Overall safety profile of each study treatment regimen characterized by the type, frequency, 
severity, timing of onset, duration, and relationship to study therapy of any adverse events or 
abnormalities of laboratory tests; serious adverse events; or adverse events leading to 
discontinuation of study drug
3.1.6.
Pharmacoeconomics

Change in health status – defined as the change from baseline in overall health and 
single-item dimension scores as assessed using the EuroQoL Five-Dimension (EQ-5D) utility 
measure (Appendix 4)

Health resource measures, including resource utilization, total costs, and measures of cost per 
unit of benefit (eg, cost per additional progression-free month, cost per quality-adjusted 
life-year)
Endpoint Selection Rationale
3.2.
The proposed endpoints have been chosen based on relevance to the pathophysiology and 
clinical manifestations of CLL, the known pharmacology of idelalisib, and the goals of the study 
in documenting idelalisib benefit-to-risk ratio. These types of endpoints have been employed in 
prior studies in CLL and can be evaluated with acceptable reliability and accuracy.


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3.2.1.
Tumor Control Endpoints
Assessments of the magnitude and duration of changes in tumor size are routinely employed in 
registration-directed oncology clinical studies to determine therapeutic effect. Unlike OS, these 
endpoints directly assess the ability of the drug to control the malignancy. Such assessments are 
also integral to treatment decisions; because subjects are being treated until disease progression, 
repeated tumor assessment must be performed in order to define the proper duration of treatment 
for each study participant. Standard response and progression criteria have been established by 
the International Workshop on CLL (IWCLL) {12154}; the assessments of treatment effects in 
this study will be based on these criteria, taking into account the specific pharmacology of 
idelalisib.
In CLL, disease-related nodal enlargement is a major cause of patient discomfort and can cause 
organ dysfunction {19448}. Extensive lymphadenopathy constitutes a reason to treat CLL and 
controlling the size of pathologically enlarged lymph nodes is an important therapeutic goal for 
improving patient well-being and relieving obstructive symptoms {12154}. Given that the natural 
history of recurrent CLL is inexorable nodal growth, enhancing tumor shrinkage and prolonging 
tumor control provides strong evidence of pharmacological activity. 
Endpoints of overall tumor control as evaluated in this trial are customarily assessed and reported 
in studies of new therapies in patients with cancer. PFS offers a well established outcome 
measure that directly measures treatment effect, conveys important longitudinal information 
regarding tumor control, can be characterized in all subjects using intention-to-treat (ITT) 
principles, and is readily analyzed using statistical methods such as Kaplan-Meier techniques. 
ORR provides an integrated assessment of the magnitude and extent of changes in 
lymphadenopathy, organomegaly, bone marrow infiltration, and bone marrow function that 
conveniently categorizes and describes treatment effects. TTR and DOR are important in 
characterizing the rapidity of achieving tumor shrinkage and the duration of tumor control. 
Beyond providing descriptions on overall response assessment using ORR, this protocol will also 
seek to characterize the individual components of response that are important in assessment of 
CLL {12154}. Thus, changes in lymph node area and in the proportion of subjects having a 
lymph node response will be analyzed. In addition, among subjects who enter the study with 
splenomegaly or hepatomegaly, the proportion of subjects who achieve substantial (50%) 
reductions in spleen or liver size will be assessed. Similarly, the proportions of subjects who 
experience improvements in ALC, platelets, hemoglobin, and neutrophil counts will be 
characterized in order to provide specific insight into the degree to which therapy alters these 
individual parameters. 
Because idelalisib mobilizes CLL cells from tissues into the peripheral blood as part of its 
pharmacological effect, there is a risk of falsely declaring a subject to have experienced disease 
progression if lymphocyte count is considered as the sole basis for potential CLL worsening. To 
account for this potential problem, changes in lymphocyte count will not be considered in 
determining whether a subject has progressive disease, ie, subjects will only be declared to have 
progressive CLL if they meet any of the IWCLL criteria for progressive disease other than 
lymphocytosis alone. Thus, subjects with worsening lymphadenopathy, organomegaly, bone 


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marrow involvement, progressive cytopenias, appearance of new disease, or transformation to an 
aggressive lymphoid malignancy histology (eg, Richter syndrome) will be considered to have 
progressed. Subjects with lymphocytosis without any of these other events will not be considered 
to have progressed. Given that lymphocytosis has no prognostic significance in patients with 
relapsed/refractory disease {24682}, {24684} and is not generally considered a reason to treat in 
patients with CLL {12154}, {17670}, {19042}, this approach does not jeopardize subject safety or 
subsequent therapy. Furthermore, it will allow complete collection of all response and 
progression data (both considering lymphocytosis and ignoring lymphocytosis) with the intent of 
providing complete information for regulatory authority review.
The current IWCLL guidelines indicate that physical examination is generally sufficient to 
evaluate nodal response and progression in patients with CLL {12154} but that radiographic 
assessments may be appropriate in clinical trials. Computed tomography (CT) is considered the 
preferred imaging method unless patients have contraindications that require use of magnetic 
resonance imaging (MRI). Given the low fluorodeoxyglucose (FDG) avidity of CLL, 
positron- emission tomography (PET) does not have a role in evaluation of this disease. The 
incremental benefits of using radiographic imaging are limited in patients undergoing long-term
follow-up following first-line therapy {24654}, {24663}. However, in the patients with advanced 
CLL and bulky adenopathy such as those who will be enrolled to this trial, it is known that CT 
scans commonly detect bulky intra-abdominal lymphadenopathy and splenomegaly that would 
be missed by palpation alone and that the presence of large-volume, intra-abdominal disease of 
the nodes and spleen is associated with a poor prognosis {24677}. Thus, while use of CT confers 
greater radiation exposure, subjects have the chance to benefit from radiographic imaging 
because it will offer more accurate information regarding their response to protocol therapy and 
the appropriate duration of protocol treatment. Having this information is particularly important 
in this trial because PI3Kinhibition precludes use of lymphocyte counts as evidence for disease 
progression. In addition, the risk is offset by the fact that the trial subjects will primarily be 
patients who have already received more potent mutagens (eg, purine analogs, alkylating agents), 
and all of whom have advanced cancer and limited treatment options at study entry. Based on 
published data {17680} {21022}, median OS for patients with comparably advanced CLL is 
<18 months, so the long-term secondary malignancy risk from CT-related radiation exposure is 
very low. Finally, in the context of a registration-directed pivotal trial of a new drug with a new 
mechanism of action, radiographic imaging is critically important to provide reassurance 
regarding subject safety and trial validity. In this regard, CT evaluations of the lung can be used 
retrospectively to assess for radiographic evidence of drug-induced lung changes {19673}, 
{19671}. Furthermore, CT measurements have greater accuracy and reproducibility than 
palpation, are subject to independent expert review, and can be audited against electronic case 
report form (eCRF) information.
The timing of radiographic tumor assessments has been carefully considered. To avoid 
duplication, the CT scan documenting CLL progression in Study GS-US-312-0116 will serve as 
the baseline CT scan for Study GS-US-312-0117. Among patients receiving idelalisib in 
Phase 1b/2 studies who experienced a nodal response (50% regression in tumor area), such 
responses were observed with the first 16 week of therapy {21030}, {19528}; the planned timing 
of tumor assessments (at Weeks 8, 16, 24, 36, 48 and then every 12 weeks thereafter) in this 


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study fits with this known timing of changes in lymph node size during idelalisib therapy. Scans 
at 8-week intervals during the first 24 weeks allow efficient documentation of response. During 
this period, early documentation of disease progression allows subjects who are not benefiting 
from study therapy to move rapidly to alternative treatments. After 24 weeks on study or after 
24 weeks cumulative treatment with idelalisib across Study GS-US-312-0116 and Study 
GS-US-312-0117, the reduction in the frequency of CT scans (to 12-week intervals) reduces the 
overall protocol burden for subjects while still allowing characterization of the expected median 
PFS in this trial. As outlined in Section 7.3, iodine-containing or gadolinium contrast material 
may be omitted in subjects for whom use of a contrast agent would be medically contraindicated.
3.2.2.
Measures of Patient Well-Being
3.2.2.1.
Overall Survival
While OS provides an ultimate measure of patient well-being, it has not routinely been used as 
the primary endpoint in CLL clinical trials. Unlike PFS, it does not specifically measure 
drug-mediated tumor control, and thus provides only an indirect assessment of treatment effect. 
Depending upon the treatment setting, long OS times in patients with CLL can preclude use of 
this endpoint as an efficient method for understanding drug benefits. In both the front-line and 
recurrent disease settings, post-study treatments can influence OS in unpredictable ways, 
potentially confounding differences between treatment groups.
However, given the life-threatening nature of systemic malignancy, documentation of OS is 
customary in oncology therapeutic clinical trials, including those evaluating subjects with 
recurrent CLL {17680}, {21022}. Evaluation of OS in this study continues the survival 
assessment from the primary study (Study GS-US-312-0116). The study program as a whole 
(considering both the primary randomized trial and secondary extension study) offers the 
potential to better understand OS and causes of death in a frail population of patients with both 
CLL, considering the consequences of the disease and comorbidities.
3.2.2.2.
Health-Related Quality of Life
Direct patient reporting of outcomes using standardized methods has become an increasingly 
important component of therapeutic assessment. Evaluation of patient-reported outcomes (PROs) 
is particularly relevant in patients who cannot be cured of disease {23859}. PRO questionnaires 
have been previously used in CLL to understand how patients differ from the general population 
in terms of health concerns {24669}, {24662}, {24681}, {24664}, to understand differences in 
perceptions of well-being in younger vs older patients {24671}, {24664}, to determine how 
treatment affects HRQL {20164}, {24662}, {24661}, and to assess the pharmacoeconomic cost of 
improvements in HRQL {24683}.
Patients with CLL have overtly impaired well-being relative to comparable controls {24669}, 
{24662}, {24681}, {24664}. Fatigue is cited as a common complaint, being present in the 
substantial majority of patients. Impairment of HRQL prior to any treatment is apparent in those 
with B symptoms or in patients with anemia, supporting the concept of initiating treatment when 
patients experience symptomatic disease. Factors associated with lower overall HRQL have 


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included older age, greater fatigue, severity of co-morbid health conditions, advanced stage, and 
ongoing treatment for CLL {24681}. Younger patients appear to have worse emotional and social 
well-being but older patients experience worse physical HRQL {24671}. In comparative 
evaluation of chemotherapy-containing regimens, differences in HRQL between therapies 
(eg, fludarabine vs fludarabine-cyclophosphamide vs chlorambucil) reflected differences in 
toxicity while improved HRQL was associated with greater efficacy {20164}, {24662}.
In this study, it is postulated that idelalisib-mediated tumor control will be correlated with greater 
positive changes in HRQL and that assessments of the drug’s safety profile will be supported by 
HRQL evaluations. The FACT-Leu (Appendix 2) has been selected to evaluate such outcomes 
for the study. The FACT-Leu comprises a general HRQL measure for patients receiving cancer 
treatment that yields a total score and subscales for physical, functional, social/family and 
emotional well-being {23894} and a diagnosis-specific measure for patients with leukemia 
{24808}. The FACT-Leu was developed to assess symptoms (eg, fevers, chills, night sweats, 
nodal swelling, fatigue) specifically relevant to patients with leukemia. FACT instruments have 
documented psychometric properties {23894}, {24808}, {23848}, {23847}, {23827}.
The FACT-Leu instrument is available in appropriate languages for this study. FACT-Leu data 
will be obtained at baseline and during each investigational clinic visit during treatment. Having 
FACT-Leu data concurrent with tumor response information will allow an evaluation of the 
potential relationship between tumor response and symptomatic changes as reported by patients. 
To avoid biasing HRQL results, the FACT-Leu will be administered at each visit before other 
procedures are performed and before any study information is conveyed to the subject.
3.2.2.3.
Changes in Performance Status
Performance status evaluation provides an integrated assessment of patient well-being before, 
during, and after treatment and, ideally, may indicate how drug efficacy and toxicity affect 
patient functioning. In patients with CLL performance status can be predictive of PFS or OS 
{26559}, {26534}, {26551}.
In this study, it is hypothesized that idelalisib-mediated tumor control will be correlated with 
changes in performance status and that assessments of the drug’s safety profile might be 
supported by performance status evaluations. The well-established, reliable, and validated 
Karnofsky performance score {23840}, {23824}, {22654} (see Appendix 3) will be employed in 
the trial for characterization of the subject population and repeated assessment of performance 
status.
3.2.3.
Pharmacodynamic Markers of Drug Activity and Resistance
In CLL, disease-related perturbations in inflammatory status can be clinically overt; patients 
often develop bothersome B symptoms (fevers, night sweats, and weight loss) that are 
characteristic of excessive systemic inflammation {20168}. Consistent with such disease 
manifestations, the PI3K/AKT/mTOR pathway is constitutively overactive in circulating CLL 
cells {21030}. In addition, chemokines and cytokines that are markers of aberrant B-cell 
trafficking or perturbations in inflammation are overexpressed by CLL tissues or by stromal cells 


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and circulate in plasma {23884}, {21030}. In Phase 1 studies of idelalisib it has been confirmed 
that idelalisib largely normalizes AKT phosphorylation and induces dose-dependent reductions 
in plasma concentrations of circulating chemokines and cytokines in patients with CLL {21030}.
In this study, it is hypothesized that incremental changes in these biomarkers provide direct 
evidence of mechanism-specific idelalisib effects on PI3Kδ activity or indirectly document drug 
effects on overall tumor cell volume. In either case, improvements in these pharmacodynamic 
measures provide corroborative evidence in support of idelalisib pharmacological activity; 
conversely, worsening of these biomarkers may indicate acquisition of resistance to idelalisib. In 
addition, it is possible that disease-or inflammation-related biomarkers may provide corollary 
information relating to the adverse effects of idelalisib on the liver; such data might allow better 
prediction of which subjects might be most susceptible to ALT/AST elevations during idelalisib
treatment. Finally, it can also be postulated that genetic, protein, or metabolic changes in CLL 
cells could provide signatures that would correlate with drug sensitivity and resistance.
Based on these considerations, this study will evaluate PI3K/AKT/mTOR pathway activation 
status in CLL cells. For this purpose, blood will be evaluated by flow cytometry using a 
clinically validated assay {23401}. CLL cells will be identified using anti-CD5 and anti-CD19
antibodies. AKT activation will be determined by quantifying phosphorylation at the Ser473 and 
Thr308 AKT sites using specific anti-pAKT Thr308 and anti-pAKT Ser473 antibodies. 
Additional assessments of PI3K/AKT/mTOR pathway signaling (eg, evaluating phosphorylation 
state for other downstream enzymes) may also be explored.
Plasma will be collected for assessment of circulating concentrations of relevant chemokines and 
cytokines with a particular focus on CCL2, CCL3, CCL4, CXCL12, CXCL13, CCL17, CCL19, 
CCL21, CCL22, sCD40 ligand, tumor necrosis factor-α, and C-reactive protein. In addition 
serum markers of iron metabolism (eg, hepcidin, iron, ferritin, transferrin) that might provide 
markers linking disease-related inflammation with perturbations of liver iron and sensitivity to 
liver injury will be evaluated {23835}, {23843}. Clinically validated assays (eg, enzyme-linked 
immunosorbent assays [ELISAs]) will be used to measure circulating concentrations of 
chemokines and cytokines at baseline and during the course of idelalisib therapy.
CLL cell deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein will be collected at 
baseline and at the conclusion of a subject’s treatment on study. DNA and RNA samples will be 
analyzed using gene array technologies to evaluate for changes in DNA mutations or in RNA 
expression patterns that might be associated with intrinsic or acquired resistance to study 
treatments. Similarly, protein will be evaluated for state-specific changes in protein 
phosphorylation to evaluate for differences in pathway activation at baseline or during therapy 
that might be associated with differences in response or in acquisition of resistance to therapy.
3.2.4.
Assessments of Exposure
3.2.4.1.
Study Drug Administration and Compliance
Evaluation of study drug administration and compliance provides context for assessments of 
safety, pharmacokinetics, and pharmacological activity. Evaluations of treatment administration 


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and modifications from planned therapy document the influence of treatment-emergent adverse 
events on prescribing practice. Compliance assessment offers a general indication of patients’ 
acceptance of therapy, integrating factors of tolerability, palatability, and convenience.
In this study, information regarding planned treatment and modification from planned treatment 
(eg, dose reductions and interruptions) will be kept. The compliance of the subject will be 
verified by accounting for used and unused drug.
3.2.4.2.
Pharmacokinetics
Given the intent of this protocol to assess longer-term dosing, collection of plasma for idelalisib
concentrations is important for evaluating exposure over time. These data may allow correlations 
of exposure with measures of efficacy, toxicity, and resistance. Because the idelalisib
pharmacokinetic profile has been well characterized in Phase 1 studies, limited plasma sampling 
will be performed in this study. Samples will be collected pre-dose and 1.5 hours post-dose 
relative to the morning administration of idelalisib. Based on discussions with investigators, 
collecting more than 2 samples in the morning is not considered reasonable given the need to 
minimize time requirements for study participants and to avoid substantial inconvenience for 
clinic staff.
Evaluation of idelalisib plasma concentrations will be performed using liquid chromatography 
with tandem mass spectrometry. The method has been fully validated in the context of prior 
Phase 1 studies. Plasma samples will be retained for potential later analyses of idelalisib
metabolites.
3.2.5.
Evaluations of Safety
In defining the therapeutic relevance of a drug in a particular clinical setting, it is imperative that 
its safety profile be fully characterized. As is conventional in all clinical studies, proper 
description of each adverse event or laboratory abnormality requires an understanding of the 
type, incidence, timing, severity, and relatedness to study drug. While information on all reported 
adverse events will be collected, listed, and summarized, particular focus will be placed on 
monitoring and reporting adverse events and laboratory abnormalities that were encountered in 
the prior toxicology studies and clinical experience with idelalisib. Safety parameters of specific 
interest in reporting study results will include those relating to bone marrow function, 
dermatological events, gastrointestinal inflammation, infection, pulmonary events 
(eg, pneumonia/pneumonitis), and liver injury. Additional scrutiny will be applied to Grade 3-4 
adverse events, to adverse events causing interruption or discontinuation of idelalisib, and to 
serious adverse events.
In addition, the protocol will evaluate for potential adverse idelalisib effects on laboratory 
parameters of immune function; the absolute number of CD4+, CD5+,CD8+, CD16/CD56+, 
CD19+, and CD20+ cells will be assessed by flow cytometry. Serum concentrations of IgA, IgE, 
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For consistency of interpretation, adverse events will be coded using the standard Medical 
Dictionary for Regulatory Activities (MedDRA) [http://www.meddramsso.com]), and the 
severity adverse events and laboratory abnormalities will be graded using the well-defined 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). 
Standard definitions for seriousness will be applied (see Section 8.1.2).
3.2.6.
Pharmacoeconomic Measures
It is increasingly important to understand the potential cost implications of introducing a new 
medication into patient care for CLL {26545}, {26535}. In order to analyze the 
pharmacoeconomic consequences of idelalisib administration, data will be collected regarding 
the health status of subjects and regarding health care resource utilization.
Heath status information will be obtained with the EQ-5D, which is a self-administered, generic, 
indirect utility measure {24948} (Appendix 4). The EQ-5D consists of a visual analogue scale on 
which subjects are asked to rate their current overall health status and 5 single-item dimensions 
which ask subjects to rate their health in terms of mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. For each of the 5 items, patients must choose between 
3 levels of difficulty in accomplishing tasks in that dimension. The visual analog scale is then 
used in combination with the dimension scores to generate a health utility score that can be 
incorporated into analyses of cost effectiveness. The EQ-5D has been successfully used in the 
evaluation of patients with B-cell and other cancers {26305}, {26277}, {26308}.
The EQ-5D instrument is available in appropriate languages for this study. EQ-5D data will be 
obtained at baseline and during each investigational clinic visit during treatment. The EQ-5D 
will be administered immediately after administration of the FACT-Leu instrument, before other 
procedures are performed and before any study information is conveyed to the subject. The 
EQ-5D instrument takes only 5 minutes to complete.
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach will be to combine the resource utilization data from the trial with data on 
unit prices (collected separately) to estimate total costs. The costs will be described relative to 
the health care findings as measured by duration of tumor control, the symptom-free survival 
period, and/or utility outcomes or some other appropriate measure of clinical benefits.


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4.
SUBJECT POPULATION
Number of Subjects
4.1.
The planned sample size is ~160 subjects but will be bounded by the number of subjects enrolled 
to the primary clinical trial (Study GS-US-312-0116).
Subject Selection Criteria
4.2.
Subjects in the primary Phase 3 study (GS-US-312-0116) who are compliant, are tolerating 
primary study therapy, and 1) have definitive progression of CLL while receiving primary study 
drug therapy (idelalisib /placebo) or 2) are actively participating in Study GS-US-312-0116 at 
the time the study is stopped, including if stopped early due to overwhelming efficacy following 
an interim analysis are eligible to enroll in the extension study. Eligibility criteria may not be 
waived by the investigator and conformance to the eligibility criteria is subject to review in the 
case of a Good Clinical Practice (GCP) or a regulatory authority audit. Any questions regarding a 
subject’s eligibility should be discussed with the study sponsor medical monitor prior to 
enrollment.
4.2.1.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while receiving study drug therapy 
(idelalisib/placebo) in Study GS-US-312-0116. Note: Definitive disease progression is CLL 
progression based on standard criteria and occurring for any reason (ie, increasing 
lymphadenopathy, organomegaly, or bone marrow involvement; decreasing platelet count, 
hemoglobin, or neutrophil count; or worsening of disease-related symptoms) other than 
lymphocytosis. Subjects must have confirmation by the sponsor working in collaboration 
with an independent review committee (IRC) that the disease has progressed on the 
clinical trial (Study GS-US-312-0116) before receiving secondary idelalisib therapy on this 
extension trial (Study GS-US-312-0117).
3) Presence of radiographically measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures 2.0 cm in the longest diameter [LD] and 1.0 cm in the 
longest perpendicular diameter [LPD] as assessed by CT or MRI). 
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab and idelalisib/placebo) 
and no intervening or continuing therapy (including radiotherapy, chemotherapy, 
immunotherapy, or investigational therapy) for the treatment of CLL. Note: Subjects may 
receive corticosteroids to manage CLL manifestations.


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5) The time from permanent cessation of Study GS-US-312-0116 treatment (rituximab and/or 
idelalisib/placebo) and the initiation of Study GS-US-312-0117 therapy is 12 weeks. Note:
Study procedures performed as part of Study GS-US-312-0116 need not be repeated and 
can be used as screening procedures for Study GS-US-312-0117 if performed within 4 
weeks prior to initiation of study drug therapy on Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation of study treatment) as 
shown in the table below. Note: Confirmation should be considered for out-of-range values 
to determine if the abnormality is real or artifactual. Values should be obtained within the 
screening period and should generally be the most recent measurement obtained. Subjects 
with any degree of neutropenia, thrombocytopenia, or anemia due to CLL or prior therapy 
may enroll.
Table 4-1.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCra
>30 ml/min
Pregnancy
-HCGb
Negative 
a
As calculated by the Cockcroft-Gault formula (see Appendix 5) {2202}
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or urine 
dipstick pregnancy test must be negative at start of study treatment (Visit 2)
Abbreviations: -HCG= beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
eCCr=estimated creatinine clearance, ULN=upper limit of normal
8) For female subjects of childbearing potential, willingness to use a protocol-recommended 
method of contraception (as outlined in section 5.6.4) from the screening visit (Visit 1) 
throughout the study and for 30 days following the last dose of study drug. Note: A female 
subject is considered to be of childbearing potential unless she has had a hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian 
failure (with serum estradiol and follicle-stimulating hormone [FSH] levels within the 
institutional postmenopausal range and a negative serum or urine HCG), or is 
menopausal (age >55 with amenorrhea for >12 months or amenorrhea for > 6 months 
with serum estradiol and FSH levels within the institutional postmenopausal range). 


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9) For male subjects of childbearing potential having intercourse with females of childbearing 
potential, willingness to use a protocol-recommended method of contraception (as outlined in 
section 5.6.4) from the start of study drug (Visit 2) throughout the study and for 90 days 
following the last dose of study drug and to refrain from sperm donation from the start of 
study drug (Visit 2) throughout the study and for 90 days following the last dose of study 
drug. Note: A male subject is considered able to father a child unless he has had a bilateral 
vasectomy with documented aspermia or a bilateral orchiectomy, or has ongoing testicular 
suppression with a depot luteinizing hormone- releasing hormone (LH-RH) agonist 
(eg, goserelin acetate [Zoladex®]), leuprolide acetate  [Lupron®]), or triptorelin pamoate 
[Trelstar®]).
10) In the judgment of the investigator, participation in the protocol offers an acceptable benefit-
to-risk ratio when considering current CLL disease status, medical condition, and the 
potential benefits and risks of alternative treatments for CLL. 
11) Willingness and ability to comply with scheduled visits, drug administration plan, imaging 
studies, laboratory tests, other study procedures, and study restrictions. Note: Psychological, 
social, familial, or geographical factors that might preclude adequate study participation 
should be considered.
12) Evidence of a personally signed informed consent indicating that the subject is aware of the 
neoplastic nature of the disease and has been informed of the procedures to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study participation.
4.2.2.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
1) Known histological transformation from CLL to an aggressive lymphoma 
(ie, Richter transformation). Note: Biopsy documentation of the absence or presence of 
transformation is not required.
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of the start of 
study treatment (Visit 2). Note: Subjects with localized fungal infections of skin or nails are 
eligible. Subjects may be receiving prophylactic antiviral or antibacterial therapies at the 
discretion of the investigator; anti-pneumocystis prophylaxis is encouraged. For subjects 
who are at substantial risk of an infection (eg, influenza) that may be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of 
protocol therapy.
3) Pregnancy or breastfeeding. 
4) Intentional breaking of the blind in Study GS-US-312-0116 by the investigator or the study 
subject.


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5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical condition, surgical history, physical 
finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the 
investigator’s opinion, could adversely affect the safety of the subject or impair the 
assessment of study results.
Enrollment Criteria Rationale
4.3.
The eligibility criteria are designed to limit enrollment to subjects who participated in the 
primary clinical trial (Study GS-US-312-0116), are compliant, have been generally able to 
tolerate study therapy and study procedures, and have experienced definitive CLL progression 
while receiving study treatment (rituximab and/or idelalisib/placebo) in the primary study or who 
are actively participating in Study GS-US-312-0116 at the time the study is stopped, including if 
stopped early due to overwhelming efficacy.
The requirement of measurable lymphadenopathy to enter the blinded portion of the study 
ensures that subjects have disease that can adequately be assessed for evidence of drug activity.
Prior therapy provisions are intended to ensure that subjects are transitioning directly from 
Study GS-US-312-0116 to Study GS-US-312-0117 without receiving intervening treatments. 
The stipulation of 12-week interval from Study GS-US-312-0116 treatment until 
Study GS-US-312-0117 treatment precludes excessively protracted intervals between 
participation in the 2 studies but also permits sufficient time for clinicians and subjects to 
determine whether participation is appropriate. 
In the blinded portion of the study, to ensure that subjects are not so acutely ill from 
life-threatening comorbidities that they require hospitalization and stabilization, subjects with 
Karnofsky performance scores <40 (ie, those who are bed-bound or hospitalized) will not be 
enrolled. Baseline laboratory evaluations are designed to limit participation to subjects who have 
not developed serious organ compromise that would pose a safety risk or confound the 
interpretation of adverse effects. Pregnancy testing and restrictions on eligibility relating to 
reproduction, pregnancy, and nursing are important because idelalisib is a new chemical entity 
with teratogenic effects in rats and it is unknown if it may have adverse effects on conception, on 
fetal development, or on the health of a breast-feeding child. To minimize missing data and 
premature discontinuations, subjects should have sufficient psychological and social resources to 
comply with study procedures and restrictions. Consistent with GCP guidelines, subjects must 
provide informed consent before initiation of any study procedures.


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5.
TREATMENT OF SUBJECTS
Enrollment
5.1.
5.1.1.
Interactive Web Response System
An IWRS will be employed to manage the conduct of the trial. The IWRS will be used to 
maintain a central log documenting enrollment, to manage dose modifications, to assess current 
inventories of study drug, to initiate any necessary resupply of study drug, and to document 
discontinuation of study .
5.1.2.
Treatment Assignment
After a subject has completed the necessary documentation of definitive CLL progression in the 
primary clinical trial (GS-US-312-0116) and has been confirmed to be eligible, the subject can 
be entered into this trial (Study GS-US-312-0117). In order to obtain a treatment arm allocation 
for a subject, a site representative will access the IWRS and supply the system with the required 
information.
Subjects will be assigned to either of the following treatment assignments with allocation based 
on the original primary study randomization:
Treatment Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117)
Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly enrolled subjects will 
receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly enrolled subjects will 
receive 150 mg BID
Note: At the Investigator’s discretion, subjects who were randomized to placebo on 
study GS-US-312-0116 may delay initiation of idelalisib following enrollment on 
Study GS-US-312-0117 until the time of disease progression or until the investigator 
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Treatment Assignment

Assignment to Arm A or Arm B with allocation based on the original primary study 
randomization

Implementation through an interactive web response system (IWRS)
The IWRS will assign blister card, or bottle numbers and instructions for dispensing of blinded 
study drug (high-dose or standard-dose idelalisib). It is anticipated that subjects will usually 
begin study drug immediately at Visit 2 of the study. 
5.1.3.
Blinding
During the blinded portion of the study, the identity of the treatments will be concealed by 
central blinding of study drug assignments. Blinding will be accomplished through use of a 
placebo that is well-matched to the active drug in appearance, packaging, labeling, and schedule 
of administration (see Section 5.2.1). During the study, subjects, caregivers, investigational site 
personnel, Gilead Sciences study team members, and all other study personnel will remain 
blinded to the identity of the treatment assignments; these assignments will be available only to 
the IWRS, the data monitoring committee (DMC) for the study, an independent bioanalytical 
group that supports the DMC, and drug safety personnel who are not part of the study team.
Unblinding an individual subject’s treatment assignment during the study will only occur in the 
case of subject emergencies (see Section 5.5) or in the event the study is discontinued by the
Sponsor, a Regulatory Agency, or an IRB or EC (see Section 5.9). Where required by local 
regulation, expedited reporting of serious adverse events to specific regulatory authorities will 
include information regarding the study drug treatment assignment (high-dose or standard-dose 
idelalisib); this will be done in such a way that subjects, investigational site personnel, 
institutional review board/independent ethics committees (IRB/IEC), and study team members 
remain blinded as to the treatment assignment for the subject described in the adverse event 
report.
The unblinded analysis of the study will be performed when the database is completed and 
locked following unblinding of Study GS-US-312-0116 and Study GS-US-312-0117. The final 
analysis of the open label portion of the study will occur once the open label portion is stopped.
While bioanalytical assays to determine idelalisib concentrations may be performed prior to 
unblinding, pharmacokinetic data that would allow identification of treatment assignments for 
individual subjects will not be available to the study team until after the blind is broken and the 
primary analysis has occurred. Except for emergency unblinding, individual subjects, caregivers, 
and site personnel will not be informed of the treatment assignments until the implications of 
revealing such data for the overall idelalisib study program have been determined by the clinical 
project leader for the idelalisib development program.


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Investigational Study Drug (Idelalisib/Placebo)
5.2.
5.2.1.
Description
Subjects allocated to Arm A in the blinded portion of the study will be provided with 2 tablets of 
active idelalisib for oral administration at each dose. Each tablet contains 150 mg or 100 mg of 
active idelalisib. The 150-mg tablets will be used for initial therapy; the 100-mg tablets are 
provided for use by those subjects who require a dose reduction (see Table 5-1). 
Subjects allocated to Arm B in the blinded portion of the study will be provided with 1 tablet of 
active idelalisib and 1 tablet of placebo for oral administration at each dose. Each active tablet 
contains 150 mg or 100 mg of active idelalisib. The 150-mg tablets (and matching placebo) will 
be used for initial therapy; the 100-mg tablets (and matching placebo) are provided for use by 
those subjects who require a dose reduction. 
In the open-label portion of the study, subjects will be provided with 150 mg tablets of idelalisib.
The 150-mg tablets are pink, film-coated, and include the following inactive excipients: 
microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch 
glycolate, magnesium stearate, red iron oxide, polyethylene glycol, talc, polyvinyl alcohol
(PVA), and titanium dioxide. The 100-mg tablets are orange, film-coated, and include the 
following inactive excipients: microcrystalline cellulose, hydroxypropyl cellulose, 
croscarmellose sodium, sodium starch glycolate, magnesium stearate, yellow iron oxide, 
polyethylene glycol, talc, PVA, and titanium dioxide.
The placebo tablets match the active idelalisib formulations in appearance. The placebo tablets 
matching the 150-mg tablets are pink, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium stearate, 
red iron oxide, polyethylene glycol, talc, PVA, and titanium dioxide. The placebo tablets 
matching the 100-mg tablets are orange, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium stearate, 
yellow iron oxide, polyethylene glycol, talc, PVA and titanium dioxide.
5.2.2.
Source
Both active idelalisib and placebo will be supplied free of charge by Gilead Sciences. 
5.2.3.
Packaging and Labeling
During the blinded portion of the study, study drug (idelalisib or idelalisib/placebo) will be 
provided in blister cards. The blister cards are made of polyvinyl 
chloride/polychlorotrifluoroethylene (PVC/PCTFE) film and have aluminum foil lidding 
materials. Each blister card contains 120 tablets (4-week supply plus a modest overage) of one of 
the relevant dose strengths. The 100-mg or 150-mg and matching placebo tablets will be 
combined in order to obtain the daily doses to be used in this study. Thus, in Arm A, the 300-mg 
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dose will be obtained by administering two 100-mg tablets. In Arm B, the 150-mg idelalisib dose 
will be obtained by administering one 150-mg tablet and one placebo tablet and the 100-mg 
idelalisib dose will be obtained by administering one 100-mg tablet and one placebo tablet. 
Each blister card will have a unique number. Labeling for blister cards dispensed to subjects in 
Arm A will appear identical to blister cards dispensed to subjects in Arm B, and may include 
either idelalisib or placebo. 
When the primary study (GS-US-312-0116) is stopped including if early after an interim 
analysis, GS-US-312-0116 active study subjects will become eligible for participation on 
Study GS-US-312-0117. Active GS-US-312-0117 study subjects will be transitioned to 
open-label idelalisib at this time. Each bottle contains 60 tablets (4 week supply plus a modest 
overage) of one of the relevant dose strengths (150 mg, 100 mg) and a polyester coil. Bottles are 
white and are made of high-density polyethylene. Each bottle is closed with a white, 
continuous-thread, child-resistant, polypropylene screw cap fitted with an induction-sealed, 
aluminum-faced liner.
All labels for study drugs to be distributed to centers in the United States, the EU, and other 
countries will meet all applicable requirements of the United States Food and Drug 
Administration (FDA), the EU Annex 13 of Current Good Manufacturing Practice (cGMP) 
(Manufacture of Investigational Medicinal Products, July 2010), and/or other local regulations as 
applicable.
5.2.4.
Storage and Handling
Blister cards or bottles containing tablets of study drug (idelalisib or idelalisib/placebo) should
be stored at controlled room temperature (ie, ~25°C, with a range of 15 to 30°C). While the 
stability of study drug tablets stored at controlled room temperature has been confirmed, brief 
excursions to temperatures as low as -20°C or as high as 40°C (eg, during shipping) will not 
adversely affect the drug. Updated stability data will be provided to the sites, as appropriate.
5.2.5.
Dispensing
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing 
study drug according to the IWRS directions. It is planned that drug will be dispensed at 4-week 
intervals through the first 24 weeks of treatment and at 12-week intervals thereafter, or on a 
frequency consistent with the subject’s visit schedule. Sufficient study drug will be provided for 
each study period at the beginning of the period. Multiple blister cards or bottles may be 
dispensed at a single visit. Tablets should be kept in the original blister cards or bottles provided
until they are self-administered by the subject.
At the time of starting study treatment, the IWRS will provide the clinic staff with the blister 
card numbers designating the blister cards to be dispensed, or the quantity of open-label bottles 
to be dispensed. The clinic staff (eg, pharmacist or other qualified person) will write the subject 
number on each blister card or bottle that is dispensed. Immediately before dispensing, the clinic 


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staff will write the blister card or bottle number in the study drug administration record 
corresponding to the subject number.
5.2.6.
Return
The study drug should be retrieved from each subject at the end of each dispensing interval. The 
quantity of study drug and the date returned by the subject should be recorded in the study drug 
accountability records. When possible, all study drug returned by the subject should be retained 
for review by the study site monitor prior to return to Gilead Sciences or destruction.
5.2.7.
Accountability
The disposition of all study drug should be documented from the time of receipt at the site 
through subject dispensing and return.
Study personnel must ensure that all study drug is kept in a secure locked area with access 
limited to authorized personnel. The study drug must not be used outside the context of this 
protocol. Under no circumstances should the investigator or site personnel supply study drug to 
other investigators or clinics, or allow the study drug to be used other than as directed by this 
protocol.
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by Gilead Sciences or its designee, including, but not limited to, 
the date received, lot number, amount received, and the disposition of all study drug. Upon 
receipt of a drug shipment, the shipment must be logged into the IWRS. Study drug 
accountability records must also be maintained that include the subject number to whom the 
study drug was dispensed and the date, quantity and lot number of the study drug dispensed.
Depending upon the decision of Gilead Sciences, remaining unused study drug supply will be 
returned to Gilead Sciences or its designee after the study is completed or will be discarded or 
destroyed at the clinical site. If the study drug is discarded or destroyed at the clinical site, 
standard institutional policy should be followed. Records documenting the date of study drug 
shipping or destruction, relevant lot numbers, and amount shipped or destroyed should be 
maintained.
5.2.8.
Overdose Precautions
In Phase 1 studies, an MTD for idelalisib was not reached when the drug was administered 
continuously at dose levels through 350 mg/dose BID (700 mg per day) {21030}, {21036}. 
However, in this protocol, an overdose is defined as administration of more than the prescribed 
daily dose (ie, >600 mg in a single day). In a subject who experiences an overdose consideration 
should be given as to whether idelalisib administration should be temporarily interrupted. If the 
overdose ingestion is recent and substantial, and if there are no medical contraindications, use of 
gastric lavage or induction of emesis may be considered. Observation for any symptomatic side 
effects should be instituted, and biochemical and hematological parameters should be followed 


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closely (consistent with the protocol or more frequently, as needed). Appropriate supportive 
management to mitigate adverse effects should be initiated.
The Gilead Sciences medical monitor should be contacted if a study drug overdose occurs. Cases 
of study drug overdose will result in specific reporting requirements (see Section 8.8).
5.2.9.
Inadvertent Exposure and Spill Precautions
Based on available data from nonclinical studies, idelalisib does not appear to be acutely toxic, 
genotoxic, or irritative at levels that are likely to result from inadvertent exposure to the contents 
of broken tablets. However, personnel handling the drug should use reasonable precautions to 
avoid eye contact, skin contact, inhalation, or ingestion of the study drug product. For further 
information regarding inadvertent exposure and spill precautions, please consult the idelalisib
investigator brochure.
Study Drug Administration
5.3.
5.3.1.
Premedication
No specific premedications or supporting medications are required in conjunction with study 
drug administration.
5.3.2.
Administration Instructions
The prescribed dose of study drug (idelalisib/placebo) should be taken orally. At each dose 
administration, the tablet number corresponding to the appropriate dose of study drug is to be 
swallowed whole with 100 to 200 mL (~ 4 to 8 ounces) of water. In case of breakage of the 
tablets in the oral cavity, additional water should be taken as a rinse. 
Study drug may be taken with or without food. There are no known dietary restrictions related to 
study drug use.
5.3.3.
Dosing Schedule
Study drug should be taken on a BID schedule at approximately the same times each day. Ideally,
doses should be taken at ~12-hour intervals (eg, at ~7 AM and at ~7 PM). While it is realized 
that variations in dosing schedule may occur in the outpatient setting, the prescribed regimen 
should be followed as closely as possible, especially in the clinic.
At specified clinic visits, the study drug will be administered in the clinic with dosing 
appropriately timed relative to blood sampling for idelalisib pharmacokinetics. As detailed in 
Section 6.2, clinic staff should record idelalisib administration information, including the exact 
clock time of each dose, for doses of study drug administered in the clinic or hospital. Thereafter, 
subjects will be given an adequate supply of tablets to take at home.


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5.3.4.
Dose Levels
Study drug dose levels for Arm A and Arm B are described in Table 5-1. The lower dose level
(Dose Level -1) is provided in case a subject requires a study drug dose modification.
Table 5-1.
Study Drug Dose Levels
Treatment Arm
Starting Dose
Dose Level -1
Arm A
300 mg/dose BID
200 mg/dose BID
Arm B
150 mg/dose BID
100 mg/dose BID
Abbreviation: BID=twice per day
When the primary study (GS-US-312-0116) is stopped, and GS-US-312-0116 active study 
subjects become eligible for participation on Study GS-US-312-0117 subjects will be enrolled 
into Study GS-US-312-0117 at open label 150 mg BID. Subjects already participating in 
Study GS-US-312-0117 will remain on the same dose.
5.3.5.
Dose Schedule Interruptions and Vomited Doses
Subjects who have a delay in administration of a dose of the study drug of <6 hours should take 
the planned dose as soon as possible after the intended time of administration. For subjects who 
have a delay in administration of study drug of 6 hours, the dose should not be taken. Study 
drug administration may continue but the missed dose should not be made up and the planned 
timing of subsequent study drug dosing should not be altered.
Vomited doses may be retaken, but only if the tablet is visible in the vomitus.
5.3.6.
Safety Monitoring and Study Drug Interruption/Dose Modification
Subjects must be monitored closely for adverse events or laboratory abnormalities during the
course of the study. Reference should be made to the CTCAE, Version 4.03 for grading the 
severity of adverse events and laboratory abnormalities.
Based on Phase 1 clinical experience adverse events potentially attributable to idelalisib in 
patients with CLL have included infrequent hepatic events (manifest primarily as asymptomatic 
and isolated elevations in serum ALT/AST).  Other adverse events potentially related to 
idelalisib have included instances of pneumonitis, gastrointestinal inflammation, or rash.
Myelosuppression has not been an overt toxicity of idelalisib in previous experience but 
provisions for intervention in subjects experiencing very protracted treatment-emergent 
neutropenia or thrombocytopenia are provided as a precaution. It is possible that idelalisib is 
responsible for other adverse events for which a causal relationship has not yet been established.
Recommendations for modifications of the dosing regimens based on the drug and the type and 
severity of adverse events or laboratory abnormalities are provided in Table 5-2 below. The dose 
modification instructions focus on the types of events most commonly attributed to each of the 


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study agents. The recommendations provided in Table 5-2 comprise only guidelines; variations 
from these recommendations may be warranted based on an investigator’s individual judgment 
in considering potential risks, benefits, and therapeutic alternatives available to each subject.
Consistent with Table 5-2, if a subject experiences an adverse event that is suspected to be 
related to study drug and requires a dose modification during the course of study therapy, then 
study drug administration should be held, as necessary, until the adverse event resolves or 
stabilizes to an acceptable degree (generally to Grade 1). Thereafter, study drug may be 
reinstituted, but the dose should be reduced to Dose Level -1 (see Table 5-1). If the adverse event 
occurs again, one further attempt at reinitiation of therapy at Dose Level -1 may be attempted if 
the investigator feels that a second rechallenge is medically appropriate. If the subject cannot 
tolerate idelalisib at Dose Level -1 after 2 rechallenges, then the subject should be discontinued 
from study drug therapy unless continued therapy is permitted by the Gilead Sciences medical 
monitor.
After the study drug dose is reduced, the dose need not be re-escalated, even if there is minimal 
or no toxicity with the reduced dose. However, if the subject tolerates the lower dose level of 
study drug for ≥4 weeks then the dose level may be increased to the starting dose level 
(see Table 5-1) at the discretion of the investigator. Such re-escalation may be particularly 
warranted if further evaluation reveals that the adverse event that led to the dose reduction was 
not study-drug-related. The starting dose level should not intentionally be exceeded in this study.
Whenever possible, any dose adjustment of study drug should be discussed between the 
investigator and the Gilead Sciences medical monitor prior to implementation. To implement 
either a dose reduction or a dose reescalation, the investigator/study staff member will call the 
IWRS, enter the subject number, and inform the IWRS of the need for dose titration. The IWRS 
will provide details regarding the blister card to be dispensed to the subject. The appropriate 
clinic staff should instruct the subject/caregiver about the change in dose.
Recommendations for dose modification based on the type and severity of adverse events or 
laboratory abnormalities are provided in Table 5-2 below.


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Table 5-2.
Recommendations for Study Drug Dose Modifications Based on Type 
and Severity of Treatment-Related Adverse Events or Laboratory
Abnormalities
NCI CTCAE Grade
Recommendation
Idelalisib
HEMATOLOGICAL ADVERSE EVENTS
Neutropenia
Grade 2 neutropenia
Maintain current dose level and schedule.
Grade 3 neutropenia
During combination or continuing single-agent therapy periods, maintain current idelalisib 
dose level and schedule. Consider G-CSF support.
Grade 4 neutropenia (or 
occurrence of 
neutropenic fever or 
infection)
During combination therapy period, consider G-CSF support and maintain current 
idelalisib dose level and schedule. During continuing single-agent idelalisib therapy 
period, consider G-CSF support and continue idelalisib at initial or lower dose level at 
investigator discretion.
Thrombocytopenia
Grade 3
Maintain current dose level and schedule.
Grade 4
During combination therapy period, maintain current idelalisib dose level and schedule. 
During continuing single-agent idelalisib therapy period, withhold for bruising or bleeding 
until Grade 3. May resume idelalisib at initial or lower dose level at investigator 
discretion.
NON-HEMATOLOGICAL ADVERSE EVENTS
Dermatological
Grade 1
Maintain current dose level and schedule.
Grade 2
Withhold idelalisib until Grade 1. Resume idelalisib at current dose level. If rechallenge 
at current dose level results in recurrence, may resume at same or lower idelalisib dose 
level at investigator discretion.
Grade 3 or 4
Withhold idelalisib until Grade 1. May resume at lower dose level or discontinue 
idelalisib at investigator discretion.
Gastrointestinal Inflammation/Diarrhea
Grade 1
Provide anti-diarrheal (eg, loperamide) and maintain current idelalisib dose level and 
schedule.
Grade 2
Provide anti-diarrheal (eg, loperamide). Withhold idelalisib until Grade 1. Resume 
idelalisib at current dose level. If rechallenge results in recurrence, may resume at initial 
or lower dose level at investigator discretion. Consider addition of anti-inflammatory (eg, 
sulfasalazine, budesonide).
Grade 3
Provide anti-diarrheal (eg, loperamide). Withhold idelalisib until Grade 1. Resume at 
lower dose level. Consider addition of anti-inflammatory (eg, sulfasalazine, budesonide).
Grade 4
Provide anti-diarrheal (eg, loperamide). Withhold idelalisib until Grade 1. May resume 
at lower dose level or discontinue idelalisib at investigator discretion. Consider addition of 
anti-inflammatory (eg, sulfasalazine, budesonide).


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NCI CTCAE Grade
Recommendation
Idelalisib
Hepatic Adverse Events (elevations in ALT, AST, or bilirubin)
Grade 1
(ALT/AST3xULN)
(Bilirubin1.5xULN)
Maintain current dose level and schedule.
Grade 2
(ALT/AST>3-5xULN)
(Bilirubin>1.5-
3xULN)
Maintain current dose level and schedule. Monitor ALT, AST, ALP, and bilirubin at least 
1x per week.
Grade 3
(ALT/AST>5-20xULN)
(Bilirubin>3-10xULN)
Withhold idelalisib. Monitor ALT, AST, ALP, and bilirubin at least 1x per week until all 
abnormalities are Grade 1. If bilirubin abnormality was Grade <3, resume idelalisib at 
same dose level. If bilirubin abnormality was Grade 3, resume at lower dose level.
Grade 4
(ALT/AST>20xULN)
(Bilirubin>10xULN)
Withhold idelalisib. Monitor ALT, AST, ALP, and bilirubin at least 1x per week until all 
abnormalities are Grade 1. If bilirubin abnormality was Grade <4, resume idelalisib at 
lower dose level. If bilirubin abnormality was Grade 4, discontinue idelalisib.
Pneumonitis (dyspnea, cough, hypoxia and/or diffuse interstitial pattern or ground-glass opacities on chest 
CT and no obvious infectious cause)
Grade 1
Maintain current dose level and schedule. Consider pneumocystis prophylaxis.
Grade 2
Withhold idelalisib until Grade 1, consider systemic corticosteroids and 
pneumocystistreatment. May resume at initial or lower dose level at investigator 
discretion.
Grade 3
Withhold idelalisib until Grade 1, consider systemic corticosteroids and consider 
pneumocystis treatment. May resume at lower dose level or discontinue idelalisib at 
investigator discretion.
Other Nonhematological Adverse Events
Grade 2
Maintain current dose level and schedule
Grade 3
Withhold idelalisib until Grade 1. May resume idelalisib at initial or lower dose level or 
discontinue idelalisib at investigator discretion.
Abbreviations:  ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST= aspartate aminotransferase, ANC=absolute 
neutrophil count, CTCAE=Common Terminology Criteria for Adverse Events, G-CSF=granulocyte colony-stimulating factor, 
NCI=National Cancer Institute, ULN=upper limit of normal
Recommendations for Evaluation, Intervention, and Drug Discontinuation
5.4.
for Specific Adverse Events or Conditions
5.4.1.
Dermatological Events
Idelalisib administration has occasionally been associated with the occurrence of a 
maculopapular rash affecting the trunk and extremities. Based on skin biopsy data in several 
subjects, the findings have been consistent with a delayed-type hypersensitivity reaction. 
Rechallenge with idelalisib has resulted in recurrence of rash in some but not all subjects.


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In subjects who develop a rash while on study drug, causes related to concomitant medications, 
environmental exposures, or infection should be considered and eliminated. Depending upon the 
severity of the initial dermatological event, rechallenge with study drug therapy at the same or a 
lower dose level (see Table 5-2) should be considered if continued drug administration offers the 
potential for clinical benefit.
5.4.2.
Gastrointestinal Events
Inflammation of the tongue has been noted in rats undergoing repeated gavage administration of 
idelalisib; this inflammation may have represented a drug-related exacerbation of 
gavage-mediated irritation. Mild congestion or hemorrhage in the large intestine has been seen in 
dogs receiving high doses of idelalisib. In patients, isolated cases of gastrointestinal 
inflammation (eg, stomatitis, colitis, cecitis) have been noted. While disease-related factors, 
neutropenia, toxicity from prior therapies, effects of ongoing supportive care, or pre-existing 
cholelithiasis may have initiated such events, it is possible that idelalisib played a contributory 
role. In such subjects, rechallenge with idelalisib has been possible and has not been associated 
with other severe adverse events. Patients who have developed evidence of enteritis during 
idelalisib therapy have been successfully treated with antidiarrheals (eg, loperamide) and with 
enteric steroidal (eg, budesonide) or non-steroidal (eg sulfasalazine [Azulfidine®]) 
anti-inflammatory agents and have been able to continue or resume idelalisib.
For study subjects who develop severe abdominal pain, particularly if early during therapy, the 
possibility of a bowel obstruction or perforation should be considered. Appropriate clinical and 
radiographic examination should be performed and supportive care and surgical intervention 
should be considered. Upon recovery, study therapy may be continued if appropriate for the 
clinical situation.
For subjects who develop persistent diarrhea, causes related to concomitant medications or 
gastrointestinal infection should be considered and eliminated. Depending upon the clinical 
circumstances, endoscopy and biopsy may be warranted. Providing an antidiarrheal
(eg, loperamide) may lessen symptoms. Consideration should be given to intervention with 
enteric steroidal (eg, budesonide) or non-steroidal (eg, sulfasalazine) anti-inflammatory agents.In 
such subjects, rechallenge with idelalisib at a lower dose level has resulted in recurrence of 
symptoms in some but not all subjects and has not been associated with other severe adverse 
events. One patient who developed evidence of inflammatory bowel disease during idelalisib
therapy has been treated with sulfasalazine (Azulfidine®) and antidiarrheals (eg, loperamide) 
while continuing on idelalisib.
Thus, depending upon the type and severity of the initial gastrointestinal event, rechallenge with 
study drug at a reduced dose level and with and appropriate support care may be warranted if 
continued drug administration offers the potential for clinical benefit.


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5.4.3.
Hepatic Events
In patients with lymphoid malignancies, reversible serum ALT/AST elevations have been 
observed {21030}, {21036}. In these patients, the onset of Grade 3 or 4 transaminase elevations 
has typically occurred within approximately 4 to 8 weeks of starting idelalisib therapy
(median 5.7, Q1-Q3 3.9-8.1). Among patients with Grade 1-2 ALT/AST abnormalities, 
continued dosing has been possible; transaminase values commonly resolve despite continued 
idelalisib treatment. For those with Grade 3-4 ALT/AST elevations, drug interruption has 
resulted in resolution over 2 to 6 weeks. Successful rechallenge at lower dose levels of idelalisib
has been achieved in the majority of patients. Thus, in subjects with uncomplicated hepatic 
events, the instructions in Table 5-2 should be followed in an attempt to maximize the potential 
that subjects who appear to be benefiting can continue with study drug treatment.
In selected subjects who experience more complicated hepatic adverse events, further work-up 
may be warranted, as requested by the Gilead Sciences medical monitor. Such an evaluation may 
be particularly warranted in subjects who first experience a serum ALT/AST elevation 
12 weeks from the start of study drug therapy, who have an elevation in serum bilirubin 
concentration or coagulation parameters, or who have other characteristics that suggest an 
atypical change in transaminase values. Further workup may include: obtaining a history of 
recent symptoms/illnesses and of relevant past history (eg, history of hepatitis or of hepatitis A or 
hepatitis B vaccination); obtaining information regarding concomitant drug use (prescription and 
nonprescription medications, dietary supplements, alcohol, illicit drugs, special diets); 
questioning the subject regarding potential exposure to environmental toxins; ruling out viral 
hepatitis A, B, C, D (if hepatitis B is positive), and E, Epstein-Barr virus, cytomegalovirus, 
autoimmune hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis, hypoxic/ischemic 
hepatopathy, and biliary tract disease; obtaining additional tests to evaluate liver function 
(eg, prothrombin time [PT], activated partial thromboplastin time [aPTT], international 
normalized ratio [INR], albumin); and considering gastroenterology or hepatology consultation 
{15648}.
Of note, HBV reactivation can occur in patients treated with rituximab with a median time to 
diagnosis of hepatitis among patients with hematologic malignancies of 4 months after the 
initiation of rituximab but such events can occur months after completion of rituximab therapy. 
The risk is very low among patients with negative anti-HBc serology {24673} and/or 
undetectable HBV DNA as assessed by quanititative PCR. Because subjects with such evidence 
of persistent HBV infection are excluded from this study, reactivation is not anticipated. 
However, among subjects with evidence of Grade 3 serum ALT/AST abnormalities, evaluation 
for HBV reactivation (manifest as positivity for serum HBsAg) should be considered as a 
precautionary measure. In a subject with active HBV, anti-HBV antiviral agents should be 
initiated. At the discretion of the investigators, study drug may be continued if HBV infection 
can be adequately controlled, particularly if the subject is experiencing clinical benefit from 
study therapy and there are few other options for treating the subject’s CLL.


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5.4.4.
Hematological and Immunological Events
In the Phase 1 experience with idelalisib in CLL, patients with Grade3 neutropenia, anemia, 
and and/or thrombocytopenia were enrolled to clinical trials. Decreased levels of neutrophil 
counts, hemoglobin, or platelet counts during therapy were largely due to minor fluctuations in 
these parameters among patients with pre-existing hematological abnormalities due to disease or 
prior therapy. Thus, idelalisib did not appear to induce overt myelosuppression. Obvious patterns 
of drug-mediated reductions in circulating CD4+ lymphocyte counts or suppression of serum 
IgG levels were also not observed.
Given that patients with CLL commonly have Grade 3 hematological abnormalities due to 
underlying disease or prior therapy and that idelalisib is not associated with substantial 
myelotoxicity or off-target immunosuppression, alterations in study drug dose level for such 
events should only focus on subjects with protracted or symptomatic neutropenia or 
thrombocytopenia, unresponsive to G-CSF supportive care. No modification of idelalisib for 
changes in circulating CD4+ counts or Ig levels is planned.
5.4.5.
Infectious Events
Patients with CLL receiving idelalisib have developed serious bacterial, fungal, and viral 
infections during therapy. Similarly, serious bacterial, fungal, and new or reactivated viral 
infections have also occurred during and for ~1 year following rituximab-based therapy {24667}. 
New or reactivated viral infections in patients receiving rituximab have included 
cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, 
HBV (see Section 5.4.3) and HCV. Because patients with lymphoid malignancies 
(particularly those with CLL) are susceptible to infection due to the underlying disease, 
neutropenia, and the effects of prior therapy, the specific causal role of idelalisib or rituximab in 
any of these types of events is unclear.
Patients with previously treated CLL have developed Pneumocystis (carinii) jiroveci pneumonia 
while receiving idelalisib. While idelalisib has not specifically been implicated in such cases, 
patients with lymphoid malignancies (particularly those with CLL) may be susceptible to 
pneumocystis infections due to the underlying disease and the effects of prior therapy. 
Pre-existing risk factors of specific concern may include previous pneumocystis pneumonia, 
underlying disease (eg, CLL), prior therapy (eg, alemtuzumab, progenitor cell transplantation), 
or immunocompromised status (low CD4+ lymphocyte counts, HIV infection) {17881}.
In a subject with a history of recurrent infections, prophylaxis with intravenous Ig should be 
considered {23885}. Unless there is a contra-indication in a specific study subject, consideration 
should be given to initiation of antibiotic prophylaxis against pneumocystis infection 
(eg, with trimethoprim-sulfamethoxazole, dapsone, aerosolized pentamidine, or atovaquone) 
beginning prior to study drug administration. Such support may also offer the benefit of reducing 
the risk for other bacterial infections {17881}. Local practices or guidelines regarding infection 
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For subjects who develop an infection, appropriate medical therapy (with antibiotics, antifungals, 
or antiviral) or other interventions should be instituted. Whenever appropriate, subjects should 
continue with study drug during treatment for the infection.
5.4.6.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) due to polyomavirus JC has been observed 
in patients who have received rituximab therapy {24656} for hematologic malignancies. The 
specific causal role of rituximab is unknown because many of these patients had other risk 
factors (eg, low CD4+ counts) and the majority had received rituximab in combination with 
chemotherapy or as part of a hematopoietic stem cell transplant. Most cases of PML were 
diagnosed within 12 months of the last infusion of rituximab.
The diagnosis of PML should be considered in any subject presenting with new-onset or 
worsening neurologic manifestations, especially weakness or paralysis, vision loss, impaired 
speech, or cognitive deterioration. Evaluation of PML should include consultation with a 
neurologist, brain MRI, and lumbar puncture. In subjects diagnosed with PML, study drug 
should also be permanently discontinued.
5.4.7.
Pulmonary Events
Documented bacterial, fungal, viral, and pneumocystis pneumonias have been observed in 
patients receiving idelalisib, primarily in patients with CLL. Some patients receiving idelalisib
alone or in combination have developed evidence of pneumonitis without documented lung 
infection. The specific role of idelalisib in these events is unclear; nonclinical evaluations of 
pulmonary function and pathology do not indicate a direct toxic effect of idelalisib on the lungs 
and disease-related factors or toxicity from prior or concomitant therapies may have contributed 
to these clinical events. Rituximab-related noninfectious pneumonitis has been described {24807}
with an incidence of ~4.3% {19677}. In patients developing rituximab-associated pneumonitis, 
the mean time from the first rituximab infusion to the onset of respiratory symptoms was 
3 months, with a peak incidence after administration of a mean cumulative dosage of 
1600 mg/m2 {19670}.
Given the potential for infectious or drug-related adverse events, clinicians should be particularly 
observant for evidence of respiratory events in subjects participating in this trial. Subjects should 
be evaluated who describe pulmonary symptoms (eg, dyspnea on exertion, cough, shortness of 
breath); manifest a decline from baseline of 5% in oxygen saturation, or demonstrate evidence 
of pulmonary inflammation (eg, focal or diffuse interstitial pattern or ground-glass opacities on 
chest CT). Potential bacterial, fungal, or viral etiologies should be assessed. 
Pneumocystis (carinii) jiroveci should be considered, especially if the subject is not receiving 
pneumocystis prophylaxis. Depending upon the changes observed and the response to antibiotic 
intervention, recommended diagnostic work-up may include blood and sputum cultures; 
polymerase chain reaction or antigen testing for pneumocystis and respiratory viruses
(eg, CMV, influenza virus, respiratory syncytial virus, parainfluenza virus, rhinovirus); chest 
X-ray, CT or other imaging methods; pulmonary function testing and diffusing capacity of the 
lung for carbon monoxide (DLCO); bronchoscopic lavage and/or biopsy; or open-lung biopsy. 


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Noninfectious etiologies such as pulmonary edema or thromboembolism should also be 
considered.
As appropriate for the clinical situation and culture results, subjects should be treated empirically 
or given specific antibiotics, antifungals, or antiviral agents for a cultured organism. Supportive 
care, including oxygen or mechanical ventilation, should be provided as necessary. 
For subjects with a symptomatic pneumonitis (eg, onset of cough, dyspnea, hypoxia and/or a 
diffuse interstitial pattern or ground-glass opacities on chest (CT), study drug should be 
interrupted and therapy with systemic corticosteroids (eg, prednisone, 60 mg/day) should be 
instituted rapidly {19670}. Resumption of study drug at Dose Level -1 should only be considered 
if the subject is experiencing evidence of clinical benefit from study drug; reoccurrence of 
drug-related pneumonitis upon rechallenge should result in permanent discontinuation of study 
drug.
5.4.8.
Tumor Lysis Syndrome
Patients with tumor lysis syndrome may experience hyperkalemia, hypocalcemia, hyperuricemia, 
hyperphosphatemia, cardiac dysrhythmias, and acute renal failure.
Tumor lysis syndrome has not been observed with idelalisib monotherapy. However, if tumor 
lysis were to occur in a subject participating in this study, the subject should receive rapid 
reversal of hyperkalemia, intravenous hydration, antihyperuricemic agents, and appropriate 
cardiac and renal support, including dialysis as indicated. Upon recovery to baseline functioning, 
such subjects should continue study therapy to maintain tumor control.
5.4.9.
Pregnancy, Lactation, and Reproduction
Idelalisib has induced embryo lethality and teratogenicity when administered to pregnant female 
rats at maternally toxic doses. However, definitive reproductive toxicology studies in animals 
have not yet been performed and the specific effects of idelalisib on human embryogenesis or 
fetal development are unknown. Whether idelalisib is excreted in human breast milk is unknown. 
General toxicology studies in rats and dogs indicated dose-dependent reductions in testicular 
weights, with persistent minimal to mild degeneration of the seminiferous tubules and decreased 
spermatozoa in rats and hypospermatogenesis in dogs. The implications of these testicular 
changes for animal or human fertility are unknown.
Given the preliminary nature of data regarding the risks to a fetus or infant as a result of 
exposure to idelalisib, women of reproductive potential entering this study must have a negative 
serum pregnancy test at baseline and must not be breastfeeding. Males and females of 
childbearing potential should abstain from sexual intercourse or use an effective form of 
contraception (see Section 5.6.4). If a female study participant becomes pregnant or decides to 
breastfeed during the course of the study, all study therapy must be discontinued. Study 
candidates will be informed of the testicular findings through the informed consent process.


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5.4.10.
Ultraviolet Exposure
In vitro studies indicate enhanced cytotoxicity when embryonic murine fibroblasts treated with 
GS-563117 (the major metabolite of idelalisib) are simultaneously exposed to ultraviolet light.  
While nonclinical findings suggest the hypothetical potential for phototoxicity in humans, 
available clinical data do not reveal a photosafety concern. Although specific clinical correlates 
for these nonclinical data are not available, investigators and study subjects should be observant 
for the possibility that study participants may have exaggerated sunburn reactions (eg, burning, 
erythema, exudation, vesicles, blistering, edema) involving areas of skin exposed to ultraviolet 
light.
Emergency Unblinding
5.5.
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IWRS system 
for that subject.  Gilead recommends but does not require that the investigator contact the Gilead 
medical monitor before breaking the blind. Treatment assignment should remain blinded unless 
that knowledge is necessary to determine subject emergency medical care. The rationale for 
unblinding must be clearly explained in source documentation and on the case report 
form/ electronic case report form (CRF/eCRF), along with the date on which the treatment 
assignment was obtained. The investigator is requested to contact the Gilead medical monitor 
promptly in case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).
Concomitant and Supportive Therapy
5.6.
To the extent possible, administration of any prescription or over-the-counter drug products other 
than study medication should be minimized during the study period. Subjects should be 
discouraged from use of street drugs, herbal remedies, self-prescribed drugs, tobacco products, or 
excessive alcohol at any time during the clinical study.
If considered necessary for the subject’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator. The decision to 
authorize the use of any drug other than study drug should take into account subject safety, the 
medical need, the potential for drug interactions, the possibility for masking symptoms of a more 
significant underlying event, and whether use of the drug will compromise the outcome or 
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Subjects should be instructed about the importance of the need to inform the clinic staff of the 
use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and during 
the course of the study. Any concomitant drugs taken by a subject during the course of the study 
and the reason for use should be recorded on the eCRFs.
Information regarding use or restrictions on specific concomitant medications, dietary measures, 
or other interventions is provided below.
5.6.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments
Except for corticosteroids (See Section 5.6.5), no other anticancer therapies (including 
chemotherapy, radiation, antibody therapy, immunotherapy, or other experimental therapies) of 
any kind are permitted. Subjects are not allowed to participate concurrently in any other 
therapeutic clinical study.
5.6.2.
Antibiotics
Except in a subject who has a contra-indication, investigators should consider initiation of 
antibiotic prophylaxis against pneumocystis infection (eg, with trimethoprim-sulfamethoxazole, 
dapsone, aerosolized pentamidine, or atovaquone) beginning prior to study drug administration. 
Such support may also offer the benefit of reducing the risk for other bacterial infections 
{17881}. Investigator discretion and local practices or guidelines may be followed.
For subjects who develop an infection, appropriate medical therapy (with antibiotics, antifungals, 
or antiviral) or other interventions should be instituted. Whenever appropriate, subjects may 
continue with study drug during treatment for the infection.
5.6.3.
Antiemetics and Antidiarrheals
Drug-related nausea and/or vomiting have not been commonly observed with idelalisib in prior 
studies. However, subjects who experience nausea or vomiting while on study therapy may 
receive antiemetics based on the judgment of the treating physician and local institutional 
practices. At the occurrence of persistent nausea or vomiting of severity Grade 1, it is suggested 
that the subject receive an oral or transdermal serotonin antagonist (eg, dolasetron, granisetron, 
ondansetron, tropisetron, palonosetron). Other classes of antiemetic medications that may be 
employed include dopamine antagonists or benzodiazepines. As needed, subjects may be 
prescribed loperamide (Imodium® or others) or diphenoxylate and atropine (Lomotil®) to control 
diarrheal symptoms.
5.6.4.
Contraception
In the context of this protocol, a female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, a bilateral tubal ligation, or a bilateral oophorectomy; has 
medically documented ovarian failure (with serum estradiol and FSH levels within the 
institutional postmenopausal range and a negative serum or urine HCG); or is menopausal 
(age >55 years with amenorrhea for >12 months or amenorrhea for >6 months with serum 
estradiol and FSH levels within the institutional postmenopausal range).


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Sexually active females of childbearing potential must agree to use a protocol-recommended 
method of contraception during heterosexual intercourse throughout the study treatment period 
and for 30 days following the last dose of the study drug. The investigator should counsel 
subjects on the most effective methods for avoiding pregnancy during the trial. 
Protocol-recommended contraceptive methods are described in Table 5-3.
Table 5-3.
Protocol-Recommended Contraceptive Methods
Individual Methods
Combination Methods
Hormonal Methods
(One method to be used 
with a barrier method)
Barrier Methods
(Both of these methods to be used OR one of these 
methods to be used with a hormonal method)
IUD
Estrogen and progesterone
Diaphragm with spermicidea
Copper T 380A IUD
Oral contraceptives
Male condom (with spermicidea)
LNg 20 IUD
Transdermal patch
Tubal sterilization
Vaginal ring
Hysterectomy
Progesterone
Injection
Implant
a
If available/approved for use in the specific country
Abbreviation: IUD=intrauterine device
In the context of this protocol, a male subject is considered able to father a child unless he has 
had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or is receiving
ongoing testicular suppression with a depot luteinizing hormone-releasing hormone (LH-RH) 
agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or triptorelin pamoate 
[Trelstar®]).
Sexually active male subjects who can father a child must accept continuous heterosexual 
abstinence as a lifestyle choice; limit intercourse to female partners who are surgically sterile, 
post-menopausal, or using effective contraception (as noted in Table 5-3); or agree to use a 
protocol-recommended method of contraception during heterosexual intercourse throughout the 
study treatment period and for 90 days following discontinuation of the study drug (as noted in 
Table 5-3). 
The Gilead Sciences medical monitor should be consulted regarding any questions relating to 
childbearing status or contraception.


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5.6.5.
Corticosteroids
Subjects may receive topical, inhaled, enteric, or systemic corticosteroids while on study. It 
should be realized that the use of systemic corticosteroids in patients with CLL may confound 
interpretation of antitumor effects mediated by study drug therapy. However, subjects who 
develop conditions that may be alleviated by systemic corticosteroid therapy are permitted to 
receive such drugs and are not required to discontinue study participation.
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin
Granulocyte-macrophage colony-stimulating factor (GM-CSF) should not be administered given 
the potential for GM-CSF-related inflammatory symptoms.
G-CSF (filgrastim, PEG-filgrastim, lenograstim) may be administered in response to Grade 4
neutropenia or neutropenic complications; use should be particularly considered if providing 
hematopoietic support might help to maintain study drug treatment (see Table 5-2).
While erythropoietic agents (eg, erythropoietin or darbepoetin) may be administered for Grade 
3 anemia, their use in this study is discouraged given the potential to confound assessments of 
improvements in bone marrow function related to study drug.
Reference may be made to the American Society of Clinical Oncology guidelines {22486}, 
{22483}.
5.6.7.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism
Idelalisib is metabolized primarily via aldehyde oxidase and in part by CYP3A.  A clinical drug-
drug interaction study indicated that administration of a potent CYP3A inhibitor together with 
idelalisib resulted in a ~80% increase in idelalisib plasma exposures (AUC) (see Section 1.3.5.1), 
which is not considered to be clinically relevant and suggesting that idelalisib is a weak CYP3A 
substrate. Preliminary data indicate when coadministered with rifampin, a highly potent inducer 
of CYP3A, idelalisib exposures are ~75% lower. Coadministration of potent inducers of CYP3A 
with idelalisib should be avoided; a list of strong inducers is provided in Table 5-4:
Table 5-4.
Known Strong Inducers of CYP3A
Effect on 
CYP3A 
Drug Class
Medications
Strong CYP3A 
Inducers
Antimycobacterial
Rifampin
Anticonvulsants
carbamazepine, phenytoin
Foods/herbs
St. John’s wort
Abbreviation: CYP=cytochrome P450 enzyme


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5.6.8.
Drugs that undergo CYP3A-Dependent Metabolism
The major metabolite of idelalisib, GS-563117, is a competitive and time dependent inhibitor of 
CYP3A; accordingly coadministration of idelalisib with midazolam, a probe CYP3A substrate, 
resulted in a ~5-fold increase in midazolam systemic exposure (AUC). Coadministration of 
CYP3A substrates with idelalisib may result in an increase in their systemic exposures 
(eg, antiarrhythmics, calcium channel blockers, benzodiazepines, certain HMG-CoA reductase 
inhibitors, phosphodiesterase-5 (PDE5) inhibitors, warfarin). Particular caution is recommended 
during coadministration of drugs that are narrow therapeutic index CYP3A substrates 
(eg, alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, fentanyl, quinidine, 
ergotamine, dihydroergotamine, astemizole, terfenadine) with idelalisib.
5.6.9.
Immunization
Because of its actions to inhibit PI3Kδ-dependent B-cell function, high doses of idelalisib can 
impair primary or secondary responses to immunization in animals.
The specific clinical relevance of these findings with idelalisib is unknown. However, for 
subjects who are at substantial risk of an infection (eg, influenza) that might be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of study 
therapy.
Of note, the safety of immunization with live viral vaccines following idelalisib therapy has not 
been studied and vaccination with live virus vaccines during study treatment is not 
recommended.
5.6.10.
Surgery
There are no known effects of idelalisib on coagulation or wound healing. Pending receipt of 
additional information, study drug may be continued in the peri-procedural period in subjects
who require surgery or invasive procedures.
5.6.11.
Diet
There are no specific dietary restrictions in the study. Study drug may be taken with or without 
food.
Duration of Study Drug
5.7.
Subjects may continue receiving study drug until the occurrence of any events requiring study 
drug discontinuation as defined in Section 5.8.


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Discontinuation of Study Drug
5.8.
All study participants may receive study drug indefinitely; however:

Any subject has the right to discontinue study drug at any time.

Any subject who has objective evidence based on IRC review of definitive CLL progression
will discontinue study drug.

Any subject unable to tolerate a second rechallenge with protocol-described, dose-modified 
idelalisib at Dose Level –1 (see Section 5.2) should discontinue study drug.

Any subject who becomes pregnant or begins breastfeeding should discontinue study drug.

Any subject who becomes significantly noncompliant with study drug administration, study 
procedures, or study requirements should discontinue study drug.

Any subject for whom the blind is intentionally broken by the subject or the study site should 
discontinue study drug (only applicable to the blinded portion of the study).

The investigator, in consultation with the Gilead Sciences medical monitor, may discontinue
study drug, if, it is not in the subject’s best interest to continue. 

If allowed by local regulations, Gilead Sciences may transition subjects from study drug to 
commercial drug supply when idelalisib becomes commercially available in the country 
where the subject is living.
Subjects who permanently discontinue study drug for a reason other than disease progression 
(as determined by the IRC) shall continue with assessments per the schedule of procedures until 
disease progression or until another anticancer or experimental therapy is initiated. 
Discontinuation from Study
5.9.
Subject study participation will be ended due to any of the following reasons:

Adverse event.

Disease progression.

Withdrawal of consent.

Significant subject noncompliance with study drug administration, study procedures, or study 
requirements.


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
Initiation of any additional anticancer therapies (other than corticosteroids, see Section 5.6.5) 
including chemotherapy, radiation, antibody therapy, immunotherapy, or other experimental 
treatment.

Physician’s decision to remove the subject from the study.

Pregnancy.

The subject is lost to follow-up.

Death.

Discontinuation of study by the Sponsor, a Regulatory Agency, or an IRB or EC.
Study Treatment Rationale
5.10.
Subjects will be assigned to treatment (Arm A or Arm B) in this study based on their 
randomization in the primary study. The 1:1 randomization in the primary trial
(GS-US-312-0116) ensures that sufficient Arm B subjects will cross over from rituximab alone 
to single-agent idelalisib at the 150-mg/dose BID starting dose level in this extension trial
(GS-US-312-0117) to allow an adequate evaluation of efficacy and safety in this trial. The 
randomization and allocation processes will be established and performed through an IWRS; the 
intent is to maximize the integrity and security of the subject disposition and to ensure 
appropriate access and convenience-of-use by the investigational sites.
Double blinding is included to provide protection against biased interpretations of efficacy and 
safety data by subjects, caregivers, investigators, Gilead Sciences personnel, or others involved 
in study conduct. 
Selection of the idelalisib treatment regimen (including starting dose level, dose-modifications 
and supportive care, schedule, duration, and conditions of administration) for this study program 
has been based primarily on safety, exposure, and activity profiles from previous Phase 1 clinical 
studies involving healthy volunteers, patients with allergic rhinitis, and patients with 
refractory/relapsed lymphoid malignancies {20361}, {21030}, {21036}. The following 
information was considered in selecting the study drug dosing regimen for the primary study and 
this companion extension study:

Idelalisib was symptomatically well tolerated in patients with lymphoid malignancies 
receiving dose levels of 50 mg/dose BID through 350 mg/dose BID (the highest dose level 
tested). No specific MTD was apparent over the dose range tested. However, monitorable, 
reversible transaminase elevations were observed in some patients and may have been more 
frequent at higher dose levels (~10% rate among patients with CLL receiving starting doses 
of 150 mg/dose). Thus, while doses through 350 mg/dose BID are tolerable, the starting 
dose of 150 mg/dose BID appears to appropriately balance safety with efficacy in 
idelalisib-naïve subjects. The starting dose of 300 mg/dose BID in this study also appears 
appropriate for evaluation; it is lower than the dose level of 350 mg/dose BID that has been 


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tolerable in prior studies and is likely to be suitable in subjects who have already been 
tolerating idelalisib therapy at 100 mg/dose BID. 

Upon disease progression, permitting escalation from 150 mg/dose BID to 300 mg/dose BID 
among subjects allocated to Arm A offers a systematic evaluation of higher doses in subjects 
who are tolerating idelalisib treatment and might benefit from increased PI3Kinhibition. 
The pharmacological basis for considering such an intervention is based on the concept that 
some individuals might have lower-than-expected plasma exposures or dose-dependent 
resistance to the compound at 150 mg/dose BID and might benefit from a higher dose. The 
intent is to determine if the higher dose can reestablish disease control or whether absolute 
resistance to PI3Kinhibition has been acquired. The safety data obtained in these subjects 
would add to the overall safety database.

In an allergic rhinitis study, idelalisib induced statistically significant improvements in 
clinical and pharmacodynamic endpoints when administered at 100 mg/dose BID over 
7 days. These data support the pharmacological relevance of idelalisib-mediated PI3Kδ 
inhibition when administered at the dose-levels to be used in this study.

A positive correlation was noted between idelalisib dose and measures of tumor control and 
chemokine normalization in patients with B-cell malignancies. The majority of patients 
appear to have tumor responses and protracted PFS when receiving starting doses of 
100 mg/dose BID. Thus, treatment with a idelalisib at a starting dose of 150 mg/dose BID 
appears to offer most patients the potential to benefit from therapy and the dose level of 
300 mg/dose BID may provide additional benefit in patients with disease resistance as 
systematically evaluated in this trial. 

Increases in idelalisib plasma Cmax, AUC, and Ctrough values were less than dose-proportional 
in subjects with lymphoid malignancies; the dose-exposure evaluation indicated modest 
increases in plasma exposure at dose levels >150 mg BID.  Thus, administration of starting 
doses of idelalisib of 150 mg/dose BID appears appropriate to ensure adequate exposure in 
the majority of patients. 

In Phase 1 studies, the mean plasma t1/2 of idelalisib was ~6.5 to 9.8 hours across all dose 
levels and there was no substantive plasma accumulation over 7 or 28 days.

The changes in exposure observed when administering idelalisib after a high-fat, high-calorie 
meal are modest (~40% increase in mean AUC with no change in mean Cmax). Thus, 
idelalisib can be administered with or without food. 

The idelalisib dose modification provisions described in the protocol are designed to balance 
a primary concern for subject safety with the potential for observing pharmacological and 
antitumor activity in circumstances under which a subject experiencing an adverse event may 
still be able to continue on therapy at a lower idelalisib dose level. The enhanced monitoring 
to be performed and the actions to be taken in response to toxicity are based on experience 
with interruption, dose-modification, rechallenge, and re-escalation already piloted in 
idelalisib Phase 1 trials. In addition, idelalisib antitumor activity has been observed in the 


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Phase 1 studies across all dose levels tested, including doses in the range of the modified 
dose levels planned for this protocol. Thus, use of the lower dose level to accommodate 
individual subject tolerability in this protocol is justified because subjects receiving such an
idelalisib dose level still have the potential for benefit.

In both the primary and extension studies, study treatment will be continued for each subject
until the occurrence of disease progression. Such a strategy is considered appropriate under 
the assumption that persistent interference with PI3Ksignaling is likely to extend treatment 
effect. In addition, this design permits collection of further single-agent safety information 
and thus is likely to enhance understanding of the overall safety profile of idelalisib. 


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6.
STUDY PROCEDURES
Enrollment and Study Management Procedures
6.1.
6.1.1.
Subject Recruitment
Study candidates are limited to those subjects who participated in the primary clinical trial
(Study GS-US-312-0116) and meet the entry criteria for this trial (Study GS-US-312-0117).
Subjects will be enrolled from investigational sites in the United States and Europe. The site 
principal investigator, designated sub-investigators, or other designees will discuss the possibility 
of participation directly with subjects who participated in the primary study. 
The study sponsor will post a description of the study on the ClinicalTrials.gov website. Any 
promotional information generated by the sponsor or investigational sites will be submitted for 
IRB/IEC review.
6.1.2.
Subject Compensation for Participation
For subjects requesting such assistance, reasonable reimbursements for the costs of travel 
required to participate in this study will be provided by the study sponsor. To receive payment 
for travel, subjects will need to submit the original travel receipts to the research study staff at 
the investigational site.
However, other than medical care that may be provided, subjects will not be paid for 
participation in the study. Payments for such items as lost wages, disability, discomfort due to 
injury, or meals obtained while waiting at the clinical research center will not be provided. 
Through the informed consent process, study candidates will be notified that their insurance 
company could be charged for standard care that is a component of this research study and that 
subjects may be responsible for co-payments and deductible payments that are typical for their 
insurance coverage.
6.1.3.
Screening
The investigator must inform each prospective subject of the nature of the study, explain the 
potential risks, and obtain written informed consent from the subject and/or a legal guardian 
prior to performing any study-related screening procedures. At the time the study candidate signs 
the informed consent, a site representative should access the IWRS to indicate that a study 
candidate is being screened. The user will need to supply the IWRS with required information 
identifying the site and the subject number as already assigned in Study GS-US-312-0116.
Any consented subject who is excluded from the study before initiation of study treatment will 
be considered a screen failure. All screen failures must be documented along with an adequate 
description of the reason the subject was considered a screen failure. If available, information 
should be provided as to why the subject did not meet eligibility criteria, withdrew consent, 
experienced an intercurrent illness, or had other events that precluded treatment on this study.


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Explanation of Study Visits
6.2.
The specific study procedures to be conducted for each subject enrolled in the study are 
presented in tabular form in Appendix 7 and are described in the sections that follow. Additional 
information on the study procedures is provided in the study manual.
For visits at which HRQL and healthy utility data are obtained, it is important that the subject be 
administered the FACT-Leu and the EQ-5D before any other procedures are performed and 
before any study-related information is communicated to the subject; this is necessary to avoid 
biasing the PRO responses provided by the subject. Once the subject has completed the 
FACT-Leu and the EQ-5D assessments, the remaining procedures may be performed.
At visits involving idelalisib administration and pharmacokinetic sampling in the clinic, care 
should be taken to perform procedures with the appropriate timing relative to idelalisib
administration. The actual sample collection times of pharmacokinetic blood specimens should 
be recorded. If a heparinized venous catheter is placed for sample collection in order to avoid 
repeated needle sticks, at least 2 mL of blood should be removed and discarded prior to each 
sample collection in order to avoid heparin contamination of the sample.
At the visit designated as a laboratory-only visit (Visit 7), subjects will have laboratory 
assessments that may be performed at the investigational site or at an accredited local laboratory 
or clinic that is convenient for the subject/caregiver. If blood is collected at a local laboratory, 
samples are not to be analyzed at the local laboratory. For these visits, subjects and/or caregivers 
will be provided with central laboratory kits that will contain materials necessary for the 
collection and shipment of the laboratory samples by the local laboratory clinic to the central 
laboratory.
Local lab results may be requested in the event central laboratory results are not available for 
assessment of disease response, progression, or the evaluation of a significant event. In addition 
to clinical assessments of tumor status, CT or MRI imaging of the neck, chest, abdomen, and 
pelvis will be performed as a component of tumor assessments during the study based on the 
rationale provided in Section 3.2.1.
Following unblinding of the study:

Subjects who were randomized to idelalisib on Study GS-US-312-0116 and who received 
≥24 weeks idelalisib will complete Visit 16+ twelve weeks from the date of their last 
radiology assessment (CT/MRI) and study visits will continue every 12 weeks thereafter.
Visits 3 through 15 will not be required.

Subjects who have received < 24 weeks of idelalisib will have all Study GS-US-312-0117 
assessments completed per the Schedule of Procedures until they have received idelalisib for 
24 weeks cumulative across both studies. After completion of 24 weeks of cumulative 
idelalisib treatment, Visit16+ will be conducted 12 weeks from the date of their last 
radiology assessment (CT/MRI), after which time study visits will occur every 12 weeks.


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6.2.1.
Visit 1 and Screening Period (Clinic Visit)
The initial screening visit is designated as Visit 1. At Visit 1, the investigator must inform each 
prospective study participant of the nature of the study, explain the potential risks, and obtain 
written informed consent from the study candidate and/or legal guardian prior to performing any 
study-related screening procedures. Once the informed consent document has been signed, the 
subject may undergo the screening procedures.
In order to optimize scheduling convenience for the subject and for the investigational staff, 
study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be 
used as screening procedures for Study GS-US-312-0117 if performed within 4 weeks prior to 
initiation of study drug therapy on Study GS-US-312-0117. In addition, screening procedures 
may be performed over as many days as necessary provided that screening is completed within 
4 weeks prior to initiation of study drug therapy on Study GS-US-312-0117. 
The tests and evaluations outline in Table 6-1 will be performed at Visit 1 or during the 
screening period prior to initiation of study treatment.


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Table 6-1.
Procedures and Assessments at Visit 1 (During Screening Period)
Assessment 
or Procedure
Explanationa
Informed consent
To be obtained before any screening procedures are initiated
IWRS access
Access IWRS to document that subject is in screening and provide the subject number from 
Study GS-US-312-0116
CIRS assessment
Recording of current comorbid conditions using the CIRS scoring instrument
(see Appendix 6)
Concomitant
medications
Recording of ongoing concomitant medication use
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including height, weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Serum β-HCG
Women of childbearing potential only
CLL peripheral 
blood evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 12 trisomy; 
DNA mutational analysis for p53, IgHV (including IgHV3-21), and other genes of interest in 
CLL (eg, Notch); flow cytometry for CD5, CD10, CD11c, CD19, CD20, CD23, CD38, 
CD45, kappa and lambda light chains, and ZAP-70; cytology for karyotyping.
CLL serology
Serum 2 microglobulin
 
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis, to be scheduled with 4 weeks prior 
to initiation of study treatment at Visit 2
Bone marrow 
biopsy and aspirate
To be performed at investigator discretion to determine extent of CLL involvement and bone 
marrow cellularity.
a
Study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be used as screening 
procedures for Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117.
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase,
AST=aspartate aminotransferase, CIRS=cumulative illness rating scale, CLL=chronic lymphocytic leukemia, CT=computed 
tomography, DNA=deoxyribonucleic acid, FISH= fluorescence in-situ hybridization, GGT=gamma--glutamyltransferase, 
Ig=immunoglobulin, IgHV=immunoglobulin heavy chain variable region, IWRS=interactive web response system, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging, RNA=ribonucleic acid, ZAP-70=zeta-associated protein 70
PPD


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6.2.2.
Visit 2 (Day 1) (Clinic Visit)
Subjects will be assessed to determine if they still meet eligibility criteria and can initiate study 
treatment. Study drug holds from primary study GS-US-312-0116 may continue as medically 
appropriate. The procedures outlined in Table 6-2 will be performed at Visit 2 (Day 1).
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1)
Assessment or 
Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the 
subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant 
medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly
β-HCG
For women of child-bearing potential only; serum -HCG or urine dipstick pregnancy test must 
be negative prior to initial study treatment
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Idelalisib
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the date 
and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration
Study drug 
administrationa
First dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib
pharmacokineticsa
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours ± 30 mins
after study drug administration (with recording of the date and actual clock time of blood 
collection)
Study drug dispensinga
Dispensing of 4-week supply of study drug to the subject with instructions for self-
administration at home
Instruction regarding 
study drug dosing at 
next full clinic visita
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 3.
a
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll on Study GS-US-312-0117 following 
unblinding may have idelalisib treatment (and associated PK testing) delayed at the Investigator’s discretion until the time of 
disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib treatment
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response 
system, LDH=lactate dehydrogenase, RNA=ribonucleic acid


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6.2.3.
Visit 3 (Day 15) (Clinic Visit)
The procedures outlined in Table 6-3 will be performed at Visit 3 (Day 15 [±2 days]). 
Table 6-3.
Procedures and Assessments at Visit 3 (Day 15)
Assessment or 
Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the 
subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant 
medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib
pharmacokinetics
Recording of the date and actual clock time of the last prior subject self-administration of study 
drug (should be the prior evening dose)Pre-dose collection of plasma sample for idelalisib
pharmacokinetics (with recording of the date and actual clock time of the date and actual clock 
time of blood collection)
IWRS access
Access of IWRS to document subject visit
Study Therapy Administration
Study drug 
administration
Study drug to be administered to the subject (with recording of the date and actual clock time of 
the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours ± 30 mins
after study drug administration (with recording of the date and actual clock time of blood 
collection)
Instruction regarding 
study drug dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 4.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, EQ-5D=EuroQoL 
Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, HRQL=health-related quality of life, 
GGT=gamma-glutamyltransferase, IWRS=interactive web response system, LDH=lactate dehydrogenase


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6.2.4.
Visit 4 (Day 29) (Clinic Visit)
The procedures outlined in Table 6-4 will be performed at Visit 4 (Day 29 [±2 days]).
Table 6-4.
Procedures and Assessments at Visit 4 (Day 29)
Assessment or 
Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated to 
the subject
Adverse events 
Recording of adverse events occurring since Visit 3
Concomitant 
medications
Recording of concomitant medication used since Visit 3
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last prior 
subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration and Dispensing
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration)


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Assessment or 
Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours ± 30 mins
after study drug administration (with recording of the date and actual clock time of blood 
collection)
Study drug 
dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for self-
administration at home
Instruction 
regarding dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the day 
of Visit 5.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed 
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging


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6.2.5.
Visit 5 (Day 43) (Clinic Visit)
The procedures outlined in Table 6-5 will be performed at Visit 5 (Day 43 [±2 days]). 
Table 6-5.
Procedures and Assessments at Visit 5 (Day 43)
Assessment or 
Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated 
to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant 
medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
IWRS access
Access of IWRS to document subject visit
Post-Therapy Procedures and Assessments
Instruction regarding 
study drug dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the day 
of Visit 6.
Scheduling of Visit 6 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 6.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, EQ-5D=EuroQoL 
Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, HRQL=health-related quality of life, 
GGT=gamma-glutamyltransferase, IWRS=interactive web response system, LDH=lactate dehydrogenase


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6.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit)
The procedures outlined in Table 6-6 will be performed at Visit 6 (Day 57 [±2 days]). 
Table 6-6.
Procedures and Assessments at Visit 6 (Day 57)
Assessment or 
Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the 
assessment should be done even if study drug has been interrupted. 
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated 
to the subject
Adverse events 
Recording of adverse events occurring since Visit 5
Concomitant 
medications
Recording of concomitant medication used since Visit 5
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last prior 
subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow 
biopsy and aspirate
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not 
necessary to obtain a follow-up bone marrow biopsy/aspirate to establish CR.


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Assessment or 
Procedure
Explanation
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug bottle number
Study Therapy Administration
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours ± 30 mins
after study drug administration (with recording of the date and actual clock time of blood 
collection)
Study drug 
dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for self-
administration at home
Instruction 
regarding dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the day 
of Visit 8.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging
6.2.7.
Visit 7 (Day 71) (Laboratory Visit)
The procedures outlined in Table 6-7 will be performed at Visit 7 (Day 71 [±2 days]).
Table 6-7.
Procedures and Assessments at Visit 7 (Day 71)
Assessment or 
Procedure
Explanation
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including ALT, AST, ALP, GGT, total bilirubin, LDH
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
GGT=gamma-glutamyltransferase, LDH=lactate dehydrogenase


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6.2.8.
Visit 8 (Day 85) (Clinic Visit)
The procedures outlined in Table 6-8 will be performed at Visit 8 (Day 85 [±2 days]).
Table 6-8.
Procedures and Assessments at Visit 8 (Day 85)
Assessment or 
Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated to 
the subject
Adverse events 
Recording of adverse events occurring since Visit 6
Concomitant 
medications
Recording of concomitant medication used since Visit 6
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last prior 
subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration and Dispensing
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration)


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Assessment or 
Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours ± 30 mins
after study drug administration (with recording of the date and actual clock time of blood 
collection)
Study drug 
dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for self-
administration at home
Instruction 
regarding dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the day 
of Visit 9.
Scheduling of 
Visit 9 radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 9.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed 
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging


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6.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit)
The procedures outlined in Table 6-9 will be performed at Visit 9 (Day 113 [±3 days]).
Table 6-9.
Procedures and Assessments at Visit 9 (Day 113)
Assessment or 
Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit the 
assessment should be done even if study drug has been interrupted.
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated 
to the subject
Adverse events 
Recording of adverse events occurring since Visit 8
Concomitant 
medications
Recording of concomitant medication used since Visit 8
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last prior 
subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow 
biopsy and aspirate
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not 
necessary to obtain a follow-up bone marrow biopsy/aspirate to establish CR.


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Assessment or 
Procedure
Explanation
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours ± 30 mins
after study drug administration (with recording of the date and actual clock time of blood 
collection)
Study drug 
dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for self-
administration at home
Instruction 
regarding dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the day 
of Visit 10.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging


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6.2.10.
Visit 10 (Day 141) (Clinic Visit)
The procedures outlined in Table 6-10 will be performed at Visit 10 (Day 141 [±3 days]) 
Table 6-10.
Procedures and Assessments at Visit 10 (Day 141)
Assessment or 
Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated to 
the subject
Adverse events 
Recording of adverse events occurring since Visit 9
Concomitant 
medications
Recording of concomitant medication used since Visit 9
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last prior 
subject self-administration of study drug (should be the prior evening dose)
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug  blister card number
Study Therapy Administration
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours ± 30 mins
after study drug administration (with recording of the date and actual clock time of blood 
collection)


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Assessment or 
Procedure
Explanation
Study drug 
dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction 
regarding dosing at 
next full clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on the day 
of Visit 11.
Scheduling of 
Visit 11 radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 11.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed 
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging


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6.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit)
The procedures outlined in Table 6-11 will be performed at Visit 11 (Day 169 [±3 days]). 
Table 6-11.
Procedures and Assessments at Visit 11 (Day 169)
Assessment or 
Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the 
assessment should be done even if study drug has been interrupted. 
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated to 
the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant
medications
Recording of concomitant medication used since Visit 10
Study drug 
return/accounting
Counting returned study drug. Recording of the date and actual clock time of the last prior 
subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow 
biopsy and aspirate
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not 
necessary to obtain a follow-up bone marrow biopsy/aspirate to establish CR.


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Assessment or 
Procedure
Explanation
Idelalisib 
pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study Therapy Administration
Study drug 
administration
Dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib 
pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours ± 30 mins
after study drug administration (with recording of the date and actual clock time of blood 
collection)
Study drug 
dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for self-
administration at home.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging


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6.2.12.
Visit 12 (Day 211) (Clinic Visit)
The procedures outlined in Table 6-12 will be performed at Visit 12 (Day 211 [±3 days]) 
Table 6-12.
Procedures and Assessments at Visit 12 (Day 211)
Assessment or 
Procedure
Explanation
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated to 
the subject
Adverse events 
Recording of adverse events occurring since Visit 11
Concomitant 
medications
Recording of concomitant medication used since Visit 11
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit
Study drug 
administration
Subject to continue with study drug as prescribed.
Scheduling of 
Visit 13 radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 13.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed 
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging


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6.2.13.
Visit 13 (Day 253) (Clinic and Radiology Visit)
The procedures outlined in Table 6-13 will be performed at Visit 13 (Day 253 [±3 days]). 
Table 6-13.
Procedures and Assessments at Visit 13 (Day 253)
Assessment or 
Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the 
assessment should be done even if study drug has been interrupted. 
During-Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the 
subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant 
medications
Recording of concomitant medication used since Visit 10
Study drug 
return/accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy 
and aspirate
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR.
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study drug 
administration
Subject to continue with study drug as prescribed.
Study drug 
dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for self-
administration at home.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging


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6.2.14.
Visit 14 (Day 295) (Clinic Visit)
The procedures outlined in Table 6-14 will be performed at Visit 14 (Day 295 [±3 days]) 
Table 6-14.
Procedures and Assessments at Visit 14 (Day 295)
Assessment or 
Procedure
Explanation
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated to 
the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant 
medications
Recording of concomitant medication used since Visit 10
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, 
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit
Study drug 
administration
Subject to continue with study drug as prescribed.
Scheduling of 
Visit 15 radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 15.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed 
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging


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6.2.15.
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks) (Clinic and 
Radiology Visits)
The procedures outlined in Table 6-15 will be performed at Visit 15 (Day 337 [±3 days]) and 
every 12 weeks thereafter [±7 Days]).
Table 6-15.
Procedures and Assessments at Visit 15 and Subsequent Visits
(Day 337 and Every 12 Weeks)
Assessment or 
Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the 
assessment should be done even if study drug has been interrupted.
During-Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is communicated to 
the subject
Adverse events 
Recording of adverse events occurring since prior visit
Concomitant 
medications
Recording of concomitant medication used since prior visit
Study drug 
return/accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG 
dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol,
triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM


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Assessment or 
Procedure
Explanation
Bone marrow 
biopsy and aspirate
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not 
necessary to obtain a follow-up bone marrow biopsy/aspirate to establish CR.
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study drug 
administration
Subject to continue with study drug as prescribed.
Study drug 
dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for self-
administration at home
Scheduling of next 
visit radiology 
assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for next clinic visit 
(every 12 weeks).
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging
6.2.16.
End-of-Study Visit (Clinic Visit)
At the time of discontinuation from the study, the subject should have the procedures and 
assessments performed as documented in Table 6-16. An end-of-study CT/MRI tumor 
assessment should be performed unless the subject already has radiographic confirmation of 
definitive disease progression 4 weeks prior to study discontinuation. 


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Table 6-16.
Procedures and Assessments at End-of-Study Visit
Assessment or 
Procedure
Explanation
Radiology 
assessmenta
CT or MRI imaging of neck, chest, abdomen, and pelvis
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are performed
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed
Adverse events 
Recording of adverse events occurring since prior visit; if a clinically significant adverse event or 
abnormal result is observed that is not resolved by the end-of treatment visit, repeat evaluations 
should be performed to document resolution or stabilization of the abnormality
Concomitant 
medications
Recording of concomitant medication used since prior visit
Study drug 
return/accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical 
examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly
Serum β-HCG
Women of childbearing potential only
CLL peripheral 
blood evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 12 trisomy; DNA 
mutational analysis for p53, IgHV (including IgHV3-21), and other genes of interest in CLL (eg, 
Notch); flow cytometry for CD5, CD10, CD11c, CD19, CD20, CD23, CD38, CD45, kappa and 
lambda light chains, and ZAP-70; cytology for karyotyping
CLL serology
Serum 2 microglobulin
 
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS
Access IWRS to document that subject has permanently discontinued study therapy and to indicate 
whether subject agrees to continue to undergo long-term follow-up
a
An end-of-study CT/MRI tumor assessment should be performed unless the subject has per-protocol CT/MRI assessments 
4 weeks prior to end-of-study discontinuation.
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, CLL=chronic lymphocytic leukemia, CT=computed tomography, FISH= fluorescence in-situ 
hybridization, GGT=gamma-glutamyltransferase, IgHV=immunoglobulin heavy-chain variable-region, IWRS=interactive web 
response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, RNA=ribonucleic acid, 
ZAP-70=zeta-associated protein 70
PPD


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6.2.17.
30 Day and Long-Term Follow-up
A 30 Day follow-up visit will be performed 30 (+ 5) days following the end-of-study visit; 
however, it may be waived for subjects who have permanently discontinued study drug and have 
had a study visit > 30 days after the last dose of study drug.
Long-term, follow-up will be requested of all subjects who withdraw from study for any reason.
The long-term follow-up for survival will be conducted at ~6-month intervals for 5 years, 
starting at the end-of-study visit. Information may be gathered during a routine clinic visit or 
other contact with the subject, or via telephone. Information gathered will include medical status, 
anti-tumor treatments, secondary malignancies, and survival.
Sample Storage
6.3.
 
 
 
  
 
  
Blood Collection
6.4.
The maximum amount of blood to be drawn at a visit ~115 mL and the total amount of blood to 
be drawn over the initial 52-week study period (including the 4-week screening period and 
through Week 48 of the study including a possible end-of-therapy visit) is ~560 mL. For a 40-kg 
person (the smallest participant expected to enroll in the study), this equates to maximum blood 
volume per body weight per visit of ~2.8 mL/kg and a total blood volume per body weight per 
average 6-week period of ~1.6 mL/kg. These quantities of blood are within accepted limits of 
3.0 mL/kg of body weight for a single blood draw and 7.0 mL/kg of body weight for a 6-week 
period.
Specific details regarding blood sample collection and processing requirements will be provided 
separately in the study manual.
 
 
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Study Procedure Rationale
6.5.
The planned study assessments and timing have been selected as appropriate for screening of 
subjects, for determination of idelalisib-related or disease-related toxicities, for dose 
modification during the study, for characterization of drug exposure and desired pharmacological 
effects, and for evaluation of drug activity. The scheduling of testing is designed to collect a 
complete safety and pharmacology data set while maintaining subject tolerance of study 
procedures. The planned schedule of tumor assessments is consistent with expected rate of 
changes and appropriately balances precise measurement of tumor control with the expense and 
subject inconvenience associated with clinical and radiological procedures. For discussion of the 
rationale for endpoint selection, see Section 3.2.


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7.
EFFICACY ASSESSMENTS
Tumor Status Assessments
7.1.
The determination of CLL response and progression will be based on standardized IWCLL
criteria {12154}, as specifically modified for this study to reflect current recommendations which 
consider the mechanism of action of idelalisib and similar drugs {22541}. Treatment decisions by 
the investigator in this study will be based on these assessments. Radiographic and clinical tumor 
assessments will be subject to independent confirmation by the IRC (see Section 10.4.2).
Method of Assessment
7.2.
In addition to clinical examination, imaging-based evaluation will be used in this study in all 
subjects enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI 
scanning may be used at the investigator’s discretion in subjects for whom this may be a 
preferred alternative to CT scanning; however, if MRI is performed, a non-contrast CT of the 
chest should be performed. Contrast-enhanced scanning is preferred, but iodine-containing or 
gadolinium contrast material may be omitted in subjects for whom use of a contrast agent would 
be medically contraindicated. Chest x-ray, ultrasound, endoscopy, laparoscopy, PET, 
radionuclide scans, or tumor markers will not be considered for response assessment.
For radiographic evaluations, the same method of assessment and the same technique 
(eg, scan type, scanner, subject position, dose of contrast, injection/scan interval) should be used 
to characterize each identified and reported lesion at baseline and during study treatment and 
follow-up. 
All relevant clinical and radiographic information required to make each tumor status assessment 
must be made available for source verification and for submission to the IRC 
(see Section 10.4.2).
Timing of Assessments
7.3.
All baseline clinical and CT/MRI tumor assessments should be performed within 4 weeks prior 
to initiation of study drug therapy. In order to optimize scheduling convenience for the subject 
and for the investigational staff, clinical and CT/MRI tumor assessments performed as part of 
Study GS-US-312-0116 need not be repeated and can be used as baseline tumor assessments for 
Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117. Clinical tumor assessments should be performed at each clinical visit. 
On-study CT/MRI tumor assessments should be performed at ~8- to 12-week intervals as 
dictated by the study protocol. An end-of-study CT/MRI tumor assessment should be performed 
unless the subject has per-protocol CT/MRI assessments 4 weeks prior. If a subject 
permanently discontinues study drug prior to objective documentation of CLL progression, 
investigators should continue further follow-up at ~12-week intervals until CLL progression is 
documented by the central IRC.


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Identification and Measurement of Tumor Lesions and Organomegaly
7.4.
7.4.1.
Index Lesions
At baseline, up to 6 lymph nodes should be selected as index lesions that will be used to 
quantitate the status of the disease during study treatment. Ideally, the index lesions should be 
located in disparate regions of the body. Only peripheral nodes need be selected as index lesions. 
However, it is optimal if mediastinal and retroperitoneal areas of disease are assessed whenever 
these sites are involved.
Index lesions will be measured and recorded at baseline and at the stipulated intervals. The 
cross-sectional dimensions (the largest cross-sectional diameter, ie, the LD × LPD) will be 
recorded (in cm) for each index lesion. The product of the perpendicular diameters (PPD) 
(in cm2) for each index lesion and the sum of the products (SPDs) (in cm2) for all index lesions 
will be calculated and recorded. The baseline SPDs will be used as references by which tumor 
response will be characterized during treatment. The nadir LD of individual lesions and the nadir 
SPD will be used as references by which CLL progression will be characterized. All LD and 
LPD diameters will be reported in centimenters and all PPDs and SPDs will be reported in 
centimeters squared.
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable at 
baseline. A lymph node lesion is considered abnormal if it has a single diameter that is 1.5 cm 
and is considered measurable if it has 2 perpendicular diameters that can be accurately measured 
in cross section with the LD being 1.0 cm and the LPD also being 1.0 cm.
At follow-up time points, the LDs for individual lesions and the SPD of all nodal index lesions 
will be considered. Because nodal index lesions that have one or both diameters >0 cm and 
1.0 cm cannot be reliably measured, a default value of 1.0 cm will be assigned for each 
diameter that meets these criteria and the resulting PPD will be used in SPD calculations. Based 
on this convention, a CR may be achieved even if an SPD value is >0 cm2, (ie, if all lymph nodes 
measure <1.0 cm2).
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD will be considered 
progressive disease.
In cases in which a large lymph node mass has split into multiple components, all 
subcomponents regardless of size will be used in calculating the SPD. Progression of the lesion 
will be based on the SPD of sub-components. Lesion sub-components will have the true PPDs 
calculated. Similarly, lesion sub-components that are visible but neither abnormal nor 
measurable will have the default PPD of 1.0 cm2 (1.0 cm 1.0 cm) used in calculating the SPD.
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer 
be separated by this boundary, the newly merged lesion will be measured bi-dimensionally.


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7.4.2.
Spleen and Liver
Both the spleen and liver will be assessed by CT/MRI scan at baseline and at the stipulated 
intervals during treatment. The baseline and nadir values for the longest vertical dimension 
(LVD) of each organ will be used as reference to further characterize the objective tumor 
response of the measurable dimensions of the CLL during treatment. All spleen and liver LVD 
measurements should be recorded in centimeters.
By imaging, the spleen will be considered enlarged if it is >12 cm in LVD {22487}, {22959}.  
For subjects with splenomegaly at baseline or at the splenic LVD nadir, respective response and 
progression evaluations of the spleen will consider only changes relative to the enlargement of 
the spleen at baseline or nadir, not changes relative to the total splenic LVD. 
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen in its LVD or 
decrease to ≤12 cm in the LVD, is required for declaration of a splenomegaly response. 
Conversely, an increase in splenic enlargement by ≥50% from nadir (with a minimum 2 cm 
increase) is required for declaration of splenic progression. 
By imaging, the liver will be considered enlarged if it is >18 cm in LVD {22485}.
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the liver in its LVD or 
decrease to ≤ 18 cm in the LVD is required for declaration of a hepatomegaly response. 
Conversely, an increase in liver enlargement by ≥50% from nadir (with a minimum 2 cm 
increase) is required for declaration of hepatic progression.
7.4.3.
Non-Index Lesions
Any other measurable and abnormal nodal lesions not selected for quantitation as index lesions 
may be considered non-index lesions. In addition, non-measurable evidence of CLL such as 
nodal lesions with both diameters <1.0 cm, extra-nodal lesions, bone lesions, leptomeningeal 
disease, ascites, pleural or pericardial effusions, lymphangitis of the skin or lung, abdominal 
masses that are not confirmed and followed by imaging techniques, cystic lesions, previously 
irradiated lesions, lesions with artifacts, and may be considered as non-index disease.
The presence or absence of non-index disease should be recorded at baseline and at the stipulated 
intervals during treatment. If present at baseline, up to 6 non-index lesions should be recorded. 
The non-index disease at baseline will be used as a general reference to further characterize 
regression or progression of CLL during assessments of the objective tumor response during 
treatment. Measurements are not required and these lesions should be followed as “present” or 
“absent”.


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Definitions of Tumor Response and Progression
7.5.
Responses will be categorized by the IRC as CR, PR, SD, or PD. In addition, a response category 
of not evaluable (NE) is provided for situations in which there is inadequate information to 
otherwise categorize response status. A response category of no disease (ND) is included for 
situations in which there is absence of tumor both at baseline and on treatment.
The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until disease/recurrence progression (taking as a reference 
for disease progression the smallest measurements recorded since treatment started). Subjects 
with a best overall response of NE or ND will be counted in the denominators in calculations of 
tumor response rates.
7.5.1.
Complete Response
To satisfy criteria for a CR, all of the following criteria must be met:

No evidence of new disease

ALC in peripheral blood of <4 x 109/L

Regression of all index nodal masses to normal size (1.5 cm in the LD)

Normal spleen and liver size

Regression to normal of all nodal non-index disease and disappearance of all detectable 
non-nodal, non-index disease

Morphologically negative bone marrow defined as <30% of nucleated cells being lymphoid 
cells and no lymphoid nodules in a bone marrow sample that is normocellular for age

Peripheral blood counts meeting all of the following criteria:
— ANC >1.5 x 109/L without need for exogenous growth factors (eg, G-CSF)
— Platelet count 100 x 109/L without need for exogenous growth factors
— Hemoglobin 110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (eg, erythropoietin)
Note: Subjects who fulfill all the criteria for a CR (including bone marrow criteria) but who 
have a persistent anemia, thrombocytopenia, or neutropenia or a hypocellular bone marrow 
that is related to prior or ongoing drug toxicity (and not to CLL) will be considered as a CR 
with incomplete marrow recovery (CRi).


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7.5.2.
Partial Response
To satisfy criteria for a PR, all of the following criteria must be met:

No evidence of new disease

A change in disease status meeting 2 of the following criteria, with 2 exceptions in which 
only 1 criterion is needed: (1) Only lymphadenopathy is present at baseline; (2) Only 
lymphadenopathy and lymphocytosis are present at baseline. In these 2 cases, only 
lymphadenopathy must improve to the extent specified below:
— In a subject with baseline lymphocytosis (ALC4 x 109/L), a decrease in peripheral blood 
ALC by 50% from baseline or a decrease to <4 x 109/L
— A decrease by 50% from the baseline in the SPD of the index nodal lesions
— In a subject with enlargement of the spleen at baseline, a splenomegaly response, defined 
as a ≥ 50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen or 
decrease to ≤12 cm in the LVD by imaging
— In a subject with enlargement of the liver at baseline, a hepatomegaly response, defined 
as a ≥ 50% decrease (minimum 2 cm) from baseline in the enlargement of the liver or 
decrease to ≤18 cm in the LVD by imaging
— A decrease by 50% from baseline in the CLL marrow infiltrate or in B-lymphoid 
nodules

No index, splenic, liver, or non-index disease with worsening that meets the criteria for 
definitive PD

Peripheral blood counts meeting 1 of the following criteria:
— ANC >1.5 x 109/L or 50% increase over baseline without need for exogenous growth 
factors (eg, G-CSF)
— Platelet count 100 x 109/L or 50% increase over baseline without need for exogenous 
growth factors
— Hemoglobin 110 g/L (11.0 g/dL) or 50% increase over baseline without red blood cell 
transfusions or need for exogenous growth factors (eg, erythropoietin)
7.5.3.
Stable Disease
To satisfy criteria for stable disease (SD), the following criteria must be met:

No evidence of new disease

There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD


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7.5.4.
Definitive Progressive Disease
The occurrence of any of the following events indicates definitive PD:

Evidence of any new disease:
— A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD
— New or recurrent splenomegaly, with a minimum LVD of 14 cm
— New or recurrent hepatomegaly, with a minimum LVD of 20 cm
— Unequivocal reappearance of an extra-nodal lesion that had resolved   
— A new unequivocal extra-nodal lesion of any size
— New non-index disease (eg, effusions, ascites, or other organ abnormalities related to 
CLL)
Note: Isolated new effusions, ascites, or other organ abnormalities are not sufficient evidence 
alone of PD unless histologically confirmed. Thus, a declaration of PD should not be made if 
this is the only manifestation of apparently new disease.

Evidence of worsening of index lesions, spleen or liver, or non-index disease:
— Increase by 50% from the nadir in the SPD of index lesions
— Increase from the nadir by 50% in the LD of an individual node or extra-nodal mass that 
now has an LD of >1.5 cm and an LPD of > 1.0 cm
— Splenic progression, defined as an increase in splenic enlargement by 50% from nadir 
(with a minimum 2 cm increase and a minimum LVD of 14 cm)
— Hepatic progression, defined as an increase in hepatic enlargement by 50% from nadir 
(with a minimum 2 cm increase and minimum LVD of 20 cm)
— Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or other 
organ abnormalities related to CLL) 
— Transformation to a more aggressive histology (eg, Richter syndrome) as established by 
lymph node or other tissue biopsy, or fluid cytology (with the biopsy or fluid cytology 
date being considered the date of CLL progression if the subject has no earlier objective 
documentation of CLL progression).


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
Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to an 
autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an infiltrate of 
clonal CLL cells
— The current platelet count is <100 x 109/L and there has been a decrease by >50% from 
the highest on-study platelet count 
— The current hemoglobin is <110 g/L (11.0 g/dL) and there has been a decrease by 
>20 g/L (2 g/dL) from the highest on-study hemoglobin
Note: If there is uncertainty regarding whether there is true progression, the subject should 
continue study treatment and remain under close observation (eg, evaluated at 4-week 
intervals) pending confirmation of progression status by the IRC. In particular, worsening of 
constitutional symptoms in the absence of objective evidence of worsening CLL will not be 
considered definitive disease progression; in such subjects, both CLL-related and 
non-CLL-related causes for the constitutional symptoms should be considered. Worsening of 
disease during temporary interruption of study treatment (eg, for intercurrent illness) is not 
necessarily indicative of resistance to study treatment. In these instances, CT/MRI or other 
relevant evaluations should be considered in order to document whether definitive disease 
progression has occurred. If subsequent evaluations suggest that the subject has experienced 
persistent definitive CLL progression, then the date of progression should be the timepoint at 
which progression was first objectively documented.
7.5.5.
Non-Evaluable
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE: 

There are no images or inadequate or missing images

Images of the liver and spleen are missing at that time point (with the exception that absence 
of splenic images will not result in an NE designation in a subject known to have undergone 
splenectomy).
Note: A time-point will be considered to have a response of NE if any index lesion is missing. 
PD may be assigned at any time point regardless of the extent of missing index or non-index 
lesions. Missing non-index lesions will not impact the ability to assess for response or disease 
progression.
7.5.6.
No Disease
Subjects have a status of ND if all of the following conditions occur:

No index disease noted at baseline or on-treatment 

No non-index disease noted at baseline or on-treatment.


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
No enlargement of the liver or spleen at baseline or on-treatment

No abnormalities of peripheral blood counts (elevated ALC or abnormally low ANC, platelet 
count, or hemoglobin) and no evidence of CLL in bone marrow (if available) at baseline or 
on treatment
7.5.7.
Lymphocytosis During Therapy
Idelalisib can mobilize CLL cells from tissues into the peripheral blood. This characteristic 
pharmacological action can be prominent early in therapy but can persist over time and should 
not be confused with disease progression in subjects who have persistent control of other 
CLL-related signs and symptoms. In the absence of other objective evidence of disease 
progression, lymphocytosis alone will not preclude subjects from meeting the criteria for PR if 
other criteria for PR are met and will not be considered evidence of disease progression if 
occurring in isolation. Subjects with lymphocytosis should be continued on study drug until the 
occurrence of definitive disease progression (ie, disease progression that is manifest by 
worsening CLL-related signs other than lymphocytosis alone), or the occurrence of another 
reason to discontinue study therapy as described in Section 5.8.
7.5.8.
Documentation of Definitive CLL Progression
Of importance, CLL response and progression data collected from the primary study will be 
subjected to IRC review (see Section 10.4.2). Subjects must have confirmation by the sponsor 
working in collaboration with the IRC that the disease has progressed on the primary clinical 
trial (Study GS-US-312-0116) before being permitted to receive secondary idelalisib therapy 
on this extension trial ( GS-US-312-0117). Subjects should continue study drug pending 
confirmation of progression status. CT/MRI should be attempted in order to document definitive 
disease progression by the IRC. The end-of study scan from the primary study can serve as the 
baseline scan for the extension study if obtained within the specific screening period for the 
extension study. If obtained within the specified screening period for the extension study, this 
scan can serve as the baseline scan for the extension study.


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8.
SAFETY ASSESSMENTS
Adverse Event Definitions
8.1.
8.1.1.
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical product which; does not necessarily have a causal relationship 
with study drug administration or usage. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Lymphocytosis

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 5.2.8)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
In this study, any of the following events will be considered an adverse event:

Any complication that occurs as a result of a protocol-mandated procedure (eg, venipuncture, 
biopsy) in the screening, on-treatment, or post-treatment periods.

Any pre-existing condition that increases in severity or changes in nature during or as a 
consequence of study drug administration. Worsening manifestations of the underlying 
cancer (eg, increase in pain, tumor flare reaction, tumor lysis syndrome) may be considered 
adverse events in this study.


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
Any injury or accident occurring during the screening, on-treatment, or post-treatment 
periods. If a medical condition is known to have caused the injury or accident (eg, a fall 
secondary to dizziness), the medical condition (dizziness) and the accident (fall) should be 
reported as 2 separate adverse events. 

Any abnormality in physiological testing or a physical examination finding that requires 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test).

Any laboratory (eg, clinical chemistry, hematology, urinalysis) or investigational  
abnormality (eg, ECG, X-ray) independent of the underlying medical condition that requires
clinical intervention, results in further investigation (beyond ordering a repeat [confirmatory] 
test), or leads to investigational medicinal product interruption or discontinuation unless it is
associated with an already reported clinical event. If the laboratory abnormality is part of a 
syndrome, the syndrome or diagnosis (eg, anemia) not the laboratory result (eg, decreased 
hemoglobin) should be recorded. 

A complication related to pregnancy or termination of a pregnancy (see Section 5.4.9 for 
additional information).
8.1.2.
Serious Adverse Event
A serious adverse event (SAE) is defined as an event that results in any of the following:

Death

Life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe.) 

In-patient hospitalization or prolongation of existing hospitalization.  

Persistent or significant disability/incapacity.

A congenital anomaly/birth defect

A medically important event or reaction. Such events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the outcomes listed above.Examples of such events 
might include:
— Allergic bronchospasm requiring intensive treatment in an emergency room or at home
— New cancers or blood dyscrasias
— Convulsions that do not result in hospitalization


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— Development of drug dependency or drug abuse
Medical and scientific judgment must be exercised to determine whether such an event is 
reportable under expedited reporting rules. 
Infections resulting from contaminated medicinal product will be considered a medically 
important event and subject to expedited reporting requirements.
Given the endpoints of the study, in order to maintain the integrity of the study the following 
events that are assessed as unrelated to IMP will not be considered SAEs:

Progression of CLL

Death related to progression of CLL
Disease progression and death from disease progression should be reported as SAEs by the 
investigator only if it is assessed that the IMPs caused or contributed to the disease progression 
(i.e., by a means other than lack of effect). Unrelated disease progression and death due to 
disease progression should be captured on the eCRF.
These events will be reported, as appropriate, in the final clinical study report and in any relevant 
aggregate safety reports. The safety information from this study will also be reviewed by an 
independent DMC on an ongoing basis. The DMC can have access to partially blinded or 
unblinded data in order to determine if it is safe to continue the study according to the protocol.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Section 8.5.  If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result (ie, decreased 
hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 5.4.
Assessment of Adverse Events and Serious Adverse Events
8.2.
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.


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8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
Investigator Requirements and Instructions for Reporting Adverse Events 
8.3.
and Serious Adverse Events to Gilead
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed from screening 
onwards.
All AEs, regardless of cause or relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP must be reported to the CRF/eCRF database as 
instructed. 
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported. 
All AEs should be followed up until resolution if possible. If by the last day on study 
(including the off-study medication follow-up period) the AE has not resolved, then the AE will 
be followed up until the investigator and/or Gilead Sciences determine that the subject's 
condition is stable. However, Gilead Sciences may request that certain AEs be followed until 
resolution.


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Investigators are not obligated to actively seek SAEs after the above period. However, if the 
investigator learns of any SAEs that occur after study participation has concluded and the event 
is deemed relevant to the use of IMP, he/she should promptly document and report the event to 
Gilead DSPH.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 

At the time of study start, SAEs will be reported using a paper serious adverse event 
reporting form. During the study conduct, sites may transition to an electronic SAE (eSAE) 
system. Gilead will notify sites in writing and provide training and account information prior 
to implementing an eSAE system.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by faxing 
the report form within 24 hours of the investigator’s knowledge of the event to the attention 
of Gilead DSPH or to the designated CRO.
Gilead Reporting Requirements
8.4.
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the IRB or IEC of SUSAR reports as soon as is practical, where this is 
required by local regulatory agencies, and in accordance with the local institutional policy.
Grading of the Severity of an Adverse Event
8.5.
The severity of adverse events will be graded using the CTCAE, Version 4.03 (provided in study 
manual and available at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). For
each episode, the highest severity grade attained should be reported.


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If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: Grade 1 
(mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal) to 
describe the maximum intensity of the adverse event. For purposes of consistency with the 
CTCAE, these intensity grades are defined in Table 8-1.
Table 8-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Sign or symptom is present, but it is easily tolerated, is not expected to have a 
clinically significant effect on the subject’s overall health and well-being, does not 
interfere with the subject’s usual function, and is not likely to require medical 
attention.
Grade 2
Moderate
Sign or symptom causes interference with usual activity or affect clinical status, and 
may require medical intervention.
Grade 3
Severe
Sign or symptom is incapacitating or significantly affects clinical status and likely 
requires medical intervention and/or close follow-up.
Grade 4
Life-threatening
Sign or symptom results in a potential threat to life.
Grade 5
Fatal
Sign or symptom results in death.
The distinction between the seriousness and the severity of an adverse event should be noted. 
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For 
example, a headache may be severe in intensity, but would not be classified as serious unless it 
met one of the criteria for serious events listed in Section 8.1.2 above.
Adverse Event Reporting Period
8.6.
The start of the adverse event reporting for a study subject will coincide with signing of the 
informed consent for Study GS-US-312-0117. Any new adverse events occurring thereafter 
should not be reported within Study GS-US-312-0116, but instead should be reported within
Study GS-US-312-0117. The end of the adverse-event-reporting period for 
Study GS-US-312-0117 occurs 30 days after the discontinuation from study drug or when any 
ongoing drug-related adverse events and/or serious adverse events have resolved or become 
stable. A subject withdrawn from the study because of an adverse event must be followed until 
the clinical outcome from the adverse event is determined. The investigator should use 
appropriate judgment in ordering additional tests as necessary to monitor the resolution of events 
ongoing at the completion of study treatment. Gilead Sciences may request that certain adverse 
events be followed longer.
Investigators are not obligated to actively seek information regarding the occurrence of new 
serious adverse events beginning after the 30-day post-study period. However, if the investigator 
learns of such a serious adverse event and that event is deemed relevant to the use of the study 
drug, he/she should promptly document and report the event. A longer reporting period applies in 
the case of pregnancy (see Section 8.9.1)


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Adverse Event Reporting Requirements
8.7.
8.7.1.
Site Reporting Requirements
Classification of an event as serious or nonserious (see Section 8.1.2) determines the reporting 
procedures to be followed by the site. 
Site reporting requirements for adverse events are summarized in Table 8-2, below.
Table 8-2.
Site Reporting Requirements for Adverse Events
Classification
Reporting Time
Reporting Action
Serious
Within 24 hours
Fax report on designated serious adverse event report form to 
PPD Pharmacovigilancea, and to the site IRB/IEC, as per local IRB/IEC 
requirements; include copies of relevant source documentsb (eg, progress 
notes, autopsy reports, laboratory and diagnostic test results, discharge 
summaries) in communication to PPD Pharmacovigilancea
Per eCRF submission 
procedurec
Record and submit information on appropriate eCRFs
Nonserious
Per eCRF submission 
procedure
Record and submit information on appropriate eCRFs
a
See contact information in Table 8-3 below.
b
Subject name, address, and other personal identifiers should be obscured but without losing the traceability of a document to 
the study subject identifiers.
c
CLL progression or death due to CLL progression should be reported by the investigator as a serious adverse event only if it 
is assessed that the study drugs caused or contributed to the CLL progression (ie, by a means other than lack of effect). 
Unrelated events of CLL progression should be captured on the appropriate eCRF. 
Abbreviations: CLL = chronic lymphocytic leukemia, eCRF=case report form, IRB/IEC= Institutional Review 
Board/Independent Ethics Committee
For serious adverse events, in addition to completing the adverse event portion of the eCRF, the 
serious adverse event report form must also be completed. The information in the adverse event 
portion of the eCRF page and the serious adverse event report form(s) must match or be 
reconciled. Where the same data are collected, the forms must be completed in a consistent 
manner. For example, the same adverse event term should be used on both forms. Particularly for 
fatal or life-threatening events, copies of progress notes, autopsy reports, laboratory and 
diagnostic test results, discharge summaries, and other relevant documents should be faxed when 
requested and applicable. Follow-up information to the serious adverse event should be clearly 
documented as “follow up” in the serious adverse event report form and must be faxed to these 
same parties. Gilead Sciences may request additional information from the investigator to ensure 
the timely completion of accurate safety reports.
The subject’s name, address, and other personal identity information should be obscured on any 
source documents (eg, progress notes, nurses’ notes, laboratory and diagnostic test results, 
discharge summaries). Only the subject’s study number, initials, or date of birth are to be 
provided.


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The serious adverse event report form must be communicated to PPD Pharmacovigilance and to 
the site IRB/IEC (if required by local regulations) within 24 hours. In the rare event that the 
investigator does not become aware of the occurrence of a serious adverse event immediately 
(for example, if a subject initially seeks treatment elsewhere), the investigator is to report the 
event within 24 hours after learning of it and to document his/her first awareness of the adverse 
event.
Contact details for PPD Pharmacovigilance and for the Gilead study medical monitor are 
provided in Table 8-3:
Table 8-3.
Contact Information for Reporting Serious Adverse Events
Function
Contact Information
PPD Pharmacovigilance
(US)
Facsimile:
 
PPD Pharmacovigilance 
(International)
Facsimile:
Gilead Sciences Medical 
Monitor
Name:
Title:
Associate Director, Clinical Research
Office Telephone:
Mobile Telephone:
Facsimile:
E-mail:
8.7.2.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population
To maintain the integrity of the study, progression of CLL and death related to progression of 
CLL will not be reported to Gilead Sciences as serious adverse events unless it is assessed that 
the study drug caused or contributed to CLL progression or death related to CLL progression 
(ie, by a means other than lack of effect). These events will be exempt from global expedited 
reporting requirements for the duration of the study because they define the primary efficacy 
endpoint for this study. All events of progression of CLL and death related to progression of 
CLL, regardless of relationship to study drug, will be reported in the eCRFs and, as appropriate, 
in the final clinical study report and in any relevant aggregate safety reports.  Disease 
progression information from this study will be reviewed by an independent DMC on an ongoing 
basis. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Special Situations Reporting Requirements 
8.8.
8.8.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, lack of 
effect reports and pregnancy reports regardless of an associated AE.  Also includes reports of 
adverse reactions in infants following exposure from breastfeeding, and reports of adverse 
reactions associated with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following possible maternal or paternal 
exposure to the medicinal product.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer. 
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Lack of effect is defined as a situation where there is apparent failure of the medicinal product or 
medical technology to bring about the intended beneficial effect on the individual in a defined 
population with a given medical problem, under ideal conditions of use. 
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.  
Instructions for Reporting Special Situations
8.9.
8.9.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (ie, signs the informed consent) and throughout the study, including the 
post study drug follow-up period, to the  or Gilead DSPH ] using the pregnancy report form 
within 24 hours of becoming aware of the pregnancy. Refer to the CRF/eCRF completion 
guidelines for full instructions on the mechanism of pregnancy reporting.


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The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE, and therefore should be reported as 
such. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must be 
reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to PPD Pharmacovigilance or Gilead DSPH using 
the pregnancy outcome report form. If the end of the pregnancy occurs after the study has been 
completed, the outcome should be reported directly to Gilead DSPH. Gilead DSPH contact 
information is as follows: Email: 
 and Fax: 
 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to PPD Pharmacovigilance 
or Gilead DSPH using the pregnancy and pregnancy outcome forms within 24 hours. Monitoring 
of the subject should continue until the conclusion of the pregnancy. If the end of the pregnancy 
occurs after the study has been completed, the outcome should be reported directly to Gilead 
DSPH, fax number 
 or email 
8.9.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to PPD Pharmacovigilance or Gilead DSPH within 24 hours of the investigator 
becoming aware of the situation. These reports must consist of situations that involve study IMP, 
but do not apply to concomitant medications. Except for situations that result in AEs, special 
situations involving concomitant medications will not be reported. Any inappropriate use of 
medications prohibited by this protocol should not be reported as “misuse,” but may be more 
appropriately documented as a protocol deviation.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.
PPD
PPD
PPD
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9.
STATISTICAL CONSIDERATIONS
Analysis Objectives
9.1.
As described in Section 3, the objectives of this clinical trial will focus on determining the effect 
of idelalisib on the onset, magnitude, and duration of tumor control; measures of patient 
well-being (including OS, HRQL; and changes in subject performance status); disease-associated 
biomarkers and potential mechanisms of resistance; treatment administration; safety; and health 
resource utilization.
Analysis Endpoints
9.2.
The endpoints of the study are defined in Section 3.1, grouped in categories relating to tumor 
control, patient well-being, pharmacodynamic markers of drug activity and resistance, exposure, 
safety, and pharmacoeconomics.
Analysis Conventions
9.3.
9.3.1.
Analysis Sets
9.3.1.1.
Intent-to-Treat Analysis Set
The ITT analysis set includes all subjects who receive 1 dose of any study treatment (high-dose 
idelalisib or standard-dose idelalisib). In the ITT analysis set, study drug assignment will be 
designated according to planned allocation in this study, regardless of whether subjects receive a 
different study therapy from that to which they were allocated. 
This analysis set will be used in the analyses of subject characteristics and all the tumor control 
and patient well-being endpoints. Subjects in the ITT analysis set who do not have sufficient 
baseline or on-study tumor status information to be adequately assessed for response status will 
be included in the denominators in the calculation of response rates. 
9.3.1.2.
Per-Protocol Analysis Set
The PP analysis set includes data from subjects in the ITT analysis set who meet the general 
criteria defining the target population for this study, are adherent to the protocol, are compliant 
with study drug treatment, and are evaluable for relevant efficacy endpoints. Treatment 
assignment will be designated according to the actual treatment received. The specific 
classification of subjects to be included in the PP analysis set will be included in the statisticial 
analysis plan which will be finalized prior to the database lock. 
The PP analysis set will be used in sensitivity analyses of these tumor control and patient 
well-being endpoints: PFS, ORR, lymph node response rate, OS and CR rate.


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9.3.1.3.
Safety Analysis Set
A safety analysis set will include subjects in the ITT analysis set grouped for analyses with 
treatment assignments designated according to the actual study drug received. 
This analysis set will be used in the analyses of safety variables as well as study treatment 
administration, and health economic variables.
9.3.1.4.
Pharmacodynamic and/or Pharmacokinetic Analysis Sets
The pharmacodynamic and/or pharmacokinetic analysis sets include data from subjects in the 
safety analysis set who have the necessary baseline and on-study measurements to provide 
interpretable results for the specific parameters of interest. 
These analysis sets will be used in the analyses of AKT phosphorylation, chemokines/cytokines, 
and idelalisib plasma concentrations.
9.3.2.
Data Handling Conventions
9.3.2.1.
General Methods 
By-subject listings will be created for important variables from each eCRF module. Summary 
tables for continuous variables will contain the following statistics: N (number in population), n 
(number with data), mean, standard deviation, 95% confidence intervals (CIs) on the mean, 
median, minimum, and maximum. Summary tables for categorical variables will include: N, n, 
percentage, and 95% CIs on the percentage. Unless otherwise indicated, 95% CIs for binary 
variables will be calculated using the binomial distribution (exact method) and will be 2-sided. 
Data will be described and summarized by relevant treatment arm, analysis set, and timepoint. 
As appropriate, changes from baseline to each subsequent timepoint will be described and 
summarized by treatment arm. Similarly, as appropriate, the best change from baseline during 
the study will also be described and summarized by treatment arm. Graphical techniques 
(eg, waterfall plots, Kaplan-Meier curves, line plots) may be used when such methods are 
appropriate and informative. 
Data from all sites will be pooled for all analyses. Analyses will be based upon the observed data 
unless methods for handling missing data are specified. If there is a significant degree of 
non-normality, analyses may be performed on log-transformed data or nonparametric tests may 
be applied, as appropriate. 
9.3.2.2.
Double-Blinded Portion of the Study Analyses
Efficacy and safety data collected during the blinded portion of Study GS-US-312-0117 will be 
presented in the following 2 groups:


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
•IDELA 300 mg BID: Subjects who have PD per IRC confirmation in Arm A of Study 
GS-US-312-0116 and subsequently enroll into Study GS-US-312-0117 to receive IDELA 
300 mg BID during the double-blind portion of the study

•Placebo in Study GS-US-312-0116 + IDELA 150 mg BID in Study GS-US-312-0117: 
Subjects who have PD per IRC confirmation in Arm B of Study GS-US312-0116 and 
subsequently enroll Study GS-US-312-0117 to receive IDELA 150 mg BID during the 
double-blind portion of the study
All analyses will be performed based on the data collected during the blinded-portion of the 
extension study. Time-to-event analyses will reference to the date of first treatment on this 
clinical trial (Study GS-US-312-0117). Similarly, evaluations of on-therapy changes will 
reference the baseline values obtained prior to treatment in this study. The baseline value used in 
each analysis will be the last (most recent) pre-treatment value. Analyses will be descriptive in 
nature and formal comparisons of outcomes in the 2 groups are not planned. 
9.3.2.3.
Open-Label Extension Study Analyses
GS-US-312-0117 will become an open-label study offering idelalisib 150 mg BID to 
GS-US-312-0116 subjects who were randomized to Arm B. Subjects randomized to Arm A will 
continue idelalisib at 150 mg BID. Efficacy and safety data collected during the primary and 
open-label extension studies will be presented in the following 4 groups:

•IDELA 150 mg BID: Subjects who are randomized to Arm A in Study GS-US-312-0116 
and transition to Study GS-US-312-0117 during the open-label portion of the study to 
continue IDELA 150 mg BID

•Placebo in GS-US-312-0116 + IDELA 150 mg BID (open-label): Subjects who are 
randomized to Arm B in Study GS-US-312-0116 and transition to receive IDELA 150 mg 
BID during the open-label portion of the study

•IDELA 300 mg BID: Subjects who have PD per IRC confirmation in Arm A of Study 
GS-US-312-0116 and subsequently enroll Study GSUS-312-0117 to receive IDELA 300 mg 
BID during double-blind portion of the study

•Placebo in GS-US-312-0116 + IDELA 150 mg BID in GS-US-312-0117: Subjects who 
have PD per IRC confirmation in Arm B of Study GS-US-312-0116 and subsequently enroll 
Study GS-US-312-0117 to receive IDELA 150 mg BID during double-blind portion of the 
study.
Depending on the endpoints, analyses may be based on the combined data from both primary and 
extension studies or data from the extension study alone. Analyses will be descriptive in nature 
and formal comparisons of outcomes in the 4 groups are not planned. A separate statistical 
analysis plan will be created for the open-label portion of the study.


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9.3.2.4.
Calculation of Tumor Control and Patient Well-Being Variables
Tumor control assessments will be based on standardized IWCLL criteria {12154} {22541}, as 
specifically modified for this study considering the pharmacology of idelalisib. The individual 
and composite endpoints of response and progression (considering changes in lymph node area, 
liver and spleen size, bone marrow, platelet counts, hemoglobin, neutrophil counts, and 
peripheral blood lymphocyte counts) will be determined. Tumor control will be documented at 
each assessment by response category (eg, CR, PR, SD, definitive PD, NE, ND) as defined for 
each response parameter, SPD value, percentage change in SPD values from baseline or nadir, 
date that response is first documented and date of definitive CLL progression. 
The date of definitive CLL progression will be the timepoint at which progression is 
first identified by relevant objective radiographic or laboratory data. Because of the characteristic 
redistribution lymphocytosis that is expected with PI3Kinhibition, lymphocyte count will be 
ignored in the evaluation of progression. Changes in tumor status as provided by the investigator 
and changes in tumor status as adjudicated by the IRC (see Section 10.4.2) will be described. 
The findings of the IRC will be considered primary for analyses of all tumor control endpoints.
The following censoring conventions will be applied:

PFS and DOR: Data from surviving, non-progressing subjects will be censored at the earliest 
of the time of initiation of antitumor treatment other than the study treatment or the last time 
that lack of definitive CLL progression was objectively documented. Data from subjects 
who have CLL progression or die after 2 consecutive missing tumor assessments will be 
censored at the last time prior to the missing assessments that lack of definitive CLL 
progression was objectively documented.

OS: Data from surviving subjects will be censored at the last time that the subject was known 
to be alive. 
Analysis Plan
9.4.
9.4.1.
Subject Disposition and Baseline Characteristics
A listing of all ITT analysis subjects will be generated to describe site, subject number, 
first screening date, first treatment date, allocated study drug assignment, actual study drug 
assignment, the longest duration of study drug treatment, and the reason for discontinuing study 
treatment. Available information on subjects who were screened or registered but not treated will
be listed separately. A table will be created summarizing these categories in terms of number and 
percent for the ITT analysis set.
Subject baseline characteristics will be listed and summarized by treatment arm for the ITT 
analysis set. As appropriate for the specific variable, subject baseline characteristics acquired in 
Study GS-US-312-0116 will be referenced in Study GS-US-312-0117. 


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9.4.2.
Efficacy Analyses
9.4.2.1.
Time-to-Event Tumor Control and Survival Endpoints
PFS, DOR and OS will be described in the ITT analysis set using Kaplan-Meier methods by 
treatment group. Medians, ranges, and corresponding 95% CIs will be presented.
The Cox regression approach may be used to explore the influence of the primary study 
stratification factors and other baseline characteristics on PFS and OS. The stratification 
variables from the primary study and additional baseline subject characteristics may be included 
as covariates, focusing on those with expected prognostic significance. 
9.4.2.2.
Categorical Endpoints 
Response rates, lymph node response rate, splenomegaly response rate, hepatomegaly response 
rate, ALC response rate, platelet response rate, hemoglobin response rate, and neutrophil 
response rate will be described. In the calculation of response rates, subjects who do not have 
sufficient baseline or on-study tumor assessment to characterize response will be included in the 
denominator. For all analyses, the corresponding 95% CIs will be presented.
The potential influence of subject baseline characteristics on response rates may be explored
with multiple logistic regression modeling.
9.4.2.3.
Continuous Endpoints
Changes in lymph node area and changes in performance status, PI3K/AKT/mTOR pathway 
activation, and plasma chemokines/cytokines will be assessed by treatment group. Both changes 
from baseline to each subsequent timepoint and best overall on-study changes will be analyzed 
using appropriate methods (eg, analysis of covariance [ANCOVA] or paired t-tests). Means and 
standard errors will be presented.
9.4.2.4.
Health-Related Quality of Life and Performance Status
The FACT-Leu questionnaire data will be scored and processed according to the user manual. 
Missing items in a subscale will be imputed consistent with the user manual instructions. Data 
collected from the FACT-Leu instrument will not be reconciled with adverse event or laboratory 
data or with EQ-D5 findings.
As a baseline, the last value obtained prior to receiving the first idelalisib dose of 150 mg and 
300 mg will be used, depending on the treatment group assigned.
The mean and change from baseline in mean scores to each subsequent assessment will be 
summarized for the FACT-Lym subscale and composite scores. The best change from baseline 
during the study, defined as the highest positive value among all post-baseline visits minus the 
baseline value, will also be summarized.


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9.4.3.
Exposure and Safety Analyses
9.4.3.1.
Treatment Administration and Study Drug Compliance
Descriptive information will be provided by treatment arm regarding the number of doses of 
study therapy prescribed, the total number of doses taken, the percent of expected doses taken, 
the number of days of treatment, and the number and timing of prescribed dose reductions and 
interruptions.
Study drug compliance will be described by treatment arm in terms of the proportion of study 
drug actually taken based on returned pill count relative to the amount that was dispensed (taking 
into account physician-prescribed reductions and interruptions).
9.4.3.2.
Idelalisib Plasma Concentrations
Bioanalytical analyses will performed independently so that the study team and investigators will 
not have knowledge of data from individual subjects. Idelalisib plasma concentrations 
immediately pre-dose and at 1.5 hours after administration of the dose of study drug at each 
relevant clinic visit will be summarized by treatment and visit using descriptive statistics.
9.4.3.3.
Prior, Concomitant, and Post-Treatment Medication Use
Prior, concomitant, and post-treatment medications will be coded by means of the World Health 
Organization Drug Dictionary (WHODRUG) dictionary into Anatomical-Therapeutic-Chemical 
classification (ATC) codes.
Descriptions of prior medication use will be focused on drugs and regimens used as treatments 
for CLL. Information regarding CLL therapy that was administered prior to 
Study GS-US-312-0116 will be referenced in reporting the results of Study GS-US-312-0117. In 
addition, relevant treatment administration information collected during Study GS-US-312-0116 
will be referenced in reporting the results of this study. As appropriate and if available, 
information on the sequencing, type, dose, schedule, timing, duration of use, and efficacy of 
prior regimens will be provided, focusing particularly on findings observed in 
Study GS-US-312-0116.
The type and timing of use of concomitant medications will be listed and summarized by type 
and treatment arm. Information regarding the type and use of specific supportive medications 
(eg, pneumocystis prophylaxis, hematopoietic growth factors, corticosteroids) during study 
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The number, type, and timing of post-study-treatment regimens for CLL will be summarized by 
treatment arm, characterizing the disposition of all subjects who were eligible for post-study 
treatment and also those who were not eligible for post-study treatment (eg, subjects who are 
never treated at all, die while on study treatment, are still on study, are lost to follow-up, etc).
9.4.3.4.
Adverse Events
All adverse events will be listed. The focus of adverse event summarization will be on 
treatment-emergent adverse events. A treatment-emergent adverse event is defined as an adverse 
event that occurs or worsens in the period from the first dose of study treatment to 30 days after 
the last dose of study treatment. 
Adverse events will be classified using MedDRA (http://www.meddramsso.com) with 
descriptions by System Organ Class, High-Level Group Term, High-Level Term, Preferred 
Term, and Lower-Level Term. The severity of adverse events will be graded by the investigator 
according to the CTCAE, Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf), 
whenever possible. If a CTCAE criterion does not exist for a specific type of adverse event, the 
grade corresponding to the appropriate adjective will be used by the investigator to describe the 
maximum intensity of the adverse event: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), 
Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the adverse event to the study 
drug will be categorized as related or unrelated.
Treatment-emergent adverse events will be summarized by treatment arm and by visit. Summary 
tables will be presented to show the number of subjects reporting treatment-emergent adverse 
events by severity grade and corresponding percentages. A subject who reports multiple 
treatment-emergent adverse events within the same Preferred Term (or System Organ Class) is 
counted only once for that Preferred Term (or System Organ Class) using the worst severity 
grade. Adverse event descriptions will be presented by decreasing frequency for a given System 
Organ Class and Preferred Term.
Separate listings and summaries will be prepared for the following types of treatment-emergent 
adverse events:

Study-drug-related adverse events

Adverse events that are Grade 3 in severity

Adverse events leading to study drug interruption and/or dose modification

Adverse events leading to study drug discontinuation

Serious adverse events (with categorization of the primary reason that the adverse event is 
considered serious, eg, death, hospitalization, etc)


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Separate listings and summaries will be prepared for long-term follow-up safety data 
(see Section 6.2.17).
9.4.3.5.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed data. 
The focus of laboratory data summarization will be on treatment-emergent laboratory 
abnormalities. A treatment-emergent laboratory abnormality is defined as an abnormality that, 
compared to baseline, worsens by 1 grade in the period from the first dose of study drug to
30 days after the last dose of study drug. If baseline data are missing, then any graded 
abnormality (ie, an abnormality that is Grade 1 in severity) will be considered treatment 
emergent. Hematological, serum biochemistry, and urine data will be programmatically graded 
according to CTCAE severity grade, when applicable. For parameters for which a CTCAE scale 
does not exist, reference ranges from the central laboratory will be used to determine 
programmatically if a laboratory parameter is below, within, or above the normal range for the 
subject’s age, sex, etc.
Hematological and serum biochemistry and their changes from baseline will be summarized by 
treatment arm and by visit. Summary tables will be presented for each relevant assay to show the 
number of subjects by CTCAE severity grade with corresponding percentages. For parameters 
for which a CTCAE scale does not exist, the frequency of subjects with values below, within, 
and above the normal ranges will be summarized. Subjects will be characterized only once for a 
given assay, based on their worst severity grade observed during a period of interest 
(eg, during the study or from baseline to a particular visit).
Shift tables for hematology and serum biochemistry will also be presented by showing change in 
CTCAE severity grade from baseline to the worst grade post baseline. Separate listings and 
summaries will be prepared for laboratory abnormalities that are Grade 3 in severity.
9.4.3.6.
Oxygen Saturation Values
All oxygen saturation data will be listed. Summaries of oxygen saturation data will be based on 
observed data and will be reported as % saturation. Data and changes from baseline will be 
summarized by treatment arm and by visit. Summary tables will be presented for values below 
92% and for declines from baseline of 5% to show the number of subjects with corresponding 
percentages. Subjects will be characterized only once for each of these categorizations, based on 
their lowest value observed during a period of interest (eg, during the study or from baseline to a 
particular visit).
9.4.4.
Other Analyses
9.4.4.1.
Between-Study Comparisons
It is expected that patients with a progressive malignancy like CLL will normally fare better 
with an earlier therapy than with a later therapy. However, if the converse situation proves true –
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than a standard treatment (rituximab) administered earlier – strong evidence of investigational 
drug effect is demonstrated. Evaluating data derived from the same study subjects during their 
sequential participation in 2 clinical trials offers unique analytical challenges. However, in this 
integrated Phase 3 study program, it is likely that comparing baseline characteristics and 
outcomes among Arm B subjects participating in Study GS-US-312-0116 and 
Study GS-US-312-0117 will be informative. Such an evaluation characterizes how the subjects
and the CLL disease process change with time and treatment. In addition, such an analysis 
provides relevant supporting information documenting the benefits of single-agent idelalisib
relative to single-agent rituximab in the same subjects.
Accordingly, baseline characteristics, time-to-event efficacy variables (eg, PFS, TTR, DOR), 
categorical variables (eg, ORR, lymph node response rate, splenomegaly response rate, 
hepatomegaly response rate), and continuous variables (eg, percentage changes in lymph node 
area; changes in performance status, PI3K/AKT/mTOR pathway activation and plasma 
chemokines/cytokines)  may be evaluated between Study GS-US-312-0116 and Study 
GS-US-312-0117 for Arm B subjects.
9.4.4.2.
Health Care Resource Utilization
The EQ-D5 questionnaire data will be scored, processed, and standardized according to the user 
manual. Change from baseline in EQ-5D visual analogue scale and EQ-5D index will be 
summarized. As for the FACT-Leu, data will be analyzed using appropriate methods to account 
for incomplete completion of questionnaires. Data collected from the EQ-D5 will not be 
reconciled with adverse event or laboratory data or with FACT-Leu findings.
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach to the health economic analysis will be to combine the resource utilization 
data from the trial with data on unit prices (collected separately) to estimate total costs. 
The perspective of this analysis will be that of the third-party payer(s) and the hospital over a 
lifetime horizon in the base case. The costs will be described relative to the health care findings 
as measured by duration of tumor control, the symptom-free survival period, life-years, utility 
outcomes, or other measure of appropriate clinical benefits. In order to facilitate the calculation 
of utilities for use in the cost effectiveness analyses, the health status of subjects will be 
evaluated using PFS, Karnofsky performance status, FACT-Leu, and EQ-5D.
9.4.4.3.
Data Explorations
Changes in biomarkers during acquisition of resistance will be evaluated descriptively. Data 
explorations may be performed to evaluate potential associations between subject characteristics 
and outcome measures. Explorations may be performed to assess the potential associations 
between different outcomes measures (eg, relationships between HRQL changes and 
clinical/radiographic endpoints of tumor control).


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Sample Size
9.5.
The sample size for this extension study is not based upon a formal statistical hypothesis. The 
upper bound of the sample size in this study is determined by the sample size of the preceding 
primary study (Study GS-US-312-0116) in which ~220 subjects (~110 per arm) are expected to 
be enrolled. It is estimated that this extension study (Study GS-US-312-0117) will have a total 
idelalisib-treated N~180 (assuming a ~10% dropout rate during Study GS-US-312-0116 and a 
further ~10% dropout rate in the transition from the primary study to the extension study).
Timing of Analyses
9.6.
The DMC will have access to serious adverse events requiring expedited reporting and will be 
provided with accumulating safety data on a regular basis. Interim safety reviews will be 
conducted by the DMC in conjunction with safety reviews of the primary clinical trial
(Study GS-US-312-0116) if applicable. Thus, interim safety reviews will be performed by the 
DMC at intervals of ~6 months; the specific frequency of these reviews will depend upon the 
rate at which the trials are enrolled, the nature of any emerging safety signals, and monitoring 
recommendations from the DMC. At each review, all available safety data will be summarized 
and evaluated.
An interim efficacy analysis of this clinical trial (Study GS-US-312-0117) is planned to take 
place at the time of the final blinded analysis of the primary study (GS-US-312-0116). The intent 
is to provide the data from this extension study in support of regulatory review of data from the 
primary study. An analysis of efficacy and safety may be performed to satisfy regulatory 
requirements and to perform long-term efficacy, safety and OS follow-up. The timing of the final
analysis is expected to occur within 48 months of accrual of the final subject to 
Study GS-US-312-0117.


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10.
RESPONSIBILITIES
Investigator Responsibilities
10.1.
10.1.1.
Compliance with Ethical and Regulatory Guidelines
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), with ICH guidelines, or with the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the study subject. These 
standards are consistent with the European Union Clinical Trials Directive 2001/20/EC and 
Good Clinical Practice Directive 2005/28/EC. The investigator will ensure adherence to the 
basic principles of GCP as outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and 
Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 1993, 
“Retention of Bioavailability and Bioequivalence Testing Samples.”
Because this is a “covered” clinical trial, the investigator will ensure adherence to 21 CFR, 
Part 54, 1998; a covered clinical trial is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or FDA 
relies on to establish that the product is effective (including studies that show equivalence to an 
effective product) or that make a significant contribution to the demonstration of safety.” This 
requires that investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with Gilead Sciences, or proprietary interests in the drug being studied. 
This documentation must be provided before participation of the investigator and any 
subinvestigator in the trial. The investigator or subinvestigator agrees to notify Gilead Sciences 
of any change in reportable financial interests during the study and for 1 year following 
completion of the study. Study completion is defined as the date that the last subject has 
completed the protocol-defined activities.
10.1.2.
Institutional Review Board/Independent Ethics Committee
This protocol and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain informed 
consent) will be submitted by the investigator to an IRB (for sites enrolling in the United States)
and to an IEC for sites enrolling outside of the United States). Approval from the IRB/IEC must 
be obtained before starting the study and should be documented in a letter to the investigator 
specifying the protocol number, protocol version, protocol date, documents reviewed, and date 
on which the committee met and granted the approval.


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Any modifications or amendments made to the protocol after receipt of the initial 
IRB/IECapproval must also be submitted to the IRB/IEC for approval before implementation.
Only changes necessary to eliminate apparent immediate hazards to the subjects may be initiated 
prior to IRB/IEC approval. In that event, the investigator must notify the IRB/IEC and 
Gilead Sciences in writing within 5 working days after implementation.
The investigator shall submit a progress report, at least once yearly, to the IRB/IEC, and must 
provide a copy to Gilead Sciences. As soon as possible after completion or termination of the 
study, the investigator will submit a final report to the IRB/IEC and to Gilead Sciences. This 
report should include the dates of initiation and completion of the trial, a description of any 
changes in study procedures or amendments to the protocol, any deviations from the protocol, 
the number and type of subjects evaluated, the number of subjects who discontinued (and the 
reasons for discontinuation), the number of subjects who completed the trial, and the results of 
the trial, including a description of any adverse events. Gilead Sciences will assist the 
investigator in the preparation of this report, as needed.
10.1.3.
Informed Consent
After adequately, explaining the aims, methods, objectives, and potential hazards of the study 
and before undertaking any study-related procedures, the investigator is responsible for obtaining 
written informed consent from each individual participating in this study. The investigator must 
utilize an IRB/IEC-approved consent form for documenting written informed consent. Each 
informed consent will be appropriately signed and dated by the subject or the subject’s legally 
authorized representative and the person obtaining consent.
The approved informed consent must not be changed without prior approval by Gilead Sciences
and the IRB/IEC.
10.1.4.
Confidentiality
The investigator must assure that each subject’s anonymity will be strictly maintained and that 
each subject’s identity is protected from unauthorized parties. Only subject initials, date of birth, 
and an identification code (but no subject names) should be recorded on any form or biological 
sample submitted to the Gilead Sciences or designees (eg, laboratories), or to the IRB/IEC.
However, sufficient information must be retained at the site to permit sample data and data in the 
database to be connected with the unique subject number assigned to each study participant.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the idelalisib investigator brochure, this protocol, eCRFs, the investigational new drug, 
and any other study information, remain the sole and exclusive property of Gilead Sciences
during the conduct of the study and thereafter. This information is not to be disclosed to any third 
party (except employees or agents directly involved in the conduct of the study or as required by 
law) without prior written consent from Gilead Sciences. The investigator further agrees to take 
all reasonable precautions to prevent the disclosure by any employee or agent of the study site to 
any third party or otherwise into the public domain.


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10.1.5.
Study Files and Retention of Records and Biological Samples
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator’s study file, and (2) subject 
clinical source documents.
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, the 
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data referenced in the monitoring plan for the study, and should include 
sequential notes containing at least the following information for each subject:

Subject identification (name, date of birth, gender)

Documentation that subject meets eligibility criteria, eg, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria)

Participation in trial (including trial number)

Trial discussed and date of informed consent

Dates of all visits

Documentation that protocol-specific procedures were performed

Results of efficacy parameters, as required by the protocol

Start and end date (including dose regimen) of trial medication (including relevant drug 
dispensing and return information)

Record of all adverse events and other safety parameters (including start and end date, 
causality and intensity)

Concomitant medication (including start and end date and dose if relevant dose changes 
occur)

Date of trial completion and reason for discontinuation, if applicable
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (ie, the United States, Europe, or 
Japan) and until there are no pending or contemplated marketing applications in an ICH region; 
or, if no application is filed or if the application is not approved for such indication, until 2 years 
after the investigation is discontinued and regulatory authorities have been notified. Investigators 
may be required to retain documents longer if required by applicable regulatory requirements, by 
local regulations, or by an agreement with Gilead Sciences. The investigator must notify 


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Gilead Sciences before destroying any clinical study records. The investigator will promptly 
notify Gilead Sciences in the event of accidental loss or destruction of any study records. 
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead Sciences must be notified in advance.
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead Sciences
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site.
Biological samples including tissue and blood samples collected as a study procedure or as 
standard of care during study participation will be stored and maintained by the investigator until 
notification is received from Gilead Sciences that the retained samples and records no longer 
required. The investigator must obtain written permission from Gilead Sciences before disposing 
of any retained samples. The investigator should promptly notify Gilead Sciences in the event of 
accidental loss or destruction of any study samples. With the permission of Gilead Sciences, the 
retained samples may be transferred to an acceptable designee, such as another investigator, 
another institution, a contract storage site, or to Gilead Sciences.
10.1.6.
Case Report Forms
An eCRF is required and must be completed for each enrolled subject, with all required study 
data accurately recorded such that the information matches the data contained in medical records 
(eg, physicians’ notes, nurses’ notes, clinic charts, or other study-specific source documents). As 
required by the protocol, eCRFs should also be completed for those subjects who fail to complete 
the study (even during the screening period). If a subject withdraws from the study, the reason 
must be noted on the eCRF. If a subject is withdrawn from the study because of a 
treatment-limiting adverse event, thorough efforts should be made to clearly document the 
outcome.
The eCRFs for this study will exist within a Web-based electronic data capture (EDC) system. 
After the investigator or the investigator’s designees (eg, research coordinators) have been 
appropriately trained, they will be given access to the EDC system and will enter the data 
required by the protocol into the EDC system. Any change of data will be made via the EDC 
system, with all changes tracked by the system to provide an audit trail.
The eCRF must be completed and signed by the principal investigator or subinvestigator 
(as appropriate) within a reasonable time period after data collection. This signature serves to 
attest that the information contained in the eCRF is true.
10.1.7.
Drug Accountability 
As described in the relevant section (see Section 5.2.7), the investigator is responsible for 
ensuring adequate accountability of all used and unused investigational medicinal product, 


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placebos, and comparators. This responsibility includes acknowledgment of receipt of each 
shipment of study product (quantity and condition), subject dispensing records, and returned or 
destroyed study product. Dispensing records will document quantities received from 
Gilead Sciences and quantities dispensed to subjects, including lot number, date dispensed, 
subject identifier number, subject initials, and the initials of the person dispensing the 
medication.
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Sciences’ requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRB/IECs, 
and to regulatory authority or health authority inspectors. It is important that the investigator and 
relevant institutional personnel are available during monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
Sponsor Responsibilities
10.2.
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, will be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB/IEC in 
accordance with local requirements. Except as noted in Section 10.1.2, IRB/IEC approval must 
be obtained before changes can be implemented.
10.2.2.
Communications with Regulatory Authorities
Gilead Sciences, working either directly or through designees, will assume responsibility for 
regulatory interactions with relevant regulatory authorities. Gilead Sciences will maintain an 


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IND for idelalisib in support of the study in the United States and will maintain similar 
regulatory applications with other regulatory authorities, as required for conduct of the study. In 
fulfilling this responsibility, Gilead Sciences (or a designee) will collect, assemble, and 
communicate all required regulatory documents (eg, Form FDA 1572, investigator financial 
disclosure forms, protocol and protocol amendments, investigator brochures, informed consent 
documents, annual reports) as required by regulation. Gilead Sciences (or a designee) will also 
assume responsibility for adverse event reporting to regulatory authorities as described in 
Section 8.7.2.
10.2.3.
Data Management
Electronic data capture will be used to enter study data eCRFs and to transfer the data into a 
study-specific electronic database. During the data collection process, automated quality 
assurance programs will be used to identify missing data, selected protocol violations, 
out-of-range data, and other data inconsistencies. Requests for data clarification or correction 
will be forwarded to the investigative site for resolution. As appropriate, eCRFs, listings, tables, 
and SAS datasets will be provided to the investigational sites for review.
Quality assurance and quality control systems will be implemented and maintained according to 
written standard operating procedures to ensure that the data are generated, recorded, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements. Data 
collection and storage systems will provide audit trail, security mechanisms, and electronic 
signature capabilities that meet the requirements of FDA Title 21 of CFR Part 11 regarding 
electronic records and electronic signatures.
Data security will be controlled through appropriate and specific restriction of access only to data 
and systems required by individual users to accomplish their roles in the data management 
process. Individual login and password protections will be employed at study sites and at 
Gilead Sciences or its designee. The database will exist on physically secured servers. Data 
backups will be done regularly and will be stored in separate facilities. Printed documents 
relating to the study will be secured when not under review. 
10.2.4.
Study Reporting and Publication
Gilead Sciences may make information obtained during this study available in order to further 
the scientific or business needs of the company or as required by law or regulation. In this 
regard, Gilead Sciences may provide study information to private or public organizations 
(eg, business partners, collaborators, consultants, CROs, investors, other physicians who are 
conducting similar studies, funding organizations, regulatory authorities, or other government 
authorities). 
Gilead Sciences will prepare a clinical study report for submission to relevant regulatory 
agencies. Gilead Sciences will ensure that the report meets the standards set out in the ICH 
Guideline for Structure and Content of Clinical Study Reports (ICH E3). An abbreviated report 
may be prepared in certain cases, as appropriate.


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Gilead Sciences intends that the data from this study will be presented and published. 
Gilead Sciences will work in collaboration with the principal investigators in preparing 
presentations and writing manuscripts for publication. 

Investigators may publish or present the results of the study generated by their individual site 
either with the advanced written consent of Gilead or > 2 years after the completion of this 
extension study (GS-US-312-0117) at all participating institutions.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information (see Section 10.1.4).
The investigator will submit to Gilead Sciences any proposed publication or presentation along 
with the respective scientific journal or presentation forum prior to submission of the publication 
(at least 30 days prior to manuscripts and 15 days prior for abstracts and oral presentations). The 
investigator will comply with Gilead Sciences’ request to delete references to its confidential 
information (other than the study results) in any paper or presentation. If deemed necessary by 
Gilead Sciences, the investigator also agrees to withhold publication or presentation for an 
additional 60 days in order to obtain patent protection.
Joint Investigator/Sponsor Responsibilities
10.3.
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the eCRFs for consistency.
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.
10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences may conduct inspections or audits 
of the clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.
10.3.3.
Public Notification of Study Conduct
Consistent with Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and 
with requirements of the International Committee of Medical Journal Editors (ICMJE) as a 
condition of consideration for publication of study results, Gilead Sciences will be responsible 


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for ensuring that this protocol is listed at the ClinicalTrials.gov website (or equivalent) and that 
information at the website relating to study design and conduct is appropriately updated during 
the course of the study. In order to facilitate this process, investigators will need to supply 
Gilead Sciences with appropriate contact information for study site personnel.
10.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authorities and IRB/IECs. In terminating the study, Gilead Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests. 
Study Committees
10.4.
10.4.1.
Data Monitoring Committee
A DMC, operating autonomously from Gilead Sciences, the clinical investigators, and the SSC, 
will be responsible for providing independent recommendations to Gilead Sciences about 
evolving risk-benefit observed in the course of the study and any modifications required during 
the course of the study. The DMC will consist of a biostatistician and 2 physicians experienced 
in treating patients with lymphoid malignancies. The DMC will be chaired by one of these 
individuals. DMC members must not be actively involved in study design, conduct, or subject
accrual and must not have financial, proprietary, professional, or other interests that may affect 
impartial, independent decision-making. Specialists may be invited to participate as non-voting 
members at any time if additional expertise is desired. The DMC will formally interact with the 
external SSC members through the sharing of meeting minutes. Informal interactions between 
the DMC and external SSC members will be limited. The DMC will operate under a charter 
developed as a collaborative document between Gilead Sciences and the DMC. It is expected 
that the members of the DMC will be the same as those for the primary study 
(Study GS-US-312-0116). 
The primary responsibility of the DMC is to protect the safety and welfare of subjects 
participating in this clinical trial and to ensure the integrity of the clinical trial. In general, the 
DMC will be responsible for:

Reviewing the general progress of the study as regards subject accrual, study conduct, and 
protocol violations

Examining accumulated safety, efficacy, and other relevant data at prespecified points during 
the course of the study 

Reviewing major study design modifications prior to implementation of those modifications

Making recommendations concerning continuation, modification, interruption, or termination
of each study


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
Advising the company on changes to informed consent documents

Proposing updates to the DMC monitoring plan, changes in the DMC membership, actions to 
be taken relating to conflict of interest or confidentiality breaches, the need for additional 
expertise during DMC deliberations, revisions to the DMC charter, or alterations in the 
support provided to the DMC

Providing expert advice to the Gilead Science medical monitor on an ad hoc basis regarding 
matters such as safety concerns or diagnostic evaluations in individual subjects
Based on the results of its deliberations during the course of the study, the DMC can recommend 
appropriate actions (eg, continuation of the study unchanged, continuation of the study with 
modifications in design or monitoring plan, interruption of study accrual, study termination).
10.4.2.
Independent Review Committee
An IRC will be established to provide a blinded review of radiographic data and pertinent 
clinical data in order to provide expert interpretation of changes in tumor status. The IRC will 
include 1 independent board-certified radiologist and 1 independent board-certified 
hematologist or oncologist, and will be managed by a CRO selected by Gilead Sciences. The 
review of radiographic and clinical data by the IRC will be performed on an ongoing basis until 
the primary analysis . The specifics of the IRC’s processes and reading methods will be 
described in an independent review charter developed by the contracted imaging facility in 
conjunction with Gilead Sciences. The same organization that is providing IRC services for 
Study GS-US-312-0116 will provide IRC services for this study. 


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11.
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Hallek M, Wanders L, Ostwald M, Busch R, Senekowitsch R, Stern S, et al. Serum 
beta(2)-microglobulin and serum thymidine kinase are independent predictors of 
progression-free survival in chronic lymphocytic leukemia and immunocytoma. Leuk 
Lymphoma 1996;22 (5-6):439-47.


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26535
Hornberger J, Reyes C, Shewade A, Lerner S, Friedmann M, Han L, et al. Cost-
effectiveness of adding rituximab to fludarabine and cyclophosphamide for the 
treatment of previously untreated chronic lymphocytic leukemia. Leuk Lymphoma 
2012;53 (2):225-34.
26545
Main C, Pitt M, Moxham T, Stein K. The clinical effectiveness and cost-effectiveness 
of rituximab for the first-line treatment of chronic lymphocytic leukaemia: an evidence 
review of the submission from Roche. Health Technol Assess 2010;14 (Suppl. 2):27-
32.
26551
Youngson JH, Jones JM, Chang JG, Harris M, Banergee SS. Treatment and survival of 
lymphoid malignancy in the north-west of England: a population-based study. Br J 
Cancer 1995;72 (3):757-65.
26559
Sorensen JM, Vena DA, Fallavollita A, Chun HG, Cheson BD. Treatment of 
refractory chronic lymphocytic leukemia with fludarabine phosphate via the group C 
protocol mechanism of the National Cancer Institute: five-year follow-up report. J Clin 
Oncol 1997;15 (2):458-65.


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Version 5.0
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12.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
Appendix 3.
Performance Status Scoring System
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D)
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Appendix 6.
Cumulative Illness Rating Scale (CIRS)
Appendix 7.
Schedule of Study Procedures


PPDPPD
PPD
Idelalisib 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Version 5.0 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
199 EAST BLAINE STREET 
SEATTLE, WA 98102 
STUDY ACKNOWLEDGEMENT 
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and Safety of 
Two Different Dose Levels of Single-Agent ldelalisib (GS-1101) for Previously Treated 
Chronic Lymphocytic Leukemia 
GS-US-312-0117 Version 5.0, 27 May 2014 
This protocol has been approved by Gilead Sciences, Inc. The following signa re documents 
this 
I. 
I 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator 
Printed N arne 
Date 
CONFIDENTIAL 
Page 150 
Signature 
Site Number 
27 May 2014 


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Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
FACT-Leu (Version 4) 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
PHYSICAL WELL-BEING 
GPI 
l have a lack of energy 
GP2 
I have nausea ................................................................... . 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family 
............... . 
GP4 
I have pain ........................... . 
GP> 
r am bothered by side effects of treatment 
GP6 
1 feel ill. 
GP7 
I am forced to spend time in bed ................ ... . 
SOCIAL!FAMIL Y WELL-BEING 
GSI 
I feel close to my friends 
GS2 
I get emotional support from my family 
GS3 
I get support from my friends .......... . 
GS4 
My family has accepted my illness . 
GS5 
I am satisfied with family communication about my 
Not 
at all 
0 
0 
0 
0 
0 
0 
0 
A little 
Some-
bit 
what 
2 
2 
2 
2 
2 
2 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
Not 
A little 
Some-
Quite 
at all 
bit 
what 
a bit 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
illness... ........... ... 
. . ... ........ . .. .. .. ... .... ....... ...... 
0 
2 
3 
GS6 
I feel close to my partner (or the person who is my main 
support) 
0 
Ql 
Regardless of your current level of sexual activity, please 
answer the following question. If you pr~fer not /o answer il, 
please mark this box 0 and go to the next section. 
GS7 
I am satisfied with my sex life .......................................... . 
Engl1sh(Universal) 
Ccy}nght 1987.1997 
0 
2 
3 
2 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
19 November 2007 
Page 1 of3 


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Version 5.0
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FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
EMOTIONAL WELL-BEING 
GEl 
I feel sad ............... 
................ . . . . . . . . . . . . . . . ' 
GEl 
I am satisfied with how I am coping with my illness .. 
GE3 
I am losing hope in the fight against my illness 
GE4 
I feel nervous ............... 
. ............... 
GEl 
I worry about dying 
GE6 
I worry that my condition will get worse .... 
FUNCTIONAL WELL-BEING 
GFI 
I am able to work (include work at home) ..... 
GF2 
My work (include work at home) is fulfilling. 
GF3 
I am able to enjoy life ..... 
GF4 
1 have accepted my illness 
GFS 
I am sleeping well .................. 
GF6 
I am enjoying the things I usually do for fun 
GF7 
I am content with the quality of my life right now. 
Englash (Universal) 
Cop)right 1987, 1997 
Not 
A little 
Some-
at all 
bit 
what 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Not 
A little 
Some-
at all 
bit 
what 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
19 Novem ber 2007 
Page2 of3 


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Version 5.0
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Page 153
27 May 2014
FACT-Leu (Version 4) 
Please circle or ma rk one number per line to indicate your response as it applies to the past 7 
days. 
ADDITIONAL CONCERNS 
BRM3 
I am bothered by fevers (episodes of high body 
temperature) 
.................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
P2 
I have certain parts of my body where I experience pain 
BRM2 
I am bothered by the chills . 
ES3 
I have night sweats .............. 
LEU I 
l am bothered by lumps or swelling in certain parts of 
my body (e.g., neck, armpits, or groin) .. 
THI 
I bleed easily ... 
.... ·········· 
Tlll 
I bruise easily 
11112 
I feel weak all over 
B1-ff6 
I get tired easily. 
Cl 
I am losing weight 
C6 
I have a good appetite 
An7 
I am able to do my usual activities 
N3 
I worry about getting infections .. . . . . . . . . . . . . . . . . 
LEUS 
I feel uncertain about my future health 
LEU6 
I worry that I might get new symptoms of my illness 
BRM9 
I have emotional ups and downs .... 
LF.U7 
I feel isolated from others because of my illness or 
treatment . . . .. .. ..... . ... ..... .. . ... ... .•. . ... . ... .... . .... ....... .. . ..... .. . .. . .. •· · 
Englash (Universal) 
Cop)right 1987, 1997 
Not 
A little Some-
at all 
bit 
what 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Ve.-y 
much 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
19 November 2007 
Page 3 of3 


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Appendix 3.
Performance Status Scoring System
Karnofsky Performance Status
General Description
Score
Specific Description
Able to carry on normal 
activity and to work; no 
special care needed.
100
Normal; no complaints; no evidence of disease.
90
Able to carry on normal activity; minor signs or symptoms of 
disease.
80
Normal activity with effort; some signs or symptoms of disease.
Unable to work; able to live at 
home and care for most 
personal needs; varying 
amount of assistance needed.
70
Cares for self; unable to carry on normal activity or to do active 
work.
60
Requires occasional assistance, but is able to care for most of 
personal needs.
50
Requires considerable assistance and frequent medical care.
Unable to care for self; 
requires equivalent of 
institutional or hospital care; 
disease may be progressing 
rapidly.
40
Disabled; requires special care and assistance.
30
Severely disabled; hospital admission is indicated although death 
not imminent.
20
Very sick; hospital admission necessary; active supportive 
treatment necessary.
10
Moribund; fatal processes progressing rapidly.
0
Dead


Idelalisib 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Version 5.0 
Appendix 4. 
EuroQoL-5 Dimensions (EQ-5D) 
EuroQoL-5 Dimensions (EQ-5D) 
By placing a chec.kmark m one bo.."\: m each group belo·w. please indicate whtch 
sfatemems best descnl>e your own health mre today 
Mobility 
I have no probtems in •Nalking abot.n 
I have some problems 11"1 v.'3lking about 
I am con.1red to bed 
Self-Care 
I ha\'e no problems wid! self-care 
I have some prob-'ems washing o dressl'lg myself 
I am unable to wash or dress mys.el' 
Usual Activitif's (e.g., work, study, housework, fumity, or leisure activities) 
I ~\'~ no problems with pcrormill9 my usual acll~1ies 
I have some proh ems 'lAth performirg my usual actM1ies 
I am unable to oerlorm my usua! actri~s 
P a iniDiscomfort 
I ha ... e no ~ain or discomfon 
I have moderate pan or disoomzort 
I ha•.'e extreme pa 11 or d:soomiort 
Anxiety/De pression 
I am nni anxious or dep essed 
I am moderately anxious or dep essed 
I am extremely anxious or depressed 
CONFIDENTIAL 
Page 155 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
27May2014 


Idelalisib 
Protocol GS-US-312-0117 
Gilead Sciences, Inc. 
To help people say how good or bad a health state i ~ 
we have dra\\>11 a scale (rather like a thennometer) on 
wluth the best state you can uuagine lS marked 100 
and the worst state you can imagine is marked 0. 
We would like you to mdicate on this scale how good 
or bad your own health is today. in your opinion. 
Please do thi~ by drawing a line from the box below 
to wluchever pomt on the scale mdicates how good or 
bad your bealth state is today. 
CONFIDENTIAL 
Your own 
hl'alth sratl' 
today 
Page 156 
Best 
lllla!l!II3bl~ 
bealthmte 
100 
J. 
I 
\Ve»"O< 
ima:in;ab!e 
~lfh~ 
Final 
Version 5.0 
27May2014 


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27 May 2014
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance 
Formulas for calculating the estimated creatinine clearance (eCcr) are provided in the table 
below. The formula appropriate to the units in which serum creatinine was measured and the 
subject’s gender should be used.
Cockcroft-Gault Formulas for Calculating Estimated Creatinine Clearance
Serum 
Creatinine Units
Gender
Formula
mg/dL
Males
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1
72 subject serum creatinine [mg/dl]
Females
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 0.85
72 subject serum creatinine [mg/dl]
M/dL
Males
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.23
Subject serum creatinine [mg/dl]
Females
eCcr [mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.04
Subject serum creatinine [mg/dl]
Abbreviation: eCcr=estimated creatinine clearance


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Gilead Sciences, Inc.
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Appendix 6.
Cumulative Illness Rating Scale (CIRS)
The CIRS used in this protocol is designed to provide an assessment of recurrent or ongoing 
chronic comorbid conditions, classified by 14 organ systems. Using the drop-down lists of 
organ-specific diagnoses, please select any conditions present in the study subject. If the subject
has a recurrent or ongoing chronic conditions that are not described in the list for a given organ 
system, please indicate the name of the conditions under “other chronic condition” for that organ 
system. Please take into account that CLL-induced discomfort, symptoms, or disability should 
not be considered. If additional explanation would be helpful, text comments may be inserted. 
CIRS List of Comorbid Conditions
Organ System
Diagnosis
Comment
Cardiac
Chronic heart failure
Angina pectoris
Medically relevant arrhythmia
Valve dysfunction
Congenital heart disease
Cardiomyopathy
Myocarditis
Chronic pericarditis
Endocarditis
Other chronic cardiac condition:
Other chronic cardiac condition:
Vascular
Hypertension
Thrombosis
Peripheral diabetic microvascular disease
Peripheral artery disease
Aortic aneurysm
Aortitis
Raynaud disease
Vasculitis
Other chronic vascular condition:
Other chronic vascular condition


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Organ System
Diagnosis
Comment
Hematological/
immunological
Sickle cell anemia
Hemoglobinopathy
Polycythemia
Thrombocythemia
Hemophilia
Paroxysmal nocturnal hemoglobinuria
Thrombotic thrombocytopenic purpura
Dysfibrinogenemia
HIV
Other chronic hematological or immunological 
condition:
Other chronic hematological or immunological 
condition
Abbreviation:  CIRS=Cumulative Illness Rating Scale
For each condition selected from the CIRS List of Comorbid Conditions, please rate the severity 
of that condition. For the severity rating, please use the scoring guidelines shown in the table 
below, considering the magnitude of symptoms, how manageable the condition is, and the extent 
of intervention required:
CIRS Rating Scale
Score
Severity
Findings
1
Mild
Mild discomfort, symptoms or disability
Easy to control
Requiring either no therapy/medication or only as needed
2
Moderate
Moderate  discomfort, symptoms or disability
Manageable
Requiring daily treatment or first-line therapy
3
Severe
Severe discomfort, symptoms or disability
Hard to control
Requiring second-line therapy or multiple medications
4
Extremely
severe
Life threatening, permanently disabling disability, causing organ failure
Poorly manageable
Requiring urgent intervention or resistant to therapy
Abbreviation:  CIRS=Cumulative Illness Rating Scale


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Appendix 7.
Schedule of Study Procedures
Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4 a
5a
6 a
7a
8 a
9 a
10 a
11
12
13
14
15
16+d
End of 
Study
30 
days
Long-
term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12 
Weeks
Study Day
Within 
-28 
Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within 
+30 
days
To  
+5 
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Informed consent
X
CIRS assessment
X
β-HCG (women of childbearing 
potential)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CLL peripheral blood evaluation
X
X
CLL serology
X
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HRQL/healthy utility – FACT-
Leu/EQ-5D
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exam (includes nodes, liver, 
spleen)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Oxygen saturation (by pulse oximetry)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Circulating cells
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biomarkers
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PPD


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Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4 a
5a
6 a
7a
8 a
9 a
10 a
11
12
13
14
15
16+d
End of 
Study
30 
days
Long-
term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12 
Weeks
Study Day
Within 
-28 
Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within 
+30 
days
To  
+5 
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Serum Igs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug administration in clinic
Xb
X
X
X
X
X
X
X
Idelalisib pharmacokineticsb
X
X
X
X
X
X
X
X
Study drug dispensing/accountingb
X
X
X
X
X
X
X
X
X
X
X
Radiology assessment (CT/MRI)
X
Xe
Xe
Xe
Xe
Xe
Xe
Xe, f
Bone marrow biopsy/aspiratec
X
X
X
X
X
X
X
X
Post-treatment CLL therapy
X
Long-term follow-up 
X
a
Following unblinding of the study, the visit schedule will be modified per Section 6.2 and Visits 3 – 15 may not be applicable for subjects who were randomized to idelalisib 
on Study GS-US-312-0116 or who were randomized to placebo on GS-US-312-0116 and have received 24 weeks cumulative treatment with idelalisib
b
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll following unblinding, may have idelalisib treatment (and associated PK testing) delayed at 
the Investigator’s discretion until the time of disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib treatment
c
At screening, to be performed at investigator discretion to determine extent of CLL involvement and bone marrow cellularity. Post-screening, to be performed to confirm CR 
or PD; if the subject does not otherwise meet criteria for CR or if the nature of PD does not require bone marrow confirmations, it is not necessary to obtain a follow-up bone 
marrow biopsy/aspirate
d
Following unblinding, Visit 16+ may be completed prior to 48 weeks as subjects transition to a Q12 week visit schedule 
e
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the assessment should be done even if study drug has been interrupted
f
An end-of-study CT/MRI tumor assessment should be performed unless the subject already has radiographic confirmation of definitive disease progression < 4 weeks prior to 
study discontinuation
Abbreviations: -HCG=beta human chorionic gonadotropin, CIRS=chronic illness rating scale, CLL=chronic lymphocytic leukemia, CR=complete response, CT=computed
tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy- Leukemia, HRQL= health-related quality of life, Ig=immunoglobulin, 
IWRS=interactive web response system, MRI= magnetic resonance imaging.

Prot_001.pdf: 
 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 3, Double-Blind Extension Study Evaluating the 
Efficacy and Safety of Two Different Dose Levels of 
Single-Agent Idelalisib (GS-1101) for Previously Treated 
Chronic Lymphocytic Leukemia 
A Companion Trial to Study GS-US-312-0116: A Phase 3, 
Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Efficacy and Safety of Idelalisib (GS-1101) 
in Combination with Rituximab for Previously Treated 
Chronic Lymphocytic Leukemia 
Sponsor: 
Gilead Sciences, Inc. 
199 East Blaine Street 
Seattle, WA 98102 
USA 
 
333 Lakeside Drive 
Foster City, CA 94404 
USA 
IND Number: 
101254 
EudraCT Number: 
2011-006293-72 
Indication: 
Chronic Lymphocytic Leukemia  
Protocol ID: 
GS-US-312-0117 
Gilead Sciences Medical 
Monitor: 
Name: 
 
Office Telephone: 
 
Office Fax: 
 
Mobile Telephone: 
 
E-mail: 
 
Protocol Version/Date: 
Version 1.0 (Original) 23 January 2012 
Version 2.0 
23 January 2013  
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable institutional review board or independent ethics committee. This information is 
only to be used by you in connection with authorized clinical studies of the investigational 
drug described in the protocol. You must not disclose any of the information to others 
without written authorization from Gilead Sciences, Inc., except to the extent necessary to 
obtain informed consent from those persons to whom the drug may be administered. 
PPD
PPD
PPD
PPD
PPD
PPD


Idelalisib 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Version 2.0 
 
 
CONFIDENTIAL 
Page 2 
23 January 2013 
TABLE OF CONTENTS 
TABLE OF CONTENTS ....................................................................................................................................... 2 
LIST OF IN-TEXT TABLES ................................................................................................................................. 6 
LIST OF IN-TEXT FIGURES ............................................................................................................................... 6 
PROTOCOL SYNOPSIS ....................................................................................................................................... 7 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................ 16 
1. 
INTRODUCTION ....................................................................................................................................... 19 
1.1. 
Chronic Lymphocytic Leukemia ..................................................................................................... 19 
1.2. 
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies ............................................................ 20 
1.3. 
Idelalisib (formerly GS-1101) ......................................................................................................... 21 
1.3.1. 
Discovery and Efficacy Pharmacology ......................................................................... 21 
1.3.2. 
Safety Pharmacology .................................................................................................... 21 
1.3.3. 
Nonclinical Pharmacology and Metabolism ................................................................. 22 
1.3.4. 
Toxicology .................................................................................................................... 22 
1.3.5. 
Idelalisib Clinical Studies.............................................................................................. 24 
1.4. 
Summary and Justification for the Current Study ........................................................................... 28 
2. 
STUDY DESIGN ........................................................................................................................................ 31 
2.1. 
Design Overview and Study Schema .............................................................................................. 31 
2.2. 
Design Rationale ............................................................................................................................. 32 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................................................. 34 
3.1. 
Endpoints ........................................................................................................................................ 34 
3.1.1. 
Tumor Control ............................................................................................................... 34 
3.1.2. 
Patient Well-Being ........................................................................................................ 35 
3.1.3. 
Pharmacodynamic Markers of Drug Activity and Resistance ....................................... 35 
3.1.4. 
Exposure ........................................................................................................................ 36 
3.1.5. 
Safety ............................................................................................................................ 36 
3.1.6. 
Pharmacoeconomics ...................................................................................................... 36 
3.2. 
Endpoint Selection Rationale .......................................................................................................... 36 
3.2.1. 
Tumor Control Endpoints ............................................................................................. 36 
3.2.2. 
Measures of Patient Well-Being ................................................................................... 39 
3.2.3. 
Pharmacodynamic Markers of Drug Activity and Resistance ....................................... 40 
3.2.4. 
Assessments of Exposure .............................................................................................. 41 
3.2.5. 
Evaluations of Safety .................................................................................................... 42 
3.2.6. 
Pharmacoeconomic Measures ....................................................................................... 43 
4. 
SUBJECT POPULATION ........................................................................................................................... 44 
4.1. 
Number of Subjects ......................................................................................................................... 44 
4.2. 
Subject Selection Criteria ................................................................................................................ 44 
4.2.1. 
Inclusion Criteria ........................................................................................................... 44 
4.2.2. 
Exclusion Criteria .......................................................................................................... 46 
4.3. 
Enrollment Criteria Rationale ......................................................................................................... 47 
5. 
TREATMENT OF SUBJECTS ................................................................................................................... 48 
5.1. 
Enrollment....................................................................................................................................... 48 
5.1.1. 
Interactive Web Response System ................................................................................ 48 
5.1.2. 
Treatment Assignment .................................................................................................. 48 
5.1.3. 
Blinding ......................................................................................................................... 48 
5.2. 
Investigational Study Drug (Idelalisib/Placebo) ............................................................................. 49 


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5.2.1. 
Description .................................................................................................................... 49 
5.2.2. 
Source ........................................................................................................................... 50 
5.2.3. 
Packaging and Labeling ................................................................................................ 50 
5.2.4. 
Storage and Handling .................................................................................................... 50 
5.2.5. 
Dispensing ..................................................................................................................... 50 
5.2.6. 
Return ............................................................................................................................ 51 
5.2.7. 
Accountability ............................................................................................................... 51 
5.2.8. 
Overdose Precautions .................................................................................................... 51 
5.2.9. 
Inadvertent Exposure and Spill Precautions .................................................................. 52 
5.3. 
Study Drug Administration ............................................................................................................. 52 
5.3.1. 
Premedication ................................................................................................................ 52 
5.3.2. 
Administration Instructions ........................................................................................... 52 
5.3.3. 
Dosing Schedule............................................................................................................ 52 
5.3.4. 
Dose Levels ................................................................................................................... 53 
5.3.5. 
Dose Schedule Interruptions and Vomited Doses ......................................................... 53 
5.3.6. 
Safety Monitoring and Study Drug Interruption/Dose Modification ............................ 53 
5.4. 
Recommendations for Evaluation, Intervention, and Drug Discontinuation for Specific 
Adverse Events or Conditions ......................................................................................................... 56 
5.4.1. 
Dermatological Events .................................................................................................. 56 
5.4.2. 
Gastrointestinal Events .................................................................................................. 56 
5.4.3. 
Hepatic Events .............................................................................................................. 57 
5.4.4. 
Hematological and Immunological Events ................................................................... 58 
5.4.5. 
Infectious Events ........................................................................................................... 59 
5.4.6. 
Progressive Multifocal Leukoencephalopathy .............................................................. 59 
5.4.7. 
Pulmonary Events ......................................................................................................... 60 
5.4.8. 
Tumor Lysis Syndrome ................................................................................................. 61 
5.4.9. 
Pregnancy, Lactation, and Reproduction ...................................................................... 61 
5.4.10. 
Ultraviolet Exposure ..................................................................................................... 61 
5.5. 
Emergency Unblinding ................................................................................................................... 62 
5.6. 
Concomitant and Supportive Therapy ............................................................................................. 62 
5.6.1. 
Anticancer or Experimental Therapies Other than Investigational 
Treatments ..................................................................................................................... 63 
5.6.2. 
Antibiotics ..................................................................................................................... 63 
5.6.3. 
Antiemetics and Antidiarrheals ..................................................................................... 63 
5.6.4. 
Contraception ................................................................................................................ 63 
5.6.5. 
Corticosteroids .............................................................................................................. 64 
5.6.6. 
Granulocyte Colony-Stimulating Factors and Erythropoietin ....................................... 65 
5.6.7. 
Drugs that Alter CYP3A4-Dependent Metabolism ....................................................... 65 
5.6.8. 
Surgery .......................................................................................................................... 67 
5.6.9. 
Diet ................................................................................................................................ 67 
5.7. 
Duration of Study Drug ................................................................................................................... 67 
5.8. 
Discontinuation of Study Drug ....................................................................................................... 67 
5.9. 
Discontinuation from Study ............................................................................................................ 68 
5.10. 
Study Treatment Rationale .............................................................................................................. 68 
6. 
STUDY PROCEDURES ............................................................................................................................. 71 
6.1. 
Enrollment and Study Management Procedures ............................................................................. 71 
6.1.1. 
Subject Recruitment ...................................................................................................... 71 
6.1.2. 
Subject Compensation for Participation ........................................................................ 71 
6.1.3. 
Screening ....................................................................................................................... 71 
6.2. 
Explanation of Study Visits ............................................................................................................ 72 
6.2.1. 
Visit 1 and Screening Period (Clinic Visit) ................................................................... 72 
6.2.2. 
Visit 2 (Day 1) (Clinic Visit) ......................................................................................... 74 
6.2.3. 
Visit 3 (Day 15) (Clinic Visit) ....................................................................................... 75 


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6.2.4. 
Visit 4 (Day 29) (Clinic Visit) ....................................................................................... 76 
6.2.5. 
Visit 5 (Day 43) (Clinic Visit) ....................................................................................... 77 
6.2.6. 
Visit 6 (Day 57) (Clinic and Radiology Visit) .............................................................. 78 
6.2.7. 
Visit 7 (Day 71) (Laboratory Visit) ............................................................................... 79 
6.2.8. 
Visit 8 (Day 85) (Clinic Visit) ....................................................................................... 80 
6.2.9. 
Visit 9 (Day 113) (Clinic and Radiology Visit) ............................................................ 81 
6.2.10. 
Visit 10 (Day 141) (Clinic Visit) ................................................................................... 82 
6.2.11. 
Visit 11 (Day 169) (Clinic and Radiology Visit) .......................................................... 83 
6.2.12. 
Visit 12 (Day 211) (Clinic Visit) ................................................................................... 84 
6.2.13. 
Visit 13 (Day 253) (Clinic and Radiology Visit) .......................................................... 85 
6.2.14. 
Visit 14 (Day 295) (Clinic Visit) ................................................................................... 86 
6.2.15. 
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks) 
(Clinic and Radiology Visits) ........................................................................................ 87 
6.2.16. 
End-of-Study Visit (Clinic Visit) .................................................................................. 88 
6.2.17. 
30 Day and Long-Term Follow-up ............................................................................... 89 
6.3. 
Blood Collection ............................................................................................................................. 89 
6.4. 
Study Procedure Rationale .............................................................................................................. 91 
7. 
EFFICACY ASSESSMENTS ..................................................................................................................... 92 
7.1. 
Tumor Status Assessments .............................................................................................................. 92 
7.2. 
Method of Assessment .................................................................................................................... 92 
7.3. 
Timing of Assessments ................................................................................................................... 92 
7.4. 
Identification and Measurement of Tumor Lesions and Organomegaly ......................................... 93 
7.4.1. 
Index Lesions ................................................................................................................ 93 
7.4.2. 
Spleen and Liver ........................................................................................................... 94 
7.4.3. 
Non-Index Lesions ........................................................................................................ 95 
7.5. 
Definitions of Tumor Response and Progression ............................................................................ 95 
7.5.1. 
Complete Response ....................................................................................................... 95 
7.5.2. 
Partial Response ............................................................................................................ 96 
7.5.3. 
Stable Disease ............................................................................................................... 97 
7.5.4. 
Definitive Progressive Disease ...................................................................................... 97 
7.5.5. 
Non-Evaluable .............................................................................................................. 99 
7.5.6. 
No Disease .................................................................................................................... 99 
7.5.7. 
Lymphocytosis During Therapy .................................................................................... 99 
7.5.8. 
Documentation of Definitive CLL Progression ............................................................ 99 
8. 
SAFETY ASSESSMENTS ........................................................................................................................ 101 
8.1. 
Adverse Event Definitions ............................................................................................................ 101 
8.1.1. 
Adverse Event ............................................................................................................. 101 
8.1.2. 
Serious Adverse Event ................................................................................................ 102 
8.1.3. 
Unexpected Adverse Event ......................................................................................... 103 
8.1.4. 
Adverse Drug Reactions.............................................................................................. 103 
8.2. 
Eliciting Adverse Event Information ............................................................................................ 103 
8.3. 
Recording Adverse Events ............................................................................................................ 104 
8.4. 
Grading of the Severity of an Adverse Event ............................................................................... 104 
8.5. 
Describing Adverse Event Relationship to Study Drug and Study Procedures ............................ 105 
8.6. 
Adverse Event Reporting Period ................................................................................................... 106 
8.7. 
Adverse Event Reporting Requirements ....................................................................................... 106 
8.7.1. 
Site Reporting Requirements ...................................................................................... 106 
8.7.2. 
Gilead Sciences Reporting Requirements ................................................................... 108 
8.7.3. 
Reporting of Adverse Events Relating to the Primary Endpoint and 
Other Anticipated Medical Events in the Study Population ........................................ 109 
8.8. 
Special Situations Reporting Requirements .................................................................................. 109 
8.9. 
Special Situations Reporting Requirements .................................................................................. 109 


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8.9.1. 
Definitions of Special Situations ................................................................................. 109 
8.9.2. 
Pregnancy .................................................................................................................... 109 
8.9.3. 
Instructions for Reporting Special Situations .............................................................. 110 
9. 
STATISTICAL CONSIDERATIONS ....................................................................................................... 112 
9.1. 
Analysis Objectives....................................................................................................................... 112 
9.2. 
Analysis Endpoints ....................................................................................................................... 112 
9.3. 
Analysis Conventions ................................................................................................................... 112 
9.3.1. 
Analysis Sets ............................................................................................................... 112 
9.3.2. 
Data Handling Conventions ........................................................................................ 113 
9.4. 
Analysis Plan ................................................................................................................................ 114 
9.4.1. 
Subject Disposition and Baseline Characteristics ....................................................... 114 
9.4.2. 
Efficacy Analyses ........................................................................................................ 115 
9.4.3. 
Other Analyses ............................................................................................................ 118 
9.5. 
Sample Size ................................................................................................................................... 120 
9.6. 
Timing of Analyses ....................................................................................................................... 120 
9.6.1. 
Interim Analysis .......................................................................................................... 120 
9.6.2. 
Final Analysis ............................................................................................................. 121 
10. RESPONSIBILITIES ................................................................................................................................ 122 
10.1. 
Investigator Responsibilities ......................................................................................................... 122 
10.1.1. 
Compliance with Ethical and Regulatory Guidelines .................................................. 122 
10.1.2. 
Institutional Review Board/Independent Ethics Committee ....................................... 122 
10.1.3. 
Informed Consent ........................................................................................................ 123 
10.1.4. 
Confidentiality ............................................................................................................ 123 
10.1.5. 
Study Files and Retention of Records and Biological Samples .................................. 124 
10.1.6. 
Case Report Forms ...................................................................................................... 125 
10.1.7. 
Drug Accountability .................................................................................................... 126 
10.1.8. 
Inspections .................................................................................................................. 126 
10.1.9. 
Protocol Compliance ................................................................................................... 126 
10.2. 
Sponsor Responsibilities ............................................................................................................... 126 
10.2.1. 
Protocol Modifications ................................................................................................ 126 
10.2.2. 
Communications with Regulatory Authorities ............................................................ 127 
10.2.3. 
Data Management ....................................................................................................... 127 
10.2.4. 
Study Reporting and Publication ................................................................................. 127 
10.3. 
Joint Investigator/Sponsor Responsibilities .................................................................................. 128 
10.3.1. 
Access to Information for Monitoring ......................................................................... 128 
10.3.2. 
Access to Information for Auditing or Inspections ..................................................... 128 
10.3.3. 
Public Notification of Study Conduct ......................................................................... 129 
10.3.4. 
Study Discontinuation ................................................................................................. 129 
10.4. 
Study Committees ......................................................................................................................... 129 
10.4.1. 
Study Steering Committee .......................................................................................... 129 
10.4.2. 
Data Monitoring Committee ....................................................................................... 129 
10.4.3. 
Independent Review Committee ................................................................................. 130 
11. REFERENCES .......................................................................................................................................... 132 
12. APPENDICES ........................................................................................................................................... 146 
 
Appendix 1. 
Investigator Signature Page ......................................................................................... 147 
Appendix 2. 
Functional Assessment of Cancer Therapy: Leukemia 
(FACT-Leu) ................................................................................................................ 148 
Appendix 3. 
Performance Status Scoring System ............................................................................ 151 
Appendix 4. 
EuroQoL-5 Dimensions (EQ-5D) ............................................................................... 152 


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Appendix 5. 
Cockcroft-Gault Method for Estimating Creatinine Clearance ................................... 154 
Appendix 6. 
Cumulative Illness Rating Scale (CIRS) ..................................................................... 155 
Appendix 7. 
Schedule of Study Procedures ..................................................................................... 160 
LIST OF IN-TEXT TABLES 
Table 4-1. 
Required Screening Laboratory Values ........................................................................ 45 
Table 5-1. 
Study Drug Dose Levels ............................................................................................... 53 
Table 5-2. 
Recommendations for Study Drug Dose Modifications Based on 
Type and Severity of Adverse Events or Laboratory 
Abnormalities ................................................................................................................ 55 
Table 5-3. 
Protocol-Recommended Contraceptive Methods .......................................................... 64 
Table 5-4. 
Known Inhibitors or Inducers of CYP3A ...................................................................... 66 
Table 6-1. 
Procedures and Assessments at Visit 1 (During Screening 
Period) ........................................................................................................................... 73 
Table 6-2. 
Procedures and Assessments at Visit 2 (Day 1) ............................................................ 74 
Table 6-3. 
Procedures and Assessments at Visit 3 (Day 15) .......................................................... 75 
Table 6-4. 
Procedures and Assessments at Visit 4 (Day 29) .......................................................... 76 
Table 6-5. 
Procedures and Assessments at Visit 5 (Day 43) .......................................................... 77 
Table 6-6. 
Procedures and Assessments at Visit 6 (Day 57) .......................................................... 78 
Table 6-7. 
Procedures and Assessments at Visit 7 (Day 71) .......................................................... 79 
Table 6-8. 
Procedures and Assessments at Visit 8 (Day 85) .......................................................... 80 
Table 6-9. 
Procedures and Assessments at Visit 9 (Day 113) ........................................................ 81 
Table 6-10. 
Procedures and Assessments at Visit 10 (Day 141) ...................................................... 82 
Table 6-11. 
Procedures and Assessments at Visit 11 (Day 169) ...................................................... 83 
Table 6-12. 
Procedures and Assessments at Visit 12 (Day 211) ...................................................... 84 
Table 6-13. 
Procedures and Assessments at Visit 13 (Day 253) ...................................................... 85 
Table 6-14. 
Procedures and Assessments at Visit 14 (Day 295) ...................................................... 86 
Table 6-15. 
Procedures and Assessments at Visit 15 and Subsequent Visits 
(Day 337 and Every 12 Weeks) .................................................................................... 87 
Table 6-16. 
Procedures and Assessments at End-of-Study Visit ...................................................... 88 
Table 6-17. 
Blood Drawing Requirements Through Visit 15 (Week 48) ......................................... 90 
Table 8-1. 
Grading of Adverse Event Severity ............................................................................. 105 
Table 8-2. 
Site Reporting Requirements for Adverse Events ....................................................... 107 
Table 8-3. 
Contact Information for Reporting Serious Adverse Events ....................................... 108 
LIST OF IN-TEXT FIGURES 
Figure 2-1. 
Study Design ................................................................................................................. 31 


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PROTOCOL SYNOPSIS 
Gilead Sciences, Inc 
199 East Blaine Street 
Seattle, WA 98102, USA 
Study Title:  
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and 
Safety of Two Different Dose Levels of Single-Agent Idelalisib (GS-1101) 
as Therapy for Patients with Previously Treated Chronic Lymphocytic 
Leukemia 
A Companion Study to Study GS-US-312-0116: A Phase 3, Randomized, 
Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety 
of Idelalisib (GS-1101) in Combination with Rituximab as Therapy for 
Patients with Previously Treated Chronic Lymphocytic Leukemia 
Study Centers 
Planned: 
Approximately 90 centers in the United States and in Europe 
IND Number: 
101254 
EudraCT 
Number: 
2011-006293-72 
Objectives: 
• To evaluate the effect of idelalisib (formerly GS-1101) on the onset, 
magnitude, and duration of tumor control  
• To compare tumor control in subjects receiving rituximab alone in 
Study GS-US-312-0116 to that observed in the same subjects when 
receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117 
• To assess the effect of idelalisib on measures of subject well-being, 
including overall survival (OS), health-related quality of life (HRQL), 
and performance status 
• To assess the effects of idelalisib on disease-associated biomarkers and 
to evaluate potential mechanisms of resistance to idelalisib 
• To characterize exposure to idelalisib as determined by treatment 
administration and evaluation of idelalisib plasma concentrations over 
time 
• To describe the safety profile observed with idelalisib  
• To estimate health resource utilization associated with administration of 
idelalisib  


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Study Design: 
This study is being conducted as part of an overall clinical program 
evaluating the efficacy and safety of idelalisib in the therapy of patients 
with previously treated chronic lymphocytic leukemia (CLL).  
Within this program, the primary clinical trial (Study GS-US-312-0116) is 
a Phase 3, multicenter, 2-arm, randomized, double-blind, placebo-
controlled, parallel-group study. 
This clinical trial (Study GS-US-312-0117) is a separate, multicenter, 
2-arm, double-blind, parallel-group extension study that is a companion 
trial to Study GS-US-312-0116; in this trial, compliant subjects from 
GS-US-312-0116 who are tolerating primary study therapy but experience 
definitive CLL progression are eligible to receive active blinded idelalisib 
therapy at the standard dose or a higher dose, with allocation based on the 
original primary study randomization. 
Study Schema: 
Randomized
Double-Blind
Initial Therapy
Idelalisib, 150 mg BID
Until PD
Placebo BID 
Until PD
Disease 
progression
Double-Blind
Continuing  Therapy
Double-Blind
Extension
Therapy
Idelalisib, 150 mg BID
R, 375 mg/m2 Wk 0
R 500 mg/m2 Wk 2,4,6,8,12,16,20
Stratification and 
Randomization
Idelalisib, 150 mg BID
Until PD
Idelalisib, 300 mg BID
Until PD
Placebo
R, 375 mg/m2 Wk 0
R 500 mg/m2 Wk 2,4,6,8,12,16,20
Screening
Primary Study
Study GS-US-312-0116
Extension Study
Study GS-US-312-0117
Arm A
N=80
Arm B
N=80
 
 
 
Treatment Groups 
• Arm A: Idelalisib + rituximab (Study GS-US-312-0116) 
high-dose Idelalisib (300 mg BID) (Study GS-US-312-0117) 
• Arm B: Placebo + rituximab (Study GS-US-312-0116) 
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117) 
Treatment Assignment 
• Assignment to Arm A or Arm B with allocation based on the original 
primary study randomization 
• Implementation through an interactive web response system (IWRS) 
Stratification 
Not applicable for Study GS-US-312-0117 
Number of 
Subjects 
Planned: 
Total of up to ~160 subjects (up to ~80 subjects per treatment arm) 


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Target 
Population 
Subjects in the primary Phase 3 study (Study GS-US-312-0116) who are 
compliant, are tolerating primary study therapy, and have definitive 
progression of CLL while receiving primary study drug therapy (idelalisib 
/placebo). 
Diagnosis and 
Main Eligibility 
Criteria: 
Inclusion Criteria 
Subjects must meet all of the following conditions to be eligible for 
enrollment into the study: 
1) Participation in Study GS-US-312-0116. 
2) Occurrence of confirmed, definitive CLL progression while receiving 
study drug therapy (idelalisib /placebo) in Study GS-US-312-0116. 
Note: Definitive disease progression is CLL progression based on 
standard criteria and occurring for any reason (ie, increasing 
lymphadenopathy, organomegaly, or bone marrow involvement; 
decreasing platelet count, hemoglobin, or neutrophil count; or 
worsening of disease-related symptoms) other than lymphocytosis. 
Subjects must have confirmation by the sponsor working in 
collaboration with an independent review committee (IRC) that the 
disease has progressed on the primary clinical trial 
(Study GS-US-312-0116) before receiving secondary idelalisib therapy 
on this extension trial (Study GS-US-312-0117). 
3) Presence of measurable lymphadenopathy (defined as the presence of 
1 nodal lesion that measures ≥2.0 cm in the longest diameter [LD] and 
≥1.0 cm in the longest perpendicular diameter [LPD] as assessed by 
computed tomography [CT] or magnetic resonance imaging [MRI]).  
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab 
and/or idelalisib/placebo) and no intervening or continuing therapy 
(including radiotherapy, chemotherapy, immunotherapy, or 
investigational therapy) for the treatment of CLL. Note: Subjects may 
receive corticosteroids to manage CLL manifestations. 
5) The time from permanent cessation of Study GS-US-312-0116 
treatment (rituximab and/or idelalisib/placebo) and the initiation of 
Study GS-US-312-0117 therapy is ≤12 weeks. Note: Study procedures 
performed as part of Study GS-US-312-0116 need not be repeated and 
can be used as screening procedures for Study GS-US-312-0117 if 
performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117. 
6) Karnofsky performance score of 40. 


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7) Required baseline laboratory data (within 4 weeks prior to initiation of 
study treatment) as shown in the table below. Note: Confirmation 
should be considered for out-of-range values to determine if the 
abnormality is real or artifactual. Values should be obtained within 
the screening period and should generally be the most recent 
measurement obtained. Subjects with any degree of neutropenia, 
thrombocytopenia, or anemia due to CLL or prior therapy may enroll.
Required Screening Laboratory Values 
Organ System 
Parameter 
Required Value 
Hepatic 
Serum total bilirubin 
≤1.5 x ULN (unless elevated due to Gilbert’s syndrome) 
Serum ALT 
≤2.5 x ULN 
Serum AST 
Renal 
eCCr
a 
>30 ml/min 
Pregnancy 
β-HCGb 
Negative  
a As calculated by the Cockcroft-Gault formula 
b For women of child-bearing potential only; serum β-HCG must be negative during screening and serum β-HCG 
or urine dipstick pregnancy test must be negative at randomization (Visit 2) 
Abbreviations: β-HCG=beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate 
aminotransferase, eCCr=estimated creatinine clearance, ULN=upper limit of normal
 
8) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening 
visit (Visit 1) throughout the study treatment period and for 30 days 
following the last dose of study drug. Note: A female subject is 
considered to be of childbearing potential unless she has had a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has 
medically documented ovarian failure (with serum estradiol and 
follicle-stimulating hormone [FSH] levels within the institutional 
postmenopausal range and a negative serum or urine βHCG), or is 
menopausal (age >55 years with amenorrhea for >12 months or 
amenorrhea for >6 months with serum estradiol and FSH levels 
within the institutional postmenopausal range).  
9) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a protocol-
recommended method of contraception from the start of study therapy 
(Visit 2) throughout the study and for 90 days following the last dose of 
study drug and to refrain from sperm donation from the start of study 
treatment (Visit 2) throughout the study and for 90 days following the 
last dose of study drug. Note: A male subject is considered able to 
father a child unless he has had a bilateral vasectomy with 
documented aspermia or a bilateral orchiectomy, or has ongoing 
testicular suppression with a depot luteinizing hormone- releasing 
hormone (LH-RH) agonist (eg, goserelin acetate [Zoladex®]), 
leuprolide acetate [Lupron®]), or triptorelin pamoate [Trelstar®]).


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10) In the judgment of the investigator, participation in the protocol offers 
an acceptable benefit-to-risk ratio when considering current CLL 
disease status, medical condition, and the potential benefits and risks of 
alternative treatments for CLL.  
11) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, 
familial, or geographical factors that might preclude adequate study 
participation should be considered. 
12) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature of 
the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study 
participation. 
 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria are not to be 
enrolled in this study: 
1) Known histological transformation from CLL to an aggressive 
lymphoma (ie, Richter transformation).  
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at the 
time of the start of study treatment (Visit 2). Note: Subjects with 
localized fungal infections of skin or nails are eligible. Subjects may 
be receiving prophylactic antiviral or antibacterial therapies at the 
discretion of the investigator; anti-pneumocystis prophylaxis is 
encouraged.  
3) Pregnancy or breastfeeding.  
4) Intentional breaking of the blind in Study GS-US-312-0116 by the 
investigator or the study subject. 
5) Concurrent participation in another therapeutic clinical trial. 
6) Prior or ongoing clinically significant illness, medical condition, 
surgical history, physical finding, electrocardiogram (ECG) finding, or 
laboratory abnormality that, in the investigator’s opinion, could 
adversely affect the safety of the subject or impair the assessment of 
study results. 
Study 
Procedures/ 
Frequency: 
Subjects participating in the extension study will be assigned to 1 of the 
2 treatment arms, with allocation based on the original randomization in the 
primary study. In the extension study, blinded idelalisib high-dose or 
standard-dose therapy will be taken orally, twice per day (BID), 
continuously.  


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Clinic/laboratory visits will occur every 2 weeks for the first 12 weeks, 
every 4 weeks between Weeks 12 and 24, and every 6 weeks between 
Weeks 24 and 48. Subjects continuing on study drug past Week 48 will 
have clinic visits every 12 weeks. Subjects will be assessed for safety at 
each visit. Subjects will be assessed for CLL disease status by physical and 
laboratory examinations at each visit and by CT or MRI at Weeks 8, 16, 24, 
36, and 48 and every 12 weeks thereafter. 
Test Therapy, 
Dose, and  
Mode of 
Administration: 
• Arm A: Idelalisib, 300 mg/dose BID starting on Day 1 and administered 
continuously thereafter; the study drug will be provided as 2 tablets of 
active idelalisib for oral administration 
• Arm B: Idelalisib, 150 mg/dose BID starting on Day 1 and administered 
continuously thereafter; the study drug will be provided as 1 tablet of 
active idelalisib and 1 tablet of placebo for oral administration 
Reference 
Therapy, Dose, 
and Mode of 
Administration: 
Not applicable 
Duration of 
Treatment: 
Study drug will be taken continuously until the earliest of subject 
withdrawal from study, definitive progression of CLL, intolerable study 
drug-related toxicity, pregnancy, substantial noncompliance with study 
procedures, or study discontinuation. 
Criteria for 
Evaluation: 
Tumor Control  
• Progression-free survival (PFS) – defined as the interval from the start 
of study therapy to the earlier of the first documentation of definitive 
disease progression or death from any cause; definitive disease 
progression is CLL progression based on standard criteria other than 
lymphocytosis alone 
• Overall response rate (ORR) – defined as the proportion of subjects 
who achieve a complete response (CR) or partial response (PR)  
• Lymph node response rate – defined as the proportion of subjects who 
achieve a ≥50% decrease from baseline in the SPD of index lymph 
nodes 
• CR rate – defined as the proportion of subjects who achieve a CR 
• Time to response (TTR) – defined as the interval from start of study 
therapy to the first documentation of CR or PR 
• Duration of response (DOR) – defined as the interval from the first 
documentation of CR or PR to the earlier of the first documentation of 
definitive disease progression or death from any cause 
• Percent change in lymph node area – defined as the percent change 
from baseline in the SPD of index lymph nodes 


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• Splenomegaly response rate – defined as the proportion of subjects with 
baseline splenomegaly who achieve an on-study normalization or a 
decrease by ≥50% from baseline in the pretreatment enlargement of the 
vertical splenic dimension  
• Hepatomegaly response rate – defined as the proportion of subjects with 
baseline hepatomegaly who achieve an on-study normalization or a 
decrease by ≥50% from baseline in the pretreatment enlargement of the 
liver  
• ALC response rate – defined as the proportion of subjects with baseline 
lymphocytosis (ALC≥4 x 109/L) who achieve an on-study ALC <4 x 
109/L or demonstrate a ≥50% decrease in ALC from baseline 
• Platelet response rate – defined as the proportion of subjects with 
baseline thrombocytopenia (platelet count <100 x 109/L) who achieve 
an on-study platelet count ≥100 x 109/L or demonstrate a ≥50% increase 
in platelet count from baseline 
• Hemoglobin response rate – defined as the proportion of subjects with 
baseline anemia (hemoglobin <110 g/L [11.0 g/dL]) who achieve an on-
study hemoglobin ≥110 g/L (11.0 g/dL) or demonstrate a ≥50% 
increase in hemoglobin from baseline 
• Neutrophil response rate – defined as the proportion of subjects with 
baseline neutropenia (absolute neutrophil count [ANC] <1 x 109/L) who 
achieve an ANC ≥1 x 109/L or demonstrate a ≥50% increase in ANC 
from baseline 
Patient Well-Being 
• Overall survival (OS) – defined as the interval from start of study 
therapy to death from any cause 
• Change from baseline in HRQL domain and symptom scores based on  
the Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) 
(See Appendix 2)   
• Changes from baseline in Karnofsky performance status (See Appendix 
3)  
Pharmacodynamic Markers of Drug Activity and Resistance 
• Changes from baseline in PI3K/AKT/mTOR pathway activation as a 
measure of PI3Kδ pathway activity  
• Changes from baseline in the plasma concentrations of disease-
associated chemokines and cytokines 
Exposure 
• Study drug administration as assessed by prescribing records and 
compliance as assessed by quantification of used and unused drug 


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• Trough (pre-dose) and peak (1.5-hour samples) of idelalisib plasma 
concentrations as assessed by a validated bioanalytical method 
Safety 
• Overall safety profile of each regimen characterized by the type, 
frequency, severity, timing of onset, duration, and relationship to study 
therapy of any adverse events or abnormalities of laboratory tests; 
serious adverse events; or adverse events leading to discontinuation of  
study drug  
Pharmacoeconomics 
• Change in health status – defined as the change from baseline in overall 
health and single-item dimension scores as assessed using the EuroQoL 
Five-Dimension (EQ-5D) utility measure  
Health resource measures, including resource utilization, total costs, and 
measures of cost per unit of benefit (eg, cost per additional progression-free 
month, cost per quality-adjusted life-year) 
Statistical 
Methods: 
Appropriate data analysis sets will be defined. The intent-to-treat (ITT) 
analysis set will include data from all subjects who receive ≥1 dose of any 
study therapy on this study; in this data set, study drug assignment (high-
dose or standard-dose idelalisib) will be designated according to the planned 
allocation to this study. A safety analysis set will comprise data from subjects 
in the ITT analysis set with treatment assignments designated according to 
the actual study drug (high-dose or standard-dose idelalisib) received. Other 
analysis sets [per-protocol (PP) and pharmacodynamic/pharmacokinetic 
analysis sets] will be used for certain analyses as well. 
Subject characteristics and study results will be described and summarized 
by treatment arm and assessment for the relevant analysis sets. Descriptive 
summaries will be prepared to show sample size, mean, standard deviation, 
95% confidence intervals (CIs) on the mean, median, minimum, and 
maximum for continuous variables and counts, percentages, and 95% CIs 
on the percentage for categorical variables. 
An independent review committee (IRC) will review radiographic data and 
pertinent clinical data in order to provide expert evaluation of tumor status. 
The findings of the IRC will be considered primary for analyses of PFS and 
other tumor control endpoints. 
For endpoints relating to tumor control, patient well-being, and biomarkers, 
analyses will be done based on ITT, PP or pharmacodynamic data sets, as 
appropriate. Time-to-event analyses will be performed with reference to the 
date of first treatment on this study (Study GS-US-312-0117). Similarly, 
evaluations of on-therapy changes will reference the baseline values 
obtained prior to treatment in this study. Analyses will focus on evaluation 
of outcomes within each treatment arm and will be largely descriptive in  


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nature; formal comparisons of outcomes in Arm A vs Arm B are not 
planned. Time-to-event endpoints will be summarized using Kaplan-Meier 
methods; medians, ranges, and the corresponding 95% CI will be presented. 
Continuous and categorical variables will also be summarized as 
appropriate. Changes from baseline in categorical variables and changes 
from baseline in continuous endpoints will be analyzed using appropriate 
methods. 
Efficacy outcomes among subjects receiving rituximab alone in 
Study GS-US-312-0116 will be evaluated relative to those same outcomes 
among the same subjects receiving standard-dose idelalisib alone in Study 
GS-US-312-0117. More specifically, time-to-event endpoints will be 
compared using the paired Prentice-Wilcoxon test; continuous endpoints 
will be compared using the paired t-test; and categorical or non-normal data 
will be compared using the Wilcoxon signed-rank test. 
Based on the safety analysis set, information regarding study drug 
administration, study drug compliance, safety variables, and post-study 
therapies will be described and summarized. Using data from the 
pharmacokinetic analysis set, idelalisib plasma concentrations will also be 
described and summarized. 
 
Sample Size Calculation 
The sample size for this extension study is not based upon a formal 
statistical hypothesis. The upper bound of the sample size in this study is 
determined by the sample size of the preceding primary clinical trial 
(Study GS-US-312-0116) in which ~160 subjects (~80 per arm) are 
expected to be enrolled. Assuming a ~10% dropout rate during 
Study GS-US-312-0116 and a further ~10% dropout rate in the transition 
from the primary study to the extension study, ~130 subjects are expected 
to be enrolled into Study GS-US-312-0117. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice 
(GCP), including archiving of essential documents. 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS 
β-HCG 
Beta human chorionic gonadotropin 
ABCG2 
adenosine triphosphate-binding cassette sub-family G member 2 (see also BCRP) 
AKT 
AKT (a serine/threonine protein kinase) 
ALC 
absolute lymphocyte count 
ALL 
acute lymphocytic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
ATC 
Anatomical-Therapeutic-Chemical classification system for drugs  
BCRP 
breast cancer resistance protein (see also ABCG2) 
BID 
twice per day 
BTK 
Bruton tyrosine kinase 
CAL-101 
Former name for GS-1101 
CCL 
chemokine (C-C motif) ligand 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIRS 
Cumulative Illness Rating Scale 
CLL 
chronic lymphocytic leukemia 
cGMP 
current Good Manufacturing Practice 
Cmax 
maximum concentration 
CMV 
cytomegalovirus 
CR 
complete response 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
trough concentration 
CXCL 
chemokine (C-X-C motif) ligand 
CYP 
cytochrome P450 enzyme 
DLCO 
diffusing capacity of the lung for carbon monoxide 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSPH 
Gilead Sciences Department of Safety and Public Health 
ECG 
electrocardiogram 
eCCr 
estimated creatinine clearance 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EQ-5D 
EuroQoL Five-Dimension utility measure 
FACT-Leu 
Functional Assessment of Cancer Therapy: Leukemia questionnaire 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED) 
FCİRI 
high-affinity IgE receptor 
FDA 
United States Food and Drug Administration 
FDAMA 
Food and Drug Modernization Act 
FDG 
fluorodeoxyglucose (18F) 
FISH 
fluorescence in-situ hybridization, 
FSH 
follicle-stimulating hormone 
G-CSF 
granulocyte colony-stimulating factor 
GGT 
gamma-glutamyltransferase 
GLP 
Good Laboratory Practice 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HBc antibody 
anti-hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
hERG 
human ether-à-go-go-related gene 
HL 
Hodgkin lymphoma 
HIV 
human immunodeficiency virus 
HRQL 
health-related quality of life 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
idelalisib 
formerly CAL-101 and GS-1101 
IEC 
independent ethics committee 
Ig 
immunoglobulin (including subtypes A, E, G, and M) 
IgHV 
immunoglobulin heavy chain variable region 
IND 
Investigational New Drug (application) 
iNHL 
indolent non-Hodgkin lymphoma 
INR 
international normalized ratio 
IRB 
institutional review board 
IRC 
independent review committee 
ITT 
intention to treat 
IUD 
intrauterine device 
IWCLL 
International Workshop on CLL 
IWRS 
interactive web response system 
JAK 
Janus kinase 
K2-EDTA 
potassium-ethylenediaminetetraacetic acid 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
LH-RH 
luteinizing hormone-releasing hormone 
LLN 
lower limit of normal 
LPD 
longest perpendicular diameter 
LVD 
longest vertical dimension 
MTD 
maximum tolerated dose 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED) 
mTOR 
mammalian target of rapamycin 
ND 
no disease 
NHL 
non-Hodgkin lymphoma 
NOAEL 
no-observed-adverse effect level 
NOEL 
no-observed-effect level 
OCT 
organic cation transporter 
ORR 
overall response rate 
OS 
overall survival 
pAKT 
phosphorylated AKT 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PET 
positron-emission tomography 
PI3K 
phosphatidylinositol 3-kinase 
PI3Kδ 
phosphatidylinositol 3-kinase p110δ isoform 
PFS 
progression-free survival 
PML 
progressive multifocal leukoencephalopathy 
PP 
per-protocol 
PPD 
product of the perpendicular diameters 
PRO 
patient-reported outcome 
PR 
partial response 
PT 
prothrombin time 
PVA 
polyvinyl alcohol 
PVC/PCTFE 
polyvinyl chloride/polychlorotrifluoroethylene 
QD 
once per day 
QT (interval) 
measure of time between start of Q wave and end of T wave in electrical cycle of heart 
RNA 
ribonucleic acid 
SADR 
serious adverse drug reaction 
SD 
stable disease 
SPD 
sum of the products of the perpendicular diameters of measured lymph nodes 
SSC 
study steering committee 
SUSAR 
suspected, unexpected, serious adverse reaction 
SYK 
spleen tyrosine kinase 
t1/2 
half-life 
Tmax 
time of maximum concentration 
TTR 
time to response 
UGT 
uridine 5'-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 
WHODRUG 
World Health Organization Drug Dictionary 
ZAP-70 
zeta-associated protein 70 


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1. 
INTRODUCTION 
1.1. 
Chronic Lymphocytic Leukemia 
Chronic lymphocytic leukemia (CLL) is a neoplasia resulting from the progressive 
accumulation of functionally incompetent monoclonal B lymphocytes in blood, bone 
marrow, lymph nodes, spleen, and liver [Dighiero 2008]. CLL constitutes the most 
commonly occurring leukemia in Europe and the United States [Sant 2010, SEER 2011]. 
While some patients never require treatment, many will need therapy for disfiguring or 
obstructing lymphadenopathy, debilitating constitutional B symptoms (fevers, night sweats, 
fatigue, weight loss) [Redaelli 2004], or recurrent cytopenias and infections [Perkins 2002, 
Keating 2002a]. CLL is largely a disease of the elderly; at diagnosis, 70% of patients are 
≥65 years of age and the median age is 72 years [SEER 2011]. 
In younger and relatively healthy patients with CLL, chemoimmunotherapy regimens that 
include the anti-CD20 monoclonal antibody, rituximab, are commonly employed to control 
disease manifestations [Gribben 2011]. Such combination therapies are effective in providing 
durable remissions [Byrd 2005, Hallek 2010, Robak 2010, Fischer 2011, and Iannitto 2011]. 
However, while rituximab is usually well tolerated [Gentile 2010], the chemotherapeutic 
agents (typically fludarabine, cyclophosphamide, or bendamustine) in such regimens are 
acutely cytotoxic, induce permanent bone marrow compromise, and can cause secondary 
malignancies [Kyasa 2004, Tam 2008, Carney 2010]. Furthermore, in elderly patients or in 
those with comorbid conditions, such regimens are associated with less efficacy and greater 
toxicity [Tam 2008, Eichhorst 2009b, Goede 2011]. 
Increasing attention has been paid to the problem of treating patients with CLL who have 
comorbidities. Because of the relatively late age of diagnosis, a large proportion (~90%) of 
patients with CLL have co-morbidities and a substantial proportion (~45%) have major 
chronic conditions such as coronary artery disease, diabetes, or chronic obstructive 
pulmonary disease [Thurmes 2008]. At the time the disease is first identified, ~25% of 
patients with CLL do not meet conventional criteria for participation in clinical studies 
containing cytotoxic agents [Thurmes 2008]. By the time treatment is necessary or during 
treatment for CLL, patients continue to advance in age and have new or worsening chronic 
conditions; as a result, the proportion of patients with comorbidities increases during the 
course of the illness. Such patients have been substantially underrepresented in clinical trials 
due to concerns regarding the ability of such patients to tolerate intensive 
chemoimmunotherapy [Thurmes 2008, Eichhorst 2009a]. Instruments such as the 
Cumulative Illness Rating Scale (CIRS) [Linn 1968] are now being applied in order to 
categorize patient populations as fit or relatively unfit and to evaluate regimens tailored to 
these groups of patients [Eichhorst 2009a, Hallek 2010, Giudice 2011]. 
Health constraints in older or compromised patients have prompted noncytotoxic approaches 
to therapy. Alternative immunotherapeutics, such as the monoclonal antibodies, 
alemtuzumab [Keating 2002b] or ofatumumab [Wierda 2010], have been developed. 


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However the therapeutic utility of these drugs is modest; median progression-free survival 
(PFS) values in patients with recurrent CLL have been 4.7 months and 5.8 months, 
respectively. Moreover, these treatments can have clinical liabilities. Alemtuzumab causes 
extreme immunosuppression that leads to frequent opportunistic infection. Administration of 
the large amounts of protein recommended in ofatumumab product labeling results in 
frequent infusion reactions and cumbersome infusion schedules. 
In view of these issues, repeated use of rituximab monotherapy or rituximab-corticosteroid 
combinations have been advocated in treatment guidelines for older or frail patients with 
recurrent CLL [Eichhorst 2010, Zelenetz 2011]. While single-agent rituximab use can offer 
palliative benefit with good tolerability in some patients with previously treated CLL, tumor 
control is not lasting, especially in patients with bulky adenopathy [Gentile 2010]. Addition 
of high-dose corticosteroids to rituximab can extend median PFS up to 12 months, but this 
combination is commonly associated with severe hyperglycemia and frequent 
life-threatening or fatal infections [Bowen 2007, Dungarwalla 2008]. New, noncytotoxic, 
well-tolerated, and convenient therapies that can successfully be combined with rituximab or 
given as single-agent therapy are needed in order to enhance and prolong tumor control in 
patients with comorbid conditions. 
1.2. 
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies 
Phosphatidylinositol 3-kinases (PI3Ks) are enzymes that regulate several cellular functions 
including motility, proliferation, and survival [Okkenhaug 2003a]. PI3K activation recruits 
and activates numerous intracellular signaling enzymes. The most important of these is the 
serine/threonine kinase, AKT, which mediates a positive pleiotropic effect on cell survival, 
proliferation, growth, and metabolism [Engelman 2006] acting by signaling through 
mammalian target of rapamycin (mTOR) [Hay 2005, Osaki 2004]. 
PI3K signaling is mediated by 4 catalytic isoforms of the p110 subunit of the enzyme – α, β, 
γ, and δ. While potentially important in multiple cell types, PI3K p110δ (PI3Kδ) shows an 
expression pattern that is particularly prominent in cells of hematopoietic origin 
[Vanhaesebroeck 2005]. Mice deficient in PI3Kδ have no gross abnormalities, are fertile, 
fecund, and live a normal life span without an increased susceptibility to infections 
[Okkenhaug 2003b]. However, the B-lymphocyte population in these animals shows a 
decrease in maturation, diminished receptor-induced proliferation, and increased 
susceptibility to apoptotic cell death. Conversely, mice with aberrantly elevated PI3K 
signaling develop lymphadenopathy and have an increased incidence of lymphoma 
[Donahue 2004]. In CLL, sustained activation of the PI3K/AKT/mTOR pathway has been 
shown to promote malignant B-cell survival through mechanisms that are dependent on the 
PI3Kδ isoform [Cuni 2004, Herman 2010, Lannutti 2011]. 
Knowledge of the critical importance of PI3Kį in B-cell biology and neoplasia has 
encouraged a search for inhibitors of this enzyme that could provide new options in the 
therapy of lymphoid malignancies, including CLL. 


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1.3. 
Idelalisib (formerly GS-1101) 
1.3.1. 
Discovery and Efficacy Pharmacology 
Gilead Sciences, Inc has developed novel drugs that can suppress tumor growth through 
targeting of PI3Kį activity. High-throughput screening was the basis for the discovery of 
novel agents that selectively inhibit PI3Kδ function but spare other PI3K isoforms and other 
kinases. Chemical optimization, pharmacological characterization, and toxicological 
evaluation have led to identification of idelalisib (also known as GS-1101), a 415-dalton, 
orally bioavailable, new chemical entity with potential clinical utility in the treatment of 
cancers [Gilead Sciences 2011]. 
In primary tumor samples and in cell lines derived from patients with CLL, indolent 
non-Hodgkin lymphoma (iNHL), mantle cell lymphoma (MCL), B-cell acute lymphocytic 
leukemia (ALL), or Hodgkin lymphoma (HL), idelalisib induces dose-dependent reductions 
in AKT phosphorylation [Herman 2010, Meadows 2010, Lannutti 2011]. In addition, 
idelalisib disrupts the PI3Kδ activation and supportive intercellular signaling observed when 
CLL or HL cells are cocultured with stromal cells [Meadows 2010, Hoellenriegel 2011]. 
These effects have therapeutic consequences. In multiple lymphoid primary tumors and 
malignant cell lines, idelalisib enhances apoptosis and concentration-dependent cell killing 
when applied as a single agent and increases the therapeutic efficacy of other antineoplastic 
agents when given in combination [Hoellenriegel 2011, Meadows 2011]. In preclinical 
systems, coadministration of idelalisib with rituximab has not impaired rituximab-mediated 
activity [Herman 2010]. 
1.3.2. 
Safety Pharmacology 
In vitro and in vivo safety pharmacology studies with idelalisib have demonstrated a 
favorable non-clinical safety profile [Gilead Sciences 2011]. These studies indicate that the 
drug may minimally slow bone marrow progenitor proliferation and differentiation and that it 
has expected inhibitory effects on B-cell response to antigen challenge. However, the data 
indicate that idelalisib is unlikely to cause serious off-target effects or adverse effects on 
critical organ systems. idelalisib has no meaningful effect on the human ether-à-go-go-related 
gene (hERG) channel, indicating that idelalisib would not be expected to induce clinical QT 
prolongation. 
The drug has also proved well tolerated in standard in vivo Good Laboratory Practice (GLP) 
studies of pharmacological safety. A functional observation battery in rats revealed no 
adverse effects on behavior or on autonomic, neuromuscular, or sensorimotor function. In a 
cardiopulmonary function study in awake, telemeterized male beagle dogs, single doses of 
idelalisib induced no meaningful abnormalities in pulmonary, cardiovascular, arterial blood 
gas, or electrocardiographic (ECG) (including QT interval) parameters. In an assessment of 
bacterial challenge in rats, idelalisib enhanced, rather than impaired, the phagocytic host 
clearance of staphylococcal bacteria. 


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1.3.3. 
Nonclinical Pharmacology and Metabolism 
In rats and dogs, plasma-concentration time profiles of idelalisib are available following 
single oral and intravenous administration as well as following repeated oral administration 
as part of toxicology studies [Gilead Sciences 2011]. The metabolism of idelalisib has been 
studied in vitro and in vivo; the major metabolite has been identified and characterized in 
rats, dogs, and humans. No human-specific metabolites have been identified. 
Drug disposition data document idelalisib oral bioavailability in test species, characterize 
similar plasma protein binding across species, and demonstrate that idelalisib metabolism is 
dependent upon both hepatic oxidation catalyzed in part by cytochrome P450 (CYP) 3A4 and 
on glucuronidation mediated by uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A4. 
Nonclinical findings show that biliary excretion and hepatic metabolism to renal excretion 
products are important in idelalisib elimination. Nonclinical drug-drug interaction data show 
that idelalisib is unlikely to alter CYP-dependent metabolism of other drugs but could alter 
absorption or disposition of agents that are substrates for P-glycoprotein, the organic cation 
transporter-2 (OCT2), or the adenosine triphosphate-binding cassette sub-family G 
member 2 (ABCG2) transporter (also known as the breast cancer resistance protein [BCRP]). 
1.3.4. 
Toxicology 
In support of clinical development in patients with lymphoid cancers, idelalisib has 
undergone toxicological evaluation in conformance with the International Conference on 
Harmonisation (ICH) S9 guidance on nonclinical evaluation for anticancer pharmaceuticals 
[FDA 2010]. 
1.3.4.1. 
General Toxicology 
Completed GLP toxicology studies have included 28-day evaluations in both rats and dogs 
and a study evaluating the hematological effects of co-administration of idelalisib and 
cyclophosphamide [Gilead Sciences 2011]. These studies have shown idelalisib to be 
tolerated at exposure levels greater than those expected to provide therapeutic activity and 
have identified signals to be monitored in the clinic. Reversible lymphoid depletion in rats 
and dogs was consistent with idelalisib-mediated inhibition of PI3Kδ. In rats, partially 
reversible inflammation of the tongue was noted in idelalisib-treated animals; this may have 
represented an exaggeration of background effects related to gavage-mediated irritation. Mild 
congestion or hemorrhage in the large intestine has been seen in dogs receiving high doses of 
idelalisib. Rats also showed cardiac and hepatic chronic inflammatory infiltrates, although 
attribution to idelalisib was uncertain because background infiltrates of a similar nature were 
observed in control recovery animals. In dogs, evidence of hepatocellular injury and chronic 
inflammation was accompanied by elevations of serum transaminase values (serum alanine 
aminotransferase [ALT] and serum aspartate aminotransferase [AST]). These hepatic effects 
appeared dose-related, reversible, and monitorable using standard serum chemistry 
laboratory parameters. In both rats and dogs, persistent minimal to mild degeneration of the 
seminiferous tubules and decreased spermatozoa were present in male animals receiving 


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idelalisib. When co-administered with cyclophosphamide in rats, idelalisib did not worsen 
cyclophosphamide-mediated changes in hematological parameters. 
Data from completed 13-week GLP toxicology studies in rats and dogs are available. These 
data confirm the 28-day toxicology findings. Idelalisib was well tolerated with no notable 
clinical observation or changes in body weight at exposure levels approximating or 
exceeding those observed in subjects at the planned clinical starting dose of 150 mg/dose 
administered twice per day (BID). In both species, dose-dependent lymphoid depletion was 
observed that was consistent with PI3Kδ inhibition by idelalisib. In dogs, expected transient 
low-level elevations of serum ALT in 2 animals receiving the highest idelalisib dose were 
observed at Day 29 of the study; of note, animals showed spontaneous recovery during 
continued idelalisib dosing, with no elevations at Day 60 or Day 90. Microscopic review of 
dog tissues indicated no evidence of persistent or residual liver pathology at the conclusion of 
the study. Consistent with previous studies, findings of persistent hypospermatogenesis and 
decreased testicular weight were observed in both species. 
In an investigative study, a further characterization of the pattern of serum transaminase 
changes associated with administration of high-dose of idelalisib to dogs confirmed hepatic 
adaptation to the effect. In this study, mean serum ALT/AST values peaked at approximately 
Day 24 to Day 27 and resolved spontaneously as the dogs continued on idelalisib through the 
end of the study on Day 44. 
1.3.4.2. 
Genotoxicity 
idelalisib was not genotoxic in a standard battery of assays [Gilead Sciences 2011]. In the 
Ames assay, idelalisib did not cause mutagenic effects. In human peripheral blood 
lymphocytes, the compound induced no chromosomal aberrations. In a rat micronucleus 
study, idelalisib did not show evidence of clastogenicity. 
1.3.4.3. 
Reproductive Toxicology 
A definitive embryo-fetal developmental toxicity study of idelalisib was performed in 
time-mated pregnant female rats. Maternal toxicity was demonstrated by dose-dependent 
decreases in the body weight gains of the dams. Dose-dependent developmental findings 
included decreased fetal viability, greater numbers of early and late fetal resorptions, and 
reduced fetal weights. Dose-dependent external malformations included short tail or no tail in 
multiple fetuses, and 1 instance each of hydrocephaly and microphthalmia. The results of this 
study indicate that oral administration of idelalisib is embryolethal and teratogenic in rats at 
maternally toxic doses.   
As noted in Section 1.3.4.1, 28-day and 13-week general toxicology studies in rats and dogs 
indicated dose-dependent reductions in testicular weights, with persistent minimal to mild 
degeneration of the seminiferous tubules and decreased spermatozoa in rats and 
hypospermatogenesis in dogs. The impact of these testicular changes on fertility, if any, has 
not been assessed. 


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1.3.4.4. 
Phototoxicity  
In vitro studies in embryonic murine fibroblasts have yielded equivocal results relating to the 
phototoxicity of idelalisib but suggest that its major oxidative metabolite, GS-563117, may 
enhance cytotoxicity when cells are simultaneously exposed to ultraviolet light. While 
nonclinical findings suggest the hypothetical potential for phototoxicity in humans, available 
clinical data do not reveal a photosafety concern [Gilead Sciences 2012]. 
1.3.5. 
Idelalisib Clinical Studies 
1.3.5.1. 
Phase 1 Studies in Healthy Subjects and in Patients with Allergic Rhinitis 
Three studies in healthy subjects (Studies 101-01, 101-04, and 101-05) have provided 
information regarding drug safety, pharmacokinetics, food effects, and the potential for drug 
interactions with CYP3A4 inhibitors [Webb 2010, Gilead Sciences 2011]. One of these trials 
also included a preliminary evaluation of absorption, metabolism and excretion in healthy 
volunteers; in this trial, unlabeled idelalisib was co-administered with a trace amount of [14C] 
idelalisib given either orally or intravenously and biological samples were assessed by 
accelerator mass spectrometry. 
Safety results from these studies indicated that idelalisib was well tolerated when 
administered to healthy subjects at single doses through 400 mg (the highest dose level 
tested) and was also generally well tolerated when administered to healthy subjects over 
7 days at dose levels through 200 mg/dose BID (the highest dose level tested). Dosing with 
200 mg/dose BID for 7 days resulted in a skin rash in 3 out of 6 subjects; histological 
findings were consistent with a delayed-type hypersensitivity maculopapular exanthema. 
Rashes have sometimes occurred in patients with hematological malignancies receiving 
idelalisib, but have not typically proved dose- or treatment-limiting. In placebo-controlled 
single-dose and multiple-dose trials, repeated ECG evaluations performed in tandem with 
pharmacokinetic monitoring showed no evidence of drug-, dose-, or exposure-dependent 
effects on cardiac rhythm or cardiac intervals (eg, QT interval). 
Pharmacokinetic results indicated that increases in plasma idelalisib maximum concentration 
(Cmax) and area under the concentration-time curve (AUC) values were dose-proportional 
with increasing single-dose administration but less-than-dose-proportional with increasing 
multiple-dose administration. There was only modest accumulation with BID dosing over 
7 days. Consistent with mean half-life (t1/2) values in the range of 6 to 10 hours, steady state 
was achieved within 7 days of repeated dosing. Mean plasma idelalisib trough concentrations 
(Ctrough) exceeded target values known to be associated with pharmacological activity based 
on nonclinical testing. 
Ingestion of a high-fat, high-calorie meal just prior to administration of idelalisib moderately 
delayed absorption, increasing the drug’s median time of maximum concentration (Tmax) 
from 0.75 hours to 3 hours without altering mean Cmax. The aggregate effect was an increase 
of 1.4-fold in mean AUC. While the data indicate a food effect, the changes in idelalisib 
pharmacokinetics were modest; thus, idelalisib may be given with or without food. 


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When idelalisib was administered following 4 days of daily dosing with ketoconazole 
(a potent inhibitor of CYP3A4), increases in mean idelalisib Cmax and AUC values were 
1.3- and 1.8-fold, respectively. The data indicate that some alterations in idelalisib 
pharmacokinetics occur but that idelalisib is not a sensitive substrate for CYP3A4. Thus, 
co-administration of CYP3A4 inhibitors and idelalisib is not contraindicated and does not 
require special monitoring. 
The 14C-labeled idelalisib results showed that the drug has an oral bioavailability of 56%. 
Hepatic metabolism and biliary excretion appeared to be particularly important in idelalisib 
elimination. Consistent with the metabolism data from animal studies, an oxidation product 
was observed in human plasma and a hydrolyzed product was observed in urine and feces. 
[14C]- idelalisib-derived materials were primarily excreted in feces (>65% of total dose) with 
lesser elimination via urine (<15% of total dose). 
Pharmacodynamic results showed that a idelalisib dose of 200 mg inhibited ex vivo basophil 
activation via the PI3Kδ-specific, high-affinity immunoglobulin (Ig)E receptor (anti-FCεR1) 
in basophils collected from healthy volunteers. The findings were confirmed when the drug 
was assessed over 7 days in a Phase 1b study in subjects with allergic rhinitis. In this study, 
idelalisib at a dose level of 100 mg/dose BID showed clinical and pharmacodynamic activity 
(attenuating adverse responses to allergenic challenge and decreasing markers of 
inflammation) and was well tolerated. 
1.3.5.2. 
Phase 1 Studies in Patients with Hematological Malignancies 
1.3.5.2.1. 
Phase 1 Monotherapy Study in Patients with Hematological Malignancies 
A Phase 1 dose-ranging study (Study 101-02) of single-agent idelalisib extended safety and 
pharmacokinetic observations; documented the clinical and pharmacodynamic activity of 
idelalisib in subjects with iNHL, MCL, and CLL; and provided dosing information in support 
of further development [Brown 2011, Coutre 2011, Gilead 2011, Kahl 2011]. In this study, 
idelalisib was administered in cohorts of subjects across a range of dose levels from 
50 mg/dose BID to 350 mg/dose BID. Idelalisib administration was continued as long as 
individual subjects were safely benefitting from therapy. Subjects were evaluated in 4-week 
cycles; response and progression assessments were based on standard criteria [Hallek 2008]. 
Altogether, 192 subjects were enrolled to the study, including 55 subjects with CLL. As 
expected given the demographics of these diseases, subjects were predominantly male and 
were often elderly, ranging in age to 82 years for the subjects with CLL. The majority (82%) 
of the subjects with CLL had bulky tumors (≥1 lymph node ≥5 cm in diameter) and 31% had 
the adverse prognostic factor of a 17p chromosomal deletion (which commonly confers a 
p53 mutation in the tumors of these subjects). Subjects were heavily pretreated with 
chemoimmunotherapy; the median number of prior therapies by disease was 5 among 
subjects with CLL, but ranged up to 15 prior treatments. Among those with CLL, prior 
rituximab, alkylator, and fludarabine use were nearly universal and 33% had received prior 
alemtuzumab. Considering only rituximab use after initial therapy, 35% had received 


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single-agent rituximab at least once (some patients up to 3 times) and a total of 51/54 (94%) 
had received rituximab given alone or in combination with other agents. In the estimation of 
the investigators, a substantial proportion (72%) of these subjects had disease that was 
refractory to the last prior therapy. In these subjects, therapy was administered for a median 
of 9 cycles, ranging up to 24 cycles (ie, 96 weeks). 
In this single-agent experience, idelalisib was generally well tolerated at dose levels through 
350 mg BID (the highest dose tested). No maximum tolerated dose (MTD) was apparent 
within the tested dose range. Furthermore, subjects typically found the drug tolerable over 
periods extending to >2 years; there was no profile suggestive of bothersome chronic events 
such as headache, nausea, diarrhea, or fatigue. No subject had tumor lysis syndrome. No 
overt pattern of myelosuppression was associated with idelalisib treatment. The data also did 
not suggest drug-related reductions in circulating CD4+ cells or serum Igs. 
Among Grade 3-4 nonhematological adverse events, pneumonia/pneumonitis was observed 
most frequently, occurring in 24% of subjects with CLL. In most instances, these cases were 
considered bacterial in origin, based either on culture results or on response to conventional 
antibiotics. Subjects with CLL have occasionally been diagnosed with Pneumocystis (carinii) 
jiroveci pneumonia; the specific causal role of idelalisib has been difficult to elucidate 
because infection was sometimes present before starting idelalisib or the subjects had other 
pre-existing risk factors. Such subjects were not receiving pneumocystis prophylaxis. The 
rate of pneumonia over time (0.045 events/subject/month) with idelalisib was not worse than 
the expected rate (0.06 events/patient/month) reported historically in comparable patients 
with recurrent CLL [Perkins 2002]. 
Monitorable, reversible elevations of hepatic transaminases were observed in some subjects; 
~5% of subjects with previously treated CLL had Grade 3-4 increases in serum ALT or AST. 
The onset of changes was time-dependent; among those with serum ALT/AST abnormalities, 
onset typically occurred 2 to 8 weeks after idelalisib initiation. In subjects with Grade 1-2 
events, serum ALT/AST elevations resolved despite continued idelalisib dosing. In subjects 
with Grade 3-4 events, idelalisib was temporarily interrupted. Upon resolution of serum 
ALT/AST abnormalities, resumption of idelalisib at a reduced dose did not result in 
recurrence of serum transaminase increases in the majority (>70%) of subjects who were 
rechallenged. This pattern suggests an adaptation to the effect similar to that observed in 
dogs receiving idelalisib. Such an adaptive response is commonly observed with other drugs 
that induce transaminase elevations [Tujios 2011]. 
Idelalisib proved highly active in subjects with CLL, iNHL, and MCL. Among subjects with 
CLL, idelalisib reduced lymphadenopathy in all 51 (100%) of those with 1 post-treatment 
tumor assessment. In subjects with CLL tumors having a known 17p chromosomal deletion, 
substantial antitumor activity was observed, although PFS appeared shorter in these subjects 
relative to other trial participants without such a deletion or in whom the 17p chromosomal 
deletion status was unknown. 


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The pattern of changes in CLL was particular notable. Rapid and substantial reductions in 
lymph node size were observed in subjects with CLL with >80% of subjects showing a 
lymph node response (≥50% reductions in index nodal lesions). Among subjects who entered 
the trial with baseline thrombocytopenia or anemia, idelalisib induced sustained increases in 
mean platelet counts and hemoglobin levels. In study participants who entered the study with 
enlarged spleens due to CLL, >70% showed a resolution in splenomegaly. The median PFS 
was 14 months, with some subjects having tumor controlling for durations exceeding 2 years. 
Antitumor activity and tumor control were longest in subjects starting idelalisib at doses of 
≥150 mg/dose BID. 
A characteristic finding in the single-agent experience was that the majority of subjects had 
an initial increase in peripheral absolute lymphocyte count (ALC) from baseline. The 
increase was maximal during the first 2 cycles and generally decreased thereafter but could 
be persistent in some subjects or could be seen repeatedly in subjects who had interruption 
and resumption of drug therapy (eg, due to intercurrent illness). The characteristics of this 
lymphocytosis indicated a mobilization of CLL cells from tissues rather than a proliferative 
event or a disease flair. The effect was evident within 4 hours of initiating treatment, was 
asymptomatic, and was associated with quiescence of CLL cells as indicated by reductions in 
AKT phosphorylation and decreases in circulating levels of disease-associated chemokines, 
CCL3 and CCL4, and the stroma-derived chemokine, CXCL13. The lymphocyte 
mobilization phenomenon is consistent with in vitro data showing that idelalisib depresses 
chemokine-mediated signaling between CLL cells and stromal cells [Hoellenriegel 2011]. 
These preclinical data support the concept that drug-mediated PI3Kδ inhibition releases CLL 
cells from sanctuary sites in lymph nodes and bone marrow. This action is not unique to 
idelalisib alone. Drugs that inhibit spleen tyrosine kinase (SYK) [Friedberg 2010], Bruton 
tyrosine kinase (BTK) [Burger 2010a], or mTOR [Zent 2010] cause a CLL cell redistribution 
from tissue sites to the peripheral blood. Because of the occurrence of this type of pattern, 
investigators working with idelalisib or inhibitors of these other pathways now rely upon 
measures of disease control other than peripheral blood lymphocyte count in determining 
whether a patient’s disease has progressed. 
An analysis of steady-state idelalisib plasma concentrations (Day 28 Cmax, AUC0-6h, or 
Ctrough) relative to dose in subjects with both NHL and CLL showed increases in these 
parameters through the dose level of 150 mg/dose BID. At higher doses, flattening of the 
mean dose-plasma exposure curve was observed, resulting in smaller incremental increases 
in exposure. Considering all safety, efficacy, and pharmacokinetic findings together, the data 
supported 150 mg/dose BID as an appropriate idelalisib monotherapy starting dose for future 
studies in patients with CLL and other lymphoid malignancies. 
1.3.5.2.2. 
Phase 1 Combination Study in Patients with Hematological Malignancies 
A separate Phase 1 trial (Study 101-07) has evaluated the safety and preliminary activity of 
idelalisib given in combination with rituximab to subjects with recurrent iNHL or CLL 
[Brown 2011, Leonard 2011]. 


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In this study, rituximab was administered at a standard dose of 375 mg/m2 per infusion 
weekly for 8 weeks in all subjects. Idelalisib was started simultaneously with the rituximab, 
first at a dose level of 100 mg/dose BID (n=13) and then at a dose level of 150 mg/dose BID 
(n=12) and was administered continuously to both subjects with CLL (n=13) and subjects 
with iNHL (n=12) for as long as individual subjects were safely benefiting from therapy. 
Subjects were evaluated in 4-week cycles; response and progression assessments were based 
on standard criteria [Hallek 2008]. 
Among the subjects with CLL, the median age was 63 and ranged to 85 years. Bulky tumors 
(≥1 lymph node ≥5 cm in diameter) were present in 63% of the subjects. The median number 
of prior therapies by disease was 2 and ranged up to 8 prior treatments. All had received prior 
rituximab and the majority had received prior fludarabine or alkylating agents. 
Approximately one-third of subjects had CLL that was refractory to the last prior therapy. At 
the time of data cut-off, therapy had been administered for a median of 5 cycles, ranging up 
to 12 cycles (ie, 48 weeks). 
No idelalisib-related dose-limiting toxicities were observed within the tested subject cohorts. 
Grade 3-4 adverse events largely comprised background events resulting from pre-existing 
disease- or treatment-related conditions or from intercurrent illness. Among subjects with 
CLL, 2 (15%) developed pneumonia. For subjects receiving idelalisib together with 
rituximab, Grade 3-4 elevations in ALT/AST were not observed in those with CLL, although 
3 subjects (25%) of those with iNHL had such events. 
The idelalisib plus rituximab combination showed a high level of antitumor activity in both 
subjects with CLL and those with iNHL. Altogether 92% of subjects with CLL receiving the 
combination of idelalisib and rituximab had reductions in nodal size and 77% showed a 
lymph node response (≥50% reduction in index nodal lesions). Although concomitant 
administration of rituximab did not eliminate the redistribution lymphocytosis that is 
associated with idelalisib, it blunted the magnitude of the change. As a result, the overall 
response rate (ORR) was also 77% among subjects participating in this study. At the time of 
last data analysis, PFS through 48 weeks was 70% and a median PFS had not yet been 
observed. 
Collectively, the emerging data from this study support further evaluation of idelalisib 
together with rituximab in subjects with CLL and indicate that co-administration of idelalisib 
with rituximab is tolerable when using idelalisib at full dose, ie, at a starting dose level of 
150 mg/dose BID. 
1.4. 
Summary and Justification for the Current Study 
Gilead Sciences is conducting this Phase 3 study program to evaluate the efficacy and safety 
of idelalisib in patients with previously treated, recurrent CLL. Collectively the data derived 
from the primary clinical trial (Study GS-US-312-0116) and from this extension trial 
(Study GS-US-312-0117) address the activity of idelalisib together with rituximab, the 


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activity of idelalisib when given alone, and the potential for dose-dependent restoration of 
drug activity in subjects who have disease that appears to be drug resistant. 
The design and conduct of this clinical trial program is supported by knowledge of the 
demographics of patients with CLL, the natural history and current therapies for the disease, 
and the nonclinical and clinical information regarding idelalisib. The collective data support 
the following conclusions: 
• CLL is a serious, disabling, and potentially life-threatening disorder of older patients that 
requires sequential treatment with agents that provide alternative mechanisms of tumor 
control. Existing cytotoxic agents have serious acute and chronic toxicities, making them 
less suitable for frail or unfit patients. Single-agent rituximab can offer disease palliation 
with good tolerability in some patients with relapsed CLL but tumor control is not 
lasting, especially in patients with bulky adenopathy. Development of a non-cytotoxic 
combination therapy of idelalisib with rituximab or a monotherapy regimen of idelalisib 
that can address disease pathogenesis with a new mechanism of action and might offer 
complementary nodal and peripheral blood activity would address an unmet medical 
need, particularly when applied in patients with substantial comorbidities or 
myelosuppression from prior chemotherapies. 
• PI3Kį over-expression plays an important role in CLL biology. Further evaluation of 
idelalisib as a potential treatment for CLL has sound scientific rationale founded on 
knowledge of the actions of the drug to selectively abrogate PI3Kį activity and to inhibit 
malignant cell growth and stromal cell signaling in nonclinical models of CLL. These 
data are supported by clinical documentation of idelalisib inhibition of PI3Kį signaling in 
patients with CLL. 
• The potential for clinical efficacy of idelalisib monotherapy or of idelalisib plus 
rituximab in patients with relapsed or refractory CLL is supported by the observed 
antitumor activity of idelalisib – given alone or in combination with rituximab – in 
patients with heavily pretreated CLL and iNHL. 
• The safety of advancing development of the idelalisib monotherapy and of a regimen of 
idelalisib plus rituximab in this Phase 3 clinical trial program is well supported by safety 
pharmacology and toxicology studies and by Phase 1 single-agent and combination safety 
data obtained in healthy volunteers and in subjects with lymphoid cancers.  
• Dose-safety, dose-exposure, and dose-activity relationships identified in Phase 1 studies 
have established a firm basis for the dosing regimen and dose modification provisions in 
this study. 
• Observations relating to patterns of CLL response among subjects receiving idelalisib 
alone or in combination with rituximab in Phase 1 trials provide the foundation for 
efficacy monitoring in this trial. Of particular note is that idelalisib mobilizes CLL cells 
from tissues into the peripheral blood. This characteristic pharmacological action is 


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prominent early in therapy but can persist over time and should not be confused with 
disease progression in patients who have persistent control of other CLL-related signs 
and symptoms. For this reason, in this Phase 3 study program, subjects will be continued 
on therapy until the occurrence of definitive disease progression, ie, disease progression 
that is manifest by worsening CLL-related signs or symptoms other than lymphocytosis 
alone.  
• Thorough nonclinical and clinical characterization of the type, severity, manifestations, 
and expected timing of adverse events establish the safety monitoring plan in this trial 
program. 
• The scientific correlative work performed in prior preclinical and clinical studies 
provides strong scientific underpinnings for the companion laboratory studies to be 
performed as a component of this clinical trial program. 
• Given the seriousness of previously treated CLL in patients with substantial comorbidity, 
and the aggregate potential benefits considered in the context of potential risks, further 
development of idelalisib in this Phase 3 clinical trial program is justified. 
The rationale for specific design features is provided in relevant sections of the protocol, 
including Section 3.2 (Endpoint Selection Rationale), Section 2.2 (Design Rationale), 
Section 4.3 (Enrollment Criteria Rationale), Section 5.10 (Study Treatment Rationale), and 
Section 6.4 (Study Procedure Rationale). 


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2. 
STUDY DESIGN 
2.1. 
Design Overview and Study Schema 
This study is being conducted as part of an overall clinical program that is evaluating the 
efficacy and safety of idelalisib in the therapy of patients with previously treated CLL 
(see Figure 2-1). Within this program, the primary clinical trial (Study GS-US-312-0116) is a 
Phase 3, multicenter, 2-arm, randomized, double-blind, placebo-controlled, parallel-group 
study. This clinical trial (Study GS-US-312-0117) is a separate, multicenter, 2-arm, 
double-blind, parallel-group extension study that is a companion study to the primary study. 
Figure 2-1. 
Study Design 
Randomized
Double-Blind
Initial Therapy
Idelalisib, 150 mg BID
Until PD
Placebo BID 
Until PD
Disease 
progression
Double-Blind
Continuing  Therapy
Double-Blind
Extension
Therapy
Idelalisib, 150 mg BID
R, 375 mg/m2 Wk 0
R 500 mg/m2 Wk 2,4,6,8,12,16,20
Stratification and 
Randomization
Idelalisib, 150 mg BID
Until PD
Idelalisib, 300 mg BID
Until PD
Placebo
R, 375 mg/m2 Wk 0
R 500 mg/m2 Wk 2,4,6,8,12,16,20
Screening
Primary Study
Study GS-US-312-0116
Extension Study
Study GS-US-312-0117
Arm A
N=80
Arm B
N=80
 
 
Candidates for the primary study will be adults with previously treated recurrent CLL who 
have measurable lymphadenopathy, require therapy for CLL, have experienced CLL 
progression <24 months since the completion of the last prior therapy, and are currently not 
sufficiently fit to receive cytotoxic therapy because of chemotherapy-induced bone marrow 
damage or comorbidities. 
Primary study subjects will be stratified based on 17p deletion and/or a p53 mutation status 
(either vs neither), immunoglobulin heavy chain variable region (IgHV) mutation status 
(unmutated vs mutated), and any prior therapy with an anti-CD20 therapeutic monoclonal 
antibody (yes vs no) and randomized in a 1:1 ratio to receive 1 of the 2 treatment arms.  
In the primary study, subjects will be administered rituximab intravenously in the clinic 
starting at a dose of 375 mg/m2 on Day 1 (Week 0) and will continue with a dose of 
500 mg/m2 on Day 15 (Week 2), Day 29 (Week 4), Day 43 (Week 6), Day 57 (Week 8), 
Day 85 (Week 12), Day 113 (Week 16), Day 141 (Week 20) (for a total of 8 infusions). 
Rituximab will be administered until the earliest of subject withdrawal from study, definitive 


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progression of CLL, intolerable rituximab-related toxicity, pregnancy, substantial 
noncompliance with study procedures, study discontinuation, or a maximum of 8 infusions. 
Idelalisib or placebo will be taken orally, BID continuously.  Subjects will continue 
whichever study drug (idelalisib/placebo or rituximab) continues to be tolerated, even if the 
other drug has been discontinued due to toxicity. 
If permanent discontinuation of study drug, occurs prior to definitive progression of CLL, 
subjects shall remain on study until definitive progression of CLL or withdrawal from the 
study for reasons specified in Section 5.7 
Compliant subjects who are tolerating therapy but who develop definitive disease 
progression in the primary clinical trial (Study GS-US-312-0116) can consider enrollment in 
this separate companion extension trial (Study GS-US-312-0117). In the extension trial, 
subjects will take active blinded idelalisib therapy, either at a higher starting dose or at the 
standard starting dose, with allocation based on the original primary study randomization. 
The primary objective of Study GS-US-312-0116 will be to evaluate the effect of the 
addition of idelalisib to rituximab on PFS. Secondary and tertiary objectives will focus on 
determining the effect of the addition of idelalisib to rituximab on the onset, magnitude, and 
duration of tumor control; overall survival (OS); health-related quality of life (HRQL); 
changes in subject performance status; disease-associated biomarkers and potential 
mechanisms of resistance; treatment administration; safety; and health resource utilization. In 
Study GS-US-312-0117, the same endpoints will be assessed as in Study GS-US-312-0116; 
the focus of the analysis will be largely descriptive except for the within-subject assessment 
of treatment effects among subjects receiving first rituximab alone and then idelalisib alone 
on Arm B of each trial. No formal comparisons of outcomes in Arm A vs Arm B are planned 
within Study GS-US-312-0117. 
2.2. 
Design Rationale 
The randomized, add-on design for the primary trial (Study GS-US-312-0116) is customary 
in the comparative evaluation of new therapies for cancer. While this design provides 
idelalisib efficacy and safety information only in the context of administration of a 
companion antineoplastic agent, it is appropriate because it documents the incremental 
benefit and toxicity of the investigational therapy in the context of a controlled clinical trial 
while ensuring that all participants receive potentially active treatment. 
This separate extension trial (Study GS-US-312-0117) enhances subject acceptance of 
randomization in the primary study and provides further information regarding idelalisib 
efficacy, resistance, and safety. Among subjects in Arm A, escalation to a higher dose level 
allows evaluation of dose-dependent resistance and a determination if a higher dose can 
reestablish disease control. The safety data obtained in these subjects will add to the overall 
safety database. Among subjects randomized to Arm B in the primary study, evaluation of 
idelalisib at a starting dose of 150 mg/dose BID in the extension study may permit a 
within-subject assessment of the treatment effects with single-agent idelalisib relative to the 


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effects previously observed with rituximab alone. Of importance, the extension study 
maintains the partial blinding of the primary study, thus minimizing the bias that might occur 
if the overall design entailed only a 1-way crossover to open-label idelalisib among subjects 
who had received placebo on Arm B of the primary study. To ensure confirmation of disease 
progression, tumor size data collected from the primary study will be subjected to 
independent review by an independent review committee (IRC) (see Section 10.4.3); subjects 
will continue with study therapy pending confirmation of progression status by the sponsor 
working in collaboration with the IRC. Subjects must have confirmation that the disease has 
progressed on the primary study before being permitted to receive secondary idelalisib 
therapy on the extension study. 


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3. 
OBJECTIVES AND ENDPOINTS 
• To evaluate the effect of idelalisib on the onset, magnitude, and duration of tumor control 
• To compare tumor control in subjects receiving rituximab alone in Study 
GS-US-312-0116 to that observed in the same subjects when receiving the standard dose 
of idelalisib alone in Study GS-US-312-0117 
• To assess the effect of idelalisib on measures of subject well-being, including overall 
survival (OS), health-related quality of life (HRQL), and performance status 
• To assess the effects of idelalisib on disease-associated biomarkers and to evaluate 
potential mechanisms of resistance to idelalisib 
• To characterize exposure to idelalisib as determined by treatment administration and 
evaluation of idelalisib plasma concentrations over time 
• To describe the safety profile observed with idelalisib  
• To estimate health resource utilization associated with administration of idelalisib 
3.1. 
Endpoints 
3.1.1. 
Tumor Control 
• Progression-free survival (PFS) – defined as the interval from the start of study therapy to 
the earlier of the first documentation of definitive disease progression or death from any 
cause; definitive disease progression is CLL progression based on standard criteria other 
than lymphocytosis alone 
• ORR – defined as the proportion of subjects who achieve a CR or partial response (PR)  
• Lymph node response rate – defined as the proportion of subjects who achieve a ≥50% 
decrease from baseline in the SPD of index lymph nodes 
• CR rate – defined as the proportion of subjects who achieve a CR 
• Time to response (TTR) – defined as the interval from start of study therapy to the first 
documentation of CR or PR 
• Duration of response (DOR) – defined as the interval from the first documentation of CR 
or PR to the earlier of the first documentation of definitive disease progression or death 
from any cause 


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• Percent change in lymph node area – defined as the percent change from baseline in the 
sum of the products of the greatest perpendicular diameters (SPD) of index lymph nodes 
• Splenomegaly response rate – defined as the proportion of subjects with a 50% decrease 
from baseline (minimum decrease of 2 cm) in the enlargement of the spleen in its LVD or 
to ≤12 cm by imaging, or regression to a spleen LVD of ≤0 cm by physical examination  
• Hepatomegaly response rate – defined as the proportion of subjects with a 50% decrease 
(minimum decrease of 2 cm) from baseline in the enlargement of the liver in its LVD or 
to ≤18 cm by imaging, or regression to a liver LVD of ≤15 cm by physical examination  
• ALC response rate – defined as the proportion of subjects with baseline lymphocytosis 
(ALC≥4 x 109/L) who achieve an on-study ALC <4 x 109/L or demonstrate a ≥50% 
decrease in ALC from baseline 
• Platelet response rate – defined as the proportion of subjects with baseline 
thrombocytopenia (platelet count <100 x 109/L) who achieve an on-study platelet count 
≥100 x 109/L or demonstrate a ≥50% increase in platelet count from baseline 
• Hemoglobin response rate – defined as the proportion of subjects with baseline anemia 
(hemoglobin <110 g/L [11.0 g/dL]) who achieve an on-study hemoglobin ≥110 g/L 
(11.0 g/dL) or demonstrate a ≥50% increase in hemoglobin from baseline 
• Neutrophil response rate – defined as the proportion of subjects with baseline neutropenia 
(absolute neutrophil count [ANC] <1 x 109/L) who achieve an ANC ≥1 x 109/L or 
demonstrate a ≥50% increase in ANC from baseline 
3.1.2. 
Patient Well-Being 
• Overall survival (OS) – defined as the interval from start of study therapy to death from 
any cause 
• Change from baseline in HRQL domain and symptom scores based on  the Functional 
Assessment of Cancer Therapy: Leukemia (FACT-Leu) (see Appendix 2)  
• Changes from baseline in Karnofsky performance status – defined as the change from 
baseline in the performance status (see Appendix 3)  
3.1.3. 
Pharmacodynamic Markers of Drug Activity and Resistance 
• Changes from baseline in PI3K/AKT/mTOR pathway activation as a measure of PI3Kδ 
pathway activity 
• Changes from baseline in the plasma concentrations of disease-associated chemokines 
and cytokines 


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3.1.4. 
Exposure 
• Study drug administration as assessed by prescribing records and compliance as assessed 
by quantification of used and unused drug 
• Trough (pre-dose) and peak (1.5-hour samples) of idelalisib plasma concentrations as 
assessed by a validated bioanalytical method 
3.1.5. 
Safety 
• Overall safety profile of each study treatment regimen characterized by the type, 
frequency, severity, timing of onset, duration, and relationship to study therapy of any 
adverse events or abnormalities of laboratory tests; serious adverse events; or adverse 
events leading to discontinuation of study drug 
3.1.6. 
Pharmacoeconomics 
• Change in health status – defined as the change from baseline in overall health and 
single-item dimension scores as assessed using the EuroQoL Five-Dimension (EQ-5D) 
utility measure (Appendix 4) 
• Health resource measures, including resource utilization, total costs, and measures of cost 
per unit of benefit (eg, cost per additional progression-free month, cost per 
quality-adjusted life-year) 
3.2. 
Endpoint Selection Rationale 
The proposed endpoints have been chosen based on relevance to the pathophysiology and 
clinical manifestations of CLL, the known pharmacology of idelalisib, and the goals of the 
study in documenting idelalisib benefit-to-risk ratio. These types of endpoints have been 
employed in prior studies in CLL and can be evaluated with acceptable reliability and 
accuracy. 
3.2.1. 
Tumor Control Endpoints 
Assessments of the magnitude and duration of changes in tumor size are routinely employed 
in registration-directed oncology clinical studies to determine therapeutic effect. Unlike OS, 
these endpoints directly assess the ability of the drug to control the malignancy. Such 
assessments are also integral to treatment decisions; because subjects are being treated until 
disease progression, repeated tumor assessment must be performed in order to define the 
proper duration of treatment for each study participant. Standard response and progression 
criteria have been established by the International Workshop on CLL (IWCLL) 
[Hallek 2008]; the assessments of treatment effects in this study will be based on these 
criteria, taking into account the specific pharmacology of idelalisib. 


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In CLL, disease-related nodal enlargement is a major cause of patient discomfort and can 
cause organ dysfunction [Dighiero 2008]. Extensive lymphadenopathy constitutes a reason to 
treat CLL and controlling the size of pathologically enlarged lymph nodes is an important 
therapeutic goal for improving patient well-being and relieving obstructive symptoms 
[Hallek 2008]. Given that the natural history of recurrent CLL is inexorable nodal growth, 
enhancing tumor shrinkage and prolonging tumor control provides strong evidence of 
pharmacological activity.  
Endpoints of overall tumor control as evaluated in this trial are customarily assessed and 
reported in studies of new therapies in patients with cancer. PFS offers a well established 
outcome measure that directly measures treatment effect, conveys important longitudinal 
information regarding tumor control, can be characterized in all subjects using intention-to-
treat (ITT) principles, and is readily analyzed using statistical methods such as Kaplan-Meier 
techniques. ORR provides an integrated assessment of the magnitude and extent of changes 
in lymphadenopathy, organomegaly, bone marrow infiltration, and bone marrow function 
that conveniently categorizes and describes treatment effects. TTR and DOR are important in 
characterizing the rapidity of achieving tumor shrinkage and the duration of tumor control. 
Beyond providing descriptions on overall response assessment using ORR, this protocol will 
also seek to characterize the individual components of response that are important in 
assessment of CLL [Hallek 2008]. Thus, changes in lymph node area and in the proportion of 
subjects having a lymph node response will be analyzed. In addition, among subjects who 
enter the study with splenomegaly or hepatomegaly, the proportion who achieve substantial 
(≥50%) reductions in spleen or liver size will be assessed. Similarly, the proportions of 
subjects who experience improvements in ALC, platelets, hemoglobin, and neutrophil counts 
will be characterized in order to provide specific insight into the degree to which therapy 
alters these individual parameters.  
Because idelalisib mobilizes CLL cells from tissues into the peripheral blood as part of its 
pharmacological effect, there is a risk of falsely declaring a subject to have experienced 
disease progression if lymphocyte count is considered as the sole basis for potential CLL 
worsening. To account for this potential problem, changes in lymphocyte count will not be 
considered in determining whether a subject has progressive disease, ie, subjects will only be 
declared to have progressive CLL if they meet any of the IWCLL criteria for progressive 
disease other than lymphocytosis alone. Thus, subjects with worsening lymphadenopathy, 
organomegaly, bone marrow involvement, progressive cytopenias, appearance of new 
disease, or transformation to an aggressive lymphoid malignancy histology 
(eg, Richter syndrome) will be considered to have progressed. Subjects with lymphocytosis 
without any of these other events will not be considered to have progressed. Given that 
lymphocytosis has no prognostic significance in patients with relapsed/refractory disease 
[Silverman 2002, Tsimberidou 2007] and is not generally considered a reason to treat in 
patients with CLL [Hallek 2008, Eichhorst 2010, Zelenetz 2011], this approach does not 
jeopardize subject safety or subsequent therapy. Furthermore, it will allow complete 
collection of all response and progression data (both considering lymphocytosis and ignoring 
lymphocytosis) with the intent of providing complete information for regulatory authority 
review. 


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The current IWCLL guidelines indicate that physical examination is generally sufficient to 
evaluate nodal response and progression in patients with CLL [Hallek 2008] but that 
radiographic assessments may be appropriate in clinical trials. Computed tomography (CT) is 
considered the preferred imaging method unless patients have contraindications that require 
use of magnetic resonance imaging (MRI). Given the low fluorodeoxyglucose (FDG) avidity 
of CLL, positron- emission tomography (PET) does not have a role in evaluation of this 
disease. The incremental benefits of using radiographic imaging are limited in patients 
undergoing long-term follow-up following first-line therapy [Blum 2007, Eichhorst 2011]. 
However, in the patients with advanced CLL and bulky adenopathy such as those who will 
be enrolled to this trial, it is known that CT scans commonly detect bulky intra-abdominal 
lymphadenopathy and splenomegaly that would be missed by palpation alone and that the 
presence of large-volume, intra-abdominal disease of the nodes and spleen is associated with 
a poor prognosis [Norin 2010]. Thus, while use of CT confers greater radiation exposure, 
subjects have the chance to benefit from radiographic imaging because it will offer more 
accurate information regarding their response to protocol therapy and the appropriate 
duration of protocol treatment. Having this information is particularly important in this trial 
because PI3Kδ inhibition precludes use of lymphocyte counts as evidence for disease 
progression. In addition, the risk is offset by the fact that the trial subjects will primarily be 
patients who have already received more potent mutagens (eg, purine analogs, alkylating 
agents), and all of whom have advanced cancer and limited treatment options at study entry. 
Based on published data [Keating 2002, Wierda 2010], median OS for patients with 
comparably advanced CLL is <18 months, so the long-term secondary malignancy risk from 
CT-related radiation exposure is very low. Finally, in the context of a registration-directed 
pivotal trial of a new drug with a new mechanism of action, radiographic imaging is critically 
important to provide reassurance regarding subject safety and trial validity. In this regard, CT 
evaluations of the lung can be used retrospectively to assess for radiographic evidence of 
drug-induced lung changes [White 2010, Maroto 2011]. Furthermore, CT measurements 
have greater accuracy and reproducibility than palpation, are subject to independent expert 
review, and can be audited against electronic case report form (eCRF) information. 
The timing of radiographic tumor assessments has been carefully considered. To avoid 
duplication, the CT scan documenting CLL progression in Study GS-US-312-0116 will serve 
as the baseline CT scan for Study GS-US-312-0117. Among patients receiving idelalisib in 
Phase 1b/2 studies who experienced a nodal response (≥50% regression in tumor area), such 
responses were observed with the first 16 week of therapy [Coutre 2011, Leonard 2011]; the 
planned timing of tumor assessments (at Weeks 8, 16, 24, 36, 48 and then every 12 weeks on 
thereafter) in this study fits with this known timing of changes in lymph node size during 
idelalisib therapy. Scans at 8-week intervals during the first 24 weeks allow efficient 
documentation of response. During this period, early documentation of disease progression 
allows subjects who are not benefiting from study therapy to move rapidly to alternative 
treatments. After 24 weeks on study, the reduction in the frequency of CT scans (to 12-week 
intervals) reduces the overall protocol burden for subjects while still allowing 
characterization of the expected median PFS in this trial. As outlined in Section 7.3, 
iodine-containing or gadolinium contrast material may be omitted in subjects for whom use 
of a contrast agent would be medically contraindicated. 


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3.2.2. 
Measures of Patient Well-Being 
3.2.2.1. 
Overall Survival 
While OS provides an ultimate measure of patient well-being, it has not routinely been used 
as the primary endpoint in CLL clinical trials. Unlike PFS, it does not specifically measure 
drug-mediated tumor control, and thus provides only an indirect assessment of treatment 
effect. Depending upon the treatment setting, long OS times in patients with CLL can 
preclude use of this endpoint as an efficient method for understanding drug benefits. In both 
the front-line and recurrent disease settings, post-study treatments can influence OS in 
unpredictable ways, potentially confounding differences between treatment groups. 
However, given the life-threatening nature of systemic malignancy, documentation of OS is 
customary in oncology therapeutic clinical trials, including those evaluating subjects with 
recurrent CLL [Keating 2002, Wierda 2010]. Evaluation of OS in this study continues the 
survival assessment from the primary study (Study GS-US-312-0116). The study program as 
a whole (considering both the primary randomized trial and secondary extension study) 
offers the potential to better understand OS and causes of death in a frail population of 
patients with both CLL, considering the consequences of the disease and comorbidities. 
3.2.2.2. 
Health-Related Quality of Life 
Direct patient reporting of outcomes using standardized methods has become an increasingly 
important component of therapeutic assessment. Evaluation of patient-reported outcomes 
(PROs) is particularly relevant in patients who cannot be cured of disease [Fairclough 2002]. 
PRO questionnaires have been previously used in CLL to understand how patients differ 
from the general population in terms of health concerns [Holzner 2004, Eichhorst 2007, 
Shanafelt 2007, Else 2008], to understand differences in perceptions of well-being in younger 
vs older patients [Levin 2007, Else 2008], to determine how treatment affects HRQL 
[Catovksy 2007, Eichhorst 2007, Efficace 2008], and to assess the pharmacoeconomic cost 
of improvements in HRQL [Stephens 2005]. 
Patients with CLL have overtly impaired well-being relative to comparable controls 
[Holzner 2004, Eichhorst 2007, Shanafelt 2007, Else 2008]. Fatigue is cited as a common 
complaint, being present in the substantial majority of patients. Impairment of HRQL prior to 
any treatment is apparent in those with B symptoms or in patients with anemia, supporting 
the concept of initiating treatment when patients experience symptomatic disease. Factors 
associated with lower overall HRQL have included older age, greater fatigue, severity of 
co-morbid health conditions, advanced stage, and ongoing treatment for CLL 
[Shanafelt 2007]. Younger patients appear to have worse emotional and social well-being but 
older patients experience worse physical HRQL [Levin 2007]. In comparative evaluation of 
chemotherapy-containing regimens, differences in HRQL between therapies (eg, fludarabine 
vs fludarabine-cyclophosphamide vs chlorambucil) reflected differences in toxicity while 
improved HRQL was associated with greater efficacy [Catovksy 2007, Eichhorst 2007]. 


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In this study, it is postulated that idelalisib-mediated tumor control will be correlated with 
greater positive changes in HRQL and that assessments of the drug’s safety profile will be 
supported by HRQL evaluations. The FACT-Leu (Appendix 2) has been selected to evaluate 
such outcomes for the study. The FACT-Leu comprises a general HRQL measure for patients 
receiving cancer treatment that yields a total score and subscales for physical, functional, 
social/family and emotional well-being [Cella 1993] and a diagnosis-specific measure for 
patients with leukemia [Webster 2002]. The FACT-Leu was developed to assess symptoms 
(eg, fevers, chills, night sweats, nodal swelling, fatigue) specifically relevant to patients with 
leukemia. FACT instruments have documented psychometric properties [Cella 1993, 
Webster 2002, Brucker 2005, Cella 2005, Victorson 2008]. 
The FACT-Leu instrument is available in appropriate languages for this study. FACT-Leu 
data will be obtained at baseline and during each investigational clinic visit during treatment. 
Having FACT-Leu data concurrent with tumor response information will allow an evaluation 
of the potential relationship between tumor response and symptomatic changes as reported by 
patients. To avoid biasing HRQL results, the FACT-Leu will be administered at each visit 
before other procedures are performed and before any study information is conveyed to the 
subject. 
3.2.2.3. 
Changes in Performance Status 
Performance status evaluation provides an integrated assessment of patient well-being 
before, during, and after treatment and, ideally, may indicate how drug efficacy and toxicity 
affect patient functioning. In patients with CLL performance status can be predictive of PFS 
or OS [Sorensen 1997, Hallek 1996, Youngson 1995]. 
In this study, it is hypothesized that idelalisib-mediated tumor control will be correlated with 
changes in performance status and that assessments of the drug’s safety profile might be 
supported by performance status evaluations. The well-established, reliable, and validated 
Karnofsky performance score [Karnofsky 1949, Yates 1980, Schag 1984] (see Appendix 3) 
will be employed in the trial for characterization of the subject population and repeated 
assessment of performance status. 
3.2.3. 
Pharmacodynamic Markers of Drug Activity and Resistance 
In CLL, disease-related perturbations in inflammatory status can be clinically overt; patients 
often develop bothersome B symptoms (fevers, night sweats, and weight loss) that are 
characteristic of excessive systemic inflammation [Redaelli 2004]. Consistent with such 
disease manifestations, the PI3Kδ/AKT/mTOR pathway is constitutively overactive in 
circulating CLL cells [Coutre 2011]. In addition, chemokines and cytokines that are markers 
of aberrant B-cell trafficking or perturbations in inflammation are overexpressed by CLL 
tissues or by stromal cells and circulate in plasma [Burger 2010b, Coutre 2011]. In Phase 1 
studies of idelalisib it has been confirmed that idelalisib largely normalizes AKT 
phosphorylation and induces dose-dependent reductions in plasma concentrations of 
circulating chemokines and cytokines in patients with CLL [Coutre 2011]. 


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In this study, it is hypothesized that incremental changes in these biomarkers provide direct 
evidence of mechanism-specific idelalisib effects on PI3Kį activity or indirectly document 
drug effects on overall tumor cell volume. In either case, improvements in these 
pharmacodynamic measures provide corroborative evidence in support of idelalisib 
pharmacological activity; conversely, worsening of these biomarkers may indicate 
acquisition of resistance to idelalisib. In addition, it is possible that disease-or 
inflammation-related biomarkers may provide corollary information relating to the adverse 
effects of idelalisib on the liver; such data might allow better prediction of which subjects 
might be most susceptible to ALT/AST elevations during idelalisib treatment. Finally, it can 
also be postulated that genetic, protein, or metabolic changes in CLL cells could provide 
signatures that would correlate with drug sensitivity and resistance. 
Based on these considerations, this study will evaluate PI3K/AKT/mTOR pathway activation 
status in CLL cells. For this purpose, blood will be evaluated by flow cytometry using a 
clinically validated assay [Hoellenriegel 2011]. CLL cells will be identified using anti-CD5 
and anti-CD19 antibodies. AKT activation will be determined by quantifying 
phosphorylation at the Ser473 and Thr308 AKT sites using specific anti-pAKT Thr308 and 
anti-pAKT Ser473 antibodies. Additional assessments of PI3K/AKT/mTOR pathway 
signaling (eg, evaluating phosphorylation state for other downstream enzymes) may also be 
explored. 
Plasma will be collected for assessment of circulating concentrations of relevant chemokines 
and cytokines with a particular focus on CCL2, CCL3, CCL4, CXCL12, CXCL13, CCL17, 
CCL19, CCL21, CCL22, sCD40 ligand, tumor necrosis factor-Į, and C-reactive protein. In 
addition serum markers of iron metabolism (eg, hepcidin, iron, ferritin, transferrin) that might 
provide markers linking disease-related inflammation with perturbations of liver iron and 
sensitivity to liver injury will be evaluated [Nemeth 2003, Ferrucci 2010]. Clinically 
validated assays (eg, enzyme-linked immunosorbent assays [ELISAs]) will be used to 
measure circulating concentrations of chemokines and cytokines at baseline and during the 
course of idelalisib therapy. 
CLL cell deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein will be 
collected at baseline and at the conclusion of a subject’s treatment on study. DNA and RNA 
samples will be analyzed using gene array technologies to evaluate for changes in DNA 
mutations or in RNA expression patterns that might be associated with intrinsic or acquired 
resistance to study treatments. Similarly, protein will be evaluated for state-specific changes 
in protein phosphorylation to evaluate for differences in pathway activation at baseline or 
during therapy that might be associated with differences in response or in acquisition of 
resistance to therapy. 
3.2.4. 
Assessments of Exposure 
3.2.4.1. 
Study Drug Administration and Compliance 
Evaluation of study drug administration and compliance provides context for assessments of 
safety, pharmacokinetics, and pharmacological activity. Evaluations of treatment 


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administration and modifications from planned therapy document the influence of 
treatment-emergent adverse events on prescribing practice. Compliance assessment offers a 
general indication of patients’ acceptance of therapy, integrating factors of tolerability, 
palatability, and convenience. 
In this study, information regarding planned treatment and modification from planned 
treatment (eg, dose reductions and interruptions) will be kept. The compliance of the subject 
will be verified by accounting for used and unused drug. 
3.2.4.2. 
Pharmacokinetics 
Given the intent of this protocol to assess longer-term dosing, collection of plasma for 
idelalisib concentrations is important for evaluating the steady-state maintenance of exposure 
over time. These data may allow correlations of exposure with measures of efficacy, toxicity, 
and resistance, will be important part of exploring exploration of 2 different idelalisib dose 
levels. Because the idelalisib pharmacokinetic profile has been well characterized in Phase 1 
studies, limited plasma sampling will be performed in this study. Samples will be collected 
pre-dose and 1.5 hours post-dose relative to the morning administration of idelalisib. This 
approach will provide information regarding plasma Ctrough values and will describe drug 
absorption as characterized by plasma concentrations at the approximate Tmax after the 
morning dose. The 1.5-hour timepoint has been assessed in prior Phase 1 studies, allowing 
across-study correlations of exposure. Based on discussions with investigators, collecting 
more than 2 samples in the morning is not considered reasonable given the need to minimize 
time requirements for study participants and to avoid substantial inconvenience for clinic 
staff. 
Evaluation of idelalisib plasma concentrations will be performed using liquid 
chromatography with tandem mass spectrometry. The method has been fully validated in the 
context of prior Phase 1 studies. Plasma samples will be retained for potential later analyses 
of idelalisib metabolites. 
3.2.5. 
Evaluations of Safety 
In defining the therapeutic relevance of a drug in a particular clinical setting, it is imperative 
that its safety profile be fully characterized. As is conventional in all clinical studies, proper 
description of each adverse event or laboratory abnormality requires an understanding of the 
type, incidence, timing, severity, and relatedness to study drug. While information on all 
reported adverse events will be collected, listed, and summarized, particular focus will be 
placed on monitoring and reporting adverse events and laboratory abnormalities that were 
encountered in the prior toxicology studies and clinical experience with idelalisib. Safety 
parameters of specific interest in reporting study results will include those relating to 
infection, pulmonary events (eg, pneumonia/pneumonitis), liver injury, rash, and bone 
marrow dysfuntion.  Additional scrutiny will be applied to Grade 3-4 adverse events, to 
adverse events causing interruption or discontinuation of idelalisib, and to serious adverse 
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In addition, the protocol will evaluate for potential adverse idelalisib effects on laboratory 
parameters of immune function; the absolute number of CD4+, CD5+,CD8+, CD16/CD56+, 
CD19+, and CD20+ cells will be assessed by flow cytometry. Serum concentrations of IgA, 
IgE, IgG, and IgM will be obtained. 
For consistency of interpretation, adverse events will be coded using the standard Medical 
Dictionary for Regulatory Activities (MedDRA) [http://www.meddramsso.com]), and the 
severity adverse events and laboratory abnormalities will be graded using the well-defined 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). 
Standard definitions for seriousness will be applied (see Section 8.1.2). 
3.2.6. 
Pharmacoeconomic Measures 
It is increasingly important to understand the potential cost implications of introducing a new 
medication into patient care for CLL [Main 2010, Hornberger 2011]. In order to analyze the 
pharmacoeconomic consequences of idelalisib administration, data will be collected 
regarding the health status of subjects and regarding health care resource utilization. 
Heath status information will be obtained with the EQ-5D, which is a self-administered, 
generic, indirect utility measure [EuroQoL Group 1990] (Appendix 4). The EQ-5D consists 
of a visual analogue scale on which subjects are asked to rate their current overall health 
status and 5 single-item dimensions which ask subjects to rate their health in terms of 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. For each of the 
5 items, patients must choose between 3 levels of difficulty in accomplishing tasks in that 
dimension. The visual analog scale is then used in combination with the dimension scores to 
generate a health utility score that can be incorporated into analyses of cost effectiveness. 
The EQ-5D has been successfully used in the evaluation of patients with B-cell and other 
cancers [Doorduijn 2005, Witzens-Harig 2009, Yang 2010]. 
The EQ-5D instrument is available in appropriate languages for this study. EQ-5D data will 
be obtained at baseline and during each investigational clinic visit during treatment. The 
EQ-5D will be administered immediately after administration of the FACT-Leu instrument, 
before other procedures are performed and before any study information is conveyed to the 
subject. The EQ-5D instrument takes only 5 minutes to complete. 
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations. 
The basic approach will be to combine the resource utilization data from the trial with data 
on unit prices (collected separately) to estimate total costs. The costs will be described 
relative to the health care findings as measured by duration of tumor control, the 
symptom-free survival period, and/or utility outcomes or some other appropriate measure of 
clinical benefits. 


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4. 
SUBJECT POPULATION 
4.1. 
Number of Subjects 
The planned sample size is ~160 subjects but will be bounded by the number of subjects 
enrolled to the primary clinical trial (Study GS-US-312-0116). 
4.2. 
Subject Selection Criteria 
The following eligibility criteria are designed to select subjects for whom study participation 
is considered appropriate. All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether this protocol is suitable for a particular subject. 
Eligibility criteria may not be waived by the investigator and conformance to the eligibility 
criteria is subject to review in the case of a Good Clinical Practice (GCP) or a regulatory 
authority audit. Any questions regarding a subject’s eligibility should be discussed with the 
study sponsor medical monitor prior to enrollment. 
4.2.1. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in 
this study: 
1) Participation in Study GS-US-312-0116. 
2) Occurrence of confirmed, definitive CLL progression while receiving study drug therapy 
(idelalisib/placebo) in Study GS-US-312-0116. Note: Definitive disease progression is 
CLL progression based on standard criteria and occurring for any reason 
(ie, increasing lymphadenopathy, organomegaly, or bone marrow involvement; 
decreasing platelet count, hemoglobin, or neutrophil count; or worsening of 
disease-related symptoms) other than lymphocytosis. Subjects must have confirmation 
by the sponsor working in collaboration with an independent review committee (IRC) 
that the disease has progressed on the clinical trial (Study GS-US-312-0116) before 
receiving secondary idelalisib therapy on this extension trial (Study GS-US-312-0117). 
3) Presence of radiographically measurable lymphadenopathy (defined as the presence of 
1 nodal lesion that measures ≥2.0 cm in the longest diameter [LD] and ≥1.0 cm in the 
longest perpendicular diameter [LPD] as assessed by CT or MRI).  
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab and 
idelalisib/placebo) and no intervening or continuing therapy (including radiotherapy, 
chemotherapy, immunotherapy, or investigational therapy) for the treatment of CLL. 
Note: Subjects may receive corticosteroids to manage CLL manifestations. 
5) The time from permanent cessation of Study GS-US-312-0116 treatment (rituximab 
and/or idelalisib/placebo) and the initiation of Study GS-US-312-0117 therapy is 
≤12 weeks. Note: Study procedures performed as part of Study GS-US-312-0116 need 
not be repeated and can be used as screening procedures for Study GS-US-312-0117 if 


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performed within 4 weeks prior to initiation of study drug therapy on Study GS-US-
312-0117. 
6) Karnofsky performance score of 40. 
7) Required baseline laboratory data (within 4 weeks prior to initiation of study treatment) 
as shown in the table below. Note: Confirmation should be considered for out-of-range 
values to determine if the abnormality is real or artifactual. Values should be obtained 
within the screening period and should generally be the most recent measurement 
obtained. Subjects with any degree of neutropenia, thrombocytopenia, or anemia due 
to CLL or prior therapy may enroll. 
Table 4-1. 
Required Screening Laboratory Values 
Organ System 
Parameter 
Required Value 
Hepatic 
Serum total bilirubin 
≤1.5 x ULN (unless elevated due to Gilbert’s syndrome) 
Serum ALT 
≤2.5 x ULN 
Serum AST 
Renal 
eCCra 
>30 ml/min 
Pregnancy 
β-HCGb 
Negative  
a 
As calculated by the Cockcroft-Gault formula (see Appendix 5) 
b 
For women of child-bearing potential only; serum β-HCG must be negative during screening and serum β-HCG or 
urine dipstick pregnancy test must be negative at start of study treatment (Visit 2) 
Abbreviations: β-HCG= beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate 
aminotransferase, eCCr=estimated creatinine clearance, ULN=upper limit of normal 
 
8) For female subjects of childbearing potential, willingness to abstain from heterosexual 
intercourse or use a protocol-recommended method of contraception from the screening 
visit (Visit 1) throughout the study treatment period and for 30 days following the last 
dose of study drug. Note: A female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; 
has medically documented ovarian failure (with serum estradiol and follicle-
stimulating hormone [FSH] levels within the institutional postmenopausal range and a 
negative serum or urine βHCG), or is menopausal (age >55 with amenorrhea for 
>12 months or amenorrhea for > 6 months with serum estradiol and FSH levels within 
the institutional postmenopausal range).  
9) For male subjects of childbearing potential having intercourse with females of 
childbearing potential, willingness to use a protocol-recommended method of 
contraception from the start of study therapy (Visit 2) throughout the study and for 
90 days following the last dose of study drug and to refrain from sperm donation from the 
start of study treatment (Visit 2) throughout the study treatment period and for 90 days 
following the last dose of study drug. Note: A male subject is considered able to father a 
child unless he has had a bilateral vasectomy with documented aspermia or a bilateral 
orchiectomy, or has ongoing testicular suppression with a depot luteinizing hormone- 


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releasing hormone (LH-RH) agonist (eg, goserelin acetate [Zoladex®]), leuprolide 
acetate  [Lupron®]), or triptorelin pamoate [Trelstar®]). 
10) In the judgment of the investigator, participation in the protocol offers an acceptable 
benefit-to-risk ratio when considering current CLL disease status, medical condition, and 
the potential benefits and risks of alternative treatments for CLL.  
11) Willingness and ability to comply with scheduled visits, drug administration plan, 
imaging studies, laboratory tests, other study procedures, and study restrictions. Note: 
Psychological, social, familial, or geographical factors that might preclude adequate 
study participation should be considered. 
12) Evidence of a personally signed informed consent indicating that the subject is aware of 
the neoplastic nature of the disease and has been informed of the procedures to be 
followed, the experimental nature of the therapy, alternatives, potential benefits, possible 
side effects, potential risks and discomforts, and other pertinent aspects of study 
participation. 
4.2.2. 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study: 
1) Known histological transformation from CLL to an aggressive lymphoma 
(ie, Richter transformation). 
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of the start 
of study treatment (Visit 2). Note: Subjects with localized fungal infections of skin or 
nails are eligible. Subjects may be receiving prophylactic antiviral or antibacterial 
therapies at the discretion of the investigator; anti-pneumocystis prophylaxis is 
encouraged.  
3) Pregnancy or breastfeeding.  
4) Intentional breaking of the blind in Study GS-US-312-0116 by the investigator or the 
study subject. 
5) Concurrent participation in another therapeutic clinical trial. 
6) Prior or ongoing clinically significant illness, medical condition, surgical history, 
physical finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the 
investigator’s opinion, could adversely affect the safety of the subject or impair the 
assessment of study results. 


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4.3. 
Enrollment Criteria Rationale 
The eligibility criteria are designed to limit enrollment to subjects who participated in the 
primary clinical trial (Study GS-US-312-0116), are compliant, have been generally able to 
tolerate study therapy and study procedures, and have experienced definitive CLL 
progression while receiving study treatment (rituximab and/or idelalisib/placebo) in the 
primary study. 
The requirement of measurable lymphadenopathy ensures that subjects have disease that can 
adequately be assessed for evidence of drug activity. Prior therapy provisions are intended to 
ensure that subjects are transitioning directly from Study GS-US-312-0116 to Study 
GS-US-312-0117 without receiving intervening treatments. The stipulation of ≤12-week 
interval from Study GS-US-312-0116 treatment until Study GS-US-312-0117 treatment 
precludes excessively protracted intervals between participation in the 2 studies but also 
permits sufficient time for clinicians and subjects to determine whether participation is 
appropriate.  
To ensure that subjects are not so acutely ill from life-threatening comorbidities that they 
require hospitalization and stabilization, subjects with Karnofsky performance scores 
<40 (ie, those who are bed-bound or hospitalized) will not be enrolled. Baseline laboratory 
evaluations are designed to limit participation to subjects who have not developed serious 
organ compromise that would pose a safety risk or confound the interpretation of adverse 
effects. Pregnancy testing and restrictions on eligibility relating to reproduction, pregnancy, 
and nursing are important because idelalisib is a new chemical entity with teratogenic effects 
in rats and it is unknown if it may have adverse effects on conception, on fetal development, 
or on the health of a breast-feeding child. To minimize missing data and premature 
discontinuations, subjects should have sufficient psychological and social resources to 
comply with study procedures and restrictions. Consistent with GCP guidelines, subjects 
must provide informed consent before initiation of any study procedures. 


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5. 
TREATMENT OF SUBJECTS 
5.1. 
Enrollment 
5.1.1. 
Interactive Web Response System 
An IWRS will be employed to manage the conduct of the trial. The IWRS will be used to 
maintain a central log documenting enrollment, to manage dose modifications, to assess 
current inventories of study drug, to initiate any necessary resupply of study drug, and to 
document discontinuation of study. 
5.1.2. 
Treatment Assignment 
After a subject has completed the necessary documentation of definitive CLL progression in 
the primary clinical trial (GS-US-312-0116) and has been confirmed to be eligible, the 
subject can be entered into this trial (Study GS-US-312-0117). In order to obtain a treatment 
arm allocation for a subject, a site representative will access the IWRS and supply the system 
with the required information. 
Subjects will be assigned to either of the following treatment assignments with allocation 
based on the original primary study randomization: 
• Arm A: Idelalisib + rituximab (Study GS-US-312-0116) 
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117) 
• Arm B: Placebo + rituximab (Study GS-US-312-0116) 
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117) 
The IWRS will assign blister card numbers and instructions for dispensing of blinded study 
drug (high-dose or standard-dose idelalisib). It is anticipated that subjects will usually begin 
study drug immediately at Visit 2 of the study.  
5.1.3. 
Blinding 
The identity of the treatments will be concealed by central blinding of study drug 
assignments. Blinding will be accomplished through use of a placebo that is well-matched to 
the active drug in appearance, packaging, labeling, and schedule of administration 
(see Section 5.2.1). During the study, subjects, caregivers, investigational site personnel, 
Gilead Sciences study team members, and all other study personnel will remain blinded to 
the identity of the treatment assignments; these assignments will be available only to the 
IWRS, the data monitoring committee (DMC) for the study, an independent bioanalytical 
group that supports the DMC, and drug safety personnel who are not part of the study team. 
Unblinding during the study will only occur in the case of subject emergencies 
(see Section 5.5) or as requested by the DMC. Where required by local regulation, expedited 
reporting of serious adverse events to specific regulatory authorities will include information 


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regarding the study drug treatment assignment (high-dose or standard-dose idelalisib); this 
will be done in such a way that subjects, investigational site personnel, institutional review 
board/independent ethics committees (IRB/IEC), and study team members remain blinded as 
to the treatment assignment for the subject described in the adverse event report. 
The final unblinded analysis of the study will only be performed when the database is 
completed and locked. While bioanalytical assays to determine idelalisib concentrations may 
be performed prior to unblinding, pharmacokinetic data that would allow identification of 
treatment assignments for individual subjects will not be available to the study team until 
after the blind is broken and the primary analysis has occurred. Except for emergency 
unblinding, individual subjects, caregivers, and site personnel will not be informed of the 
treatment assignments until the implications of revealing such data for the overall idelalisib 
study program have been determined by the clinical project leader for the idelalisib 
development program. 
5.2. 
Investigational Study Drug (Idelalisib/Placebo) 
5.2.1. 
Description 
Subjects allocated to Arm A of the study will be provided with 2 tablets of active idelalisib 
for oral administration at each dose. Each tablet contains 150 mg or 100 mg of active 
idelalisib. The 150-mg tablets will be used for initial therapy; the 100-mg tablets are 
provided for use by those subjects who require a dose reduction (see Table 5-1).  
Subjects allocated to Arm B of the study will be provided with 1 tablet of active idelalisib 
and 1 tablet of placebo for oral administration at each dose. Each active tablet contains 
150 mg or 100 mg of active idelalisib. The 150-mg tablets (and matching placebo) will be 
used for initial therapy; the 100-mg tablets (and matching placebo) are provided for use by 
those subjects who require a dose reduction.  
The 150-mg tablets are pink, film-coated, and include the following inactive excipients: 
microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch 
glycolate, magnesium stearate, red iron oxide, polyethylene glycol, talc, polyvinyl alcohol 
(PVA), and titanium dioxide. The 100-mg tablets are orange, film-coated, and include the 
following inactive excipients: microcrystalline cellulose, hydroxypropyl cellulose, 
croscarmellose sodium, sodium starch glycolate, magnesium stearate, yellow iron oxide, 
polyethylene glycol, talc, PVA, and titanium dioxide. 
The placebo tablets match the active idelalisib formulations in appearance. The placebo 
tablets matching the 150-mg tablets are pink, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium 
stearate, red iron oxide, polyethylene glycol, talc, PVA, and titanium dioxide. The placebo 
tablets matching the 100-mg tablets are orange, film-coated, and include the following 
inactive ingredients: silicified microcrystalline cellulose, sodium starch glycolate, 
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5.2.2. 
Source 
Both active idelalisib and placebo will be supplied free of charge by Gilead Sciences.  
5.2.3. 
Packaging and Labeling 
Study drug (idelalisib or idelalisib/placebo) will be provided in blister cards. The blister cards 
are made of polyvinyl chloride/polychlorotrifluoroethylene (PVC/PCTFE) film and have 
aluminum foil lidding materials. Each blister card contains 120 tablets (4-week supply plus a 
modest overage) of one of the relevant dose strengths. The 100-mg or 150-mg and matching 
placebo tablets will be combined in order to obtain the daily doses to be used in this study. 
Thus, in Arm A, the 300-mg idelalisib dose will be obtained by administering two 150-mg 
tablets and the 200-mg idelalisib dose will be obtained by administering two 100-mg tablets. 
In Arm B, the 150-mg idelalisib dose will be obtained by administering one 150-mg tablet 
and one placebo tablet and the 100-mg idelalisib dose will be obtained by administering one 
100-mg tablet and one placebo tablet.  
Each blister card will have a unique number. Labeling for blister cards dispensed to subjects 
in Arm A will appear identical to blister cards dispensed to subjects in Arm B, and may 
include either idelalisib or GS-1101. All labels for study drugs to be distributed to centers in 
the United States, the EU, and other countries will meet all applicable requirements of the 
United States Food and Drug Administration (FDA), the EU Annex 13 of Current Good 
Manufacturing Practice (cGMP) (Manufacture of Investigational Medicinal Products, 
July 2003), and/or other local regulations as applicable. 
5.2.4. 
Storage and Handling 
Blister cards containing tablets of study drug (idelalisib or idelalisib/placebo) should be 
stored at controlled room temperature (ie, ~25°C, with a range of 15 to 30°C). While the 
stability of study drug tablets stored at controlled room temperature has been confirmed, brief 
excursions to temperatures as low as -20°C or as high as 40°C (eg, during shipping) will not 
adversely affect the drug. Updated stability data will be provided to the sites, as appropriate. 
5.2.5. 
Dispensing 
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing 
study drug according to the IWRS directions. It is planned that drug will be dispensed at 
4-week intervals through the first 24 weeks of treatment and at 12-week intervals thereafter. 
Sufficient study drug will be provided for each study period at the beginning of the period. 
Multiple blister cards may be dispensed at a single visit. Tablets should be kept in the 
original blister cards provided until they are self-administered by the subject. 
At the time of starting study treatment, the IWRS will provide the clinic staff with the blister 
card numbers designating the blister cards to be dispensed. The clinic staff (eg, pharmacist or 
other qualified person) will write the subject number on each blister card that is dispensed. 
Immediately before dispensing, the clinic staff will write the blister card number for each 


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dispensed blister card in the study drug administration record corresponding to the subject 
number. 
5.2.6. 
Return 
The study drug should be retrieved from each subject at the end of each dispensing interval. 
The quantity of study drug and the date returned by the subject should be recorded in the 
study drug accountability records. When possible, all study drug returned by the subject 
should be retained for review by the study site monitor prior to return to Gilead Sciences or 
destruction. 
5.2.7. 
Accountability 
The disposition of all study drug should be documented from the time of receipt at the site 
through subject dispensing and return. 
Study personnel must ensure that all study drug is kept in a secure locked area with access 
limited to authorized personnel. The study drug must not be used outside the context of this 
protocol. Under no circumstances should the investigator or site personnel supply study drug 
to other investigators or clinics, or allow the study drug to be used other than as directed by 
this protocol. 
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by Gilead Sciences or its designee, including, but not 
limited to, the date received, lot number, amount received, and the disposition of all study 
drug. Upon receipt of a drug shipment, the shipment must be logged into the IWRS. Study 
drug accountability records must also be maintained that include the subject number to whom 
the study drug was dispensed and the date, quantity and lot number of the study drug 
dispensed. 
Depending upon the decision of Gilead Sciences, remaining unused study drug supply will be 
returned to Gilead Sciences or its designee after the study is completed or will be discarded 
or destroyed at the clinical site. If the study drug is discarded or destroyed at the clinical site, 
standard institutional policy should be followed. Records documenting the date of study drug 
shipping or destruction, relevant lot numbers, and amount shipped or destroyed should be 
maintained. 
5.2.8. 
Overdose Precautions 
In Phase 1 studies, an MTD for idelalisib was not reached when the drug was administered 
continuously at dose levels through 350 mg/dose BID (700 mg per day) [Coutre 2011, 
Kahl 2011]. However, in this protocol, an overdose is defined as administration of more than 
the prescribed daily dose (ie, >600 mg in a single day). In a subject who experiences an 
overdose consideration should be given as to whether idelalisib administration should be 
temporarily interrupted. If the overdose ingestion is recent and substantial, and if there are no 
medical contraindications, use of gastric lavage or induction of emesis may be considered. 


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Observation for any symptomatic side effects should be instituted, and biochemical and 
hematological parameters should be followed closely (consistent with the protocol or more 
frequently, as needed). Appropriate supportive management to mitigate adverse effects 
should be initiated. 
The Gilead Sciences medical monitor should be contacted if a study drug overdose occurs. 
Cases of study drug overdose will result in specific reporting requirements 
(see Section 5.2.8.). 
5.2.9. 
Inadvertent Exposure and Spill Precautions 
Based on available data from nonclinical studies, idelalisib does not appear to be acutely 
toxic, genotoxic, or irritative at levels that are likely to result from inadvertent exposure to 
the contents of broken tablets. However, personnel handling the drug should use reasonable 
precautions to avoid eye contact, skin contact, inhalation, or ingestion of the study drug 
product. For further information regarding inadvertent exposure and spill precautions, please 
consult the idelalisib investigator brochure. 
5.3. 
Study Drug Administration 
5.3.1. 
Premedication 
No specific premedications or supporting medications are required in conjunction with study 
drug administration. 
5.3.2. 
Administration Instructions 
The prescribed dose of study drug (idelalisib/placebo) should be taken orally. At each dose 
administration, the tablet number corresponding to the appropriate dose of study drug is to be 
swallowed whole with 100 to 200 mL (~ 4 to 8 ounces) of water. In case of breakage of the 
tablets in the oral cavity, additional water should be taken as a rinse.  
Study drug may be taken with or without food. There are no known dietary restrictions 
related to study drug use. 
5.3.3. 
Dosing Schedule 
Study drug should be taken on a BID schedule at approximately the same times each day. 
Ideally, doses should be taken at ~12-hour intervals (eg, at ~7 AM and at ~7 PM). While it is 
realized that variations in dosing schedule may occur in the outpatient setting, the prescribed 
regimen should be followed as closely as possible, especially in the clinic. 
At specified clinic visits, the study drug will be administered in the clinic with dosing 
appropriately timed relative to blood sampling for idelalisib pharmacokinetics. As detailed in 
Section 6.2, clinic staff should record idelalisib administration information, including the 


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exact clock time of each dose, for doses of study drug administered in the clinic or hospital. 
Thereafter, subjects will be given an adequate supply of tablets to take at home. 
5.3.4. 
Dose Levels 
Study drug dose levels for Arm A and Arm B are described in Table 5-1. The lower dose 
level (Dose Level -1) is provided in case a subject requires a study drug dose modification. 
Table 5-1. 
Study Drug Dose Levels 
Treatment Arm 
Starting Dose 
Dose Level -1 
Arm A 
300 mg/dose BID 
200 mg/dose BID 
Arm B 
150 mg/dose BID 
100 mg/dose BID 
Abbreviation: BID=twice per day 
 
5.3.5. 
Dose Schedule Interruptions and Vomited Doses 
Subjects who have a delay in administration of a dose of the study drug of <6 hours should 
take the planned dose as soon as possible after the intended time of administration. For 
subjects who have a delay in administration of study drug of ≥6 hours, the dose should not be 
taken. Study drug administration may continue but the missed dose should not be made up 
and the planned timing of subsequent study drug dosing should not be altered. 
Vomited doses may be retaken, but only if the tablet is visible in the vomitus. 
5.3.6. 
Safety Monitoring and Study Drug Interruption/Dose Modification 
Subjects must be monitored closely for adverse events or laboratory abnormalities during the 
course of the study. Reference should be made to the CTCAE, Version 4.03 for grading the 
severity of adverse events and laboratory abnormalities. 
Based on Phase 1 clinical experience adverse events potentially attributable to idelalisib in 
patients with CLL have included infrequent hepatic events (manifest primarily as 
asymptomatic and isolated elevations in serum ALT/AST).  Other adverse events potentially 
related to idelalisib have included  instances of pneumonitis, gastrointestinal inflammation, 
or rash. Myelosuppression has not been an overt toxicity of idelalisib in previous experience 
but provisions for intervention in subjects experiencing very protracted treatment-emergent 
neutropenia or thrombocytopenia are provided as a precaution. It is possible that idelalisib is 
responsible for other adverse events for which a causal relationship has not yet been 
established. 
Recommendations for modifications of the dosing regimens based on the drug and the type 
and severity of adverse events or laboratory abnormalities are provided in Table 5-2 below. 
The dose modification instructions focus on the types of events most commonly attributed to 
each of the study agents. The recommendations provided in Table 5-2 comprise only 


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guidelines; variations from these recommendations may be warranted based on an 
investigator’s individual judgment in considering potential risks, benefits, and therapeutic 
alternatives available to each subject. 
Consistent with table 5-2, if a subject experiences an adverse event that is suspected to be 
related to study drug and requires a dose modification during the course of study therapy, 
then study drug administration should be held, as necessary, until the adverse event resolves 
or stabilizes to an acceptable degree (generally to Grade ≤1). Thereafter, study drug may be 
reinstituted, but the dose should be reduced to Dose Level -1 (see Table 5-1). If the adverse 
event occurs again, one further attempt at reinitiation of therapy at Dose Level -1 may be 
attempted if the investigator feels that a second rechallenge is medically appropriate. If the 
subject cannot tolerate idelalisib at Dose Level -1 after 2 rechallenges, then the subject 
should be discontinued from study drug therapy unless continued therapy is permitted by the 
Gilead Sciences medical monitor. 
After the study drug dose is reduced, the dose need not be re-escalated, even if there is 
minimal or no toxicity with the reduced dose. However, if the subject tolerates the lower 
dose level of study drug for 4 weeks then the dose level may be increased to the starting 
dose level (see Table 5-1) at the discretion of the investigator. Such re-escalation may be 
particularly warranted if further evaluation reveals that the adverse event that led to the dose 
reduction was not study-drug-related. The starting dose level should not intentionally be 
exceeded in this study. 
Whenever possible, any dose adjustment of study drug should be discussed between the 
investigator and the Gilead Sciences medical monitor prior to implementation. To implement 
either a dose reduction or a dose reescalation, the investigator/study staff member will call 
the IWRS, enter the subject number, and inform the IWRS of the need for dose titration. The 
IWRS will provide details regarding the blister card to be dispensed to the subject. The 
appropriate clinic staff should instruct the subject/caregiver about the change in dose. 
Recommendations for dose modification based on the type and severity of adverse events or 
laboratory abnormalities are provided in Table 5-2 below. 


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Table 5-2. 
Recommendations for Study Drug Dose Modifications Based on 
Type and Severity of Adverse Events or Laboratory Abnormalities 
Hepatic Study-Drug-Related Event (Elevation in ALT, AST, or Bilirubin) 
CTCAE Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ALT/AST 
>ULN-3 x ULN 
>3-5 x ULN 
>5-20 ULN 
>20 x ULN 
Bilirubin 
>ULN-1.5 x ULN 
>1.5-3 x ULN 
>3-10 x ULN 
>10 x ULN 
GS-1101 Dosing 
Recommendation 
Maintain dose level 
Maintain dose level. 
Monitor ALT, AST, 
ALP, and bilirubin at 
least 1x per week 
until all 
abnormalities  
are ≤Grade 1 
Withhold study drug and confirm 
abnormalities within 3 days. Monitor ALT, 
AST, ALP, and bilirubin at least 1x per 
week until all abnormalities are Grade ≤1. 
May resume drug at next lower dose level. 
Cutaneous Study-Drug-Related Event  
CTCAE Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
GS-1101 Dosing 
Recommendation 
Withhold study drug until toxicity is 
Grade 0.  
Resume study drug at current dose level. If 
rechallenge at same dose level results in 
recurrent rash, may resume study drug at 
next lower dose level. 
Withhold study drug until toxicity is 
Grade 0. May resume study drug at next 
lower dose level. 
Hematological Study-Drug-Related Event 
CTCAE Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neutropenia 
(ANC x 109/μL) 
ANC <LLN-1.5 
ANC <1.5-1.0 
ANC <1.0-0.5 
ANC <0.5 
Thrombocytopenia 
(platelets x 109/μL) 
Platelets <LLN-75 
Platelets <75-50 
Platelets<50-25 
Platelets<25 
GS-1101 Dosing 
Recommendation  
Maintain dose level 
Maintain dose level 
Maintain dose level 
For neutropenia 
of Grade 4 for 
14 days, consider 
G-CSF support or 
may withhold study 
drug until Grade ≤3. 
May resume study 
drug at next lower 
dose.  
For Grade 4 
thrombocytopenia 
with bruising or 
bleeding, withhold 
study drug until 
Grade ≤3. May 
resume study drug at 
next lower dose 
level. 


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Other Study-Drug-Related Event 
CTCAE Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
GS-1101 Dosing 
Recommendation 
Maintain dose level 
Maintain dose level 
Withhold study drug until toxicity is 
Grade ≤1. May resume study drug at next 
lower dose level unless subject has 
developed a condition requiring 
discontinuation of therapy (see Section 5.8).
Abbreviations:   ALP=alkaline phosphatase, ALT=alanine aminotransferase, ANC=absolute neutrophil count, 
AST=aspartate aminotransferase, CTCAE=Common Terminology Criteria for Adverse Events, G-CSF=granulocyte-colony-
stimulating factor, LLN= lower limit of normal, ULN=upper limit of normal 
 
5.4. 
Recommendations for Evaluation, Intervention, and Drug 
Discontinuation for Specific Adverse Events or Conditions 
5.4.1. 
Dermatological Events 
idelalisib administration has occasionally been associated with the occurrence of a 
maculopapular rash affecting the trunk and extremities [Gilead Sciences 2011]. Based on 
skin biopsy data in several subjects, the findings have been consistent with a delayed-type 
hypersensitivity reaction. Rechallenge with idelalisib has resulted in recurrence of rash in 
some but not all subjects. 
In subjects who develop a rash while on study drug, causes related to concomitant 
medications, environmental exposures, or infection should be considered and eliminated. 
Depending upon the severity of the initial dermatological event, rechallenge with study drug 
therapy at the same or a lower dose level (see Table 5-2) should be considered if continued 
drug administration offers the potential for clinical benefit. 
5.4.2. 
Gastrointestinal Events 
Inflammation of the tongue has been noted in rats undergoing repeated gavage administration 
of idelalisib; this inflammation may have represented a drug-related exacerbation of 
gavage-mediated irritation. Mild congestion or hemorrhage in the large intestine has been 
seen in dogs receiving high doses of idelalisib. In patients, isolated cases of gastrointestinal 
inflammation (eg, stomatitis, colitis, cecitis) have been noted. While disease-related factors, 
neutropenia, toxicity from prior therapies, effects of ongoing supportive care, or pre-existing 
cholelithiasis may have initiated such events, it is possible that idelalisib played a 
contributory role [Gilead Sciences 2011]. In such subjects, rechallenge with idelalisib has 
been possible and has not been associated with other severe adverse events. Patients who 
have developed evidence of enteritis during idelalisib therapy have been successfully treated 
with antidiarrheals (eg, loperamide) and with enteric steroidal (eg, budesonide) or 
non-steroidal (eg sulfasalazine [Azulfidine®]) anti-inflammatory agents and have been able 
to continue or resume idelalisib. 


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For study subjects who develop severe abdominal pain, particularly if early during therapy, 
the possibility of a bowel obstruction or perforation should be considered. Appropriate 
clinical and radiographic examination should be performed and supportive care and surgical 
intervention should be considered. Upon recovery, study therapy may be continued if 
appropriate for the clinical situation. 
For subjects who develop persistent diarrhea, causes related to concomitant medications or 
gastrointestinal infection should be considered and eliminated. Depending upon the clinical 
circumstances, endoscopy and biopsy may be warranted. Providing an antidiarrheal 
(eg, loperamide) may lessen symptoms. Consideration should be given to intervention with 
enteric steroidal (eg, budesonide) or non-steroidal (eg sulfasalazine) anti-inflammatory 
agents.In such subjects, rechallenge with idelalisib at a lower dose level has resulted in 
recurrence of symptoms in some but not all subjects and has not been associated with other 
severe adverse events. One patient who developed evidence of inflammatory bowel disease 
during idelalisib therapy has been treated with sulfasalazine (Azulfidine®) and antidiarrheals 
(eg, loperamide) while continuing on idelalisib. 
Thus, depending upon the type and severity of the initial gastrointestinal event, rechallenge 
with study drug at a reduced dose level and with and appropriate support care may be 
warranted if continued drug administration offers the potential for clinical benefit. 
5.4.3. 
Hepatic Events 
Dogs receiving idelalisib for 28 days were observed to have dose-related hepatic 
inflammation and cellular necrosis, primarily affecting sinusoids in the centrilobular to 
midzonal regions of the liver [Gilead Sciences 2011]. The changes were associated with 
elevations in serum ALT/AST concentrations. In dogs, serum transaminase elevations 
typically reversed despite continued administration of idelalisib. In some patients with 
lymphoid malignancies, reversible serum ALT/AST elevations have been observed 
[Coutre 2011, Kahl 2011]. In these patients, onset has typically occurred within 2 to 8 weeks 
of starting idelalisib therapy. Patients with NHL have been affected more commonly than 
those with CLL, suggesting that disease-related factors may alter the sensitivity to 
idelalisib-mediated hepatic effects. While conclusive evidence for a dose-response 
relationship does not exist, higher doses or exposures of idelalisib may be associated with a 
greater risk of adverse hepatic events. 
Among patients with Grade 1-2 ALT/AST abnormalities, continued dosing has been 
possible; transaminase values commonly resolve despite continued idelalisib treatment. For 
those with Grade 3-4 ALT/AST elevations, drug interruption has resulted in resolution over 
2 to 6 weeks. Successful rechallenge at lower dose levels of idelalisib has been achieved in 
the majority of patients. Thus, in subjects with uncomplicated hepatic events, the instructions 
in Table 5-2 should be followed in an attempt to maximize the potential that subjects who 
appear to be benefiting can continue with study drug treatment. 
In selected subjects who experience more complicated hepatic adverse events, further 
work-up may be warranted, as requested by the Gilead Sciences medical monitor. Such an 


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evaluation may be particularly warranted in subjects who first experience a serum ALT/AST 
elevation ≥12 weeks from the start of study drug therapy, who have an elevation in serum 
bilirubin concentration or coagulation parameters, or who have other characteristics that 
suggest an atypical change in transaminase values. Further workup may include: obtaining a 
history of recent symptoms/illnesses and of relevant past history (eg, history of hepatitis or of 
hepatitis A or hepatitis B vaccination); obtaining information regarding concomitant drug use 
(prescription and nonprescription medications, dietary supplements, alcohol, illicit drugs, 
special diets); questioning the subject regarding potential exposure to environmental toxins; 
ruling out viral hepatitis A, B, C, D (if hepatitis B is positive), and E, Epstein-Barr virus, 
cytomegalovirus, autoimmune hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis, 
hypoxic/ischemic hepatopathy, and biliary tract disease; obtaining additional tests to evaluate 
liver function (eg, prothrombin time [PT], activated partial thromboplastin time [aPTT], 
international normalized ratio [INR], albumin); and considering gastroenterology or 
hepatology consultation [FDA 2009]. 
Of note, HBV reactivation can occur in patients treated with rituximab with a median time to 
diagnosis of hepatitis among patients with hematologic malignancies of 4 months after the 
initiation of rituximab but such events can occur months after completion of rituximab 
therapy. The risk is very low among patients with negative anti-HBc serology [Matsue 2010] 
and/or undetectable HBV DNA as assessed by quanititative PCR. Because subjects with such 
evidence of persistent HBV infection are excluded from this study, reactivation is not 
anticipated.  However, among subjects with evidence of Grade ≥3 serum ALT/AST 
abnormalities, evaluation for HBV reactivation (manifest as positivity for serum HBsAg) 
should be considered as a precautionary measure. In a subject with active HBV, anti-HBV 
antiviral agents should be initiated. At the discretion of the investigators, study drug may be 
continued if HBV infection can be adequately controlled, particularly if the subject is 
experiencing clinical benefit from study therapy and there are few other options for treating 
the subject’s CLL. 
5.4.4. 
Hematological and Immunological Events 
In the Phase 1 experience with idelalisib in CLL, patients with Grade≥3 neutropenia, anemia, 
and and/or thrombocytopenia were enrolled to clinical trials. Decreased levels of neutrophil 
counts, hemoglobin, or platelet counts during therapy were largely due to minor fluctuations 
in these parameters among patients with pre-existing hematological abnormalities due to 
disease or prior therapy. Thus, idelalisib did not appear to induce overt myelosuppression. 
Obvious patterns of drug-mediated reductions in circulating CD4+ lymphocyte counts or 
suppression of serum IgG levels were also not observed. 
Given that patients with CLL commonly have Grade ≥3 hematological abnormalities due to 
underlying disease or prior therapy and that idelalisib is not associated with substantial 
myelotoxicity or off-target immunosuppression, alterations in study drug dose level for such 
events should only focus on subjects with protracted or symptomatic neutropenia or 
thrombocytopenia, unresponsive to G-CSF supportive care. No modification of idelalisib for 
changes in circulating CD4+ counts or Ig levels is planned. 


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5.4.5. 
Infectious Events 
Patients with CLL receiving idelalisib have developed serious bacterial, fungal, and viral 
infections during therapy [Gilead Sciences 2011]. Similarly, serious bacterial, fungal, and 
new or reactivated viral infections have also occurred during and for ~1 year following 
rituximab-based therapy [Gea-Banacloche 2010]. New or reactivated viral infections in 
patients receiving rituximab have included cytomegalovirus, herpes simplex virus, 
parvovirus B19, varicella zoster virus, West Nile virus, HBV (see Section 5.4.3) and HCV. 
Because patients with lymphoid malignancies (particularly those with CLL) are susceptible 
to infection due to the underlying disease, neutropenia, and the effects of prior therapy, the 
specific causal role of idelalisib or rituximab in any of these types of events is unclear. 
Patients with previously treated CLL have developed Pneumocystis (carinii) jiroveci 
pneumonia while receiving idelalisib. While idelalisib has not specifically been implicated in 
such cases, patients with lymphoid malignancies (particularly those with CLL) may be 
susceptible to pneumocystis infections due to the underlying disease and the effects of prior 
therapy. Pre-existing risk factors of specific concern may include previous pneumocystis 
pneumonia, underlying disease (eg, CLL), prior therapy (eg, alemtuzumab, progenitor cell 
transplantation), or immunocompromised status (low CD4+ lymphocyte counts, HIV 
infection) [Green 2007]. 
In a subject with a history of recurrent infections, prophylaxis with intravenous Ig should be 
considered [Raanani 2009]. Unless there is a contra-indication in a specific study subject, 
consideration should be given to initiation of antibiotic prophylaxis against pneumocystis 
infection (eg, with trimethoprim-sulfamethoxazole, dapsone, aerosolized pentamidine, or 
atovaquone) beginning prior to study drug administration. Such support may also offer the 
benefit of reducing the risk for other bacterial infections [Green 2007]. Local practices or 
guidelines regarding infection prophylaxis may be followed. 
For subjects who develop an infection, appropriate medical therapy (with antibiotics, 
antifungals, or antiviral) or other interventions should be instituted. Whenever appropriate, 
subjects should continue with study drug during treatment for the infection. 
5.4.6. 
Progressive Multifocal Leukoencephalopathy 
Progressive multifocal leukoencephalopathy (PML) due to polyomavirus JC has been 
observed in patients who have received rituximab therapy [Carson 2009] for hematologic 
malignancies. The specific causal role of rituximab is unknown because many of these 
patients had other risk factors (eg, low CD4+ counts) and the majority had received 
rituximab in combination with chemotherapy or as part of a hematopoietic stem cell 
transplant. Most cases of PML were diagnosed within 12 months of the last infusion of 
rituximab. 
The diagnosis of PML should be considered in any subject presenting with new-onset 
neurologic manifestations. Evaluation of PML may include consultation with a neurologist, 


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brain MRI, and lumbar puncture. In subjects diagnosed with PML, study drug should also be 
permanently discontinued. 
5.4.7. 
Pulmonary Events 
Documented bacterial, fungal, viral, and pneumocystis pneumonias have been observed in 
patients receiving idelalisib, primarily in patients with CLL. Some patients receiving 
idelalisib alone or in combination have developed evidence of pneumonitis without 
documented lung infection. The specific role of idelalisib in these events is unclear; 
nonclinical evaluations of pulmonary function and pathology do not indicate a direct toxic 
effect of idelalisib on the lungs [Gilead Sciences 2011] and disease-related factors or toxicity 
from prior or concomitant therapies may have contributed to these clinical events. 
Rituximab-related noninfectious pneumonitis has been described [Subramanian 2010] with 
an incidence of ~4.3% [Salmasi 2010]. In patients developing rituximab-associated 
pneumonitis, the mean time from the first rituximab infusion to the onset of respiratory 
symptoms was 3 months, with a peak incidence after administration of a mean cumulative 
dosage of 1600 mg/m2 [Lioté 2010]. 
Given the potential for infectious or drug-related adverse events, clinicians should be 
particularly observant for evidence of respiratory events in subjects participating in this trial. 
Subjects should be evaluated who describe pulmonary symptoms (eg, dyspnea on exertion, 
cough, shortness of breath); manifest a decline from baseline of ≥5% in oxygen saturation, or 
demonstrate evidence of pulmonary inflammation (eg, focal or diffuse interstitial pattern or 
ground-glass opacities on chest CT). Potential bacterial, fungal, or viral etiologies should be 
assessed. Pneumocystis (carinii) jiroveci should be considered, especially if the subject is not 
receiving pneumocystis prophylaxis. Depending upon the changes observed and the response 
to antibiotic intervention, recommended diagnostic work-up may include blood and sputum 
cultures; polymerase chain reaction or antigen testing for pneumocystis and respiratory 
viruses (eg, CMV, influenza virus, respiratory syncytial virus, parainfluenza virus, 
rhinovirus); chest X-ray, CT or other imaging methods; pulmonary function testing and 
diffusing capacity of the lung for carbon monoxide (DLCO); bronchoscopic lavage and/or 
biopsy; or open-lung biopsy. Noninfectious etiologies such as pulmonary edema or 
thromboembolism should also be considered. 
As appropriate for the clinical situation and culture results, subjects should be treated 
empirically or given specific antibiotics, antifungals, or antiviral agents for a cultured 
organism. Supportive care, including oxygen or mechanical ventilation, should be provided 
as necessary.  
For subjects with a symptomatic pneumonitis (eg, onset of cough, dyspnea, hypoxia and/or a 
diffuse interstitial pattern or ground-glass opacities on chest (CT), study drug should be 
interrupted and therapy with systemic corticosteroids (eg, prednisone, 60 mg/day) should be 
instituted rapidly [Lioté 2010]. Resumption of study drug at Dose Level -1 should only be 
considered if the subject is experiencing evidence of clinical benefit from study drug; 


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reoccurrence of drug-related pneumonitis upon rechallenge should result in permanent 
discontinuation of study drug. 
5.4.8. 
Tumor Lysis Syndrome 
Patients with tumor lysis syndrome may experience hyperkalemia, hypocalcemia, 
hyperuricemia, hyperphosphatemia, cardiac dysrhythmias, and acute renal failure. 
Tumor lysis syndrome has not been observed with idelalisib monotherapy. However, if tumor 
lysis were to occur in a subject participating in this study, the subject should receive rapid 
reversal of hyperkalemia, intravenous hydration, antihyperuricemic agents, and appropriate 
cardiac and renal support, including dialysis as indicated. Upon recovery to baseline 
functioning, such subjects should continue study therapy to maintain tumor control. 
5.4.9. 
Pregnancy, Lactation, and Reproduction 
Idelalisib has induced embryo lethality and teratogenicity when administered to pregnant 
female rats at maternally toxic doses [Gilead Sciences 2012]. However, definitive 
reproductive toxicology studies in animals have not yet been performed and the specific 
effects of idelalisib on human embryogenesis or fetal development are unknown. Whether 
idelalisib is excreted in human breast milk is unknown. General toxicology studies in rats and 
dogs indicated dose-dependent reductions in testicular weights, with persistent minimal to 
mild degeneration of the seminiferous tubules and decreased spermatozoa in rats and 
hypospermatogenesis in dogs. The implications of these testicular changes for animal or 
human fertility are unknown. 
Given the preliminary nature of data regarding the risks to a fetus or infant as a result of 
exposure to idelalisib, women of reproductive potential entering this study must have a 
negative serum pregnancy test at baseline and must not be breastfeeding. Males and females 
of childbearing potential should abstain from sexual intercourse or use an effective form of 
contraception (see Section 5.6.4). If a female study participant becomes pregnant or decides 
to breastfeed during the course of the study, all study therapy must be discontinued. Study 
candidates will be informed of the testicular findings through the informed consent process. 
5.4.10. 
Ultraviolet Exposure 
In vitro studies indicate enhanced cytotoxicity when embryonic murine fibroblasts treated 
with GS-563117 (the major metabolite of idelalisib) are simultaneously exposed to 
ultraviolet light.  While nonclinical findings suggest the hypothetical potential for 
phototoxicity in humans, available clinical data do not reveal a photosafety concern 
[Gilead Sciences 2012]. Although specific clinical correlates for these nonclinical data are 
not available, investigators and study subjects should be observant for the possibility that 
study participants may have exaggerated sunburn reactions (eg, burning, erythema, 
exudation, vesicles, blistering, edema) involving areas of skin exposed to ultraviolet light. 


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5.5. 
Emergency Unblinding 
Every attempt should be made to preserve the integrity of study drug dose assignment 
blinding. Unblinding in individual subjects who experience adverse events is rarely required 
to provide effective intervention and support. For subjects having adverse events or 
laboratory abnormalities that require drug cessation or medical intervention, the 
investigational staff should strive to provide necessary support to the subject without 
breaking the blind. In the exceptional circumstance that knowledge of the study drug dose 
assignment appears essential for providing appropriate medical management, the investigator 
should contact the Gilead Sciences medical monitor to discuss the rationale for breaking the 
blind and the adverse consequences of the unblinding for the subject’s continued 
participation on study drug. If the investigator still believes that unblinding is warranted, the 
investigator will be able to access the allocation system in order to obtain the treatment 
assignment for that subject. No randomization lists or other unblinding information will be 
provided to the site. After breaking the blind, the investigational site staff should record 
details regarding the reasons for breaking the blind and any adverse events leading to the 
breaking of the blind in the source documents and in the appropriate eCRF. 
If the site breaks the blind, the appropriateness of continued study drug therapy should be 
discussed with the Gilead Sciences medical monitor. Subjects who intentionally subvert the 
blind (eg, through chemical analysis of the drug) should be discontinued from study drug 
therapy.  
5.6. 
Concomitant and Supportive Therapy 
To the extent possible, administration of any prescription or over-the-counter drug products 
other than study medication should be minimized during the study period. Subjects should be 
discouraged from use of street drugs, herbal remedies, self-prescribed drugs, tobacco 
products, or excessive alcohol at any time during the clinical study. 
If considered necessary for the subject’s well-being, drugs for concomitant medical 
conditions or for symptom management may be given at the discretion of the investigator. 
The decision to authorize the use of any drug other than study drug should take into account 
subject safety, the medical need, the potential for drug interactions, the possibility for 
masking symptoms of a more significant underlying event, and whether use of the drug will 
compromise the outcome or integrity of the study 
Subjects should be instructed about the importance of the need to inform the clinic staff of 
the use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and 
during the course of the study. Any concomitant drugs taken by a subject during the course 
of the study and the reason for use should be recorded on the eCRFs. 
Information regarding use or restrictions on specific concomitant medications, dietary 
measures, or other interventions is provided below. 


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5.6.1. 
Anticancer or Experimental Therapies Other than Investigational 
Treatments 
Except for corticosteroids, no other anticancer therapies (including chemotherapy, radiation, 
antibody therapy, immunotherapy, or other experimental therapies) of any kind are permitted. 
Subjects are not allowed to participate concurrently in any other therapeutic clinical study. 
5.6.2. 
Antibiotics 
Except in a subject who has a contra-indication, investigators should consider initiation of 
antibiotic prophylaxis against pneumocystis infection (eg, with trimethoprim-
sulfamethoxazole, dapsone, aerosolized pentamidine, or atovaquone) beginning prior to study 
drug administration. Such support may also offer the benefit of reducing the risk for other 
bacterial infections [Green 2007]. Investigator discretion and local practices or guidelines 
may be followed. 
For subjects who develop an infection, appropriate medical therapy (with antibiotics, 
antifungals, or antiviral) or other interventions should be instituted. Whenever appropriate, 
subjects may continue with study drug during treatment for the infection. 
5.6.3. 
Antiemetics and Antidiarrheals 
Drug-related nausea and/or vomiting have not been commonly observed with idelalisib in 
prior studies. However, subjects who experience nausea or vomiting while on study therapy 
may receive antiemetics based on the judgment of the treating physician and local 
institutional practices. At the occurrence of persistent nausea or vomiting of severity 
Grade ≥1, it is suggested that the subject receive an oral or transdermal serotonin antagonist 
(eg, dolasetron, granisetron, ondansetron, tropisetron, palonosetron). The neurokinin receptor 
antagonist, aprepitant, may be considered but is a mild inhibitor of CYP3A4 and so may 
modestly increase idelalisib plasma exposures. Other classes of antiemetic medications that 
may be employed include dopamine antagonists or benzodiazepines. As needed, subjects 
may be prescribed loperamide (Imodium® or others) or diphenoxylate and atropine 
(Lomotil®) to control diarrheal symptoms. 
5.6.4. 
Contraception 
In the context of this protocol, a female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, a bilateral tubal ligation, or a bilateral oophorectomy; has 
medically documented ovarian failure (with serum estradiol and FSH levels within the 
institutional postmenopausal range and a negative serum or urine βHCG); or is menopausal 
(age >55 years with amenorrhea for >12 months or amenorrhea for >6 months with serum 
estradiol and FSH levels within the institutional postmenopausal range). 
Sexually active females of childbearing potential must agree to use a protocol-recommended 
method of contraception during heterosexual intercourse throughout the study treatment 
period and for 30 days following discontinuation of the study drug. The investigator should 


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counsel subjects on the most effective methods for avoiding pregnancy during the trial. 
Protocol-recommended contraceptive methods are described in Table 5-3. 
Table 5-3. 
Protocol-Recommended Contraceptive Methods 
Individual Methods 
Combination Methods 
Hormonal Methods 
(One method to be used 
with a barrier method) 
Barrier Methods 
(Both of these methods to be used OR one of these 
methods to be used with a hormonal method) 
IUD 
Estrogen and progesterone 
Diaphragm with spermicide 
Copper T 380A IUD 
Oral contraceptives 
Male condom (with spermicide) 
LNg 20 IUD 
Transdermal patch 
 
Tubal sterilization 
Vaginal ring 
 
Hysterectomy 
Progesterone 
 
 
Injection 
 
 
Implant 
 
Abbreviation: IUD=intrauterine device 
 
In the context of this protocol, a male subject is considered able to father a child unless he 
has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or is 
receiving ongoing testicular suppression with a depot luteinizing hormone-releasing hormone 
(LH-RH) agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or 
triptorelin pamoate [Trelstar®]). 
Sexually active male subjects who can father a child must accept continuous heterosexual 
abstinence as a lifestyle choice; limit intercourse to female partners who are surgically sterile, 
post-menopausal, or using effective contraception (as noted in Table 5-3); or agree to use a 
protocol-recommended method of contraception during heterosexual intercourse throughout 
the study treatment period and for 90 days following discontinuation of the study drug 
(as noted in Table 5-3).  
The Gilead Sciences medical monitor should be consulted regarding any questions relating to 
childbearing status or contraception. 
5.6.5. 
Corticosteroids 
Subjects may receive topical, inhaled, enteric, or systemic corticosteroids while on study. It 
should be realized that the use of systemic corticosteroids in patients with CLL may 
confound interpretation of antitumor effects mediated by study drug therapy. However, 
subjects who develop conditions that may be alleviated by systemic corticosteroid therapy 
are permitted to receive such drugs and are not required to discontinue study participation. 


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5.6.6. 
Granulocyte Colony-Stimulating Factors and Erythropoietin 
Granulocyte-macrophage colony-stimulating factor (GM-CSF) should not be administered 
given the potential for GM-CSF-related inflammatory symptoms. 
G-CSF (filgrastim, PEG-filgrastim, lenograstim) may be administered in response to Grade 4 
neutropenia or neutropenic complications; use should be particularly considered if providing 
hematopoietic support might help to maintain study drug treatment (see Table 5-2). 
While erythropoietic agents (eg, erythropoietin or darbepoetin) may be administered for 
Grade ≥3 anemia, their use in this study is discouraged given the potential to confound 
assessments of improvements in bone marrow function related to study drug. 
Reference may be made to the American Society of Clinical Oncology guidelines 
[Rizzo 2008, Smith 2006]. 
5.6.7. 
Drugs that Alter CYP3A4-Dependent Metabolism 
Idelalisib is metabolized in part by CYP3A4. A clinical drug-drug interaction study indicated 
that administration of a potent CYP3A4 inhibitor together with idelalisib induced a modest 
(1.8-fold) increase in idelalisib plasma AUC (see Section 1.3.5.1). These data imply that 
strong inhibitors of CYP3A4 may increase plasma concentrations of idelalisib. While no 
clinical data are available, it is also theoretically possible that strong inducers of CYP3A4 
may decrease plasma concentrations of idelalisib. Thus, there is the potential that subjects 
receiving potent CYP3A4 inhibitors may have exaggerated pharmacological or toxic 
responses or that those receiving potent CYP3A4 inducers may have reduced idelalisib 
activity. A list of potent CYP3A inhibitors and inducers is provided in Table 5-4.  


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Table 5-4. 
Known Inhibitors or Inducers of CYP3A 
Effect on 
CYP3A 4 
Drug Class 
Medications 
Moderate to 
Strong 
CYP3A4 
Inhibitors 
Antibiotics 
chloramphenicol, ciprofloxacin, clarithromycin, 
erythromycin, telithromycin 
Antiemetic 
aprepitant 
Antifungals 
ketoconazole, fluconazole, itraconazole, posaconazole, 
voriconazole 
Antiviral 
protease inhibitors 
amprenavir, atazanavir, boceprevir, cobicistat, darunavir, 
elvitegravir, fosamprenavir, indinavir, lopinavir, nelfinavir, 
ritonavir, saquinavir, telaprevir, tenofovir, tipranavir 
Calcium-channel blockers 
diltiazem, mibifradil, verapamil 
Foods/herbs 
grapefruit juice 
Serotonin antagonist 
nefazodone 
Tyrosine kinase inhibitor 
imatinib 
Vasopressin antagonists 
conivaptan 
Strong 
CYP3A4 
Inducers 
Antibiotics 
rifampin 
Anticonvulsants 
carbamazepine, phenobarbital, phenytoin 
Foods/herbs 
St. John’s wort 
Abbreviation: CYP=cytochrome P450 enzyme 
 
Caution is warranted when coadministering a strong CYP3A4 inhibitor or inducer together 
with idelalisib. However, such use is not contraindicated and does not require specific 
monitoring. Depending upon the clinical circumstances, investigators may wish to minimize 
or avoid concurrent administration of these types of drugs in subjects receiving idelalisib or, 
when possible, use therapeutic alternatives that would not be expected to affect CYP3A4 
activity. Immunization 
Because of its actions to inhibit PI3Kį-dependent B-cell function, high doses of idelalisib 
can impair primary or secondary responses to immunization in animals 
[Gilead Sciences 2011]. 
The specific clinical relevance of these findings with idelalisib is unknown. However, for 
subjects who are at substantial risk of an infection (eg, influenza) that might be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of 
study therapy. 
Of note, the safety of immunization with live viral vaccines following idelalisib therapy has 
not been studied and vaccination with live virus vaccines during study treatment is not 
recommended. 


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5.6.8. 
Surgery 
There are no known effects of idelalisib on coagulation or wound healing. Pending receipt of 
additional information, study drug may be continued in the peri-procedural period in subjects 
who require surgery or invasive procedures. 
5.6.9. 
Diet 
There are no specific dietary restrictions in the study. Study drug may be taken with or 
without food. 
5.7. 
Duration of Study Drug 
Subjects may continue receiving study drug until the occurrence of any events requiring 
study drug discontinuation as defined in Section 5.8. 
5.8. 
Discontinuation of Study Drug 
All study participants may receive study drug indefinitely; however: 
• Any subject has the right to discontinue study drug at any time. 
• Any subject who has objective evidence based on IRC review of definitive CLL 
progression will discontinue study drug. 
• Any subject unable to tolerate a second rechallenge with protocol-described, 
dose-modified idelalisib at Dose Level –1 (see Section 5.2) should discontinue study 
drug. 
• Any subject who becomes pregnant or begins breastfeeding should discontinue study 
drug. 
• Any subject who becomes significantly noncompliant with study drug administration, 
study procedures, or study requirements should discontinue study drug. 
• Any subject for whom the blind is intentionally broken by the subject or the study site 
should discontinue study drug. 
• The investigator, in consultation with the Gilead Sciences medical monitor, may 
discontinue study drug, if, it is not in the subject’s best interest to continue.  
• If allowed by local regulations, Gilead Sciences may transition subjects from study drug 
to commercial drug supply when idelalisib becomes commercially available in the 
country where the subject is living. 


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Subjects who permanently discontinue study drug for a reason other than disease progression 
(as determined by the IRC) shall continue with assessments per the schedule of procedures 
until disease progression or until study participation is ended.   
5.9. 
Discontinuation from Study 
Subject study participation will be ended due to any of the following reasons: 
• Adverse event; 
• Disease progression; 
• Withdrawal of consent; 
• Physician’s decision to remove the subject from the study; 
• Pregnancy; 
• The subject is lost to follow-up;  
• Death; 
• Discontinuation of study by the Sponsor, a Regulatory Agency, or an IRB or EC.  
5.10. 
Study Treatment Rationale 
Subjects will be assigned to treatment (Arm A or Arm B) in this study based on their 
randomization in the primary study. The 1:1 randomization in the primary trial 
(GS-US-312-0116) ensures that sufficient Arm B subjects will cross over from rituximab 
alone to single-agent idelalisib at the 150-mg/dose BID starting dose level in this extension 
trial (GS-US-312-0117) to allow an adequate evaluation of efficacy and safety in this trial. 
The randomization and allocation processes will be established and performed through an 
IWRS; the intent is to maximize the integrity and security of the subject disposition and to 
ensure appropriate access and convenience-of-use by the investigational sites. 
Double blinding is included to provide protection against biased interpretations of efficacy 
and safety data by subjects, caregivers, investigators, Gilead Sciences personnel, or others 
involved in study conduct.  
Selection of the idelalisib treatment regimen (including starting dose level, 
dose-modifications and supportive care, schedule, duration, and conditions of administration) 
for this study program has been based primarily on safety, exposure, and activity profiles 
from previous Phase 1 clinical studies involving healthy volunteers, patients with allergic 
rhinitis, and patients with refractory/relapsed lymphoid malignancies [Webb 2010, 
Coutre 2011, Kahl 2011]. The following information was considered in selecting the study 
drug dosing regimen for the primary study and this companion extension study: 


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• Idelalisib was symptomatically well tolerated in patients with lymphoid malignancies 
receiving dose levels of 50 mg/dose BID through 350 mg/dose BID (the highest dose 
level tested). No specific MTD was apparent over the dose range tested. However, 
monitorable, reversible transaminase elevations were observed in some patients and may 
have been more frequent at higher dose levels (~10% rate among patients with CLL 
receiving starting doses of ≥150 mg/dose). Thus, while doses through 350 mg/dose BID 
are tolerable, the starting dose of 150 mg/dose BID appears to appropriately balance 
safety with efficacy in idelalisib-naïve subjects. The starting dose of 300 mg/dose BID in 
this study also appears appropriate for evaluation; it is lower than the dose level of 
350 mg/dose BID that has been tolerable in prior studies and is likely to be suitable in 
subjects who have already been tolerating idelalisib therapy at ≥100 mg/dose BID.  
• Upon disease progression, permitting escalation from 150 mg/dose BID to 
300 mg/dose BID among subjects allocated to Arm A offers a systematic evaluation of 
higher doses in subjects who are tolerating idelalisib treatment and might benefit from 
increased PI3Kδ inhibition. The pharmacological basis for considering such an 
intervention is based on the concept that some individuals might have 
lower-than-expected plasma exposures or dose-dependent resistance to the compound at 
150 mg/dose BID and might benefit from a higher dose. The intent is to determine if the 
higher dose can reestablish disease control or whether absolute resistance to PI3Kδ 
inhibition has been acquired. The safety data obtained in these subjects would add to the 
overall safety database. 
• In an allergic rhinitis study, idelalisib induced statistically significant improvements in 
clinical and pharmacodynamic endpoints when administered at 100 mg/dose BID over 
7 days. These data support the pharmacological relevance of idelalisib-mediated PI3Kį 
inhibition when administered at the dose-levels to be used in this study. 
• A positive correlation was noted between idelalisib dose and measures of tumor control 
and chemokine normalization in patients with B-cell malignancies. The majority of 
patients appear to have tumor responses and protracted PFS when receiving starting doses 
of ≥100 mg/dose BID. Thus, treatment with a idelalisib at a starting dose of 150 mg/dose 
BID appears to offer most patients the potential to benefit from therapy and the dose level 
of 300 mg/dose BID may provide additional benefit in patients with disease resistance as 
systematically evaluated in this trial.  
• Based on evaluations of idelalisib steady-state plasma Cmax, AUC, and Ctrough values over 
a range of doses, administration of starting doses of idelalisib of ≥150 mg/dose BID 
appears appropriate to ensure adequate exposure in the majority of patients.  
• In Phase 1 studies, the mean plasma t1/2 of idelalisib was ~6.5 to 9.8 hours across all dose 
levels and there was no substantive plasma accumulation over 7 or 28 days. The 
collective data support a study drug administration schedule of BID administration to 
maintain idelalisib plasma Ctrough values without inducing excessively high plasma Cmax 
values.  


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• The changes in exposure observed when administering idelalisib after a high-fat, 
high-calorie meal are modest (~40% increase in mean AUC with no change in mean 
Cmax). Thus, idelalisib can be administered with or without food.  
• Clinical evidence suggests that potent inhibitors of CYP3A4 may cause a modest increase 
in idelalisib plasma concentrations in humans. Alternatively, CYP3A4 inducers might 
theoretically decrease idelalisib plasma concentrations in humans. Given the fact that 
idelalisib is well tolerated and appears to be a relatively weak substrate for CYP3A4, 
administration of CYP3A4 inhibitors together with idelalisib does not appear to be 
contraindicated and specific monitoring does  not appear necessary. The effects of 
administration of CYP3A4 inducers together with idelalisib are unknown. In view of 
these findings, it is prudent to advise investigators that that they may wish to avoid 
prescribing agents that may potently affect CYP3A4 activity or consider using 
therapeutic alternatives that do not affect CYP3A4 activity. 
• The idelalisib dose modification provisions described in the protocol are designed to 
balance a primary concern for subject safety with the potential for observing 
pharmacological and antitumor activity in circumstances under which a subject 
experiencing an adverse event may still be able to continue on therapy at a lower 
idelalisib dose level. The enhanced monitoring to be performed and the actions to be 
taken in response to toxicity are based on experience with interruption, 
dose-modification, rechallenge, and re-escalation already piloted in idelalisib Phase 1 
trials. In addition, idelalisib antitumor activity has been observed in the Phase 1 studies 
across all dose levels tested, including doses in the range of the modified dose levels 
planned for this protocol. Thus, use of the lower dose level to accommodate individual 
subject tolerability in this protocol is justified because subjects receiving such a idelalisib 
dose level still have the potential for benefit. 
• In both the primary and extension studies, study treatment will be continued for each 
subject until the occurrence of disease progression. Such a strategy is considered 
appropriate under the assumption that persistent interference with PI3Kδ signaling is 
likely to extend treatment effect. In addition, this design permits collection of further 
single-agent safety information and thus is likely to enhance understanding of the overall 
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6. 
STUDY PROCEDURES 
6.1. 
Enrollment and Study Management Procedures 
6.1.1. 
Subject Recruitment 
Study candidates are limited to those subjects who participated in the primary clinical trial 
(Study GS-US-312-0116) and meet the entry criteria for this trial (Study GS-US-312-0117). 
Subjects will be enrolled from investigational sites in the United States and Europe. The site 
principal investigator, designated sub-investigators, or other designees will discuss the 
possibility of participation directly with subjects who participated in the primary study.  
The study sponsor will post a description of the study on the ClinicalTrials.gov website. Any 
promotional information generated by the sponsor or investigational sites will be submitted 
for IRB/IEC review. 
6.1.2. 
Subject Compensation for Participation 
For subjects requesting such assistance, reasonable reimbursements for the costs of travel 
required to participate in this study will be provided by the study sponsor. To receive 
payment for travel, subjects will need to submit the original travel receipts to the research 
study staff at the investigational site. 
However, other than medical care that may be provided, subjects will not be paid for 
participation in the study. Payments for such items as lost wages, disability, discomfort due 
to injury, or meals obtained while waiting at the clinical research center will not be provided. 
Through the informed consent process, study candidates will be notified that their insurance 
company could be charged for standard care that is a component of this research study and 
that subjects may be responsible for co-payments and deductible payments that are typical 
for their insurance coverage. 
6.1.3. 
Screening 
The investigator must inform each prospective subject of the nature of the study, explain the 
potential risks, and obtain written informed consent from the subject and/or a legal guardian 
prior to performing any study-related screening procedures. At the time the study candidate 
signs the informed consent, a site representative should access the IWRS to indicate that a 
study candidate is being screened. The user will need to supply the IWRS with required 
information identifying the site and the subject number as already assigned in 
Study GS-US-312-0116. 
Any consented subject who is excluded from the study before initiation of study treatment 
will be considered a screen failure. All screen failures must be documented along with an 
adequate description of the reason the subject was considered a screen failure. If available, 
information should be provided as to why the subject did not meet eligibility criteria, 


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withdrew consent, experienced an intercurrent illness, or had other events that precluded 
treatment on this study. 
6.2. 
Explanation of Study Visits 
The specific study procedures to be conducted for each subject enrolled in the study are 
presented in tabular form in Appendix 7 and are described in the sections that follow. 
Additional information on the study procedures is provided in the study manual. 
For visits at which HRQL and healthy utility data are obtained, it is important that the subject 
be administered the FACT-Leu and the EQ-5D before any other procedures are performed 
and before any study-related information is communicated to the subject; this is necessary to 
avoid biasing the PRO responses provided by the subject. Once the subject has completed the 
FACT-Leu and the EQ-5D assessments, the remaining procedures may be performed. 
At visits involving idelalisib administration and pharmacokinetic sampling in the clinic, care 
should be taken to perform procedures with the appropriate timing relative to idelalisib 
administration. The actual sample collection times of pharmacokinetic blood specimens 
should be recorded. If a heparinized venous catheter is placed for sample collection in order 
to avoid repeated needle sticks, at least 2 mL of blood should be removed and discarded prior 
to each sample collection in order to avoid heparin contamination of the sample. 
At the visit designated as a laboratory-only visit (Visit 7), subjects will have laboratory 
assessments that may be performed at the investigational site or at an accredited local 
laboratory or clinic that is convenient for the subject/caregiver. If blood is collected at a local 
laboratory, samples are not to be analyzed at the local laboratory. For these visits, subjects 
and/or caregivers will be provided with central laboratory kits that will contain materials 
necessary for the collection and shipment of the laboratory samples by the local laboratory 
clinic to the central laboratory. 
In addition to clinical assessments of tumor status, CT or MRI imaging of the neck, chest, 
abdomen, and pelvis will be performed as a component of tumor assessments during the 
study based on the rationale provided in Section 3.2.1. 
6.2.1. 
Visit 1 and Screening Period (Clinic Visit) 
The initial screening visit is designated as Visit 1. At Visit 1, the investigator must inform 
each prospective study participant of the nature of the study, explain the potential risks, and 
obtain written informed consent from the study candidate and/or legal guardian prior to 
performing any study-related screening procedures. Once the informed consent document has 
been signed, the subject may undergo the screening procedures. 
In order to optimize scheduling convenience for the subject and for the investigational staff, 
study procedures performed as part of Study GS-US-312-0116 need not be repeated and can 
be used as screening procedures for Study GS-US-312-0117 if performed within 4 weeks 
prior to initiation of study drug therapy on Study GS-US-312-0117. In addition, screening 


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procedures may be performed over as many days as necessary provided that screening is 
completed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117.  
The tests and evaluations outline in Table 6-1 will be performed at Visit 1 or during the 
screening period prior to initiation of study treatment. 
Table 6-1. 
Procedures and Assessments at Visit 1 (During Screening Period) 
Assessment  
or Procedure 
Explanationa 
Informed consent 
To be obtained before any screening procedures are initiated 
IWRS access 
Access IWRS to document that subject is in screening and provide  the subject number from 
Study GS-US-312-0116 
CIRS assessment 
Recording of current comorbid conditions using the CIRS scoring instrument (see Appendix 6) 
Concomitant 
medications 
Recording of ongoing concomitant medication use 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including height, weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly 
Serum ȕ-HCG 
Women of childbearing potential only 
CLL peripheral blood 
evaluation 
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 12 trisomy; DNA 
mutational analysis for p53, IgHV (including IgHV3-21), and other genes of interest in CLL (eg, 
Notch); flow cytometry for CD5, CD10, CD11c, CD19, CD20, CD23, CD38, CD45, kappa and 
lambda light chains, and ZAP-70; cytology for karyotyping. 
CLL serology 
Serum β2 microglobulin 
 
 
 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Radiology assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis, to be scheduled with 4 weeks prior to 
initiation of study treatment at Visit 2 
Bone marrow biopsy 
and aspirate 
To be performed at investigator discretion to determine extent of CLL involvement and bone 
marrow cellularity. 
a 
Study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be used as screening 
procedures for Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117. 
Abbreviations: β-HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, CIRS=cumulative illness rating scale, CLL=chronic lymphocytic leukemia, CT=computed 
tomography, DNA=deoxyribonucleic acid, FISH= fluorescence in-situ hybridization, GGT=gamma--glutamyltransferase, 
Ig=immunoglobulin, IgHV=immunoglobulin heavy chain variable region, IWRS=interactive web response system, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, RNA=ribonucleic acid, ZAP-70=zeta-associated 
protein 70 
PPD


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6.2.2. 
Visit 2 (Day 1) (Clinic Visit) 
Subjects will be assessed to determine if they still meet eligibility criteria and can initiate 
study treatment. The procedures outlined in Table 6-2 will be performed at Visit 2 (Day 1). 
Table 6-2. 
Procedures and Assessments at Visit 2 (Day 1) 
Assessment or 
Procedure 
Explanation 
Pre-Dose Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the 
subject 
Adverse events 
Recording of adverse events occurring since the initiation of the screening period 
Concomitant 
medications 
Recording of concomitant medication use since the initiation of the screening period 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
ȕ-HCG 
For women of child-bearing potential only; serum β-HCG or urine dipstick pregnancy test must 
be negative prior to initial study treatment 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Idelalisib 
pharmacokinetics 
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the date 
and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug blister card number 
Study Therapy Administration 
Study drug 
administration 
First dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration) 
Post-Therapy Procedures and Assessments 
Idelalisib 
pharmacokinetics 
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after study 
drug administration (with recording of the date and actual clock time of blood collection) 
Study drug dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
study drug dosing at 
next full clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 3. 
Abbreviations: β-HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web 
response system, LDH=lactate dehydrogenase, RNA=ribonucleic acid 


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6.2.3. 
Visit 3 (Day 15) (Clinic Visit) 
The procedures outlined in Table 6-3 will be performed at Visit 3 (Day 15 [±2 days]).  
Table 6-3. 
Procedures and Assessments at Visit 3 (Day 15) 
Assessment or 
Procedure 
Explanation 
Pre-Dose Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the 
subject 
Adverse events 
Recording of adverse events occurring since the initiation of the screening period 
Concomitant 
medications 
Recording of concomitant medication use since the initiation of the screening period 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Idelalisib 
pharmacokinetics 
Recording of the date and actual clock time of the last prior subject self-administration of study 
drug (should be the prior evening dose)Pre-dose collection of plasma sample for idelalisib 
pharmacokinetics (with recording of the date and actual clock time of the date and actual clock 
time of blood collection) 
IWRS access 
Access of IWRS to document subject visit 
Study Therapy Administration 
Study drug 
administration 
Study drug to be administered to the subject (with recording of the date and actual clock time of 
the study drug administration) 
Post-Therapy Procedures and Assessments 
Idelalisib 
pharmacokinetics 
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after study 
drug administration (with recording of the date and actual clock time of blood collection) 
Instruction regarding 
study drug dosing at 
next full clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 4. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, HRQL=health-
related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, LDH=lactate 
dehydrogenase 


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6.2.4. 
Visit 4 (Day 29) (Clinic Visit) 
The procedures outlined in Table 6-4 will be performed at Visit 4 (Day 29 [±2 days]). 
Table 6-4. 
Procedures and Assessments at Visit 4 (Day 29) 
Assessment or 
Procedure 
Explanation 
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 3 
Concomitant 
medications 
Recording of concomitant medication used since Visit 3 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Urine ȕ-HCG 
dipstick 
For women of child-bearing potential only 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Idelalisib 
pharmacokinetics 
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug blister card number 
Study Therapy Administration and Dispensing 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
Idelalisib 
pharmacokinetics 
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
dosing at next full 
clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 5. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-
Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging 


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6.2.5. 
Visit 5 (Day 43) (Clinic Visit) 
The procedures outlined in Table 6-5 will be performed at Visit 5 (Day 43 [±2 days]).  
Table 6-5. 
Procedures and Assessments at Visit 5 (Day 43) 
Assessment or 
Procedure 
Explanation 
Pre-Dose Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the 
subject 
Adverse events 
Recording of adverse events occurring since the initiation of the screening period 
Concomitant 
medications 
Recording of concomitant medication use since the initiation of the screening period 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
IWRS access 
Access of IWRS to document subject visit 
Study Therapy Administration 
Study drug 
administration 
Study drug to be administered to the subject (with recording of the date and actual clock time of 
the study drug administration) 
Post-Therapy Procedures and Assessments 
Instruction regarding 
study drug dosing at 
next full clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 6. 
Scheduling of Visit 6 
radiology assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 6. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, HRQL=health-
related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, LDH=lactate 
dehydrogenase 


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6.2.6. 
Visit 6 (Day 57) (Clinic and Radiology Visit) 
The procedures outlined in Table 6-6 will be performed at Visit 6 (Day 57 [±2 days]).  
Table 6-6. 
Procedures and Assessments at Visit 6 (Day 57) 
Assessment or 
Procedure 
Explanation 
Pre-Visit Tumor Assessment 
Radiology assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the 
assessment should be done even if study drug has been interrupted.  
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 5 
Concomitant 
medications 
Recording of concomitant medication used since Visit 5 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Urine ȕ-HCG dipstick 
For women of child-bearing potential only 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and CD+20 cells by flow 
cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Bone marrow biopsy 
and aspirate 
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR. 
Idelalisib 
pharmacokinetics 
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug bottle number 
Study Therapy Administration 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
Idelalisib 
pharmacokinetics 
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after study 
drug administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
dosing at next full 
clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 8. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment 
of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging 


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6.2.7. 
Visit 7 (Day 71) (Laboratory Visit) 
The procedures outlined in Table 6-7 will be performed at Visit 7 (Day 71 [±2 days]). 
Table 6-7. 
Procedures and Assessments at Visit 7 (Day 71) 
Assessment or 
Procedure 
Explanation 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including ALT, AST, ALP, GGT, total bilirubin, LDH 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
GGT=gamma-glutamyltransferase, LDH=lactate dehydrogenase 


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6.2.8. 
Visit 8 (Day 85) (Clinic Visit) 
The procedures outlined in Table 6-8 will be performed at Visit 8 (Day 85 [±2 days]). 
Table 6-8. 
Procedures and Assessments at Visit 8 (Day 85) 
Assessment or 
Procedure 
Explanation 
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 6 
Concomitant 
medications 
Recording of concomitant medication used since Visit 6 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Urine ȕ-HCG 
dipstick 
For women of child-bearing potential only 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Idelalisib 
pharmacokinetics 
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug blister card number 
Study Therapy Administration and Dispensing 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
Idelalisib 
pharmacokinetics 
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
dosing at next full 
clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 9. 
Scheduling of Visit 9 
radiology assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 9. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-
Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging 


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6.2.9. 
Visit 9 (Day 113) (Clinic and Radiology Visit) 
The procedures outlined in Table 6-9 will be performed at Visit 9 (Day 113 [±3 days]). 
Table 6-9. 
Procedures and Assessments at Visit 9 (Day 113) 
Assessment or 
Procedure 
Explanation 
Pre-Visit Tumor Assessment 
Radiology assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit the 
assessment should be done even if study drug has been interrupted.  
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 8 
Concomitant 
medications 
Recording of concomitant medication used since Visit 8 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Urine ȕ-HCG 
dipstick 
For women of child-bearing potential only 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and CD+20 cells by flow 
cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Bone marrow biopsy 
and aspirate 
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR. 
Idelalisib 
pharmacokinetics 
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug blister card number 
Study Therapy Administration 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
Idelalisib 
pharmacokinetics 
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after study 
drug administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
dosing at next full 
clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 10. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment 
of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging 


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6.2.10. 
Visit 10 (Day 141) (Clinic Visit) 
The procedures outlined in Table 6-10 will be performed at Visit 10 (Day 141 [±3 days])  
Table 6-10. 
Procedures and Assessments at Visit 10 (Day 141) 
Assessment or 
Procedure 
Explanation 
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 9 
Concomitant 
medications 
Recording of concomitant medication used since Visit 9 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Urine ȕ-HCG 
dipstick 
For women of child-bearing potential only 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Idelalisib 
pharmacokinetics 
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug  blister card number 
Study Therapy Administration 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
Idelalisib 
pharmacokinetics 
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
dosing at next full 
clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 11. 
Scheduling of 
Visit 11 radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 11. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-
Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging 


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6.2.11. 
Visit 11 (Day 169) (Clinic and Radiology Visit) 
The procedures outlined in Table 6-11 will be performed at Visit 11 (Day 169 [±3 days]).  
Table 6-11. 
Procedures and Assessments at Visit 11 (Day 169) 
Assessment or 
Procedure 
Explanation 
Pre-Visit Tumor Assessment 
Radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the 
assessment should be done even if study drug has been interrupted.  
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 10 
Concomitant 
medications 
Recording of concomitant medication used since Visit 10 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Urine ȕ-HCG 
dipstick 
For women of child-bearing potential only 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Bone marrow biopsy 
and aspirate 
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR. 
Idelalisib 
pharmacokinetics 
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug blister card numbers 
Study Therapy Administration 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
Idelalisib 
pharmacokinetics 
Post-dose collection of plasma sample for idelalisib pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 12-week supply of study drug to the subject with instructions for self-administration 
at home.  
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment 
of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging 


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6.2.12. 
Visit 12 (Day 211) (Clinic Visit) 
The procedures outlined in Table 6-12 will be performed at Visit 12 (Day 211 [±3 days])  
Table 6-12. 
Procedures and Assessments at Visit 12 (Day 211) 
Assessment or 
Procedure 
Explanation 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 11 
Concomitant 
medications 
Recording of concomitant medication used since Visit 11 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Urine ȕ-HCG 
dipstick 
For women of child-bearing potential only 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
IWRS access 
Access of IWRS to document subject visit 
Study drug 
administration 
Subject to continue with study drug as prescribed. 
Scheduling of 
Visit 13 radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 13. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-
Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging 


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6.2.13. 
Visit 13 (Day 253) (Clinic and Radiology Visit) 
The procedures outlined in Table 6-13 will be performed at Visit 13 (Day 253 [±3 days]).  
Table 6-13. 
Procedures and Assessments at Visit 13 (Day 253) 
Assessment or 
Procedure 
Explanation 
Pre-Visit Tumor Assessment 
Radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the 
assessment should be done even if study drug has been interrupted.  
During-Visit Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 10 
Concomitant 
medications 
Recording of concomitant medication used since Visit 10 
Study drug 
return/accounting 
Counting returned study drug.  
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Urine ȕ-HCG 
dipstick 
For women of child-bearing potential only 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Bone marrow biopsy 
and aspirate 
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR. 
IWRS access 
Access of IWRS to obtain study drug blister card numbers 
Study drug 
administration 
Subject to continue with study drug as prescribed. 
Study drug 
dispensing 
Dispensing of 12-week supply of study drug to the subject with instructions for self-administration 
at home.   
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment 
of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging 


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6.2.14. 
Visit 14 (Day 295) (Clinic Visit) 
The procedures outlined in Table 6-14 will be performed at Visit 14 (Day 295 [±3 days])  
Table 6-14. 
Procedures and Assessments at Visit 14 (Day 295) 
Assessment or 
Procedure 
Explanation 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is 
communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 10 
Concomitant 
medications 
Recording of concomitant medication used since Visit 10 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical 
examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly 
Urine ȕ-HCG 
dipstick 
For women of child-bearing potential only 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, 
total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, 
cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by 
flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
IWRS access 
Access of IWRS to document subject visit 
Study drug 
administration 
Subject to continue with study drug as prescribed. 
Scheduling of 
Visit 15 radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 15. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-
Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging 


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6.2.15. 
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks) (Clinic and 
Radiology Visits) 
The procedures outlined in Table 6-15 will be performed at Visit 15 (Day 337 [±3 days]) and 
every 12 weeks thereafter [±7 Days]). 
Table 6-15. 
Procedures and Assessments at Visit 15 and Subsequent Visits 
(Day 337 and Every 12 Weeks) 
Assessment or 
Procedure 
Explanation 
Pre-Visit Tumor Assessment 
Radiology 
assessmenta 
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the 
assessment should be done even if study drug has been interrupted.  
During-Visit Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since prior visit 
Concomitant 
medications 
Recording of concomitant medication used since prior visit 
Study drug 
return/accounting 
Counting returned study drug.  
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Urine ȕ-HCG 
dipstick 
For women of child-bearing potential only 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Bone marrow biopsy 
and aspirate 
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR. 
IWRS access 
Access of IWRS to obtain study drug blister card numbers 
Study drug 
administration 
Subject to continue with study drug as prescribed. 
-Study drug 
dispensing 
Dispensing of 12-week supply of study drug to the subject with instructions for self-administration 
at home   
Scheduling of next 
visit radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for next clinic visit (every 
12 weeks). 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment 
of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging 


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6.2.16. 
End-of-Study Visit (Clinic Visit) 
At the time of discontinuation from the study, the subject should have the procedures and 
assessments performed as documented in Table 6-16. An end-of-study CT/MRI tumor 
assessment should be performed unless the subject already has radiographic confirmation of 
definitive disease progression ≤4 weeks prior to study discontinuation.  
Table 6-16. 
Procedures and Assessments at End-of-Study Visit 
Assessment or 
Procedure 
Explanation 
Radiology 
assessmenta 
CT or MRI imaging of neck, chest, abdomen, and pelvis 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed  
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed 
Adverse events  
Recording of adverse events occurring since prior visit; if a clinically significant adverse event or 
abnormal result is observed that is not resolved by the end-of treatment visit, repeat evaluations 
should be performed to document resolution or stabilization of the abnormality 
Concomitant 
medications 
Recording of concomitant medication used since prior visit 
Study drug 
return/accounting 
Counting returned study drug.  
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical 
examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Serum ȕ-HCG 
Women of childbearing potential only 
CLL peripheral 
blood evaluation 
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 12 trisomy; DNA 
mutational analysis for p53, IgHV (including IgHV3-21), and other genes of interest in CLL (eg, 
Notch); flow cytometry for CD5, CD10, CD11c, CD19, CD20, CD23, CD38, CD45, kappa and 
lambda light chains, and ZAP-70; cytology for karyotyping 
CLL serology 
Serum β2 microglobulin 
 
 
 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total protein, 
albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
IWRS 
Access IWRS to document that subject has permanently discontinued study therapy and to indicate 
whether subject agrees to continue to undergo long-term follow-up 
a 
An end-of-study CT/MRI tumor assessment should be performed unless the subject already has radiographic 
confirmation of definitive disease progression ≤4 weeks prior to end-of-study discontinuation. 
Abbreviations: β-HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, CLL=chronic lymphocytic leukemia, CT=computed tomography, FISH= fluorescence in-
situ hybridization, GGT=gamma-glutamyltransferase, IgHV=immunoglobulin heavy-chain variable-region, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, 
RNA=ribonucleic acid, ZAP-70=zeta-associated protein 70 
PPD


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6.2.17. 
30 Day and Long-Term Follow-up 
A 30 Day follow-up visit will be performed 30 (+ 5) days following the end-of-study visit; 
however, it may be waived for subjects who have permanently discontinued study drug and 
have had a study visit > 30 days after the last dose of study drug.  
Long-term, follow-up will be requested of all subjects who withdraw from study for any 
reason. 
The long-term follow-up for survival will be conducted  at ~6-month intervals for 5 years, 
starting at the end-of-study visit. Information may be gathered during a routine clinic visit or 
other contact with the subject, or via telephone. 
6.3. 
Blood Collection 
Computations of blood drawing requirements for this study are shown in Table 6-17. The 
maximum amount of blood to be drawn at a visit is 105 mL and the total amount of blood to 
be drawn over the initial 52-week study period (including the 4-week screening period and 
through Week 48 of the study including a possible end-of-therapy visit) is ~551 mL. For a 
40-kg person (the smallest participant expected to enroll in the study), this equates to 
maximum blood volume per body weight per visit of ~2.8 mL/kg and a total blood volume 
per body weight per average 6-week period of ~1.6 mL/kg. These quantities of blood are 
within accepted limits of 3.0 mL/kg of body weight for a single blood draw and 7.0 mL/kg of 
body weight for a 6-week period [National Institutes of Health 2003]. 


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Table 6-17. 
Blood Drawing Requirements Through Visit 15 (Week 48) 
Test 
Sample 
Type 
Tube 
Type 
Blood Per 
Tube 
(mL) 
Tubes (n) 
Blood Volume (mL) 
Maximum 
Per Visit 
Total in 
Studya 
Maximum 
Per Visit 
Total in 
Studya 
CLL peripheral blood 
evaluation 
Plasma 
Sodium 
heparin 
10 
5 
2 
50 
100 
Genotyping 
and 
expression 
analysis 
DNA 
RNA 
Cells 
K2-EDTA
Paxgene  
12 
1 
2 
12 
24 
Protein 
Cells 
K2-EDTA
8 
1 
2 
8 
16 
Coagulation 
Plasma 
Citrate 
4 
1 
1 
4 
4 
Hematology 
Plasma 
K2-EDTA
3 
1 
16 
3 
48 
Serum chemistry 
(including β-HCG and 
CLL serology) 
Serum 
Clot 
5 
1 
16 
5 
80 
Circulating cells for 
PI3K/AKT/mTOR 
pathway activation 
and 
immunophenotyping 
Cells 
K2-EDTA 
4 
1 
13 
4 
52 
Biomarkers 
Plasma 
K2-EDTA 
5 
1 
13 
5 
65 
Serum 
Clot 
5 
1 
13 
5 
65 
Serum Igs 
Serum 
Clot 
5 
1 
13 
5 
65 
Idelalisib 
pharmacokinetics  
Plasma 
K2-EDTA 
2 
2 
8 
4 
32 
Total 
 
 
 
 
 
105 
551 
a 
Computed for initial 52-week period (considering 4 weeks for screening and 48 weeks on study) 
Abbreviations: β-HCG=beta human chorionic gonadotropin, AKT =AKT (a serine/threonine protein kinase ), 
CLL=chronic lymphocytic leukemia, DNA=deoxyribonucleic acid, Ig=immunoglobulin, K2-EDTA=potassium-
ethylenediaminetetraacetic acid, mTOR=mammalian target of rapamycin, PI3K=phosphatidylinositol 3-kinase, 
RNA=ribonucleic acid 
 
Specific details regarding blood sample collection and processing requirements will be 
provided separately in the study manual. 
 
 
 
 
PPD


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6.4. 
Study Procedure Rationale 
The planned study assessments and timing have been selected as appropriate for screening of 
subjects, for determination of idelalisib-related or disease-related toxicities, for dose 
modification during the study, for characterization of drug exposure and desired 
pharmacological effects, and for evaluation of drug activity. The scheduling of testing is 
designed to collect a complete safety and pharmacology data set while maintaining subject 
tolerance of study procedures. The planned schedule of tumor assessments is consistent with 
expected rate of changes and appropriately balances precise measurement of tumor control 
with the expense and subject inconvenience associated with clinical and radiological 
procedures. For discussion of the rationale for endpoint selection, see Section 3.2. 


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7. 
EFFICACY ASSESSMENTS 
7.1. 
Tumor Status Assessments 
The determination of CLL response and progression will be based on standardized IWCLL 
criteria [Hallek 2008], as specifically modified for this study to reflect current 
recommendations which consider the mechanism of action of idelalisib and similar drugs 
[Cheson 2012]. Treatment decisions by the investigator in this study will be based on these 
assessments. Radiographic and clinical tumor assessments will be subject to independent 
confirmation by the IRC (see Section 10.4.3).  
7.2. 
Method of Assessment 
In addition to clinical examination, imaging-based evaluation will be used in this study in all 
subjects enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI 
scanning may be used at the investigator’s discretion in subjects for whom this may be a 
preferred alternative to CT scanning; however, if MRI is performed, a non-contrast CT of the 
chest should be performed. Contrast-enhanced scanning is preferred, but iodine-containing or 
gadolinium contrast material may be omitted in subjects for whom use of a contrast agent 
would be medically contraindicated. Chest x-ray, ultrasound, endoscopy, laparoscopy, PET, 
radionuclide scans, or tumor markers will not be considered for response assessment. 
For radiographic evaluations, the same method of assessment and the same technique 
(eg, scan type, scanner, subject position, dose of contrast, injection/scan interval) should be 
used to characterize each identified and reported lesion at baseline and during study 
treatment and follow-up. However, if a subject is imaged without contrast at baseline, 
subsequent assessments should be performed with contrast, unless the subject cannot tolerate 
the contrast. 
All relevant clinical and radiographic information required to make each tumor status 
assessment must be made available for source verification and for submission to the IRC 
(see Section 10.4.3). 
7.3. 
Timing of Assessments 
All baseline clinical and CT/MRI tumor assessments should be performed within 4 weeks 
prior to the start of treatment. In order to optimize scheduling convenience for the subject and 
for the investigational staff, clinical and CT/MRI tumor assessments performed as part of 
Study GS-US-312-0116 need not be repeated and can be used as baseline tumor assessments 
for Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug 
therapy on Study GS-US-312-0117. Clinical tumor assessments should be performed at each 
clinical visit. On-study CT/MRI tumor assessments should be performed at ~8- to 12-week 
intervals as dictated by the study protocol. An end-of-study CT/MRI tumor assessment 
should be performed unless the subject already has radiographic confirmation of disease 
progression ≤4 weeks prior. If a subject permanently discontinues study drug prior to 


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objective documentation of CLL progression, investigators should continue further follow-up 
at ~12-week intervals until CLL progression is documented by the central IRC. 
7.4. 
Identification and Measurement of Tumor Lesions and Organomegaly 
7.4.1. 
Index Lesions 
At baseline, up to 6 lymph nodes should be selected as index lesions that will be used to 
quantitate the status of the disease during study treatment. Ideally, the index lesions should 
be located in disparate regions of the body. Only peripheral nodes need be selected as index 
lesions. However, it is optimal if mediastinal and retroperitoneal areas of disease are assessed 
whenever these sites are involved. 
Index lesions will be measured and recorded at baseline and at the stipulated intervals. The 
cross-sectional dimensions (the largest cross-sectional diameter, ie, the LD × LPD) will be 
recorded (in cm) for each index lesion. The product of the perpendicular diameters (PPD) 
(in cm2) for each index lesion and the  sum of the products (SPDs) (in cm2) for all index 
lesions will be calculated and recorded. The baseline SPDs will be used as references by 
which tumor response will be characterized during treatment. The nadir LD of individual 
lesions and the nadir SPD will be used as references by which CLL progression will be 
characterized. All LD and LPD diameters will be reported in centimenters and all PPDs and 
SPDs will be reported in centimeters squared. 
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable 
at baseline. A lymph node lesion is considered abnormal if it has a single diameter that is 
>1.5 cm and is considered measurable if it has 2 perpendicular diameters that can be 
accurately measured in cross section with the LD being ≥1.0 cm and the LPD also being 
≥1.0 cm. 
Index lesions measuring >1.5 cm in the LD, regardless of the measurement of the LPD, will 
be prioritized during baseline index lesion selection. 
At follow-up time points, the LDs for individual lesions and the SPD of all nodal index 
lesions will be considered. Because nodal index lesions that have one or both diameters 
>0 cm and <1.0 cm cannot be reliably measured, a default value of 1.0 cm will be assigned 
for each diameter that meets these criteria and the resulting PPD will be used in SPD 
calculations. Based on this convention, a CR may be achieved even if an SPD value is 
>0 cm2, (ie, if all lymph nodes measure <1.0 cm2). 
A new node that measures >1.5 cm in any diameter will be considered progressive disease. 
In cases in which a large lymph node mass has split into multiple components, only those 
elements that are >1.0 cm in at least 1 diameter will be considered abnormal and used in 
calculating the SPD. Progression of the lesion can only be based on the SPD of abnormal 
sub-components. Lesion sub-components that are considered normal but measurable will 
have the true PPDs calculated, with the result used only for calculating an accurate nadir. 


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Similarly, lesion sub-components that are visible but neither abnormal nor measurable will 
have the default PPD of 1.0 cm2 (1.0 cm × 1.0 cm), stored only for the purposes of 
calculating the nadir SPD value. 
If lesions merge, a boundary between the lesions will be established so the LD of each 
individual lesion can continue to be measured. If the lesions have merged in a way that they 
can no longer be separated by this boundary, the newly merged lesion will be measured bi-
dimensionally. 
7.4.2. 
Spleen and Liver 
Both the spleen and liver will be assessed by CT/MRI scan and by physical examination at 
baseline and at the stipulated intervals during treatment. The baseline and nadir values for the 
longest vertical dimension (LVD) of each organ will be used as reference to further 
characterize the objective tumor response of the measurable dimensions of the CLL during 
treatment. All spleen and liver LVD measurements should be recorded in centimeters.  
Physical examination of the spleen should comprise assessment of its LVD below the left 
costal margin by palpation. By physical examination, the spleen will be considered enlarged 
if it is palpable below the left costal margin. If the spleen is not palpable below the left costal 
margin, it should be assigned a value of 0 cm for physical examination assessment. By 
imaging, the spleen will be considered enlarged if it is >12 cm in LVD [Bezerra 2005, 
Asghar 2011], with the LVD being obtained by multiplying the number of sections on which 
the spleen is visualized by the thickness of the sections (eg, if the spleen is seen in 
14 contiguous cross-sectional images with 0.5-cm thickness, the LVD is recorded as 7 cm).   
For subjects with splenomegaly at baseline or at the splenic LVD nadir, respective response 
and progression evaluations of the spleen will consider only changes relative to the 
enlargement of the spleen (ie, the portion of the LVD that is >0 cm by physical examination 
or >12 cm by imaging) at baseline or nadir, not changes relative to the total splenic LVD.  
A 50% decrease from baseline (minimum decrease of 2 cm) in the enlargement of the spleen 
in its LVD or to ≤12 cm by imaging, or regression to a spleen LVD of ≤0 cm by physical 
examination, is required for declaration of a splenomegaly response. Conversely, an increase 
in splenic enlargement by ≥50% (minimum increase of 2 cm) from nadir is required for 
declaration of splenic progression. Subjects with a normal spleen LVD (ie, a LVD of ≤0 cm 
by physical examination or ≤12 cm by imaging) at nadir will only be considered to have 
progressed if the spleen attains a LVD of >14 cm by imaging or >2 cm by physical exam. 
Physical examination of the liver should comprise assessment of its LVD at the right 
midclavicular line by percussion.  By physical examination, the liver will be considered 
enlarged if it is >15 cm in LVD as assessed by percussion [Walker 1990].  
By imaging, the liver will be considered enlarged if it is >18 cm in LVD [Erturk 2006].  


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A 50% decrease (minimum decrease of 2 cm) from baseline in the enlargement of the liver in 
its LVD or to ≤18 cm by imaging, or regression to a liver LVD of ≤15 cm by physical 
examination, is required for declaration of a hepatomegaly response. Conversely, an increase 
in liver enlargement by ≥50% (minimum increase of 2 cm) from nadir is required for 
declaration of hepatic progression. Subjects with a normal liver LVD (ie, a LVD of ≤15 cm 
by physical examination or ≤18 cm by imaging) at nadir will only be considered to have 
progressed if the liver attains a LVD of >20 cm by imaging or >17 cm by physical exam. 
7.4.3. 
Non-Index Lesions 
Any other measurable and abnormal nodal lesions not selected for quantitation as index 
lesions may be considered non-index lesions. In addition, non-measurable evidence of CLL 
such as nodal lesions with both diameters <1.0 cm, extra-nodal lesions, bone lesions, 
leptomeningeal disease, ascites, pleural or pericardial effusions, lymphangitis of the skin or 
lung, abdominal masses that are not confirmed and followed by imaging techniques, cystic 
lesions, previously irradiated lesions, lesions with artifacts, and may be considered as 
non-index disease. 
The presence or absence of non-index disease should be recorded at baseline and at the 
stipulated intervals during treatment. If present at baseline, up to 6 non-index lesions should 
be recorded. The non-index disease at baseline will be used as a general reference to further 
characterize regression or progression of CLL during assessments of the objective tumor 
response during treatment. Measurements are not required and these lesions should be 
followed as “present” or “absent”. 
7.5. 
Definitions of Tumor Response and Progression  
Responses will be categorized by the IRC as CR, PR, SD, or PD. In addition, a response 
category of not evaluable (NE) is provided for situations in which there is inadequate 
information to otherwise categorize response status. A response category of no disease (ND) 
is included for situations in which there is absence of tumor both at baseline and on 
treatment. 
The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until disease/recurrence progression (taking as a 
reference for disease progression the smallest measurements recorded since treatment started.  
Subjects with a best overall response of NE or ND will be counted in the denominators in 
calculations of tumor response rates. Where imaging data are available, these data will 
supersede physical examination data in determining tumor status. 
7.5.1. 
Complete Response 
To satisfy criteria for a CR, all of the following criteria must be met: 
• No evidence of new disease 


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• ALC in peripheral blood of <4 x 109/L 
• Regression of all index nodal masses to normal size (≤1.5 cm in the LD)   
• Normal spleen and liver size 
• Regression to normal of all nodal non-index disease and disappearance of all detectable 
non-nodal, non-index disease 
• Morphologically negative bone marrow defined as <30% of nucleated cells being 
lymphoid cells and no lymphoid nodules in a bone marrow sample that is normocellular 
for age 
• Peripheral blood counts meeting all of the following criteria: 
— ANC ≥1.5 x 109/L without need for exogenous growth factors (eg, G-CSF) 
— Platelet count ≥100 x 109/L without need for exogenous growth factors 
— Hemoglobin ≥110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (eg, erythropoietin) 
Note: Subjects who fulfill all the criteria for a CR (including bone marrow criteria) but 
who have a persistent anemia, thrombocytopenia, or neutropenia or a hypocellular bone 
marrow that is related to prior or ongoing drug toxicity (and not to CLL) will be 
considered as a CR with incomplete marrow recovery (CRi).  
7.5.2. 
Partial Response 
To satisfy criteria for a PR, all of the following criteria must be met: 
• No evidence of new disease 
• A change in disease status meeting ≥2 of the following criteria, with 2 exceptions in 
which only 1 criterion is needed: (1) Only lymphadenopathy is present at baseline; (2) 
Only lymphadenopathy and lymphocytosis are present at baseline. In these 2 cases, only 
lymphadenopathy must improve to the extent specified below: 
— Decrease in peripheral blood ALC by ≥50% from baseline 
— A decrease by ≥50% from the baseline in the SPD of the index nodal lesions 
— In a subject with enlargement of the spleen at baseline, a splenomegaly response 
defined in Section 7.4.2.  


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— In a subject with enlargement of the liver at baseline, a hepatomegaly response as 
defined in Section 7.4.2.  
— A decrease by ≥50% from baseline in the CLL marrow infiltrate or in B-lymphoid 
nodules 
• No index, splenic, liver, or non-index disease with worsening that meets the criteria for 
definitive PD 
• Peripheral blood counts meeting ≥1 of the following criteria: 
— ANC ≥1.5 x 109/L or ≥50% increase over baseline without need for exogenous 
growth factors (eg, G-CSF) 
— Platelet count ≥100 x 109/L or ≥50% increase over baseline without need for 
exogenous growth factors 
— Hemoglobin ≥110 g/L (11.0 g/dL) or ≥50% increase over baseline without red blood 
cell transfusions or need for exogenous growth factors (eg, erythropoietin) 
7.5.3. 
Stable Disease 
To satisfy criteria for stable disease (SD), the following criteria must be met: 
• No evidence of new disease 
• There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD 
7.5.4. 
Definitive Progressive Disease 
The occurrence of any of the following events indicates definitive PD:  
• Evidence of any new disease: 
— A new node that measures >1.5 cm in any diameter 
— New splenomegaly as defined in Section 7.4.2.  
— New hepatomegaly as defined in Section 7.4.2.  
— New non-index disease (eg, effusions, ascites, or other organ abnormalities related to 
CLL) 
Note: Isolated new effusions, ascites, or other organ abnormalities are not 
sufficient evidence alone of PD unless histologically confirmed. Thus, a declaration 


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of PD should not be made if this is the only manifestation of apparently new 
disease. 
• Evidence of worsening of index lesions, spleen or liver, or non-index disease:  
— Increase by ≥50% from the nadir in the SPD of index lesions 
— Increase from the nadir by ≥50% in the LD of an individual node or extra-nodal mass 
that now has an LD of >1.5 cm and an LPD of > 1.0 cm  
— Splenic progression as defined in Section 7.4.2. 
— Hepatic progression as defined in Section 7.4.2. 
— Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or other 
organ abnormalities related to CLL)  
— Transformation to a more aggressive histology (eg, Richter syndrome) as established 
by lymph node biopsy (with the date of the lymph node biopsy being considered the 
date of CLL progression if the subject has no earlier objective documentation of CLL 
progression). 
• Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to 
an autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an 
infiltrate of clonal CLL cells 
— The current platelet count is <100 x 109/L and there has been a decrease by >50% 
from the highest on-study platelet count  
— The current hemoglobin is <110 g/L (11.0 g/dL) and there has been a decrease by 
>20 g/L (2 g/dL) from the highest on-study hemoglobin  
Note: If there is uncertainty regarding whether there is true progression, the subject 
should continue study treatment and remain under close observation (eg, evaluated at 
4-week intervals) pending confirmation of progression status by the IRC. In particular, 
worsening of constitutional symptoms in the absence of objective evidence of worsening 
CLL will not be considered definitive disease progression; in such subjects, both 
CLL-related and non-CLL-related causes for the constitutional symptoms should be 
considered. Worsening of disease during temporary interruption of study treatment (eg, for 
intercurrent illness) is not necessarily indicative of resistance to study treatment. In these 
instances, CT/MRI or other relevant evaluations should be considered in order to 
document whether definitive disease progression has occurred. If subsequent evaluations 
suggest that the subject has experienced persistent definitive CLL progression, then the 
date of progression should be the timepoint at which progression was first objectively 
documented. 


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7.5.5. 
Non-Evaluable 
In a subject who does not have evidence of PD, the occurrence of any of the following 
conditions indicates a response status of NE:  
• There are no images or inadequate or missing images 
• Images of the liver and spleen are missing at that time point (with the exception that 
absence of splenic images will not result in an NE designation in a subject known to have 
undergone splenectomy). 
7.5.6. 
No Disease 
Subjects have a status of ND if all of the following conditions occur:  
• No index disease noted at baseline or on-treatment  
• No non-index disease noted at baseline or on-treatment. 
• No enlargement of the liver or spleen at baseline or on-treatment 
• No abnormalities of peripheral blood counts (elevated ALC or abnormally low ANC, 
platelet count, or hemoglobin) and no evidence of CLL in bone marrow (if available) at 
baseline or on treatment 
7.5.7. 
Lymphocytosis During Therapy 
Idelalisib can mobilize CLL cells from tissues into the peripheral blood. This characteristic 
pharmacological action can be prominent early in therapy but can persist over time and 
should not be confused with disease progression in subjects who have persistent control of 
other CLL-related signs and symptoms. In the absence of other objective evidence of 
disease progression, lymphocytosis alone will not preclude subjects from meeting the 
criteria for PR if other criteria for PR are met and will not be considered evidence of 
disease progression if occurring in isolation. Subjects with lymphocytosis should be 
continued on study drug until the occurrence of definitive disease progression (ie, disease 
progression that is manifest by worsening CLL-related signs other than lymphocytosis 
alone), or the occurrence of another reason to discontinue study therapy as described in 
Section 5.8. 
7.5.8. 
Documentation of Definitive CLL Progression 
Of importance, CLL response and progression data collected from the primary study will be 
subjected to IRC review (see Section 10.4.3). Subjects must have confirmation by the 
sponsor working in collaboration with the IRC that the disease has progressed on the 
primary clinical trial (Study GS-US-312-0116) before being permitted to receive secondary 
idelalisib therapy on this extension trial ( GS-US-312-0117). Subjects should continue study 
drug pending confirmation of progression status. CT/MRI should be attempted in order to 
document definitive disease progression by the IRC. The end-of therapy scan from the 
primary study can serve as the baseline scan for the extension study if obtained within the 


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specific screening period for the extension study. If obtained within the specified screening 
period for the extension study, this scan can serve as the baseline scan for the extension 
study. 


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8. 
SAFETY ASSESSMENTS 
8.1. 
Adverse Event Definitions 
8.1.1. 
Adverse Event 
An adverse event (adverse event) is any untoward medical occurrence in a clinical 
investigation subject administered a medicinal product; the event does not necessarily have a 
causal relationship with study drug administration or usage. An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. 
In this study, any of the following events will be considered an adverse event: 
• Any complication that occurs as a result of a protocol-mandated procedure 
(eg, venipuncture, biopsy) in the screening, on-treatment, or post-treatment periods. 
• Any pre-existing condition that increases in severity or changes in nature during or as a 
consequence of study drug administration. Worsening manifestations of the underlying 
cancer (eg, increase in pain, tumor flare reaction, tumor lysis syndrome) may be 
considered adverse events in this study. 
• Any injury or accident occurring during the screening, on-treatment, or post-treatment 
periods. If a medical condition is known to have caused the injury or accident (eg, a fall 
secondary to dizziness), the medical condition (dizziness) and the accident (fall) should 
be reported as 2 separate adverse events.  
• Any abnormality in physiological testing or a physical examination finding that requires 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test). 
• Any laboratory (eg, clinical chemistry, hematology, urinalysis) or investigational  
abnormality (eg, ECG, X-ray) independent of the underlying medical condition that 
requires clinical intervention, results in further investigation (beyond ordering a repeat 
[confirmatory] test), or leads to investigational medicinal product interruption or 
discontinuation unless it is associated with an already reported clinical event. If the 
laboratory abnormality is part of a syndrome, the syndrome or diagnosis (eg, anemia) not 
the laboratory result (eg, decreased hemoglobin) should be recorded.  
• A complication related to pregnancy or termination of a pregnancy (see Section 5.4.9 for 
additional information). 


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None of the following events is considered an adverse event: 
• Lymphocytosis 
• Laboratory abnormalities not requiring clinical intervention or further investigation. Such 
abnormalities will be captured as part of overall laboratory monitoring. 
• A diagnostic, medical or surgical procedure (eg, surgery, endoscopy, tooth extraction, 
transfusion). However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an adverse event. For example, an acute 
appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event and the resulting appendectomy should be recorded in the source 
documents.  
• A pre-existing disease or condition or laboratory abnormality present or detected before 
the initial screening visit and that does not worsen. 
• An intervention not associated with an untoward medical occurrence (eg, hospitalization 
for elective surgery or for social and/or convenience reasons). 
• An overdose without clinical sequelae (see Section 5.2.8) 
8.1.2. 
Serious Adverse Event 
A serious adverse event is defined is an untoward medical occurrence that results in any of 
the following outcomes: 
• Death (ie, all deaths occurring between signing of the consent form to within 30 days 
after last study drug administration). Deaths that occur as a result of an adverse event that 
started during the study period should be reported. The reported adverse event should be 
the event that caused the death. Death is the outcome of this serious adverse event. 
• Life-threatening situation (ie, with an immediate risk of death from the event as it 
occurred but not including an event that, had it occurred in a more serious form, might 
have caused death). 
• In-patient hospitalization or prolongation of existing hospitalization. Of note, an 
untoward medical occurrence that occurs during hospitalization is an adverse event but a 
complication that prolongs hospitalization is a serious adverse event. In-patient 
hospitalization comprises formal admission to a hospital for medical reasons, for any 
length of time, whether or not hospitalization extends overnight. However, hospital 
admissions for administration of the study drug, procedures required by the study 
protocol, or tumor-related diagnostic procedures are not considered serious.  
• Persistent or significant disability/incapacity. 


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• Congenital anomaly/birth defect in the offspring of a subject who received the 
investigational medicinal product. 
• Other medically significant event. Such events may not be immediately life-threatening 
or result in death or hospitalization, but based upon appropriate medical and scientific 
judgment, may jeopardize the subject or may require medical or surgical intervention to 
prevent one of the outcomes listed above. Examples of such events might include: 
— Allergic bronchospasm requiring intensive treatment in an emergency room or at 
home 
— New cancers or blood dyscrasias 
— Convulsions that do not result in hospitalization 
— Development of drug dependency or drug abuse 
8.1.3. 
Unexpected Adverse Event 
An unexpected adverse event is defined as an event that has a nature or severity, or 
specificity that is not consistent with the applicable investigator brochure or that is 
symptomatically and pathophysiologically related to a known toxicity but differs because of 
greater severity or specificity. For example, under this definition, hepatic necrosis would be 
unexpected (by virtue of greater severity) if the investigator brochure only referred to 
elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure 
only listed cerebral vascular accidents. “Unexpected,” as used in this definition, refers to an 
adverse drug experience that has not been previously observed and reported rather than an 
experience that has not been anticipated based on the pharmacological properties of the study 
drug.  
8.1.4. 
Adverse Drug Reactions 
An adverse drug reaction (ADR) is defined as an adverse event that is considered causally 
related to an investigational medicinal product. A serious adverse drug reaction (SADR) is an 
ADR which meets the criteria for being serious.  Suspected, unexpected, serious adverse 
reactions (SUSARs) are events that may require expedited reporting (see Section 8.7.1). 
8.2. 
Eliciting Adverse Event Information 
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study subject. In addition, each study subject will be 
questioned about adverse events at each scheduled clinic visit or during each telephone 
contact with the subject following initiation of study treatment. The type of question asked 
should be open-ended, eg, "Have you had any new health problems?” or a similar type of 
query.  


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8.3. 
Recording Adverse Events 
All adverse events will be assessed by the investigator or qualified designee and recorded in 
the eCRFs. The investigator should attempt to establish a diagnosis of the event on the basis 
of signs, symptoms and/or other clinical information. In such cases, the diagnosis should be 
documented as the adverse event and/or serious adverse event and not described as the 
individual signs or symptoms. The following information should be recorded: 
• Description of the adverse event using concise medical terminology 
• Description as to whether or not the adverse event is serious (see Section 8.1.2) 
• The start date (date of adverse event onset) 
• The stop date (date of adverse event resolution) 
• The severity of the adverse event (see Section 8.4) 
• A description of the potential relatedness of the adverse event to study drug or a study 
procedure (see Section 8.5)  
• The action taken due to the adverse event 
• The outcome of the adverse event 
8.4. 
Grading of the Severity of an Adverse Event 
The severity of adverse events will be graded using the CTCAE, Version 4.03 (provided in 
study manual and available at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf). For each episode, the highest severity grade attained should 
be reported.  
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 
(fatal) to describe the maximum intensity of the adverse event. For purposes of consistency 
with the CTCAE, these intensity grades are defined in Table 8-1. 


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Table 8-1. 
Grading of Adverse Event Severity 
Grade 
Adjective 
Description 
Grade 1 
Mild 
Sign or symptom is present, but it is easily tolerated, is not expected to have a 
clinically significant effect on the subject’s overall health and well-being, does not 
interfere with the subject’s usual function, and is not likely to require medical 
attention. 
Grade 2 
Moderate 
Sign or symptom causes interference with usual activity or affect clinical status, 
and may require medical intervention. 
Grade 3 
Severe 
Sign or symptom is incapacitating or significantly affects clinical status and likely 
requires medical intervention and/or close follow-up. 
Grade 4 
Life-threatening Sign or symptom results in a potential threat to life. 
Grade 5 
Fatal 
Sign or symptom results in death. 
 
The distinction between the seriousness and the severity of an adverse event should be noted. 
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. 
For example, a headache may be severe in intensity, but would not be classified as serious 
unless it met one of the criteria for serious events listed in Section 8.1.2 above. 
8.5. 
Describing Adverse Event Relationship to Study Drug and Study 
Procedures 
The relationship of an adverse event to study drug should be assessed using clinical 
judgment, describing the event as either unrelated (no) or related (yes) consistent with the 
following definitions: 
• No: Evidence exists that the adverse event had an etiology other than the study drug. For 
serious adverse events, an alternative causality must be provided (eg, pre-existing 
condition, underlying disease, intercurrent illness, or concomitant medication). 
• Yes:  A temporal relationship exists between the adverse event onset and administration 
of the investigational medicinal product that cannot be readily explained by the subject’s 
clinical state or concomitant therapies. Furthermore, the adverse event appears with some 
degree of certainty to be related to the study drug based on the known therapeutic and 
pharmacologic actions or adverse event profile of the investigational medicinal product. 
In case of cessation or reduction of the dose, the adverse event abates or resolves. In case 
of interruption and rechallenge, the event reappears upon rechallenge. 
Of note, even in circumstances when the study drug is given intermittently or is interrupted 
temporarily before the onset of the adverse event, consideration should be given as to 
whether the study drug may have contributed to the event.  


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As noted in Section 5.5, unblinding should be avoided unless absolutely necessary for a 
subject’s well-being; breaking the blind should not be performed merely to obtain enhanced 
certainty regarding the relationship of an adverse event to study drug.  
The relationship to protocol-mandated study procedures (eg, procedures such as venipuncture 
or biopsy) should be assessed using the following considerations: 
• No: Evidence exists that the adverse event has an etiology other than the study procedure. 
• Yes: The adverse event occurred as a result of a protocol-mandated procedure.  
8.6. 
Adverse Event Reporting Period 
The start of the adverse event reporting for a study subject will coincide with signing of the 
informed consent for Study GS-US-312-0117. Any new adverse events occurring thereafter 
should not be reported within Study GS-US-312-0116, but instead should be reported within 
Study GS-US-312-0117. The end of the adverse-event-reporting period for 
Study GS-US-312-0117 occurs 30 days after the discontinuation from study or when any 
ongoing drug-related adverse events and/or serious adverse events have resolved or become 
stable. A subject withdrawn from the study because of an adverse event must be followed 
until the clinical outcome from the adverse event is determined. The investigator should use 
appropriate judgment in ordering additional tests as necessary to monitor the resolution of 
events ongoing at the completion of study treatment. Gilead Sciences may request that 
certain adverse events be followed longer.  
Investigators are not obligated to actively seek information regarding the occurrence of new 
serious adverse events beginning after the 30-day post-study period. However, if the 
investigator learns of such a serious adverse event and that event is deemed relevant to the 
use of the study drug, he/she should promptly document and report the event. A longer 
reporting period applies in the case of pregnancy (see Section 8.9.2) 
8.7. 
Adverse Event Reporting Requirements 
8.7.1. 
Site Reporting Requirements 
Classification of an event as serious or nonserious (see Section 8.1.2) determines the 
reporting procedures to be followed by the site.  
Site reporting requirements for adverse events are summarized in Table 8-2, below. 


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Table 8-2. 
Site Reporting Requirements for Adverse Events 
Classification 
Reporting Time 
Reporting Action 
Serious 
Within 24 hours 
Fax report on designated serious adverse event report form to 
PPD Pharmacovigilancea, and to the site IRB/IEC, as per 
local IRB/IEC requirements; include copies of relevant 
source documentsb (eg, progress notes, autopsy reports, 
laboratory and diagnostic test results, discharge summaries) 
in communication to PPD Pharmacovigilancea 
Per eCRF submission 
procedurec 
Record and submit information on appropriate eCRFs 
Nonserious 
Per eCRF submission 
procedure 
Record and submit information on appropriate eCRFs 
a 
See contact information in Table 8-3 below. 
b 
Subject name, address, and other personal identifiers should be obscured but without losing the traceability of a 
document to the study subject identifiers. 
c 
CLL progression or death due to CLL progression should be reported by the investigator as a serious adverse event 
only if it is assessed that the study drugs caused or contributed to the CLL progression (ie, by a means other than lack 
of effect). Unrelated events of CLL progression should be captured on the appropriate eCRF.  
Abbreviations: CLL = chronic lymphocytic leukemia, eCRF=case report form, IRB/IEC= Institutional Review 
Board/Independent Ethics Committee 
 
For serious adverse events, in addition to completing the adverse event portion of the eCRF, 
the serious adverse event report form must also be completed. The information in the adverse 
event portion of the eCRF page and the serious adverse event report form(s) must match or 
be reconciled. Where the same data are collected, the forms must be completed in a 
consistent manner. For example, the same adverse event term should be used on both forms. 
Particularly for fatal or life-threatening events, copies of progress notes, autopsy reports, 
laboratory and diagnostic test results, discharge summaries, and other relevant documents 
should be faxed when requested and applicable. Follow-up information to the serious adverse 
event should be clearly documented as “follow up” in the serious adverse event report form 
and must be faxed to these same parties. Gilead Sciences may request additional information 
from the investigator to ensure the timely completion of accurate safety reports. 
The subject’s name, address, and other personal identity information should be obscured on 
any source documents (eg, progress notes, nurses’ notes, laboratory and diagnostic test 
results, discharge summaries). Only the subject’s study number, initials, or date of birth are 
to be provided. 
The serious adverse event report form must be communicated to PPD Pharmacovigilance and 
to the site IRB/IEC (if required by local regulations) within 24 hours. In the rare event that 
the investigator does not become aware of the occurrence of a serious adverse event 
immediately (for example, if a subject initially seeks treatment elsewhere), the investigator is 
to report the event within 24 hours after learning of it and to document his/her first awareness 
of the adverse event. 


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Contact details for PPD Pharmacovigilance and for the Gilead study medical monitor are 
provided in Table 8-3: 
Table 8-3. 
Contact Information for Reporting Serious Adverse Events 
Function 
Contact Information 
PPD Pharmacovigilance 
(US) 
Facsimile: 
  
PPD Pharmacovigilance 
(International) 
Facsimile: 
 
Gilead Sciences Medical 
Monitor 
Name: 
 
Title: 
Associate Director, Clinical Research 
Office Telephone: 
 
Mobile Telephone: 
 
Facsimile: 
 
E-mail: 
 
 
8.7.2. 
Gilead Sciences Reporting Requirements 
Gilead Sciences is required to expedite reports to regulatory authorities worldwide relating to 
serious adverse events including events related to study procedures; serious adverse drug 
reactions (SADRs); or suspected, unexpected, serious adverse reactions (SUSARs) consistent 
with relevant legislation or regulations, including the applicable US FDA Code of Federal 
Regulations (CFR), the European Commission Clinical Trials Directive (2001/20/EC, and 
revisions), and other country-specific legislation or regulations.  
Each serious adverse event report received from the investigator through PPD 
Pharmacovigilance will be evaluated by Gilead Sciences Drug Safety and Public Health 
(DSPH). Gilead Sciences DSPH will assess the seriousness of the event (see Section 8.1.2), 
the expectedness of the event (see Section 8.1.3), and the relationship to participation in the 
study (see Section 8.5). For regulatory reporting purposes, Gilead Sciences will determine 
expectedness relating to idelalisib using reference safety information specified in the 
idelalisib investigator brochure and the event will be classified as related if either the 
investigator or Gilead Sciences determines that the event may be related to the study drug 
(see Section 8.5). 
Gilead Sciences or its designee will also provide all investigators and the DMC with a safety 
letter e-mail, fax, or overnight mail notifying them of a SUSAR. Investigators will be 
requested to provide written notification of the SUSAR to the IRB/IEC as soon as is 
practical, consistent with local regulatory requirements and local institutional policy. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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8.7.3. 
Reporting of Adverse Events Relating to the Primary Endpoint and 
Other Anticipated Medical Events in the Study Population 
To maintain the integrity of the study, progression of CLL and death related to progression of 
CLL will not be reported to Gilead Sciences as serious adverse events unless it is assessed 
that the study drug caused or contributed to CLL progression or death related to CLL 
progression (ie, by a means other than lack of effect). These events will be exempt from 
global expedited reporting requirements for the duration of the study because they define the 
primary efficacy endpoint for this study. All events of progression of CLL and death related 
to progression of CLL, regardless of relationship to study drug, will be reported in the eCRFs 
and, as appropriate, in the final clinical study report and in any relevant aggregate safety 
reports.  Disease progression information from this study will be reviewed by an independent 
DMC on an ongoing basis.  
8.8. 
Special Situations Reporting Requirements  
8.9. 
Special Situations Reporting Requirements  
8.9.1. 
Definitions of Special Situations  
Special situation include pregnancy; medication error, abuse, misuse, or overdose; and 
adverse reactions associated with product complaints. 
• Information regarding pregnancy is provided in Section 8.9.2.  
• A medication error is any preventable event that can cause or lead to inappropriate 
medication use or subject harm while the medication is in the control of a healthcare 
professional, subject, or consumer.  
• Abuse is defined as persistent, sporadic or intentionally excessive use of a drug by a 
subject when such use is accompanied by harmful physical and/or psychological effects. 
• An overdose is defined as a dose taken (accidentally or intentionally) exceeding the dose 
as prescribed by the protocol (see Section 5.2.8).  In cases of a discrepancy in drug 
accountability, overdose will be established only when it is clear that the subject has 
taken excess doses or the investigator has reason to suspect that the subject has taken the 
additional dose(s).  
• A product complaint is defined as any written or verbal report arising from potential 
deviations in the manufacture, packaging or distribution of the product. 
8.9.2. 
Pregnancy  
Each female subject should be instructed to discontinue further study drug and inform the 
investigator immediately if she becomes pregnant at any time between the initiation of study 
treatment throughout 30 days after the last use of a study drug.  


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The investigator should counsel the subject regarding the possible effects of prior 
investigational medicinal product exposure on the fetus and the need to inform the study site 
of the outcome of the pregnancy. 
Neither the pregnancy itself nor an induced elective abortion to terminate the pregnancy 
without medical reasons is considered an adverse event; such occurrences should be reported 
on the appropriate pregnancy report forms. However, if the outcome of the pregnancy meets 
the criteria for classification as a serious adverse event (ie, spontaneous abortion, induced 
abortion due to complications, stillbirth, neonatal death, or congenital anomaly 
[including that in an aborted fetus]), the investigator should follow the procedures for 
reporting serious adverse events, ie, report the event to PPD Pharmacovigilance by telephone 
and follow up by submission of the appropriate adverse event eCRFs (see Section 8.7.1). 
Additional information about pregnancy outcomes that are classified as serious adverse 
events includes:  
• Any spontaneous abortion, including miscarriage and missed abortion will be reported as 
a serious adverse event. 
• An induced therapeutic abortion to terminate any pregnancy due to complications or 
other medical reasons will be recorded as a serious adverse event. The underlying 
medical reason for this procedure should be recorded as the adverse event term. 
• All neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as serious adverse events. In addition, any infant death after 1 month that the 
investigator assesses as possibly related to the in utero exposure to the study drug should 
also be reported. 
• In the case of a live birth, the “normality” of the newborn can be assessed at time of birth 
(ie, there is no required minimum follow-up of a presumably normal infant before the 
Pregnancy Outcome Report eCRF can be completed). 
• The “normality” of an aborted fetus can be assessed by gross visual inspection unless 
there are pre-abortion laboratory findings suggestive of a congenital anomaly, in which 
case pathologic examination should be requested.  
8.9.3. 
Instructions for Reporting Special Situations 
Information regarding any pregnancy in a study subject or the female partner of a male 
subject must be documented on the Pregnancy Report Form and forwarded to PPD 
Pharmacovigilance within 24 hours of learning of the pregnancy. Monitoring of the 
pregnancy in both female study subjects and female partner of male study subjects should 
continue until the conclusion of the pregnancy. The outcome of the pregnancy should be 
reported on the Pregnancy Outcome Report Form within 5 days of the conclusion of the 
pregnancy. If the end of the pregnancy occurs after the study has been completed, the 
outcome should be reported directly to Gilead Sciences DSPH 
(facsimile: 
 e-mail: 
 
PPD
PPD


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Information regarding all other special situations must be documented on the Special 
Situations Report Form and forwarded to PPD Pharmacovigilance within 24 hours of 
learning of the event.   
Along with information regarding the circumstances of the special situation, any clinical 
sequelae occurring in association with that situation should be reported as adverse events or 
serious adverse events according to the reporting requirements for those events 
(see Section 8.1.2). Details of signs or symptoms, clinical management, and outcome should 
be reported, if available. 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Analysis Objectives 
As described in Section 3, the objectives of this clinical trial will focus on determining the 
effect of idelalisib on the onset, magnitude, and duration of tumor control; measures of 
patient well-being (including OS, HRQL; and changes in subject performance status); 
disease-associated biomarkers and potential mechanisms of resistance; treatment 
administration; safety; and health resource utilization. 
9.2. 
Analysis Endpoints 
The endpoints of the study are defined in Section 3.1, grouped in categories relating to tumor 
control, patient well-being, pharmacodynamic markers of drug activity and resistance, 
exposure, safety, and pharmacoeconomics. 
9.3. 
Analysis Conventions 
9.3.1. 
Analysis Sets 
9.3.1.1. 
Intent-to-Treat Analysis Set 
The ITT analysis set includes all subjects who receive ≥1 dose of any study treatment 
(high-dose idelalisib or standard-dose idelalisib). In the ITT analysis set, study drug 
assignment will be designated according to planned allocation in this study, regardless of 
whether subjects receive a different study therapy from that to which they were allocated.  
This analysis set will be used in the analyses of subject characteristics and all the tumor 
control and patient well-being endpoints. Subjects in the ITT analysis set who do not have 
sufficient baseline or on-study tumor status information to be adequately assessed for 
response status will be included in the denominators in the calculation of response rates.  
9.3.1.2. 
Per-Protocol Analysis Set 
The PP analysis set includes data from subjects in the ITT analysis set who meet the general 
criteria defining the target population for this study, are adherent to the protocol, are 
compliant with study drug treatment, and are evaluable for relevant efficacy endpoints. 
Treatment assignment will be designated according to the actual treatment received. The 
specific classification of subjects to be included in the PP analysis set will be included in the 
statisticial analysis plan which will be finalized prior to the database lock.  
The PP analysis set will be used in sensitivity analyses of these tumor control and patient 
well-being endpoints: PFS, ORR, lymph node response rate, CR rate, and OS. 


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9.3.1.3. 
Safety Analysis Set 
A safety analysis set will include subjects in the ITT analysis set grouped for analyses with 
treatment assignments designated according to the actual study drug received.  
This analysis set will be used in the analyses of safety variables as well as study treatment 
administration, post-study therapy, and health economic variables. 
9.3.1.4. 
Pharmacodynamic/Pharmacokinetic Analysis Sets 
The pharmacodynamic/pharmacokinetic analysis sets include subjects in the safety analysis 
set who have the necessary baseline and on-study measurements to provide interpretable 
results for specific parameters of interest.  
These analysis sets will be used in the analyses of AKT phosphorylation, 
chemokines/cytokines, and idelalisib plasma concentrations. 
9.3.2. 
Data Handling Conventions 
9.3.2.1. 
General Methods  
By-subject listings will be created for important variables from each eCRF module. 
Summary tables for continuous variables will contain the following statistics: N (number in 
population), n (number with data), mean, standard deviation, 95% confidence intervals (CIs) 
on the mean, median, minimum, and maximum. Summary tables for categorical variables 
will include: N, n, percentage, and 95% CIs on the percentage. Unless otherwise indicated, 
95% CIs for binary variables will be calculated using the binomial distribution 
(exact method) and will be 2-sided. Data will be described and summarized by relevant 
treatment arm, analysis set, and timepoint. As appropriate, changes from baseline to each 
subsequent timepoint will be described and summarized by treatment arm. Similarly, as 
appropriate, the best change from baseline during the study will also be described and 
summarized by treatment arm. Graphical techniques (eg, waterfall plots, Kaplan-Meier 
curves, line plots) may be used when such methods are appropriate and informative.  
Time-to-event analyses will be performed with reference to the date of first treatment on this 
clinical trial (Study GS-US-312-0117). Similarly, evaluations of on-therapy changes will 
reference the baseline values obtained prior to treatment in this study. The baseline value 
used in each analysis will be the last (most recent) pre-treatment value. Data from all sites 
will be pooled for all analyses. Analyses will be based upon the observed data unless 
methods for handling missing data are specified. If there is a significant degree of 
non-normality, analyses may be performed on log-transformed data or nonparametric tests 
may be applied, as appropriate.  
Analyses will generally focus on evaluation of outcomes within each treatment arm; formal 
analyses comparing outcomes in Arm A to those in Arm B are not planned. Unless otherwise 
specified, all analyses will be 2-sided at the 0.05 level of significance.  


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9.3.2.2. 
Calculation of Tumor Control and Patient Well-Being Variables 
Tumor control assessments will be based on standardized IWCLL criteria [Hallek 2008] 
[Cheson 2012], as specifically modified for this study considering the pharmacology of 
idelalisib. The individual and composite endpoints of response and progression 
(considering changes in lymph node area, liver and spleen size, bone marrow, platelet counts, 
hemoglobin, neutrophil counts, and peripheral blood lymphocyte counts) will be determined. 
Tumor control will be documented at each assessment by response category (eg, CR, PR, SD, 
definitive PD, NE, ND) as defined for each response parameter, SPD value, percentage 
change in SPD values from baseline or nadir, date that response is first documented, date that 
response is confirmed, and date of definitive CLL progression.  
The date of definitive CLL progression will be the timepoint at which progression is first 
identified by relevant objective radiographic or laboratory data. Because of the characteristic 
redistribution lymphocytosis that is expected with PI3Kδ inhibition, lymphocyte count will 
be ignored in the evaluation of progression. Changes in tumor status as provided by the 
investigator and changes in tumor status as adjudicated by the IRC (see Section 10.4.3) will 
be described. The findings of the IRC will be considered primary for analyses of all tumor 
control endpoints. 
• The following censoring conventions will be applied:PFS and DOR: Data from surviving, 
non-progressing subjects will be censored at the earliest of the time of initiation of 
antitumor treatment other than the study treatment or the last time that lack of definitive 
CLL progression was objectively documented.   Data from subjects who have CLL 
progression or die after ≥2 consecutive missing tumor assessments will be censored at the 
last time prior to the missing assessments that lack of definitive CLL progression was 
objectively documented. 
• OS: Data from surviving subjects will be censored at the last time that the subject was 
known to be alive.  
9.4. 
Analysis Plan 
9.4.1. 
Subject Disposition and Baseline Characteristics 
A listing of all ITT analysis subjects will be generated to describe site, subject number, first 
screening date, first treatment date, allocated study drug assignment, actual study drug 
assignment, the longest duration of study drug treatment, and the reason for discontinuing 
study treatment. Available information on subjects who were screened or registered but not 
treated will be listed separately. A table will be created summarizing these categories in 
terms of number and percent for the ITT analysis set. 
Subject baseline characteristics will be listed and summarized by treatment arm for the ITT 
analysis set. As appropriate for the specific variable, subject baseline characteristics acquired 
in Study GS-US-312-0116 will be referenced in Study GS-US-312-0117. Subject 
characteristics between Arm A and Arm B may be compared using the Wilcoxon rank-sum 


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test for continuous variables and the Fisher’s exact test for categorical variables. Similarly, 
within each arm, subject characteristics between GS-US-312-0116 and GS-US-312-0117 
may also be compared. 
9.4.2. 
Efficacy Analyses 
9.4.2.1. 
Time-to-Event Tumor Control and Survival Endpoints 
PFS, DOR and OS will be described in the ITT analysis set using Kaplan-Meier methods by 
treatment group. Medians, ranges, and corresponding 95% CIs  will be presented.  
The Cox regression approach may be used to explore the influence of the primary study 
stratification factors and other baseline characteristics on PFS and OS. The stratification 
variables from the primary study and additional baseline subject characteristics may be 
included as covariates, focusing on those with expected prognostic significance.  
9.4.2.2. 
Categorical Endpoints  
Response rates, lymph node response rate, splenomegaly response rate, hepatomegaly 
response rate, ALC response rate, platelet response rate, hemoglobin response rate, and 
neutrophil response rate will be described. In the calculation of response rates, subjects who 
do not have sufficient baseline or on-study tumor assessment to characterize response will be 
included in the denominator. For all analyses, the corresponding 95% CIs will be presented. 
The potential influence of subject baseline characteristics on response rates may be explored 
with multiple logistic regression modeling. 
9.4.2.3. 
Continuous Endpoints 
Changes in lymph node area and changes in performance status, PI3K/AKT/mTOR pathway 
activation, and plasma chemokines/cytokines will be assessed by treatment group. Both 
changes from baseline to each subsequent timepoint and best overall on-study changes will 
be analyzed using appropriate methods (eg, analysis of covariance [ANCOVA] or paired 
t-tests). Means and standard errors will be presented. 
9.4.2.4. 
Health-Related Quality of Life and Performance Status 
The FACT-Leu questionnaire data will be scored and processed according to the user 
manual. Missing items in a subscale will be imputed consistent with the user manual 
instructions. Data collected from the FACT-Leu instrument will not be reconciled with 
adverse event or laboratory data or with EQ-D5 findings. 
Because a significant portion of the study subjects will have CLL disease progression during 
the course of the study and no HRQL or performance status data will be collected after 
disease progression, the duration of data collection for these variables will vary among the 
study subjects. Hence, at each HRQL or performance status assessment timepoint, changes 


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from baseline in HRQL parameters or in performance status in the 2 treatment groups will be 
described by treatment group. considering both: 1) all subjects that have baseline and at least 
one post-baseline assessment for HRQL or performance status with the worst score assigned 
to those subjects who have progressed or died at the timepoint, and 2) all subjects that have 
baseline and at least one post-baseline assessment for HRQL or performance status who have 
not progressed or died at the timepoint. Subjects who are lost-to-follow-up without disease 
progression will be excluded, ie, missing data will not be imputed. Exposure and Safety 
Analyses 
9.4.2.5. 
Treatment Administration and Study Drug Compliance 
Descriptive information will be provided by treatment arm regarding the number of doses of 
study therapy prescribed, the total number of doses taken, the percent of expected doses 
taken, the number of days of treatment, and the number and timing of prescribed dose 
reductions and interruptions. 
Study drug compliance will be described by treatment arm in terms of the proportion of study 
drug actually taken based on returned pill count relative to the amount that was dispensed 
(taking into account physician-prescribed reductions and interruptions). 
9.4.2.6. 
Idelalisib Plasma Concentrations 
Bioanalytical analyses will performed independently so that the study team and investigators 
will not have knowledge of data from individual subjects. Idelalisib plasma concentrations 
immediately pre-dose and at 1.5 hours after administration of the dose of study drug at each 
relevant clinic visit will be summarized by treatment and visit using descriptive statistics. 
9.4.2.7. 
Prior, Concomitant, and Post-Treatment Medication Use 
Prior, concomitant, and post-treatment medications will be coded by means of the World 
Health Organization Drug Dictionary (WHODRUG) dictionary into 
Anatomical-Therapeutic-Chemical classification (ATC) codes. 
Descriptions of prior medication use will be focused on drugs and regimens used as 
treatments for CLL. Information regarding CLL therapy that was administered prior to 
Study GS-US-312-0116 will be referenced in reporting the results of Study 
GS-US-312-0117. In addition, relevant treatment administration information collected during 
Study GS-US-312-0116 will be referenced in reporting the results of this study. As 
appropriate and if available, information on the sequencing, type, dose, schedule, timing, 
duration of use, and efficacy of prior regimens will be provided, focusing particularly on 
findings observed in Study GS-US-312-0116. 
The type and timing of use of concomitant medications will be listed and summarized by 
type and treatment arm. Information regarding the type and use of specific supportive 
medications (eg, pneumocystis prophylaxis, hematopoietic growth factors, corticosteroids) 
during study treatment will be described. 


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The number, type, and timing of post-study-treatment regimens for CLL will be summarized 
by treatment arm, characterizing the disposition of all subjects who were eligible for 
post-study treatment and also those who were not eligible for post-study treatment 
(eg, subjects who are never treated at all, die while on study treatment, are still on study, are 
lost to follow-up, etc). 
9.4.2.8. 
Adverse Events 
All adverse events will be listed. The focus of adverse event summarization will be on 
treatment-emergent adverse events. A treatment-emergent adverse event is defined as an 
adverse event that occurs or worsens in the period from the first dose of study treatment to 
30 days after the last dose of study treatment. Adverse events that occur before the first dose 
of study drug. Adverse events will be classified using MedDRA 
(http://www.meddramsso.com) with descriptions by System Organ Class, High-Level Group 
Term, High-Level Term, Preferred Term, and Lower-Level Term. The severity of adverse 
events will be graded by the investigator according to the CTCAE, Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf), 
whenever possible. If a CTCAE criterion does not exist for a specific type of adverse event, 
the grade corresponding to the appropriate adjective will be used by the investigator to 
describe the maximum intensity of the adverse event: Grade 1 (mild), Grade 2 (moderate), 
Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the 
adverse event to the study drug will be categorized as related or unrelated. 
Treatment-emergent adverse events will be summarized by treatment arm and by visit. 
Summary tables will be presented to show the number of subjects reporting 
treatment-emergent adverse events by severity grade and corresponding percentages. A 
subject who reports multiple treatment-emergent adverse events within the same Preferred 
Term (or System Organ Class) is counted only once for that Preferred Term (or System 
Organ Class) using the worst severity grade. Adverse event descriptions will be presented by 
decreasing frequency for a given System Organ Class and Preferred Term. 
Separate listings and summaries will be prepared for the following types of 
treatment-emergent adverse events: 
• Study-drug-related adverse events 
• Adverse events that are Grade ≥3 in severity 
• Adverse events leading to study drug interruption and/or dose modification 
• Adverse events leading to study drug discontinuation 
• Serious adverse events (with categorization of the primary reason that the adverse event 
is considered serious, eg, death, hospitalization, etc) 


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Separate listings and summaries will be prepared for long-term follow-up safety data 
(see Section 6.2.17). 
9.4.2.9. 
Laboratory Evaluations 
All laboratory data will be listed. Summaries of laboratory data will be based on observed 
data. The focus of laboratory data summarization will be on treatment-emergent laboratory 
abnormalities. A treatment-emergent laboratory abnormality is defined as an abnormality 
that, compared to baseline, worsens by ≥1 grade in the period from the first dose of study 
drug to 30 days after the last dose of study drug. If baseline data are missing, then any graded 
abnormality (ie, an abnormality that is Grade ≥1 in severity) will be considered treatment 
emergent. Hematological, serum biochemistry, and urine data will be programmatically 
graded according to CTCAE severity grade, when applicable. For parameters for which a 
CTCAE scale does not exist, reference ranges from the central laboratory will be used to 
determine programmatically if a laboratory parameter is below, within, or above the normal 
range for the subject’s age, sex, etc. 
Hematological and serum biochemistry and their changes from baseline will be summarized 
by treatment arm and by visit. Summary tables will be presented for each relevant assay to 
show the number of subjects by CTCAE severity grade with corresponding percentages. For 
parameters for which a CTCAE scale does not exist, the frequency of subjects with values 
below, within, and above the normal ranges will be summarized. Subjects will be 
characterized only once for a given assay, based on their worst severity grade observed 
during a period of interest (eg, during the study or from baseline to a particular visit). 
Shift tables for hematology and serum biochemistry will also be presented by showing 
change in CTCAE severity grade from baseline to the worst grade post baseline. Separate 
listings and summaries will be prepared for laboratory abnormalities that are Grade ≥3 in 
severity. 
9.4.2.10. 
Oxygen Saturation Values 
All oxygen saturation data will be listed. Summaries of oxygen saturation data will be based 
on observed data and will be reported as % saturation. Data and changes from baseline will 
be summarized by treatment arm and by visit. Summary tables will be presented for values 
below 92% and for declines from baseline of ≥5% to show the number of subjects with 
corresponding percentages. Subjects will be characterized only once for each of these 
categorizations, based on their lowest value observed during a period of interest (eg, during 
the study or from baseline to a particular visit). 
9.4.3. 
Other Analyses 
9.4.3.1. 
Between-Study Comparisons 
It is expected that  patients with a progressive malignancy like CLL will normally fare better 
with an earlier therapy than with a later therapy. However, if the converse situation proves 


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true – eg, if an investigational treatment (idelalisib) administered later shows similar or 
greater benefit than a standard treatment (rituximab) administered earlier – strong evidence 
of investigational drug effect is demonstrated. Evaluating data derived from the same study 
subjects during their sequential participation in 2 clinical trials offers unique analytical 
challenges. However, in this integrated Phase 3 study program, it is likely that comparing 
baseline characteristics and outcomes among Arm B subjects participating in Study 
GS-US-312-0116 and Study GS-US-312-0117 will be informative. Such an evaluation 
characterizes how the subjects and the CLL disease process change with time and treatment. 
In addition, such an analysis provides relevant supporting information documenting the 
benefits of single-agent idelalisib relative to single-agent rituximab in the same subjects. 
Accordingly, the subject baseline characteristics at the start of Study GS-US-312-0116 
relative to those at the start of Study GS-US-312-0117 will be evaluated. Subject baseline 
characteristics between the studies may be compared using the Wilcoxon rank-sum test for 
continuous variables and the Fisher’s exact test for categorical variables.  
Time-to-event efficacy variables (eg, PFS, TTR, DOR, time to performance status, or HRQL 
changes) will be evaluated using the paired Prentice-Wilcoxon test, comparing results in 
Study GS-US-312-0116 to those in Study GS-US-312-0117 among subjects who participate 
in Arm B of both studies. Within each study period, medians, ranges, hazard ratios and 
corresponding 95% CIs will be presented using Kaplan Meier methods. As appropriate, Cox 
regression techniques may be used to explore the influence of baseline characteristics on 
treatment differences when comparing these outcomes between the studies. For categorical 
variables (eg, ORR, lymph node response rate, splenomegaly response rate, hepatomegaly 
response rate), the Wilcoxon signed-rank test will be employed to compare outcomes 
between Study GS-US-312-0116 and Study GS-US-312-0117 for Arm B subjects. For all 
analyses, odds ratios and the corresponding 95% CIs will be presented. Differences between 
studies for Arm B subjects relating to continuous variables (eg, percentage changes in lymph 
node area; changes in performance status, PI3K/AKT/mTOR pathway activation and plasma 
chemokines/cytokines) will be analyzed using appropriate methods (eg, analysis of 
covariance [ANCOVA] or paired t-tests). Means and standard errors will be presented. As 
appropriate, the potential influence of subject baseline characteristics on treatment effects 
may be explored with multiple logistic regression techniques. 
9.4.3.2. 
Health Care Resource Utilization 
The EQ-D5 questionnaire data will be scored, processed, and standardized according to the 
user manual. As for the FACT-Leu, data will be analyzed using appropriate methods to 
account for incomplete completion of questionnaires. Data collected from the EQ-D5 will not 
be reconciled with adverse event or laboratory data or with FACT-Leu findings. 
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations. 


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The basic approach to the health economic analysis will be to combine the resource 
utilization data from the trial with data on unit prices (collected separately) to estimate total 
costs.  
The perspective of this analysis will be that of the third-party payer(s) and the hospital over a 
lifetime horizon in the base case. The costs will be described relative to the health care 
findings as measured by duration of tumor control, the symptom-free survival period, 
life-years, utility outcomes, or other measure of appropriate clinical benefits. In order to 
facilitate the calculation of utilities for use in the cost effectiveness analyses, the health status 
of subjects will be evaluated using PFS, Karnofsky performance status, FACT-Leu, and 
EQ-5D. 
9.4.3.3. 
Data Explorations  
Changes in biomarkers during acquisition of resistance will be evaluated descriptively. Data 
explorations may be performed to evaluate potential associations between subject 
characteristics and outcome measures. Explorations may be performed to assess the potential 
associations between different outcomes measures (eg, relationships between HRQL changes 
and clinical/radiographic endpoints of tumor control). 
9.5. 
Sample Size 
The sample size for this extension study is not based upon a formal statistical hypothesis. The 
upper bound of the sample size in this study is determined by the sample size of the 
preceding primary study (Study GS-US-312-0116) in which ~160 subjects (~80 per arm) are 
expected to be enrolled. It is estimated that this extension study (Study GS-US-312-0117) 
will have a total idelalisib-treated N~130 (assuming a ~10% dropout rate during 
Study GS-US-312-0116 and a further ~10% dropout rate in the transition from the primary 
study to the extension study). 
9.6. 
Timing of Analyses 
9.6.1. 
Interim Analysis 
The DMC will have access to serious adverse events requiring expedited reporting and will 
be provided with accumulating safety data on a regular basis. Interim safety reviews will be 
conducted by the DMC in conjunction with safety reviews of the primary clinical trial 
(Study GS-US-312-0116). Thus, interim safety reviews will be performed by the DMC at 
intervals of ~6 months; the specific frequency of these reviews will depend upon the rate at 
which the trials are enrolled, the nature of any emerging safety signals, and monitoring 
recommendations from the DMC. At each review, all available safety data will be 
summarized and evaluated.  
An interim efficacy analysis of this clinical trial (Study GS-US-312-0117) is planned that 
take place at the time of the final analysis of the primary study (Study GS-US-312-0116). 
The intent is to provide the data from this extension study in support of regulatory review of 


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data from the primary study. The blind will be broken to the study team at Gilead Sciences 
for analysis purposes. However, the study will be continued to obtain further follow-up 
efficacy and safety information; individual subjects, caregivers, and site personnel will not be 
informed of the treatment assignments until the implications of revealing such data for the 
overall idelalisib study program have been determined. 
9.6.2. 
Final Analysis 
An additional, final analysis of efficacy and safety may be performed to satisfy regulatory 
requirements and to perform long-term efficacy, safety and OS follow-up. The timing of this 
analysis is expected to occur within 36 months of accrual of the final subject to 
Study GS-US-312-0117. 


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10. 
RESPONSIBILITIES 
10.1. 
Investigator Responsibilities 
10.1.1. 
Compliance with Ethical and Regulatory Guidelines 
The investigator will ensure that this study is conducted in accordance with the principles of 
the “Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), with ICH guidelines, or with the laws and regulations of the country in which 
the research is conducted, whichever affords the greater protection to the study subject. For 
studies conducted under a United States Investigational New Drug (IND) application, the 
investigator will ensure adherence to the basic principles of GCP as outlined in 21 CFR 312, 
subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 1998, and 
21 CFR, part 56, 1998. 
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 
1993, “Retention of Bioavailability and Bioequivalence Testing Samples.” 
Because this is a “covered” clinical trial, the investigator will ensure adherence to 21 CFR, 
Part 54, 1998; a covered clinical trial is any “study of a drug or device in humans submitted 
in a marketing application or reclassification petition subject to this part that the applicant or 
FDA relies on to establish that the product is effective (including studies that show 
equivalence to an effective product) or that make a significant contribution to the 
demonstration of safety.” This requires that investigators and all sub-investigators must 
provide documentation of their financial interest or arrangements with Gilead Sciences, or 
proprietary interests in the drug being studied. This documentation must be provided before 
participation of the investigator and any subinvestigator in the trial. The investigator or 
subinvestigator agrees to notify Gilead Sciences of any change in reportable financial 
interests during the study and for 1 year following completion of the study. Study completion 
is defined as the date that the last subject has completed the protocol-defined activities. 
10.1.2. 
Institutional Review Board/Independent Ethics Committee 
This protocol and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) will be submitted by the investigator to an IRB (for sites enrolling in the 
United States) and to an IEC for sites enrolling outside of the United States). Approval from 
the IRB/IEC must be obtained before starting the study and should be documented in a letter 
to the investigator specifying the protocol number, protocol version, protocol date, 
documents reviewed, and date on which the committee met and granted the approval. 
Any modifications or amendments made to the protocol after receipt of the initial IRB/IEC 
approval must also be submitted to the IRB/IEC for approval before implementation. Only 
changes necessary to eliminate apparent immediate hazards to the subjects may be initiated 


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prior to IRB/IEC approval. In that event, the investigator must notify the IRB/IEC and 
Gilead Sciences in writing within 5 working days after implementation. 
The investigator shall submit a progress report, at least once yearly, to the IRB/IEC, and must 
provide a copy to Gilead Sciences. As soon as possible after completion or termination of the 
study, the investigator will submit a final report to the IRB/IEC and to Gilead Sciences. This 
report should include the dates of initiation and completion of the trial, a description of any 
changes in study procedures or amendments to the protocol, any deviations from the 
protocol, the number and type of subjects evaluated, the number of subjects who 
discontinued (and the reasons for discontinuation), the number of subjects who completed the 
trial, and the results of the trial, including a description of any adverse events. 
Gilead Sciences will assist the investigator in the preparation of this report, as needed. 
10.1.3. 
Informed Consent 
After adequately, explaining the aims, methods, objectives, and potential hazards of the study 
and before undertaking any study-related procedures, the investigator is responsible for 
obtaining written informed consent from each individual participating in this study. The 
investigator must utilize an IRB/IEC-approved consent form for documenting written 
informed consent. Each informed consent will be appropriately signed and dated by the 
subject or the subject’s legally authorized representative and the person obtaining consent. 
The approved informed consent must not be changed without prior approval by 
Gilead Sciences and the IRB/IEC. 
10.1.4. 
Confidentiality 
The investigator must assure that each subject’s anonymity will be strictly maintained and 
that each subject’s identity is protected from unauthorized parties. Only subject initials, date 
of birth, and an identification code (but no subject names) should be recorded on any form or 
biological sample submitted to the Gilead Sciences or designees (eg, laboratories), or to the 
IRB/IEC. However, sufficient information must be retained at the site to permit sample data 
and data in the database to be connected with the unique subject number assigned to each 
study participant. 
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the idelalisib investigator brochure, this protocol, eCRFs, the investigational new 
drug, and any other study information, remain the sole and exclusive property of 
Gilead Sciences during the conduct of the study and thereafter. This information is not to be 
disclosed to any third party (except employees or agents directly involved in the conduct of 
the study or as required by law) without prior written consent from Gilead Sciences. The 
investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain. 


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10.1.5. 
Study Files and Retention of Records and Biological Samples 
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into at least the following 2 categories: (1) investigator’s 
study file, and (2) subject clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
the IRB/IEC and governmental approval with correspondence, informed consent, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 
The required source data referenced in the monitoring plan for the study, and should include 
sequential notes containing at least the following information for each subject: 
• Subject identification (name, date of birth, gender) 
• Documentation that subject meets eligibility criteria, eg, history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria) 
• Participation in trial (including trial number) 
• Trial discussed and date of informed consent 
• Dates of all visits 
• Documentation that protocol-specific procedures were performed 
• Results of efficacy parameters, as required by the protocol 
• Start and end date (including dose regimen) of trial medication (including relevant drug 
dispensing and return information) 
• Record of all adverse events and other safety parameters (including start and end date, 
causality and intensity) 
• Concomitant medication (including start and end date and dose if relevant dose changes 
occur) 
• Date of trial completion and reason for discontinuation, if applicable 
All clinical study documents must be retained by the investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (ie, the United States, Europe, 
or Japan) and until there are no pending or contemplated marketing applications in an ICH 
region; or, if no application is filed or if the application is not approved for such indication, 
until 2 years after the investigation is discontinued and regulatory authorities have been 


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notified. Investigators may be required to retain documents longer if required by applicable 
regulatory requirements, by local regulations, or by an agreement with Gilead Sciences. The 
investigator must notify Gilead Sciences before destroying any clinical study records. The 
investigator will promptly notify Gilead Sciences in the event of accidental loss or 
destruction of any study records.  
Should the investigator wish to assign the study records to another party or move them to 
another location, Gilead Sciences must be notified in advance. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all 
of the documents, special arrangements must be made between the investigator and 
Gilead Sciences to store these in sealed containers outside of the site so that they can be 
returned sealed to the investigator in case of a regulatory audit. When source documents are 
required for the continued care of the subject, appropriate copies should be made for storage 
outside of the site. 
Biological samples retained by the investigator will be stored and maintained by the 
investigator until notification is received from Gilead Sciences that the retained samples and 
records no longer need to be retained. The investigator must obtain written permission from 
Gilead Sciences before disposing of any retained samples. The investigator should promptly 
notify Gilead Sciences in the event of accidental loss or destruction of any study samples. 
With the permission of Gilead Sciences, the retained samples may be transferred to an 
acceptable designee, such as another investigator, another institution, a contract storage site, 
or to Gilead Sciences. 
10.1.6. 
Case Report Forms 
An eCRF is required and must be completed for each enrolled subject, with all required study 
data accurately recorded such that the information matches the data contained in medical 
records (eg, physicians’ notes, nurses’ notes, clinic charts, or other study-specific source 
documents). As required by the protocol, eCRFs should also be completed for those subjects 
who fail to complete the study (even during the screening period). If a subject withdraws 
from the study, the reason must be noted on the eCRF. If a subject is withdrawn from the 
study because of a treatment-limiting adverse event, thorough efforts should be made to 
clearly document the outcome.  
The eCRFs for this study will exist within a Web-based electronic data capture (EDC) 
system. After the investigator or the investigator’s designees (eg, research coordinators) have 
been appropriately trained, they will be given access to the EDC system and will enter the 
data required by the protocol into the EDC system. Any change of data will be made via the 
EDC system, with all changes tracked by the system to provide an audit trail. 
The eCRF must be completed and signed by the principal investigator or subinvestigator 
(as appropriate) within a reasonable time period after data collection. This signature serves to 
attest that the information contained in the eCRF is true. 


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10.1.7. 
Drug Accountability  
As described in the relevant section (see Section 5.2.7), the investigator is responsible for 
ensuring adequate accountability of all used and unused investigational medicinal product, 
placebos, and comparators. This responsibility includes acknowledgment of receipt of each 
shipment of study product (quantity and condition), subject dispensing records, and returned 
or destroyed study product. Dispensing records will document quantities received from 
Gilead Sciences and quantities dispensed to subjects, including lot number, date dispensed, 
subject identifier number, subject initials, and the initials of the person dispensing the 
medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during 
the study if appropriate. At the end of the study, following final drug inventory reconciliation 
by the monitor, the study site will dispose of and/or destroy all unused investigational 
medicinal product supplies, including empty containers, according to these procedures. If the 
site cannot meet Gilead Sciences’ requirements for disposal, arrangements will be made 
between the site and Gilead Sciences or its representative for destruction or return of unused 
investigational medicinal product supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by 
the study monitor over the course of the study. 
10.1.8. 
Inspections 
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from Gilead Sciences or its representatives, to 
IRB/IECs, and to regulatory authority or health authority inspectors. It is important that the 
investigator and relevant institutional personnel are available during monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process. 
10.1.9. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
10.2. 
Sponsor Responsibilities 
10.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, will 
be made only by Gilead Sciences. All protocol modifications must be submitted to the 
IRB/IEC in accordance with local requirements. Except as noted in Section 10.1.2, IRB/IEC 
approval must be obtained before changes can be implemented. 


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10.2.2. 
Communications with Regulatory Authorities 
Gilead Sciences, working either directly or through designees, will assume responsibility for 
regulatory interactions with relevant regulatory authorities. Gilead Sciences will maintain an 
IND for idelalisib in support of the study in the United States and will maintain similar 
regulatory applications with other regulatory authorities, as required for conduct of the study. 
In fulfilling this responsibility, Gilead Sciences (or a designee) will collect, assemble, and 
communicate all required regulatory documents (eg, Form FDA 1572, investigator financial 
disclosure forms, protocol and protocol amendments, investigator brochures, informed 
consent documents, annual reports) as required by regulation. Gilead Sciences (or a designee) 
will also assume responsibility for adverse event reporting to regulatory authorities as 
described in Section 8.7.2. 
10.2.3. 
Data Management 
Electronic data capture will be used to enter study data eCRFs and to transfer the data into a 
study-specific electronic database. During the data collection process, automated quality 
assurance programs will be used to identify missing data, selected protocol violations, out-of-
range data, and other data inconsistencies. Requests for data clarification or correction will 
be forwarded to the investigative site for resolution. As appropriate, eCRFs, listings, tables, 
and SAS datasets will be provided to the investigational sites for review. 
Quality assurance and quality control systems will be implemented and maintained according 
to written standard operating procedures to ensure that the data are generated, recorded, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements. Data 
collection and storage systems will provide audit trail, security mechanisms, and electronic 
signature capabilities that meet the requirements of FDA Title 21 of CFR Part 11 regarding 
electronic records and electronic signatures.  
Data security will be controlled through appropriate and specific restriction of access only to 
data and systems required by individual users to accomplish their roles in the data 
management process. Individual login and password protections will be employed at study 
sites and at Gilead Sciences or its designee. The database will exist on physically secured 
servers. Data backups will be done regularly and will be stored in separate facilities. Printed 
documents relating to the study will be secured when not under review.  
10.2.4. 
Study Reporting and Publication 
Gilead Sciences may make information obtained during this study available in order to 
further the scientific or business needs of the company or as required by law or regulation. In 
this regard, Gilead Sciences may provide study information to private or public organizations 
(eg, business partners, collaborators, consultants, CROs, investors, other physicians who are 
conducting similar studies, funding organizations, regulatory authorities, or other government 
authorities).  


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Gilead Sciences will prepare a clinical study report for submission to relevant regulatory 
agencies. Gilead Sciences will ensure that the report meets the standards set out in the ICH 
Guideline for Structure and Content of Clinical Study Reports (ICH E3). An abbreviated 
report may be prepared in certain cases, as appropriate. 
Gilead Sciences intends that the data from this study will be presented and published. 
Gilead Sciences will work in collaboration with the principal investigators in preparing 
presentations and writing manuscripts for publication.  
• Investigators may publish or present the results of the study generated by their individual 
site either with the advanced written consent of Gilead or > 2 years after the completion 
of this extension study (GS-US-312-0117) at all participating institutions.  
No such communication, presentation, or publication will include Gilead Sciences’ 
confidential information (see Section 10.1.4). 
The investigator will submit to Gilead Sciences any proposed publication or presentation 
along with the respective scientific journal or presentation forum prior to submission of the 
publication (at least 30 days prior to manuscripts and 15 days prior for abstracts and oral 
presentations). The investigator will comply with Gilead Sciences’ request to delete 
references to its confidential information (other than the study results) in any paper or 
presentation. If deemed necessary by Gilead Sciences, the investigator also agrees to 
withhold publication or presentation for an additional 60 days in order to obtain patent 
protection. 
10.3. 
Joint Investigator/Sponsor Responsibilities 
10.3.1. 
Access to Information for Monitoring 
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor 
must have direct access to the investigator’s source documentation in order to verify the data 
recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy 
of the data being entered on them. The monitor should have access to any subject records 
needed to verify the entries on the eCRFs. The investigator agrees to cooperate with the 
monitor to ensure that any problems detected in the course of these monitoring visits are 
resolved. 
10.3.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of Gilead Sciences may conduct inspections or 
audits of the clinical study. If the investigator is notified of an inspection by a regulatory 
authority the investigator agrees to notify the Gilead Sciences medical monitor immediately. 
The investigator agrees to provide to representatives of a regulatory agency or 


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Gilead Sciences access to records, facilities, and personnel for the effective conduct of any 
inspection or audit. 
10.3.3. 
Public Notification of Study Conduct 
Consistent with Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and 
with requirements of the International Committee of Medical Journal Editors (ICMJE) as a 
condition of consideration for publication of study results, Gilead Sciences will be 
responsible for ensuring that this protocol is listed at the ClinicalTrials.gov website 
(or equivalent) and that information at the website relating to study design and conduct is 
appropriately updated during the course of the study. In order to facilitate this process, 
investigators will need to supply Gilead Sciences with appropriate contact information for 
study site personnel. 
10.3.4. 
Study Discontinuation 
Both the sponsor and the investigator reserve the right to terminate the study at any time. 
Should this be necessary, both parties will arrange discontinuation procedures and notify the 
appropriate regulatory authorities and IRB/IECs. In terminating the study, Gilead Sciences 
and the investigator will assure that adequate consideration is given to the protection of the 
subjects’ interests.  
10.4. 
Study Committees 
10.4.1. 
Study Steering Committee 
A study steering committee (SSC) will be responsible for assisting Gilead Sciences with 
protocol development, review of any study amendments, coordination of study conduct, 
interpretation of data, and presentation and publication of study results. The SSC comprises 
the Gilead Sciences medical monitor for the study, the Gilead Sciences study director, and 
several clinicians with expertise in the care of subjects with CLL. Other specialists may be 
invited to participate as members of the SSC at any time if additional expertise is desired. 
Academic SSC members may be involved in accruing subjects to the study. The 
Gilead Sciences study director serves as the chair of the SSC. It is expected that the members 
of the SSC will be the same as those for the SSC of the primary clinical trial 
(Study GS-US-312-0116).  
10.4.2. 
Data Monitoring Committee 
A DMC, operating autonomously from Gilead Sciences, the clinical investigators, and the 
SSC, will be responsible for providing independent recommendations to Gilead Sciences 
about evolving risk-benefit observed in the course of the study and any modifications 
required during the course of the study. The DMC will consist of a biostatistician and 
≥2 physicians experienced in treating patients with lymphoid malignancies. The DMC will 
be chaired by one of these individuals. DMC members must not be actively involved in study 
design, conduct, or subject accrual and must not have financial, proprietary, professional, or 


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other interests that may affect impartial, independent decision-making. Specialists may be 
invited to participate as non-voting members at any time if additional expertise is desired. 
The DMC will formally interact with the external SSC members through the sharing of 
meeting minutes. Informal interactions between the DMC and external SSC members will be 
limited. The DMC will operate under a charter developed as a collaborative document 
between Gilead Sciences and the DMC. It is expected that the members of the DMC will be 
the same as those for the primary study (Study GS-US-312-0116).  
The primary responsibility of the DMC is to protect the safety and welfare of subjects 
participating in this clinical trial and to ensure the integrity of the clinical trial. In general, the 
DMC will be responsible for: 
• Reviewing the general progress of the study as regards subject accrual, study conduct, 
and protocol violations 
• Examining accumulated safety, efficacy, and other relevant data at prespecified points 
during the course of the study  
• Reviewing major study design modifications prior to implementation of those 
modifications 
• Making recommendations concerning continuation, modification, interruption, or 
termination of each study 
• Advising the company on changes to informed consent documents 
• Proposing updates to the DMC monitoring plan, changes in the DMC membership, 
actions to be taken relating to conflict of interest or confidentiality breaches, the need for 
additional expertise during DMC deliberations, revisions to the DMC charter, or 
alterations in the support provided to the DMC 
• Providing expert advice to the Gilead Science medical monitor on an ad hoc basis 
regarding matters such as safety concerns or diagnostic evaluations in individual subjects 
Based on the results of its deliberations during the course of the study, the DMC can 
recommend appropriate actions (eg, continuation of the study unchanged, continuation of the 
study with modifications in design or monitoring plan, interruption of study accrual, study 
termination). 
10.4.3. 
Independent Review Committee 
An IRC will be established to provide a blinded review of radiographic data and pertinent 
clinical data in order to provide expert interpretation of changes in tumor status. The IRC will 
include ≥1 independent board-certified radiologist and ≥1 independent board-certified 
hematologist or oncologist, and will be managed by a CRO selected by Gilead Sciences. The 
review of radiographic and clinical data by the IRC will be performed on an ongoing basis. 


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The specifics of the IRC’s processes and reading methods will be described in an 
independent review charter developed by the contracted imaging facility in conjunction with 
Gilead Sciences. The same organization that is providing IRC services for 
Study GS-US-312-0116 will provide IRC services for this study.  


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11. 
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12. 
APPENDICES 
Appendix 1. 
Investigator Signature Page 
Appendix 2. 
Functional Assessment of Cancer Therapy: Leukemia 
(FACT-Leu) 
Appendix 3. 
Performance Status Scoring System 
Appendix 4. 
EuroQoL-5 Dimensions (EQ-5D) 
Appendix 5. 
Cockcroft-Gault Method for Estimating Creatinine Clearance 
Appendix 6. 
Cumulative Illness Rating Scale (CIRS) 
Appendix 7. 
Schedule of Study Procedures 


PPDPPD
PPD


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Appendix 2. 
Functional Assessment of Cancer Therapy: Leukemia 
(FACT-Leu) 
 


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Appendix 3. 
Performance Status Scoring System 
Karnofsky Performance Status 
General Description 
Score 
Specific Description 
Able to carry on normal 
activity and to work; no 
special care needed. 
100 
Normal; no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of 
disease. 
80 
Normal activity with effort; some signs or symptoms of 
disease. 
Unable to work; able to live 
at home and care for most 
personal needs; varying 
amount of assistance needed. 
70 
Cares for self; unable to carry on normal activity or to do 
active work. 
60 
Requires occasional assistance, but is able to care for most of 
personal needs. 
50 
Requires considerable assistance and frequent medical care. 
Unable to care for self; 
requires equivalent of 
institutional or hospital care; 
disease may be progressing 
rapidly. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is indicated although 
death not imminent. 
20 
Very sick; hospital admission necessary; active supportive 
treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead 
 


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Appendix 4. 
EuroQoL-5 Dimensions (EQ-5D) 
EuroQoL-5 Dimensions (EQ-5D) 
 
Sample 


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Sample 


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Appendix 5. 
Cockcroft-Gault Method for Estimating Creatinine Clearance  
Formulas for calculating the estimated creatinine clearance (eCcr) are provided in the table 
below. The formula appropriate to the units in which serum creatinine was measured and the 
subject’s gender should be used. 
Cockcroft-Gault Formulas for Calculating Estimated Creatinine Clearance 
Serum  
Creatinine Units Gender 
Formula 
 
 
 
 
 
 
mg/dL 
Males 
eCcr 
[mL/min] 
= (140-subject age [years]) × subject weight [kilograms] × 1
72 × subject serum creatinine [mg/dl] 
 
 
 
 
 
 
 
 
Females 
eCcr 
[mL/min] 
= 
(140-subject age [years]) × subject weight [kilograms] × 
0.85 
72 × subject serum creatinine [mg/dl] 
 
 
 
 
 
 
 
 
 
 
μM/dL 
Males 
eCcr 
[mL/min] 
= 
(140-subject age [years]) × subject weight [kilograms] × 
1.23 
Subject serum creatinine [mg/dl] 
 
 
 
 
 
 
 
 
Females 
eCcr 
[mL/min] 
= 
(140-subject age [years]) × subject weight [kilograms] × 
1.04 
Subject serum creatinine [mg/dl] 
 
 
 
 
 
Abbreviation: eCcr=estimated creatinine clearance 


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Appendix 6. 
Cumulative Illness Rating Scale (CIRS) 
The CIRS used in this protocol is designed to provide an assessment of recurrent or ongoing 
chronic comorbid conditions, classified by 14 organ systems. Using the drop-down lists of 
organ-specific diagnoses, please select any conditions present in the study subject. If the 
subject has a recurrent or ongoing chronic conditions that are not described in the list for a 
given organ system, please indicate the name of the conditions under “other chronic 
condition” for that organ system. Please take into account that CLL-induced discomfort, 
symptoms, or disability should not be considered. If additional explanation would be helpful, 
text comments may be inserted.  
CIRS List of Comorbid Conditions 
Organ System 
Diagnosis 
Comment 
Cardiac 
Chronic heart failure 
 
Angina pectoris 
 
Medically relevant arrhythmia 
 
Valve dysfunction 
 
Congenital heart disease 
 
Cardiomyopathy 
 
Myocarditis 
 
Chronic pericarditis 
 
Endocarditis 
 
Other chronic cardiac condition: 
 
Other chronic cardiac condition: 
 
Vascular 
Hypertension 
 
Thrombosis 
 
Peripheral diabetic microvascular disease 
 
Peripheral artery disease 
 
Aortic aneurysm 
 
Aortitis 
 
Raynaud disease 
 
Vasculitis 
 
Other chronic vascular condition: 
 
Other chronic vascular condition 
 
Hematological/ 
immunological 
Sickle cell anemia 
 
Hemoglobinopathy 
 
Polycythemia 
 
Thrombocythemia 
 
Hemophilia 
 
Paroxysmal nocturnal hemoglobinuria 
 
Thrombotic thrombocytopenic purpura 
 
Dysfibrinogenemia 
 
HIV 
 
Other chronic hematological or immunological 
condition: 
 
Other chronic hematological or immunological condition 
 


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Organ System 
Diagnosis 
Comment 
Respiratory  
Asthma 
 
Chronic obstructive pulmonary disease 
 
Cystic fibrosis 
 
Emphysema 
 
Chronic bronchitis 
 
Chronic pleural effusions 
 
Pulmonary fibrosis 
 
Sarcoidosis 
 
Pulmonary embolism 
 
Pulmonary arterial hypertension 
 
Lung cancer 
 
Other chronic respiratory condition: 
 
Other chronic respiratory condition 
 
Ophthalmological/ 
otolaryngological 
Loss of vision  
 
Glaucoma 
 
Cataract 
 
Macular degeneration 
 
Diabetic retinopathy 
 
Loss of hearing 
 
Otitis/chronic otitis 
 
Vestibular impairment 
 
Vertigo 
 
Temporomandibular disorder 
 
Sialolithiasis  
 
Chronic sinusitis 
 
Laryngeal/pharyngeal disorders 
 
Other chronic ophthalmological or otolaryngological 
condition: 
 
Upper  
gastrointestinal 
Chronic esophagitis 
 
Dysphagia 
 
Achalasia 
 
Gastroduodenal ulceration 
 
Celiac disease 
 
Irritable bowel syndrome 
 
Short bowel syndrome 
 
Malnutrition 
 
Malabsorption 
 
Small bowel obstruction 
 
Hernia 
 
Pseudomyxoma peritonei 
 
Upper gastrointestinal cancer 
 
Other chronic upper gastrointestinal condition: 
 
Other chronic upper gastrointestinal condition: 
 
Lower 
gastrointestinal 
Diverticulitis 
 
Inflammatory Hernia bowel disease 
 
Volvulus 
 
Colon cancer 
 
Other chronic lower gastrointestinal condition: 
 
Other chronic lower gastrointestinal condition: 
 
Hepatic/ 
pancreatic 
Chronic hepatitis or hepatic cirrhosis 
 
Biliary obstructive disorders 
 
Pancreatitis 
 
Hepatic, biliary, or pancreatic cancer 
 
Other chronic hepatic or pancreatic condition: 
 
Other chronic hepatic or pancreatic condition: 
 


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Organ System 
Diagnosis 
Comment 
Renal  
Chronic kidney disease 
 
Diabetic nephropathy 
 
Pyelonephritis 
 
Renal cancer 
 
Other chronic renal condition: 
 
Other chronic renal condition 
 
Gynecological/ 
urological 
Recurrent/chronic urinary tract infection 
 
Nephrolithiasis 
 
Bladder dysfunction 
 
Vaginal/vulvar disease 
 
Uterine/ovarian disease 
 
Prostatitis 
 
Bladder, uterine, ovarian, prostate, or other cancer 
 
Prostate hypertrophy 
 
Other chronic gynecological or urological condition: 
 
Other chronic gynecological or urological condition: 
 
Dermatologic/ 
musculoskeletal 
Dermatitis 
 
Dermatomyositis 
 
Myopathy 
 
Gout 
 
Psoriasis 
 
Keratosis 
 
Urticaria 
 
Scleroderma 
 
Basal cell carcinoma 
 
Squamous cell carcinoma 
 
Melanoma 
 
Osteomyelitis 
 
Osteoarthritis 
 
Rheumatoid arthritis 
 
Spondyloarthritis 
 
Temporal arteritis/polymyalgia rheumatica 
 
Polychondritis 
 
Fibromyalgia 
 
Osteoporosis 
 
Systemic lupus erythematosus 
 
Dermatomyositis 
 
Sjögren syndrome 
 
Other chronic dermatological or musculoskeletal 
condition: 
 
Other chronic dermatological or musculoskeletal 
condition: 
 


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Organ System 
Diagnosis 
Comment 
Neurological 
Cerebrovascular disease (transient ischemic 
attack/stroke/hemorrhage) 
 
Dementia 
 
Parkinson disease 
 
Non-Parkinsonian movement disorder (eg, ataxia/chorea)
 
Leukodystrophic disorders 
 
Amyotrophic lateral sclerosis 
 
Multiple sclerosis 
 
Demyelinating disease 
 
Guillain-Barré syndrome 
 
Paralysis (eg, paraplegia/quadriplegia/hemiplegia) 
 
Myelopathy 
 
Cranial nerve disorder 
 
Degenerative disk disease with nerve root compression 
 
Migraine headaches 
 
Seizure disorder 
 
Secondary neuropathy (eg, 
diabetic/alcoholic/autoimmune) 
 
Neurofibromatosis/tuberous sclerosis 
 
Benign or malignant central nervous system tumor 
 
Other chronic neurological condition: 
 
Other chronic neurological condition: 
 
Endocrine/ 
metabolic 
Diabetes 
 
Adrenal disorder 
 
Thyroid disorder 
 
Parathyroid disorder 
 
Pheochromocytoma 
 
Pituitary disorder 
 
Hemochromatosis 
 
Porphyria 
 
Paget's disease 
 
Endocrine or neuroendocrine tumor 
 
Other chronic endocrine or metabolic condition: 
 
Other chronic endocrine or metabolic condition: 
 
Psychiatric 
Depression 
 
Anxiety 
 
Bipolar disorder 
 
Paranoia 
 
Schizophrenia 
 
Neurosis 
 
Personality disorder 
 
Substance addiction/abuse 
 
Posttraumatic stress disorder 
 
Chronic fatigue syndrome 
 
Other chronic psychiatric condition: 
 
Other chronic psychiatric condition: 
 
Abbreviation:  CIRS=Cumulative Illness Rating Scale 


Idelalisib 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Version 2.0 
 
 
CONFIDENTIAL 
Page 159 
23 January 2013 
For each condition selected from the CIRS List of Comorbid Conditions, please rate the 
severity of that condition. For the severity rating, please use the scoring guidelines shown in 
the table below, considering the magnitude of symptoms, how manageable the condition is, 
and the extent of intervention required: 
CIRS Rating Scale 
Score 
Severity 
Findings 
1 
Mild 
Mild discomfort, symptoms or disability 
Easy to control 
Requiring either no therapy/medication or only as needed 
2 
Moderate 
Moderate  discomfort, symptoms or disability 
Manageable 
Requiring daily treatment or first-line therapy 
3 
Severe 
Severe discomfort, symptoms or disability 
Hard to control 
Requiring second-line therapy or multiple medications 
4 
Extremely 
severe 
Life threatening, permanently disabling disability, causing organ 
failure 
Poorly manageable 
Requiring urgent intervention or resistant to therapy 
Abbreviation:  CIRS=Cumulative Illness Rating Scale 
 


PPD

SAP_009.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy 
and Safety of Two Different Dose Levels of Single-Agent Idelalisib
(GS-1101) for Previously Treated Chronic Lymphocytic Leukemia
A Companion Trial to Study GS-US-312-0116: A Phase 3, 
Randomized, Double-Blind, Placebo-Controlled Study Evaluating the 
Efficacy and Safety of Idelalisib (GS-1101) in Combination with 
Rituximab for Previously Treated Chronic Lymphocytic Leukemia
Name of Test Drug:
Zydelig® (Idelalisib; IDELA; GS-1101)
Study Number:
GS-US-312-0117
Protocol Version:
Version 6.0
Protocol Date:
27 May 2014
Analysis Type:
Interim (Open-label Portion of Study GS-US-312-0117) and Final
Analysis Plan Version:
1.0
Analysis Plan Date:
26 January 2015
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................3
LIST OF ABBREVIATIONS........................................................................................................................................4
1.
INTRODUCTION ................................................................................................................................................6
1.1.
Study Objectives ......................................................................................................................................6
1.2.
Study Design............................................................................................................................................6
1.3.
Sample Size and Power..........................................................................................................................11
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................12
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................13
3.1.
Analysis Sets..........................................................................................................................................13
3.1.1.
Intent-to-Treat Analysis Set .................................................................................................13
3.1.2.
Full Analysis Set ..................................................................................................................13
3.1.3.
Pharmacokinetic/Pharmacodynamic Analysis Sets..............................................................13
3.2.
Strata and Covariates..............................................................................................................................13
3.3.
Examination of Subject Subsets.............................................................................................................13
3.4.
Missing Data and Outliers......................................................................................................................14
3.5.
Data Handling Conventions and Transformations .................................................................................14
3.5.1.
Data Handling for Treatment Groups...................................................................................15
3.5.2.
Data Handling for Efficacy and Safety Endpoints ...............................................................19
3.5.3.
Data Handling for Laboratory data.......................................................................................19
3.6.
Visit Windows........................................................................................................................................19
3.6.1.
Analysis Windows................................................................................................................19
3.6.2.
Selection of Data in the Event of Multiple Records in a Window .......................................20
4.
SUBJECT DISPOSITION ..................................................................................................................................21
4.1.
Subject Enrollment.................................................................................................................................21
4.2.
Disposition of Subjects ..........................................................................................................................21
4.3.
Extent of Exposure.................................................................................................................................22
4.3.1.
Duration of Exposure to Study Drugs ..................................................................................22
4.4.
Protocol Deviations................................................................................................................................22
5.
BASELINE DATA .............................................................................................................................................23
5.1.
Demographics and Baseline Characteristics ..........................................................................................23
5.2.
Medical History......................................................................................................................................23
6.
EFFICACY ANALYSES ...................................................................................................................................24
6.1.
Efficacy Endpoints.................................................................................................................................24
6.1.1.
Definition of Efficacy Endpoints..........................................................................................24
6.1.2.
Analysis Methods for Efficacy Endpoints............................................................................25
6.1.3.
Between-Study Comparisons ...............................................................................................30
6.2.
Changes From Protocol-Specified Efficacy Analyses............................................................................30
7.
SAFETY ANALYSES........................................................................................................................................31
7.1.
Adverse Events and Deaths....................................................................................................................31
7.1.1.
Adverse Event Dictionary ....................................................................................................31
7.1.2.
Adverse Event Severity........................................................................................................31
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................31
7.1.4.
Serious Adverse Events........................................................................................................31


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7.1.5.
Treatment-Emergent Adverse Events...................................................................................32
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................32
7.1.7.
Treatment-Emergent Adverse Events of Interest .................................................................33
7.1.8.
Exposure-adjusted TEAE Rate.............................................................................................35
7.2.
Laboratory Evaluations ..........................................................................................................................35
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................35
7.2.2.
Summaries of Categorical Laboratory Results.....................................................................35
7.2.3.
Graded Laboratory Values ...................................................................................................36
7.2.4.
Shift in CTCAE Grade Relative to Baseline ........................................................................36
7.2.5.
Transaminase Elevations......................................................................................................37
7.2.6.
Liver-Related Laboratory Tests............................................................................................37
7.3.
Prior Therapy .........................................................................................................................................38
7.4.
Concomitant Medications ......................................................................................................................38
7.5.
Other Safety Measures ...........................................................................................................................39
7.6.
Changes From Protocol-Specified Safety Analyses...............................................................................39
8.
PHARMACOKINETIC ANALYSES ................................................................................................................40
9.
PHARMACODYNAMIC ANALYSES .............................................................................................................41
10.
REFERENCES ...................................................................................................................................................42
11.
SOFTWARE.......................................................................................................................................................43
12.
SAP REVISION..................................................................................................................................................44
13.
APPENDICES ....................................................................................................................................................45
Appendix 1.
Table of Contents for Statistical Tables, Figures, and Listings ..............................................46
Appendix 2.
Schedule of Study Procedures................................................................................................58
LIST OF IN-TEXT TABLES
Table 3-1.
Baseline for Data Summaries by Treatment Group................................................................18
Table 3-2.
Analysis Visit Window...........................................................................................................20


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LIST OF ABBREVIATIONS
AE
adverse event
AEI
adverse event of interest
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATC
Anatomical-Therapeutic-Chemical classification 
BID
twice per day
BMI
body mass index
CDF
cumulative distribution function
CI
confidence interval
CIRS
Cumulative Illness Rating Scale
CLL
chronic lymphocytic leukemia
CR
complete response
CSR
clinical study report
CT
computerized tomography
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DOR
duration of response
DSPH
Gilead Sciences Drug Safety and Public Health
eCRF
electronic case report form
ECG
electrocardiogram
EOT
end of treatment
EQ-5D
EuroQoL Five-Dimension utility measure
EWB
emotional well-being
FACT-Leu
Functional Assessment of Cancer Therapy: Leukemia
FAS
full analysis set
FWB
functional well-being 
HLGT
high-level group term
HLT
high-level term
HRQL
health-related quality of life
IRC
Independent Review Committee
ITT
intent-to-treat
IWCLL
International Workshop on CLL
IWRS
interactive web response system
LeuS
leukemia-specific subscale
LD
longest diameter


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LIST OF ABBREVIATIONS (CONTINUED)
LLT
low level term
LNR
lymph node response
LPD
longest perpendicular diameter
LVD
longest vertical dimension
MedDRA
Medical Dictionary for Regulatory Activities
MID
minimally important difference
MRI
magnetic resonance imaging
ND
no disease
NE
not evaluable
ORR
overall response rate
OS
overall survival
PD
progressive disease
PK
pharmacokinetic
PK/PD
pharmacokinetic/pharmacodynamic
PFS
progression-free survival
PR
partial response
PT
preferred term
PWB
physical well-being
RPSFT
rank-preserving structural failure time
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SOC
system organ class 
SPD
sum of the products of the perpendicular diameters 
StD
standard deviation
SWB
social/family well-being
TEAE
treatment-emergent adverse event
TFL
table, figure, listing
TOI
trial outcome index
TTR
time to response
ULN
upper limit normal
VAS
visual analogue scale
WHODRUG
World Health Organization Drug Dictionary


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1.
INTRODUCTION
This document details the planned interim and final analyses for the open-label portion of 
Study GS-US-312-0117, a Phase 3, double-blind extension study evaluating the efficacy and 
safety of 2 different dose levels of single-agent idelalisib (IDELA) for previously treated 
chronic lymphocytic leukemia (CLL). Related documents are the study protocol and 
electronic case report form (eCRF).
1.1.
Study Objectives
Study Objectives

To evaluate the effect of idelalisib on the onset, magnitude, and 
duration of tumor control

To compare tumor control in subjects receiving rituximab alone 
in Study GS-US-312-0116 to that observed in the same subjects 
when receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject 
well-being, including overall survival (OS), health-related 
quality of life (HRQL), and performance status

To assess the effects of idelalisib on disease-associated 
biomarkers and to evaluate potential mechanisms of resistance 
to idelalisib

To characterize exposure to idelalisib as determined by 
treatment administration and evaluation of idelalisib plasma 
concentrations over time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with 
administration of idelalisib
1.2.
Study Design
Design Configuration 
and Subject Population
Study GS-US-312-0117 is a separate, multicenter, 2-arm, 
double-blind, parallel-group extension study that is a companion 
trial to Study GS-US-312-0116; in this trial, compliant subjects 
from GS-US-312-0116 who are tolerating primary study therapy 
but experience definitive CLL progression are eligible to receive 
active blinded idelalisib therapy at the standard dose or a higher 
dose, with allocation based on the original primary study 
randomization.


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Since GS-US-312-0116 was stopped early due to overwhelming 
efficacy following an interim analysis, subjects who were on 
Study GS-US-312-0116 at that time transitioned to 
GS-US-312-0117. Additionally, GS-US-312-0117 became an 
open-label study offering idelalisib 150 mg BID to 
GS-US-312-0116 subjects who were randomized to placebo, and 
subjects randomized to idelalisib continued idelalisib at 
150 mg BID.
Target Population: Subjects in the primary Phase 3 study 
(GS-US-312-0116) who are compliant, are tolerating primary study 
therapy, and 1) have definitive progression of CLL while receiving 
primary study drug therapy (idelalisib/placebo) or 2) are actively 
participating in Study GS-US-312-0116 at the time the study is 
stopped, including if stopped early due to overwhelming efficacy 
following an interim analysis.
Treatment Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) 
(Study GS-US-312-0117)
Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and 
newly enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and 
newly enrolled subjects will receive 150 mg BID


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Key Eligibility Criteria
Key Inclusion Criteria
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while 
receiving study drug therapy (idelalisib/placebo) in
Study GS-US-312-0116. Note: Definitive disease progression 
is CLL progression based on standard criteria and occurring 
for any reason (ie, increasing lymphadenopathy, 
organomegaly, or bone marrow involvement; decreasing 
platelet count, hemoglobin, or neutrophil count; or worsening 
of disease-related symptoms) other than lymphocytosis. 
Subjects must have confirmation by the sponsor working in 
collaboration with an independent review committee (IRC) 
that the disease has progressed on the primary clinical trial
(Study GS-US-312-0116) before receiving secondary idelalisib
therapy on this extension trial (Study GS-US-312-0117).
3) Presence of measurable lymphadenopathy (defined as the 
presence of ≥1 nodal lesion that measures 2.0 cm in the 
longest diameter [LD] and 1.0 cm in the longest perpendicular 
diameter [LPD] as assessed by computed tomography [CT] or 
magnetic resonance imaging [MRI]).
4) Permanent cessation of Study GS-US-312-0116 treatment 
(rituximab and/or idelalisib/placebo) and no intervening or 
continuing therapy (including radiotherapy, chemotherapy, 
immunotherapy, or investigational therapy) for the treatment of 
CLL. Note: Subjects may receive corticosteroids to manage 
CLL manifestations.
5) The time from permanent cessation of Study GS-US-312-0116 
treatment (rituximab and/or idelalisib/placebo) and the initiation 
of Study GS-US-312-0117 therapy is 12 weeks. Note: Study 
procedures performed as part of Study GS-US-312-0116 need 
not be repeated and can be used as screening procedures for 
Study GS-US-312-0117 if performed within 4 weeks prior to 
initiation of study drug therapy on Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to 
initiation of study treatment) as shown in the table below. 
Note: Confirmation should be considered for out-of-range 
values to determine if the abnormality is real or artifactual. 
Values should be obtained within the screening period and 
should generally be the most recent measurement obtained. 
Subjects with any degree of neutropenia, thrombocytopenia, 
or anemia due to CLL or prior therapy may enroll.


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Key Exclusion Criteria
1) Known histological transformation from CLL to an aggressive 
lymphoma (ie, Richter transformation).
2) Evidence of ongoing systemic bacterial, fungal, or viral 
infection at the time of the start of study treatment (Visit 2).
Note: Subjects with localized fungal infections of skin or nails 
are eligible. Subjects may be receiving prophylactic antiviral 
or antibacterial therapies at the discretion of the investigator; 
anti-pneumocystis prophylaxis is encouraged. 
3) Pregnancy or breastfeeding. 
4) Intentional breaking of the blind in Study GS-US-312-0116 by 
the investigator or the study subject.
5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical 
condition, surgical history, physical finding, electrocardiogram 
(ECG) finding, or laboratory abnormality that, in the 
investigator’s opinion, could adversely affect the safety of the 
subject or impair the assessment of study results.
In the event Study GS-US-312-0116 is stopped early, subjects who 
are actively participating in Study GS-US-312-0116 will become 
eligible for this study, provided the following inclusion are met: 
1) Participation in Study GS-US-312-0116 within 12 weeks of 
enrollment onto GS-US-312-0117.
2) For female subjects of childbearing potential, willingness to use 
a protocol-recommended method of contraception from the 
screening visit (Visit 1) throughout the study and for 30 days 
from the last dose of study drug. 
3) For male subjects of childbearing potential having intercourse 
with females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start 
of study drug (Visit 2) throughout the study and for 90 days 
following the last dose of study drug and to refrain from sperm 
donation from the start of study drug (Visit 2) throughout the 
study and for 90 days following the last dose of study drug.
4) In the judgment of the investigator, participation in the protocol 
offers an acceptable benefit-to-risk ratio when considering 
current CLL disease status, medical condition, and the potential 
benefits and risks of alternative treatments for CLL.


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5) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other
study procedures, and study restrictions. Note: Psychological, 
social, familial, or geographical factors that might preclude 
adequate study participation should be considered.
6) Evidence of a personally signed informed consent indicating 
that the subject is aware of the neoplastic nature of the disease 
and has been informed of the procedures to be followed, the 
experimental nature of the therapy, alternatives, potential 
benefits, possible side effects, potential risks and discomforts, 
and other pertinent aspects of study participation.
Study Periods/Phases
Clinic/laboratory visits will occur every 2 weeks for the first 
12 weeks, every 4 weeks between Weeks 12 and 24, and every 
6 weeks between Weeks 24 and 48. Subjects continuing on study 
drug past Week 48 will have clinic visits every 12 weeks. Subjects 
will be assessed for safety at each visit. Subjects will be assessed 
for CLL disease status by physical and laboratory examinations at 
each visit and by CT or MRI at Weeks 8, 16, 24, 36, and 48 and 
every 12 weeks thereafter.
Following unblinding of the study:

Subjects who were randomized to idelalisib on 
Study GS-US-312-0116 and who received ≥24 weeks idelalisib 
will have Visit 16+, conducted 12 weeks from the date of their 
last radiology assessment (CT/MRI) and study visits will 
continue every 12 weeks thereafter. Visits 3 through 15 will not 
be required.

Subjects who have received < 24 weeks idelalisib will have all 
Study GS-US-312-0117 assessments completed per the 
Schedule of Procedures until they have received idelalisib for 
24 weeks cumulative across both studies. After completion of 
24 weeks of cumulative idelalisib treatment, Visit 16+ will be 
conducted 12 weeks from the date of their last radiology 
assessment (CT/MRI), after which time study visits will occur 
every 12 weeks.


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Schedule of Assessments
The schedule of assessments is located in Appendix 2 of this statistical analysis plan (SAP).
Treatment Assignment

Assignment to Arm A or Arm B with allocation based on the 
original primary study randomization

Implementation through an interactive web response system 
(IWRS)
Site and/or Stratum 
Enrollment Limits
Approximately 90 centers in the United States and in Europe.
Study Duration
Study drug will be taken continuously until the earliest of subject 
withdrawal from study drug, definitive progression of CLL, 
intolerable study drug-related toxicity, pregnancy, substantial 
noncompliance with study procedures, or study discontinuation.
1.3.
Sample Size and Power
Planned Sample Size
Total of up to ~180 subjects (up to ~90 subjects per treatment arm)
Power Statement
The sample size for this extension study is not based upon a formal 
statistical hypothesis. The upper bound of the sample size in this 
study is determined by the sample size of the preceding primary 
clinical trial (Study GS-US-312-0116). Assuming a ~10% dropout 
rate during Study GS-US-312-0116 and a further ~10% dropout 
rate in the transition from the primary study to the extension study, 
~180 subjects are expected to be enrolled into 
Study GS-US-312-0117.
Actual Enrollment and 
Impact on Power

Actual enrollment: 161 subjects enrolled into 
Study GS-US-312-0117.

Impact on power: Not applicable


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2.
TYPE OF PLANNED ANALYSIS
The data monitoring committee (DMC) will have access to serious adverse events requiring 
expedited reporting and will be provided with accumulating safety data on a regular basis. 
Interim safety reviews will be conducted by the DMC in conjunction with safety reviews of the 
primary clinical trial (Study GS-US-312-0116), if applicable, at intervals of ~6 months; the 
specific frequency of these reviews will depend upon the rate at which the trials are enrolled, the 
nature of any emerging safety signals, and monitoring recommendations from the DMC. At each 
review, all available safety data will be summarized and evaluated.
The efficacy analysis of the blinded portion of this clinical trial (Study GS-US-312-0117) is 
planned to take place at the time of the final analysis of the blinded portion of the primary study 
(GS-US-312-0116). Once outstanding data queries have been resolved, the database will be 
finalized for the blinded portion, and the blind will be broken.
Following unblinding, interim and final analyses are planned to be performed in support of 
regulatory review of data from the primary study. An analysis of efficacy and safety may be 
included to satisfy regulatory requirements and to perform long-term efficacy, safety, and 
OS follow-up. The timing of the final analysis is expected to occur within 48 months of accrual 
of the final subject to Study GS-US-312-0117.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
3.1.
Analysis Sets
3.1.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set includes all subjects who are randomized in 
Study GS-US-312-0116 regardless of whether subjects receive any study drug(s), or receive a 
different regimen from the regimen they were randomized to. Treatment assignment will be 
designated according to randomization. This analysis set will be used for OS analyses.
3.1.2.
Full Analysis Set
The full analysis set (FAS) includes all subjects in the ITT analysis set who receive 1 dose of 
IDELA, with treatment assignments designated according to randomization. Because all the 
subjects received correct treatment as randomized, this analysis set will be used for both the 
efficacy and safety analyses.
3.1.3.
Pharmacokinetic/Pharmacodynamic Analysis Sets
The pharmacokinetic/pharmacodynamic (PK/PD) analysis sets include data from subjects in the 
FAS who have the necessary baseline and on-study measurements to provide interpretable results 
for the specific parameters of interest.
These analysis sets will be used in the analyses of IDELA plasma concentrations.
3.2.
Strata and Covariates
Not applicable.
3.3.
Examination of Subject Subsets
Selected efficacy endpoints will be summarized in the following subgroups:

Prognostic factors
17p deletion and/or p53 mutation: either or neither
17p deletion: Yes or No
AEs and lab abnormalities will be examined in the following subgroups:

Gender (Male or Female)

Age group (< 65 or ≥ 65)

Race (White or Non-White)


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3.4.
Missing Data and Outliers
Missing Data
A missing data point for a given study visit may be due to any of the following reasons:

A visit occurred in the window but data were not collected or were unusable

A visit did not occur in the window

A subject permanently discontinued from the study before reaching the window
In general, values for missing data will not be imputed unless methods for handling missing data 
are specified.
Missing data in Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) will be 
handled according to the administration and scoring guidelines.
Outliers
No data will be excluded from the analyses, including any outliers.
3.5.
Data Handling Conventions and Transformations

By-subject listings will be created for important variables in each eCRF module, and sorted 
by subject number, visit, and time (if applicable).

Summary tables for continuous variables will contain the following statistics: N (number in 
analysis set), n (number with data), mean, standard deviation (StD), median, Q1, Q3, 
minimum, and maximum. The same number of decimal places as in the raw data will be 
presented when reporting minimum and maximum, 1 more decimal place than in the raw 
data will be presented when reporting mean, median and 2 more decimal places than in the 
raw data will be presented when reporting StD.

Summary tables for categorical variables for baseline and safety data will include: 
N, n, percentage. The tables for efficacy endpoints will include standard error, and 
95% confidence intervals (CI) on the percentage, where appropriate. Unless otherwise 
indicated, 95% CIs for binary variables will be calculated using the binomial distribution. 
The denominator for the percentages will be the number of subjects in the specified analysis 
set at the same treatment or total as appropriate, unless otherwise specified. Missing data will 
be included as a row in tables where it is appropriate. All percentages will be presented as 
1-decimal point, unless otherwise specified. Percent equal to 100 will be presented as 
100% and percent will not be presented for zero frequencies.

Data from all sites will be pooled for all analyses.


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
Analyses will be based upon the observed data unless methods for handling missing data are 
specified.

For Kaplan-Meier estimates, the 95% CIs will be calculated using the Greenwood’s formula 
with (complementary) log-log transformation.
3.5.1.
Data Handling for Treatment Groups
Subjects who developed disease progression, confirmed by independent review committee 
(IRC), in Study GS-US-312-0116 could consider participation in Study GS-US-312-0117. Upon 
enrollment, subjects who were randomized into Arm A received IDELA 300 mg BID and those 
who were randomized into Arm B received IDELA 150 mg BID.
Study GS-US-312-0116 was stopped early due to overwhelming efficacy based on results from 
the first interim analysis and the primary study was unblinded. Under the protocol amendment, 
all remaining subjects were given the opportunity to enroll in Study GS-US-312-0117 and 
received IDELA 150 mg BID. The dose increase to IDELA 300 mg BID after confirmed PD on 
Arm A was no longer offered.
For disposition data summaries, subjects will be assigned into 1 of the following 
4 treatment groups: 

IDELA 150 mg BID in GS-US-312-0116 and GS-US-312-0117:
Includes all subjects who are randomized to Arm A in Study GS-US-312-0116 except for 
those who take IDELA 300 mg BID in Study GS-US-312-0117
Referred to ‘IDELA+R/IDELA’ throughout this SAP and the tables, figures, and listings 
(TFLs)
Baseline for efficacy endpoints will be the date of randomization in 
Study GS-US-312-0116. 
Baseline for safety endpoints will be the first dosing of IDELA in 
Study GS-US-312-0116.
In the analysis, the Study GS-US-312-0117 portion will include all the data collected on 
or after the enrollment date of Study GS-US-312-0117.

IDELA 150 mg BID in GS-US-312-0116 + IDELA 300 mg BID in GS-US-312-0117:
Includes subjects who experience IRC confirmed progressive disease (PD) in Arm A of 
Study GS-US-312-0116 and subsequently enroll into Study GS-US-312-0117 to receive 
IDELA 300 mg BID during the double-blind portion of the study
Referred to ‘IDELA+R (PD)/IDELA’ throughout this SAP and the TFLs


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Baseline for efficacy and safety endpoints will be the first dosing of IDELA 300 mg BID, 
unless otherwise specified.
In the analysis, the Study GS-US-312-0117 portion will include all the data collected on 
or after the enrollment date of Study GS-US-312-0117.

Placebo in GS-US-312-0116 + IDELA 150 mg BID (open-label):
Includes subjects who are randomized to Arm B in Study GS-US-312-0116 and transition
to receive IDELA 150 mg BID during the open-label portion of the study
Referred to ‘Placebo+R/IDELA’ throughout this SAP and the TFLs
Baseline for efficacy and safety endpoints will be the first dosing of IDELA, unless 
otherwise specified.
In the analysis, the Study GS-US-312-0117 portion will include all the data collected on 
or after the first dosing date of IDELA. The Study GS-US-312-0117 portion may include 
data collected in Study GS-US-312-0116, if a subject switches to open-label IDELA in 
Study GS-US-312-0116 while waiting for the protocol amendment.

Placebo in GS-US-312-0116 + IDELA 150 mg BID in GS-US-312-0117:
Includes subjects who experience IRC confirmed PD in Arm B of 
Study GS-US-312-0116 and subsequently enroll into Study GS-US-312-0117 to receive 
IDELA 150 mg BID during the double-blind portion of the study
Referred to ‘Placebo+R (PD)/IDELA’ throughout this SAP and the TFLs
Baseline for efficacy and safety endpoints will be the first dosing of IDELA, unless 
otherwise specified.
In the analysis, the Study GS-US-312-0117 portion will include all the data collected on 
or after the enrollment date of Study GS-US-312-0117.
Efficacy and safety data collected during the primary and extension studies will be presented in 
the following 3 treatment groups:

IDELA+R (PD, non-PD)/IDELA
Includes all subjects who are randomized to Arm A in Study GS-US-312-0116
(ie, all subjects in IDELA+R/IDELA and IDELA+R (PD)/IDELA)
For those in IDELA+R (PD)/IDELA, only data collected in Study GS-US-312-0116
(ie, while taking IDELA 150 mg BID) will be included. For those in IDELA+R/IDELA, 
all the data collected across Study GS-US-312-0116 and GS-US-312-0117 will be 
included. By this summary, the efficacy and safety profile of IDELA 150 mg BID can be 
explored for subjects randomized to Arm A in Study GS-US-312-0116.


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Baseline for efficacy endpoints will be the date of randomization in 
Study GS-US-312-0116. 
Baseline for safety endpoints will be the first dosing of IDELA 150 mg BID in 
Study GS-US-312-0116.

Placebo+R/IDELA

Placebo+R (PD)/IDELA
Due to the small sample size (N = 4) for the IDELA + R (PD)/IDELA group, data collected from 
this group in Study GS-US-312-0117 (ie, while taking IDELA 300 mg BID) will only be 
presented in listings.
Baseline for each data summary is described in Table 3-1.


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Table 3-1.
Baseline for Data Summaries by Treatment Group
Treatment Group
Baseline for Disposition Summary
Baseline for Efficacy Summary
Baseline for 
Safety Summary
312-0116
312-0117
All endpoints 
except for OS
OS
All endpoints
IDELA+R/IDELA
Date of randomization in
Study GS-US-312-0116
Enrollment date of 
Study GS-US-312-0117
Date of randomization in
Study GS-US-312-0116
Date of randomization in
Study GS-US-312-0116
First dosing date of 
IDELA in 
Study GS-US-312-0116
IDELA+R (PD)/IDELA
Date of randomization in
Study GS-US-312-0116
Enrollment date of 
Study GS-US-312-0117
First dosing date of 
IDELA 300 mg BID in 
Study GS-US-312-0117
First dosing date of 
IDELA 300 mg BID in 
Study GS-US-312-0117
Placebo+R/IDELA
Not applicable
First dosing date of 
IDELA (Switching date 
to open-label IDELA)
First dosing date of 
IDELA (Switching date 
to open-label IDELA)
First dosing date of 
IDELA (Switching date 
to open-label IDELA)
Placebo+R (PD)/IDELA
Not applicable
Enrollment date of 
Study GS-US-312-0117
First dosing date of 
IDELA 150 mg BID in 
Study GS-US-312-0117
First dosing date of 
IDELA 150 mg BID in 
Study GS-US-312-0117
IDELA+R(PD, non-PD)/
IDELA
Not applicable
Not applicable
Date of randomization in
Study GS-US-312-0116
First dosing date of 
IDELA in 
Study GS-US-312-0116


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Data from subjects who are randomized to Arm B in Study GS-US-312-0116 and never received
IDELA in Study GS-US-312-0117 will be excluded from the analyses, unless otherwise 
specified.
3.5.2.
Data Handling for Efficacy and Safety Endpoints

If there is a significant degree of non-normality for a continuous endpoint, analyses may be 
performed on log-transformed data or using nonparametric methods, as appropriate.

Analyses will be descriptive in nature and formal comparisons of outcomes between 
treatment groups are not planned.
3.5.3.
Data Handling for Laboratory data
Laboratory data that are continuous in nature but are less than the lower limit of quantitation or 
above the upper limit of quantitation will be imputed as follows:

A value that is 1 unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the data is reported in the form of “< x” (x is considered the 
limit of quantitation). For example, if the values are reported as < 50 and < 5.0, then values 
of 49 and 4.9 will be used for calculation of summary statistics, respectively. However, for 
direct bilirubin, a value of “< 0.1” will be treated as 0.05 for calculation of summary 
statistics. 

A value that is 1 unit above the limit of quantitation will be used for calculation of 
descriptive statistics if the data is reported in the form of “> x” (x is considered the 
limit of quantitation). For example, if the values are reported as > 50 and > 5.0, then values 
of 51 and 5.1 will be used for calculation of summary statistics, respectively. 

The limit of quantitation will be used for calculation of descriptive statistics if the data is 
reported in the form of “≤ x” or “≥ x” (x is considered as the limit of quantitation).
3.6.
Visit Windows
3.6.1.
Analysis Windows
When applicable, the nominal visit as recorded on the eCRF will be used. For parameters 
assessed at the end of treatment (EOT) visit, the assessment results will be assigned to the next 
scheduled visit where the respective data were scheduled to be collected for summary. 
Unscheduled scans will be used for determination of the time-to-event and tumor response 
efficacy endpoints.
For data collected after unblinding of the study, nominal visit may no longer be applicable. In 
such case, summary by visit will be based on the following visit windows as described in 
Table 3-2.


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Table 3-2.
Analysis Visit Window
Start (day)
Stop (day)
Scheduled Visit day
Week
1
1
1
0
2
21
15
2
22
35
29
4
36
49
43
6
:
:
:
:
7*(X-1)+1
7*(X+1)
X*7+1
X
3.6.2.
Selection of Data in the Event of Multiple Records in a Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value per visit, 
whereas a time-to-event analysis would not require 1 value per analysis window but rather 
1 value for the study. Unless otherwise noted throughout the rest of this document, when a 
single value is needed, the following rule(s) will be used:

If more than 1 assessment occurs during the same nominal visit, select the record closest to 
the nominal day for that visit.

If there are 2 assessments that are equidistant from the nominal day, the data of the 
assessment after the scheduled study day will be used.

The last measurement will be used if multiple measurements are all taken on the same day.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment
A listing of all subjects in the FAS will be generated to describe site, subject number, first and 
last IDELA dosing dates, treatment group, the reason for discontinuing study treatment, and the 
reason for discontinuing study. The site summary will be based on the original site ID from 
Study GS-US-312-0116.
A by-subject listing for subjects who were screened but not treated in Study GS-US-312-0117 
will be listed separately.
4.2.
Disposition of Subjects
A summary of subject disposition will be provided for the FAS.
Study treatment disposition will present the number of subjects who:

were treated in Study GS-US-312-0116

completed/discontinued treatment in Study GS-US-312-0116 and were not treated in 
Study GS-US-312-0117
met primary study endpoint according to the investigator
discontinued study drug with summary of reason for discontinuation

were treated in Study GS-US-312-0117

has treatment ongoing in Study GS-US-312-0117

completed/discontinued treatment in Study GS-US-312-0117
met primary study endpoint according to the investigator
discontinued study drug with summary of reason for discontinuation
Study disposition will present the number of subjects who:

were randomized in Study GS-US-312-0116

completed/discontinued Study GS-US-312-0116 and were not enrolled into
Study GS-US-312-0117
met primary study endpoint according to the investigator
discontinued study with summary of reason for discontinuation


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
enrolled into Study GS-US-312-0117

are ongoing in Study GS-US-312-0117

completed/discontinued Study GS-US-312-0117
met primary study endpoint according to the investigator
discontinued study with summary of reason for discontinuation
Long-term follow-up disposition will present the number of subjects who:

entered long-term follow-up

completed long-term follow-up 

are ongoing with long-term follow-up 

discontinued the long-term follow-up with summary of reasons for discontinuation
The denominator for the percentages of subjects in each category will be the number of subjects 
in the FAS. No inferential statistics will be generated.
4.3.
Extent of Exposure
4.3.1.
Duration of Exposure to Study Drugs
Duration of exposure to IDELA will be defined as minimum of (last IDELA dosing date, 
data cutoff date) – first IDELA dosing date +1, regardless of temporary interruptions in study 
drug administration, and will be expressed in months. For subjects who are randomized to 
Arm A, exposure duration will reference to the first dosing date of IDELA in 
Study GS-US-312-0116.
Duration of exposure to IDELA will be summarized for the FAS using descriptive statistics and 
as the number and percentage of subjects exposed for at least 2, 4, and 6 months, and every 
6 months thereafter.
Number and percentage of subjects who had IDELA dose modification (dose reduction and dose 
re-escalation) will also be summarized. IDELA dosing records, drug accountability 
(dispense and return), and dose modification records will be listed in detail.
4.4.
Protocol Deviations
Protocol deviations will be categorized before database finalization by Gilead. The important 
(major) protocol deviations will be summarized by type of deviation in the clinical study report 
(CSR) for subjects who enroll into Study GS-US-312-0117. A listing will be provided for 
important protocol deviations.


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5.
BASELINE DATA
5.1.
Demographics and Baseline Characteristics
Demographics including gender, race, ethnicity, age (years), weight (kg), height (cm), and 
body mass index (BMI, kg/m2) will be summarized for the FAS. Gender, race, ethnicity, and 
Karnofsky performance status will be summarized by using summary statistics for categorical 
variables. Age (years), weight (kg), and height (cm) will be summarized using summary statistics 
for continuous variables. Age will be calculated as the number of years between date of birth and 
date of randomization in Study GS-US-312-0116.
Age (years) = (date of randomization in Study GS-US-312-0116 – date of birth + 1) / 365.25 
(round down to an integer)
BMI (kg/m2) = weight / (height)2 (round to 1 decimal point)
Number and percentage of subjects < 65 and 65 years will also be summarized. A data listing 
will be presented.
5.2.
Medical History
A listing of total cumulative illness rating scale (CIRS) scores and medical history will be 
provided.


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6.
EFFICACY ANALYSES
An IRC was established for this study and includes primary board-certified radiologists and a 
board-certified adjudicating radiologist from a pool of radiologists, and an independent 
board-certified hematologist or oncologist to perform an independent review of response and 
disease progression for each subject. The review will comprise an assessment of radiographic 
images and prospectively defined clinical data acquired during the study according to the 
Gilead Protocol GS-US-312-0117 Imaging Charter. The determination of CLL response and 
progression will be based on standardized criteria promulgated by the International Workshop 
on CLL (IWCLL) {12154}, as specifically modified for this study to reflect current 
recommendations which consider the mechanism of action of IDELA and similar drugs {22541}.
The findings of the IRC will be considered primary for analyses of tumor control endpoints.
6.1.
Efficacy Endpoints
6.1.1.
Definition of Efficacy Endpoints

Progression-free survival (PFS) – defined as the interval from the baseline reference date for 
efficacy endpoints, as defined in Section 3.5.1, to the earlier of the first documentation of 
definitive disease progression or death from any cause; definitive disease progression is CLL 
progression based on standard criteria {12154}, {22541} other than lymphocytosis alone.

Overall response rate (ORR) – defined as the proportion of subjects who achieve a complete 
response (CR) or partial response (PR)

Lymph node response (LNR) rate – defined as the proportion of subjects who achieve a 
≥50% decrease from baseline in the sum of the products of the greatest perpendicular 
diameters (SPD) of index lesions per IRC assessments

Complete response (CR) rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from the baseline reference date for 
efficacy endpoints to the first documentation of CR or PR

Duration of response (DOR) – defined as the interval from the first documentation of 
CR or PR to the earlier of the first documentation of definitive disease progression or death 
from any cause

Percent change in lymph node area – defined as the percent change from baseline in the SPD 
of index lymph nodes

Splenomegaly response rate – defined as the proportion of subjects with baseline 
splenomegaly who achieve an on-study normalization or a 50% decrease (minimum 2 cm) 
from baseline in the enlargement of the splenic longest vertical dimension (LVD) by 
imaging.


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
Hepatomegaly response rate – defined as the proportion of subjects with baseline 
hepatomegaly who achieve an on-study normalization or a 50% decrease (minimum 2 cm) 
from baseline the hepatic LVD by imaging.

Absolute lymphocyte count (ALC) response rate – defined as the proportion of subjects with 
baseline lymphocytosis (ALC ≥ 4 × 109/L) who achieve an on-study ALC < 4 × 109/L or 
demonstrate a ≥50% decrease in ALC from baseline; ALC values within 4 weeks 
post-baseline will be excluded from the ALC response rate evaluation.

Platelet response rate – defined as the proportion of subjects with baseline thrombocytopenia 
(platelet count < 100 × 109/L) who achieve an on-study platelet count ≥100 × 109/L or 
demonstrate a ≥50% increase in platelet count from baseline without need for exogenous 
growth factors. Platelet values within 4 weeks post-baseline or after 8 days post transfusion 
will be excluded from the platelet response rate evaluation.

Hemoglobin response rate – defined as the proportion of subjects with baseline anemia 
(hemoglobin < 110 g/L [11.0 g/dL]) who achieve an on-study hemoglobin ≥110 g/L 
(11.0 g/dL) or demonstrate a ≥ 50% increase in hemoglobin from baseline without 
red blood cell transfusions or need for exogenous growth factors. Hemoglobin values within 
4 weeks post-baseline or after 4 weeks of receiving packed cell/whole blood transfusion or 
after 6 weeks receiving exogenous growth factors (e.g., Darbepoetin alfa) will be excluded 
for the hemoglobin response evaluation.

Neutrophil response rate – defined as the proportion of subjects with baseline neutropenia 
(absolute neutrophil count [ANC] ≤1.5 × 109/L) who achieve an ANC > 1.5 × 109/L or 
demonstrate a ≥50% increase in ANC from baseline without need for exogenous growth 
factors. ANC values within 4 weeks of post-baseline or after 2 weeks of receiving exogenous 
growth factors (e.g., Filgrastim, G-CSF, Lenograstim) or after 4 weeks of receiving Neulasta 
will be excluded for the neutrophil response evaluation.

Overall Survival (OS) – defined as the interval from the date of randomization in 
Study GS-US-312-0116 to death from any cause during the study or long term follow up

Change from baseline in HRQL using FACT-Leu scores

Changes from baseline in Karnofsky performance status

Change from baseline in overall health and summary of single-item dimension scores as 
assessed using the EuroQoL Five-Dimension (EQ-5D) utility measure
6.1.2.
Analysis Methods for Efficacy Endpoints
6.1.2.1.
Progression-Free Survival
PFS will be described in the FAS using Kaplan-Meier methods by treatment groups. Median PFS
with Q1 and Q3, the Kaplan-Meier estimates of PFS rate with corresponding 95% CIs will be 
presented at 24, 48 weeks and so forth depending on the follow-up duration. The 
Kaplan-Meier curve will also be plotted.


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The date of definitive CLL progression will be the timepoint at which progression is 
first identified by relevant objective radiographic or clinical data by the IRC.
Data will be censored on the date of the last tumor assessment (including assessments with a 
not evaluable [NE] outcome) for subjects who do not have disease progression, or who do not 
die on study. Data will also be censored on the date of the last tumor assessment (including NE) 
prior to the initiation of new anti-tumor therapy, or prior to ≥2 consecutive missing tumor 
assessments before disease progression or death. Subjects without adequate baseline tumor 
response evaluation will be censored on the baseline reference date for efficacy endpoints.
For subjects with disease progression by the IRC, the reasons for PD will be summarized by 
treatment groups.
The following disease progression criteria will be included:

Progression based on index lesion
Increase from the nadir by ≥50% in the SPD of index lesions
A new node that measures > 1.5 cm in the LD and >1.0 cm in the LPD
Increase from the nadir by ≥50% in the LD of an individual node

Progression based on non-index lesion
Unequivocal increase in the size of non-index disease

Progression based on hepatomegaly
New or recurrent hepatomegaly
Hepatic progression

Progression based on splenomegaly
New or recurrent splenomegaly
Splenic progression 

Progression based on hematological parameters confirmed by bone marrow
The current platelet count is < 100 × 109/L and there has been a decrease by >50% from 
the highest on-study platelet count
The current hemoglobin is < 110 g/L (11.0 g/dL) and there has been a decrease by 
> 20 g/L (2 g/dL) from the highest on-study hemoglobin

Transformation to a more aggressive histology


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6.1.2.2.
Overall Response Rate
Responses will be categorized as CR, PR, stable disease (SD), or PD. In addition, a response 
category of not evaluable (NE) is provided for situations in which there is inadequate 
information to otherwise categorize response status. A response category of no disease (ND) is 
included for situations in which there is no evidence of tumor either at baseline or on study.
The ORR using the IRC assessments will be presented with 95% CI by treatment groups. In the 
calculation of response rates, subjects who do not have sufficient baseline or on-study tumor 
assessment to characterize response will be included in the denominator.
6.1.2.3.
Lymph Node Response Rate
LNR rate will be presented with 95% CI by treatment groups. Only subjects that have both
baseline and ≥1 evaluable post-baseline SPD will be included for this analysis.
6.1.2.4.
Complete Response Rate
The same analyses as specified for ORR in Section 6.1.2.2 will be performed for the CR rate. 
6.1.2.5.
Time to Response and Duration of Response
TTR and DOR will be evaluated using IRC assessments based on subjects who achieve a CR or 
PR. Descriptive statistics will be provided for TTR. DOR will be summarized using 
Kaplan-Meier methods (medians, Q1, Q3, and corresponding 95% CIs) and the 
Kaplan-Meier curves will also be provided by treatment groups.
For the DOR analysis, data will be censored with the same manner as described in 
Section 6.1.2.1 for subjects who do not have disease progression, or who do not die on study, or
start new anti-tumor therapy, or have 2 consecutive missing tumor assessments before disease 
progression or death.
6.1.2.6.
Best Percent Change in Lymph Node Area
The best percent change in SPD from baseline during the study will be summarized using 
descriptive statistics. The summary is based on subjects with sufficient baseline and on-study 
tumor measurements for the SPD calculation per IRC. The best percent change from baseline in 
SPD is defined as the largest decrease in tumor size during the study. The baseline SPD will be 
the last value collected prior to the baseline reference date for efficacy endpoints. Note that for 
subjects who only have increases in tumor size from baseline, the smallest increase will be 
considered as the best change from baseline in SPD. Waterfall plots of best on-study percent 
change in SPD will be provided for each treatment group using IRC data.


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6.1.2.7.
Other Categorical Endpoints
Splenomegaly response rate, hepatomegaly response rate, ALC response rate, 
platelet response rate, hemoglobin response rate, and neutrophil response rate will be presented 
with 95% CIs. In the calculation of response rates, only subjects who have relevant abnormality, 
sufficient baseline and post-baseline assessments to characterize response will be included in the 
analysis.
The ALC, platelet, hemoglobin, and neutrophil responses will be listed with flags to indicate the 
use of any supportive care for corresponding hematologic lab parameters.
6.1.2.8.
Overall Survival
OS will be described in the ITT analysis set using Kaplan-Meier methods by treatment group
according to the original randomization in Study GS-US-312-0116. Median OS with Q1, Q3, and 
the Kaplan-Meier estimates of OS rate by every 6 months with corresponding 95% CIs will be 
presented. The Kaplan-Meier curve will also be plotted.
Data from surviving subjects will be censored at the last time that the subject was known to be 
alive on study or long term follow up.
Sensitivity analyses will be conducted by censoring OS on the first date of IDELA dosing for 
subjects in Arm B. OS will also be analyzed using the rank-preserving structural failure time 
(RPSFT) model {33006} to adjust for cross over effects.
6.1.2.9.
Health-Related Quality of Life
The FACT-Leu questionnaire includes subscales for physical well-being (PWB, 7 items), 
social/family well-being (SWB, 7 items), emotional well-being (EWB, 6 items), functional 
well-being (FWB, 7 items), and additional concerns (Leukemia-Specific Subscale [LeuS], 
17 items). The FACT-Leu scoring guide identifies those negatively stated items that must be 
reversed before being added to obtain subscale totals. Negatively stated items are reversed by 
subtracting the response from “4”. After reversing proper items, all subscale items are summed 
to a total, which is the subscale score. For all FACT-Leu scales and symptom indices, the higher 
score is associated with the better quality of life. The scores in the following items need to be 
reversed according to the standard scoring guidelines:

Physical well-being: all individual items

Social/family well-being: none

Emotional well-being: 5 individual items (except for GE2: “I am satisfied with how I am 
coping with my illness”)

Functional well-being: none

Additional concerns: all individual items (except for C6: “I have a good appetite” and An7: 
“I am able to do my usual activities”)


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The subscale scores will be a summation of each individual item score. If ≤50% of item scores 
are missing, the subscale score will be calculated by multiplying the sum of the item scores by 
the number of items in the subscale, then divided by the number of non-missing item scores. This 
imputes the missing scores by the mean of the non-missing scores within a subscale.
Prorated subscale score = [sum of item scores] × [N of items in subscale] / [N of items answered]
The following composite scores will be derived from the above subscale total scores:

Trial Outcome Index (TOI, score range: 0-124) = PWB + FWB + LeuS

FACT-G Total Score (score range: 0-108) = PWB + SWB + EWB + FWB

FACT-Leu Total Score (score range: 0-176) = PWB + SWB + EWB + FWB + LeuS
The total scores will be set to missing if 20% or more of the included items are missing or any of 
the component subscales are missing. TOI scores are set to missing if any of the component 
subscales are missing.
As a baseline, the last value obtained prior to the baseline reference date for efficacy endpoints, 
as defined in Section 3.5.1, will be used. The mean and change from baseline in mean scores to 
each subsequent assessment will be summarized for the subscale and composite scores. The best 
change from baseline during the study, defined as the highest positive value among all 
post-baseline visits minus the baseline value, will also be summarized.
Each subject’s FACT-Leu subscales (ie, PWB, EWB, SWB, and FWB) scores at each 
assessment will be compared to their baseline scores. The minimally important difference (MID) 
for these subscales is 3 points {26297}. An increase of at least 3 points will be required as a 
definition of symptom improvement. The cumulative distribution function (CDF) of best change 
from baseline will be provided. For the MID improvement comparison, subjects with baseline 
score > 55 will be excluded (ie, subjects with no room for improvement). Time to symptom 
response will be assessed by defining the first occurrence of symptom improvement as an event. 
Subjects who do not experience a symptom improvement compared to baseline will be censored 
at their last available FACT-Leu assessment time.
A data listing for each individual item, the subscale scores, and the composite scores will be 
presented for each subject at each time point.
6.1.2.10.
Karnofsky Performance Status
The Karnofsky performance status scores and the change from baseline scores to each 
subsequent assessment will be summarized. The best change from baseline, defined as the 
highest change from baseline during the study, will also be summarized.


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6.1.2.11.
EQ-5D
The EQ-5D questionnaire data will be scored, processed, and standardized according to the user 
manual. As for the FACT-Leu, data will be analyzed using appropriate methods specified in the 
user manual to account for incomplete completion of questionnaires. A single utility index of 
EQ-5D will be derived by applying US preference-weighted index {28010}. Data collected from 
the EQ-5D will not be reconciled with adverse event or laboratory data or with FACT-Leu 
findings.
Each EQ-5D dimension will be summarized using frequency and proportion. Change from 
baseline in EQ-5D visual analogue scale (VAS) and EQ-5D index will be summarized.
6.1.3.
Between-Study Comparisons
 
 
 
 
 
 
 
6.2.
Changes From Protocol-Specified Efficacy Analyses
The per-protocol analysis set and the safety analysis set are no longer applicable. The FAS will 
be used for both efficacy and safety analyses.
PPD


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
The focus of adverse event (AE) summarization will be on treatment-emergent AEs (TEAEs). 
All AEs and deaths happened on study will be summarized by treatment group and will be listed 
in detail based on the FAS.
7.1.1.
Adverse Event Dictionary
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) by 
system organ class (SOC), high level group term (HLGT), high level term (HLT), preferred term 
(PT), and lower level term (LLT).
7.1.2.
Adverse Event Severity
The severity of AEs will be graded by the investigator according to the common terminology 
criteria for adverse events (CTCAE), Version 4.03, whenever possible. If a CTCAE criterion 
does not exist, the grade corresponding to the appropriate adjective will be used by the 
investigator to describe the maximum intensity of the AE.  The severity grade will be categorized 
as:

Grade 1 (mild)

Grade 2 (moderate) 

Grade 3 (severe)

Grade 4 (life threatening), or 

Grade 5 (fatal)
A missing severity grade will be considered as missing.
7.1.3.
Relationship of Adverse Events to Study Drug
The relationship of an AE to IDELA should be assessed using clinical judgment by the 
investigator, describing the event as either unrelated or related. Events for which the investigator 
did not record relationship to IDELA will be considered related to IDELA. Data listings will 
show relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) are those identified as serious in the clinical database. The 
clinical database will be reconciled with the SAE database from the Drug Safety and 
Public Health (DSPH) Department before database finalization.


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7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent
TEAEs are events in a given study period that meet one of the following criteria:

Events with onset dates on or after the start of IDELA and up to 30 days after the permanent 
discontinuation of IDELA.

AEs resulting in IDELA discontinuation after the start of treatment.
7.1.5.2.
Incomplete Dates
All AEs with partial onset or stop dates will be identified and the partial dates will be imputed as 
follows:

For AE onset date: If day and month are missing but year is available, then the imputed day 
and month will be 01Jan or the first dosing date of IDELA if they have the same year, 
whichever is later. If day is missing but the month and year are available, then the imputed 
day will be the first day of the month or the first dosing date of IDELA if they have the same 
month and year, whichever is later.

For AE stop date: If day and month are missing but year is available, then the imputed day 
and month will be 31Dec or 30 days after the last dose of study treatment if they have the 
same year, whichever is earlier. If day is missing but the month and year are available, then 
the imputed day will be the last day of the month or 30 days after the last dose of study 
treatment if they have the same month and year, whichever is earlier.
7.1.6.
Summaries of Adverse Events and Deaths
A brief summary of TEAEs by treatment group will show the number and percentage of subjects 
who (1) had any AE, (2) had any Grade ≥3 AE, (3) had any IDELA-related AE, (4) had any 
Grade ≥3 IDELA-related AE, (5) had any SAE, (6) had any IDELA-related SAE, 
(7) discontinued from study drug due to an AE, (8) dose interruption due to an AE, (9) dose 
reduction due to an AE, (10) dose modification (interruption and/or reduction) due to an AE, 
(11) death due to AEs.
Summaries (number and percentage of subjects) of TEAEs (by SOC, HLT and PT) will be 
provided by treatment group using the FAS as follows:

AEs

AEs by CTCAE Grade

Grade ≥3 AE 


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
IDELA-related AEs

SAEs

IDELA-related SAEs 

AEs leading to IDELA modification (reduction and/or interruption)

AEs leading to IDELA reduction

AEs leading to IDELA interruption

AEs leading to permanent discontinuation from IDELA

AEs leading to death

TEAE incidence rate adjusted for total exposure
Multiple events will be counted once only per subject in each summary. For data presentation, 
SOC, HLT and PT will be sorted by decreasing frequency based on IDELA + R/IDELA
treatment group. For summaries by severity grade, the most severe event will be selected. In 
addition to the presentation by SOC and HLT, selected summary will also be presented by 
preferred term only, ordered by decreasing frequency. 
In addition to the by-treatment summaries, data listings will be provided for the following:

All TEAEs

SAEs

AEs leading to discontinuation of IDELA

Deaths
Relative day from the baseline reference date for safety endpoints, as defined in Section 3.5.1., 
will be provided for each AE in the listings. The relative day will be calculated as 
(AE onset date - baseline reference date for safety endpoints + 1).
7.1.7.
Treatment-Emergent Adverse Events of Interest
The treatment-emergent AEs of interest (AEI) include:

Rash based on Gilead medical search list including multiple MedDRA preferred terms 
dermatitis exfoliative, drug eruption, rash, rash erythematous, rash generalised, rash macular, 
rash maculo-papular, rash papular, rash prutitic, rash morbilliform, and exfoliative rash

Diarrhea/Colitis including diarrhea or colitis


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
Pneumonitis

Anaphylaxis including anaphylactic reaction, anaphylactic shock, anaphylactic transfusion 
reaction, anaphylactoid reaction, anaphylactoid shock, circulatory collapse, first use 
syndrome, kounis syndrome, shock, type I hypersensitivity

Bowel perforation including rectal perforation, duodenal perforation, duodenal ulcer 
perforation, duodenal ulcer perforation obstructive, diverticular perforation, gastrointestinal 
perforation, gastrointestinal ulcer perforation, appendicitis perforated, ileal perforation, 
ileal ulcer perforation, intestinal perforation, intestinal ulcer perforation, jejunal perforation, 
jejunal ulcer perforation, large intestinal ulcer perforation, large intestine perforation,
small intestinal perforation, small intestinal ulcer perforation
Summaries of TEAEs of interest will be provided for the following:

AEIs by CTCAE Grade

AEIs leading to modification (interruption and/or reduction)

AEIs leading to interruption

AEIs leading to reduction

AEIs leading to IDELA discontinuation

AEIs by time interval (12 weeks intervals)
Incidence and prevalence of AEIs by time interval will be summarized by 12 weeks intervals 
up to 84 weeks (eg, 0 to < 12 weeks, 12 to < 24 weeks, … ,72 to < 84 weeks) and ≥84 weeks. 
Incidence of AEIs in the interval is defined as the proportion of subjects with onset of AEI in that 
interval out of those at risk at the beginning of the interval. Prevalence of AEI is defined as the 
proportion of subjects experiencing AEI in that interval out of those at risk at the beginning of 
the interval. The subjects at risk include those on IDELA or within 30 days post last dose date 
for subjects who didn’t die at the beginning of the interval.

Time to first onset and resolution of AEIs
Time to onset of AEIs (in weeks) is defined as time from the baseline reference date for safety 
endpoints to the date of first incident of AEI. In the absence of an event, the onset date will be 
censored at the earliest from the following dates: last IDELA dosing date (ie, captured on 
study drug completion CRF page) + 30 days, analysis data cut-off date and death date. Time to 
resolution of AEIs is calculated as (AEI stop date −start date of first occurrence of AEI + 1) / 7.


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7.1.8.
Exposure-adjusted TEAE Rate
The exposure-adjusted TEAE rate is defined as the number of subjects with a specific event 
divided by the total exposure-time among the subjects in the treatment group and at risk of an 
initial occurrence of the event. Specifically,
Exposure-Adjusted TEAE Rate ൌ
௡
்ൌ
௡
∑௧೔
Where n is the number of subjects with events, ti is the ith subject exposure time in years and 
T is the total exposure time in years of all subjects. If a subject has multiple events, the ti is the 
time of the first event. For a subject with no event, the ti will be censored at the time of data 
cut-off date if the subject is still taking IDELA; and the ti will be censored at the time of last does 
date plus 30 days or data cutoff date whichever is earlier if the subject discontinues IDELA.
The exposure-adjusted TEAE rate will be summarized for AEI by treatment group based on the 
FAS.
7.2.
Laboratory Evaluations
Summaries of laboratory data (including hematology, serum chemistry, urinalysis, and selected 
immunoglobulin parameters) will be provided. Summaries of laboratory data will be based on 
observed data and will be reported using SI units. The focus of laboratory data summarization 
will be on treatment-emergent laboratory abnormalities using the FAS. 
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics (sample size, mean, StD, median, Q1, Q3, minimum and maximum) will be 
provided for each laboratory test specified in the study protocol as follows:

Baseline values

Values at each post-baseline visit

Change from baseline at each post-baseline visit
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.6.2. In addition, mean change from baseline (standard error) and 
median (Q1/Q3) for selected lab parameters will be plotted over time by treatment groups.
7.2.2.
Summaries of Categorical Laboratory Results
Laboratory data that are categorical will be summarized using number and percentage of subjects 
in the study with the given response by treatment groups and visit based on analysis window.


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7.2.3.
Graded Laboratory Values
Applicable hematological and serum biochemistry laboratory data will be programmatically 
graded according to CTCAE, Version 4.03 severity grade [grade laboratory results as Grade 0, 
mild (Grade 1), moderate (Grade 2), severe (Grade 3), or life threatening (Grade 4)]. Grade 0 
includes all values that do not meet criteria for an abnormality of at least Grade 1. Some 
laboratory tests have criteria for both increased and decreased levels; analyses for each direction 
(ie, increased, decreased) will be presented separately. For all laboratory tests except for lipids 
(cholesterol and triglyceride), lab normal ranges will override the common terminology criteria 
(CTC) grade criteria (ie, all labs within normal ranges will be programmatically assigned a 
CTCAE grade of 0) when lab normal ranges overlaps with CTC grade criteria. Local labs will be 
graded with central lab normal ranges with Gilead in-house macro. Local labs of ANC, 
lymphocytes, Platelet, hemoglobin, aspartate aminotransferase, alanine aminotransferase, total 
bilirubin, and alkaline phosphatase are included in the table summaries when central labs are not 
available. All other local labs are listed.
7.2.3.1.
Treatment-Emergent Laboratory Abnormalities
A treatment-emergent laboratory abnormality is defined as an abnormality that, compared to 
baseline, worsens by ≥1 grade during the post-baseline period up to 30 days after the last dose of 
study treatment. If baseline data are missing, then any graded abnormality (ie, an abnormality 
that is Grade ≥1 in severity) will be considered treatment-emergent.
7.2.3.2.
Summaries of Laboratory Abnormalities
Summary (number and percentage of subjects) of baseline and worst post-baseline 
treatment-emergent laboratory abnormalities will be provided by treatment groups. Subjects will 
be categorized according to most severe abnormality grade.
For all summaries of laboratory abnormalities, the denominator is the number of subjects in the 
FAS. A listing of treatment-emergent laboratory abnormalities will be provided.
7.2.3.3.
Exposure-adjusted Treatment-Emergent Laboratory Abnormalities Rate
The exposure-adjusted treatment-emergent lab abnormalities will be analyzed similarly to the 
exposure-adjusted TEAE rates (outlined in Section 7.1.8).
7.2.4.
Shift in CTCAE Grade Relative to Baseline
Shift tables will be presented by showing change in CTCAE severity grade from baseline to the 
worst grade post baseline.


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7.2.5.
Transaminase Elevations
Analyses of transaminase elevations will be based on laboratory values using the FAS. Number 
and percentage of subjects will be summarized by treatment groups for subjects:

with Grade 3 or 4 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) 
elevation 

with Grade 3 or 4 ALT/AST elevation resolved to both ALT/AST of Grade 1 or less

re-challenged after dose interruption

with recurrence of Grade 3 or 4 ALT/AST elevation among re-challenged

with recurrent Grade 3 or 4 ALT/AST elevation resolved to both ALT/AST of
Grade 1 or less
Kaplan-Meier curves and estimates will be provided for time to onset of first Grade 3 or 4 
treatment-emergent ALT/AST elevations. Time to onset of first event is defined as time from 
the baseline reference date for safety endpoints to the start date of first Grade 3 or 4 
treatment-emergent ALT/AST elevation, ie, time in weeks is calculated as (start date of 
first occurrence – baseline reference date for safety endpoints + 1) / 7. In the absence of an event, 
the censoring date applied will be the earliest from the following dates: last dose date 
(if treatment discontinued) + 30 days, analysis data cut-off date and death date.
For subjects with at least 1 episode of Grade 3 or 4 ALT/AST elevation, time to resolution of the 
first episode of treatment-emergent Grade 3 or 4 ALT/AST elevation to Grade 1 or less will be 
summarized using Kaplan-Meier estimates. The same censoring rule described above for time to 
onset will be used.
7.2.6.
Liver-Related Laboratory Tests
The number and percentage of subjects will be summarized for the following liver-related 
laboratory tests and categories:

AST: (a) 3 to < 5 × upper limit normal (ULN), (b) 5 to < 10 × ULN, (c) 10 to < 20 × ULN, 
(d) ≥ 20 × ULN

ALT: (a) 3 to < 5 × ULN, (b) 5 to < 10 × ULN, (c) 10 to < 20 × ULN, (d) ≥ 20 × ULN

AST or ALT: (a) 3 to < 5 × ULN, (b) 5 to < 10 × ULN, (c) 10 to < 20 × ULN, 
(d) ≥20 × ULN

Total bilirubin: (a) > ULN, (b) > 1.5 × ULN, (c) > 2 × ULN 

AST or ALT > 3 × ULN and total bilirubin > 1.5 × ULN


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
AST or ALT > 3 × ULN and total bilirubin > 2 × ULN

Alkaline Phosphatase > 1.5 × ULN
For individual laboratory tests, subjects will be counted once based on the most severe 
post-baseline values.
Among the subjects with elevated AST or ALT (> 3 × ULN), the following 2 approaches will be 
used for counting subjects with total bilirubin elevation/normal alkaline phosphatase 
(≤1.5 × ULN):

Subjects will be counted once when total bilirubin elevation/normal alkaline phosphatase 
occurred at any post-baseline visit.

Subjects will be counted once when total bilirubin elevation/normal alkaline phosphatase 
occurred concurrently at the same post-baseline visit with AST or ALT elevation.
In addition, a listing of subjects meeting each category will be provided.
7.3.
Prior Therapy
Number of prior regimens and time since the completion of last regimen collected in 
study GS-US-312-0116 will be summarized by treatment groups using descriptive statistics (n, 
mean, StD, median, Q1, Q3, minimum and maximum) based on the FAS. A partial completion 
date will be imputed using the following algorithm for the last regimen:

If day and month are missing but year is available, then the imputed day and month will be 
01Jan or the starting date of the last regimen, whichever is later;

If day is missing but the month and year are available, then the imputed day will be the first 
day of the month, or the starting date of the last regimen, whichever is later;

If year is missing, no imputation will be done and the completion date will be treated as 
missing.
Number (%) of subjects who received 1, 2, 3, ... prior regimens and the type of prior regimens 
that the subjects received will be summarized. The last prior regimen subjects received prior to 
study entry of GS-US-312-0116 will be summarized.
7.4.
Concomitant Medications
Concomitant medications will be coded by means of the World Health Organization Drug 
Dictionary (WHODRUG) dictionary, Q2 2014 into Anatomical-Therapeutic-Chemical 
classification (ATC) codes.
Concomitant medications are defined as any medications meeting the following criteria


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
Starting on or after the baseline reference date for safety endpoints, up to 30 days post the 
last dose

Starting before and continuing after the baseline reference date for safety endpoints, up to 
30 days post the last dose
The incomplete dates handling method for AE will be used for concomitant medication 
summaries (Section 7.1.5.2).
Summaries of the number and percentage of subjects who use concomitant medications will be
presented in tabular form by preferred drug name based on the FAS. The summary tables will be
sorted by descending frequency based on IDELA + R/IDELA treatment group. Subjects will
only be counted once for multiple drug use (by preferred drug name).
The summaries and listings of concomitant medications will be based on the FAS.
7.5.
Other Safety Measures
Physical examination results will be summarized by body system and analysis visit. All results 
will be listed.
A data listing will be provided for subjects experiencing pregnancy during the study.
7.6.
Changes From Protocol-Specified Safety Analyses
Summary of study drug compliance will be removed as the accurate calculation of drug 
accountability is not feasible for subjects who cross over to open-label IDELA in 
Study GS-US-312-0116.


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8.
PHARMACOKINETIC ANALYSES
Bioanalytical analyses will be performed independently so that the study team and investigators 
will not have knowledge of data from individual subjects. IDELA plasma concentrations 
immediately pre-dose and at 1.5 hours after administration of the dose of study drug at each 
relevant clinic visit will be summarized by visit using descriptive statistics.


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9.
PHARMACODYNAMIC ANALYSES
A separate biomarker analysis plan will be prepared to detail pharmacodynamics and biomarker 
analyses.


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10.
REFERENCES
12154
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, 
et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: 
a report from the International Workshop on Chronic Lymphocytic Leukemia 
(IWCLL) updating the National Cancer Institute-Working Group (NCI-WG) 1996 
guidelines. Blood 2008;111 (12):5446-56.
22541
Cheson BD, Byrd JC, Rai KR, Kay NE, O'Brien SM, Flinn IW, et al. Novel 
targeted agents and the need to refine clinical end points in chronic lymphocytic 
leukemia. J Clin Oncol 2012;30 (23):2820-2.
26297
Yost KJ, Eton DT. Combining distribution- and anchor-based approaches to 
determine minimally important differences: the FACIT experience. Evaluation & 
the health professions 2005;28 (2):172-91.
28010
Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: 
development and testing of the D1 valuation model. Medical care 2005;43 
(3):203-20.
33006
Robins JM, Tsiatis AA. Correcting for Non-Compliance in Randomized Trials 
Using Rank Preserving Structural Failure Time Models. Communication in 
Statistics-Theory and Methods 1991;20 (8):2609–31.


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11.
SOFTWARE
SAS® Software Version 9.2. SAS Institute Inc., Cary, NC, USA.


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12.
SAP REVISION
Revision Date
(dd month, yyyy)
Section
Summary of Revision
Reason for Revision


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13.
APPENDICES
Appendix 1.
Table of Contents for Statistical Tables, Figures, and Listings
Appendix 2.
Schedule of Study Procedures


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Appendix 1.
Table of Contents for Statistical Tables, Figures, and Listings
Table Number
Title
Analysis Set
1.1
Subject Study Disposition
FAS
1.2
Subject Study Treatment Disposition
FAS
1.3
Subject Long-Term Follow-Up (LTFU) Disposition
FAS
1.4
Analysis Sets
1.5
Important Protocol Deviations
FAS
1.6
Subject Distribution by Stratification Factors
FAS
1.7
Subject Demographics and Baseline Characteristics
FAS
1.8
CLL Disease History
FAS
1.9
Prior Therapy
FAS
1.10.1
Study Drug (IDELA) Exposure
FAS
1.10.2
Summary of Dose Modification of IDELA
FAS
2.1.1
Progression-free Survival by IRC Assessment
FAS
2.1.2
Progression-free Survival by IRC Assessment -
del17p/TP53 Mutation (Either)
FAS
2.1.3
Progression-free Survival by IRC Assessment -
del17p/TP53 Mutation (Neither)
FAS
2.1.4
Progression-free Survival by IRC Assessment - 17p deletion
FAS
2.1.5
Progression-free Survival by IRC Assessment - No 17p deletion
FAS
2.1.6
Disease Progression Criteria
FAS
2.1.7
Progression-free Survival by IRC Assessment 
(Between-Study Analysis)
Placebo+R (PD)/IDELA
2.2.1
Overall Response Rate (ORR) by IRC Assessment
FAS
2.2.2
Overall Response Rate (ORR) by IRC Assessment -
del17p/TP53 Mutation (Either)
FAS
2.2.3
Overall Response Rate (ORR) by IRC Assessment -
del17p/TP53 Mutation (Neither)
FAS
2.2.4
Overall Response Rate (ORR) by IRC Assessment - 17p deletion
FAS
2.2.5
Overall Response Rate (ORR) by IRC Assessment - No 17p deletion
FAS
2.2.6
Overall Response Rate (ORR) by IRC Assessment
(Between-Study Analysis)
Placebo+R (PD)/IDELA
2.3.1
Lymph Node Response (LNR) Rate by IRC Assessment
FAS
2.3.2
Lymph Node Response (LNR) Rate by IRC Assessment -
del17p/TP53 Mutation (Either)
FAS
2.3.3
Lymph Node Response (LNR) Rate by IRC Assessment -
del17p/TP53 Mutation (Neither)
FAS


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Table Number
Title
Analysis Set
2.3.4
Lymph Node Response (LNR) Rate by IRC Assessment -
17p deletion
FAS
2.3.5
Lymph Node Response (LNR) Rate by IRC Assessment –
No 17p deletion
FAS
2.4.1
Overall Survival (OS)
ITT Analysis Set
2.4.2
Overall Survival (OS) - del17p/TP53 Mutation (Either)
ITT Analysis Set
2.4.3
Overall Survival (OS) - del17p/TP53 Mutation (Neither)
ITT Analysis Set
2.4.4
Overall Survival (OS) - 17p deletion
ITT Analysis Set
2.4.5
Overall Survival (OS) - No 17p deletion
ITT Analysis Set
2.4.6
Overall Survival (OS) Sensitivity Analysis
ITT Analysis Set
2.4.7
Overall Survival (OS) Adjusted for Treatment Crossover
ITT Analysis Set
2.5.1
Time to Response (TTR) by IRC Assessment
FAS
2.5.2
Time to Response (TTR) by IRC Assessment - del17p/TP53 Mutation 
(Either)
FAS
2.5.3
Time to Response (TTR) by IRC Assessment - del17p/TP53 Mutation 
(Neither)
FAS
2.5.4
Time to Response (TTR) by IRC Assessment - 17p deletion
FAS
2.5.5
Time to Response (TTR) by IRC Assessment - No 17p deletion
FAS
2.6.1
Duration of Response (DOR) by IRC Assessment
FAS
2.6.2
Duration of Response (DOR) by IRC Assessment -
del17p/TP53 Mutation (Either)
FAS
2.6.3
Duration of Response (DOR) by IRC Assessment -
del17p/TP53 Mutation (Neither)
FAS
2.6.4
Duration of Response (DOR) by IRC Assessment - 17p deletion
FAS
2.6.5
Duration of Response (DOR) by IRC Assessment - No 17p deletion
FAS
2.7
Best Percent Change in SPD - IRC assessment
FAS
2.8
Splenomegaly Response Rate - IRC Assessment
FAS
2.9
Hepatomegaly Response Rate - IRC Assessment
FAS
2.10
ALC Response Rate
FAS
2.11
Platelet Response Rate
FAS
2.12
Hemoglobin Response Rate
FAS
2.13
Neutrophil Response Rate
FAS
2.14
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) -
Actual and Change from Baseline
FAS
2.15
Karnofsky Performance Status - Observed and Change from Baseline
FAS


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Version 1.0
CONFIDENTIAL
Page 48
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Table Number
Title
Analysis Set
2.16.1
Summary of EuroQoL Five Dimension Descriptive System (EQ-5D) 
by Dimension
FAS
2.16.2
Summary of EuroQol Visual Analogue Score (VAS) - Actual Values 
and Change from Baseline
FAS
3.1.1
Overall Summary of Adverse Events
FAS
3.1.1.1
Overall Summary of Adverse Events - Male
FAS
3.1.1.2
Overall Summary of Adverse Events - Female
FAS
3.1.1.3
Overall Summary of Adverse Events - Age < 65 (years)
FAS
3.1.1.4
Overall Summary of Adverse Events - Age ≥65 (years)
FAS
3.1.1.5
Overall Summary of Adverse Events - Race White
FAS
3.1.1.6
Overall Summary of Adverse Events - Race Non-White
FAS
3.1.2
Treatment-Emergent Adverse Events by MedDRA SOC, HLT and PT
FAS
3.1.2.1
Treatment-Emergent Adverse Events by MedDRA SOC, HLT and PT -
Male
FAS
3.1.2.2
Treatment-Emergent Adverse Events by MedDRA SOC, HLT and PT -
Female
FAS
3.1.2.3
Treatment-Emergent Adverse Events by MedDRA SOC, HLT and PT -
Age < 65 (years)
FAS
3.1.2.4
Treatment-Emergent Adverse Events by MedDRA SOC, HLT and PT 
- Age ≥ 65 (years)
FAS
3.1.2.5
Treatment-Emergent Adverse Events by MedDRA SOC, HLT and PT -
Race White
FAS
3.1.2.6
Treatment-Emergent Adverse Events by MedDRA SOC, HLT and PT -
Race Non-White
FAS
3.1.3
Treatment-Emergent Adverse Events by MedDRA SOC, HLT, PT 
and CTCAE Grade
FAS
3.1.4
Treatment-Emergent Adverse Events Related to IDELA by MedDRA 
SOC, HLT, PT and CTCAE Grade
FAS
3.1.5
Grade ≥3 Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT and PT
FAS
3.1.6
Grade ≥3 Treatment-Emergent Adverse Events Related to IDELA by 
MedDRA SOC, HLT and PT
FAS
3.1.7
Serious Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT and PT
FAS
3.1.7.1
Serious Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT and PT - Male
FAS
3.1.7.2
Serious Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT and PT - Female
FAS


Idelalisib (IDELA)
GS-US-312-0117
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Version 1.0
CONFIDENTIAL
Page 49
26 January 2015
Table Number
Title
Analysis Set
3.1.7.3
Serious Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT and PT - Age < 65 (years)
FAS
3.1.7.4
Serious Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT and PT - Age ≥65 (years)
FAS
3.1.7.5
Serious Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT and PT - Race White
FAS
3.1.7.6
Serious Treatment-Emergent Adverse Events by MedDRA SOC, 
HLT and PT - Race Non-White
FAS
3.1.8
Serious Treatment-Emergent Adverse Events Related to IDELA by 
MedDRA SOC, HLT and PT
FAS
3.1.9
Treatment-Emergent Adverse Events Leading to Modification of 
IDELA by MedDRA SOC, HLT, PT and CTCAE Grade
FAS
3.1.10
Treatment-Emergent Adverse Events Leading to IDELA Reduction 
by MedDRA SOC, HLT, PT and CTCAE Grade
FAS
3.1.11
Treatment-Emergent Adverse Events Leading to IDELA Interruption 
by MedDRA SOC, HLT, PT and CTCAE Grade
FAS
3.1.12
Treatment-Emergent Adverse Events Leading to IDELA 
Discontinuation by MedDRA SOC, HLT and PT
FAS
3.1.13
Treatment-Emergent Adverse Events Leading to Death by MedDRA 
SOC, HLT and PT
FAS
3.1.14
Treatment-Emergent Adverse Events by MedDRA PT and 
CTCAE Grade
FAS
3.1.14.1
Treatment-Emergent Adverse Events by MedDRA PT and 
CTCAE Grade - Male
FAS
3.1.14.2
Treatment-Emergent Adverse Events by MedDRA PT and 
CTCAE Grade - Female
FAS
3.1.14.3
Treatment-Emergent Adverse Events by MedDRA PT and 
CTCAE Grade - Age < 65 (years)
FAS
3.1.14.4
Treatment-Emergent Adverse Events by MedDRA PT and 
CTCAE Grade - Age ≥65 (years)
FAS
3.1.14.5
Treatment-Emergent Adverse Events by MedDRA PT and 
CTCAE Grade - Race White
FAS
3.1.14.6
Treatment-Emergent Adverse Events by MedDRA PT and 
CTCAE Grade - Race Non-White
FAS
3.1.15
All Grades and Grade ≥3 Treatment-Emergent Adverse Events by 
MedDRA PT
FAS
3.1.16
All Grades and Grade ≥ 3 Treatment-Emergent Adverse Events 
Related to IDELA by MedDRA PT
FAS
3.1.17
Serious Treatment-Emergent Adverse Events by MedDRA PT
FAS


Idelalisib (IDELA)
GS-US-312-0117
Final
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 50
26 January 2015
Table Number
Title
Analysis Set
3.1.18
Treatment-Emergent Adverse Events Leading to Modification of 
IDELA by MedDRA PT and CTCAE grade
FAS
3.1.19
Treatment-Emergent Adverse Events Leading to Reduction of 
IDELA by MedDRA PT and CTCAE grade
FAS
3.1.20
Treatment-Emergent Adverse Events Leading to Interruption of 
IDELA by MedDRA PT and CTCAE grade
FAS
3.1.21
Treatment-Emergent Adverse Events Leading to IDELA 
Discontinuation by MedDRA PT
FAS
3.1.22
Treatment-Emergent Adverse Events Leading to Death by 
MedDRA PT
FAS
3.1.23
Exposure-Adjusted Incidence Rate of Treatment-Emergent
Adverse Events
FAS
3.1.24.1
Treatment-Emergent Adverse Events of Interest by MedDRA PT and 
CTCAE Grade
FAS
3.1.24.2
Treatment-Emergent Adverse Events of Interest Leading to 
Modification of IDELA/Placebo by MedDRA PT and CTCAE Grade
FAS
3.1.24.3
Treatment-Emergent Adverse Events of Interest Leading to 
Reduction of IDELA/Placebo by MedDRA PT and CTCAE Grade
FAS
3.1.24.4
Treatment-Emergent Adverse Events of Interest Leading to 
Interruption of IDELA/Placebo by MedDRA PT and CTCAE Grade
FAS
3.1.24.5
Treatment-Emergent Adverse Events of Interest Leading to 
IDELA/Placebo Discontinuation by MedDRA PT
FAS
3.1.24.6
Incidence of Treatment-Emergent Adverse Events of Interest by 
12-weeks Intevals
FAS
3.1.24.7
Prevalence of Treatment-Emergent Adverse Events of Interest by 
12-weeks Intevals
FAS
3.1.24.8
Time to First Onset and Resolution of Treatment-Emergent 
Adverse Events of Interest
FAS
3.1.24.9
Exposure-Adjusted Incidence Rate of Treatment-Emergent 
Adverse Events of Interest
FAS
3.1.25
Summary of Malignant Transformation and Second Malignancies
FAS
3.1.26
Summary of Deaths
FAS
3.2.1
Hematology: Summary of Actual Values and Change from Baseline
FAS
3.2.2
Hematology: Summary of Treatment-Emergent Laboratory 
Abnormalities
FAS
3.2.3
Hematology: Shift from Baseline to worst CTCAE Severity Grade
FAS
3.2.4
Hematology: Exposure-adjusted Incidence Rate of 
Treatment-Emergent Lab Abnormalities
FAS


Idelalisib (IDELA)
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Version 1.0
CONFIDENTIAL
Page 51
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Table Number
Title
Analysis Set
3.3.1
Serum Chemistry: Summary of Actual Values and Change from 
Baseline
FAS
3.3.2
Serum Chemistry: Summary of Treatment-Emergent Laboratory 
Abnormalities
FAS
3.3.3
Serum Chemistry: Shift from Baseline to worst CTCAE Severity 
Grade
FAS
3.3.4
Serum Chemistry: Exposure-adjusted Incidence Rate of 
Treatment-Emergent Lab Abnormalities
FAS
3.4
Summary of Liver-related Laboratory Abnormalities
FAS
3.5
Urinalysis: Summary of Actual Values at Baseline
FAS
3.6.1
Summary of Transaminase Elevations
FAS
3.6.2
Time to First Onset and Resolution of Treatment-Emergent 
Transaminase Elevation
FAS
3.6.3
Immunoglobulin: Summary of Actual Values and Change from 
Baseline
FAS
3.7
Concomitant Medications
FAS
4.1
Idelalisib Plasma Pharmacokinetic Concentration (ng/mL)
PK Analysis Set
4.2
Idelalisib Metabolite GS-563117 Plasma Pharmacokinetic
Concentration (ng/mL)
PK Analysis Set


Idelalisib (IDELA)
GS-US-312-0117
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Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 52
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Listing Number
Title
Analysis Set
1.1
Screen Failures
1.2.1
Subject Study Disposition
FAS
1.2.2
Subject Study Treatment Disposition
FAS
1.3
Subjects Excluded From Any Analysis Set
FAS
1.4
Important Protocol Deviations
FAS
1.5
Medical History
FAS
1.6.1
IDELA Interruption and Modification
FAS
1.6.2
IDELA Accountability
FAS
1.6.3
IDELA Administration
FAS
1.6.4
IDELA Assignment by IWRS
FAS
2.1.1
Tumor Assessment: Index Lesions - IRC Assessment
FAS
2.1.2
Tumor Assessment: Non-index Lesions - IRC Assessment
FAS
2.1.3
Spleen and Liver Assessment - IRC Assessment
FAS
2.1.4
Tumor Response Assessment - IRC Assessment
FAS
2.1.5
Tumor Assessment: Index Lesions - IRC Assessment 
(Between-Study Analysis)
Placebo+R (PD)/IDELA
2.1.6
Tumor Assessment: Non-index Lesions - IRC Assessment 
(Between-Study Analysis)
Placebo+R (PD)/IDELA
2.1.7
Spleen and Liver Assessment - IRC Assessment 
(Between-Study Analysis)
Placebo+R (PD)/IDELA
2.1.8
Tumor Response Assessment - IRC Assessment 
(Between-Study Analysis)
Placebo+R (PD)/IDELA
2.2.1
CLL Assessment by Physical Examination - Investigator Assessment
FAS
2.2.2
CLL Assessment by CT/MRI Scan - Investigator Assessment
FAS
2.2.3
Overall CLL Assessment - Investigator Assessment
FAS
2.3.1
Progression-free Survival
FAS
2.3.2
Progression-free Survival (Between-Study Analysis)
Placebo+R (PD)/IDELA
2.4
Overall Survival (Study 116 and 117)
ITT Analysis Set
2.5.1
Time to First Response and Duration of Response
FAS
2.5.2
Time to First Response and Duration of Response 
(Between-Study Analysis)
Placebo+R (PD)/IDELA
2.6.1
ALC Response
FAS
2.6.2
Platelet Response and Supportive Cares
FAS
2.6.3
Hemoglobin Response and Supportive Cares
FAS
2.6.4
Neutrophil Response and Supportive Cares
FAS


Idelalisib (IDELA)
GS-US-312-0117
Final
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Version 1.0
CONFIDENTIAL
Page 53
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Listing Number
Title
Analysis Set
2.7.1
Other Efficacy Response Assessment
FAS
2.7.2
Other Efficacy Response Assessment (Between-Study Analysis)
Placebo+R (PD)/IDELA
2.8
Bone Marrow Aspirate and Biopsy
FAS
2.9
Organ Biopsy
FAS
2.10.1
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) 
Scores
FAS
2.10.2
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) 
Scores (Between-Study Analysis)
Placebo+R (PD)/IDELA
2.11.1
Karnofsky Performance Status
FAS
2.11.2
Karnofsky Performance Status (Between-Study Analysis)
Placebo+R (PD)/IDELA
2.12.1
EuroQoL Five-Dimension
FAS
2.12.2
EuroQoL Five-Dimension (Between-Study Analysis)
Placebo+R (PD)/IDELA
3.1.1
Laboratory Tests: Hematology
FAS
3.1.2
Laboratory Tests: Chemistry
FAS
3.1.3
Laboratory Tests: Urinalysis
FAS
3.1.4
Laboratory Tests: Immunoglobulin
FAS
3.1.5
Laboratory Tests: Circulating Cells
FAS
3.2
Transaminase Elevations
FAS
3.3
Listing of liver-related Laboratory Abnormalities
FAS
3.4.1
All Adverse Events
FAS
3.4.2
Serious Treatment Emergent Adverse Events
FAS
3.4.3
TEAEs Leading to Interruption or Modification of IDELA
FAS
3.4.4
TEAEs Leading to IDELA Discontinuation
FAS
3.4.5
Adverse Events Leading to Death
FAS
3.4.6
Second Malignancies
FAS
3.4.7
CLL Transformation
FAS
3.4.8
All Deaths
FAS
3.4.9
Non-Treatment Emergent Adverse Events
FAS
3.5
Subject Characteristics and Oxygen Saturation
FAS
3.6
Prior and Concomitant Medications
FAS
3.7
Concomitant Therapy Status
FAS
3.8
Transfusion Log
FAS
3.9
Surgical and Medical Procedures
FAS


Idelalisib (IDELA)
GS-US-312-0117
Final
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Version 1.0
CONFIDENTIAL
Page 54
26 January 2015
Listing Number
Title
Analysis Set
3.10
Hospitalization
FAS
3.11
Pregnancy
FAS
3.12.1
Long-term Follow-up
FAS
3.12.2
Post Study Anti-Cancer Therapy in Long-term Follow-up
FAS
3.13
Comment
FAS


Idelalisib (IDELA)
GS-US-312-0117
Final
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 55
26 January 2015
Figure Number
Title
Analysis Set
1.1
Kaplan-Meier Curve of Progression-free Survival by IRC Assessment
FAS
1.1.1
Kaplan-Meier Curve of Progression-free Survival by IRC Assessment -
del17p/TP53 Mutation (Either)
FAS
1.1.2
Kaplan-Meier Curve of Progression-free Survival by IRC Assessment -
del17p/TP53 Mutation (Neither)
FAS
1.1.3
Kaplan-Meier Curve of Progression-free Survival by IRC Assessment -
17p deletion
FAS
1.1.4
Kaplan-Meier Curve of Progression-free Survival by IRC Assessment -
No 17p deletion
FAS
1.2
Kaplan-Meier Curve of Overall Survival
ITT Analysis Set
1.2.1
Kaplan-Meier Curve of Overall Survival - del17p/TP53 Mutation 
(Either)
ITT Analysis Set
1.2.2
Kaplan-Meier Curve of Overall Survival - del17p/TP53 Mutation 
(Neither)
ITT Analysis Set
1.2.3
Kaplan-Meier Curve of Overall Survival - 17p Deletion
ITT Analysis Set
1.2.4
Kaplan-Meier Curve of Overall Survival - No 17p Deletion
ITT Analysis Set
1.3
Kaplan-Meier Curve of Duration of Response by IRC Assessment
FAS
1.3.1
Kaplan-Meier Curve of Duration of Response by IRC Assessment -
del17p/TP53 Mutation (Either)
FAS
1.3.2
Kaplan-Meier Curve of Duration of Response by IRC Assessment -
del17p/TP53 Mutation (Neither)
FAS
1.3.3
Kaplan-Meier Curve of Duration of Response by IRC Assessment -
17p Deletion
FAS
1.3.4
Kaplan-Meier Curve of Duration of Response by IRC Assessment -
No 17p Deletion
FAS
1.4
Kaplan-Meier Curve of Time to Response by IRC Assessment
FAS
1.4.1
Kaplan-Meier Curve of Time to Response by IRC Assessment -
del17p/TP53 Mutation (Either)
FAS
1.4.2
Kaplan-Meier Curve of Time to Response by IRC Assessment -
del17p/TP53 Mutation (Neither)
FAS
1.4.3
Kaplan-Meier Curve of Time to Response by IRC Assessment -
17p Deletion
FAS
1.4.4
Kaplan-Meier Curve of Time to Response by IRC Assessment –
No 17p Deletion
FAS
1.5
Waterfall Plot of Best Percent Change from Baseline in SPD by 
IRC Assessment
FAS
1.5.1
Waterfall Plot of Best Percent Change from Baseline in SPD by 
IRC Assessment - del17p/TP53  Mutation (Either)
FAS


Idelalisib (IDELA)
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Version 1.0
CONFIDENTIAL
Page 56
26 January 2015
Figure Number
Title
Analysis Set
1.5.2
Waterfall Plot of Best Percent Change from Baseline in SPD by 
IRC Assessment - del17p/TP53  Mutation (Neither)
FAS
1.5.3
Waterfall Plot of Best Percent Change from Baseline in SPD by 
IRC Assessment - 17p deletion
FAS
1.5.4
Waterfall Plot of Best Percent Change from Baseline in SPD by 
IRC Assessment - No 17p deletion
FAS
2.1.1
Cumulative Distribution Function of Best Change from Baseline: 
FACT-Leu Physical Well-being
FAS
2.1.2
Cumulative Distribution Function of Best Change from Baseline: 
FACT-Leu Social/Family Well-being
FAS
2.1.3
Cumulative Distribution Function of Best Change from Baseline: 
FACT-Leu Emotional Well-being
FAS
2.1.4
Cumulative Distribution Function of Best Change from Baseline: 
FACT-Leu Functional Well-being
FAS
2.1.5
Cumulative Distribution Function of Best Change from Baseline: 
FACT-Leu Additional Concerns
FAS
2.2.1
Change from Baseline: FACT-Leu Physical Well-being
FAS
2.2.2
Change from Baseline: FACT-Leu Social/Family Well-being
FAS
2.2.3
Change from Baseline: FACT-Leu Emotional Well-being
FAS
2.2.4
Change from Baseline: FACT-Leu Functional Well-being
FAS
2.2.5
Change from Baseline: FACT-Leu Additional Concerns
FAS
2.2.6
Change from Baseline: FACT-Leu Total Outcome Index
FAS
2.2.7
Change from Baseline: FACT-Leu Total Score
FAS
2.3.1
Change from Baseline: EQ VAS
FAS
2.3.2
Change from Baseline: EQ-5D Utility Index (US)
FAS
3.1.1
Median Over Time: Hemoglobin (g/L)
FAS
3.1.2
Median Over Time: Hemoglobin (g/L) - Subjects with Abnormality at 
Baseline and at Least One Post-baseline Measurements
FAS
3.1.3
Median Over Time: Platelets (x10^9/L)
FAS
3.1.4
Median Over Time: Platelets (x10^9/L) - Subjects with Abnormality 
at Baseline and at Least One Post-baseline Measurements
FAS
3.1.5
Median Over Time: Neutrophils (x10^9/L)
FAS
3.1.6
Median Over Time: Neutrophils (x10^9/L) - Subjects with 
Abnormality at Baseline and at Least One Post-baseline 
Measurements
FAS
3.1.7
Median Over Time: ALT (U/L)
FAS
3.1.8
Median Over Time: AST (U/L)
FAS


Idelalisib (IDELA)
GS-US-312-0117
Final
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Version 1.0
CONFIDENTIAL
Page 57
26 January 2015
Figure Number
Title
Analysis Set
3.1.9
Median Over Time: Lymphocytes (x10^9/L)
FAS
3.1.10
Median Over Time: Total Bilirubin (umol/L)
FAS
3.1.11
Median Over Time: Triglycerides (mmol/L)
FAS
3.1.12
Median Over Time: Serum Glucose (mmol/L)
FAS
3.2.1
Change From Baseline: Hemoglobin (g/L)
FAS
3.2.2
Change From Baseline: Hemoglobin (g/L) - Subjects with 
Abnormality at Baseline and at Least One Post-baseline 
Measurements
FAS
3.2.3
Change From Baseline: Platelets (x10^9/L)
FAS
3.2.4
Change From Baseline: Platelets (x10^9/L) - Subjects with 
Abnormality at Baseline and at Least One Post-baseline 
Measurements
FAS
3.2.5
Change From Baseline: Neutrophils (x10^9/L)
FAS
3.2.6
Change From Baseline: Neutrophils (x10^9/L) - Subjects with 
Abnormality at Baseline and at Least One Post-baseline 
Measurements
FAS
3.2.7
Change From Baseline: ALT (U/L)
FAS
3.2.8
Change From Baseline: AST (U/L)
FAS
3.2.9
Change From Baseline: Lymphocytes (x10^9/L)
FAS
3.2.10
Change From Baseline: Total Bilirubin (umol/L)
FAS
3.2.11
Change From Baseline: Triglycerides (mmol/L)
FAS
3.2.12
Change From Baseline: Serum Glucose (mmol/L)
FAS
4.1.1
Kaplan-Meier Curve of Time to Onset of First Episode of 
Grade 3 and Above Transaminase Elevation
FAS
4.1.2
Kaplan-Meier Curve of Time to Resolution of First Episode of 
Grade 3 and Above Transaminase Elevation
FAS


Idelalisib (IDELA)
GS-US-312-0117
Final
Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 58
26 January 2015
Appendix 2.
Schedule of Study Procedures
Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4
5a
6
7a
8
9
10
11
12
13
14
15
16+
End of 
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28
Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30
days
To
+5 years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Informed consent
X
CIRS assessment
X
β-HCG (women of
childbearing 
potential)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CLL peripheral 
blood evaluation
X
X
CLL serology
X
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Genotyping and 
expression 
analysis
X
X
HRQL/
healthy utility –
FACT-Leu/EQ-5D
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Idelalisib (IDELA)
GS-US-312-0117
Final
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Version 1.0
CONFIDENTIAL
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Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4
5a
6
7a
8
9
10
11
12
13
14
15
16+
End of 
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28
Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30
days
To
+5 years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Performance 
status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exam 
(includes nodes, 
liver, spleen)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Oxygen saturation
(by pulse oximetry)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Circulating cells
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biomarkers
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Igs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug 
administration in 
clinic
Xb
X
X
X
X
X
X
X
Idelalisib 
pharmacokineticsb
X
X
X
X
X
X
X
X
Study drug 
dispensing/
accountingb
X
X
X
X
X
X
X
X
X
X
X


Idelalisib (IDELA)
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Version 1.0
CONFIDENTIAL
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Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4
5a
6
7a
8
9
10
11
12
13
14
15
16+
End of 
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28
Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30
days
To
+5 years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Radiology 
assessment 
(CT/MRI)d
X
X
X
X
X
X
X
X
Bone marrow 
biopsy/aspiratec
X
X
X
X
X
X
X
X
Post-treatment 
CLL therapy
X
Long-term 
follow-up 
X
a
Following unblinding of the study, visits 3, 5, and 7 will not be applicable for subjects who were randomized to idelalisib on Study GS-US-312-0116
b
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll following unblinding, may have idelalisib treatment (and associated PK testing) delayed at 
the Investigator’s discretion until the time of disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib treatment
c
At screening, to be performed at investigator discretion to determine extent of CLL involvement and bone marrow cellularity. Post-screening, to be performed to confirm 
CR or PD; if the subject does not otherwise meet criteria for CR or if the nature of PD does not require bone marrow confirmations, it is not necessary to obtain a follow-up 
bone marrow biopsy/aspirate
d
Following unblinding of the study, the imaging schedule will follow standard of care for subjects who were randomized to idelalisib on Study GS-US-312-0116 and subjects 
who were randomized to placebo on Study GS-US-312-0116 and enroll on Study GS-US-312-0117 will follow local standard of care for follow-up imaging until initiation of 
idelalisib, at which time the per-protocol schedule will be followed
Abbreviations: -HCG = beta human chorionic gonadotropin, CIRS = chronic illness rating scale, CLL = chronic lymphocytic leukemia, CR = complete response, 
CT = computed tomography, EQ-5D = EuroQoL Five-Dimension, FACT-Leu = Functional Assessment of Cancer Therapy- Leukemia, HRQL = health-related quality of life, 
Ig = immunoglobulin, IWRS = interactive web response system, MRI = magnetic resonance imaging.

Prot_006.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and 
Safety of Two Different Dose Levels of Single-Agent Idelalisib
(GS-1101) for Previously Treated Chronic Lymphocytic Leukemia
A Companion Trial to Study GS-US-312-0116: A Phase 3, Randomized, 
Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of Idelalisib (GS-1101) in Combination with Rituximab for 
Previously Treated Chronic Lymphocytic Leukemia
Sponsor:
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102
USA
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
EudraCT Number:
101254
2011-006293-72
Indication:
Chronic Lymphocytic Leukemia 
Protocol ID:
GS-US-312-0117
Gilead Sciences
Medical Monitor:
Name:
Telephone:
Office Fax:
Mobile Telephone:
E-mail:
Protocol Version/Date:
Version 1.0 (Original)
23 January 2012
Version 2.0 (Amendment 1)
23 January 2013
Version 3.0 (Amendment 2)
10 September 2013
Version 4.0 (Amendment 3)
16 December 2013
Version 5.0 (Amendment 4)
27 May 2014
Version 6.0 (Amendment 5)
10 October 2014
Version 7.0 (Amendment 6)
28 March 2016
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or under 
control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable institutional review board 
or independent ethics committee. This information is only to be used by you in connection with 
authorized clinical studies of the investigational drug described in the protocol. You must not 
disclose any of the information to others without written authorization from Gilead Sciences, Inc., 
except to the extent necessary to obtain informed consent from those persons to whom the drug may 
be administered.
PPD
PPD
PPD
PPD
PPD


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Final
Gilead Sciences, Inc.
Version 7.0
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................6
LIST OF IN-TEXT FIGURES ......................................................................................................................................6
PROTOCOL SYNOPSIS ..............................................................................................................................................7
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................19
1.
INTRODUCTION ..............................................................................................................................................23
1.1.
Chronic Lymphocytic Leukemia............................................................................................................23
1.2.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies....................................................................24
1.3.
Idelalisib (formerly GS-1101)................................................................................................................25
1.3.1.
General Information .............................................................................................................25
1.3.2.
Safety Pharmacology............................................................................................................25
1.3.3.
Nonclinical Pharmacology and Metabolism.........................................................................26
1.3.4.
Toxicology ...........................................................................................................................27
1.3.5.
Idelalisib Clinical Studies.....................................................................................................27
1.4.
Summary and Justification for the Current Study ..................................................................................31
2.
STUDY DESIGN................................................................................................................................................34
2.1.
Design Overview and Study Schema .....................................................................................................34
2.2.
Design Rationale ....................................................................................................................................35
3.
OBJECTIVES AND ENDPOINTS ....................................................................................................................37
3.1.
Endpoints ...............................................................................................................................................37
3.1.1.
Tumor Control......................................................................................................................37
3.1.2.
Patient Well-Being ...............................................................................................................38
3.1.3.
Pharmacodynamic Markers of Drug Activity and Resistance..............................................39
3.1.4.
Exposure...............................................................................................................................39
3.1.5.
Safety....................................................................................................................................39
3.1.6.
Pharmacoeconomics.............................................................................................................39
3.2.
Endpoint Selection Rationale.................................................................................................................39
3.2.1.
Tumor Control Endpoints.....................................................................................................39
3.2.2.
Measures of Patient Well-Being...........................................................................................42
3.2.3.
Pharmacodynamic Markers of Drug Activity and Resistance..............................................43
3.2.4.
Assessments of Exposure .....................................................................................................45
3.2.5.
Evaluations of Safety............................................................................................................45
3.2.6.
Pharmacoeconomic Measures ..............................................................................................46
4.
SUBJECT POPULATION..................................................................................................................................47
4.1.
Number of Subjects................................................................................................................................47
4.2.
Subject Selection Criteria.......................................................................................................................47
4.2.1.
Inclusion Criteria..................................................................................................................47
4.2.2.
Exclusion Criteria.................................................................................................................49
4.3.
Enrollment Criteria Rationale ................................................................................................................50
5.
TREATMENT OF SUBJECTS ..........................................................................................................................51
5.1.
Enrollment..............................................................................................................................................51
5.1.1.
Interactive Web Response System .......................................................................................51
5.1.2.
Treatment Assignment .........................................................................................................51
5.1.3.
Blinding................................................................................................................................52


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5.2.
Investigational Study Drug (Idelalisib/Placebo) ....................................................................................53
5.2.1.
Description ...........................................................................................................................53
5.2.2.
Source...................................................................................................................................53
5.2.3.
Packaging and Labeling .......................................................................................................53
5.2.4.
Storage and Handling...........................................................................................................54
5.2.5.
Dispensing............................................................................................................................54
5.2.6.
Return...................................................................................................................................55
5.2.7.
Accountability......................................................................................................................55
5.2.8.
Overdose Precautions...........................................................................................................55
5.2.9.
Inadvertent Exposure and Spill Precautions.........................................................................56
5.3.
Study Drug Administration ....................................................................................................................56
5.3.1.
Premedication.......................................................................................................................56
5.3.2.
Administration Instructions..................................................................................................56
5.3.3.
Dosing Schedule...................................................................................................................56
5.3.4.
Dose Levels..........................................................................................................................56
5.3.5.
Dose Schedule Interruptions and Vomited Doses ................................................................57
5.3.6.
Safety Monitoring and Study Drug Interruption/Dose Modification ...................................57
5.4.
Recommendations for Evaluation, Intervention, and Drug Discontinuation for Specific 
Adverse Events or Conditions................................................................................................................62
5.4.1.
Dermatological Events .........................................................................................................62
5.4.2.
Gastrointestinal Events.........................................................................................................63
5.4.3.
Hepatic Events......................................................................................................................65
5.4.4.
Hematological and Immunological Events...........................................................................65
5.4.5.
Infectious Events..................................................................................................................66
5.4.6.
Progressive Multifocal Leukoencephalopathy .....................................................................67
5.4.7.
Pulmonary Events ................................................................................................................67
5.4.8.
Secondary Malignancies.......................................................................................................68
5.4.9.
Tumor Lysis Syndrome........................................................................................................68
5.4.10.
Pregnancy, Lactation, and Reproduction..............................................................................68
5.4.11.
Ultraviolet Exposure ............................................................................................................69
5.4.12.
Further Safety Information...................................................................................................70
5.5.
Emergency Unblinding ..........................................................................................................................70
5.6.
Concomitant and Supportive Therapy....................................................................................................70
5.6.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments............................................................................................................................71
5.6.2.
Antibiotics............................................................................................................................71
5.6.3.
Antiemetics and Antidiarrheals............................................................................................71
5.6.4.
Contraception .......................................................................................................................71
5.6.5.
Corticosteroids .....................................................................................................................72
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin..............................................72
5.6.7.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism..................................................73
5.6.8.
Drugs that undergo CYP3A-Dependent Metabolism...........................................................73
5.6.9.
Immunization .......................................................................................................................74
5.6.10.
Surgery .................................................................................................................................74
5.6.11.
Diet.......................................................................................................................................74
5.7.
Duration of Study Drug..........................................................................................................................74
5.8.
Discontinuation of Study Drug ..............................................................................................................74
5.9.
Discontinuation from Study ...................................................................................................................75
5.10.
Study Treatment Rationale.....................................................................................................................75
6.
STUDY PROCEDURES ....................................................................................................................................78
6.1.
Enrollment and Study Management Procedures ....................................................................................78
6.1.1.
Subject Recruitment .............................................................................................................78
6.1.2.
Subject Compensation for Participation...............................................................................78


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6.1.3.
Screening..............................................................................................................................78
6.2.
Explanation of Study Visits....................................................................................................................79
6.2.1.
Visit 1 and Screening Period (Clinic Visit)..........................................................................80
6.2.2.
Visit 2 (Day 1) (Clinic Visit)................................................................................................82
6.2.3.
Visit 3 (Day 15) (Clinic Visit)..............................................................................................83
6.2.4.
Visit 4 (Day 29) (Clinic Visit)..............................................................................................84
6.2.5.
Visit 5 (Day 43) (Clinic Visit)..............................................................................................86
6.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit) .....................................................................87
6.2.7.
Visit 7 (Day 71) (Laboratory Visit)......................................................................................88
6.2.8.
Visit 8 (Day 85) (Clinic Visit)..............................................................................................89
6.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit) ...................................................................91
6.2.10.
Visit 10 (Day 141) (Clinic Visit)..........................................................................................93
6.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit) .................................................................95
6.2.12.
Visit 12 (Day 211) (Clinic Visit)..........................................................................................97
6.2.13.
Visit 13 (Day 253) (Clinic and Radiology Visit) .................................................................98
6.2.14.
Visit 14 (Day 295) (Clinic Visit)..........................................................................................99
6.2.15.
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks) (Clinic 
and Radiology Visits).........................................................................................................100
6.2.16.
End-of-Study Visit (Clinic Visit) .......................................................................................102
6.2.17.
30 Day and Long-Term Follow-up.....................................................................................103
6.3.
Sample Storage.....................................................................................................................................103
6.4.
Blood Collection ..................................................................................................................................104
6.5.
Study Procedure Rationale...................................................................................................................104
7.
EFFICACY ASSESSMENTS...........................................................................................................................105
7.1.
Tumor Status Assessments...................................................................................................................105
7.2.
Method of Assessment .........................................................................................................................105
7.3.
Timing of Assessments ........................................................................................................................105
7.4.
Identification and Measurement of Tumor Lesions and Organomegaly ..............................................106
7.4.1.
Index Lesions .....................................................................................................................106
7.4.2.
Spleen and Liver.................................................................................................................107
7.4.3.
Non-Index Lesions .............................................................................................................107
7.5.
Definitions of Tumor Response and Progression.................................................................................107
7.5.1.
Complete Response............................................................................................................108
7.5.2.
Partial Response .................................................................................................................108
7.5.3.
Stable Disease ....................................................................................................................109
7.5.4.
Definitive Progressive Disease...........................................................................................110
7.5.5.
Non-Evaluable....................................................................................................................111
7.5.6.
No Disease .........................................................................................................................111
7.5.7.
Lymphocytosis During Therapy.........................................................................................112
7.5.8.
Documentation of Definitive CLL Progression..................................................................112
8.
SAFETY ASSESSMENTS...............................................................................................................................113
8.1.
Adverse Event Definitions ...................................................................................................................113
8.1.1.
Adverse Event ....................................................................................................................113
8.1.2.
Serious Adverse Event .......................................................................................................114
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .......................................................................115
8.2.
Assessment of Adverse Events and Serious Adverse Events...............................................................115
8.2.1.
Assessment of Causality for Study Drugs and Procedures.................................................116
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.....................................................................................................................116
8.4.
Gilead Reporting Requirements...........................................................................................................117
8.5.
Grading of the Severity of an Adverse Event.......................................................................................117


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8.6.
Adverse Event Reporting Period..........................................................................................................118
8.7.
Adverse Event Reporting Requirements ..............................................................................................118
8.7.1.
Site Reporting Requirements..............................................................................................118
8.7.2.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population.........................................................120
8.8.
Special Situations Reporting Requirements.........................................................................................120
8.8.1.
Definitions of Special Situations........................................................................................120
8.9.
Instructions for Reporting Special Situations.......................................................................................121
8.9.1.
Instructions for Reporting Pregnancies ..............................................................................121
8.9.2.
Reporting Other Special Situations ....................................................................................122
9.
STATISTICAL CONSIDERATIONS..............................................................................................................123
9.1.
Analysis Objectives..............................................................................................................................123
9.2.
Analysis Endpoints...............................................................................................................................123
9.3.
Analysis Conventions...........................................................................................................................123
9.3.1.
Analysis Sets ......................................................................................................................123
9.3.2.
Data Handling Conventions ...............................................................................................124
9.4.
Analysis Plan........................................................................................................................................126
9.4.1.
Subject Disposition and Baseline Characteristics...............................................................126
9.4.2.
Efficacy Analyses...............................................................................................................127
9.4.3.
Exposure and Safety Analyses ...........................................................................................128
9.4.4.
Other Analyses ...................................................................................................................130
9.5.
Sample Size..........................................................................................................................................131
9.6.
Timing of Analyses..............................................................................................................................132
10.
RESPONSIBILITIES........................................................................................................................................133
10.1.
Investigator Responsibilities ................................................................................................................133
10.1.1.
Compliance with Ethical and Regulatory Guidelines.........................................................133
10.1.2.
Institutional Review Board/Independent Ethics Committee ..............................................133
10.1.3.
Informed Consent...............................................................................................................134
10.1.4.
Confidentiality....................................................................................................................134
10.1.5.
Study Files and Retention of Records and Biological Samples..........................................134
10.1.6.
Case Report Forms.............................................................................................................136
10.1.7.
Drug Accountability...........................................................................................................136
10.1.8.
Inspections..........................................................................................................................137
10.1.9.
Protocol Compliance..........................................................................................................137
10.2.
Sponsor Responsibilities ......................................................................................................................137
10.2.1.
Protocol Modifications.......................................................................................................137
10.2.2.
Communications with Regulatory Authorities...................................................................137
10.2.3.
Data Management ..............................................................................................................138
10.2.4.
Study Reporting and Publication........................................................................................138
10.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................139
10.3.1.
Access to Information for Monitoring................................................................................139
10.3.2.
Access to Information for Auditing or Inspections ............................................................139
10.3.3.
Public Notification of Study Conduct ................................................................................139
10.3.4.
Study Discontinuation........................................................................................................139
10.4.
Study Committees ................................................................................................................................140
10.4.1.
Data Monitoring Committee ..............................................................................................140
10.4.2.
Independent Review Committee ........................................................................................141
11.
REFERENCES .................................................................................................................................................142


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12.
APPENDICES ..................................................................................................................................................152
Appendix 1.
Investigator Signature Page..................................................................................................153
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) ...................................154
Appendix 3.
Performance Status Scoring System.....................................................................................157
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D) ........................................................................................158
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance ............................................160
Appendix 6.
Cumulative Illness Rating Scale (CIRS) ..............................................................................161
Appendix 7.
Schedule of Study Procedures..............................................................................................163
LIST OF IN-TEXT TABLES
Table 4-1.
Required Screening Laboratory Values..................................................................................48
Table 5-1.
Study Drug Dose Levels.........................................................................................................57
Table 5-2.
Recommendations for Study Drug Dose Modifications Based on Type and Severity 
of Treatment-Related Adverse Events or Laboratory Abnormalities .....................................59
Table 5-3.
Protocol-Recommended Contraceptive Methods ...................................................................72
Table 5-4.
Known Strong Inducers of CYP3A........................................................................................73
Table 6-1.
Procedures and Assessments at Visit 1 (During Screening Period)........................................81
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1) .....................................................................82
Table 6-3.
Procedures and Assessments at Visit 3 (Day 15) ...................................................................83
Table 6-4.
Procedures and Assessments at Visit 4 (Day 29) ...................................................................84
Table 6-5.
Procedures and Assessments at Visit 5 (Day 43) ...................................................................86
Table 6-6.
Procedures and Assessments at Visit 6 (Day 57) ...................................................................87
Table 6-7.
Procedures and Assessments at Visit 7 (Day 71) ...................................................................88
Table 6-8.
Procedures and Assessments at Visit 8 (Day 85) ...................................................................89
Table 6-9.
Procedures and Assessments at Visit 9 (Day 113) .................................................................91
Table 6-10.
Procedures and Assessments at Visit 10 (Day 141) ...............................................................93
Table 6-11.
Procedures and Assessments at Visit 11 (Day 169) ...............................................................95
Table 6-12.
Procedures and Assessments at Visit 12 (Day 211) ...............................................................97
Table 6-13.
Procedures and Assessments at Visit 13 (Day 253) ...............................................................98
Table 6-14.
Procedures and Assessments at Visit 14 (Day 295) ...............................................................99
Table 6-15.
Procedures and Assessments at Visit 15 and Subsequent Visits (Day 337 and Every 
12 Weeks).............................................................................................................................100
Table 6-16.
Procedures and Assessments at End-of-Study Visit.............................................................102
Table 8-1.
Grading of Adverse Event Severity......................................................................................118
Table 8-2.
Site Reporting Requirements for Adverse Events ................................................................119
Table 8-3.
Contact Information for Reporting Serious Adverse Events ................................................120
LIST OF IN-TEXT FIGURES
Figure 2-1.
Study Design ..........................................................................................................................34
Figure 5-1.
Kaplan-Meler Time to Diarrhea or Colitis .............................................................................64


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102, USA
Study Title:
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and 
Safety of Two Different Dose Levels of Single-Agent Idelalisib
(GS-1101) as Therapy for Patients with Previously Treated Chronic 
Lymphocytic Leukemia
A Companion Study to Study GS-US-312-0116: A Phase 3, Randomized, 
Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of Idelalisib (GS-1101) in Combination with Rituximab as 
Therapy for Patients with Previously Treated Chronic Lymphocytic 
Leukemia
Study Centers 
Planned:
Approximately 90 centers in the United States and in Europe
IND Number:
EudraCT Number:
101254
2011-006293-72
Objectives:

To evaluate the effect of idelalisib (formerly GS-1101) on the onset, 
magnitude, and duration of tumor control

To compare tumor control in subjects receiving rituximab alone in 
Study GS-US-312-0116 to that observed in the same subjects when 
receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject well-being, 
including overall survival (OS), health-related quality of life 
(HRQL), and performance status

To assess the effects of idelalisib on disease-associated biomarkers 
and to evaluate potential mechanisms of resistance to idelalisib

To characterize exposure to idelalisib as determined by treatment 
administration and evaluation of idelalisib plasma concentrations 
over time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with 
administration of idelalisib


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Study Design:
This study is being conducted as part of an overall clinical program 
evaluating the efficacy and safety of idelalisib in the therapy of patients 
with previously treated chronic lymphocytic leukemia (CLL).
Within this program, the primary clinical trial (Study GS-US-312-0116)
is a Phase 3, multicenter, 2-arm, randomized, double-blind, 
placebo-controlled, parallel-group study.
This clinical trial (Study GS-US-312-0117) is a separate, multicenter, 
2-arm, double-blind, parallel-group extension study that is a companion 
trial to Study GS-US-312-0116; in this trial, compliant subjects from 
GS-US-312-0116 who are tolerating primary study therapy but 
experience definitive CLL progression are eligible to receive active 
blinded idelalisib therapy at the standard dose or a higher dose, with 
allocation based on the original primary study randomization. In the 
event GS-US-312-0116 is stopped early due to overwhelming efficacy 
following an interim analysis or at the final analysis, subjects who are on 
Study GS-US-312-0116 at that time may transition to GS-US-312-0117. 
Additionally, GS-US-312-0117 will become an open-label study
offering idelalisib 150 mg BID to GS-US-312-0116 subjects who were
randomized to placebo, and subjects randomized to idelalisib will 
continue idelalisib at 150 mg BID.
Study Schema:
Treatment Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117)


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Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID
Treatment Assignment

Assignment to Arm A or Arm B with allocation based on the 
original primary study randomization

Implementation through an interactive web response system (IWRS)
Stratification
Not applicable for Study GS-US-312-0117
Number of 
Subjects Planned:
Total of up to ~180 subjects (up to ~90 subjects per treatment arm)
Target 
Population:
Subjects in the primary Phase 3 study (GS-US-312-0116) who are 
compliant, are tolerating primary study therapy, and 1) have definitive 
progression of CLL while receiving primary study drug therapy 
(idelalisib/placebo) or 2) are actively participating in 
Study GS-US-312-0116 at the time the study is stopped, including if 
stopped early due to overwhelming efficacy following an interim 
analysis.
Duration of 
Treatment:
Study drug will be taken continuously until the earliest of subject 
withdrawal from study drug, definitive progression of CLL, intolerable 
study drug-related toxicity, pregnancy, substantial noncompliance with 
study procedures, or study discontinuation.
Diagnosis and 
Main Eligibility 
Criteria:
Inclusion Criteria
Subjects must meet all of the following conditions to be eligible for 
enrollment into the study:
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while 
receiving study drug therapy (idelalisib /placebo) in 
Study GS-US-312-0116. Note: Definitive disease progression is 
CLL progression based on standard criteria and occurring for any 
reason (ie, increasing lymphadenopathy, organomegaly, or bone 
marrow involvement; decreasing platelet count, hemoglobin, or 
neutrophil count; or worsening of disease-related symptoms) other 
than lymphocytosis. Subjects must have confirmation by the 
sponsor working in collaboration with an independent review 
committee (IRC) that the disease has progressed on the primary 


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clinical trial (Study GS-US-312-0116) before receiving secondary 
idelalisib therapy on this extension trial (Study GS-US-312-0117).
3) Presence of measurable lymphadenopathy (defined as the presence 
of ≥1 nodal lesion that measures 2.0 cm in the longest diameter 
[LD] and 1.0 cm in the longest perpendicular diameter [LPD] as 
assessed by computed tomography [CT] or magnetic resonance 
imaging [MRI]).
4) Permanent cessation of Study GS-US-312-0116 treatment 
(rituximab and/or idelalisib/placebo) and no intervening or 
continuing therapy (including radiotherapy, chemotherapy, 
immunotherapy, or investigational therapy) for the treatment of 
CLL. Note: Subjects may receive corticosteroids to manage CLL 
manifestations.
5) The time from permanent cessation of Study GS-US-312-0116 
treatment (rituximab and/or idelalisib/placebo) and the initiation of 
Study GS-US-312-0117 therapy is 12 weeks. Note: Study 
procedures performed as part of Study GS-US-312-0116 need not 
be repeated and can be used as screening procedures for 
Study GS-US-312-0117 if performed within 4 weeks prior to 
initiation of study drug therapy on Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation 
of study treatment) as shown in the table below. Note: Confirmation 
should be considered for out-of-range values to determine if the 
abnormality is real or artifactual. Values should be obtained within 
the screening period and should generally be the most recent 
measurement obtained. Subjects with any degree of neutropenia, 
thrombocytopenia, or anemia due to CLL or prior therapy may 
enroll.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCr
a
>30 ml/min
Pregnancy
-HCGb
Negative
a
As calculated by the Cockcroft-Gault formula {Cockcroft et al 1976}
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or 
urine dipstick pregnancy test must be negative at randomization (Visit 2)
Abbreviations: -HCG=beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
eCCr=estimated creatinine clearance, ULN=upper limit of normal


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8) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening 
visit (Visit 1) throughout the study and for 30 days from the last dose 
of study drug. Note: A female subject is considered to be of 
childbearing potential unless she has had a hysterectomy, bilateral 
tubal ligation, or bilateral oophorectomy; has medically 
documented ovarian failure (with serum estradiol and 
follicle-stimulating hormone [FSH] levels within the institutional 
postmenopausal range and a negative serum or urine -HCG), or 
is menopausal (defined as age ≥54 years with amenorrhea for 
>12 months or amenorrhea for >6 months with serum estradiol 
and FSH levels within the institutional postmenopausal range).
9) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of 
study drug (Visit 2) throughout the study and for 90 days following 
the last dose of study drug and to refrain from sperm donation from 
the start of study drug (Visit 2) throughout the study and for 90 days 
following the last dose of study drug. Note: A male subject is 
considered able to father a child unless he has had a bilateral 
vasectomy with documented aspermia or a bilateral orchiectomy, 
or has ongoing testicular suppression with a depot luteinizing 
hormone- releasing hormone (LH-RH) agonist 
(eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), 
or triptorelin pamoate [Trelstar®]).
10) In the judgment of the investigator, participation in the protocol 
offers an acceptable benefit-to-risk ratio when considering current 
CLL disease status, medical condition, and the potential benefits and 
risks of alternative treatments for CLL.
11) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, 
familial, or geographical factors that might preclude adequate 
study participation should be considered.
12) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study 
participation.


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Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be 
enrolled in this study:
1) Known histological transformation from CLL to an aggressive 
lymphoma (ie, Richter transformation). 
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at 
the time of the start of study treatment (Visit 2). Note: Subjects with 
localized fungal infections of skin or nails are eligible. Subjects 
may be receiving prophylactic antiviral or antibacterial therapies at 
the discretion of the investigator; anti-pneumocystis prophylaxis is 
encouraged. 
3) Pregnancy or breastfeeding.
4) Intentional breaking of the blind in Study GS-US-312-0116 by the 
investigator or the study subject.
5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical condition, 
surgical history, physical finding, electrocardiogram (ECG) finding, 
or laboratory abnormality that, in the investigator’s opinion, could 
adversely affect the safety of the subject or impair the assessment of 
study results.
In the event Study GS-US-312-0116 is stopped early, subjects who are 
actively participating in Study GS-US-312-0116 will become eligible for 
this study, provided the following inclusion are met:
1) Participation in Study GS-US-312-0116 within 12 weeks of 
enrollment onto GS-US-312-0117.
2) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening 
visit (Visit 1) throughout the study and for 30 days from the last dose 
of study drug. 
3) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of 
study drug (Visit 2) throughout the study and for 90 days following 
the last dose of study drug and to refrain from sperm donation from 
the start of study drug (Visit 2) throughout the study and for 90 days 
following the last dose of study drug.
4) In the judgment of the investigator, participation in the protocol 
offers an acceptable benefit-to-risk ratio when considering current 
CLL disease status, medical condition, and the potential benefits and 
risks of alternative treatments for CLL.


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5) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, 
familial, or geographical factors that might preclude adequate 
study participation should be considered.
6) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study 
participation.
Study Procedures/
Frequency:
Clinic/laboratory visits will occur every 2 weeks for the first 12 weeks, 
every 4 weeks between Weeks 12 and 24, and every 6 weeks between 
Weeks 24 and 48. Subjects continuing on study drug past Week 48 will 
have clinic visits every 12 weeks. Subjects will be assessed for safety at 
each visit. Subjects will be assessed for CLL disease status by physical 
and laboratory examinations at each visit and by CT or MRI at 
Weeks 8, 16, 24, 36, and 48 and every 12 weeks thereafter.
Following unblinding of the study:

Subjects who were randomized to idelalisib on 
Study GS-US-312-0116 and who received ≥24 weeks idelalisib will 
complete Visit 16+ twelve weeks from the date of their last 
radiology assessment (CT/MRI) and study visits will continue every 
12 weeks thereafter. Visits 3 through 15 will not be required.

Subjects who have received < 24 weeks idelalisib will have all 
Study GS-US-312-0117 assessments completed per the 
Schedule of Procedures until they have received idelalisib for 
24 weeks cumulative across both studies. After completion of 
24 weeks of cumulative idelalisib treatment, Visit 16+ will be 
conducted 12 weeks from the date of their last radiology assessment 
(CT/MRI), after which time study visits will occur every 12 weeks.
Test Therapy, Dose, 
and Mode of 
Administration:
Blinded Portion

Arm A: Idelalisib, 300 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be provided 
as 2 tablets of active idelalisib for oral administration

Arm B: Idelalisib, 150 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be provided 
as 1 tablet of active idelalisib and 1 tablet of placebo for oral 
administration


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Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID
Note: At the Investigator’s discretion, subjects who were randomized 
to placebo on study GS-US-312-0116 may delay initiation of idelalisib 
following enrollment on Study GS-US-312-0117 until the time of 
disease progression or until the investigator determines that the 
subject would benefit from initiation of idelalisib treatment
Reference Therapy, 
Dose, and Mode of 
Administration:
Not applicable
Criteria for 
Evaluation:
Tumor Control

Progression-free survival (PFS) – defined as the interval from the 
start of study therapy to the earlier of the first documentation of 
definitive disease progression or death from any cause; definitive 
disease progression is CLL progression based on standard criteria 
other than lymphocytosis alone

Overall response rate (ORR) – defined as the proportion of subjects 
who achieve a complete response (CR) or partial response (PR)

Lymph node response rate – defined as the proportion of subjects 
who achieve a 50% decrease from baseline in the sum of the 
products of the greatest perpendicular diameters (SPD) of index 
lesions

CR rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from start of study 
therapy to the first documentation of CR or PR

Duration of response (DOR) – defined as the interval from the 
first documentation of CR or PR to the earlier of the first 
documentation of definitive disease progression or death from any 
cause

Percent change in lymph node area – defined as the percent change 
from baseline in the SPD of index lymph nodes

Splenomegaly response rate – defined as the proportion of subjects 
with baseline splenomegaly who achieve an on-study normalization 
or a 50% decrease (minimum 2 cm) from baseline in the 
enlargement of the splenic LVD (by imaging)


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
Hepatomegaly response rate – defined as the proportion of subjects 
with baseline hepatomegaly who achieve an on-study normalization 
or a 50% decrease (minimum 2 cm) from baseline the hepatic 
longest vertical dimension (LVD) (by imaging)

ALC response rate – defined as the proportion of subjects with 
baseline lymphocytosis (ALC4 x 109/L) who achieve an on-study 
ALC <4 x 109/L or demonstrate a 50% decrease in ALC from 
baseline (ALC values within 4 weeks post-baseline will be excluded 
from the ALC response rate evaluation)

Platelet response rate – defined as the proportion of subjects with 
baseline thrombocytopenia (platelet count <100 x 109/L) who 
achieve an on-study platelet count 100 x 109/L or demonstrate a 
50% increase in platelet count from baseline without need for 
exogenous growth factors (Platelet values within 4 weeks 
post-baseline or within 8 days post transfusion will be excluded from 
the platelet response rate evaluation)

Hemoglobin response rate – defined as the proportion of subjects 
with baseline anemia (hemoglobin <110 g/L [11.0 g/dL]) who 
achieve an on-study hemoglobin 110 g/L (11.0 g/dL) or 
demonstrate a 50% increase in hemoglobin from baseline without 
red blood cell transfusions or need for exogenous growth factors 
(eg erythropoietin)

Neutrophil response rate – defined as the proportion of subjects with 
baseline neutropenia (absolute neutrophil count [ANC] ≤1.5 x 109/L) 
who achieve an ANC >1.5 x 109/L or demonstrate a 50% increase 
in ANC from baseline without need for exogenous growth factors 
(eg, G-CSF)
Patient Well-Being

Overall survival (OS) – defined as the interval from start of study 
therapy to death from any cause

Change from baseline in HRQL domain and symptom scores based 
on the Functional Assessment of Cancer Therapy: 
Leukemia (FACT-Leu) (See Appendix 2)

Changes from baseline in Karnofsky performance status 
(See Appendix 3)
Pharmacodynamic Markers of Drug Activity and Resistance

Changes from baseline in PI3K/AKT/mTOR pathway activation as a 
measure of PI3Kpathway activity

Changes from baseline in the plasma concentrations of 
disease-associated chemokines and cytokines


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Exposure

Study drug administration as assessed by prescribing records and 
compliance as assessed by quantification of used and unused drug

Trough (pre-dose) and peak (~1.5-hour samples) of idelalisib plasma 
concentrations as assessed by a validated bioanalytical method
Safety

Overall safety profile of each regimen characterized by the type, 
frequency, severity, timing of onset, duration, and relationship to 
study therapy of any adverse events or abnormalities of laboratory 
tests; serious adverse events; or adverse events leading to 
discontinuation of study drug
Pharmacoeconomics

Change in health status – defined as the change from baseline in 
overall health and single-item dimension scores as assessed using the 
EuroQoL Five-Dimension (EQ-5D) utility measure

Health resource measures, including resource utilization, total costs, 
and measures of cost per unit of benefit (eg, cost per additional 
progression-free month, cost per quality-adjusted life-year)
Statistical Methods:
Appropriate data analysis sets will be defined. The intent-to-treat (ITT) 
analysis set will include data from all subjects who receive 1 dose of 
any study therapy on this study; in this data set, study drug assignment 
(high-dose or standard-dose idelalisib) will be designated according to 
the planned allocation to this study. A safety analysis set will comprise 
data from subjects in the ITT analysis set with treatment assignments 
designated according to the actual study drug (high-dose or 
standard-dose idelalisib) received. Other analysis sets [per-protocol (PP) 
and pharmacodynamic/pharmacokinetic analysis sets] will be used for 
certain analyses as well.
Subject characteristics and study results will be described and 
summarized by treatment arm and assessment for the relevant analysis 
sets. Descriptive summaries will be prepared to show sample size, mean, 
standard deviation, 95% confidence intervals (CIs) on the mean, median, 
minimum, and maximum for continuous variables and counts, 
percentages, and 95% CIs on the percentage for categorical variables.
An independent review committee (IRC) will review radiographic data 
and pertinent clinical data in order to provide expert evaluation of tumor 
status. The findings of the IRC will be considered primary for analyses 
of PFS and other tumor control endpoints.


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For endpoints relating to tumor control, patient well-being, and 
biomarkers, analyses will be done based on ITT, PP or 
pharmacodynamic data sets, as appropriate. Blinded portion of the study 
analyses will be presented in the following two groups:

IDELA 300 mg BID: Subjects who have PD per IRC confirmation in 
Arm A of Study GS-US-312-0116 and subsequently enroll into 
Study GS-US-312-0117 to receive IDELA 300 mg BID during the 
double-blind portion of the study

Placebo in GS-US-312-0116 + IDELA 150 mg BID in 
GS-US-312-0117: Subjects who have PD per IRC confirmation in 
Arm B of Study GS-US-312-0116 and subsequently enroll in 
Study GS-US-312-0117 to receive IDELA 150 mg BID during the 
double-blind portion of the study.
After unblinding, open-label extension study analyses will be presented 
in the following 4 groups:

IDELA 150 mg BID: Subjects who are randomized to Arm A in 
Study GS-US-312-0116 and transition to Study GS-US-312-0117 
during the open-label portion of the study to continue IDELA 
150 mg BID

Placebo in GS-US-312-0116 + IDELA 150 mg BID (open-label): 
Subjects who are randomized to Arm B in Study GS-US-312-0116 
and transition to receive IDELA 150 mg BID during the open-label 
portion of the study

IDELA 300 mg BID: Subjects who have PD per IRC confirmation in 
Arm A of Study GS-US-312-0116 and subsequently enroll 
Study GS-US-312-0117 to receive IDELA 300 mg BID during the 
double-blind portion of the study

Placebo in GS-US-312-0116 + IDELA 150 mg BID in 
GS-US-312-0117: Subjects who have PD per IRC confirmation in 
Arm B of Study GS-US-312-0116 and subsequently enroll 
Study GS-US-312-0117 to receive IDELA 150 mg BID during the 
double-blind portion of the study. Analyses will focus on evaluation 
of outcomes within each treatment arm and will be descriptive in 
nature; formal comparisons of outcomes between arms are not 
planned. Time-to-event endpoints will be summarized using 
Kaplan-Meier methods; medians, ranges, and the corresponding 
95% CI will be presented. Continuous and categorical variables will 
also be summarized as appropriate. Changes from baseline in 
categorical variables and changes from baseline in continuous 
endpoints will be analyzed using appropriate methods.


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Efficacy outcomes among subjects receiving rituximab alone in 
Study GS-US-312-0116 will be evaluated relative to those same 
outcomes among the same subjects receiving standard-dose idelalisib 
alone in Study GS-US-312-0117. 
Based on the safety analysis set, information regarding study drug 
administration, study drug compliance, safety variables, and post-study 
therapies will be described and summarized. Using data from the 
pharmacokinetic analysis set, idelalisib plasma concentrations will also 
be described and summarized.
Sample Size Calculation
The sample size for this extension study is not based upon a formal 
statistical hypothesis. The upper bound of the sample size in this study is 
determined by the sample size of the preceding primary clinical trial
(Study GS-US-312-0116) in which ~180 subjects (~90 per arm) are 
expected to be enrolled. Assuming a ~10% dropout rate during 
Study GS-US-312-0116 and a further ~10% dropout rate in the 
transition from the primary study to the extension study, ~180 subjects 
are expected to be enrolled into Study GS-US-312-0117.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP), 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
-HCG
Beta human chorionic gonadotropin
ABCG2
adenosine triphosphate-binding cassette sub-family G member 2 (see also BCRP)
AKT
AKT (a serine/threonine protein kinase)
ALC
absolute lymphocyte count
ALL
acute lymphocytic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
ATC
Anatomical-Therapeutic-Chemical classification system for drugs 
BCRP
breast cancer resistance protein (see also ABCG2)
BID
twice per day
BTK
Bruton tyrosine kinase
CAL-101
Former name for GS-1101
CCL
chemokine (C-C motif) ligand
CFR
Code of Federal Regulations
CI
confidence interval
CIRS
Cumulative Illness Rating Scale
CLL
chronic lymphocytic leukemia
cGMP
current Good Manufacturing Practice
Cmax
maximum concentration
CMV
cytomegalovirus
CR
complete response
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough concentration
CXCL
chemokine (C-X-C motif) ligand
CYP
cytochrome P450 enzyme
DLCO
diffusing capacity of the lung for carbon monoxide
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DOR
duration of response
DSPH
Gilead Sciences Department of Safety and Public Health
ECG
electrocardiogram


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eCCr
estimated creatinine clearance
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EQ-5D
EuroQoL Five-Dimension utility measure
FACT-Leu
Functional Assessment of Cancer Therapy: Leukemia questionnaire
FCεRI
high-affinity IgE receptor
FDA
United States Food and Drug Administration
FDAMA
Food and Drug Modernization Act
FDG
fluorodeoxyglucose (18F)
FISH
fluorescence in-situ hybridization,
FSH
follicle-stimulating hormone
G-CSF
granulocyte colony-stimulating factor
GGT
gamma-glutamyltransferase
GLP
Good Laboratory Practice
GM-CSF
granulocyte-macrophage colony-stimulating factor
HBc antibody
anti-hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
hERG
human ether-à-go-go-related gene
HL
Hodgkin lymphoma
HIV
human immunodeficiency virus
HRQL
health-related quality of life
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
idelalisib
formerly CAL-101 and GS-1101
IEC
independent ethics committee
Ig
immunoglobulin (including subtypes A, E, G, and M)
IgHV
immunoglobulin heavy chain variable region
IND
Investigational New Drug (application)
iNHL
indolent non-Hodgkin lymphoma
INR
international normalized ratio
IRB
institutional review board
IRC
independent review committee
ITT
intention to treat
IUD
intrauterine device
IWCLL
International Workshop on CLL
IWRS
interactive web response system
JAK
Janus kinase


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K2-EDTA
potassium-ethylenediaminetetraacetic acid
LD
longest diameter
LDH
lactate dehydrogenase
LH-RH
luteinizing hormone-releasing hormone
LLN
lower limit of normal
LPD
longest perpendicular diameter
LVD
longest vertical dimension
MTD
maximum tolerated dose
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mTOR
mammalian target of rapamycin
ND
no disease
NHL
non-Hodgkin lymphoma
NOAEL
no-observed-adverse effect level
NOEL
no-observed-effect level
OCT
organic cation transporter
ORR
overall response rate
OS
overall survival
pAKT
phosphorylated AKT
PCR
polymerase chain reaction
PD
progressive disease
PET
positron-emission tomography
PFS
progression-free survival
PI3K
phosphatidylinositol 3-kinase
PI3K
phosphatidylinositol 3-kinase p110isoform
PJP
Pneumocystis jiroveci pneumonia
PML
progressive multifocal leukoencephalopathy
PP
per-protocol
PPD
product of the perpendicular diameters
PRO
patient-reported outcome
PR
partial response
PT
prothrombin time
PVA
polyvinyl alcohol
PVC/PCTFE
polyvinyl chloride/polychlorotrifluoroethylene
QD
once per day
QT (interval)
measure of time between start of Q wave and end of T wave in electrical cycle of heart
RNA
ribonucleic acid
SADR
serious adverse drug reaction
SD
stable disease


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SPD
sum of the products of the perpendicular diameters of measured lymph nodes
SSC
study steering committee
SUSAR
suspected, unexpected, serious adverse reaction
SYK
spleen tyrosine kinase
t1/2
half-life
Tmax
time of maximum concentration
TTR
time to response
UGT
uridine 5'-diphospho-glucuronosyltransferase
ULN
upper limit of normal
WHODRUG
World Health Organization Drug Dictionary
ZAP-70
zeta-associated protein 70


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1.
INTRODUCTION
1.1.
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is a neoplasia resulting from the progressive accumulation 
of functionally incompetent monoclonal B lymphocytes in blood, bone marrow, lymph nodes, 
spleen, and liver {Dighiero et al 2008}. CLL constitutes the most commonly occurring leukemia 
in Europe and the United States {Sant et al 2010}, {Surveillance Epidemiology and End Results 
(SEER) Program 2011}. While some patients never require treatment, many will need therapy 
for disfiguring or obstructing lymphadenopathy, debilitating constitutional B symptoms 
(fevers, night sweats, fatigue, weight loss) {Redaelli et al 2004}, or recurrent cytopenias and 
infections {Perkins et al 2002}, {Keating et al 2002b}. CLL is largely a disease of the elderly; at 
diagnosis, 70% of patients are 65 years of age and the median age is 72 years {Surveillance 
Epidemiology and End Results (SEER) Program 2011}.
In younger and relatively healthy patients with CLL, chemoimmunotherapy regimens that 
include the anti-CD20 monoclonal antibody, rituximab, are commonly employed to control 
disease manifestations {Gribben et al 2011}. Such combination therapies are effective in 
providing durable remissions {Byrd et al 2005}, {Hallek et al 2010}, {Robak et al 2010}, 
{Fischer et al 2011}, {Iannitto et al 2011}. However, while rituximab is usually well tolerated 
{Gentile et al 2010}, the chemotherapeutic agents (typically fludarabine, cyclophosphamide, 
or bendamustine) in such regimens are acutely cytotoxic, induce permanent bone marrow 
compromise, and can cause secondary malignancies {Kyasa et al 2004}, {Tam et al 2008}, 
{Carney et al 2010}. Furthermore, in elderly patients or in those with comorbid conditions, such 
regimens are associated with less efficacy and greater toxicity {Tam et al 2008}, {Eichhorst et al 
2009b}, {Goede et al 2011}.
Increasing attention has been paid to the problem of treating patients with CLL who have 
comorbidities. Because of the relatively late age of diagnosis, a large proportion (~90%) of 
patients with CLL have co-morbidities and a substantial proportion (~45%) have major chronic 
conditions such as coronary artery disease, diabetes, or chronic obstructive pulmonary disease 
{Thurmes et al 2008}. At the time the disease is first identified, ~25% of patients with CLL do 
not meet conventional criteria for participation in clinical studies containing cytotoxic agents 
{Thurmes et al 2008}. By the time treatment is necessary or during treatment for CLL, patients 
continue to advance in age and have new or worsening chronic conditions; as a result, the 
proportion of patients with comorbidities increases during the course of the illness. Such patients 
have been substantially underrepresented in clinical trials due to concerns regarding the ability of 
such patients to tolerate intensive chemoimmunotherapy {Thurmes et al 2008}, {Eichhorst et al 
2009a}. Instruments such as the Cumulative Illness Rating Scale (CIRS) {Linn et al 1968} are 
now being applied in order to categorize patient populations as fit or relatively unfit and to 
evaluate regimens tailored to these groups of patients {Eichhorst et al 2009a}, {Hallek et al 
2010}, {Del Giudice et al 2011}.


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Health constraints in older or compromised patients have prompted noncytotoxic approaches to 
therapy. Alternative immunotherapeutics, such as the monoclonal antibodies, alemtuzumab
{Keating et al 2002a} or ofatumumab {Wierda et al 2010}, have been developed. However the 
therapeutic utility of these drugs is modest; median progression-free survival (PFS) values in 
patients with recurrent CLL have been 4.7 months and 5.8 months, respectively. Moreover, these 
treatments can have clinical liabilities. Alemtuzumab causes extreme immunosuppression that 
leads to frequent opportunistic infection. Administration of the large amounts of protein 
recommended in ofatumumab product labeling results in frequent infusion reactions and 
cumbersome infusion schedules.
In view of these issues, repeated use of rituximab monotherapy or rituximab-corticosteroid 
combinations have been advocated in treatment guidelines for older or frail patients with 
recurrent CLL {Eichhorst et al 2010}, {Zelenetz et al 2011}. While single-agent rituximab use 
can offer palliative benefit with good tolerability in some patients with previously treated CLL, 
tumor control is not lasting, especially in patients with bulky adenopathy {Gentile et al 2010}. 
Addition of high-dose corticosteroids to rituximab can extend median PFS up to 12 months, but 
this combination is commonly associated with severe hyperglycemia and frequent 
life-threatening or fatal infections {Bowen et al 2007}, {Dungarwalla et al 2008}. New,
noncytotoxic, well-tolerated, and convenient therapies that can successfully be combined with 
rituximab or given as single-agent therapy are needed in order to enhance and prolong tumor 
control in patients with comorbid conditions.
1.2.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies
Phosphatidylinositol 3-kinases (PI3Ks) are enzymes that regulate several cellular functions 
including motility, proliferation, and survival {Okkenhaug et al 2003b}. PI3K activation recruits 
and activates numerous intracellular signaling enzymes. The most important of these is the 
serine/threonine kinase, AKT, which mediates a positive pleiotropic effect on cell survival, 
proliferation, growth, and metabolism {Engelman et al 2006} acting by signaling through 
mammalian target of rapamycin (mTOR) {Hay 2005}, {Osaki et al 2004}.
PI3K signaling is mediated by 4 catalytic isoforms of the p110 subunit of the enzyme - , , , 
and . While potentially important in multiple cell types, PI3K p110(PI3K) shows an 
expression pattern that is particularly prominent in cells of hematopoietic origin 
{Vanhaesebroeck et al 2005}. Mice deficient in PI3Khave no gross abnormalities, are fertile, 
fecund, and live a normal life span without an increased susceptibility to infections {Okkenhaug 
et al 2003a}. However, the B-lymphocyte population in these animals shows a decrease in 
maturation, diminished receptor-induced proliferation, and increased susceptibility to apoptotic 
cell death. Conversely, mice with aberrantly elevated PI3K signaling develop lymphadenopathy 
and have an increased incidence of lymphoma {Donahue et al 2004}. In CLL, sustained 
activation of the PI3K/AKT/mTOR pathway has been shown to promote malignant B-cell 
survival through mechanisms that are dependent on the PI3Kisoform {Cuni et al 2004}, 
{Herman et al 2010}, {Lannutti et al 2011}.


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Knowledge of the critical importance of PI3Kδ in B-cell biology and neoplasia has encouraged a 
search for inhibitors of this enzyme that could provide new options in the therapy of lymphoid 
malignancies, including CLL.
1.3.
Idelalisib (formerly GS-1101)
1.3.1.
General Information
Idelalisib was approved in the US on July 23, 2014 and in the European Union on 
September 18, 2014. Refer to local labeling for the approved indication statements and dosing 
recommendations.
Gilead Sciences, Inc has developed novel drugs that can suppress tumor growth through 
targeting of PI3Kδ activity. High-throughput screening was the basis for the discovery of novel 
agents that selectively inhibit PI3Kfunction but spare other PI3K isoforms and other kinases. 
Chemical optimization, pharmacological characterization, and toxicological evaluation have led 
to identification of idelalisib (also known as GS-1101), a 415-dalton, orally bioavailable, 
new chemical entity with potential clinical utility in the treatment of cancers.
In primary tumor samples and in cell lines derived from patients with CLL, indolent 
non-Hodgkin lymphoma (iNHL), mantle cell lymphoma (MCL), B-cell acute lymphocytic 
leukemia (ALL), or Hodgkin lymphoma (HL), idelalisib induces dose-dependent reductions in 
AKT phosphorylation {Herman et al 2010}, {Meadows et al 2010}, {Lannutti et al 2011}. In 
addition, idelalisib disrupts the PI3Kactivation and supportive intercellular signaling observed 
when CLL or HL cells are cocultured with stromal cells {Meadows et al 2010}, {Hoellenriegel 
et al 2011}. These effects have therapeutic consequences. In multiple lymphoid primary tumors 
and malignant cell lines, idelalisib enhances apoptosis and concentration-dependent cell killing 
when applied as a single agent and increases the therapeutic efficacy of other antineoplastic 
agents when given in combination {Hoellenriegel et al 2011}, {Meadows et al 2011}. In 
preclinical systems, coadministration of idelalisib with rituximab has not impaired 
rituximab-mediated activity {Herman et al 2010}.
1.3.2.
Safety Pharmacology
In vitro and in vivo safety pharmacology studies with idelalisib have demonstrated a favorable 
non-clinical safety profile. These studies indicate that the drug may minimally slow bone marrow 
progenitor proliferation and differentiation and that it has expected inhibitory effects on 
B-cell response to antigen challenge. However, the data indicate that idelalisib is unlikely to 
cause serious off-target effects or adverse effects on critical organ systems. Idelalisib has no 
meaningful effect on the human ether-à-go-go-related gene (hERG) channel, indicating that 
idelalisib would not be expected to induce clinical QT prolongation.
The drug has also proved well tolerated in standard in vivo Good Laboratory Practice (GLP) 
studies of pharmacological safety. A functional observation battery in rats revealed no adverse 
effects on behavior or on autonomic, neuromuscular, or sensorimotor function. In a 
cardiopulmonary function study in awake, telemeterized male beagle dogs, single doses of 


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idelalisib induced no meaningful abnormalities in pulmonary, cardiovascular, arterial blood gas, 
or electrocardiographic (ECG) (including QT interval) parameters. In an assessment of bacterial 
challenge in rats, idelalisib enhanced, rather than impaired, the phagocytic host clearance of 
staphylococcal bacteria.
1.3.3.
Nonclinical Pharmacology and Metabolism
Consistent with the moderate to high bioavailability seen in nonclinical species, idelalisib shows 
high permeability across human Caco-2 cell monolayers.  At lower concentrations, the reverse 
permeability at low concentration exceeds forward permeability, indicating efflux driven by 
transporters (eg, human P-glycoprotein (MDR1) and breast cancer resistance protein [BCRP]); 
idelalisib is a substrate for the efflux transporters MDR1 and BCRP; however, the permeability 
increases in a concentration-dependent manner, resulting in a lower efflux ratio at higher, 
clinically relevant concentrations of idelalisib.
Idelalisib exhibits moderately high plasma protein binding in mouse, rat, dog, and human. In dog 
and human plasma, the protein binding is concentration-independent between 1 and 20 µM. 
Protein binding in human plasma is slightly higher than in mouse, rat, and dog plasma, which 
have comparable free fractions.  In human plasma, idelalisib and GS-563117 
(the major metabolite of idelalisib) have an average free fraction of ~16% and ~12%, respectively.
After oral administration of 14C-idelalisib to rats and dogs, radioactivity is widely distributed, but 
relatively excluded from bone, brain, spinal cord, and eye lens in rats and from brain and eyes in 
dogs. In rats, the radioactivity declines steadily and most tissues have undetectable levels by 
72 hours post dose.  In bile duct-cannulated rats and dogs, ≥69% of radioactivity is recovered in 
bile and urine, indicating high absorption of idelalisib in vivo.
In hepatic tissues from nonclinical species, idelalisib is primarily metabolized by 
aldehyde oxidase, CYP3A, and UGT1A4.  In vitro metabolism in dog and human yields 
3 primary oxidative metabolites and 5 primary glucuronides. Of these, the oxidative product 
GS-563117 is the predominant metabolite in vitro and in vivo. In preclinical species, plasma 
levels of GS-563117 are below those of idelalisib. In humans, GS-563117 
(only circulating metabolite and formed via aldehyde oxidase) plasma levels significantly exceed 
those of idelalisib. After oral administration of 14C-idelalisib to rats and dogs, biliary excretion 
appears to be the major route of elimination of idelalisib and its metabolites as the majority of 
radioactivity is found in feces or bile and little in urine.
Idelalisib is not a substrate for the renal transporters OCT2, OAT1, and OAT3 or the 
hepatic uptake transporters OATP1B1 and OATP1B3.  GS-563117 is not a substrate for 
OATP1B1 and OATP1B3.
Idelalisib is not an inhibitor of CYP1A, CYP2B6, CYP2C9, and CYP2D6, and at concentrations 
above those observed clinically, is an inhibitor of CYP2C8 (IC50 = 13 µM), CYP2C19 
(IC50 = 76 µM), and CYP3A (IC50 = 44 µM). GS-563117 is not an inhibitor of CYP1A, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and a competitive and time dependent 
inhibitor of CYP3A (IC50 = 3.1 µM), (KI = 0.18 µM, kinact = 0.033 min-1 with midazolam as 
the probe substrate).


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In vitro, idelalisib is not an inhibitor of the transporters BCRP, OCT2, OAT1, and OAT3, and is 
an inhibitor of MDR1 (IC50 = 7.7 µM), OATP1B1 (IC50 = 10.1 µM), OATP1B3 (IC50 = 7.0 µM), 
and, at concentrations above those observed clinically, of glucuronosyltransferase UGT1A1 
(IC50 = 42.0 µM). GS-563117 is not an inhibitor of MDR1, BCRP, OATP1B1, OATP1B3, 
OAT1, OAT3, and OCT2, and at concentrations above those observed clinically, an inhibitor of
UGT1A1 (IC50 = 16.8 µM).
Any potential clinical implications of these metabolism studies were evaluated in a formal 
drug-drug interaction study (GS-US-313-0130) which evaluated the effect of idelalisib on 
cytochrome P450 3A and the drug transporters P-gp, OATP1B1, and OATP1B3. 
Study GS-US-313-0130 also evaluated the impact of an inducer of metabolizing enzymes and 
transporters (rifampin) on the PK of idelalisib in healthy human subjects. Findings from this 
study are presented in Section 1.3.5.1.
1.3.4.
Toxicology
The toxicological profile of idelalisib was well characterized through the conduct of single dose, 
repeat dose, developmental and reproductive, and genetic toxicology and local tolerance studies. 
The primary target organ toxicities following repeated dosing include the lymphoid, hepatic, 
male reproductive systems in rats and dogs, and gastrointestinal system in dogs. Adverse effects 
in the lymphoid system were primarily the result of on target pharmacology resulting in 
decreased lymphocytes in multiple lymphoid organs, primarily involving B-cell regions. Liver 
effects were transient and reversible with continued dosing and did not result in chronic liver 
injury. Reduction in sperm numbers in males were reversible and did not impact fertility or 
reproductive performance.  Gastrointestinal effects in dogs were minor, superficial, and 
considered secondary to effects on lymphocytes in Peyer’s Patches. Idelalisib was shown to be 
teratogenic and associated with embryo-fetal lethality. Effects on the reproductive system have 
been reported for inhibitors which target other isoforms of PI3K. The dose-dependence and 
potential of idelalisib to selectively inhibit additional PI3K isoforms may be responsible for the 
off-target toxicity. Additionally, the drug may have the potential to produce phototoxic reactions 
in humans. These findings represent toxicities that can be monitored, are considered clinically 
manageable, or are considered acceptable risks in the intended patient population.
Further details on the toxicology of idelalisib can be found in the Idelalisib 
Investigator’s Brochure (IB).
1.3.5.
Idelalisib Clinical Studies
1.3.5.1.
Phase 1 Studies in Healthy Subjects and in Patients with Allergic Rhinitis
Various studies in healthy subjectshave evaluatedsafety, pharmacokinetics, food effect, and the 
potential for drug interactions of idelalisib with CYP3A4 inhibitors {Webb et al 2010}.


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Safety results from these studies indicated that idelalisib was well tolerated when administered to 
healthy subjects at single doses through 400 mg (the highest dose level tested) and was also 
generally well tolerated when administered to healthy subjects over 7 days at dose levels through 
200 mg/dose BID (the highest dose level tested). Dosing with 200 mg/dose BID for 7 days 
resulted in a skin rash in 3 out of 6 subjects; histological findings were consistent with a 
delayed-type hypersensitivity maculopapular exanthema. Rashes have sometimes occurred in 
patients with hematological malignancies receiving idelalisib, but have not typically proved 
dose- or treatment-limiting. In placebo-controlled single-dose and multiple-dose trials, repeated 
ECG evaluations performed in tandem with pharmacokinetic monitoring showed no evidence of 
drug-, dose-, or exposure-dependent effects on cardiac rhythm or cardiac intervals 
(eg, QT interval). Pharmacokinetic results indicated that idelalisib appeared rapidly in plasma 
with a median Tmax of 1 to 1.5 hours. Cmax and AUC increased in a less-than-dose-proportional 
manner and mean t1/2 values were across the dose range were 6.5 to 9.8 hours.
Idelalisib dosing after a high-fat, high-calorie meal delayed median time of 
maximum concentration (Tmax) from 0.75 hours to 3 hours; mean Cmax was unaffected and 
mean AUC was ~40% higher. These changes in idelalisib exposures are considered 
modest/clinically non-relevant; thus, idelalisib may be given with or without food.
Idelalisib is metabolized in humans primarily by aldehyde oxidase, with some involvement of 
CYP3A4 and UGT1A4. Accordingly, when idelalisib was administered following 4 days of daily 
dosing with ketoconazole (a potent inhibitor of CYP3A4), modest/moderate increases in mean 
idelalisib Cmax and AUC values of ~30% and ~80% higher, respectively, which is not considered 
to be clinically relevant and suggesting that idelalisib is a weak CYP3A substrate. GS-563117 is 
formed from idelalisib primarily via aldehyde oxidase.
The 14C-labeled idelalisib human mass balance results showed that the drug has moderate to high 
oral bioavailability. Idelalisib is eliminated mainly via hepatic metabolism and biliary excretion 
in the feces (~78% of dose); recovery in urine was < 15%. GS-563117, the only circulating 
metabolite observed in human plasma, was also observed in urine and feces.
Results from the drug interaction/probe Study GS-US-313-0130 indicate that idelalisib does not 
affect the pharmacokinetics of substrates of Pgp, BCRP, OATP1B1 or OATP1B3 transporters. 
Idelalisib is not expected to affect the exposures of coadministered agents via transporter 
mediated interactions.
The exposures (AUC) of probe CYP3A substrate, midazolam, increased ~5-fold upon 
coadministration with idelalisib, driven by competitive and time-dependent CYP3A inhibition by
GS-563117, the only circulating metabolite of idelalisib. Coadministration of the highly potent 
CYP3A inducer rifampin resulted in a ~75% reduction in idelalisib systemic exposures, likely 
driven by a higher relative contribution of CYP3A to overall idelalisib clearance under the 
induced state.


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Pharmacodynamic results showed that a idelalisib dose of 200 mg inhibited ex vivo basophil 
activation via the PI3K-specific, high-affinity immunoglobulin (Ig)E receptor (anti-FCR1) in 
basophils collected from healthy volunteers. The findings were confirmed when the drug was 
assessed over 7 days in a Phase 1b study in subjects with allergic rhinitis. In this study, idelalisib
at a dose level of 100 mg/dose BID showed clinical and pharmacodynamic activity 
(attenuating adverse responses to allergenic challenge and decreasing markers of inflammation) 
and was well tolerated.
1.3.5.2.
Phase 1 Studies in Patients with Hematological Malignancies
1.3.5.2.1.
Phase 1 Monotherapy Study in Patients with Hematological Malignancies
A Phase 1 dose-ranging study (Study 101-02) of single-agent idelalisib extended safety and 
pharmacokinetic observations; documented the clinical and pharmacodynamic activity of 
idelalisib in subjects with iNHL, MCL, and CLL; and provided dosing information in support of
further development {Brown et al 2011}, {Coutre et al 2011}, {Kahl et al 2011}. In this study, 
idelalisib was administered in cohorts of subjects across a range of dose levels from 50 mg/dose 
BID to 350 mg/dose BID. Idelalisib administration was continued as long as individual subjects 
were safely benefitting from therapy. Subjects were evaluated in 4-week cycles; response and 
progression assessments were based on standard criteria {Hallek et al 2008}.
A total of 191 subjects were enrolled to the study at dose levels of 50 mg BID (n=17), 
150 mg QD (n=16), 100 mg BID (n=25), 150 mg BID (n=45), 200 mg BID (n=35), 
350 mg BID (n=17), and 300 mg QD (n=19). An additional cohort was also enrolled to receive 
idelalisib 150 mg BID in 28 day cycles (21 days on idelalisib/7 days off [n=17]). Subject
characteristics were as follows: males/females n=139 (73%)/52 (27%) with median age of 
64.5 (range 32-91) years. Diagnoses included: CLL, n=54 (28%); iNHL, n=64 (34%); aggressive 
NHL (MCL and DLBCL), n=49 (26%); AML, n=12 (6%); and MM, n=12 (6%). Categorization 
of disease by response to the last prior therapy included: refractory, n=111 (58%); 
relapsed, n=79 (42%); and unknown, n=1 (1%).  The median (range) number of prior therapies 
was 5 (1-14). Among subjects with iNHL and CLL, the majority had received prior rituximab 
and prior alkylating agent therapy.
Adverse events were usually mild to moderate and not clearly idelalisib-related. Among 
Grade ≥3 adverse events, pneumonias and diarrhea were notable. Pneumonia was observed in 
23 (12%) subjects, primarily in subjects with CLL. In most instances, these findings were 
considered bacterial in origin, based either on culture results or on response to conventional 
antibiotics. Grade ≥3 adverse events of diarrhea were seen in 11 subjects (5.8%). Other 
Grade ≥3 events included rash in 3 (1.6%) subjects. The relative contributions of disease-related 
factors, toxicity from prior therapies or ongoing supportive care, and idelalisib to these events 
was not clear.
Grade ≥3 hematological laboratory abnormalities have included neutropenia, n=46 (24%); 
thrombocytopenia, n=27 (14%), anemia, n=14 (7.3%), and lymphopenia 13 (6.8%); with 
12 subjects (6.3%) having febrile neutropenia.  The occurrence of these events was greater in 
subjects with leukemia, particularly in those with pre-existing hematological abnormalities due 
to disease or prior therapy, commonly making attribution of these events to idelalisib uncertain.


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Consistent with the observations in the 28-day dog toxicology study, reversible Grade ≥3 
ALT/AST elevations occurred in 28 (15%) subjects and have been attributed to idelalisib. Onset 
generally occurred between 2 to 16 weeks after idelalisib initiation and resolution was usually 
seen 2 to 6 weeks after idelalisib interruption.  After resolution of ALT/AST increases, 
14 subjects were rechallenged at the same or a reduced dose of idelalisib and 9 (64%) of these 
subjects were able to resume treatment without recurrence of transaminase elevations.
Two (1.0%) subjects had ≥ 2 x ULN elevations in bilirubin in the context of Grade ≥3 
elevated AST/ALT, both of whom had confounding factors (recent history of biliary obstruction 
or concomitant use of potentially hepatotoxic medications) so that a definitive causal relationship 
to idelalisib could not be established.
Pharmacokinetic analyses indicated that the increase in Cmax and AUC0-6h with dose was less 
than dose-proportional, with modest increases above the dose level of 150 mg BID.
Pharmacodynamic data supported drug activity.  In subjects with NHL, plasma concentrations of 
chemokines CCL22 and CCL17 were elevated at baseline and showed significant decreases 
within 1 cycle of idelalisib treatment (p<0.001 for both comparisons). Flow cytometry of CLL 
cells from subjects showed that idelalisib reduced constitutive expression of phosphorylated 
AKT to background levels when measured after 1 week of treatment (p<0.0001), demonstrating 
pharmacodynamic inhibition of activated PI3K signaling.  Plasma concentrations of 
chemokines CCL3, CCL4, and CXCL13 were elevated in CLL subjects at baseline and 
decreased significantly within 1 cycle of idelalisib administration (p<0.001 for all comparisons).
Tumor reductions meeting antitumor response criteria were not observed in subjects with AML 
or MM. One of 11 subjects with DLBCL achieved a PR.  In 104 subjects with iNHL and MCL, 
idelalisib induced PRs at all dose levels, with respective ORRs in enrolled subjects of 
29/64 (45%) for iNHL and 16/40 (40%) for MCL. The median DOR has not been reached in 
subjects with iNHL; 19 subjects continued to receive idelalisib in a long-term extension study. 
The median [range] DOR was 2.7 months [1 month to 8 months] in subjects with MCL; 
6 MCL subjects continued to receive idelalisib in a long-term extension study.
In subjects with CLL, idelalisib reduced lymphadenopathy in almost all subjects; 
44/54 (81.5%) achieved a lymph node response (≥50% reduction in target nodal lesions). An 
initial increase in peripheral absolute lymphocyte counts of >50% from baseline was observed in 
some subjects; increases were maximal during the first 2 cycles and decreased thereafter; the 
pattern suggested drug-mediated lymphocyte redistribution.  In 54 subjects with CLL, 
39/54 (72%) achieved a PR (includes PR with lymphocytosis).  The median DOR was not 
reached; 23 subjects continued to receive idelalisib in a long-term extension study.
1.3.5.2.2.
Phase 1 Combination Study in Patients with Hematological Malignancies
A separate Phase 1 trial (Study 101-07) has evaluated the safety and preliminary activity of 
idelalisib given in combination with rituximab to subjects with recurrent iNHL or CLL {Brown 
et al 2011}, {Leonard et al 2011}.


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In this study, rituximab was administered at a standard dose of 375 mg/m2 per infusion weekly 
for 8 weeks in all subjects. Idelalisib was started simultaneously with the rituximab, first at a 
dose level of 100 mg/dose BID (n=13) and then at a dose level of 150 mg/dose BID (n=12) and 
was administered continuously to both subjects with CLL (n=13) and subjects with iNHL (n=12)
for as long as individual subjects were safely benefiting from therapy. Subjects were evaluated in 
4-week cycles; response and progression assessments were based on standard criteria {Hallek et 
al 2008}.
Among the subjects with CLL, the median age was 63 and ranged to 85 years. Bulky tumors 
(1 lymph node 5 cm in diameter) were present in 63% of the subjects. The median number of 
prior therapies by disease was 2 and ranged up to 8 prior treatments. All had received prior 
rituximab and the majority had received prior fludarabine or alkylating agents. Approximately 
one-third of subjects had CLL that was refractory to the last prior therapy. At the time of data 
cut-off, therapy had been administered for a median of 5 cycles, ranging up to 12 cycles 
(ie, 48 weeks).
No idelalisib-related dose-limiting toxicities were observed within the tested subject cohorts. 
Grade 3-4 adverse events largely comprised background events resulting from pre-existing 
disease- or treatment-related conditions or from intercurrent illness. Among subjects with CLL, 
2 (15%) developed pneumonia. For subjects receiving idelalisib together with rituximab, 
Grade 3-4 elevations in ALT/AST were not observed in those with CLL, although 
3 subjects (25%) of those with iNHL had such events.
The idelalisib plus rituximab combination showed a high level of antitumor activity in both 
subjects with CLL and those with iNHL. Altogether 92% of subjects with CLL receiving the 
combination of idelalisib and rituximab had reductions in nodal size and 77% showed a 
lymph node response (50% reduction in index nodal lesions). Although concomitant 
administration of rituximab did not eliminate the redistribution lymphocytosis that is associated 
with idelalisib, it blunted the magnitude of the change. As a result, the overall response rate 
(ORR) was also 77% among subjects participating in this study. At the time of last data analysis, 
PFS through 48 weeks was 70% and a median PFS had not yet been observed.
Collectively, the emerging data from this study support further evaluation of idelalisib together 
with rituximab in subjects with CLL and indicate that co-administration of idelalisib with 
rituximab is tolerable when using idelalisib at full dose, ie, at a starting dose level of 
150 mg/dose BID.
For additional or updated information, please refer to the current version of the IB.
1.4.
Summary and Justification for the Current Study
Gilead Sciences is conducting this Phase 3 study program to evaluate the efficacy and safety of 
idelalisib in patients with previously treated, recurrent CLL. Collectively the data derived from 
the primary clinical trial (Study GS-US-312-0116) and from this extension trial 
(Study GS-US-312-0117) address the activity of idelalisib together with rituximab, the activity 
of idelalisib when given alone, and the potential for dose-dependent restoration of drug activity 
in subjects who have disease that appears to be drug resistant.


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The design and conduct of this clinical trial program is supported by knowledge of the
demographics of patients with CLL, the natural history and current therapies for the disease, and 
the nonclinical and clinical information regarding idelalisib. The collective data support the 
following conclusions:

CLL is a serious, disabling, and potentially life-threatening disorder of older patients that 
requires sequential treatment with agents that provide alternative mechanisms of tumor 
control. Existing cytotoxic agents have serious acute and chronic toxicities, making them less 
suitable for frail or unfit patients. Single-agent rituximab can offer disease palliation with 
good tolerability in some patients with relapsed CLL but tumor control is not lasting, 
especially in patients with bulky adenopathy. Development of a non-cytotoxic combination 
therapy of idelalisib with rituximab or a monotherapy regimen of idelalisib that can address 
disease pathogenesis with a new mechanism of action and might offer complementary 
nodal and peripheral blood activity would address an unmet medical need, particularly when 
applied in patients with substantial comorbidities or myelosuppression from prior 
chemotherapies.

PI3Kδ over-expression plays an important role in CLL biology. Further evaluation of 
idelalisib as a potential treatment for CLL has sound scientific rationale founded on 
knowledge of the actions of the drug to selectively abrogate PI3Kδ activity and to inhibit 
malignant cell growth and stromal cell signaling in nonclinical models of CLL. These data 
are supported by clinical documentation of idelalisib inhibition of PI3Kδ signaling in patients 
with CLL.

The potential for clinical efficacy of idelalisib monotherapy or of idelalisib plus rituximab in 
patients with relapsed or refractory CLL is supported by the observed antitumor activity of 
idelalisib - given alone or in combination with rituximab - in patients with heavily pretreated 
CLL and iNHL.

The safety of advancing development of the idelalisib monotherapy and of a regimen of 
idelalisib plus rituximab in this Phase 3 clinical trial program is well supported by safety 
pharmacology and toxicology studies and by Phase 1 single-agent and combination safety 
data obtained in healthy volunteers and in subjects with lymphoid cancers.

Dose-safety, dose-exposure, and dose-activity relationships identified in Phase 1 studies
support the dosing regimen and dose modification provisions in this study.

Observations relating to patterns of CLL response among subjects receiving idelalisib alone 
or in combination with rituximab in Phase 1 trials provide the foundation for efficacy
monitoring in this trial. Of particular note is that idelalisib mobilizes CLL cells from tissues 
into the peripheral blood. This characteristic pharmacological action is prominent early in 
therapy but can persist over time and should not be confused with disease progression in 
patients who have persistent control of other CLL-related signs and symptoms. For this 
reason, in this Phase 3 study program, subjects will be continued on therapy until the 
occurrence of definitive disease progression, ie, disease progression that is manifest by 
worsening CLL-related signs or symptoms other than lymphocytosis alone. 


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
Thorough nonclinical and clinical characterization of the type, severity, manifestations, and 
expected timing of adverse events establish the safety monitoring plan in this trial program.

The scientific correlative work performed in prior preclinical and clinical studies provides 
strong scientific underpinnings for the companion laboratory studies to be performed as a 
component of this clinical trial program.

Given the seriousness of previously treated CLL in patients with substantial comorbidity, and 
the aggregate potential benefits considered in the context of potential risks, further 
development of idelalisib in this Phase 3 clinical trial program is justified.
The rationale for specific design features is provided in relevant sections of the protocol, 
including Section 3.2 (Endpoint Selection Rationale), Section 2.2 (Design Rationale), 
Section 4.3 (Enrollment Criteria Rationale), Section 5.10 (Study Treatment Rationale), and 
Section 6.5 (Study Procedure Rationale).


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2.
STUDY DESIGN
2.1.
Design Overview and Study Schema
This study is being conducted as part of an overall clinical program that is evaluating the efficacy 
and safety of idelalisib in the therapy of patients with previously treated CLL (see Figure 2-1). 
Within this program, the primary clinical trial (Study GS-US-312-0116) is a Phase 3, 
multicenter, 2-arm, randomized, double-blind, placebo-controlled, parallel-group study. This 
clinical trial (Study GS-US-312-0117) is a separate, multicenter, 2-arm, double-blind, 
parallel-group extension study that is a companion study to the primary study.
Figure 2-1.
Study Design
Candidates for the primary study will be adults with previously treated recurrent CLL who have 
measurable lymphadenopathy, require therapy for CLL, have experienced CLL progression 
<24 months since the completion of the last prior therapy, and are currently not sufficiently fit to 
receive cytotoxic therapy because of chemotherapy-induced bone marrow damage or 
comorbidities.
Primary study subjects will be stratified based on 17p deletion and/or a p53 mutation status 
(either vs neither), immunoglobulin heavy chain variable region (IgHV) mutation status 
(unmutated vs mutated), and any prior therapy with an anti-CD20 therapeutic monoclonal 
antibody (yes vs no) and randomized in a 1:1 ratio to receive 1 of the 2 treatment arms.
In the primary study, subjects will be administered rituximab intravenously in the clinic starting 
at a dose of 375 mg/m2 on Day 1 (Week 0) and will continue with a dose of 500 mg/m2 on 
Day 15 (Week 2), Day 29 (Week 4), Day 43 (Week 6), Day 57 (Week 8), Day 85 (Week 12), 
Day 113 (Week 16), Day 141 (Week 20) (for a total of 8 infusions). Rituximab will be
administered until the earliest of subject withdrawal from study, definitive progression of CLL, 
intolerable rituximab-related toxicity, pregnancy, substantial noncompliance with study 
procedures, study discontinuation, or a maximum of 8 infusions.


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Idelalisib or placebo will be taken orally, BID continuously. Subjects will continue whichever 
study drug (idelalisib/placebo or rituximab) continues to be tolerated, even if the other drug has 
been discontinued due to toxicity.
If permanent discontinuation of study drug, occurs prior to definitive progression of CLL, 
subjects shall remain on study until definitive progression of CLL or withdrawal from the study 
for reasons specified in Section 5.7.
Compliant subjects who are tolerating therapy but who develop definitive disease progression in 
the primary clinical trial (Study GS-US-312-0116) can consider enrollment in this separate 
companion extension trial (Study GS-US-312-0117). In the extension trial, subjects will take 
active blinded idelalisib therapy, either at a higher starting dose or at the standard starting dose, 
with allocation based on the original primary study randomization. Following unblinding of 
Study GS-US-312-0116, subjects will be allowed to enter Study GS-US-312-0117 in the absence 
of evidence of disease progression and will take 150 mg BID idelalisib regardless of treatment 
assignment in Study GS-US-312-0116.
The primary objective of Study GS-US-312-0116 will be to evaluate the effect of the addition of 
idelalisib to rituximab on PFS. Secondary and tertiary objectives will focus on determining the 
effect of the addition of idelalisib to rituximab on the onset, magnitude, and duration of tumor 
control; overall survival (OS); health-related quality of life (HRQL); changes in subject 
performance status; disease-associated biomarkers and potential mechanisms of resistance; 
treatment administration; safety; and health resource utilization. In Study GS-US-312-0117, the 
same endpoints will be assessed as in Study GS-US-312-0116; the focus of the analysis will be 
largely descriptive except for the within-subject assessment of treatment effects among subjects 
receiving first rituximab alone and then idelalisib alone on Arm B of each trial. No formal 
comparisons of outcomes in Arm A vs Arm B are planned within Study GS-US-312-0117.
2.2.
Design Rationale
The randomized, add-on design for the primary trial (Study GS-US-312-0116) is customary in 
the comparative evaluation of new therapies for cancer. While this design provides idelalisib
efficacy and safety information only in the context of administration of a companion 
antineoplastic agent, it is appropriate because it documents the incremental benefit and toxicity 
of the investigational therapy in the context of a controlled clinical trial while ensuring that all 
participants receive potentially active treatment.
This separate extension trial (Study GS-US-312-0117) enhances subject acceptance of 
randomization in the primary study and provides further information regarding idelalisib
efficacy, resistance, and safety. Among subjects in Arm A, escalation to a higher dose level 
allows evaluation of dose-dependent resistance and a determination if a higher dose can 
reestablish disease control. The safety data obtained in these subjects will add to the overall 
safety database. Among subjects randomized to Arm B in the primary study, evaluation of 
idelalisib at a starting dose of 150 mg/dose BID in the extension study may permit a 
within-subject assessment of the treatment effects with single-agent idelalisib relative to the 
effects previously observed with rituximab alone. Of importance, the extension study maintains 


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the partial blinding of the primary study, thus minimizing the bias that might occur if the overall 
design entailed only a 1-way crossover to open-label idelalisib among subjects who had received 
placebo on Arm B of the primary study. To ensure confirmation of disease progression, tumor 
size data collected from the primary study will be subjected to independent review by an 
independent review committee (IRC) (see Section 10.4.2); subjects will continue with study 
therapy pending confirmation of progression status by the sponsor working in collaboration with 
the IRC. Subjects must have confirmation that the disease has progressed on the primary study 
before being permitted to receive secondary idelalisib therapy on the extension study, or in the 
event the primary study is stopped, subjects who have not yet progressed may enroll on the 
extension study to receive 150 mg BID idelalisib.


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3.
OBJECTIVES AND ENDPOINTS

To evaluate the effect of idelalisib on the onset, magnitude, and duration of tumor control

To compare tumor control in subjects receiving rituximab alone in Study GS-US-312-0116 to 
that observed in the same subjects when receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject well-being, including overall survival 
(OS), health-related quality of life (HRQL), and performance status

To assess the effects of idelalisib on disease-associated biomarkers and to evaluate potential 
mechanisms of resistance to idelalisib

To characterize exposure to idelalisib as determined by treatment administration and 
evaluation of idelalisib plasma concentrations over time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with administration of idelalisib
3.1.
Endpoints
3.1.1.
Tumor Control

Progression-free survival (PFS) – defined as the interval from the start of study therapy to the 
earlier of the first documentation of definitive disease progression or death from any cause; 
definitive disease progression is CLL progression based on standard criteria other than 
lymphocytosis alone

ORR – defined as the proportion of subjects who achieve a CR or partial response (PR) 

Lymph node response rate – defined as the proportion of subjects who achieve a 
50% decrease from baseline in the SPD of index lymph nodes

CR rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from start of study therapy to the first 
documentation of CR or PR

Duration of response (DOR) – defined as the interval from the first documentation of 
CR or PR to the earlier of the first documentation of definitive disease progression or death 
from any cause


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
Percent change in lymph node area – defined as the percent change from baseline in the sum 
of the products of the greatest perpendicular diameters (SPD) of index lymph nodes

Splenomegaly response rate – defined as the proportion of subjects with baseline 
splenomegaly who achieve an on-study normalization or a 50% decrease (minimum 2 cm) 
from baseline in the enlargement of the splenic LVD (by imaging)

Hepatomegaly response rate – defined as the proportion of subjects with baseline 
hepatomegaly who achieve an on-study normalization or a 50% decrease (minimum 2 cm) 
from baseline in the hepatic longest vertical dimension (LVD) (by imaging)

ALC response rate – defined as the proportion of subjects with baseline lymphocytosis 
(ALC4 x 109/L) who achieve an on-study ALC <4 x 109/L or demonstrate a 50% decrease 
in ALC from baseline; ALC values within 4 weeks post-baseline will be excluded from the 
ALC response raete evaluation

Platelet response rate – defined as the proportion of subjects with baseline thrombocytopenia 
(platelet count <100 x 109/L) who achieve an on-study platelet count 100 x 109/L or 
demonstrate a 50% increase in platelet count from baseline; platelet values within 4 weeks 
post-baseline or after 8 days post transfusion will be excluded from the platelet response rate 
evaluation

Hemoglobin response rate – defined as the proportion of subjects with baseline anemia 
(hemoglobin <110 g/L [11.0 g/dL]) who achieve an on-study hemoglobin 110 g/L 
(11.0 g/dL) or demonstrate a 50% increase in hemoglobin from baseline; hemoglobin 
values within 4 weeks post-baseline or after 4 weeks of receiving packed cell/whole blood 
transfusion or after 6 weeks of receiving exogenous growth factors (e.g., Darbepoetin alfa) 
will be excluded for the hemoglobin response evaluation

Neutrophil response rate – defined as the proportion of subjects with baseline neutropenia 
(absolute neutrophil count [ANC] ≤1.5 x 109/L) who achieve an ANC >1.5 x 109/L or 
demonstrate a 50% increase in ANC from baseline; ANC values within 4 weeks of 
post-baseline or after 2 weeks of receiving exogenous growth factors 
(e.g., Filgrastim, G-CSF, Lenograstim) or after 4 weeks of receiving Neulasta were excluded 
for response evaluation
3.1.2.
Patient Well-Being

Overall survival (OS) – defined as the interval from start of study therapy to death from any 
cause

Change from baseline in HRQL domain and symptom scores based on the 
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) (see Appendix 2)

Changes from baseline in Karnofsky performance status – defined as the change from 
baseline in the performance status (see Appendix 3)


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3.1.3.
Pharmacodynamic Markers of Drug Activity and Resistance

Changes from baseline in PI3K/AKT/mTOR pathway activation as a measure of PI3K
pathway activity

Changes from baseline in the plasma concentrations of disease-associated chemokines and 
cytokines
3.1.4.
Exposure

Study drug administration as assessed by prescribing records and compliance as assessed by 
quantification of used and unused drug

Trough (pre-dose) and peak (1.5-hour samples) of idelalisib plasma concentrations as 
assessed by a validated bioanalytical method
3.1.5.
Safety

Overall safety profile of each study treatment regimen characterized by the type, frequency, 
severity, timing of onset, duration, and relationship to study therapy of any adverse events or 
abnormalities of laboratory tests; serious adverse events; or adverse events leading to 
discontinuation of study drug
3.1.6.
Pharmacoeconomics

Change in health status – defined as the change from baseline in overall health and 
single-item dimension scores as assessed using the EuroQoL Five-Dimension (EQ-5D) utility 
measure (Appendix 4)

Health resource measures, including resource utilization, total costs, and measures of 
cost per unit of benefit (eg, cost per additional progression-free month, 
cost per quality-adjusted life-year)
3.2.
Endpoint Selection Rationale
The proposed endpoints have been chosen based on relevance to the pathophysiology and 
clinical manifestations of CLL, the known pharmacology of idelalisib, and the goals of the study 
in documenting idelalisib benefit-to-risk ratio. These types of endpoints have been employed in 
prior studies in CLL and can be evaluated with acceptable reliability and accuracy.
3.2.1.
Tumor Control Endpoints
Assessments of the magnitude and duration of changes in tumor size are routinely employed in 
registration-directed oncology clinical studies to determine therapeutic effect. Unlike OS, these 
endpoints directly assess the ability of the drug to control the malignancy. Such assessments are 
also integral to treatment decisions; because subjects are being treated until disease progression, 


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repeated tumor assessment must be performed in order to define the proper duration of treatment 
for each study participant. Standard response and progression criteria have been established by 
the International Workshop on CLL (IWCLL) {Hallek et al 2008}; the assessments of treatment 
effects in this study will be based on these criteria, taking into account the specific pharmacology 
of idelalisib.
In CLL, disease-related nodal enlargement is a major cause of patient discomfort and can cause 
organ dysfunction {Dighiero et al 2008}. Extensive lymphadenopathy constitutes a reason to 
treat CLL and controlling the size of pathologically enlarged lymph nodes is an important 
therapeutic goal for improving patient well-being and relieving obstructive symptoms {Hallek et 
al 2008}. Given that the natural history of recurrent CLL is inexorable nodal growth, enhancing 
tumor shrinkage and prolonging tumor control provides strong evidence of pharmacological 
activity.
Endpoints of overall tumor control as evaluated in this trial are customarily assessed and reported 
in studies of new therapies in patients with cancer. PFS offers a well established outcome 
measure that directly measures treatment effect, conveys important longitudinal information 
regarding tumor control, can be characterized in all subjects using intention-to-treat (ITT) 
principles, and is readily analyzed using statistical methods such as Kaplan-Meier techniques. 
ORR provides an integrated assessment of the magnitude and extent of changes in 
lymphadenopathy, organomegaly, bone marrow infiltration, and bone marrow function that 
conveniently categorizes and describes treatment effects. TTR and DOR are important in 
characterizing the rapidity of achieving tumor shrinkage and the duration of tumor control. 
Beyond providing descriptions on overall response assessment using ORR, this protocol will also 
seek to characterize the individual components of response that are important in assessment of 
CLL {Hallek et al 2008}. Thus, changes in lymph node area and in the proportion of subjects 
having a lymph node response will be analyzed. In addition, among subjects who enter the study 
with splenomegaly or hepatomegaly, the proportion of subjects who achieve substantial (50%) 
reductions in spleen or liver size will be assessed. Similarly, the proportions of subjects who 
experience improvements in ALC, platelets, hemoglobin, and neutrophil counts will be 
characterized in order to provide specific insight into the degree to which therapy alters these 
individual parameters.
Because idelalisib mobilizes CLL cells from tissues into the peripheral blood as part of its 
pharmacological effect, there is a risk of falsely declaring a subject to have experienced disease 
progression if lymphocyte count is considered as the sole basis for potential CLL worsening. To 
account for this potential problem, changes in lymphocyte count will not be considered in 
determining whether a subject has progressive disease, ie, subjects will only be declared to have 
progressive CLL if they meet any of the IWCLL criteria for progressive disease other than 
lymphocytosis alone. Thus, subjects with worsening lymphadenopathy, organomegaly, bone 
marrow involvement, progressive cytopenias, appearance of new disease, or transformation to an 
aggressive lymphoid malignancy histology (eg, Richter syndrome) will be considered to have 
progressed. Subjects with lymphocytosis without any of these other events will not be considered 
to have progressed. Given that lymphocytosis has no prognostic significance in patients with 
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generally considered a reason to treat in patients with CLL {Hallek et al 2008}, {Eichhorst et al 
2010}, {Zelenetz et al 2011}, this approach does not jeopardize subject safety or subsequent 
therapy. Furthermore, it will allow complete collection of all response and progression data (both 
considering lymphocytosis and ignoring lymphocytosis) with the intent of providing complete 
information for regulatory authority review.
The current IWCLL guidelines indicate that physical examination is generally sufficient to 
evaluate nodal response and progression in patients with CLL {Hallek et al 2008} but that 
radiographic assessments may be appropriate in clinical trials. Computed tomography (CT) is 
considered the preferred imaging method unless patients have contraindications that require use 
of magnetic resonance imaging (MRI). Given the low fluorodeoxyglucose (FDG) avidity of 
CLL, positron- emission tomography (PET) does not have a role in evaluation of this disease. 
The incremental benefits of using radiographic imaging are limited in patients undergoing 
long-term follow-up following first-line therapy {Blum et al 2007}, {Eichhorst et al 2011}. 
However, in the patients with advanced CLL and bulky adenopathy such as those who will be 
enrolled to this trial, it is known that CT scans commonly detect bulky intra-abdominal 
lymphadenopathy and splenomegaly that would be missed by palpation alone and that the 
presence of large-volume, intra-abdominal disease of the nodes and spleen is associated with a 
poor prognosis {Norin et al 2010}. Thus, while use of CT confers greater radiation exposure, 
subjects have the chance to benefit from radiographic imaging because it will offer more 
accurate information regarding their response to protocol therapy and the appropriate duration of 
protocol treatment. Having this information is particularly important in this trial because PI3K
inhibition precludes use of lymphocyte counts as evidence for disease progression. In addition, 
the risk is offset by the fact that the trial subjects will primarily be patients who have already 
received more potent mutagens (eg, purine analogs, alkylating agents), and all of whom have 
advanced cancer and limited treatment options at study entry. Based on published data {Keating 
et al 2002a} {Wierda et al 2010}, median OS for patients with comparably advanced CLL is 
<18 months, so the long-term secondary malignancy risk from CT-related radiation exposure is 
very low. Finally, in the context of a registration-directed pivotal trial of a new drug with a new 
mechanism of action, radiographic imaging is critically important to provide reassurance 
regarding subject safety and trial validity. In this regard, CT evaluations of the lung can be used 
retrospectively to assess for radiographic evidence of drug-induced lung changes {White et al 
2010}, {Maroto et al 2011}. Furthermore, CT measurements have greater accuracy and 
reproducibility than palpation, are subject to independent expert review, and can be audited 
against electronic case report form (eCRF) information.
The timing of radiographic tumor assessments has been carefully considered. To avoid 
duplication, the CT scan documenting CLL progression in Study GS-US-312-0116 will serve as 
the baseline CT scan for Study GS-US-312-0117. Among patients receiving idelalisib in 
Phase 1b/2 studies who experienced a nodal response (50% regression in tumor area), such 
responses were observed with the first 16 week of therapy {Coutre et al 2011}, {Leonard et al 
2011}; the planned timing of tumor assessments (at Weeks 8, 16, 24, 36, 48 and then every 
12 weeks thereafter) in this study fits with this known timing of changes in lymph node size 
during idelalisib therapy. Scans at 8-week intervals during the first 24 weeks allow efficient 
documentation of response. During this period, early documentation of disease progression 


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allows subjects who are not benefiting from study therapy to move rapidly to alternative 
treatments. After 24 weeks on study or after 24 weeks cumulative treatment with idelalisib 
across Study GS-US-312-0116 and Study GS-US-312-0117, the reduction in the frequency of 
CT scans (to 12-week intervals) reduces the overall protocol burden for subjects while still 
allowing characterization of the expected median PFS in this trial. As outlined in Section 7.3, 
iodine-containing or gadolinium contrast material may be omitted in subjects for whom use of a 
contrast agent would be medically contraindicated.
3.2.2.
Measures of Patient Well-Being
3.2.2.1.
Overall Survival
While OS provides an ultimate measure of patient well-being, it has not routinely been used as 
the primary endpoint in CLL clinical trials. Unlike PFS, it does not specifically measure 
drug-mediated tumor control, and thus provides only an indirect assessment of treatment effect. 
Depending upon the treatment setting, long OS times in patients with CLL can preclude use of 
this endpoint as an efficient method for understanding drug benefits. In both the front-line and 
recurrent disease settings, post-study treatments can influence OS in unpredictable ways, 
potentially confounding differences between treatment groups.
However, given the life-threatening nature of systemic malignancy, documentation of OS is 
customary in oncology therapeutic clinical trials, including those evaluating subjects with 
recurrent CLL {Keating et al 2002a}, {Wierda et al 2010}. Evaluation of OS in this study 
continues the survival assessment from the primary study (Study GS-US-312-0116). The study 
program as a whole (considering both the primary randomized trial and secondary extension 
study) offers the potential to better understand OS and causes of death in a frail population of 
patients with both CLL, considering the consequences of the disease and comorbidities.
3.2.2.2.
Health-Related Quality of Life
Direct patient reporting of outcomes using standardized methods has become an increasingly 
important component of therapeutic assessment. Evaluation of patient-reported outcomes (PROs) 
is particularly relevant in patients who cannot be cured of disease {Reeve et al 2007}. PRO 
questionnaires have been previously used in CLL to understand how patients differ from the 
general population in terms of health concerns {Holzner et al 2004}, {Eichhorst et al 2007}, 
{Shanafelt et al 2007}, {Else et al 2008}, to understand differences in perceptions of well-being 
in younger vs older patients {Levin et al 2007}, {Else et al 2008}, to determine how treatment 
affects HRQL {Catovsky et al 2007}, {Eichhorst et al 2007}, {Efficace et al 2008}, and to assess 
the pharmacoeconomic cost of improvements in HRQL {Stephens et al 2005}.
Patients with CLL have overtly impaired well-being relative to comparable controls {Holzner et 
al 2004}, {Eichhorst et al 2007}, {Shanafelt et al 2007}, {Else et al 2008}. Fatigue is cited as a 
common complaint, being present in the substantial majority of patients. Impairment of HRQL 
prior to any treatment is apparent in those with B symptoms or in patients with anemia, 
supporting the concept of initiating treatment when patients experience symptomatic disease. 
Factors associated with lower overall HRQL have included older age, greater fatigue, severity of 
co-morbid health conditions, advanced stage, and ongoing treatment for CLL {Shanafelt et al 


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2007}. Younger patients appear to have worse emotional and social well-being but older patients 
experience worse physical HRQL {Levin et al 2007}. In comparative evaluation of 
chemotherapy-containing regimens, differences in HRQL between therapies (eg, fludarabine vs 
fludarabine-cyclophosphamide vs chlorambucil) reflected differences in toxicity while improved 
HRQL was associated with greater efficacy {Catovsky et al 2007}, {Eichhorst et al 2007}.
In this study, it is postulated that idelalisib-mediated tumor control will be correlated with greater 
positive changes in HRQL and that assessments of the drug’s safety profile will be supported by 
HRQL evaluations. The FACT-Leu (Appendix 2) has been selected to evaluate such outcomes 
for the study. The FACT-Leu comprises a general HRQL measure for patients receiving cancer 
treatment that yields a total score and subscales for physical, functional, social/family and 
emotional well-being {Cella et al 1993} and a diagnosis-specific measure for patients with 
leukemia {Webster et al 2002}. The FACT-Leu was developed to assess symptoms (eg, fevers, 
chills, night sweats, nodal swelling, fatigue) specifically relevant to patients with leukemia. 
FACT instruments have documented psychometric properties {Cella et al 1993}, {Webster et al 
2002}, {Brucker et al 2005}, {Cella et al 2005}, {Victorson et al 2008}.
The FACT-Leu instrument is available in appropriate languages for this study. FACT-Leu data 
will be obtained at baseline and during each investigational clinic visit during treatment. Having
FACT-Leu data concurrent with tumor response information will allow an evaluation of the 
potential relationship between tumor response and symptomatic changes as reported by patients. 
To avoid biasing HRQL results, the FACT-Leu will be administered at each visit before other 
procedures are performed and before any study information is conveyed to the subject.
3.2.2.3.
Changes in Performance Status
Performance status evaluation provides an integrated assessment of patient well-being before, 
during, and after treatment and, ideally, may indicate how drug efficacy and toxicity affect 
patient functioning. In patients with CLL performance status can be predictive of PFS or OS 
{Sorensen et al 1997}, {Hallek et al 1996}, {Youngson et al 1995}.
In this study, it is hypothesized that idelalisib-mediated tumor control will be correlated with 
changes in performance status and that assessments of the drug’s safety profile might be 
supported by performance status evaluations. The well-established, reliable, and validated 
Karnofsky performance score {Karnofsky et al 1949}, {Yates et al 1980}, {Schag et al 1984}
(see Appendix 3) will be employed in the trial for characterization of the subject population and 
repeated assessment of performance status.
3.2.3.
Pharmacodynamic Markers of Drug Activity and Resistance
In CLL, disease-related perturbations in inflammatory status can be clinically overt; patients 
often develop bothersome B symptoms (fevers, night sweats, and weight loss) that are 
characteristic of excessive systemic inflammation {Redaelli et al 2004}. Consistent with such 
disease manifestations, the PI3K/AKT/mTOR pathway is constitutively overactive in 
circulating CLL cells {Coutre et al 2011}. In addition, chemokines and cytokines that are 
markers of aberrant B-cell trafficking or perturbations in inflammation are overexpressed by 


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CLL tissues or by stromal cells and circulate in plasma {Burger 2010}, {Coutre et al 2011}. In 
Phase 1 studies of idelalisib it has been confirmed that idelalisib largely normalizes AKT
phosphorylation and induces dose-dependent reductions in plasma concentrations of circulating 
chemokines and cytokines in patients with CLL {Coutre et al 2011}.
In this study, it is hypothesized that incremental changes in these biomarkers provide direct 
evidence of mechanism-specific idelalisib effects on PI3Kδ activity or indirectly document drug 
effects on overall tumor cell volume. In either case, improvements in these pharmacodynamic 
measures provide corroborative evidence in support of idelalisib pharmacological activity; 
conversely, worsening of these biomarkers may indicate acquisition of resistance to idelalisib. In 
addition, it is possible that disease-or inflammation-related biomarkers may provide corollary 
information relating to the adverse effects of idelalisib on the liver; such data might allow better 
prediction of which subjects might be most susceptible to ALT/AST elevations during idelalisib
treatment. Finally, it can also be postulated that genetic, protein, or metabolic changes in CLL 
cells could provide signatures that would correlate with drug sensitivity and resistance.
Based on these considerations, this study will evaluate PI3K/AKT/mTOR pathway activation 
status in CLL cells. For this purpose, blood will be evaluated by flow cytometry using a 
clinically validated assay {Hoellenriegel et al 2011}. CLL cells will be identified using anti-CD5 
and anti-CD19 antibodies. AKT activation will be determined by quantifying phosphorylation at 
the Ser473 and Thr308 AKT sites using specific anti-pAKT Thr308 and anti-pAKT
Ser473 antibodies. Additional assessments of PI3K/AKT/mTOR pathway signaling 
(eg, evaluating phosphorylation state for other downstream enzymes) may also be explored.
Plasma will be collected for assessment of circulating concentrations of relevant chemokines and 
cytokines with a particular focus on CCL2, CCL3, CCL4, CXCL12, CXCL13, CCL17, CCL19, 
CCL21, CCL22, sCD40 ligand, tumor necrosis factor-α, and C-reactive protein. In addition 
serum markers of iron metabolism (eg, hepcidin, iron, ferritin, transferrin) that might provide 
markers linking disease-related inflammation with perturbations of liver iron and sensitivity to 
liver injury will be evaluated {Nemeth et al 2003}, {Ferrucci et al 2010}. Clinically validated 
assays (eg, enzyme-linked immunosorbent assays [ELISAs]) will be used to measure circulating 
concentrations of chemokines and cytokines at baseline and during the course of idelalisib
therapy.
CLL cell deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein will be collected at 
baseline and at the conclusion of a subject’s treatment on study. DNA and RNA samples will be 
analyzed using gene array technologies to evaluate for changes in DNA mutations or in 
RNA expression patterns that might be associated with intrinsic or acquired resistance to study 
treatments. Similarly, protein will be evaluated for state-specific changes in protein 
phosphorylation to evaluate for differences in pathway activation at baseline or during therapy 
that might be associated with differences in response or in acquisition of resistance to therapy.


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3.2.4.
Assessments of Exposure
3.2.4.1.
Study Drug Administration and Compliance
Evaluation of study drug administration and compliance provides context for assessments of 
safety, pharmacokinetics, and pharmacological activity. Evaluations of treatment administration 
and modifications from planned therapy document the influence of treatment-emergent adverse 
events on prescribing practice. Compliance assessment offers a general indication of patients’ 
acceptance of therapy, integrating factors of tolerability, palatability, and convenience.
In this study, information regarding planned treatment and modification from planned treatment 
(eg, dose reductions and interruptions) will be kept. The compliance of the subject will be 
verified by accounting for used and unused drug.
3.2.4.2.
Pharmacokinetics
Given the intent of this protocol to assess longer-term dosing, collection of plasma for idelalisib
concentrations is important for evaluating exposure over time. These data may allow correlations 
of exposure with measures of efficacy, toxicity, and resistance. Because the idelalisib
pharmacokinetic profile has been well characterized in Phase 1 studies, limited plasma sampling 
will be performed in this study. Samples will be collected pre-dose and 1.5 hours post-dose 
relative to the morning administration of idelalisib. Based on discussions with investigators, 
collecting more than 2 samples in the morning is not considered reasonable given the need to 
minimize time requirements for study participants and to avoid substantial inconvenience for 
clinic staff.
Evaluation of idelalisib plasma concentrations will be performed using liquid chromatography 
with tandem mass spectrometry. The method has been fully validated in the context of prior 
Phase 1 studies. Plasma samples will be retained for potential later analyses of idelalisib
metabolites.
3.2.5.
Evaluations of Safety
In defining the therapeutic relevance of a drug in a particular clinical setting, it is imperative that 
its safety profile be fully characterized. As is conventional in all clinical studies, proper 
description of each adverse event or laboratory abnormality requires an understanding of the 
type, incidence, timing, severity, and relatedness to study drug. While information on all reported 
adverse events will be collected, listed, and summarized, particular focus will be placed on 
monitoring and reporting adverse events and laboratory abnormalities that were encountered in 
the prior toxicology studies and clinical experience with idelalisib. Safety parameters of specific 
interest in reporting study results will include those relating to bone marrow function, 
dermatological events, gastrointestinal inflammation, infection, pulmonary events 
(eg, pneumonia/pneumonitis), and liver injury. Additional scrutiny will be applied to 
Grade 3-4 adverse events, to adverse events causing interruption or discontinuation of idelalisib, 
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In addition, the protocol will evaluate for potential adverse idelalisib effects on laboratory 
parameters of immune function; the absolute number of CD4+, CD5+,CD8+, CD16/CD56+, 
CD19+, and CD20+ cells will be assessed by flow cytometry. Serum concentrations of IgA, IgE, 
IgG, and IgM will be obtained.
For consistency of interpretation, adverse events will be coded using the standard 
Medical Dictionary for Regulatory Activities (MedDRA) [http://www.meddramsso.com]), and 
the severity adverse events and laboratory abnormalities will be graded using the well-defined 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). 
Standard definitions for seriousness will be applied (see Section 8.1.2).
3.2.6.
Pharmacoeconomic Measures
It is increasingly important to understand the potential cost implications of introducing a new 
medication into patient care for CLL {Main et al 2010}, {Hornberger et al 2012}. In order to 
analyze the pharmacoeconomic consequences of idelalisib administration, data will be collected 
regarding the health status of subjects and regarding health care resource utilization.
Heath status information will be obtained with the EQ-5D, which is a self-administered, generic, 
indirect utility measure {The EuroQol Group 1990} (Appendix 4). The EQ-5D consists of a 
visual analogue scale on which subjects are asked to rate their current overall health status and 
5 single-item dimensions which ask subjects to rate their health in terms of mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression. For each of the 5 items, patients must 
choose between 3 levels of difficulty in accomplishing tasks in that dimension. The visual analog 
scale is then used in combination with the dimension scores to generate a health utility score that 
can be incorporated into analyses of cost effectiveness. The EQ-5D has been successfully used in 
the evaluation of patients with B-cell and other cancers {Doorduijn et al 2005}, {Witzens-Harig 
et al 2009}, {Yang et al 2010}.
The EQ-5D instrument is available in appropriate languages for this study. EQ-5D data will be 
obtained at baseline and during each investigational clinic visit during treatment. The EQ-5D 
will be administered immediately after administration of the FACT-Leu instrument, before other 
procedures are performed and before any study information is conveyed to the subject. The 
EQ-5D instrument takes only 5 minutes to complete.
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach will be to combine the resource utilization data from the trial with data on 
unit prices (collected separately) to estimate total costs. The costs will be described relative to 
the health care findings as measured by duration of tumor control, the symptom-free survival 
period, and/or utility outcomes or some other appropriate measure of clinical benefits.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects
The planned sample size is ~160 subjects but will be bounded by the number of subjects enrolled 
to the primary clinical trial (Study GS-US-312-0116).
4.2.
Subject Selection Criteria
Subjects in the primary Phase 3 study (GS-US-312-0116) who are compliant, are tolerating 
primary study therapy, and 1) have definitive progression of CLL while receiving primary study 
drug therapy (idelalisib /placebo) or 2) are actively participating in Study GS-US-312-0116 at 
the time the study is stopped, including if stopped early due to overwhelming efficacy following 
an interim analysis are eligible to enroll in the extension study. Eligibility criteria may not be 
waived by the investigator and conformance to the eligibility criteria is subject to review in the 
case of a Good Clinical Practice (GCP) or a regulatory authority audit. Any questions regarding a 
subject’s eligibility should be discussed with the study sponsor medical monitor prior to 
enrollment.
4.2.1.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while receiving study drug therapy 
(idelalisib/placebo) in Study GS-US-312-0116. Note: Definitive disease progression is CLL 
progression based on standard criteria and occurring for any reason 
(ie, increasing lymphadenopathy, organomegaly, or bone marrow involvement; 
decreasing platelet count, hemoglobin, or neutrophil count; or worsening of 
disease-related symptoms) other than lymphocytosis. Subjects must have confirmation by 
the sponsor working in collaboration with an independent review committee (IRC) that the 
disease has progressed on the clinical trial (Study GS-US-312-0116) before receiving
secondary idelalisib therapy on this extension trial (Study GS-US-312-0117).
3) Presence of radiographically measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures 2.0 cm in the longest diameter [LD] and 1.0 cm in the 
longest perpendicular diameter [LPD] as assessed by CT or MRI).
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab and idelalisib/placebo) 
and no intervening or continuing therapy (including radiotherapy, chemotherapy, 
immunotherapy, or investigational therapy) for the treatment of CLL. Note: Subjects may 
receive corticosteroids to manage CLL manifestations.


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5) The time from permanent cessation of Study GS-US-312-0116 treatment (rituximab and/or
idelalisib/placebo) and the initiation of Study GS-US-312-0117 therapy is 12 weeks. 
Note: Study procedures performed as part of Study GS-US-312-0116 need not be repeated 
and can be used as screening procedures for Study GS-US-312-0117 if performed within 
4 weeks prior to initiation of study drug therapy on Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation of study treatment) as 
shown in the table below. Note: Confirmation should be considered for out-of-range values 
to determine if the abnormality is real or artifactual. Values should be obtained within the 
screening period and should generally be the most recent measurement obtained. Subjects 
with any degree of neutropenia, thrombocytopenia, or anemia due to CLL or prior therapy 
may enroll.
Table 4-1.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCra
>30 ml/min
Pregnancy
-HCGb
Negative
a
As calculated by the Cockcroft-Gault formula (see Appendix 5) {Cockcroft et al 1976}
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or 
urine dipstick pregnancy test must be negative at start of study treatment (Visit 2)
Abbreviations: -HCG= beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
eCCr=estimated creatinine clearance, ULN=upper limit of normal
8) For female subjects of childbearing potential, willingness to use a protocol-recommended 
method of contraception (as outlined in Section 5.6.4) from the screening visit (Visit 1) 
throughout the study and for 30 days following the last dose of study drug.
Note: A female subject is considered to be of childbearing potential unless she has had a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically 
documented ovarian failure (with serum estradiol and follicle-stimulating hormone [FSH] 
levels within the institutional postmenopausal range and a negative serum or 
urine HCG), or is menopausal (age ≥54 with amenorrhea for >12 months or 
amenorrhea for >6 months with serum estradiol and FSH levels within the institutional 
postmenopausal range).
9) For male subjects of childbearing potential having intercourse with females of childbearing 
potential, willingness to use a protocol-recommended method of contraception 
(as outlined in Section 5.6.4) from the start of study drug (Visit 2) throughout the study and 
for 90 days following the last dose of study drug and to refrain from sperm donation from the 
start of study drug (Visit 2) throughout the study and for 90 days following the last dose of 
study drug. Note: A male subject is considered able to father a child unless he has had a 


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bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or has ongoing 
testicular suppression with a depot luteinizing hormone- releasing hormone (LH-RH) 
agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate  [Lupron®]), or 
triptorelin pamoate [Trelstar®]).
10) In the judgment of the investigator, participation in the protocol offers an acceptable 
benefit-to-risk ratio when considering current CLL disease status, medical condition, and the 
potential benefits and risks of alternative treatments for CLL. 
11) Willingness and ability to comply with scheduled visits, drug administration plan, imaging 
studies, laboratory tests, other study procedures, and study restrictions. 
Note: Psychological, social, familial, or geographical factors that might preclude adequate 
study participation should be considered.
12) Evidence of a personally signed informed consent indicating that the subject is aware of the 
neoplastic nature of the disease and has been informed of the procedures to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study participation.
4.2.2.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
1) Known histological transformation from CLL to an aggressive lymphoma 
(ie, Richter transformation). Note: Biopsy documentation of the absence or presence of 
transformation is not required.
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of the start of 
study treatment (Visit 2). Note: Subjects with localized fungal infections of skin or nails are 
eligible. Subjects may be receiving prophylactic antiviral or antibacterial therapies at the 
discretion of the investigator; anti-pneumocystis prophylaxis is encouraged. For subjects 
who are at substantial risk of an infection (eg, influenza) that may be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of 
protocol therapy.
3) Pregnancy or breastfeeding. 
4) Intentional breaking of the blind in Study GS-US-312-0116 by the investigator or the study 
subject.
5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical condition, surgical history, physical 
finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the 
investigator’s opinion, could adversely affect the safety of the subject or impair the 
assessment of study results.


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4.3.
Enrollment Criteria Rationale
The eligibility criteria are designed to limit enrollment to subjects who participated in the 
primary clinical trial (Study GS-US-312-0116), are compliant, have been generally able to 
tolerate study therapy and study procedures, and have experienced definitive CLL progression 
while receiving study treatment (rituximab and/or idelalisib/placebo) in the primary study or who 
are actively participating in Study GS-US-312-0116 at the time the study is stopped, including if 
stopped early due to overwhelming efficacy.
The requirement of measurable lymphadenopathy to enter the blinded portion of the study 
ensures that subjects have disease that can adequately be assessed for evidence of drug activity. 
Prior therapy provisions are intended to ensure that subjects are transitioning directly from 
Study GS-US-312-0116 to Study GS-US-312-0117 without receiving intervening treatments. 
The stipulation of 12-week interval from Study GS-US-312-0116 treatment until 
Study GS-US-312-0117 treatment precludes excessively protracted intervals between 
participation in the 2 studies but also permits sufficient time for clinicians and subjects to 
determine whether participation is appropriate. 
In the blinded portion of the study, to ensure that subjects are not so acutely ill from 
life-threatening comorbidities that they require hospitalization and stabilization, subjects with 
Karnofsky performance scores <40 (ie, those who are bed-bound or hospitalized) will not be 
enrolled. Baseline laboratory evaluations are designed to limit participation to subjects who have 
not developed serious organ compromise that would pose a safety risk or confound the 
interpretation of adverse effects. Pregnancy testing and restrictions on eligibility relating to 
reproduction, pregnancy, and nursing are important because idelalisib is a new chemical entity 
with teratogenic effects in rats and it is unknown if it may have adverse effects on conception, on 
fetal development, or on the health of a breast-feeding child. To minimize missing data and 
premature discontinuations, subjects should have sufficient psychological and social resources to 
comply with study procedures and restrictions. Consistent with GCP guidelines, subjects must 
provide informed consent before initiation of any study procedures.


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5.
TREATMENT OF SUBJECTS
5.1.
Enrollment
5.1.1.
Interactive Web Response System
An IWRS will be employed to manage the conduct of the trial. The IWRS will be used to 
maintain a central log documenting enrollment, to manage dose modifications, to assess current 
inventories of study drug, to initiate any necessary resupply of study drug, and to document 
discontinuation of study.
5.1.2.
Treatment Assignment
After a subject has completed the necessary documentation of definitive CLL progression in the
primary clinical trial (GS-US-312-0116) and has been confirmed to be eligible, the subject can 
be entered into this trial (Study GS-US-312-0117). In order to obtain a treatment arm allocation 
for a subject, a site representative will access the IWRS and supply the system with the required 
information.
Subjects will be assigned to either of the following treatment assignments with allocation based 
on the original primary study randomization:
Treatment Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117)
Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly enrolled subjects will 
receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly enrolled subjects will 
receive 150 mg BID
Note: At the Investigator’s discretion, subjects who were randomized to placebo on 
Study GS-US-312-0116 may delay initiation of idelalisib following enrollment on 
Study GS-US-312-0117 until the time of disease progression or until the investigator 
determines that the subject would benefit from initiation of idelalisib treatment.


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Treatment Assignment

Assignment to Arm A or Arm B with allocation based on the original primary study 
randomization

Implementation through an interactive web response system (IWRS)
The IWRS will assign blister card, or bottle numbers and instructions for dispensing of blinded 
study drug (high-dose or standard-dose idelalisib). It is anticipated that subjects will usually 
begin study drug immediately at Visit 2 of the study.
5.1.3.
Blinding
During the blinded portion of the study, the identity of the treatments will be concealed by 
central blinding of study drug assignments. Blinding will be accomplished through use of a 
placebo that is well-matched to the active drug in appearance, packaging, labeling, and schedule 
of administration (see Section 5.2.1). During the study, subjects, caregivers, investigational site 
personnel, Gilead Sciences study team members, and all other study personnel will remain 
blinded to the identity of the treatment assignments; these assignments will be available only to 
the IWRS, the data monitoring committee (DMC) for the study, an independent bioanalytical 
group that supports the DMC, and drug safety personnel who are not part of the study team.
Unblinding an individual subject’s treatment assignment during the study will only occur in the 
case of subject emergencies (see Section 5.5) or in the event the study is discontinued by the
Sponsor, a Regulatory Agency, or an IRB or EC (see Section 5.9). Where required by local 
regulation, expedited reporting of serious adverse events to specific regulatory authorities will 
include information regarding the study drug treatment assignment 
(high-dose or standard-dose idelalisib); this will be done in such a way that subjects, 
investigational site personnel, institutional review board/independent ethics committees 
(IRB/IEC), and study team members remain blinded as to the treatment assignment for the 
subject described in the adverse event report.
The unblinded analysis of the study will be performed when the database is completed and 
locked following unblinding of Study GS-US-312-0116 and Study GS-US-312-0117. The final 
analysis of the open label portion of the study will occur once the open label portion is stopped.
While bioanalytical assays to determine idelalisib concentrations may be performed prior to 
unblinding, pharmacokinetic data that would allow identification of treatment assignments for 
individual subjects will not be available to the study team until after the blind is broken and the 
primary analysis has occurred. Except for emergency unblinding, individual subjects, caregivers, 
and site personnel will not be informed of the treatment assignments until the implications of 
revealing such data for the overall idelalisib study program have been determined by the clinical 
project leader for the idelalisib development program.


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5.2.
Investigational Study Drug (Idelalisib/Placebo)
5.2.1.
Description
Subjects allocated to Arm A in the blinded portion of the study will be provided with 2 tablets of 
active idelalisib for oral administration at each dose. Each tablet contains 150 mg or 100 mg of 
active idelalisib. The 150-mg tablets will be used for initial therapy; the 100-mg tablets are 
provided for use by those subjects who require a dose reduction (see Table 5-1).
Subjects allocated to Arm B in the blinded portion of the study will be provided with 1 tablet of 
active idelalisib and 1 tablet of placebo for oral administration at each dose. Each active tablet 
contains 150 mg or 100 mg of active idelalisib. The 150-mg tablets (and matching placebo) will 
be used for initial therapy; the 100-mg tablets (and matching placebo) are provided for use by 
those subjects who require a dose reduction.
In the open-label portion of the study, subjects will be provided with 150 mg tablets of idelalisib.
The 150-mg tablets are pink, film-coated, and include the following inactive excipients: 
microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, 
sodium starch glycolate, magnesium stearate, red iron oxide, polyethylene glycol, talc, 
polyvinyl alcohol (PVA), and titanium dioxide. The 100-mg tablets are orange, film-coated, and 
include the following inactive excipients: microcrystalline cellulose, hydroxypropyl cellulose, 
croscarmellose sodium, sodium starch glycolate, magnesium stearate, yellow iron oxide, 
polyethylene glycol, talc, PVA, and titanium dioxide.
The placebo tablets match the active idelalisib formulations in appearance. The placebo tablets 
matching the 150-mg tablets are pink, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium stearate, 
red iron oxide, polyethylene glycol, talc, PVA, and titanium dioxide. The placebo tablets 
matching the 100-mg tablets are orange, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium stearate, 
yellow iron oxide, polyethylene glycol, talc, PVA and titanium dioxide.
5.2.2.
Source
Both active idelalisib and placebo will be supplied free of charge by Gilead Sciences.
5.2.3.
Packaging and Labeling
During the blinded portion of the study, study drug (idelalisib or idelalisib/placebo) will be 
provided in blister cards. The blister cards are made of polyvinyl chloride/
polychlorotrifluoroethylene (PVC/PCTFE) film and have aluminum foil lidding materials. Each 
blister card contains 120 tablets (4-week supply plus a modest overage) of one of the relevant 
dose strengths. The 100-mg or 150-mg and matching placebo tablets will be combined in order 
to obtain the daily doses to be used in this study. Thus, in Arm A, the 300-mg idelalisib dose will 
be obtained by administering two 150-mg tablets and the 200-mg idelalisib dose will be obtained 


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by administering two 100-mg tablets. In Arm B, the 150-mg idelalisib dose will be obtained by 
administering one 150-mg tablet and one placebo tablet and the 100-mg idelalisib dose will be 
obtained by administering one 100-mg tablet and one placebo tablet.
Each blister card will have a unique number. Labeling for blister cards dispensed to subjects in 
Arm A will appear identical to blister cards dispensed to subjects in Arm B, and may include 
either idelalisib or placebo.
When the primary study (GS-US-312-0116) is stopped including if early after an 
interim analysis, GS-US-312-0116 active study subjects will become eligible for participation on 
Study GS-US-312-0117. Active GS-US-312-0117 study subjects will be transitioned to 
open-label idelalisib at this time. Each bottle contains 60 tablets 
(4 week supply plus a modest overage) of one of the relevant dose strengths (150 mg, 100 mg) 
and a polyester coil. Bottles are white and are made of high-density polyethylene. Each bottle is 
closed with a white, continuous-thread, child-resistant, polypropylene screw cap fitted with an 
induction-sealed, aluminum-faced liner.
All labels for study drugs to be distributed to centers in the United States, the EU, and other 
countries will meet all applicable requirements of the United States Food and Drug 
Administration (FDA), the EU Annex 13 of Current Good Manufacturing Practice (cGMP) 
(Manufacture of Investigational Medicinal Products, July 2010), and/or other local regulations as 
applicable.
5.2.4.
Storage and Handling
Blister cards or bottles containing tablets of study drug (idelalisib or idelalisib/placebo) should
be stored at controlled room temperature (ie, ~25 °C, with a range of 15 to 30 °C). While the 
stability of study drug tablets stored at controlled room temperature has been confirmed, brief 
excursions to temperatures as low as -20 °C or as high as 40 °C (eg, during shipping) will not 
adversely affect the drug. Updated stability data will be provided to the sites, as appropriate.
5.2.5.
Dispensing
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing 
study drug according to the IWRS directions. It is planned that drug will be dispensed at 4-week 
intervals through the first 24 weeks of treatment and at 12-week intervals thereafter, or on a 
frequency consistent with the subject’s visit schedule. Sufficient study drug will be provided for 
each study period at the beginning of the period. Multiple blister cards or bottles may be 
dispensed at a single visit. Tablets should be kept in the original blister cards or bottles provided
until they are self-administered by the subject.
At the time of starting study treatment, the IWRS will provide the clinic staff with the blister 
card numbers designating the blister cards to be dispensed, or the quantity of open-label bottles 
to be dispensed. The clinic staff (eg, pharmacist or other qualified person) will write the subject 
number on each blister card or bottle that is dispensed. Immediately before dispensing, the clinic 
staff will write the blister card or bottle number in the study drug administration record 
corresponding to the subject number.


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5.2.6.
Return
The study drug should be retrieved from each subject at the end of each dispensing interval. The 
quantity of study drug and the date returned by the subject should be recorded in the study drug 
accountability records. When possible, all study drug returned by the subject should be retained 
for review by the study site monitor prior to return to Gilead Sciences or destruction.
5.2.7.
Accountability
The disposition of all study drug should be documented from the time of receipt at the site 
through subject dispensing and return.
Study personnel must ensure that all study drug is kept in a secure locked area with access 
limited to authorized personnel. The study drug must not be used outside the context of this 
protocol. Under no circumstances should the investigator or site personnel supply study drug to 
other investigators or clinics, or allow the study drug to be used other than as directed by this 
protocol.
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by Gilead Sciences or its designee, including, but not limited to, 
the date received, lot number, amount received, and the disposition of all study drug. Upon 
receipt of a drug shipment, the shipment must be logged into the IWRS. Study drug 
accountability records must also be maintained that include the subject number to whom the 
study drug was dispensed and the date, quantity and lot number of the study drug dispensed.
Depending upon the decision of Gilead Sciences, remaining unused study drug supply will be 
returned to Gilead Sciences or its designee after the study is completed or will be discarded or 
destroyed at the clinical site. If the study drug is discarded or destroyed at the clinical site, 
standard institutional policy should be followed. Records documenting the date of study drug 
shipping or destruction, relevant lot numbers, and amount shipped or destroyed should be 
maintained.
5.2.8.
Overdose Precautions
In Phase 1 studies, an MTD for idelalisib was not reached when the drug was administered 
continuously at dose levels through 350 mg/dose BID (700 mg per day) {Coutre et al 2011}, 
{Kahl et al 2011}. However, in this protocol, an overdose is defined as administration of more 
than the prescribed daily dose (ie, >600 mg in a single day). In a subject who experiences an 
overdose consideration should be given as to whether idelalisib administration should be 
temporarily interrupted. If the overdose ingestion is recent and substantial, and if there are no 
medical contraindications, use of gastric lavage or induction of emesis may be considered. 
Observation for any symptomatic side effects should be instituted, and biochemical and 
hematological parameters should be followed closely (consistent with the protocol or more 
frequently, as needed). Appropriate supportive management to mitigate adverse effects should be 
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The Gilead Sciences medical monitor should be contacted if a study drug overdose occurs. Cases 
of study drug overdose will result in specific reporting requirements (see Section 8.8).
5.2.9.
Inadvertent Exposure and Spill Precautions
Based on available data from nonclinical studies, idelalisib does not appear to be acutely toxic, 
genotoxic, or irritative at levels that are likely to result from inadvertent exposure to the contents 
of broken tablets. However, personnel handling the drug should use reasonable precautions to 
avoid eye contact, skin contact, inhalation, or ingestion of the study drug product. For further 
information regarding inadvertent exposure and spill precautions, please consult the idelalisib
investigator brochure.
5.3.
Study Drug Administration
5.3.1.
Premedication
No specific premedications or supporting medications are required in conjunction with study 
drug administration.
5.3.2.
Administration Instructions
The prescribed dose of study drug (idelalisib/placebo) should be taken orally. At each dose 
administration, the tablet number corresponding to the appropriate dose of study drug is to be 
swallowed whole with 100 to 200 mL (~ 4 to 8 ounces) of water. In case of breakage of the 
tablets in the oral cavity, additional water should be taken as a rinse. 
Study drug may be taken with or without food. There are no known dietary restrictions related to 
study drug use.
5.3.3.
Dosing Schedule
Study drug should be taken on a BID schedule at approximately the same times each day. Ideally,
doses should be taken at ~12-hour intervals (eg, at ~7 AM and at ~7 PM). While it is realized 
that variations in dosing schedule may occur in the outpatient setting, the prescribed regimen 
should be followed as closely as possible, especially in the clinic.
At specified clinic visits, the study drug will be administered in the clinic with dosing 
appropriately timed relative to blood sampling for idelalisib pharmacokinetics. As detailed in 
Section 6.2, clinic staff should record idelalisib administration information, including the exact 
clock time of each dose, for doses of study drug administered in the clinic or hospital. Thereafter, 
subjects will be given an adequate supply of tablets to take at home.
5.3.4.
Dose Levels
Study drug dose levels for Arm A and Arm B are described in Table 5-1. The lower dose level
(Dose Level -1) is provided in case a subject requires a study drug dose modification.


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Table 5-1.
Study Drug Dose Levels
Treatment Arm
Starting Dose
Dose Level -1
Arm A
300 mg/dose BID
200 mg/dose BID
Arm B
150 mg/dose BID
100 mg/dose BID
Abbreviation: BID=twice per day
When the primary study (GS-US-312-0116) is stopped, and GS-US-312-0116 active study 
subjects become eligible for participation on Study GS-US-312-0117 subjects will be enrolled 
into Study GS-US-312-0117 at open label 150 mg BID. Subjects already participating in 
Study GS-US-312-0117 will remain on the same dose.
5.3.5.
Dose Schedule Interruptions and Vomited Doses
Subjects who have a delay in administration of a dose of the study drug of <6 hours should take 
the planned dose as soon as possible after the intended time of administration. For subjects who 
have a delay in administration of study drug of 6 hours, the dose should not be taken. Study 
drug administration may continue but the missed dose should not be made up and the planned 
timing of subsequent study drug dosing should not be altered.
Vomited doses may be retaken, but only if the tablet is visible in the vomitus.
5.3.6.
Safety Monitoring and Study Drug Interruption/Dose Modification
Subjects must be monitored closely for adverse events or laboratory abnormalities during the
course of the study. Reference should be made to the CTCAE, Version 4.03 for grading the 
severity of adverse events and laboratory abnormalities.
Recommendations for modifications of the dosing regimens based on the drug and the type and 
severity of adverse events or laboratory abnormalities are provided in Table 5-2 below. The dose 
modification instructions focus on the types of events most commonly attributed to each of the 
study agents. The recommendations provided in Table 5-2 comprise only guidelines; variations 
from these recommendations may be warranted based on an investigator’s individual judgment 
in considering potential risks, benefits, and therapeutic alternatives available to each subject.
Consistent with Table 5-2, if a subject experiences an adverse event that is suspected to be 
related to study drug and requires a dose modification during the course of study therapy, then 
study drug administration should be held, as necessary, until the adverse event resolves or 
stabilizes to an acceptable degree Thereafter, study drug may be reinstituted, but the dose should 
be modified per(Table 5-1 and Table 5-2). If the adverse event occurs again, reinitiation of 
therapy may be attempted if the investigator feels that a second rechallenge is medically 
appropriate. If the subject cannot tolerate idelalisib at Dose Level -1 after 2 rechallenges, then 
the subject should be discontinued from study drug therapy unless continued therapy is discussed 
with the Gilead Sciences medical monitor.


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After the study drug dose is reduced, the dose need not be re-escalated, even if there is minimal 
or no toxicity with the reduced dose. However, if the subject tolerates the lower dose level of 
study drug for ≥4 weeks then the dose level may be increased to the starting dose level 
(see Table 5-1) at the discretion of the investigator. Such re-escalation may be particularly 
warranted if further evaluation reveals that the adverse event that led to the dose reduction was 
not study-drug-related. The starting dose level should not intentionally be exceeded in this study.
Whenever possible, any dose adjustment of study drug should be discussed between the 
investigator and the Gilead Sciences medical monitor prior to implementation. To implement 
either a dose reduction or a dose reescalation, the investigator/study staff member will call the 
IWRS, enter the subject number, and inform the IWRS of the need for dose titration. The IWRS 
will provide details regarding the blister card to be dispensed to the subject. The appropriate 
clinic staff should instruct the subject/caregiver about the change in dose.
Recommendations for dose modification based on the type and severity of adverse events or 
laboratory abnormalities are provided in Table 5-2 below.


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Table 5-2.
Recommendations for Study Drug Dose Modifications Based on Type 
and Severity of Treatment-Related Adverse Events or Laboratory 
Abnormalities
NCI CTCAE Gradea
Recommendation
Idelalisib
HEMATOLOGICAL ADVERSE EVENTS
Neutropenia
Grade 2 neutropenia
Maintain current dose level and schedule.
Grade 3 neutropenia
Maintain current idelalisib dose level and schedule. Blood counts should be monitored 
at least weekly.
Grade 4 neutropenia
(or occurrence of 
neutropenic fever 
or infection)
Delay idelalisib dosing. Blood counts should be monitored at least weekly until ANC 
≥0.5 x 109/L, at which point idelalisib dosing may be resumed at 100 mg BID.
Neutropenia should be managed according to established clinical guidelines.
Thrombocytopenia
Grade 3
Maintain current dose level and schedule.
Grade 4
Withhold for bruising or bleeding until Grade 3. May resume idelalisib at initial or 
lower dose level at investigator discretion.
NON-HEMATOLOGICAL ADVERSE EVENTS
Rash
Grade 1
Maintain current dose level and schedule.
Grade 2
Maintain current dose level and schedule.
Grade ≥3 
Withhold idelalisib until Grade 1. Resume at lower dose level or discontinue idelalisib 
at investigator discretion.
Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis
Any Grade
Discontinue idelalisib. Institute systemic immunosuppression per institutional standards.
Gastrointestinal Inflammation/Diarrhea
Grade 1
Provide anti-diarrheal (eg, loperamide) and maintain current idelalisib dose level and 
schedule.
Obtain history of onset and duration of diarrhea, include description of number of stools 
and stool composition (e.g., watery, bloody, nocturnal), travel history, dietary changes 
and a medication review to identify possible diarrheogenic agents.
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (e.g., evaluate for sepsis, bowel obstruction, dehydration).


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NCI CTCAE Gradea
Recommendation
Idelalisib
Grade 2
Provide anti-diarrheal (eg, loperamide). Consider addition of anti-inflammatory agent 
(eg, sulfasalazine, budesonide). Maintain current study drug dose and schedule.
Obtain history of onset and duration of diarrhea, include description of number of stools 
and stool composition (e.g., watery, bloody, nocturnal), travel history, dietary changes 
and a medication review to identify possible diarrheogenic agents.
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (e.g., evaluate for sepsis, bowel obstruction, dehydration).
For Grade 2 colitis or diarrhea (unless clinical diagnosis is established from medical 
history and physical examination), perform stool culture for routine pathogens 
(Salmonella, Shigella, Campylobacter species, Clostridium difficile toxin, Rotavirus, 
Cytomegalovirus, Adenovirus), ova and parasites (Cryptosporidium parvum, Isospora 
belli, Enterocytozoon bieneusi, Septata intestinalis, Strongyloides, Microsporidia, 
Entamoeba histolytica, Cyclospora), and Giardia antigen.
For persistent Grade 2 colitis or diarrhea without clear etiology (clostridium difficile 
enterocolitis), endoscopy with biopsyb is required. All biopsy samples should include 
immunohistochemistry (IHC) and PCR for CMV, Adenovirus.  (If ileal biopsy is 
performed, consider Acid Fast Bacillus staining.)
Grade 3
Withhold study drug.  Rule out infectious etiology including CMV. Consider 
anti-diarrheal (eg, loperamide) and/or addition of anti-inflammatory agent 
(eg, sulfasalazine, budesonide). At Grade 1, may resume at lower dose level or 
discontinue study drug at investigator discretion.
Obtain history of onset and duration of diarrhea, include description of number of stools 
and stool composition (e.g., watery, bloody, nocturnal), travel history, dietary changes 
and a medication review to identify possible diarrheogenic agents.
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (e.g., evaluate for sepsis, bowel obstruction, dehydration).
For Grade 3 colitis or diarrhea (unless clinical diagnosis is established from medical 
history and physical examination), perform stool culture for routine pathogens 
(Salmonella, Shigella, Campylobacter species, Clostridium difficile toxin, Rotavirus, 
Cytomegalovirus, Adenovirus), ova and parasites (Cryptosporidium parvum, Isospora 
belli, Enterocytozoon bieneusi, Septata intestinalis, Strongyloides, Microsporidia, 
Entamoeba histolytica, Cyclospora), and Giardia antigen.
For Grade 3 colitis or diarrhea without clear etiology (eg, clostridium difficile 
enterocolitis), endoscopy with biopsyb is required.  All biopsy samples should include 
immunohistochemistry (IHC) and PCR for CMV, Adenovirus. (If ileal biopsy is 
performed, consider Acid Fast Bacillus staining.)


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NCI CTCAE Gradea
Recommendation
Idelalisib
Grade 4
Withhold study drug.  Rule out infectious etiology including CMV. Consider 
anti-diarrheal (eg, loperamide) and/or addition of anti-inflammatory agent 
(eg, sulfasalazine, budesonide). At Grade 1, may resume at lower dose level or 
discontinue study drug at investigator discretion.
Obtain history of onset and duration of diarrhea, include description of number of stools 
and stool composition (e.g., watery, bloody, nocturnal), travel history, dietary changes 
and a medication review to identify possible diarrheogenic agents.
Perform physical examination including assessment for fever, dizziness, abdominal 
pain/cramping, and weakness (e.g., evaluate for sepsis, bowel obstruction, dehydration).
For Grade 4 colitis or diarrhea (unless clinical diagnosis is established from medical 
history and physical examination), perform stool culture for routine pathogens 
(Salmonella, Shigella, Campylobacter species, Clostridium difficile toxin, Rotavirus, 
Cytomegalovirus, Adenovirus), ova and parasites (Cryptosporidium parvum, Isospora 
belli, Enterocytozoon bieneusi, Septata intestinalis, Strongyloides, Microsporidia, 
Entamoeba histolytica, Cyclospora), and Giardia antigen.
For Grade 4 colitis or diarrhea without clear etiology (eg, clostridium difficile 
enterocolitis), endoscopy with biopsyb is required.  All biopsy samples should include 
immunohistochemistry (IHC) and PCR for CMV, Adenovirus. (If ileal biopsy is 
performed, consider Acid Fast Bacillus staining.)
Hepatic Adverse Events (elevations in ALT, AST, or bilirubin)
Grade 1
(ALT/AST3xULN)
(Bilirubin1.5xULN)
Maintain current dose level and schedule.
Grade 2
(ALT/AST>3-5xULN)
(Bilirubin>1.5-3xULN)
Maintain current dose level and schedule. Monitor ALT, AST, ALP, and bilirubin at 
least 1x per week.
Grade 3
(ALT/AST>5-20xULN)
(Bilirubin>3-10xULN)
Withhold idelalisib. Monitor ALT, AST, ALP, and bilirubin at least 1x per week until 
all abnormalities are Grade 1. If bilirubin abnormality was Grade <3, resume idelalisib 
at same dose level. If bilirubin abnormality was Grade 3, resume at lower dose level.
Grade 4
(ALT/AST>20xULN)
(Bilirubin>10xULN)
Withhold idelalisib. Monitor ALT, AST, ALP, and bilirubin at least 1x per week until 
all abnormalities are Grade 1. If bilirubin abnormality was Grade <4, resume idelalisib 
at lower dose level. If bilirubin abnormality was Grade 4, discontinue idelalisib.
Pneumonitis (dyspnea, cough, hypoxia without obvious infectious cause)
Grade 1
Withhold study drug until resolution to baseline. May resume at lower dose level or 
discontinue study drug at investigator discretion.. 
Grade 2
Withhold study drug and discontinue permanently.
Grade 3
Withhold study drug and discontinue permanently. Institute systemic corticosteroids
Pneumocystis pneumonia
Any Grade
Discontinue idelalisib


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NCI CTCAE Gradea
Recommendation
Idelalisib
Unequivocal CMV infectionc
Any Grade
Discontinue idelalisib
Other Nonhematological Adverse Events
Grade 2
Maintain current dose level and schedule.
Grade 3
Withhold idelalisib until Grade 1. May resume idelalisib at initial or lower dose level 
or discontinue idelalisib at investigator discretion.
a
CTCAE, Version 4.03.
b
Refer to 5.4.2.1 for recommendations if the differentiation between small-bowel and large-bowel diarrhea is unclear
c
CMV should be diagnosed using clinical or laboratory criteria per established institutional standard
Abbreviations:  ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST= aspartate aminotransferase,
CTCAE=Common Terminology Criteria for Adverse Events, CMV=cytomegalovirus, G-CSF=granulocyte colony-stimulating 
factor, NCI=National Cancer Institute, ULN=upper limit of normal
5.4.
Recommendations for Evaluation, Intervention, and Drug Discontinuation
for Specific Adverse Events or Conditions
5.4.1.
Dermatological Events
Subjects receiving idelalisib with ≥ Grade 3 rash have generally presented with a maculopapular 
rash on the trunk and extremities that is occasionally associated with fever and/or pruritus and 
responded to treatment with diphenhydramine and/or topical or oral corticosteroids. 
For subjects who develop a severe rash for which an underlying etiology cannot be identified 
(e.g., infection, co suspect drug), study drug should be interrupted. Resumption of study drug 
should be considered once rash resolves per Table 5-2.
Severe cutaneous reactions, including fatal events of Stevens-Johnson syndrome (SJS) and toxic 
epidermal necrolysis (TEN), have been reported in subjects receiving idelalisib. Assessment of 
potential causal association between idelalisib and the occurrence of SJS or TEN has been 
confounded by the coadministration of antineoplastic agents (e.g., bendamustine, rituximab) 
and/or other concomitant medications known to be associated with SJS or TEN (e.g., allopurinol).
If SJS or TEN is suspected, idelalisib and all coadministered medications associated with SJS or 
TEN should be interrupted and the subject treated accordingly. 
Subjects should be monitored for the development of SJS, TEN, or other severe cutaneous 
reactions and idelalisib treatment should be discontinued if such events occur.
Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab. 
These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid 
dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis {Genentech Inc 2011}. 
The onset of these reactions has varied from 1 to 13 weeks following initiation of rituximab 
exposure. The safety of readministration of rituximab to patients with severe mucocutaneous 
reactions has not been determined; thus, for subjects experiencing a severe mucocutaneous 
reaction, rituximab should be discontinued.


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Among patients receiving bendamustine, skin reactions have been reported in clinical trials and 
post-marketing safety reports {Cephalon 2012}. These events have included rash, toxic skin 
reactions, bullous exanthema, and purpura {Gavini et al 2012}. Cases of Stevens-Johnson 
syndrome and toxic epidermal necrolysis have been reported when bendamustine was 
administered concomitantly with allopurinol and other medications known to cause these 
syndromes. There may be an increased risk of skin toxicity in subjects receiving bendamustine 
together with trimethoprim-sulfamethoxazole. Because of coadministration of other agents, the 
precise relationship of cutaneous adverse events to bendamustine has often been uncertain. 
Where skin reactions to bendamustine do occur, they may be progressive and increase in severity 
with further treatment. Therefore, patients with skin reactions should be monitored closely. If 
skin reactions are severe or progressive, bendamustine should be discontinued.
5.4.2.
Gastrointestinal Events
Isolated cases of gastrointestinal inflammation (eg, stomatitis, colitis, cecitis) have been noted in 
subjects receiving idelalisib. Rare cases of gastrointestinal perforation have occurred, generally 
in the setting of occult carcinoma, mesenteric embolus or diverticular disease.  Idelalisib should 
be discontinued in subjects who experience bowel perforation.
Cholangitis manifest as hyperbilirubinemia out of proportion to serum transaminase elevations 
has been observed. While disease related factors, neutropenia, toxicity from prior therapies, 
effects of ongoing supportive care, or pre existing cholelithiasis may have initiated such events, 
it is possible that idelalisib played a contributory role. In such subjects, rechallenge with 
idelalisib has been possible and has not been associated with other severe adverse events. 
Subjects who have developed evidence of enteritis during idelalisib therapy have been 
successfully treated with antidiarrheals (eg, loperamide) and with enteric steroidal (eg, budesonide)
or non steroidal (eg sulfasalazine [Azulfidine®]) anti-inflammatory agents and have been able to 
continue or resume idelalisib.
For study subjects who develop severe abdominal pain the possibility of a bowel obstruction or 
perforation should be considered. Appropriate clinical and radiographic examination should be 
performed and supportive care or surgical intervention should be considered. Upon recovery, 
rituximab may be resumed. 
For subjects who develop persistent diarrhea, causes related to concomitant medications or 
gastrointestinal infections such as Clostridium difficile (particularly for patients recently treated 
with broad spectrum antibiotics), Shigella, Campylobacter, Yersinia and CMV should be 
considered and treated if appropriate. Depending upon the clinical circumstances, endoscopy and 
biopsy, with bacterial and viral IHC staining should be considered. In the event that an infectious 
cause is not identified, an antimotility agent (eg, loperamide) may lessen symptoms and 
intervention with enteric steroidal (eg, budesonide) or non-steroidal (eg, sulfasalazine) anti-
inflammatory agents should be considered. In such subjects, rechallenge with idelalisib at a 
lower dose level has resulted in recurrence of symptoms in some but not all subjects and has not 
been associated with other severe adverse events.


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Among patients receiving rituximab in combination with chemotherapy, rare instances of 
life-threatening bowel obstruction or perforation has been observed {Ram et al 2009}, primarily 
in patients with NHL. In post-marketing reports, the mean time to documented gastrointestinal 
perforation was 6 (range 1–77) days from start of chemoimmunotherapy. It is hard to draw a 
definite conclusion regarding the role of rituximab in these cases, as the affected patients had 
multiple risk factors including lymphomatous involvement of the gastrointestinal tract, other 
gastrointestinal disorders, and/or the risk of concomitant treatments with chemoradiotherapy and 
corticosteroids. Very isolated instances of inflammatory bowel disease have been seen in patients 
receiving rituximab {Ardelean et al 2010}.
5.4.2.1.
Investigation for Idelalisib Late Onset or Severe Diarrhea/Colitis
See CTCAE Version 4.03 for definitions of colitis and diarrhea.
Among idelalisib-treated patients who reported diarrhea or colitis, the median time to onset of 
any grade diarrhea or colitis was 1.9 months (range, 0.0–29.8), of grade 1 or 2 was 1.5 months 
(range, 0.0–15.2) and of grade 3 or 4 was 7.1 months (range, 0.5–29.8). Kaplan–Meier curves of 
time to onset of diarrhea or colitis are shown for all idelalisib- treated patients in Figure 5-1
{Coutre et al 2015}.
Figure 5-1.
Kaplan-Meler Time to Diarrhea or Colitis
Idelalisib-associated severe diarrhea responds poorly to antimotility agents however, median 
time to resolution ranged between 1 week and 1 month across trials following interruption of 
idelalisib treatment and, in some instances, initiation of corticosteroid treatment 
{Gilead Sciences Inc 2014}.
Differentiation between small-bowel and large-bowel diarrhea may be possible on a clinical 
basis.  If unclear, consider upper and lower tract endoscopy with biopsy.


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
Small bowel diarrhea is characterized by large volume diarrhea (more than one per day), 
possible associated dehydration weight loss and paraumbilical pain.   Consider an endoscopic 
small-bowel biopsy and evaluate other etiologies such as celiac disease.

Large-bowel diarrhea may present with lower pelvic pain, tenesmus, generally smaller stool 
volume with gross blood frquently found in the stool. Consider a colonoscopic evaluation 
and biopsy.
5.4.3.
Hepatic Events
Transaminase Elevations: Consistent with observations in a dog toxicology study, reversible 
asymptomatic ALT/AST increases were also observed early in the idelalisib program in phase 1 
studies (101-02 and 101-07) in subjects with hematologic malignancies. Transaminase elevations 
generally occurred within 4 to 12 weeks of drug initiation, and resolved spontaneously over a 
period of 2 to 4 weeks with drug being continued for Grade 1 and 2 elevations and drug withheld 
for Grade 3 or 4 elevations until resolution. These early observations have been consistent with 
the ongoing experience with idelalisib treatment and transaminase elevations are now well 
characterized as most frequently asymptomatic, transient and occurring within the first 3 months 
of treatment.
Grade 1 or 2 elevations commonly resolve despite continued idelalisib treatment and Grade 3 or 
4 elevations can be managed by temporarily withholding idelalisib. Successful rechallenge after 
resolution at either the same or lower dose level of idelalisib has been achieved in the majority of 
subjects. There has been no evidence of impaired synthetic function. Close monitoring of hepatic 
laboratory tests during therapy is important to allow for appropriate idelalisib interruption and 
reinstitution so that subjects may continue with study drug treatment.
HBV Reactivation: HBV reactivation can occur in patients treated with anti-CD20 antibodies.  
Subjects who are HBc antibody positive/HBV DNA PCR negative at screening will be 
monitored for potential HBV reactivation (manifest as detectable HBV DNA by quantitative 
PCR). Although some subjects who are HBc antibody positive with negative PCR may have had 
passive transfer of antibody from intravenous IgG, it cannot be known for certain that any such 
subject did not have natural HBV infection. Therefore, all subjects will be tested monthly for the 
duration of anti-CD20 therapy and every 3 months for 1 year following the last dose of rituximab 
during study participation. Following the completion of study participation, monitoring for HBV 
reactivation will be conducted per standard of care at the discretion of the investigator. If there is 
evidence of HBV reactivation, immediately discontinue anti-CD20 and start appropriate 
treatment for HBV.  In the event of HBV reactivation, please contact the Medical Monitor 
regarding continuation of idelalisib.
5.4.4.
Hematological and Immunological Events
In the Phase 1 experience with idelalisib in NHL and CLL, subjects with Grade3 neutropenia, 
anemia, and and/or thrombocytopenia were enrolled to clinical trials. Decreased levels of 
neutrophil counts, hemoglobin, or platelet counts during therapy were largely due to minor 
fluctuations in these parameters among patients with pre-existing hematological abnormalities


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due to disease or prior therapy. Thus, idelalisib did not appear to induce overt myelosuppression. 
Obvious patterns of drug-mediated reductions in circulating CD4+ lymphocyte counts or 
suppression of serum IgG levels were also not observed.
Treatment-emergent Grade 3 or 4 neutropenia events, including febrile neutropenia, have occurred in 
subjects treated with idelalisib. For subjects who develop ANC 0.5 to < 1.0 Gi/L, blood counts 
should be monitored at least weekly. For subjects who develop ANC < 0.5 Gi/L, idelalisib should be 
interrupted and blood counts monitored at least weekly until ANC is ≥ 0.5 Gi/L, at which point, 
idelalisib dosing may be resumed at 100 mg BID.  Neutropenia should be managed according to 
established clinical guidelines.
No modification of any drug for changes in circulating CD4+ counts or Ig levels is planned.
5.4.5.
Infectious Events
Patients with lymphoid cancers receiving idelalisib have developed serious and fatal infections 
during therapy. Opportunistic infections, most notably Pneumocystis jirovecii pneumonia (PJP) 
and CMV infection, have most frequently occurred within the first 6 months of treatment with 
idelalisib and are increased in the context of concurrent myelosuppressive therapy such as 
bendamustine.
Subjects must receive trimethoprim-sulfamethoxazole or other established prophylaxis for PJP 
throughout the course of idelalisib treatment.  Prophylaxis will continue until the CD4+ T-cell 
count is documented to be >200 cells/mcL after idelalisib treatment ends. Subjects must 
permanently discontinue idelalisib upon diagnosis of PJP.
CMV surveillance for active disease (quantitative PCR or PP65 antigen) must be conducted 
approximately every 4 weeks throughout the course of idelalisib treatment. CMV viral load 
testing should be performed from the same specimen type whenever possible and caution should 
be exercised when comparing CMV viral load results across different testing centers. If 
unequivocal clinical or laboratory evidence of CMV infection is present, the subject must 
permanently discontinue idelalisib treatment and undergo effective antiviral treatment according 
to established clinical guidelines.
Serious bacterial, fungal, and new or reactivated viral infections have occurred during and for 
~1 year following rituximab-based therapy {Gea-Banacloche 2010}. New or reactivated viral 
infections in patients receiving rituximab have included CMV, herpes simplex virus, parvovirus 
B19, varicella zoster virus, West Nile virus, HBV (see Section 5.4.3) and HCV.
In high-risk subjects (history of recurrent infection, allogeneic transplant, treatment with 
alemtuzumab, hypogammaglobulinemia) other infection prophylaxis should be considered per 
consensus guidelines. Administration of intravenous immunoglobulin is permitted per standard 
institutional practice {Raanani et al 2009}. For subjects who develop an infection, appropriate 
medical therapy should be instituted in a timely manner.


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5.4.6.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) due to polyomavirus JC has been observed 
in patients who have received rituximab therapy {Carson et al 2009} for hematologic 
malignancies. The specific causal role of rituximab is unknown because many of these patients
had other risk factors (eg, low CD4+ counts) and the majority had received rituximab in 
combination with chemotherapy or as part of a hematopoietic stem cell transplant. Most cases of 
PML were diagnosed within 12 months of the last infusion of rituximab.
The diagnosis of PML should be considered in any subject presenting with new-onset or 
worsening neurologic manifestations, especially weakness or paralysis, vision loss, impaired 
speech, or cognitive deterioration. Evaluation of PML should include consultation with a 
neurologist, brain MRI, and lumbar puncture. In subjects diagnosed with PML, study drug 
should also be permanently discontinued.
5.4.7.
Pulmonary Events
Documented bacterial, fungal, viral, and pneumocystis pneumonias have been observed in 
patients receiving idelalisib, primarily in patients with CLL. Some study subjects receiving 
idelalisib alone or in combination have developed evidence of pneumonitis without documented 
pulmonary infection.
Rituximab-related noninfectious pneumonitis has been described {Subramanian et al 2010} with 
an incidence of ~4.3% {Salmasi et al 2010}. In patients developing rituximab-associated 
pneumonitis, the mean time from the first rituximab infusion to the onset of respiratory 
symptoms was 3 months, with a peak incidence after administration of a mean cumulative 
dosage of 1600 mg/m2 {Liote et al 2010}.
Given the potential for infectious or drug-related adverse events, clinicians should be particularly 
observant for evidence of respiratory events in subjects participating in this trial. Subjects who 
describe pulmonary symptoms (eg, dyspnea on exertion, cough, shortness of breath); manifest a 
decline from baseline of 5% in oxygen saturation, or demonstrate evidence of pulmonary 
inflammation (eg, focal or diffuse interstitial pattern or ground-glass opacities on chest CT)
should be evaluated. Potential bacterial, fungal, or viral etiologies should be assessed. 
Noninfectious etiologies such as pulmonary edema or thromboembolism should also be 
considered.
As appropriate for the clinical situation and culture results, subjects should be treated empirically 
or given specific antibiotics, antifungals, or antiviral agents for a cultured organism. Supportive 
care, including oxygen or mechanical ventilation, should be provided as necessary.
For subjects with suspected pneumonitis (eg, onset of cough, dyspnea, hypoxia and/or a diffuse 
interstitial pattern or ground-glass opacities on chest imaging without obvious infectious 
etiology), study drug should be interrupted and therapy with systemic corticosteroids
(eg, prednisone, 60 mg/day) should be instituted rapidly {Liote et al 2010}. Supportive care, 
including oxygen or mechanical ventilation, should be provided as necessary. 


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5.4.8.
Secondary Malignancies
Subjects receiving idelalisib for CLL or iNHL have developed pre-malignant and secondary 
malignant diseases, such as basal cell carcinoma, myelodysplastic syndrome, myeloproliferative 
disorders, and more aggressive lymphoid malignancies (eg, have had Richter transformation). 
Generally this has occurred in subjects who have received multiple previous lines of therapy and 
when idelalisib is combined with other therapies such as rituximab or bendamustine. The specific 
association of the therapeutic agents with these types of events has not been determined.
There are reports of pre-malignant and malignant diseases that have developed in subjects who 
have been treated with bendamustine, including myelodysplastic syndrome, myeloproliferative 
disorders, acute myeloid leukemia, and bronchial carcinoma. The specific association of the 
therapeutic agents with these types of events has not been determined.
5.4.9.
Tumor Lysis Syndrome
Tumor lysis syndrome has not been observed with idelalisib monotherapy. 
Subjects with tumor lysis syndrome should receive rapid reversal of hyperkalemia, intravenous 
hydration, antihyperuricemic agents, and appropriate cardiac and renal support, including 
dialysis as indicated. Upon recovery to baseline functioning, such subjects should continue study 
treatment.
5.4.10.
Pregnancy, Lactation, and Reproduction
Idelalisib has induced embryo lethality and teratogenicity when administered to pregnant female 
rats at maternally toxic doses. However, definitive reproductive toxicology studies in animals 
have not yet been performed and the specific effects of idelalisib on human embryogenesis or 
fetal development are unknown. Whether idelalisib is excreted in human breast milk is unknown. 
General toxicology studies in rats and dogs indicated dose-dependent reductions in testicular 
weights, with persistent minimal to mild degeneration of the seminiferous tubules and decreased 
spermatozoa in rats and hypospermatogenesis in dogs. The implications of these testicular 
changes for animal or human fertility are unknown.
Given the preliminary nature of data regarding the risks to a fetus or infant as a result of 
exposure to idelalisib, women of reproductive potential entering this study must have a negative 
serum pregnancy test at baseline and must not be breastfeeding. Males and females of 
childbearing potential should abstain from sexual intercourse or use an effective form of 
contraception (see Section 5.6.4). If a female study participant becomes pregnant or decides to 
breastfeed during the course of the study, all study therapy must be discontinued.
5.4.10.1.
PJP Prophylaxis
Trimethoprim sulfamethoxazole is rated a Pregnancy category C.  In rats, oral doses of 
533 mg/kg or 200 mg/kg produced teratologic effects manifested mainly as cleft palates. 
One survey found no congenital abnormalities in 35 children whose mothers had received oral 


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sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter. Because 
sulfamethoxazole and trimethoprim may interfere with folic acid metabolism it should be used 
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Dapsone is rated a Pregnancy Category C.  Extensive, but uncontrolled experience and 
two published surveys on the use of Dapsone in pregnant women have not shown that Dapsone 
increases the risk of fetal abnormalities if administered during all trimesters of pregnancy or can 
affect reproduction capacity. Because of the lack of animal studies or controlled human 
experience, Dapsone should be given to a pregnant woman only if clearly needed. Dapsone is 
excreted in breast milk in substantial amounts. Hemolytic reactions can occur in neonates. 
Because of the potential for tumorgenicity shown for Dapsone in animal studies a decision 
should be made whether to discontinue nursing or discontinue the drug taking into account the 
importance of drug to the mother.
Atovaquone is rated a Pregnancy Category C.  Atovaquone is teratogenic and did not cause 
reproductive toxicity in rats at plasma concentrations up to 2 to 3 times the estimated human 
exposure. Atovaquone can cause maternal toxicity in rabbits at plasma concentrations that were 
approximately one half the estimated human exposure. Mean fetal body lengths and weights were 
decreased and there were higher numbers of early resorption and post-implantation loss per dam. It is 
not clear whether these effects are caused by atovaquone directly or are secondary to maternal 
toxicity. Concentrations of atovaquone in rabbit fetuses averaged 30% of the concurrent maternal 
plasma concentrations.  There are no adequate and well-controlled studies in pregnant women. 
Atovaquone should be used during pregnancy only if the potential benefit justifies the potential risk 
to the fetus. It is not known whether atovaquone is excreted into human milk. Because many drugs 
are excreted into human milk, caution should be exercised when Atovaquone is administered to a 
nursing woman. In a rat study, atovaquone concentrations in the milk were 30% of the concurrent 
atovaquone concentrations in the maternal plasma.
Aerosolized Pentamidine (NebuPent) is a Pregnancy Category C.  There are no adequate and well 
controlled studies of NebuPent in pregnant women. One literature report indicated that intravenously 
administered pentamidine in pregnant rats at 4 mg/kg/day was embryolethal; teratogenicity was not 
observed in this study. It is unknown whether pentamidine administered via the aerosolized route 
crosses the placenta at clinically significant concentrations. It is not known whether NebuPent can 
cause fetal harm when administered to a pregnant woman. NebuPent should be given to a pregnant 
woman only if clearly needed.  It is not known whether NebuPent is excreted in human milk.  
NebuPent should not be given to a nursing mother unless the potential benefits are judged to 
outweigh the unknown risks.
5.4.11.
Ultraviolet Exposure
In vitro studies indicate enhanced cytotoxicity when embryonic murine fibroblasts treated with 
GS-563117 (the major metabolite of idelalisib) are simultaneously exposed to ultraviolet light. 
While nonclinical findings suggest the hypothetical potential for phototoxicity in humans, 
available clinical data do not reveal a photosafety concern. Although specific clinical correlates 
for these nonclinical data are not available, investigators and study subjects should be observant 
for the possibility that study participants may have exaggerated sunburn reactions 
(eg, burning, erythema, exudation, vesicles, blistering, edema) involving areas of skin exposed to 
ultraviolet light.


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5.4.12.
Further Safety Information
Further safety information regarding the study drug may be found in the investigator brochure 
for idelalisib. 
5.5.
Emergency Unblinding
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IWRS system 
for that subject. Gilead recommends but does not require that the investigator contact the 
Gilead medical monitor before breaking the blind. Treatment assignment should remain blinded 
unless that knowledge is necessary to determine subject emergency medical care. The rationale 
for unblinding must be clearly explained in source documentation and on the case report 
form/ electronic case report form (CRF/eCRF), along with the date on which the treatment 
assignment was obtained. The investigator is requested to contact the Gilead medical monitor 
promptly in case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).
5.6.
Concomitant and Supportive Therapy
To the extent possible, administration of any prescription or over-the-counter drug products other 
than study medication should be minimized during the study period. Subjects should be 
discouraged from use of street drugs, herbal remedies, self-prescribed drugs, tobacco products, or 
excessive alcohol at any time during the clinical study.
If considered necessary for the subject’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator. The decision to 
authorize the use of any drug other than study drug should take into account subject safety, the 
medical need, the potential for drug interactions, the possibility for masking symptoms of a more 
significant underlying event, and whether use of the drug will compromise the outcome or 
integrity of the study
Subjects should be instructed about the importance of the need to inform the clinic staff of the 
use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and during 
the course of the study. Any concomitant drugs taken by a subject during the course of the study 
and the reason for use should be recorded on the eCRFs.
Information regarding use or restrictions on specific concomitant medications, dietary measures, 
or other interventions is provided below.


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5.6.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments
Except for corticosteroids (see Section 5.6.5), no other systemic anticancer therapies (including 
but not limited to chemotherapy, radiation, antibody therapy, immunotherapy, or other 
experimental therapies) of any kind are permitted. Subjects are not allowed to participate 
concurrently in any other therapeutic clinical study.
5.6.2.
Antibiotics
Investigators must initiate antibiotic prophylaxis against pneumocystis infection 
(eg, with trimethoprim-sulfamethoxazole, dapsone, aerosolized pentamidine, or atovaquone)
beginning prior to study drug administration. Such support may also offer the benefit of reducing 
the risk for other bacterial infections {Green et al 2007}. Investigator discretion and local 
practices or guidelines may be followed.
For subjects who develop an infection, appropriate medical therapy (with antibiotics, antifungals, 
or antiviral) or other interventions should be instituted. Whenever appropriate, subjects may 
continue with study drug during treatment for the infection; however, subjects who develop PJP
must permanently discontinue study drug.
5.6.3.
Antiemetics and Antidiarrheals
Drug-related nausea and/or vomiting have not been commonly observed with idelalisib in prior 
studies. However, subjects who experience nausea or vomiting while on study therapy may 
receive antiemetics based on the judgment of the treating physician and local institutional 
practices. At the occurrence of persistent nausea or vomiting of severity Grade 1, it is suggested 
that the subject receive an oral or transdermal serotonin antagonist (eg, dolasetron, granisetron, 
ondansetron, tropisetron, palonosetron). Other classes of antiemetic medications that may be 
employed include dopamine antagonists or benzodiazepines. As needed, subjects may be 
prescribed loperamide (Imodium® or others) or diphenoxylate and atropine (Lomotil®) to control 
diarrheal symptoms.
5.6.4.
Contraception
In the context of this protocol, a female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, a bilateral tubal ligation, or a bilateral oophorectomy; has 
medically documented ovarian failure (with serum estradiol and FSH levels within the 
institutional postmenopausal range and a negative serum or urine HCG); or is menopausal 
(age ≥54 years with amenorrhea for >12 months or amenorrhea for >6 months with serum 
estradiol and FSH levels within the institutional postmenopausal range).
Sexually active females of childbearing potential must agree to use a protocol-recommended 
method of contraception during heterosexual intercourse throughout the study treatment period 
and for 30 days following the last dose of the study drug. The investigator should counsel 
subjects on the most effective methods for avoiding pregnancy during the trial. 
Protocol-recommended contraceptive methods are described in Table 5-3.


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Table 5-3.
Protocol-Recommended Contraceptive Methods
Individual Methods
Combination Methods
Hormonal Methods
(One method to be used
with a barrier method)
Barrier Methods
(Both of these methods to be used OR
one of these methods to be used
with a hormonal method)
IUD

Copper T 380A IUD

LNg 20 IUD
Tubal sterilization
Hysterectomy
Estrogen and progesterone

Oral contraceptives

Transdermal patch

Vaginal ring
Progesterone

Injection

Implant

Diaphragm with spermicidea

Male condom
(with spermicidea)
a
If available/approved for use in the specific country
Abbreviation: IUD=intrauterine device
In the context of this protocol, a male subject is considered able to father a child unless he has 
had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or is receiving
ongoing testicular suppression with a depot luteinizing hormone-releasing hormone (LH-RH) 
agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or 
triptorelin pamoate [Trelstar®]).
Sexually active male subjects who can father a child must accept continuous heterosexual 
abstinence as a lifestyle choice; limit intercourse to female partners who are surgically sterile, 
post-menopausal, or using effective contraception (as noted in Table 5-3); or agree to use a 
protocol-recommended method of contraception during heterosexual intercourse throughout the 
study treatment period and for 90 days following discontinuation of the study drug
(as noted in Table 5-3). 
The Gilead Sciences medical monitor should be consulted regarding any questions relating to 
childbearing status or contraception.
5.6.5.
Corticosteroids
Subjects may receive topical, inhaled, enteric, or systemic corticosteroids while on study. It 
should be realized that the use of systemic corticosteroids in patients with CLL may confound 
interpretation of antitumor effects mediated by study drug therapy. However, subjects who 
develop conditions that may be alleviated by systemic corticosteroid therapy are permitted to 
receive such drugs and are not required to discontinue study participation.
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin
Granulocyte-macrophage colony-stimulating factor (GM-CSF) should not be administered given 
the potential for GM-CSF-related inflammatory symptoms.


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G-CSF (filgrastim, PEG-filgrastim, lenograstim) may be administered in response to 
Grade 4 neutropenia or neutropenic complications; use should be particularly considered if 
providing hematopoietic support might help to maintain study drug treatment (see Table 5-2).
While erythropoietic agents (eg, erythropoietin or darbepoetin) may be administered for 
Grade 3 anemia, their use in this study is discouraged given the potential to confound 
assessments of improvements in bone marrow function related to study drug.
Reference may be made to the American Society of Clinical Oncology guidelines {Rizzo et al 
2008}, {Smith et al 2006}.
5.6.7.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism
Idelalisib is metabolized primarily via aldehyde oxidase and in part by CYP3A. A clinical 
drug-drug interaction study indicated that administration of a potent CYP3A inhibitor together 
with idelalisib resulted in a ~80% increase in idelalisib plasma exposures (AUC) 
(see Section 1.3.5.1), which is not considered to be clinically relevant and suggesting that 
idelalisib is a weak CYP3A substrate. Preliminary data indicate when coadministered with 
rifampin, a highly potent inducer of CYP3A, idelalisib exposures are ~75% lower. 
Coadministration of potent inducers of CYP3A with idelalisib should be avoided; a list of strong 
inducers is provided in Table 5-4:
Table 5-4.
Known Strong Inducers of CYP3A
Effect on CYP3A
Drug Class
Medications
Strong CYP3A Inducers
Antimycobacterial
Rifampin
Anticonvulsants
carbamazepine, phenytoin
Foods/herbs
St. John’s wort
Abbreviation: CYP=cytochrome P450 enzyme
5.6.8.
Drugs that undergo CYP3A-Dependent Metabolism
The major metabolite of idelalisib, GS-563117, is a reversible and time dependent inhibitor of 
CYP3A; accordingly coadministration of idelalisib with midazolam, a probe CYP3A substrate, 
resulted in a ~5-fold increase in midazolam systemic exposure (AUC), indicating that idelalisib 
is a strong inhibitor of CYP3A. Coadministration of CYP3A substrates with idelalisib may result 
in an increase in their systemic exposures (eg, antiarrhythmics, calcium channel blockers, 
benzodiazepines, certain HMG-CoA reductase inhibitors, phosphodiesterase-5 (PDE5) 
inhibitors, warfarin). Avoid coadministration of drugs that are narrow therapeutic index CYP3A 
substrates (eg, alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, fentanyl, 
quinidine, ergotamine, dihydroergotamine, astemizole, terfenadine) with idelalisib.


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5.6.9.
Immunization
Because of its actions to inhibit PI3Kδ-dependent B-cell function, high doses of idelalisib can 
impair primary or secondary responses to immunization in animals.
The specific clinical relevance of these findings with idelalisib is unknown. However, for 
subjects who are at substantial risk of an infection (eg, influenza) that might be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of study 
therapy.
Of note, the safety of immunization with live viral vaccines following idelalisib therapy has not 
been studied and vaccination with live virus vaccines during study treatment is not 
recommended.
5.6.10.
Surgery
There are no known effects of idelalisib on coagulation or wound healing. Pending receipt of 
additional information, study drug may be continued in the peri-procedural period in subjects 
who require surgery or invasive procedures.
5.6.11.
Diet
There are no specific dietary restrictions in the study. Study drug may be taken with or without 
food.
5.7.
Duration of Study Drug
Subjects may continue receiving study drug until the occurrence of any events requiring study 
drug discontinuation as defined in Section 5.8.
5.8.
Discontinuation of Study Drug
All study participants may receive study drug indefinitely; however:

Any subject has the right to discontinue study drug at any time.

Any subject who has objective evidence based on IRC review of definitive CLL progression
will discontinue study drug.

Any subject unable to tolerate a second rechallenge with protocol-described, dose-modified 
idelalisib at Dose Level –1 (see Section 5.2) should discontinue study drug.

Any subject who becomes pregnant or begins breastfeeding should discontinue study drug.

Any subject who becomes significantly noncompliant with study drug administration, study 
procedures, or study requirements should discontinue study drug.


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
Any subject for whom the blind is intentionally broken by the subject or the study site should 
discontinue study drug (only applicable to the blinded portion of the study).

The investigator, in consultation with the Gilead Sciences medical monitor, may discontinue
study drug, if, it is not in the subject’s best interest to continue.

If allowed by local regulations, Gilead Sciences may transition subjects from study drug to 
commercial drug supply when idelalisib becomes commercially available in the country 
where the subject is living.
Subjects who permanently discontinue study drug for a reason other than disease progression 
(as determined by the IRC) shall continue with assessments per the schedule of procedures until 
disease progression or until another anticancer or experimental therapy is initiated.
5.9.
Discontinuation from Study
Subject study participation will be ended due to any of the following reasons:

Adverse event.

Disease progression.

Withdrawal of consent.

Significant subject noncompliance with study drug administration, study procedures, or study 
requirements.

Initiation of any additional systemic anticancer therapies (other than corticosteroids, 
see Section 5.6.5) including chemotherapy, radiation, antibody therapy, immunotherapy, or 
other experimental treatment.

Physician’s decision to remove the subject from the study.

Pregnancy.

The subject is lost to follow-up.

Death.

Discontinuation of study by the Sponsor, a Regulatory Agency, or an IRB or EC.
5.10.
Study Treatment Rationale
Subjects will be assigned to treatment (Arm A or Arm B) in this study based on their 
randomization in the primary study. The 1:1 randomization in the primary trial
(GS-US-312-0116) ensures that sufficient Arm B subjects will cross over from 


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rituximab alone to single-agent idelalisib at the 150-mg/dose BID starting dose level in this 
extension trial (GS-US-312-0117) to allow an adequate evaluation of efficacy and safety in this 
trial. The randomization and allocation processes will be established and performed through an 
IWRS; the intent is to maximize the integrity and security of the subject disposition and to ensure 
appropriate access and convenience-of-use by the investigational sites.
Double blinding is included to provide protection against biased interpretations of efficacy and 
safety data by subjects, caregivers, investigators, Gilead Sciences personnel, or others involved 
in study conduct.
Selection of the idelalisib treatment regimen (including starting dose level, dose-modifications 
and supportive care, schedule, duration, and conditions of administration) for this study program 
has been based primarily on safety, exposure, and activity profiles from previous Phase 1 clinical 
studies involving healthy volunteers, patients with allergic rhinitis, and patients with 
refractory/relapsed lymphoid malignancies {Webb et al 2010}, {Coutre et al 2011}, {Kahl et al 
2011}. The following information was considered in selecting the study drug dosing regimen for 
the primary study and this companion extension study:

Idelalisib was symptomatically well tolerated in patients with lymphoid malignancies receiving 
dose levels of 50 mg/dose BID through 350 mg/dose BID (the highest dose level tested). No
specific MTD was apparent over the dose range tested. However, monitorable, reversible 
transaminase elevations were observed in some patients and may have been more frequent at 
higher dose levels (~10% rate among patients with CLL receiving starting doses of 
150 mg/dose). Thus, while doses through 350 mg/dose BID are tolerable, the starting dose 
of 150 mg/dose BID appears to appropriately balance safety with efficacy in idelalisib-naïve 
subjects. The starting dose of 300 mg/dose BID in this study also appears appropriate for 
evaluation; it is lower than the dose level of 350 mg/dose BID that has been tolerable in prior 
studies and is likely to be suitable in subjects who have already been tolerating idelalisib
therapy at 100 mg/dose BID. 

Upon disease progression, permitting escalation from 150 mg/dose BID to 300 mg/dose BID 
among subjects allocated to Arm A offers a systematic evaluation of higher doses in subjects 
who are tolerating idelalisib treatment and might benefit from increased PI3Kinhibition. 
The pharmacological basis for considering such an intervention is based on the concept that 
some individuals might have lower-than-expected plasma exposures or dose-dependent 
resistance to the compound at 150 mg/dose BID and might benefit from a higher dose. The 
intent is to determine if the higher dose can reestablish disease control or whether absolute 
resistance to PI3Kinhibition has been acquired. The safety data obtained in these subjects 
would add to the overall safety database.

In an allergic rhinitis study, idelalisib induced statistically significant improvements in 
clinical and pharmacodynamic endpoints when administered at 100 mg/dose BID over 
7 days. These data support the pharmacological relevance of idelalisib-mediated 
PI3Kδ inhibition when administered at the dose-levels to be used in this study.


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
A positive correlation was noted between idelalisib dose and measures of tumor control and 
chemokine normalization in patients with B-cell malignancies. The majority of patients 
appear to have tumor responses and protracted PFS when receiving starting doses of 
100 mg/dose BID. Thus, treatment with a idelalisib at a starting dose of 150 mg/dose BID 
appears to offer most patients the potential to benefit from therapy and the dose level of 
300 mg/dose BID may provide additional benefit in patients with disease resistance as 
systematically evaluated in this trial. 

Increases in idelalisib plasma Cmax, AUC, and Ctrough values were less than dose-proportional 
in subjects with lymphoid malignancies; the dose-exposure evaluation indicated modest 
increases in plasma exposure at dose levels >150 mg BID.  Thus, administration of starting 
doses of idelalisib of 150 mg/dose BID appears appropriate to ensure adequate exposure in 
the majority of patients. 

In Phase 1 studies, the mean plasma t1/2 of idelalisib was ~6.5 to 9.8 hours across all dose 
levels and there was no substantive plasma accumulation over 7 or 28 days.

The changes in exposure observed when administering idelalisib after a high-fat, high-calorie 
meal are modest (~40% increase in mean AUC with no change in mean Cmax). 
Thus, idelalisib can be administered with or without food. 

The idelalisib dose modification provisions described in the protocol are designed to balance 
a primary concern for subject safety with the potential for observing pharmacological and 
antitumor activity in circumstances under which a subject experiencing an adverse event may 
still be able to continue on therapy at a lower idelalisib dose level. The enhanced monitoring 
to be performed and the actions to be taken in response to toxicity are based on experience 
with interruption, dose-modification, rechallenge, and re-escalation already piloted in 
idelalisib Phase 1 trials. In addition, idelalisib antitumor activity has been observed in the 
Phase 1 studies across all dose levels tested, including doses in the range of the modified 
dose levels planned for this protocol. Thus, use of the lower dose level to accommodate 
individual subject tolerability in this protocol is justified because subjects receiving such an
idelalisib dose level still have the potential for benefit.

In both the primary and extension studies, study treatment will be continued for each subject
until the occurrence of disease progression. Such a strategy is considered appropriate under 
the assumption that persistent interference with PI3Ksignaling is likely to extend treatment 
effect. In addition, this design permits collection of further single-agent safety information 
and thus is likely to enhance understanding of the overall safety profile of idelalisib. 


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6.
STUDY PROCEDURES
6.1.
Enrollment and Study Management Procedures
6.1.1.
Subject Recruitment
Study candidates are limited to those subjects who participated in the primary clinical trial
(Study GS-US-312-0116) and meet the entry criteria for this trial (Study GS-US-312-0117).
Subjects will be enrolled from investigational sites in the United States and Europe. The site 
principal investigator, designated sub-investigators, or other designees will discuss the possibility 
of participation directly with subjects who participated in the primary study.
The study sponsor will post a description of the study on the ClinicalTrials.gov website. Any 
promotional information generated by the sponsor or investigational sites will be submitted for 
IRB/IEC review.
6.1.2.
Subject Compensation for Participation
For subjects requesting such assistance, reasonable reimbursements for the costs of travel 
required to participate in this study will be provided by the study sponsor. To receive payment 
for travel, subjects will need to submit the original travel receipts to the research study staff at 
the investigational site.
However, other than medical care that may be provided, subjects will not be paid for 
participation in the study. Payments for such items as lost wages, disability, discomfort due to 
injury, or meals obtained while waiting at the clinical research center will not be provided. 
Through the informed consent process, study candidates will be notified that their insurance 
company could be charged for standard care that is a component of this research study and that 
subjects may be responsible for co-payments and deductible payments that are typical for their 
insurance coverage.
6.1.3.
Screening
The investigator must inform each prospective subject of the nature of the study, explain the 
potential risks, and obtain written informed consent from the subject and/or a legal guardian 
prior to performing any study-related screening procedures. At the time the study candidate signs 
the informed consent, a site representative should access the IWRS to indicate that a study 
candidate is being screened. The user will need to supply the IWRS with required information 
identifying the site and the subject number as already assigned in Study GS-US-312-0116.
Any consented subject who is excluded from the study before initiation of study treatment will 
be considered a screen failure. All screen failures must be documented along with an adequate 
description of the reason the subject was considered a screen failure. If available, information 
should be provided as to why the subject did not meet eligibility criteria, withdrew consent, 
experienced an intercurrent illness, or had other events that precluded treatment on this study.


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6.2.
Explanation of Study Visits
The specific study procedures to be conducted for each subject enrolled in the study are 
presented in tabular form in Appendix 7 and are described in the sections that follow. Additional 
information on the study procedures is provided in the study manual.
For visits at which HRQL and healthy utility data are obtained, it is important that the subject be 
administered the FACT-Leu and the EQ-5D before any other procedures are performed and 
before any study-related information is communicated to the subject; this is necessary to avoid 
biasing the PRO responses provided by the subject. Once the subject has completed the 
FACT-Leu and the EQ-5D assessments, the remaining procedures may be performed.
At visits involving idelalisib administration and pharmacokinetic sampling in the clinic, care 
should be taken to perform procedures with the appropriate timing relative to idelalisib
administration. The actual sample collection times of pharmacokinetic blood specimens should 
be recorded. If a heparinized venous catheter is placed for sample collection in order to avoid 
repeated needle sticks, at least 2 mL of blood should be removed and discarded prior to each 
sample collection in order to avoid heparin contamination of the sample.
At the visit designated as a laboratory-only visit (Visit 7), subjects will have laboratory 
assessments that may be performed at the investigational site or at an accredited local laboratory 
or clinic that is convenient for the subject/caregiver. If blood is collected at a local laboratory, 
samples are not to be analyzed at the local laboratory. For these visits, subjects and/or caregivers 
will be provided with central laboratory kits that will contain materials necessary for the 
collection and shipment of the laboratory samples by the local laboratory clinic to the central 
laboratory.
Local lab results may be requested in the event central laboratory results are not available for 
assessment of disease response, progression, or the evaluation of a significant event. In addition 
to clinical assessments of tumor status, CT or MRI imaging of the neck, chest, abdomen, and 
pelvis will be performed as a component of tumor assessments during the study based on the 
rationale provided in Section 3.2.1.
Following unblinding of the study:

Subjects who were randomized to idelalisib on Study GS-US-312-0116 and who received 
≥24 weeks idelalisib will complete Visit 16+ twelve weeks from the date of their last 
radiology assessment (CT/MRI) and study visits will continue every 12 weeks thereafter.
Visits 3 through 15 will not be required.

Subjects who have received < 24 weeks of idelalisib will have all Study GS-US-312-0117 
assessments completed per the Schedule of Procedures until they have received idelalisib for 
24 weeks cumulative across both studies. After completion of 24 weeks of cumulative 
idelalisib treatment, Visit 16+ will be conducted 12 weeks from the date of their last 
radiology assessment (CT/MRI), after which time study visits will occur every 12 weeks.


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6.2.1.
Visit 1 and Screening Period (Clinic Visit)
The initial screening visit is designated as Visit 1. At Visit 1, the investigator must inform each 
prospective study participant of the nature of the study, explain the potential risks, and obtain 
written informed consent from the study candidate and/or legal guardian prior to performing any 
study-related screening procedures. Once the informed consent document has been signed, the 
subject may undergo the screening procedures.
In order to optimize scheduling convenience for the subject and for the investigational staff, 
study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be 
used as screening procedures for Study GS-US-312-0117 if performed within 4 weeks prior to 
initiation of study drug therapy on Study GS-US-312-0117. In addition, screening procedures 
may be performed over as many days as necessary provided that screening is completed within 
4 weeks prior to initiation of study drug therapy on Study GS-US-312-0117.
The tests and evaluations outline in Table 6-1 will be performed at Visit 1 or during the 
screening period prior to initiation of study treatment.


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Table 6-1.
Procedures and Assessments at Visit 1 (During Screening Period)
Assessment or Procedure
Explanationa
Informed consent
To be obtained before any screening procedures are initiated
IWRS access
Access IWRS to document that subject is in screening and provide the subject number
from Study GS-US-312-0116
CIRS assessment
Recording of current comorbid conditions using the CIRS scoring instrument
(see Appendix 6)
Concomitant medications
Recording of ongoing concomitant medication use
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including height, weight, evidence of palpable lymphadenopathy, hepatomegaly, 
and/or splenomegaly
Serum β-HCG
Women of childbearing potential only
CLL peripheral blood 
evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 
12 trisomy; DNA mutational analysis for p53, IgHV (including IgHV3-21), and other 
genes of interest in CLL (eg, Notch); flow cytometry for CD5, CD10, CD11c, CD19, 
CD20, CD23, CD38, CD45, kappa and lambda light chains, and ZAP-70; 
cytology for karyotyping.
CLL serology
Serum 2 microglobulin
 
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis, to be scheduled with 
4 weeks prior to initiation of study treatment at Visit 2
Bone marrow biopsy and 
aspirate
To be performed at investigator discretion to determine extent of CLL involvement 
and bone marrow cellularity.
a
Study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be used as screening 
procedures for Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117.
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase,
AST=aspartate aminotransferase, CIRS=cumulative illness rating scale, CLL=chronic lymphocytic leukemia, CT=computed 
tomography, DNA=deoxyribonucleic acid, FISH= fluorescence in-situ hybridization, GGT=gamma--glutamyltransferase, 
Ig=immunoglobulin, IgHV=immunoglobulin heavy chain variable region, IWRS=interactive web response system, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging, RNA=ribonucleic acid, ZAP-70=zeta-associated protein 70
PPD


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6.2.2.
Visit 2 (Day 1) (Clinic Visit)
Subjects will be assessed to determine if they still meet eligibility criteria and can initiate study 
treatment. Study drug holds from primary study GS-US-312-0116 may continue as medically 
appropriate. The procedures outlined in Table 6-2 will be performed at Visit 2 (Day 1).
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
β-HCG
For women of child-bearing potential only; serum -HCG or urine dipstick pregnancy 
test must be negative prior to initial study treatment
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics
(with recording of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration
Study drug administrationa
First dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib
pharmacokineticsa
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensinga
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding study 
drug dosing at next full 
clinic visita
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 3.
a
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll on Study GS-US-312-0117 following 
unblinding may have idelalisib treatment (and associated PK testing) delayed at the Investigator’s discretion until the time of 
disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib treatment
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response 
system, LDH=lactate dehydrogenase, RNA=ribonucleic acid


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6.2.3.
Visit 3 (Day 15) (Clinic Visit)
The procedures outlined in Table 6-3 will be performed at Visit 3 (Day 15 [±2 days]).
Table 6-3.
Procedures and Assessments at Visit 3 (Day 15)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib pharmacokinetics
Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose). Pre-dose 
collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to document subject visit
Study Therapy Administration
Study drug administration
Study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Instruction regarding study 
drug dosing at next full 
clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 4.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase,
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, HRQL=health-related 
quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, LDH=lactate dehydrogenase


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6.2.4.
Visit 4 (Day 29) (Clinic Visit)
The procedures outlined in Table 6-4 will be performed at Visit 4 (Day 29 [±2 days]).
Table 6-4.
Procedures and Assessments at Visit 4 (Day 29)
Assessment or Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 3
Concomitant medications
Recording of concomitant medication used since Visit 3
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, IgM
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics
(with recording of the date and actual clock time of the date and actual clock time of 
blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration and Dispensing
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)


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Assessment or Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 5.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.5.
Visit 5 (Day 43) (Clinic Visit)
The procedures outlined in Table 6-5 will be performed at Visit 5 (Day 43 [±2 days]).
Table 6-5.
Procedures and Assessments at Visit 5 (Day 43)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
IWRS access
Access of IWRS to document subject visit
Post-Therapy Procedures and Assessments
Instruction regarding study 
drug dosing at next full 
clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 6.
Scheduling of Visit 6 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 6.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, 
LDH=lactate dehydrogenase


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6.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit)
The procedures outlined in Table 6-6 will be performed at Visit 6 (Day 57 [±2 days]).
Table 6-6.
Procedures and Assessments at Visit 6 (Day 57)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted.
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 5
Concomitant medications
Recording of concomitant medication used since Visit 5
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and 
CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug bottle number


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Assessment or Procedure
Explanation
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 8.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging
6.2.7.
Visit 7 (Day 71) (Laboratory Visit)
The procedures outlined in Table 6-7 will be performed at Visit 7 (Day 71 [±2 days]).
Table 6-7.
Procedures and Assessments at Visit 7 (Day 71)
Assessment or Procedure
Explanation
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including ALT, AST, ALP, GGT, total bilirubin, LDH
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
GGT=gamma-glutamyltransferase, LDH=lactate dehydrogenase


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6.2.8.
Visit 8 (Day 85) (Clinic Visit)
The procedures outlined in Table 6-8 will be performed at Visit 8 (Day 85 [±2 days]).
Table 6-8.
Procedures and Assessments at Visit 8 (Day 85)
Assessment or Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 6
Concomitant medications
Recording of concomitant medication used since Visit 6
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM, 
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration and Dispensing
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)


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Assessment or Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 9.
Scheduling of Visit 9 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 9.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit)
The procedures outlined in Table 6-9 will be performed at Visit 9 (Day 113 [±3 days]).
Table 6-9.
Procedures and Assessments at Visit 9 (Day 113)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit the assessment should be done even if study drug has been interrupted.
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 8
Concomitant medications
Recording of concomitant medication used since Visit 8
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and 
CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number


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Assessment or Procedure
Explanation
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 10.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.10.
Visit 10 (Day 141) (Clinic Visit)
The procedures outlined in Table 6-10 will be performed at Visit 10 (Day 141 [±3 days]).
Table 6-10.
Procedures and Assessments at Visit 10 (Day 141)
Assessment or Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 9
Concomitant medications
Recording of concomitant medication used since Visit 9
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug  blister card number
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)


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Assessment or Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 11.
Scheduling of Visit 11 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 11.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit)
The procedures outlined in Table 6-11 will be performed at Visit 11 (Day 169 [±3 days]). 
Table 6-11.
Procedures and Assessments at Visit 11 (Day 169)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted. 
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant medications
Recording of concomitant medication used since Visit 10
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card numbers


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Assessment or Procedure
Explanation
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for 
self-administration at home.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.12.
Visit 12 (Day 211) (Clinic Visit)
The procedures outlined in Table 6-12 will be performed at Visit 12 (Day 211 [±3 days]).
Table 6-12.
Procedures and Assessments at Visit 12 (Day 211)
Assessment or Procedure
Explanation
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 11
Concomitant medications
Recording of concomitant medication used since Visit 11
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit
Study drug administration
Subject to continue with study drug as prescribed.
Scheduling of Visit 13 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 13.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.13.
Visit 13 (Day 253) (Clinic and Radiology Visit)
The procedures outlined in Table 6-13 will be performed at Visit 13 (Day 253 [±3 days]).
Table 6-13.
Procedures and Assessments at Visit 13 (Day 253)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted.
During-Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant medications
Recording of concomitant medication used since Visit 10
Study drug return/
accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study drug administration
Subject to continue with study drug as prescribed.
Study drug dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for 
self-administration at home.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.14.
Visit 14 (Day 295) (Clinic Visit)
The procedures outlined in Table 6-14 will be performed at Visit 14 (Day 295 [±3 days]).
Table 6-14.
Procedures and Assessments at Visit 14 (Day 295)
Assessment or Procedure
Explanation
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant medications
Recording of concomitant medication used since Visit 10
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit
Study drug administration
Subject to continue with study drug as prescribed.
Scheduling of Visit 15 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 15.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.15.
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks)
(Clinic and Radiology Visits)
The procedures outlined in Table 6-15 will be performed at Visit 15 (Day 337 [±3 days]) and 
every 12 weeks thereafter [±7 Days]).
Table 6-15.
Procedures and Assessments at Visit 15 and Subsequent Visits
(Day 337 and Every 12 Weeks)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted.
During-Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since prior visit
Concomitant medications
Recording of concomitant medication used since prior visit
Study drug return/
accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
CMV viral load
CMV viral load testing approximately every 4 weeks throughout the course of 
idelalisib treatment
Circulating cells
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Immune monitoring
Lymphocyte subset panel using flow cytometry (immunophenotyping), 
serum CH50 level
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines


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Assessment or Procedure
Explanation
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study drug administration
Subject to continue with study drug as prescribed.
Study drug dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for 
self-administration at home
PJP prophylaxis
Subjects must receive trimethoprim-sulfamethoxazole or other established 
prophylaxis for PJP throughout the course of idelalisib treatment.  Subjects must 
permanently discontinue idelalisib upon diagnosis of PJP.
Scheduling of next visit 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for next 
clinic visit (every 12 weeks).
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CMV=cytomegalovirus, CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, 
FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related 
quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, PJP= Pneumocystis 
jirovecii pneumonia


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6.2.16.
End-of-Study Visit (Clinic Visit)
At the time of discontinuation from the study, the subject should have the procedures and 
assessments performed as documented in Table 6-16. An end-of-study CT/MRI tumor 
assessment should be performed unless the subject already has radiographic confirmation of 
definitive disease progression or a CT/MRI has been performed within 4 weeks prior to the 
end-of-study visit.
Table 6-16.
Procedures and Assessments at End-of-Study Visit
Assessment or Procedure
Explanation
Radiology assessmenta
CT or MRI imaging of neck, chest, abdomen, and pelvis
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed
Adverse events 
Recording of adverse events occurring since prior visit; if a clinically significant 
adverse event or abnormal result is observed that is not resolved by the 
end-of-treatment visit, repeat evaluations should be performed to document resolution 
or stabilization of the abnormality
Concomitant medications
Recording of concomitant medication used since prior visit
Study drug return/
accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Serum β-HCG
Women of childbearing potential only
CLL peripheral blood 
evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 
12 trisomy; DNA mutational analysis for p53, IgHV (including IgHV3-21), and other 
genes of interest in CLL (eg, Notch); flow cytometry for CD5, CD10, CD11c, CD19, 
CD20, CD23, CD38, CD45, kappa and lambda light chains, and ZAP-70; 
cytology for karyotyping
CLL serology
Serum 2 microglobulin
 
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
PPD


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Assessment or Procedure
Explanation
Circulating cells
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Immune monitoring
Lymphocyte subset panel using flow cytometry (immunophenotyping), serum CH50 
level
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
PJP prophylaxis
Subjects must receive trimethoprim-sulfamethoxazole or other established 
prophylaxis for PJP after completion of idelalisib treatment until the CD4+ T-cell 
count is > 200 cells/mcL, at which point PJP prophylaxis may be discontinued.
IWRS
Access IWRS to document that subject has permanently discontinued study therapy
and to indicate whether subject agrees to continue to undergo long-term follow-up
a
An end-of-study CT/MRI tumor assessment should be performed unless the subject has per-protocol CT/MRI assessments 
4 weeks prior to end-of-study discontinuation.
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, CLL=chronic lymphocytic leukemia, CT=computed tomography, FISH= fluorescence in-situ 
hybridization, GGT=gamma-glutamyltransferase, IgHV=immunoglobulin heavy-chain variable-region, IWRS=interactive web 
response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, PJP= Pneumocystis jirovecii pneumonia,
RNA=ribonucleic acid, ZAP-70=zeta-associated protein 70
6.2.17.
30 Day and Long-Term Follow-up
A 30 Day follow-up visit will be performed 30 (+ 5) days following the end-of-study visit; 
however, it may be waived for subjects who have permanently discontinued study drug and have 
had a study visit >30 days after the last dose of study drug.
Long-term, follow-up will be requested of all subjects who withdraw from study for any reason.
The long-term follow-up for survival will be conducted at ~6-month intervals for 5 years, 
starting at the end-of-study visit. Information may be gathered during a routine clinic visit or 
other contact with the subject, or via telephone. Information gathered will include medical status, 
anti-tumor treatments, secondary malignancies, and survival.
6.3.
Sample Storage
 
 
 
 
 
PPD


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6.4.
Blood Collection
The maximum amount of blood to be drawn at a visit ~115 mL and the total amount of blood to 
be drawn over the initial 52-week study period (including the 4-week screening period and 
through Week 48 of the study including a possible end-of-therapy visit) is ~560 mL. For a 
40-kg person (the smallest participant expected to enroll in the study), this equates to 
maximum blood volume per body weight per visit of ~2.8 mL/kg and a total blood volume 
per body weight per average 6-week period of ~1.6 mL/kg. These quantities of blood are within 
accepted limits of 3.0 mL/kg of body weight for a single blood draw and 7.0 mL/kg of 
body weight for a 6-week period.
Specific details regarding blood sample collection and processing requirements will be provided 
separately in the study manual.
 
 
 
6.5.
Study Procedure Rationale
The planned study assessments and timing have been selected as appropriate for screening of 
subjects, for determination of idelalisib-related or disease-related toxicities, for dose 
modification during the study, for characterization of drug exposure and desired pharmacological 
effects, and for evaluation of drug activity. The scheduling of testing is designed to collect a 
complete safety and pharmacology data set while maintaining subject tolerance of study 
procedures. The planned schedule of tumor assessments is consistent with expected rate of 
changes and appropriately balances precise measurement of tumor control with the expense and 
subject inconvenience associated with clinical and radiological procedures. For discussion of the 
rationale for endpoint selection, see Section 3.2.
PPD


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7.
EFFICACY ASSESSMENTS
7.1.
Tumor Status Assessments
The determination of CLL response and progression will be based on standardized IWCLL
criteria {Hallek et al 2008}, as specifically modified for this study to reflect current 
recommendations which consider the mechanism of action of idelalisib and similar drugs 
{Cheson et al 2012}. Treatment decisions by the investigator in this study will be based on these 
assessments. Radiographic and clinical tumor assessments will be subject to independent 
confirmation by the IRC (see Section 10.4.2).
7.2.
Method of Assessment
In addition to clinical examination, imaging-based evaluation will be used in this study in all 
subjects enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI 
scanning may be used at the investigator’s discretion in subjects for whom this may be a 
preferred alternative to CT scanning; however, if MRI is performed, a non-contrast CT of the 
chest should be performed. Contrast-enhanced scanning is preferred, but iodine-containing or 
gadolinium contrast material may be omitted in subjects for whom use of a contrast agent would 
be medically contraindicated. Chest x-ray, ultrasound, endoscopy, laparoscopy, PET, 
radionuclide scans, or tumor markers will not be considered for response assessment.
For radiographic evaluations, the same method of assessment and the same technique 
(eg, scan type, scanner, subject position, dose of contrast, injection/scan interval) should be used 
to characterize each identified and reported lesion at baseline and during study treatment and 
follow-up.
All relevant clinical and radiographic information required to make each tumor status assessment 
must be made available for source verification and for submission to the IRC 
(see Section 10.4.2).
7.3.
Timing of Assessments
All baseline clinical and CT/MRI tumor assessments should be performed within 4 weeks prior 
to initiation of study drug therapy. In order to optimize scheduling convenience for the subject 
and for the investigational staff, clinical and CT/MRI tumor assessments performed as part of 
Study GS-US-312-0116 need not be repeated and can be used as baseline tumor assessments for 
Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117. Clinical tumor assessments should be performed at each clinical visit. 
On-study CT/MRI tumor assessments should be performed at ~8- to 12-week intervals as 
dictated by the study protocol. An end-of-study CT/MRI tumor assessment should be performed 
unless the subject has per-protocol CT/MRI assessments 4 weeks prior. If a subject 
permanently discontinues study drug prior to objective documentation of CLL progression, 
investigators should continue further follow-up at ~12-week intervals until CLL progression is 
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7.4.
Identification and Measurement of Tumor Lesions and Organomegaly
7.4.1.
Index Lesions
At baseline, up to 6 lymph nodes should be selected as index lesions that will be used to 
quantitate the status of the disease during study treatment. Ideally, the index lesions should be 
located in disparate regions of the body. Only peripheral nodes need be selected as index lesions. 
However, it is optimal if mediastinal and retroperitoneal areas of disease are assessed whenever 
these sites are involved.
Index lesions will be measured and recorded at baseline and at the stipulated intervals. The 
cross-sectional dimensions (the largest cross-sectional diameter, ie, the LD × LPD) will be 
recorded (in cm) for each index lesion. The product of the perpendicular diameters (PPD) 
(in cm2) for each index lesion and the sum of the products (SPDs) (in cm2) for all index lesions 
will be calculated and recorded. The baseline SPDs will be used as references by which tumor 
response will be characterized during treatment. The nadir LD of individual lesions and the nadir 
SPD will be used as references by which CLL progression will be characterized. All LD and 
LPD diameters will be reported in centimenters and all PPDs and SPDs will be reported in 
centimeters squared.
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable at 
baseline. A lymph node lesion is considered abnormal if it has a single diameter that is 1.5 cm 
and is considered measurable if it has 2 perpendicular diameters that can be accurately measured 
in cross section with the LD being 1.0 cm and the LPD also being 1.0 cm.
At follow-up time points, the LDs for individual lesions and the SPD of all nodal index lesions 
will be considered. Because nodal index lesions that have one or both diameters 
>0 cm and 1.0 cm cannot be reliably measured, a default value of 1.0 cm will be assigned for 
each diameter that meets these criteria and the resulting PPD will be used in SPD calculations. 
Based on this convention, a CR may be achieved even if an SPD value is >0 cm2, 
(ie, if all lymph nodes measure <1.0 cm2).
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD will be considered 
progressive disease.
In cases in which a large lymph node mass has split into multiple components, all 
subcomponents regardless of size will be used in calculating the SPD. Progression of the lesion 
will be based on the SPD of sub-components. Lesion sub-components will have the true PPDs 
calculated. Similarly, lesion sub-components that are visible but neither abnormal nor 
measurable will have the default PPD of 1.0 cm2 (1.0 cm 1.0 cm) used in calculating the SPD.
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer 
be separated by this boundary, the newly merged lesion will be measured bi-dimensionally.


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7.4.2.
Spleen and Liver
Both the spleen and liver will be assessed by CT/MRI scan at baseline and at the stipulated 
intervals during treatment. The baseline and nadir values for the longest vertical dimension 
(LVD) of each organ will be used as reference to further characterize the objective tumor 
response of the measurable dimensions of the CLL during treatment. All spleen and liver LVD 
measurements should be recorded in centimeters.
By imaging, the spleen will be considered enlarged if it is >12 cm in LVD {Bezerra et al 2005}, 
{Asghar et al 2011}.
For subjects with splenomegaly at baseline or at the splenic LVD nadir, respective response and 
progression evaluations of the spleen will consider only changes relative to the enlargement of 
the spleen at baseline or nadir, not changes relative to the total splenic LVD.
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen in its LVD or 
decrease to ≤12 cm in the LVD, is required for declaration of a splenomegaly response. 
Conversely, an increase in splenic enlargement by ≥50% from nadir 
(with a minimum 2 cm increase) is required for declaration of splenic progression.
By imaging, the liver will be considered enlarged if it is >18 cm in LVD {Erturk et al 2006}.
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the liver in its LVD or 
decrease to ≤ 18 cm in the LVD is required for declaration of a hepatomegaly response. 
Conversely, an increase in liver enlargement by ≥50% from nadir 
(with a minimum 2 cm increase) is required for declaration of hepatic progression.
7.4.3.
Non-Index Lesions
Any other measurable and abnormal nodal lesions not selected for quantitation as index lesions 
may be considered non-index lesions. In addition, non-measurable evidence of CLL such as 
nodal lesions with both diameters <1.0 cm, extra-nodal lesions, bone lesions, leptomeningeal 
disease, ascites, pleural or pericardial effusions, lymphangitis of the skin or lung, abdominal 
masses that are not confirmed and followed by imaging techniques, cystic lesions, previously 
irradiated lesions, lesions with artifacts, and may be considered as non-index disease.
The presence or absence of non-index disease should be recorded at baseline and at the stipulated 
intervals during treatment. If present at baseline, up to 6 non-index lesions should be recorded. 
The non-index disease at baseline will be used as a general reference to further characterize 
regression or progression of CLL during assessments of the objective tumor response during 
treatment. Measurements are not required and these lesions should be followed as 
“present” or “absent”.
7.5.
Definitions of Tumor Response and Progression
Responses will be categorized by the IRC as CR, PR, SD, or PD. In addition, a response category 
of not evaluable (NE) is provided for situations in which there is inadequate information to 


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otherwise categorize response status. A response category of no disease (ND) is included for 
situations in which there is absence of tumor both at baseline and on treatment.
The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until disease/recurrence progression (taking as a reference 
for disease progression the smallest measurements recorded since treatment started). Subjects 
with a best overall response of NE or ND will be counted in the denominators in calculations of 
tumor response rates.
7.5.1.
Complete Response
To satisfy criteria for a CR, all of the following criteria must be met:

No evidence of new disease

ALC in peripheral blood of <4 x 109/L

Regression of all index nodal masses to normal size (1.5 cm in the LD)

Normal spleen and liver size

Regression to normal of all nodal non-index disease and disappearance of all detectable 
non-nodal, non-index disease

Morphologically negative bone marrow defined as <30% of nucleated cells being lymphoid 
cells and no lymphoid nodules in a bone marrow sample that is normocellular for age

Peripheral blood counts meeting all of the following criteria:
ANC >1.5 x 109/L without need for exogenous growth factors (eg, G-CSF)
Platelet count 100 x 109/L without need for exogenous growth factors or transfusions
Hemoglobin 110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (eg, erythropoietin)
Note: Subjects who fulfill all the criteria for a CR (including bone marrow criteria) but who 
have a persistent anemia, thrombocytopenia, or neutropenia or a hypocellular bone marrow 
that is related to prior or ongoing drug toxicity (and not to CLL) will be considered as a CR 
with incomplete marrow recovery (CRi).
7.5.2.
Partial Response
To satisfy criteria for a PR, all of the following criteria must be met:

No evidence of new disease


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
A change in disease status meeting 2 of the following criteria, with 2 exceptions in which 
only 1 criterion is needed: (1) Only lymphadenopathy is present at baseline; 
(2) Only lymphadenopathy and lymphocytosis are present at baseline. In these 2 cases, only 
lymphadenopathy must improve to the extent specified below:
In a subject with baseline lymphocytosis (ALC4 x 109/L), a decrease in 
peripheral blood ALC by 50% from baseline or a decrease to <4 x 109/L
A decrease by 50% from the baseline in the SPD of the index nodal lesions
In a subject with enlargement of the spleen at baseline, a splenomegaly response, defined 
as a ≥50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen or 
decrease to ≤12 cm in the LVD by imaging
In a subject with enlargement of the liver at baseline, a hepatomegaly response, defined
as a ≥50% decrease (minimum 2 cm) from baseline in the enlargement of the liver or 
decrease to ≤18 cm in the LVD by imaging
A decrease by 50% from baseline in the CLL marrow infiltrate or in 
B-lymphoid nodules

No index, splenic, liver, or non-index disease with worsening that meets the criteria for 
definitive PD

Peripheral blood counts meeting 1 of the following criteria:
ANC >1.5 x 109/L or 50% increase over baseline without need for exogenous growth 
factors (eg, G-CSF)
Platelet count 100 x 109/L or 50% increase over baseline without need for 
exogenous growth factors or transfusions
Hemoglobin 110 g/L (11.0 g/dL) or 50% increase over baseline without red blood cell 
transfusions or need for exogenous growth factors (eg, erythropoietin)
7.5.3.
Stable Disease
To satisfy criteria for stable disease (SD), the following criteria must be met:

No evidence of new disease

There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD


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7.5.4.
Definitive Progressive Disease
The occurrence of any of the following events indicates definitive PD:

Evidence of any new disease:
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD
New or recurrent splenomegaly, with a minimum LVD of 14 cm
New or recurrent hepatomegaly, with a minimum LVD of 20 cm
Unequivocal reappearance of an extra-nodal lesion that had resolved
A new unequivocal extra-nodal lesion of any size
New non-index disease (eg, effusions, ascites, or other organ abnormalities 
related to CLL)
Note: Isolated new effusions, ascites, or other organ abnormalities are not sufficient evidence 
alone of PD unless histologically confirmed. Thus, a declaration of PD should not be made if 
this is the only manifestation of apparently new disease.

Evidence of worsening of index lesions, spleen or liver, or non-index disease:
Increase by 50% from the nadir in the SPD of index lesions
Increase from the nadir by 50% in the LD of an individual node or extra-nodal mass that 
now has an LD of >1.5 cm and an LPD of > 1.0 cm
Splenic progression, defined as an increase in splenic enlargement by 50% from nadir 
(with a minimum 2 cm increase and a minimum LVD of 14 cm)
Hepatic progression, defined as an increase in hepatic enlargement by 50% from nadir 
(with a minimum 2 cm increase and minimum LVD of 20 cm)
Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or other 
organ abnormalities related to CLL) 
Transformation to a more aggressive histology (eg, Richter syndrome) as established by 
lymph node or other tissue biopsy, or fluid cytology (with the biopsy or fluid cytology 
date being considered the date of CLL progression if the subject has no earlier objective 
documentation of CLL progression).


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
Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to an 
autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an infiltrate of 
clonal CLL cells
The current platelet count is <100 x 109/L and there has been a decrease by >50% from 
the highest on-study platelet count
The current hemoglobin is <110 g/L (11.0 g/dL) and there has been a 
decrease by >20 g/L (2 g/dL) from the highest on-study hemoglobin
Note: If there is uncertainty regarding whether there is true progression, the subject should 
continue study treatment and remain under close observation 
(eg, evaluated at 4-week intervals) pending confirmation of progression status by the IRC. In 
particular, worsening of constitutional symptoms in the absence of objective evidence of 
worsening CLL will not be considered definitive disease progression; in such subjects, both 
CLL-related and non-CLL-related causes for the constitutional symptoms should be 
considered. Worsening of disease during temporary interruption of study treatment 
(eg, for intercurrent illness) is not necessarily indicative of resistance to study treatment. In 
these instances, CT/MRI or other relevant evaluations should be considered in order to 
document whether definitive disease progression has occurred. If subsequent evaluations 
suggest that the subject has experienced persistent definitive CLL progression, then the date of 
progression should be the timepoint at which progression was first objectively documented.
7.5.5.
Non-Evaluable
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE:

There are no images or inadequate or missing images

Images of the liver and spleen are missing at that time point (with the exception that absence 
of splenic images will not result in an NE designation in a subject known to have 
undergone splenectomy).
Note: A time-point will be considered to have a response of NE if any index lesion is missing. 
PD may be assigned at any time point regardless of the extent of missing index or 
non-index lesions. Missing non-index lesions will not impact the ability to assess for response 
or disease progression.
7.5.6.
No Disease
Subjects have a status of ND if all of the following conditions occur:

No index disease noted at baseline or on-treatment 

No non-index disease noted at baseline or on-treatment.


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
No enlargement of the liver or spleen at baseline or on-treatment

No abnormalities of peripheral blood counts (elevated ALC or abnormally low ANC, 
platelet count, or hemoglobin) and no evidence of CLL in bone marrow (if available) at 
baseline or on treatment
7.5.7.
Lymphocytosis During Therapy
Idelalisib can mobilize CLL cells from tissues into the peripheral blood. This characteristic 
pharmacological action can be prominent early in therapy but can persist over time and should 
not be confused with disease progression in subjects who have persistent control of other 
CLL-related signs and symptoms. In the absence of other objective evidence of disease 
progression, lymphocytosis alone will not preclude subjects from meeting the criteria for PR if 
other criteria for PR are met and will not be considered evidence of disease progression if 
occurring in isolation. Subjects with lymphocytosis should be continued on study drug until the 
occurrence of definitive disease progression (ie, disease progression that is manifest by 
worsening CLL-related signs other than lymphocytosis alone), or the occurrence of another 
reason to discontinue study therapy as described in Section 5.8.
7.5.8.
Documentation of Definitive CLL Progression
Of importance, CLL response and progression data collected from the primary study will be 
subjected to IRC review (see Section 10.4.2). Subjects must have confirmation by the sponsor 
working in collaboration with the IRC that the disease has progressed on the primary clinical 
trial (Study GS-US-312-0116) before being permitted to receive secondary idelalisib therapy 
on this extension trial (GS-US-312-0117). Subjects should continue study drug pending 
confirmation of progression status. CT/MRI should be attempted in order to document definitive 
disease progression by the IRC. The end-of study scan from the primary study can serve as the 
baseline scan for the extension study if obtained within the specific screening period for the 
extension study. If obtained within the specified screening period for the extension study, this 
scan can serve as the baseline scan for the extension study.


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8.
SAFETY ASSESSMENTS
8.1.
Adverse Event Definitions
8.1.1.
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical product which; does not necessarily have a causal relationship 
with study drug administration or usage. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Lymphocytosis

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 5.2.8)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
In this study, any of the following events will be considered an adverse event:

Any complication that occurs as a result of a protocol-mandated procedure 
(eg, venipuncture, biopsy) in the screening, on-treatment, or post-treatment periods.

Any pre-existing condition that increases in severity or changes in nature during or as a 
consequence of study drug administration. Worsening manifestations of the underlying 
cancer (eg, increase in pain, tumor flare reaction, tumor lysis syndrome) may be considered 
adverse events in this study.


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
Any injury or accident occurring during the screening, on-treatment, or post-treatment 
periods. If a medical condition is known to have caused the injury or accident 
(eg, a fall secondary to dizziness), the medical condition (dizziness) and the accident (fall) 
should be reported as 2 separate adverse events. 

Any abnormality in physiological testing or a physical examination finding that requires 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test).

Any laboratory (eg, clinical chemistry, hematology, urinalysis) or investigational abnormality 
(eg, ECG, X-ray) independent of the underlying medical condition that requires clinical
intervention, results in further investigation (beyond ordering a repeat [confirmatory] test), or 
leads to investigational medicinal product interruption or discontinuation unless it is
associated with an already reported clinical event. If the laboratory abnormality is part of a 
syndrome, the syndrome or diagnosis (eg, anemia) not the laboratory result 
(eg, decreased hemoglobin) should be recorded. 

A complication related to pregnancy or termination of a pregnancy (see Section 5.4.10 for 
additional information).
8.1.2.
Serious Adverse Event
A serious adverse event (SAE) is defined as an event that results in any of the following:

Death

Life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization.

Persistent or significant disability/incapacity.

A congenital anomaly/birth defect

A medically important event or reaction. Such events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the outcomes listed above. Examples of such events 
might include:
Allergic bronchospasm requiring intensive treatment in an emergency room or at home
New cancers or blood dyscrasias
Convulsions that do not result in hospitalization
Development of drug dependency or drug abuse


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Medical and scientific judgment must be exercised to determine whether such an event is 
reportable under expedited reporting rules.
Infections resulting from contaminated medicinal product will be considered a medically 
important event and subject to expedited reporting requirements.
Given the endpoints of the study, in order to maintain the integrity of the study the following 
events that are assessed as unrelated to IMP will not be considered SAEs:

Progression of CLL

Death related to progression of CLL
Disease progression and death from disease progression should be reported as SAEs by the 
investigator only if it is assessed that the IMPs caused or contributed to the disease progression 
(i.e., by a means other than lack of effect). Unrelated disease progression and death due to 
disease progression should be captured on the eCRF.
These events will be reported, as appropriate, in the final clinical study report and in any relevant 
aggregate safety reports. The safety information from this study will also be reviewed by an 
independent DMC on an ongoing basis. The DMC can have access to partially blinded or 
unblinded data in order to determine if it is safe to continue the study according to the protocol.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Section 8.5. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result 
(ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 5.4.
8.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.


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8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting.
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed from screening 
onwards.
All AEs, regardless of cause or relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP must be reported to the CRF/eCRF database as 
instructed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported.
All AEs should be followed up until resolution if possible. If by the last day on study 
(including the off-study medication follow-up period) the AE has not resolved, then the AE will 
be followed up until the investigator and/or Gilead Sciences determine that the subject's 
condition is stable. However, Gilead Sciences may request that certain AEs be followed until 
resolution.


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Investigators are not obligated to actively seek SAEs after the above period. However, if the 
investigator learns of any SAEs that occur after study participation has concluded and the event 
is deemed relevant to the use of IMP, he/she should promptly document and report the event to 
Gilead DSPH.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.

At the time of study start, SAEs will be reported using a paper serious adverse event 
reporting form. During the study conduct, sites may transition to an electronic SAE (eSAE) 
system. Gilead will notify sites in writing and provide training and account information prior 
to implementing an eSAE system.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by faxing 
the report form within 24 hours of the investigator’s knowledge of the event to the attention 
of Gilead DSPH or to the designated CRO.
8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to expedite 
to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the 
EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide 
regulatory agencies and the relevant IEC in concerned Member States of applicable SUSARs as 
outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the IRB or IEC of SUSAR reports as soon as is practical, where this is 
required by local regulatory agencies, and in accordance with the local institutional policy.
8.5.
Grading of the Severity of an Adverse Event
The severity of adverse events will be graded using the CTCAE, Version 4.03 (provided in 
study manual and available at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). For 
each episode, the highest severity grade attained should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or 
Grade 5 (fatal) to describe the maximum intensity of the adverse event. For purposes of 
consistency with the CTCAE, these intensity grades are defined in Table 8-1.


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Table 8-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Sign or symptom is present, but it is easily tolerated, is not expected to have a 
clinically significant effect on the subject’s overall health and well-being, does not 
interfere with the subject’s usual function, and is not likely to require medical 
attention.
Grade 2
Moderate
Sign or symptom causes interference with usual activity or affect clinical status, and 
may require medical intervention.
Grade 3
Severe
Sign or symptom is incapacitating or significantly affects clinical status and likely 
requires medical intervention and/or close follow-up.
Grade 4
Life-threatening
Sign or symptom results in a potential threat to life.
Grade 5
Fatal
Sign or symptom results in death.
The distinction between the seriousness and the severity of an adverse event should be noted. 
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For 
example, a headache may be severe in intensity, but would not be classified as serious unless it 
met one of the criteria for serious events listed in Section 8.1.2 above.
8.6.
Adverse Event Reporting Period
The start of the adverse event reporting for a study subject will coincide with signing of the 
informed consent for Study GS-US-312-0117. Any new adverse events occurring thereafter 
should not be reported within Study GS-US-312-0116, but instead should be reported within
Study GS-US-312-0117. The end of the adverse-event-reporting period for 
Study GS-US-312-0117 occurs 30 days after the discontinuation from study drug or when any 
ongoing drug-related adverse events and/or serious adverse events have resolved or become 
stable. A subject withdrawn from the study because of an adverse event must be followed until 
the clinical outcome from the adverse event is determined. The investigator should use 
appropriate judgment in ordering additional tests as necessary to monitor the resolution of events 
ongoing at the completion of study treatment. Gilead Sciences may request that certain adverse 
events be followed longer.
Investigators are not obligated to actively seek information regarding the occurrence of new 
serious adverse events beginning after the 30-day post-study period. However, if the investigator 
learns of such a serious adverse event and that event is deemed relevant to the use of the study 
drug, he/she should promptly document and report the event. A longer reporting period applies in 
the case of pregnancy (see Section 8.9.1)
8.7.
Adverse Event Reporting Requirements
8.7.1.
Site Reporting Requirements
Classification of an event as serious or nonserious (see Section 8.1.2) determines the reporting 
procedures to be followed by the site.


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Site reporting requirements for adverse events are summarized in Table 8-2, below.
Table 8-2.
Site Reporting Requirements for Adverse Events
Classification
Reporting Time
Reporting Action
Serious
Within 24 hours
Fax report on designated serious adverse event report form 
to PPD Pharmacovigilancea, and to the site IRB/IEC, 
as per local IRB/IEC requirements; include copies of 
relevant source documentsb (eg, progress notes, 
autopsy reports, laboratory and diagnostic test results, 
discharge summaries) in communication to 
PPD Pharmacovigilancea
Per eCRF submission procedurec
Record and submit information on appropriate eCRFs
Nonserious
Per eCRF submission procedure
Record and submit information on appropriate eCRFs
a
See contact information in Table 8-3 below.
b
Subject name, address, and other personal identifiers should be obscured but without losing the traceability of a document to
the study subject identifiers.
c
CLL progression or death due to CLL progression should be reported by the investigator as a serious adverse event only if it 
is assessed that the study drugs caused or contributed to the CLL progression (ie, by a means other than lack of effect). 
Unrelated events of CLL progression should be captured on the appropriate eCRF. 
Abbreviations: CLL = chronic lymphocytic leukemia, eCRF=case report form, IRB/IEC= Institutional Review Board/
Independent Ethics Committee
For serious adverse events, in addition to completing the adverse event portion of the eCRF, the 
serious adverse event report form must also be completed. The information in the adverse event 
portion of the eCRF page and the serious adverse event report form(s) must match or be 
reconciled. Where the same data are collected, the forms must be completed in a consistent 
manner. For example, the same adverse event term should be used on both forms. Particularly for 
fatal or life-threatening events, copies of progress notes, autopsy reports, laboratory and 
diagnostic test results, discharge summaries, and other relevant documents should be faxed when 
requested and applicable. Follow-up information to the serious adverse event should be clearly 
documented as “follow up” in the serious adverse event report form and must be faxed to these 
same parties. Gilead Sciences may request additional information from the investigator to ensure 
the timely completion of accurate safety reports.
The subject’s name, address, and other personal identity information should be obscured on any 
source documents (eg, progress notes, nurses’ notes, laboratory and diagnostic test results, 
discharge summaries). Only the subject’s study number, initials, or date of birth are to be 
provided.
The serious adverse event report form must be communicated to PPD Pharmacovigilance and to 
the site IRB/IEC (if required by local regulations) within 24 hours. In the rare event that the 
investigator does not become aware of the occurrence of a serious adverse event immediately 
(for example, if a subject initially seeks treatment elsewhere), the investigator is to report the 
event within 24 hours after learning of it and to document his/her first awareness of the adverse 
event.


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Contact details for PPD Pharmacovigilance and for the Gilead study medical monitor are 
provided in Table 8-3:
Table 8-3.
Contact Information for Reporting Serious Adverse Events
Function
Contact Information
PPD Pharmacovigilance
(US)
Facsimile:
PPD Pharmacovigilance
(International)
Facsimile:
Gilead Sciences
Medical Monitor
Name:
Title: 
Medical Monitor, Clinical Research
Telephone:
Facsimile:
E-mail:
8.7.2.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population
To maintain the integrity of the study, progression of CLL and death related to progression of 
CLL will not be reported to Gilead Sciences as serious adverse events unless it is assessed that 
the study drug caused or contributed to CLL progression or death related to CLL progression 
(ie, by a means other than lack of effect). These events will be exempt from global expedited 
reporting requirements for the duration of the study because they define the primary efficacy 
endpoint for this study. All events of progression of CLL and death related to progression of 
CLL, regardless of relationship to study drug, will be reported in the eCRFs and, as appropriate, 
in the final clinical study report and in any relevant aggregate safety reports. Disease progression 
information from this study will be reviewed by an independent DMC on an ongoing basis.
8.8.
Special Situations Reporting Requirements
8.8.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, lack of 
effect reports and pregnancy reports regardless of an associated AE. Also includes reports of 
adverse reactions in infants following exposure from breastfeeding, and reports of adverse 
reactions associated with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following possible maternal or paternal 
exposure to the medicinal product.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Lack of effect is defined as a situation where there is apparent failure of the medicinal product or 
medical technology to bring about the intended beneficial effect on the individual in a defined 
population with a given medical problem, under ideal conditions of use.
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
8.9.
Instructions for Reporting Special Situations
8.9.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (ie, signs the informed consent) and throughout the study, including the 
post study drug follow-up period, to the  or Gilead DSPH ] using the pregnancy report form 
within 24 hours of becoming aware of the pregnancy. Refer to the CRF/eCRF completion 
guidelines for full instructions on the mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE, and therefore should be reported as 
such. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must be 
reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to PPD Pharmacovigilance or Gilead DSPH using 
the pregnancy outcome report form. If the end of the pregnancy occurs after the study has been 
completed, the outcome should be reported directly to Gilead DSPH. Gilead DSPH 
contact information is as follows: Email:
 and Fax:
PPD
PPD


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Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to PPD Pharmacovigilance 
or Gilead DSPH using the pregnancy and pregnancy outcome forms within 24 hours. Monitoring 
of the subject should continue until the conclusion of the pregnancy. If the end of the pregnancy 
occurs after the study has been completed, the outcome should be reported directly to 
Gilead DSPH, fax number
 or email 
8.9.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to PPD Pharmacovigilance or Gilead DSPH within 24 hours of the investigator 
becoming aware of the situation. These reports must consist of situations that involve study IMP, 
but do not apply to concomitant medications. Except for situations that result in AEs, special 
situations involving concomitant medications will not be reported. Any inappropriate use of 
medications prohibited by this protocol should not be reported as “misuse,” but may be more 
appropriately documented as a protocol deviation.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.
PPD
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9.
STATISTICAL CONSIDERATIONS
9.1.
Analysis Objectives
As described in Section 3, the objectives of this clinical trial will focus on determining the effect 
of idelalisib on the onset, magnitude, and duration of tumor control; measures of patient 
well-being (including OS, HRQL; and changes in subject performance status); disease-associated 
biomarkers and potential mechanisms of resistance; treatment administration; safety; and health 
resource utilization.
9.2.
Analysis Endpoints
The endpoints of the study are defined in Section 3.1, grouped in categories relating to tumor 
control, patient well-being, pharmacodynamic markers of drug activity and resistance, exposure, 
safety, and pharmacoeconomics.
9.3.
Analysis Conventions
9.3.1.
Analysis Sets
9.3.1.1.
Intent-to-Treat Analysis Set
The ITT analysis set includes all subjects who receive 1 dose of any study treatment 
(high-dose idelalisib or standard-dose idelalisib). In the ITT analysis set, study drug assignment 
will be designated according to planned allocation in this study, regardless of whether subjects 
receive a different study therapy from that to which they were allocated.
This analysis set will be used in the analyses of subject characteristics and all the tumor control 
and patient well-being endpoints. Subjects in the ITT analysis set who do not have sufficient 
baseline or on-study tumor status information to be adequately assessed for response status will 
be included in the denominators in the calculation of response rates.
9.3.1.2.
Per-Protocol Analysis Set
The PP analysis set includes data from subjects in the ITT analysis set who meet the general 
criteria defining the target population for this study, are adherent to the protocol, are compliant 
with study drug treatment, and are evaluable for relevant efficacy endpoints. Treatment 
assignment will be designated according to the actual treatment received. The specific 
classification of subjects to be included in the PP analysis set will be included in the statisticial 
analysis plan which will be finalized prior to the database lock.
The PP analysis set will be used in sensitivity analyses of these tumor control and patient 
well-being endpoints: PFS, ORR, lymph node response rate, OS and CR rate.


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9.3.1.3.
Safety Analysis Set
A safety analysis set will include subjects in the ITT analysis set grouped for analyses with 
treatment assignments designated according to the actual study drug received.
This analysis set will be used in the analyses of safety variables as well as study treatment 
administration, and health economic variables.
9.3.1.4.
Pharmacodynamic and/or Pharmacokinetic Analysis Sets
The pharmacodynamic and/or pharmacokinetic analysis sets include data from subjects in the 
safety analysis set who have the necessary baseline and on-study measurements to provide 
interpretable results for the specific parameters of interest. 
These analysis sets will be used in the analyses of AKT phosphorylation, chemokines/cytokines, 
and idelalisib plasma concentrations.
9.3.2.
Data Handling Conventions
9.3.2.1.
General Methods 
By-subject listings will be created for important variables from each eCRF module. 
Summary tables for continuous variables will contain the following statistics: 
N (number in population), n (number with data), mean, standard deviation, 
95% confidence intervals (CIs) on the mean, median, minimum, and maximum. Summary tables 
for categorical variables will include: N, n, percentage, and 95% CIs on the percentage. Unless 
otherwise indicated, 95% CIs for binary variables will be calculated using the binomial 
distribution (exact method) and will be 2-sided. Data will be described and summarized by 
relevant treatment arm, analysis set, and timepoint. As appropriate, changes from baseline to 
each subsequent timepoint will be described and summarized by treatment arm. Similarly, as 
appropriate, the best change from baseline during the study will also be described and 
summarized by treatment arm. Graphical techniques (eg, waterfall plots, 
Kaplan-Meier curves, line plots) may be used when such methods are appropriate and 
informative.
Data from all sites will be pooled for all analyses. Analyses will be based upon the observed data 
unless methods for handling missing data are specified. If there is a significant degree of 
non-normality, analyses may be performed on log-transformed data or nonparametric tests may 
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9.3.2.2.
Double-Blinded Portion of the Study Analyses
Efficacy and safety data collected during the blinded portion of Study GS-US-312-0117 will be 
presented in the following 2 groups:

IDELA 300 mg BID: Subjects who have PD per IRC confirmation in Arm A of 
Study GS-US-312-0116 and subsequently enroll into Study GS-US-312-0117 to receive 
IDELA 300 mg BID during the double-blind portion of the study

Placebo in Study GS-US-312-0116 + IDELA 150 mg BID in Study GS-US-312-0117: 
Subjects who have PD per IRC confirmation in Arm B of Study GS-US-312-0116 and 
subsequently enroll Study GS-US-312-0117 to receive IDELA 150 mg BID during the 
double-blind portion of the study
All analyses will be performed based on the data collected during the blinded-portion of the 
extension study. Time-to-event analyses will reference to the date of first treatment on this 
clinical trial (Study GS-US-312-0117). Similarly, evaluations of on-therapy changes will 
reference the baseline values obtained prior to treatment in this study. The baseline value used in 
each analysis will be the last (most recent) pre-treatment value. Analyses will be descriptive in 
nature and formal comparisons of outcomes in the 2 groups are not planned.
9.3.2.3.
Open-Label Extension Study Analyses
GS-US-312-0117 will become an open-label study offering idelalisib 150 mg BID to 
GS-US-312-0116 subjects who were randomized to Arm B. Subjects randomized to Arm A will 
continue idelalisib at 150 mg BID. Efficacy and safety data collected during the primary and 
open-label extension studies will be presented in the following 4 groups:

IDELA 150 mg BID: Subjects who are randomized to Arm A in Study GS-US-312-0116 and 
transition to Study GS-US-312-0117 during the open-label portion of the study to continue 
IDELA 150 mg BID

Placebo in GS-US-312-0116 + IDELA 150 mg BID (open-label): Subjects who are 
randomized to Arm B in Study GS-US-312-0116 and transition to receive 
IDELA 150 mg BID during the open-label portion of the study

IDELA 300 mg BID: Subjects who have PD per IRC confirmation in Arm A of 
Study GS-US-312-0116 and subsequently enroll Study GSUS-312-0117 to receive 
IDELA 300 mg BID during double-blind portion of the study

Placebo in GS-US-312-0116 + IDELA 150 mg BID in GS-US-312-0117: Subjects who have 
PD per IRC confirmation in Arm B of Study GS-US-312-0116 and subsequently enroll 
Study GS-US-312-0117 to receive IDELA 150 mg BID during double-blind portion of the 
study.


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Depending on the endpoints, analyses may be based on the combined data from both primary and 
extension studies or data from the extension study alone. Analyses will be descriptive in nature 
and formal comparisons of outcomes in the 4 groups are not planned. A separate statistical 
analysis plan will be created for the open-label portion of the study.
9.3.2.4.
Calculation of Tumor Control and Patient Well-Being Variables
Tumor control assessments will be based on standardized IWCLL criteria {Hallek et al 2008}
{Cheson et al 2012}, as specifically modified for this study considering the pharmacology of 
idelalisib. The individual and composite endpoints of response and progression 
(considering changes in lymph node area, liver and spleen size, bone marrow, platelet counts, 
hemoglobin, neutrophil counts, and peripheral blood lymphocyte counts) will be determined. 
Tumor control will be documented at each assessment by response category (eg, CR, PR, SD, 
definitive PD, NE, ND) as defined for each response parameter, SPD value, percentage change in 
SPD values from baseline or nadir, date that response is first documented and date of definitive 
CLL progression.
The date of definitive CLL progression will be the timepoint at which progression is 
first identified by relevant objective radiographic or laboratory data. Because of the characteristic 
redistribution lymphocytosis that is expected with PI3Kinhibition, lymphocyte count will be 
ignored in the evaluation of progression. Changes in tumor status as provided by the investigator 
and changes in tumor status as adjudicated by the IRC (see Section 10.4.2) will be described. 
The findings of the IRC will be considered primary for analyses of all tumor control endpoints.
The following censoring conventions will be applied:

PFS and DOR: Data from surviving, non-progressing subjects will be censored at the earliest 
of the time of initiation of antitumor treatment other than the study treatment or the last time 
that lack of definitive CLL progression was objectively documented. Data from subjects who 
have CLL progression or die after 2 consecutive missing tumor assessments will be 
censored at the last time prior to the missing assessments that lack of definitive CLL 
progression was objectively documented.

OS: Data from surviving subjects will be censored at the last time that the subject was known 
to be alive.
9.4.
Analysis Plan
9.4.1.
Subject Disposition and Baseline Characteristics
A listing of all ITT analysis subjects will be generated to describe site, subject number, 
first screening date, first treatment date, allocated study drug assignment, actual study drug 
assignment, the longest duration of study drug treatment, and the reason for discontinuing study 
treatment. Available information on subjects who were screened or registered but not treated will 
be listed separately. A table will be created summarizing these categories in terms of number and 
percent for the ITT analysis set.


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Subject baseline characteristics will be listed and summarized by treatment arm for the 
ITT analysis set. As appropriate for the specific variable, subject baseline characteristics
acquired in Study GS-US-312-0116 will be referenced in Study GS-US-312-0117.
9.4.2.
Efficacy Analyses
9.4.2.1.
Time-to-Event Tumor Control and Survival Endpoints
PFS, DOR and OS will be described in the ITT analysis set using Kaplan-Meier methods by 
treatment group. Medians, ranges, and corresponding 95% CIs will be presented.
The Cox regression approach may be used to explore the influence of the primary study 
stratification factors and other baseline characteristics on PFS and OS. The stratification 
variables from the primary study and additional baseline subject characteristics may be included 
as covariates, focusing on those with expected prognostic significance.
9.4.2.2.
Categorical Endpoints
Response rates, lymph node response rate, splenomegaly response rate, 
hepatomegaly response rate, ALC response rate, platelet response rate, hemoglobin response 
rate, and neutrophil response rate will be described. In the calculation of response rates, subjects 
who do not have sufficient baseline or on-study tumor assessment to characterize response will 
be included in the denominator. For all analyses, the corresponding 95% CIs will be presented.
The potential influence of subject baseline characteristics on response rates may be explored
with multiple logistic regression modeling.
9.4.2.3.
Continuous Endpoints
Changes in lymph node area and changes in performance status, PI3K/AKT/mTOR pathway 
activation, and plasma chemokines/cytokines will be assessed by treatment group. Both changes 
from baseline to each subsequent timepoint and best overall on-study changes will be analyzed 
using appropriate methods (eg, analysis of covariance [ANCOVA] or paired t-tests). Means and 
standard errors will be presented.
9.4.2.4.
Health-Related Quality of Life and Performance Status
The FACT-Leu questionnaire data will be scored and processed according to the user manual. 
Missing items in a subscale will be imputed consistent with the user manual instructions. Data 
collected from the FACT-Leu instrument will not be reconciled with adverse event or laboratory 
data or with EQ-D5 findings.
As a baseline, the last value obtained prior to receiving the first idelalisib dose of 
150 mg and 300 mg will be used, depending on the treatment group assigned.
The mean and change from baseline in mean scores to each subsequent assessment will be 
summarized for the FACT-Lym subscale and composite scores. The best change from baseline 
during the study, defined as the highest positive value among all post-baseline visits minus 
the baseline value, will also be summarized.


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9.4.3.
Exposure and Safety Analyses
9.4.3.1.
Treatment Administration and Study Drug Compliance
Descriptive information will be provided by treatment arm regarding the number of doses of 
study therapy prescribed, the total number of doses taken, the percent of expected doses taken, 
the number of days of treatment, and the number and timing of prescribed dose reductions and 
interruptions.
Study drug compliance will be described by treatment arm in terms of the proportion of study 
drug actually taken based on returned pill count relative to the amount that was dispensed 
(taking into account physician-prescribed reductions and interruptions).
9.4.3.2.
Idelalisib Plasma Concentrations
Bioanalytical analyses will performed independently so that the study team and investigators will 
not have knowledge of data from individual subjects. Idelalisib plasma concentrations 
immediately pre-dose and at 1.5 hours after administration of the dose of study drug at each 
relevant clinic visit will be summarized by treatment and visit using descriptive statistics.
9.4.3.3.
Prior, Concomitant, and Post-Treatment Medication Use
Prior, concomitant, and post-treatment medications will be coded by means of the 
World Health Organization Drug Dictionary (WHODRUG) dictionary into 
Anatomical-Therapeutic-Chemical classification (ATC) codes.
Descriptions of prior medication use will be focused on drugs and regimens used as treatments 
for CLL. Information regarding CLL therapy that was administered prior to 
Study GS-US-312-0116 will be referenced in reporting the results of Study GS-US-312-0117. In 
addition, relevant treatment administration information collected during Study GS-US-312-0116 
will be referenced in reporting the results of this study. As appropriate and if available, 
information on the sequencing, type, dose, schedule, timing, duration of use, and efficacy of 
prior regimens will be provided, focusing particularly on findings observed in 
Study GS-US-312-0116.
The type and timing of use of concomitant medications will be listed and summarized by type 
and treatment arm. Information regarding the type and use of specific supportive medications 
(eg, pneumocystis prophylaxis, hematopoietic growth factors, corticosteroids) during study 
treatment will be described.
The number, type, and timing of post-study-treatment regimens for CLL will be summarized by 
treatment arm, characterizing the disposition of all subjects who were eligible for post-study 
treatment and also those who were not eligible for post-study treatment (eg, subjects who are 
never treated at all, die while on study treatment, are still on study, are lost to follow-up, etc).


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9.4.3.4.
Adverse Events
All adverse events will be listed. The focus of adverse event summarization will be on 
treatment-emergent adverse events. A treatment-emergent adverse event is defined as an adverse 
event that occurs or worsens in the period from the first dose of study treatment to 30 days after 
the last dose of study treatment.
Adverse events will be classified using MedDRA (http://www.meddramsso.com) with 
descriptions by System Organ Class, High-Level Group Term, High-Level Term, 
Preferred Term, and Lower-Level Term. The severity of adverse events will be graded by the 
investigator according to the CTCAE, Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf), 
whenever possible. If a CTCAE criterion does not exist for a specific type of adverse event, the 
grade corresponding to the appropriate adjective will be used by the investigator to describe the 
maximum intensity of the adverse event: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), 
Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the adverse event to the study 
drug will be categorized as related or unrelated.
Treatment-emergent adverse events will be summarized by treatment arm and by visit. 
Summary tables will be presented to show the number of subjects reporting treatment-emergent 
adverse events by severity grade and corresponding percentages. A subject who reports multiple 
treatment-emergent adverse events within the same Preferred Term (or System Organ Class) is 
counted only once for that Preferred Term (or System Organ Class) using the worst severity 
grade. Adverse event descriptions will be presented by decreasing frequency for a given 
System Organ Class and Preferred Term.
Separate listings and summaries will be prepared for the following types of treatment-emergent 
adverse events:

Study-drug-related adverse events

Adverse events that are Grade 3 in severity

Adverse events leading to study drug interruption and/or dose modification

Adverse events leading to study drug discontinuation

Serious adverse events (with categorization of the primary reason that the adverse event is 
considered serious, eg, death, hospitalization, etc)
Separate listings and summaries will be prepared for long-term follow-up safety data 
(see Section 6.2.17).
9.4.3.5.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed data. 
The focus of laboratory data summarization will be on treatment-emergent laboratory 
abnormalities. A treatment-emergent laboratory abnormality is defined as an abnormality that, 


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compared to baseline, worsens by 1 grade in the period from the first dose of study drug to
30 days after the last dose of study drug. If baseline data are missing, then any graded 
abnormality (ie, an abnormality that is Grade 1 in severity) will be considered treatment 
emergent. Hematological, serum biochemistry, and urine data will be programmatically graded 
according to CTCAE severity grade, when applicable. For parameters for which a CTCAE scale 
does not exist, reference ranges from the central laboratory will be used to determine 
programmatically if a laboratory parameter is below, within, or above the normal range for the 
subject’s age, sex, etc.
Hematological and serum biochemistry and their changes from baseline will be summarized by 
treatment arm and by visit. Summary tables will be presented for each relevant assay to show the 
number of subjects by CTCAE severity grade with corresponding percentages. For parameters 
for which a CTCAE scale does not exist, the frequency of subjects with values below, within, 
and above the normal ranges will be summarized. Subjects will be characterized only once for a 
given assay, based on their worst severity grade observed during a period of interest 
(eg, during the study or from baseline to a particular visit).
Shift tables for hematology and serum biochemistry will also be presented by showing change in 
CTCAE severity grade from baseline to the worst grade post baseline. Separate listings and 
summaries will be prepared for laboratory abnormalities that are Grade 3 in severity.
9.4.3.6.
Oxygen Saturation Values
All oxygen saturation data will be listed. Summaries of oxygen saturation data will be based on 
observed data and will be reported as % saturation. Data and changes from baseline will be 
summarized by treatment arm and by visit. Summary tables will be presented for values 
below 92% and for declines from baseline of 5% to show the number of subjects with 
corresponding percentages. Subjects will be characterized only once for each of these 
categorizations, based on their lowest value observed during a period of interest 
(eg, during the study or from baseline to a particular visit).
9.4.4.
Other Analyses
9.4.4.1.
Between-Study Comparisons
It is expected that patients with a progressive malignancy like CLL will normally fare better with 
an earlier therapy than with a later therapy. However, if the converse situation proves true –
eg, if an investigational treatment (idelalisib) administered later shows similar or greater benefit 
than a standard treatment (rituximab) administered earlier – strong evidence of investigational 
drug effect is demonstrated. Evaluating data derived from the same study subjects during their 
sequential participation in 2 clinical trials offers unique analytical challenges. However, in this 
integrated Phase 3 study program, it is likely that comparing baseline characteristics and 
outcomes among Arm B subjects participating in Study GS-US-312-0116 and 
Study GS-US-312-0117 will be informative. Such an evaluation characterizes how the subjects
and the CLL disease process change with time and treatment. In addition, such an analysis 
provides relevant supporting information documenting the benefits of single-agent idelalisib
relative to single-agent rituximab in the same subjects.


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Accordingly, baseline characteristics, time-to-event efficacy variables (eg, PFS, TTR, DOR), 
categorical variables (eg, ORR, lymph node response rate, splenomegaly response rate, 
hepatomegaly response rate), and continuous variables (eg, percentage changes in 
lymph node area; changes in performance status, PI3K/AKT/mTOR pathway activation and 
plasma chemokines/cytokines)  may be evaluated between Study GS-US-312-0116 and 
Study GS-US-312-0117 for Arm B subjects.
9.4.4.2.
Health Care Resource Utilization
The EQ-D5 questionnaire data will be scored, processed, and standardized according to the user 
manual. Change from baseline in EQ-5D visual analogue scale and EQ-5D index will be 
summarized. As for the FACT-Leu, data will be analyzed using appropriate methods to account 
for incomplete completion of questionnaires. Data collected from the EQ-D5 will not be 
reconciled with adverse event or laboratory data or with FACT-Leu findings.
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach to the health economic analysis will be to combine the resource utilization 
data from the trial with data on unit prices (collected separately) to estimate total costs.
The perspective of this analysis will be that of the third-party payer(s) and the hospital over a 
lifetime horizon in the base case. The costs will be described relative to the health care findings 
as measured by duration of tumor control, the symptom-free survival period, life-years, utility 
outcomes, or other measure of appropriate clinical benefits. In order to facilitate the calculation 
of utilities for use in the cost effectiveness analyses, the health status of subjects will be 
evaluated using PFS, Karnofsky performance status, FACT-Leu, and EQ-5D.
9.4.4.3.
Data Explorations
Changes in biomarkers during acquisition of resistance will be evaluated descriptively. Data 
explorations may be performed to evaluate potential associations between subject characteristics 
and outcome measures. Explorations may be performed to assess the potential associations 
between different outcomes measures (eg, relationships between HRQL changes and 
clinical/radiographic endpoints of tumor control).
9.5.
Sample Size
The sample size for this extension study is not based upon a formal statistical hypothesis. The 
upper bound of the sample size in this study is determined by the sample size of the preceding 
primary study (Study GS-US-312-0116) in which ~220 subjects (~110 per arm) are expected to 
be enrolled. It is estimated that this extension study (Study GS-US-312-0117) will have a total 
idelalisib-treated N~180 (assuming a ~10% dropout rate during Study GS-US-312-0116 and a 
further ~10% dropout rate in the transition from the primary study to the extension study).


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9.6.
Timing of Analyses
The DMC will have access to serious adverse events requiring expedited reporting and will be 
provided with accumulating safety data on a regular basis. Interim safety reviews will be 
conducted by the DMC in conjunction with safety reviews of the primary clinical trial
(Study GS-US-312-0116) if applicable. Thus, interim safety reviews will be performed by the 
DMC at intervals of ~6 months; the specific frequency of these reviews will depend upon the 
rate at which the trials are enrolled, the nature of any emerging safety signals, and monitoring 
recommendations from the DMC. At each review, all available safety data will be summarized 
and evaluated.
An interim efficacy analysis of this clinical trial (Study GS-US-312-0117) is planned to take 
place at the time of the final blinded analysis of the primary study (GS-US-312-0116). The intent 
is to provide the data from this extension study in support of regulatory review of data from the 
primary study. An analysis of efficacy and safety may be performed to satisfy regulatory 
requirements and to perform long-term efficacy, safety and OS follow-up. The timing of the final 
analysis is expected to occur within 48 months of accrual of the final subject to 
Study GS-US-312-0117.


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
Compliance with Ethical and Regulatory Guidelines
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), with ICH guidelines, or with the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the study subject. These 
standards are consistent with the European Union Clinical Trials Directive 2001/20/EC and 
Good Clinical Practice Directive 2005/28/EC. The investigator will ensure adherence to the 
basic principles of GCP as outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and 
Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 1993, 
“Retention of Bioavailability and Bioequivalence Testing Samples.”
Because this is a “covered” clinical trial, the investigator will ensure adherence to 
21 CFR, Part 54, 1998; a covered clinical trial is any “study of a drug or device in humans 
submitted in a marketing application or reclassification petition subject to this part that the 
applicant or FDA relies on to establish that the product is effective (including studies that show 
equivalence to an effective product) or that make a significant contribution to the demonstration 
of safety.” This requires that investigators and all sub-investigators must provide documentation 
of their financial interest or arrangements with Gilead Sciences, or proprietary interests in the 
drug being studied. This documentation must be provided before participation of the investigator 
and any subinvestigator in the trial. The investigator or subinvestigator agrees to notify 
Gilead Sciences of any change in reportable financial interests during the study and for 1 year 
following completion of the study. Study completion is defined as the date that the last subject 
has completed the protocol-defined activities.
10.1.2.
Institutional Review Board/Independent Ethics Committee
This protocol and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) will be submitted by the investigator to an IRB (for sites enrolling in 
the United States) and to an IEC for sites enrolling outside of the United States). Approval from 
the IRB/IEC must be obtained before starting the study and should be documented in a letter to 
the investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.
Any modifications or amendments made to the protocol after receipt of the initial IRB/IEC
approval must also be submitted to the IRB/IEC for approval before implementation. Only 
changes necessary to eliminate apparent immediate hazards to the subjects may be initiated prior 
to IRB/IEC approval. In that event, the investigator must notify the IRB/IEC and Gilead Sciences
in writing within 5 working days after implementation.


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The investigator shall submit a progress report, at least once yearly, to the IRB/IEC, and must 
provide a copy to Gilead Sciences. As soon as possible after completion or termination of the 
study, the investigator will submit a final report to the IRB/IEC and to Gilead Sciences. This 
report should include the dates of initiation and completion of the trial, a description of any 
changes in study procedures or amendments to the protocol, any deviations from the protocol, 
the number and type of subjects evaluated, the number of subjects who discontinued 
(and the reasons for discontinuation), the number of subjects who completed the trial, and the 
results of the trial, including a description of any adverse events. Gilead Sciences will assist the 
investigator in the preparation of this report, as needed.
10.1.3.
Informed Consent
After adequately, explaining the aims, methods, objectives, and potential hazards of the study 
and before undertaking any study-related procedures, the investigator is responsible for obtaining 
written informed consent from each individual participating in this study. The investigator must 
utilize an IRB/IEC-approved consent form for documenting written informed consent. Each 
informed consent will be appropriately signed and dated by the subject or the subject’s legally 
authorized representative and the person obtaining consent.
The approved informed consent must not be changed without prior approval by Gilead Sciences
and the IRB/IEC.
10.1.4.
Confidentiality
The investigator must assure that each subject’s anonymity will be strictly maintained and that 
each subject’s identity is protected from unauthorized parties. Only subject initials, date of birth, 
and an identification code (but no subject names) should be recorded on any form or biological 
sample submitted to the Gilead Sciences or designees (eg, laboratories), or to the IRB/IEC.
However, sufficient information must be retained at the site to permit sample data and data in the 
database to be connected with the unique subject number assigned to each study participant.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the idelalisib investigator brochure, this protocol, eCRFs, the investigational new drug, 
and any other study information, remain the sole and exclusive property of Gilead Sciences
during the conduct of the study and thereafter. This information is not to be disclosed to any 
third party (except employees or agents directly involved in the conduct of the study or 
as required by law) without prior written consent from Gilead Sciences. The investigator further 
agrees to take all reasonable precautions to prevent the disclosure by any employee or agent of 
the study site to any third party or otherwise into the public domain.
10.1.5.
Study Files and Retention of Records and Biological Samples
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator’s study file, and 
(2) subject clinical source documents.


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The investigator’s study file will contain the protocol/amendments, eCRF and query forms, the 
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data referenced in the monitoring plan for the study, and should include 
sequential notes containing at least the following information for each subject:

Subject identification (name, date of birth, gender)

Documentation that subject meets eligibility criteria, eg, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria)

Participation in trial (including trial number)

Trial discussed and date of informed consent

Dates of all visits

Documentation that protocol-specific procedures were performed

Results of efficacy parameters, as required by the protocol

Start and end date (including dose regimen) of trial medication (including relevant drug 
dispensing and return information)

Record of all adverse events and other safety parameters (including start and end date, 
causality and intensity)

Concomitant medication (including start and end date and dose if relevant dose changes 
occur)

Date of trial completion and reason for discontinuation, if applicable
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (ie, the United States, Europe, 
or Japan) and until there are no pending or contemplated marketing applications in an 
ICH region; or, if no application is filed or if the application is not approved for such indication, 
until 2 years after the investigation is discontinued and regulatory authorities have been notified. 
Investigators may be required to retain documents longer if required by applicable regulatory 
requirements, by local regulations, or by an agreement with Gilead Sciences. The investigator 
must notify Gilead Sciences before destroying any clinical study records. The investigator will 
promptly notify Gilead Sciences in the event of accidental loss or destruction of any study 
records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead Sciences must be notified in advance.


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If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead Sciences
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site.
Biological samples including tissue and blood samples collected as a study procedure or as 
standard of care during study participation will be stored and maintained by the investigator until 
notification is received from Gilead Sciences that the retained samples and records no longer 
required. The investigator must obtain written permission from Gilead Sciences before disposing 
of any retained samples. The investigator should promptly notify Gilead Sciences in the event of 
accidental loss or destruction of any study samples. With the permission of Gilead Sciences, the 
retained samples may be transferred to an acceptable designee, such as another investigator, 
another institution, a contract storage site, or to Gilead Sciences.
10.1.6.
Case Report Forms
An eCRF is required and must be completed for each enrolled subject, with all required study 
data accurately recorded such that the information matches the data contained in medical records 
(eg, physicians’ notes, nurses’ notes, clinic charts, or other study-specific source documents). As 
required by the protocol, eCRFs should also be completed for those subjects who fail to complete 
the study (even during the screening period). If a subject withdraws from the study, the reason 
must be noted on the eCRF. If a subject is withdrawn from the study because of a 
treatment-limiting adverse event, thorough efforts should be made to clearly document the 
outcome.
The eCRFs for this study will exist within a Web-based electronic data capture (EDC) system. 
After the investigator or the investigator’s designees (eg, research coordinators) have been 
appropriately trained, they will be given access to the EDC system and will enter the data 
required by the protocol into the EDC system. Any change of data will be made via the 
EDC system, with all changes tracked by the system to provide an audit trail.
The eCRF must be completed and signed by the principal investigator or subinvestigator 
(as appropriate) within a reasonable time period after data collection. This signature serves to 
attest that the information contained in the eCRF is true.
10.1.7.
Drug Accountability
As described in the relevant section (see Section 5.2.7), the investigator is responsible for 
ensuring adequate accountability of all used and unused investigational medicinal product, 
placebos, and comparators. This responsibility includes acknowledgment of receipt of each 
shipment of study product (quantity and condition), subject dispensing records, and returned or 
destroyed study product. Dispensing records will document quantities received from 
Gilead Sciences and quantities dispensed to subjects, including lot number, date dispensed, 
subject identifier number, subject initials, and the initials of the person dispensing the 
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At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Sciences’ requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRB/IECs, 
and to regulatory authority or health authority inspectors. It is important that the investigator and 
relevant institutional personnel are available during monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, will be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB/IEC in 
accordance with local requirements. Except as noted in Section 10.1.2, IRB/IEC approval must 
be obtained before changes can be implemented.
10.2.2.
Communications with Regulatory Authorities
Gilead Sciences, working either directly or through designees, will assume responsibility for 
regulatory interactions with relevant regulatory authorities. Gilead Sciences will maintain an 
IND for idelalisib in support of the study in the United States and will maintain similar 
regulatory applications with other regulatory authorities, as required for conduct of the study. In 
fulfilling this responsibility, Gilead Sciences (or a designee) will collect, assemble, and 
communicate all required regulatory documents (eg, Form FDA 1572, investigator financial 
disclosure forms, protocol and protocol amendments, investigator brochures, informed consent 
documents, annual reports) as required by regulation. Gilead Sciences (or a designee) will also 
assume responsibility for adverse event reporting to regulatory authorities as described in 
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10.2.3.
Data Management
Electronic data capture will be used to enter study data eCRFs and to transfer the data into a 
study-specific electronic database. During the data collection process, automated quality 
assurance programs will be used to identify missing data, selected protocol violations, 
out-of-range data, and other data inconsistencies. Requests for data clarification or correction 
will be forwarded to the investigative site for resolution. As appropriate, eCRFs, listings, tables, 
and SAS datasets will be provided to the investigational sites for review.
Quality assurance and quality control systems will be implemented and maintained according to 
written standard operating procedures to ensure that the data are generated, recorded, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements. Data 
collection and storage systems will provide audit trail, security mechanisms, and electronic 
signature capabilities that meet the requirements of FDA Title 21 of CFR Part 11 regarding 
electronic records and electronic signatures.
Data security will be controlled through appropriate and specific restriction of access only to data 
and systems required by individual users to accomplish their roles in the data management 
process. Individual login and password protections will be employed at study sites and at 
Gilead Sciences or its designee. The database will exist on physically secured servers. Data 
backups will be done regularly and will be stored in separate facilities. Printed documents 
relating to the study will be secured when not under review.
10.2.4.
Study Reporting and Publication
Gilead Sciences may make information obtained during this study available in order to further 
the scientific or business needs of the company or as required by law or regulation. In this 
regard, Gilead Sciences may provide study information to private or public organizations 
(eg, business partners, collaborators, consultants, CROs, investors, other physicians who are 
conducting similar studies, funding organizations, regulatory authorities, or other 
government authorities).
Gilead Sciences will prepare a clinical study report for submission to relevant regulatory
agencies. Gilead Sciences will ensure that the report meets the standards set out in the 
ICH Guideline for Structure and Content of Clinical Study Reports (ICH E3). An abbreviated 
report may be prepared in certain cases, as appropriate.
Gilead Sciences intends that the data from this study will be presented and published. 
Gilead Sciences will work in collaboration with the principal investigators in preparing 
presentations and writing manuscripts for publication.

Investigators may publish or present the results of the study generated by their individual site 
either with the advanced written consent of Gilead or > 2 years after the completion of this 
extension study (GS-US-312-0117) at all participating institutions.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information (see Section 10.1.4).


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The investigator will submit to Gilead Sciences any proposed publication or presentation along 
with the respective scientific journal or presentation forum prior to submission of the publication 
(at least 30 days prior to manuscripts and 15 days prior for abstracts and oral presentations). The 
investigator will comply with Gilead Sciences’ request to delete references to its confidential 
information (other than the study results) in any paper or presentation. If deemed necessary by 
Gilead Sciences, the investigator also agrees to withhold publication or presentation for an 
additional 60 days in order to obtain patent protection.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the eCRFs for consistency.
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.
10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences may conduct inspections or audits 
of the clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.
10.3.3.
Public Notification of Study Conduct
Consistent with Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and 
with requirements of the International Committee of Medical Journal Editors (ICMJE) as a 
condition of consideration for publication of study results, Gilead Sciences will be responsible 
for ensuring that this protocol is listed at the ClinicalTrials.gov website (or equivalent) and that 
information at the website relating to study design and conduct is appropriately updated during 
the course of the study. In order to facilitate this process, investigators will need to supply 
Gilead Sciences with appropriate contact information for study site personnel.
10.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authorities and IRB/IECs. In terminating the study, Gilead Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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10.4.
Study Committees
10.4.1.
Data Monitoring Committee
A DMC, operating autonomously from Gilead Sciences, the clinical investigators, and the SSC, 
will be responsible for providing independent recommendations to Gilead Sciences about 
evolving risk-benefit observed in the course of the study and any modifications required during 
the course of the study. The DMC will consist of a biostatistician and 2 physicians experienced 
in treating patients with lymphoid malignancies. The DMC will be chaired by one of these 
individuals. DMC members must not be actively involved in study design, conduct, or subject
accrual and must not have financial, proprietary, professional, or other interests that may affect 
impartial, independent decision-making. Specialists may be invited to participate as non-voting 
members at any time if additional expertise is desired. The DMC will formally interact with the 
external SSC members through the sharing of meeting minutes. Informal interactions between 
the DMC and external SSC members will be limited. The DMC will operate under a charter 
developed as a collaborative document between Gilead Sciences and the DMC. It is expected 
that the members of the DMC will be the same as those for the primary study 
(Study GS-US-312-0116). 
The primary responsibility of the DMC is to protect the safety and welfare of subjects 
participating in this clinical trial and to ensure the integrity of the clinical trial. In general, the 
DMC will be responsible for:

Reviewing the general progress of the study as regards subject accrual, study conduct, and 
protocol violations

Examining accumulated safety, efficacy, and other relevant data at prespecified points during 
the course of the study 

Reviewing major study design modifications prior to implementation of those modifications

Making recommendations concerning continuation, modification, interruption, or termination 
of each study

Advising the company on changes to informed consent documents

Proposing updates to the DMC monitoring plan, changes in the DMC membership, actions to 
be taken relating to conflict of interest or confidentiality breaches, the need for additional 
expertise during DMC deliberations, revisions to the DMC charter, or alterations in the 
support provided to the DMC

Providing expert advice to the Gilead Science medical monitor on an ad hoc basis regarding 
matters such as safety concerns or diagnostic evaluations in individual subjects
Based on the results of its deliberations during the course of the study, the DMC can recommend 
appropriate actions (eg, continuation of the study unchanged, continuation of the study with 
modifications in design or monitoring plan, interruption of study accrual, study termination).


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10.4.2.
Independent Review Committee
An IRC will be established to provide a blinded review of radiographic data and pertinent 
clinical data in order to provide expert interpretation of changes in tumor status. The IRC will 
include 1 independent board-certified radiologist and 1 independent board-certified 
hematologist or oncologist, and will be managed by a CRO selected by Gilead Sciences. The 
review of radiographic and clinical data by the IRC will be performed on an ongoing basis until 
the primary analysis . The specifics of the IRC’s processes and reading methods will be 
described in an independent review charter developed by the contracted imaging facility in 
conjunction with Gilead Sciences. The same organization that is providing IRC services for 
Study GS-US-312-0116 will provide IRC services for this study.


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12.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
Appendix 3.
Performance Status Scoring System
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D)
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Appendix 6.
Cumulative Illness Rating Scale (CIRS)
Appendix 7.
Schedule of Study Procedures


PPD
PPD
PPD
Idelalisib 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Version 7.0 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
199 EAST BLAINE STREET 
SEATTLE, WA 98102 
STUDY ACKNOWLEDGEMENT 
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and Safety of 
Two Different Dose Levels of Single-Agent Idelalisib (GS-1 I 01) for Previously Treated 
Chronic Lymphocytic Leukemia 
GS-US-312-0117, Version 7 (Amendment 6), 28 March 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
S1gnature 
Gilead Sciences Medical Monitor 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
· 
I will provide all study personnel under my supervision copies of the protocol and access to all 
infonnation provided by Gilead Sciences, lnc. f will discuss this material with them to ensure 
that they are fully infonned about the drugs and the study. 
Principal Investigator 
Printed Name 
Date 
CONFIDENTIAL 
Page 153 
Signature 
Site Number 
28 March 2016 


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 7.0
CONFIDENTIAL
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28 March 2016
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
FACT-Leu (Version 4) 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
PHYSICAL WELL-BEING 
GPI 
I have a lack of energy . . . . . . . . . . . . . . . 
GPl 
l have nausea 
.... ............ 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
GP4 
I have pain ...... ..... , 
......... ......................... 
GP5 
l am bothered by side effects of treatment 
01'6 
I feel ill . 
. ···················· 
GP7 
1 am forced to spend time in bed 
SOCIAL/FAMILY WELL-BEING 
OS! 
I feel close to my friends ...... 
.................. 
GS1 
I get emotional support from my family 
GS3 
1 get support from my friends .... 
GS4 
My family has accepted my illness 
GS5 
1 am satisfied with family communication about my 
illness .................... 
GS6 
I feel close to my partner (or the person who is my main 
support) . 
QI 
Regardless o_fyour current level of sexual activity. please 
answer the following question. ffyou prefer not to answer it, 
please mark this box 0 and go to the next section. 
GS7 
I am satisfied with my sex life ......................................... 
Engh !l.h (Universal) 
C~nglu 1987, 1997 
Not 
A little 
Some-
Quite 
at all 
bit 
what 
a bit 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
Not 
A little 
Some-
Quite 
at all 
bit 
what 
a bit 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
19 Novcmlx:r 1007 
Page I of3 


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 7.0
CONFIDENTIAL
Page 155
28 March 2016
FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
EMOTIONAL WELL-BEING 
GEl 
I feel sad ..... ................................ , 
GE2 
I am satisfied with how I am coping with my illness .... 
GE3 
I am losing hope in the fight against my illness 
GE4 
I feel nervous 
................... , 
GE5 
I worry about dying . . . . . . . . . . . . . . . . . . . . . . . . 
GE6 
I worry that my condition will get worse 
FUNCTIONAL WELL-BEING 
GFI 
I am able to work (include work at home) 
GF2 
My work (include work at home) is fulfilling ... 
GF3 
I am able to enjoy life ...... 
................. , ...... 
GF4 
1 have accepted my illness ... ................. 
GF5 
1 am sleeping well 
................................. 
GF6 
I am enjoying the things 1 usually do for fun 
GF7 
I am content with the quality of my life right now 
Enghsh (Universal) 
Cop}'right 1987, 1997 
Not 
A little 
Some-
at all 
bit 
what 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Not 
A little 
Some-
at all 
bit 
what 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
19 November 1007 
Page 2 ofJ 


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 7.0
CONFIDENTIAL
Page 156
28 March 2016
FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
ADDITIONAL CONCERNS 
Not 
A little 
Some-
at all 
bit 
what 
BRM3 
I am bothered by fevers (episodes of high body 
temperature) 
...... ........ . 
0 
2 
Pl 
I have certai n parts of my body where I experience pain.... 
0 
2 
BRMl 
ES3 
LEU I 
THI 
Till 
Hll2 
BMT6 
Cl 
C6 
An7 
N3 
LEm 
LEU6 
BRM9 
I am bothered by the chills .. .......... ... . 
I have night sweats .............................. .. 
I am bothered by lumps or swelling in certain parts of 
my body (e.g., neck, armpits, or groin) 
I bleed easily . 
1 bruise easily . 
I feel weak all over. 
I get tired easily 
I am losing weight 
I have a good appetite .......... ............ .. 
I am able to do my usual activities 
I worry about getting infections ......................... . 
I feel uncertain about my future health .................... .. 
1 worry that I might get new symptoms of my illness 
I have emotional ups and downs 
LEU7 
I feel isolated from others because of my illness or 
treatment 
Enghsh (Universal) 
Cop}'right 1987, 1997 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
19 November 1007 
Page 3 ofJ 


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 7.0
CONFIDENTIAL
Page 157
28 March 2016
Appendix 3.
Performance Status Scoring System
Karnofsky Performance Status
General Description
Score
Specific Description
Able to carry on normal activity and 
to work; no special care needed.
100
Normal; no complaints;
no evidence of disease.
90
Able to carry on normal activity;
minor signs or symptoms of disease.
80
Normal activity with effort;
some signs or symptoms of disease.
Unable to work; able to live at home 
and care for most personal needs; 
varying amount of assistance 
needed.
70
Cares for self;
unable to carry on normal activity or to do active work.
60
Requires occasional assistance,
but is able to care for most of personal needs.
50
Requires considerable assistance and frequent medical care.
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly.
40
Disabled; requires special care and assistance.
30
Severely disabled;
hospital admission is indicated although death not imminent.
20
Very sick; hospital admission necessary;
active supportive treatment necessary.
10
Moribund; fatal processes progressing rapidly.
0
Dead


Idelalisib 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Version 7.0 
Appendix 4. 
EuroQoL-5 Dimensions (EQ-SD) 
By placmg a clleckmark m one box in each group below. please ind.t~ate wbJch 
stat~mems b~1 describe your own health sEate today. 
Mobility 
I have no proWems in •11alking about 
I ha1:e some p oblems r walking about 
I am corrlir.ed to bed 
Self-Care 
I ~ve no problems wim self-care 
I have some probrems washing o dress g- myself 
I am unabla to ~'ash or dress myseli 
Usual Activities (e.g., work, study, housework, family, or leisure activities) 
I have no problems with perorming my usual ac1ivlties 
I hiwe some prob ems •1f'i1h perlormiJ'Ig my usua( activities 
I am unable to ~erform my usuaJ actvites 
Pain/Discomfort 
I have no pain o: discomfon 
I ha'o·e moderate pail or discorrrott 
I h.ave eldreme pa.n or rLsoomfort 
Anxiety!Oe pression 
I am n~ anxious ot de~ressed 
I am moderately anxi01.1s or depressed 
I am extremely anxious or depressed 
CONFIDENTIAL 
Page 158 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
28 March 2016 


Idelalisib 
Protocol GS-US-312-0117 
Gilead Sciences, Inc. 
To help people say bow good or bad a health state LS, 
we have drawn a scale (rather bke a thennometer) on 
which the best stare you can un.agine 1S marked 100 
and the worsr stare you can imagine is marked 0. 
We \Vould like you to mdicate on this scale how good 
or bad your own health is today. in your opinion. 
Please do this by drawmg a line from the box below 
to wlllcbever pomt on the scale indicates how good or 
bad your health state is today. 
CONFIDENTIAL 
Yow· own 
hPalth statl' 
toda~· 
Page 159 
B~ 
imagmable 
health SUll! 
tOO 
T 
0 
\Vm"t 
ima:inab!e 
huhh:;ute 
Final 
Version 7.0 
28 March 2016 


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 7.0
CONFIDENTIAL
Page 160
28 March 2016
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Formulas for calculating the estimated creatinine clearance (eCcr) are provided in the table 
below. The formula appropriate to the units in which serum creatinine was measured and the 
subject’s gender should be used.
Cockcroft-Gault Formulas for Calculating Estimated Creatinine Clearance
Serum
Creatinine Units
Gender
Formula
mg/dL
Males
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1
72 subject serum creatinine [mg/dl]
Females
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 0.85
72 subject serum creatinine [mg/dl]
M/dL
Males
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.23
Subject serum creatinine [mg/dl]
Females
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.04
Subject serum creatinine [mg/dl]
Abbreviation: eCcr=estimated creatinine clearance


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 7.0
CONFIDENTIAL
Page 161
28 March 2016
Appendix 6.
Cumulative Illness Rating Scale (CIRS)
The CIRS used in this protocol is designed to provide an assessment of recurrent or ongoing 
chronic comorbid conditions, classified by 14 organ systems. Using the drop-down lists of 
organ-specific diagnoses, please select any conditions present in the study subject. If the subject
has a recurrent or ongoing chronic conditions that are not described in the list for a given organ 
system, please indicate the name of the conditions under “other chronic condition” for that organ 
system. Please take into account that CLL-induced discomfort, symptoms, or disability should 
not be considered. If additional explanation would be helpful, text comments may be inserted.
CIRS List of Comorbid Conditions
Organ System
Diagnosis
Comment
Cardiac
Chronic heart failure
Angina pectoris
Medically relevant arrhythmia
Valve dysfunction
Congenital heart disease
Cardiomyopathy
Myocarditis
Chronic pericarditis
Endocarditis
Other chronic cardiac condition:
Other chronic cardiac condition:
Vascular
Hypertension
Thrombosis
Peripheral diabetic microvascular disease
Peripheral artery disease
Aortic aneurysm
Aortitis
Raynaud disease
Vasculitis
Other chronic vascular condition:
Other chronic vascular condition


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 7.0
CONFIDENTIAL
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28 March 2016
Organ System
Diagnosis
Comment
Hematological/
immunological
Sickle cell anemia
Hemoglobinopathy
Polycythemia
Thrombocythemia
Hemophilia
Paroxysmal nocturnal hemoglobinuria
Thrombotic thrombocytopenic purpura
Dysfibrinogenemia
HIV
Other chronic hematological or 
immunological condition:
Other chronic hematological or 
immunological condition
Abbreviation: CIRS=Cumulative Illness Rating Scale
For each condition selected from the CIRS List of Comorbid Conditions, please rate the severity 
of that condition. For the severity rating, please use the scoring guidelines shown in the table 
below, considering the magnitude of symptoms, how manageable the condition is, and the extent 
of intervention required:
CIRS Rating Scale
Score
Severity
Findings
1
Mild
Mild discomfort, symptoms or disability
Easy to control
Requiring either no therapy/medication or only as needed
2
Moderate
Moderate  discomfort, symptoms or disability
Manageable
Requiring daily treatment or first-line therapy
3
Severe
Severe discomfort, symptoms or disability
Hard to control
Requiring second-line therapy or multiple medications
4
Extremely severe
Life threatening, permanently disabling disability, causing organ failure
Poorly manageable
Requiring urgent intervention or resistant to therapy
Abbreviation: CIRS=Cumulative Illness Rating Scale


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Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 7.0
CONFIDENTIAL
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Appendix 7.
Schedule of Study Procedures
Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4 a
5a
6 a
7a
8 a
9 a
10 a
11 a
12 a
13 a
14 a
15 a
16+e
End
of
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28 Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30 days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Informed consent
X
CIRS assessment
X
β-HCG
(women of 
childbearing 
potential)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CLL peripheral 
blood evaluation
X
X
CLL serology
X
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HRQL/
healthy utility –
FACT-Leu/EQ-5D
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exam
(includes nodes, 
liver, spleen)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PPD


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Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 7.0
CONFIDENTIAL
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28 March 2016
Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4 a
5a
6 a
7a
8 a
9 a
10 a
11 a
12 a
13 a
14 a
15 a
16+e
End
of
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28 Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30 days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Oxygen saturation
(by pulse 
oximetry)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Circulating cells/
Immune 
monitoringb
X
X
X
X
X
X
X
X
X
X
X
X
X
Xb
Biomarkers
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Igsb
X
X
X
X
X
X
X
X
X
X
X
X
X
Xb
Study drug
administration in 
clinic
Xb
X
X
X
X
X
X
X
Idelalisib
pharmacokinetics c
X
X
X
X
X
X
X
X
Study drug
dispensing/
accounting c
X
X
X
X
X
X
X
X
X
X
X
Radiology 
assessment 
(CT/MRI)
X
Xf
Xf
Xf
Xf
Xf
Xf
X f,g
Bone marrow 
biopsy/
aspirate d
X
X
X
X
X
X
X
X
CMV viral loadh
X


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 7.0
CONFIDENTIAL
Page 165
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Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4 a
5a
6 a
7a
8 a
9 a
10 a
11 a
12 a
13 a
14 a
15 a
16+e
End
of
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28 Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30 days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
PJP prophylaxisi, j
Xi
Xj
CD4+ T-cell countj
(related to PJP 
prophylaxis)
Xj
Post-treatment 
CLL therapy
X
Long-term 
follow-up 
X
a
Following unblinding of the study, the visit schedule will be modified per Section 6.2 and Visits 3 – 15 may not be applicable for subjects who were randomized to idelalisib 
on Study GS-US-312-0116 or who were randomized to placebo on GS-US-312-0116 and have received 24 weeks cumulative treatment with idelalisib
b
Circulating cells/Immune monitoring  and Serum Igs should be performed at the the End of Study visit
c
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll following unblinding, may have idelalisib treatment (and associated PK testing) delayed at 
the Investigator’s discretion until the time of disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib treatment
d
At screening, to be performed at investigator discretion to determine extent of CLL involvement and bone marrow cellularity. Post-screening, to be performed to confirm 
response category in subjects with potential CR or to confirm a hematologically-based disease progression; if the subject does not otherwise meet criteria for CR or if the 
nature of PD does not require bone marrow confirmations, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate
e
Following unblinding, Visit 16+ may be completed prior to 48 weeks as subjects transition to a Q12 week visit schedule 
f
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the assessment should be done even if study drug has been interrupted
g
An end-of-study CT/MRI tumor assessment should be performed unless the subject already has radiographic confirmation of definitive disease progression < 4 weeks prior to 
study discontinuation
h
CMV viral load should be performed approximately every 4 weeks throughout idelalisib treatment.  If unequivocal clinical or laboratory evidence of CMV infection is 
present, the subject must permanently discontinue idelalisib treatment and undergo effective antiviral treatment according to established clinical guidelines.
i
PJP prophylaxis:  subjects must receive trimethoprim-sulfamethoxazole or other established prophylaxis for PJP throughout the course of idelalisib treatment.  Subjects must 
permanently discontinue idelalisib upon diagnosis of PJP. Prophylaxis will continue until the CD4+ T-cell count is documented to be >200 cells/mcL after idelalisib treatment ends. 
j
CD4+ T-cell countl (related to PJP prophylaxis):  PJP prophylaxis will continue until the CD4+ T-cell count is documented to be >200 cells/mcL after idelalisib treatment ends.
Abbreviations: -HCG=beta human chorionic gonadotropin, CIRS=chronic illness rating scale, CLL=chronic lymphocytic leukemia, CMV=cytomegalovirus, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy- Leukemia, HRQL= health-related quality of life, 
Ig=immunoglobulin, IWRS=interactive web response system, MRI= magnetic resonance imaging, PJP= Pneumocystis jirovecii pneumonia..

Prot_000.pdf: 
 
CLINICAL STUDY PROTOCOL 
Study Title: 
A Phase 3, Double-Blind Extension Study Evaluating the 
Efficacy and Safety of Two Different Dose Levels  of 
Single-Agent GS-1101 (CAL-101) as Therapy for Patients 
with Previously Treated Chronic Lymphocytic Leukemia 
A Companion Trial to Study GS-US-312-0116: A Phase 3, 
Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Efficacy and Safety of GS-1101 (CAL-101) 
in Combination with Rituximab as Therapy for Patients 
with Previously Treated Chronic Lymphocytic Leukemia 
Sponsor: 
Gilead Sciences, Inc. 
199 East Blaine Street 
Seattle, WA 98102 
USA 
IND Number: 
101254 
EudraCT Number: 
2011-006293-72 
Indication: 
Chronic Lymphocytic Leukemia  
Protocol ID: 
GS-US-312-0117 
Gilead Sciences Study 
Director: 
Name: 
 
Office Telephone: 
 
Office Fax: 
 
Mobile Telephone: 
 
E-mail: 
 
Gilead Sciences Medical 
Monitor: 
Name: 
 
Office Telephone: 
 
Office Fax: 
 
Mobile Telephone: 
 
E-mail: 
 
Protocol Version/Date: 
Original 
23 January 2012 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable institutional review board or independent ethics committee. This information is 
only to be used by you in connection with authorized clinical studies of the investigational 
drug described in the protocol. You must not disclose any of the information to others 
without written authorization from Gilead Sciences, Inc., except to the extent necessary to 
obtain informed consent from those persons to whom the drug may be administered. 
PPD
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GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 2 
23 January 2012 
TABLE OF CONTENTS 
TABLE OF CONTENTS .......................................................................................................................................2 
LIST OF IN-TEXT TABLES.................................................................................................................................6 
LIST OF IN-TEXT FIGURES ...............................................................................................................................6 
PROTOCOL SYNOPSIS .......................................................................................................................................7 
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................18 
1. 
INTRODUCTION .......................................................................................................................................21 
1.1. 
Chronic Lymphocytic Leukemia.....................................................................................................21 
1.2. 
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies ............................................................22 
1.3. 
GS-1101..........................................................................................................................................22 
1.3.1. 
Discovery and Efficacy Pharmacology .........................................................................22 
1.3.2. 
Safety Pharmacology ....................................................................................................23 
1.3.3. 
Nonclinical Pharmacology and Metabolism .................................................................23 
1.3.4. 
Toxicology ....................................................................................................................24 
1.3.5. 
GS-1101 Clinical Studies..............................................................................................25 
1.4. 
Summary and Justification for the Current Study...........................................................................29 
2. 
STUDY DESIGN ........................................................................................................................................32 
2.1. 
Design Overview and Study Schema..............................................................................................32 
2.2. 
Design Rationale.............................................................................................................................33 
3. 
OBJECTIVES AND ENDPOINTS .............................................................................................................35 
3.1. 
Endpoints ........................................................................................................................................35 
3.1.1. 
Tumor Control...............................................................................................................35 
3.1.2. 
Patient Well-Being........................................................................................................36 
3.1.3. 
Pharmacodynamic Markers of Drug Activity and Resistance.......................................37 
3.1.4. 
Exposure........................................................................................................................37 
3.1.5. 
Safety ............................................................................................................................37 
3.1.6. 
Pharmacoeconomics......................................................................................................37 
3.2. 
Endpoint Selection Rationale..........................................................................................................37 
3.2.1. 
Tumor Control Endpoints..............................................................................................37 
3.2.2. 
Measures of Patient Well-Being....................................................................................40 
3.2.3. 
Pharmacodynamic Markers of Drug Activity and Resistance.......................................41 
3.2.4. 
Assessments of Exposure..............................................................................................42 
3.2.5. 
Evaluations of Safety ....................................................................................................43 
3.2.6. 
Pharmacoeconomic Measures.......................................................................................44 
4. 
SUBJECT POPULATION...........................................................................................................................45 
4.1. 
Number of Subjects.........................................................................................................................45 
4.2. 
Subject Selection Criteria................................................................................................................45 
4.2.1. 
Inclusion Criteria...........................................................................................................45 
4.2.2. 
Exclusion Criteria..........................................................................................................47 
4.3. 
Enrollment Criteria Rationale .........................................................................................................47 
5. 
TREATMENT OF SUBJECTS ...................................................................................................................49 
5.1. 
Enrollment.......................................................................................................................................49 
5.1.1. 
Interactive Web Response System ................................................................................49 
5.1.2. 
Treatment Assignment ..................................................................................................49 
5.1.3. 
Blinding.........................................................................................................................49 
5.2. 
Investigational Study Drug (GS-1101/Placebo)..............................................................................50 
5.2.1. 
Description....................................................................................................................50 


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5.2.2. 
Source............................................................................................................................50 
5.2.3. 
Packaging and Labeling ................................................................................................50 
5.2.4. 
Storage and Handling....................................................................................................51 
5.2.5. 
Dispensing.....................................................................................................................51 
5.2.6. 
Return............................................................................................................................51 
5.2.7. 
Accountability...............................................................................................................52 
5.2.8. 
Overdose Precautions....................................................................................................52 
5.2.9. 
Inadvertent Exposure and Spill Precautions..................................................................52 
5.3. 
Study Drug Administration.............................................................................................................53 
5.3.1. 
Premedication................................................................................................................53 
5.3.2. 
Administration Instructions...........................................................................................53 
5.3.3. 
Dosing Schedule............................................................................................................53 
5.3.4. 
Dose Levels...................................................................................................................53 
5.3.5. 
Dose Schedule Interruptions and Vomited Doses.........................................................53 
5.3.6. 
Safety Monitoring and Study Drug Interruption/Dose Modification ............................54 
5.4. 
Recommendations for Evaluation, Intervention, and Drug Discontinuation for Specific 
Adverse Events or Conditions.........................................................................................................56 
5.4.1. 
Dermatological Events..................................................................................................56 
5.4.2. 
Gastrointestinal Events..................................................................................................56 
5.4.3. 
Hepatic Events ..............................................................................................................57 
5.4.4. 
Hematological and Immunological Events ...................................................................58 
5.4.5. 
Infectious Events...........................................................................................................58 
5.4.6. 
Progressive Multifocal Leukoencephalopathy ..............................................................59 
5.4.7. 
Pulmonary Events .........................................................................................................59 
5.4.8. 
Tumor Lysis Syndrome.................................................................................................60 
5.4.9. 
Pregnancy, Lactation, and Reproduction ......................................................................60 
5.5. 
Emergency Unblinding ...................................................................................................................60 
5.6. 
Concomitant and Supportive Therapy.............................................................................................61 
5.6.1. 
Anticancer or Experimental Therapies Other than Investigational 
Treatments.....................................................................................................................61 
5.6.2. 
Antibiotics.....................................................................................................................61 
5.6.3. 
Antiemetics and Antidiarrheals.....................................................................................62 
5.6.4. 
Contraception................................................................................................................62 
5.6.5. 
Corticosteroids ..............................................................................................................63 
5.6.6. 
Granulocyte Colony-Stimulating Factors and Erythropoietin.......................................63 
5.6.7. 
Drugs that Inhibit CYP3A4-Dependent Metabolism ....................................................64 
5.6.8. 
Immunization ................................................................................................................64 
5.6.9. 
Surgery..........................................................................................................................64 
5.6.10. 
Diet................................................................................................................................64 
5.7. 
Duration of Study Therapy..............................................................................................................64 
5.8. 
Discontinuation of Study Treatment ...............................................................................................64 
5.9. 
Study Treatment Rationale..............................................................................................................65 
6. 
STUDY PROCEDURES .............................................................................................................................69 
6.1. 
Enrollment and Study Management Procedures .............................................................................69 
6.1.1. 
Subject Recruitment......................................................................................................69 
6.1.2. 
Subject Compensation for Participation........................................................................69 
6.1.3. 
Screening.......................................................................................................................69 
6.2. 
Explanation of Study Visits ............................................................................................................70 
6.2.1. 
Visit 1 and Screening Period (Clinic Visit)...................................................................70 
6.2.2. 
Visit 2 (Day 1) (Clinic Visit).........................................................................................72 
6.2.3. 
Visit 3 (Day 15) (Clinic Visit).......................................................................................73 
6.2.4. 
Visit 4 (Day 29) (Clinic Visit).......................................................................................74 
6.2.5. 
Visit 5 (Day 43) (Clinic Visit).......................................................................................75 
6.2.6. 
Visit 6 (Day 57) (Clinic and Radiology Visit) ..............................................................76 


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6.2.7. 
Visit 7 (Day 71) (Laboratory Visit)...............................................................................77 
6.2.8. 
Visit 8 (Day 85) (Clinic Visit).......................................................................................78 
6.2.9. 
Visit 9 (Day 113) (Clinic and Radiology Visit) ............................................................79 
6.2.10. 
Visit 10 (Day 141) (Clinic Visit)...................................................................................80 
6.2.11. 
Visit 11 (Day 169) (Clinic and Radiology Visit) ..........................................................81 
6.2.12. 
Visit 12 (Day 211) (Clinic Visit)...................................................................................82 
6.2.13. 
Visit 13 (Day 253) (Clinic and Radiology Visit) ..........................................................83 
6.2.14. 
Visit 14 (Day 295) (Clinic Visit)...................................................................................84 
6.2.15. 
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks) 
(Clinic and Radiology Visits)........................................................................................85 
6.2.16. 
End-of-Treatment Visit (Clinic Visit) ...........................................................................86 
6.2.17. 
Immediate Post-Treatment Safety Follow-up ...............................................................87 
6.2.18. 
Long-Term Follow-Up..................................................................................................87 
6.3. 
Blood Collection .............................................................................................................................87 
6.4. 
Study Procedure Rationale..............................................................................................................88 
7. 
EFFICACY ASSESSMENTS .....................................................................................................................90 
7.1. 
Tumor Status Assessments..............................................................................................................90 
7.2. 
Method of Assessment....................................................................................................................90 
7.3. 
Timing of Assessments ...................................................................................................................90 
7.4. 
Identification and Measurement of Tumor Lesions and Organomegaly.........................................90 
7.4.1. 
Index Lesions ................................................................................................................90 
7.4.2. 
Spleen and Liver ...........................................................................................................91 
7.4.3. 
Non-Index Lesions........................................................................................................92 
7.5. 
Definitions of Tumor Response and Progression............................................................................92 
7.5.1. 
Complete Response.......................................................................................................93 
7.5.2. 
Partial Response............................................................................................................93 
7.5.3. 
Stable Disease ...............................................................................................................94 
7.5.4. 
Definitive Progressive Disease......................................................................................94 
7.5.5. 
Non-Evaluable...............................................................................................................96 
7.5.6. 
No Disease ....................................................................................................................96 
7.5.7. 
Lymphocytosis During Therapy....................................................................................96 
7.5.8. 
Documentation of Definitive CLL Progression ............................................................96 
8. 
SAFETY ASSESSMENTS..........................................................................................................................98 
8.1. 
Adverse Event Definitions..............................................................................................................98 
8.1.1. 
Adverse Event...............................................................................................................98 
8.1.2. 
Serious Adverse Event ..................................................................................................99 
8.1.3. 
Unexpected Adverse Event .........................................................................................100 
8.2. 
Eliciting Adverse Event Information ............................................................................................100 
8.3. 
Recording Adverse Events............................................................................................................100 
8.4. 
Grading of the Severity of an Adverse Event................................................................................100 
8.5. 
Describing Adverse Event Relationship to Study Drug and Study Procedures ............................101 
8.6. 
Adverse Event Reporting Period...................................................................................................102 
8.7. 
Adverse Event Reporting Requirements.......................................................................................102 
8.7.1. 
Site Reporting Requirements ......................................................................................102 
8.7.2. 
Gilead Sciences Reporting Requirements ...................................................................104 
8.7.3. 
Reporting of Adverse Events Relating to the Primary Endpoint and 
Other Anticipated Medical Events in the Study Population........................................104 
8.8. 
Study Drug Overdose....................................................................................................................105 
8.9. 
Pregnancy Requirements...............................................................................................................105 
9. 
STATISTICAL CONSIDERATIONS.......................................................................................................107 
9.1. 
Analysis Conventions ...................................................................................................................107 
9.1.1. 
Analysis Sets...............................................................................................................107 


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9.1.2. 
Data Handling Conventions ........................................................................................108 
9.2. 
Analysis Plan ................................................................................................................................110 
9.2.1. 
Subject Disposition and Baseline Characteristics .......................................................110 
9.2.2. 
Efficacy Analyses........................................................................................................110 
9.2.3. 
Exposure and Safety Analyses ....................................................................................111 
9.2.4. 
Other Analyses............................................................................................................114 
9.3. 
Sample Size...................................................................................................................................115 
9.4. 
Timing of Analyses.......................................................................................................................116 
9.4.1. 
Interim Analysis..........................................................................................................116 
9.4.2. 
Final Analysis .............................................................................................................116 
10. RESPONSIBILITIES ................................................................................................................................117 
10.1. 
Investigator Responsibilities .........................................................................................................117 
10.1.1. 
Compliance with Ethical and Regulatory Guidelines..................................................117 
10.1.2. 
Institutional Review Board/Independent Ethics Committee .......................................117 
10.1.3. 
Informed Consent........................................................................................................118 
10.1.4. 
Confidentiality ............................................................................................................118 
10.1.5. 
Study Files and Retention of Records and Biological Samples ..................................118 
10.1.6. 
Case Report Forms......................................................................................................120 
10.1.7. 
Drug Accountability....................................................................................................120 
10.1.8. 
Inspections ..................................................................................................................121 
10.1.9. 
Protocol Compliance...................................................................................................121 
10.2. 
Sponsor Responsibilities...............................................................................................................121 
10.2.1. 
Protocol Modifications................................................................................................121 
10.2.2. 
Communications with Regulatory Authorities............................................................121 
10.2.3. 
Data Management .......................................................................................................121 
10.2.4. 
Study Reporting and Publication.................................................................................122 
10.3. 
Joint Investigator/Sponsor Responsibilities ..................................................................................123 
10.3.1. 
Access to Information for Monitoring.........................................................................123 
10.3.2. 
Access to Information for Auditing or Inspections .....................................................123 
10.3.3. 
Public Notification of Study Conduct .........................................................................123 
10.3.4. 
Study Discontinuation.................................................................................................123 
10.4. 
Study Committees.........................................................................................................................123 
10.4.1. 
Study Steering Committee ..........................................................................................123 
10.4.2. 
Data Monitoring Committee .......................................................................................124 
10.4.3. 
Independent Review Committee .................................................................................125 
11. REFERENCES ..........................................................................................................................................126 
12. APPENDICES ...........................................................................................................................................138 
 
Appendix 1. 
Investigator Signature Page.........................................................................................139 
Appendix 2. 
Functional Assessment of Cancer Therapy: Leukemia 
(FACT-Leu) ................................................................................................................140 
Appendix 3. 
Performance Status Scoring System............................................................................143 
Appendix 4. 
EuroQoL-5 Dimensions (EQ-5D) ...............................................................................144 
Appendix 5. 
Cockcroft-Gault Method for Estimating Creatinine Clearance...................................146 
Appendix 6. 
Cumulative Illness Rating Scale (CIRS).....................................................................147 
Appendix 7. 
Schedule of Study Procedures.....................................................................................152 


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LIST OF IN-TEXT TABLES 
Table 4-1. 
Required Screening Laboratory Values ........................................................................46 
Table 5-1. 
Study Drug Dose Levels ...............................................................................................53 
Table 5-2. 
Recommendations for Study Drug Dose Modifications Based on 
Type and Severity of Adverse Events or Laboratory 
Abnormalities................................................................................................................55 
Table 5-3. 
Protocol-Recommended Contraceptive Methods..........................................................63 
Table 6-1. 
Procedures and Assessments at Visit 1 (During Screening 
Period)...........................................................................................................................71 
Table 6-2. 
Procedures and Assessments at Visit 2 (Day 1) ............................................................72 
Table 6-3. 
Procedures and Assessments at Visit 3 (Day 15) ..........................................................73 
Table 6-4. 
Procedures and Assessments at Visit 4 (Day 29) ..........................................................74 
Table 6-5. 
Procedures and Assessments at Visit 5 (Day 43) ..........................................................75 
Table 6-6. 
Procedures and Assessments at Visit 6 (Day 57) ..........................................................76 
Table 6-7. 
Procedures and Assessments at Visit 7 (Day 71) ..........................................................77 
Table 6-8. 
Procedures and Assessments at Visit 8 (Day 85) ..........................................................78 
Table 6-9. 
Procedures and Assessments at Visit 9 (Day 113) ........................................................79 
Table 6-10. 
Procedures and Assessments at Visit 10 (Day 141) ......................................................80 
Table 6-11. 
Procedures and Assessments at Visit 11 (Day 169) ......................................................81 
Table 6-12. 
Procedures and Assessments at Visit 12 (Day 211) ......................................................82 
Table 6-13. 
Procedures and Assessments at Visit 13 (Day 253) ......................................................83 
Table 6-14. 
Procedures and Assessments at Visit 14 (Day 295) ......................................................84 
Table 6-15. 
Procedures and Assessments at Visit 15 and Subsequent Visits 
(Day 337 and Every 12 Weeks) ....................................................................................85 
Table 6-16. 
Procedures and Assessments at End-of-Treatment Visit...............................................86 
Table 6-17. 
Blood Drawing Requirements Through Visit 15 (Week 48).........................................88 
Table 8-1. 
Grading of Adverse Event Severity.............................................................................101 
Table 8-2. 
Site Reporting Requirements for Adverse Events.......................................................103 
Table 8-3. 
Contact Information for Reporting Serious Adverse Events.......................................104 
LIST OF IN-TEXT FIGURES 
Figure 2-1. 
Study Design.................................................................................................................32 


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PROTOCOL SYNOPSIS 
Gilead Sciences, Inc 
199 East Blaine Street 
Seattle, WA 98102, USA 
Study Title:  
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and 
Safety of Two Different Dose Levels of Single-Agent GS-1101 (CAL-101) 
as Therapy for Patients with Previously Treated Chronic Lymphocytic 
Leukemia 
A Companion Study to Study GS-US-312-0116: A Phase 3, Randomized, 
Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety 
of GS-1101 (CAL-101) in Combination with Rituximab as Therapy for 
Patients with Previously Treated Chronic Lymphocytic Leukemia 
Study Centers 
Planned: 
Approximately 70 centers in the United States and in Europe 
IND Number: 
101254 
EudraCT 
Number: 
2011-006293-72 
Objectives: 
• To determine the effect of GS-1101 on the onset, magnitude, and 
duration of tumor control  
• To compare tumor control in subjects receiving rituximab alone in Study 
GS-US-312-0116 to that observed in the same subjects when receiving 
the standard dose of GS-1101 alone in Study GS-US-312-0117 
• To assess the effect of GS-1101 on measures of subject well-being, 
including overall survival (OS), health-related quality of life (HRQL), 
and performance status 
• To assess the effects of GS-1101 on disease-associated biomarkers and 
to evaluate potential mechanisms of resistance to GS-1101 
• To characterize exposure to GS-1101 as determined by treatment 
administration and evaluation of GS-1101 plasma concentrations over 
time 
• To describe the safety profile observed with GS-1101  
• To estimate health resource utilization associated with administration of 
GS-1101  


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Study Design: 
This study is being conducted as part of an overall clinical program 
evaluating the efficacy and safety of GS-1101 in the therapy of patients with 
previously treated chronic lymphocytic leukemia (CLL).  
Within this program, the primary clinical trial (Study GS-US-312-0116) is a 
Phase 3, multicenter, 2-arm, randomized, double-blind, placebo-controlled, 
parallel-group study. 
This clinical trial (Study GS-US-312-0117) is a separate, multicenter, 2-arm, 
double-blind, parallel-group extension study that is a companion trial to 
Study GS-US-312-0116; in this trial, compliant subjects from GS-US-312-
0116 who are tolerating primary study therapy but experience definitive 
CLL progression are eligible to receive active blinded GS-1101 therapy at 
the standard dose or a higher dose, with allocation based on the original 
primary study randomization. 
Study Schema: 
Randomized
Double-Blind
Initial Therapy
GS-1101, 150 mg BID
Until PD
Placebo BID 
Until PD
Disease 
progression
Double-Blind
Continuing  Therapy
Double-Blind
Extension
Therapy
GS-1101, 150 mg BID
R, 375 mg/m2 Wk 0
R 500 mg/m2 Wk 2,4,6,8,12,16,20
Stratification and 
Randomization
GS-1101, 150 mg BID
Until PD
GS-1101, 300 mg BID
Until PD
Placebo
R, 375 mg/m2 Wk 0
R 500 mg/m2 Wk 2,4,6,8,12,16,20
Screening
Primary Study
Study GS-US-312-0116
Extension Study
Study GS-US-312-0117
Arm A
N=80
Arm B
N=80
 
 
 
Treatment Groups 
• Arm A: GS-1101 + rituximab (Study GS-US-312-0116) 
⇒high-dose GS-1101 (300 mg BID) (Study GS-US-312-0117) 
• Arm B: Placebo + rituximab (Study GS-US-312-0116) 
⇒standard-dose GS-1101 (150 mg BID) (Study GS-US-312-0117) 
Treatment Assignment 
• Assignment to Arm A or Arm B with allocation based on the original 
primary study randomization 
• Implementation through an interactive web response system (IWRS) 
Stratification 
Not applicable for Study GS-US-312-0117 


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Number of 
Subjects 
Planned: 
Total of up to ~160 subjects (up to ~80 subjects per treatment arm) 
Target 
Population 
Subjects in the primary Phase 3 study (Study GS-US-312-0116) who are 
compliant, are tolerating primary study therapy, and have definitive 
progression of CLL while receiving primary study drug therapy 
(GS-1101/placebo). 
Diagnosis and 
Main 
Eligibility 
Criteria: 
Inclusion Criteria 
Subjects must meet all of the following conditions to be eligible for 
enrollment into the study: 
1) Participation in Study GS-US-312-0116. 
2) Occurrence of confirmed, definitive CLL progression while receiving 
study drug therapy (GS-1101/placebo) in Study GS-US-312-0116. Note: 
Definitive disease progression is CLL progression based on standard 
criteria and occurring for any reason (ie, increasing 
lymphadenopathy, organomegaly, or bone marrow involvement; 
decreasing platelet count, hemoglobin, or neutrophil count; or 
worsening of disease-related symptoms) other than lymphocytosis. 
Subjects must have confirmation by the sponsor working in 
collaboration with an independent review committee (IRC) that the 
disease has progressed on the primary clinical trial 
(Study GS-US-312-0116) before receiving secondary GS-1101 therapy 
on this extension trial (Study GS-US-312-0117). 
3) Presence of measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures ≥2.0 cm in the longest dimension [LD] 
and ≥1.0 cm in the longest perpendicular dimension [LPD] as assessed 
by computed tomography [CT] or magnetic resonance imaging [MRI]).  
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab 
and/or GS-1101/placebo) and no intervening or continuing therapy 
(including radiotherapy, chemotherapy, immunotherapy, systemic 
corticosteroids, or investigational therapy) for the treatment of CLL. 
5) The time from permanent cessation of Study GS-US-312-0116 treatment 
(rituximab and/or GS-1101/placebo) and the initiation of Study GS-US-
312-0117 therapy is ≤12 weeks. Note: Study procedures performed as 
part of Study GS-US-312-0116 need not be repeated and can be used 
as screening procedures for Study GS-US-312-0117 if performed 
within 4 weeks prior to initiation of study drug therapy on Study GS-
US-312-0117. 
6) Karnofsky performance score of ≥40. 


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7) Required baseline laboratory data (within 4 weeks prior to initiation of 
study treatment) as shown in the table below. Note: Confirmation 
should be considered for out-of-range values to determine if the 
abnormality is real or artifactual. Values should be obtained within 
the screening period and should generally be the most recent 
measurement obtained. Subjects with any degree of neutropenia, 
thrombocytopenia, or anemia due to CLL or prior therapy may enroll. 
Required Screening Laboratory Values 
Organ System 
Parameter 
Required Value 
Serum total bilirubin 
≤1.5 x ULN (unless elevated due to Gilbert’s syndrome) 
Serum ALT 
Hepatic 
Serum AST 
≤2.5 x ULN 
Renal 
eCCr
a 
>30 ml/min 
Pregnancy 
β-HCGb 
Negative  
a As calculated by the Cockcroft-Gault formula 
b For women of child-bearing potential only; serum β-HCG must be negative during screening and serum β-HCG 
or urine dipstick pregnancy test must be negative at randomization (Visit 2) 
Abbreviations: β-HCG=beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate 
aminotransferase, eCCr=estimated creatinine clearance, ULN=upper limit of normal 
 
8) For female subjects of childbearing potential, willingness to abstain 
from heterosexual intercourse or use a protocol-recommended method of 
contraception from the screening visit (Visit 1) throughout the study 
treatment period and for 30 days following the last dose of study drug. 
Note: A female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy; has medically documented ovarian failure (with serum 
estradiol and follicle-stimulating hormone [FSH] levels within the 
institutional postmenopausal range and a negative serum or urine 
βHCG), or is menopausal (age ≥55 years with amenorrhea for ≥6 
months).  
9) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to abstain from 
heterosexual intercourse or use a protocol-recommended method of 
contraception from the start of study therapy (Visit 2) throughout the 
study treatment period and for 90 days following the last dose of study 
drug and to refrain from sperm donation from the start of study 
treatment (Visit 2) throughout the study treatment period and for 90 days 
following the last dose of study drug. Note: A male subject is 
considered able to father a child unless he has had a bilateral 
vasectomy with documented aspermia or a bilateral orchiectomy, or 
has ongoing testicular suppression with a depot luteinizing hormone- 
releasing hormone (LH-RH) agonist (eg, goserelin acetate 
[Zoladex®]), leuprolide acetate [Lupron®]), or triptorelin pamoate 
[Trelstar®]). 


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10) In the judgment of the investigator, participation in the protocol offers 
an acceptable benefit-to-risk ratio when considering current CLL disease 
status, medical condition, and the potential benefits and risks of 
alternative treatments for CLL.  
11) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, familial, 
or geographical factors that might preclude adequate study 
participation should be considered. 
12) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature of 
the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study 
participation. 
 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria are not to be 
enrolled in this study: 
1) Known histological transformation from CLL to an aggressive 
lymphoma (ie, Richter transformation).  
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at the 
time of the start of study treatment (Visit 2). Note: Subjects with 
localized fungal infections of skin or nails are eligible. Subjects may 
be receiving prophylactic antiviral or antibacterial therapies at the 
discretion of the investigator; anti-pneumocystis prophylaxis is 
encouraged.  
3) Pregnancy or breastfeeding.  
4) Intentional breaking of the blind in Study GS-US-312-0116 by the 
investigator or the study subject. 
5) Concurrent participation in another therapeutic clinical trial. 
6) Prior or ongoing clinically significant illness, medical condition, surgical 
history, physical finding, electrocardiogram (ECG) finding, or 
laboratory abnormality that, in the investigator’s opinion, could 
adversely affect the safety of the subject or impair the assessment of 
study results. 


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Study 
Procedures/ 
Frequency: 
Subjects participating in the extension study will be assigned to 1 of the 
2 treatment arms, with allocation based on the original randomization in 
the primary study. In the extension study, blinded GS-1101 high-dose or 
standard-dose therapy will be taken orally, twice per day (BID), 
continuously.  
Clinic/laboratory visits will occur every 2 weeks for the first 12 weeks, 
every 4 weeks between Weeks 12 and 24, and every 6 weeks between 
Weeks 24 and 48. Subjects continuing on study treatment past Week 48 
will have clinic visits every 12 weeks. Subjects will be assessed for safety 
at each visit. Subjects will be assessed for CLL disease status by physical 
and laboratory examinations at each visit and by CT or MRI at Weeks 8, 
16, 24, 36, and 48 and every 12 weeks thereafter through Week 96. For 
follow-up visits after Week 96, CT or MRI is only required at the End-of-
Treatment visit. 
Test Therapy, 
Dose, and  
Mode of 
Administration: 
• Arm A: GS-1101, 300 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be provided 
as 2 tablets of active GS-1101 for oral administration 
• Arm B: GS-1101, 150 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be provided 
as 1 tablet of active GS-1101 and 1 tablet of placebo for oral 
administration 
Reference 
Therapy, Dose, 
and Mode of 
Administration: 
Not applicable 
Duration of 
Treatment: 
Study drug will be taken continuously until the earliest of subject 
withdrawal from study, definitive progression of CLL, intolerable study 
drug-related toxicity, pregnancy, substantial noncompliance with study 
procedures, or study discontinuation. 


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Criteria for 
Evaluation: 
Tumor Control  
• Progression-free survival (PFS) – defined as the interval from the 
start of study therapy to the earlier of the first documentation of 
definitive disease progression or death from any cause; definitive 
disease progression is CLL progression based on standard criteria and 
occurring for any reason (ie, increasing lymphadenopathy, 
organomegaly or bone marrow involvement; decreasing platelet 
count, hemoglobin, or neutrophil count; or worsening of 
disease-related symptoms) other than lymphocytosis alone 
• Overall response rate (ORR) – defined as the proportion of subjects 
who achieve a complete response (CR) or partial response (PR)  
• Time to response (TTR) – defined as the interval from start of study 
therapy to the first documentation of CR or PR 
• Duration of response (DOR) – defined as the interval from the first 
documentation of CR or PR to the earlier of the first documentation 
of definitive disease progression or death from any cause 
• Time to treatment failure (TTF) – defined as the interval from start of 
study therapy to the earliest of the first documentation of definitive 
disease progression, the permanent cessation of study drug due to an 
adverse event, or death from any cause 
• Percent change in lymph node area – defined as the percent change 
from baseline in the sum of the products of the greatest perpendicular 
diameters (SPD) of index lymph nodes 
• Lymph node response rate – defined as the proportion of subjects 
who achieve a ≥50% decrease from baseline in the SPD of index 
lymph nodes 
• Splenomegaly response rate – defined as the proportion of subjects 
with baseline splenomegaly who achieve an on-study normalization 
or a decrease by ≥50% from baseline in the pretreatment enlargement 
of the splenic longest vertical dimension (LVD) (by imaging) or in 
the pretreatment enlargement of the splenic LVD below the left costal 
margin (by palpation) 
• Hepatomegaly response rate – defined as the proportion of subjects 
with baseline hepatomegaly who achieve an on-study normalization 
or a decrease by ≥50% from baseline in the pretreatment enlargement 
of the hepatic LVD (by imaging) or in the pretreatment enlargement 
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• Platelet response rate – defined as the proportion of subjects with 
baseline thrombocytopenia (platelet count <100 x 109/L) who achieve 
an on-study platelet count ≥100 x 109/L or demonstrate a ≥50% 
increase in platelet count from baseline 
• Hemoglobin response rate – defined as the proportion of subjects with 
baseline anemia (hemoglobin <110 g/L [11.0 g/dL]) who achieve an 
on-study hemoglobin ≥110 g/L (11.0 g/dL) or demonstrate a ≥50% 
increase in hemoglobin from baseline 
• Neutrophil response rate – defined as the proportion of subjects with 
baseline neutropenia (absolute neutrophil count [ANC] <1 x 109/L) 
who achieve an ANC ≥1 x 109/L or demonstrate a ≥50% increase in 
ANC from baseline 
Patient Well-Being 
• Overall survival (OS) – defined as the interval from start of study 
therapy to death from any cause 
• Change in HRQL domain and symptom scores based on  the 
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) – 
defined as the change from baseline and the time to definitive 
increments or decrements of 10%, 20%, and 40% from baseline; time 
to definitive increment (better than baseline by the specified amount) 
is the interval from start of study therapy to the first timepoint when 
the HRQL measure is consistently better than at baseline (including 
that timepoint as well as all the subsequent timepoints) in a subject 
whose last HRQL score is better than at baseline; and time to 
definitive HRQL decrement (worse than baseline by the specified 
amount) is the interval from start of study therapy to the earliest of 
death or the first timepoint when the HRQL measure is consistently 
worse than at baseline (including that timepoint as well as all the 
subsequent timepoints) in a subject whose last performance status 
score is worse than at baseline 
• Changes in Karnofsky performance status – defined as the change 
from baseline in the performance status and the time to definitive 
performance status improvement or worsening; time to definitive 
performance status improvement (better than baseline) is the interval 
from start of study therapy to the first timepoint when the 
performance status is consistently better than at baseline (including 
that timepoint as well as all the subsequent timepoints) in a subject 
whose last performance status score is better than at baseline; and 
time to definitive performance status worsening (worse than baseline) 
is the interval from study therapy until the earliest of death or the first 
timepoint when the performance status is consistently worse than at 
baseline (including that timepoint as well as all the subsequent 


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timepoints) in a subject whose last performance status score is worse 
than at baseline 
Pharmacodynamic Markers of Drug Activity and Resistance 
• Changes from baseline in PI3K/AKT/mTOR pathway activation as a 
measure of PI3Kδ pathway activity  
• Changes from baseline in the plasma concentrations of disease-
associated chemokines and cytokines 
Exposure 
• Study drug administration as assessed by prescribing records and 
compliance as assessed by quantification of used and unused drug 
• Trough (pre-dose) and peak (1.5-hour samples) of GS-1101 plasma 
concentrations as assessed by a validated bioanalytical method 
Safety 
• Overall safety profile of each study treatment regimen characterized 
by the type, frequency, severity, timing of onset, duration, and 
relationship to study therapy of any adverse events or abnormalities 
of laboratory tests; serious adverse events; or adverse events leading 
to discontinuation of  study treatment  
Pharmacoeconomics 
• Change in health status – defined as the change from baseline in 
overall health and single-item dimension scores as assessed using the 
EuroQoL Five-Dimension (EQ-5D) utility measure  
• Health resource measures, including resource utilization, total costs, 
and measures of cost per unit of benefit (eg, cost per additional 
progression-free month, cost per quality-adjusted life-year) 
Statistical 
Methods: 
Analysis Methods  
Appropriate data analysis sets will be defined. The full-analysis set will 
include data from all subjects who receive ≥1 dose of any study therapy 
on this study; in this data set, study drug assignment (high-dose or 
standard-dose GS-1101) will be designated according to the planned 
allocation to this study. A safety analysis set will comprise data from 
subjects in the full-analysis set with treatment assignments designated 
according to the actual study drug (high-dose or standard-dose GS-1101) 
received. Other data sets (responding, evaluable, and 
pharmacodynamic/pharmacokinetic data sets) will be defined and will 
include data from subjects who have the necessary baseline and on-study 
measurements to provide interpretable results for specific parameters of 
interest.  


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Subject characteristics and study results will be described and 
summarized by treatment arm and assessment for the relevant analysis 
sets. Descriptive summaries will be prepared to show sample size, mean, 
standard deviation, 95% confidence intervals (CIs) on the mean, median, 
minimum, and maximum for continuous variables and counts, 
percentages, and 95% CIs on the percentage for categorical variables. 
For endpoints relating to tumor control, patient well-being, and 
biomarkers, analyses will be done based on the full-analysis, responding, 
evaluable, or pharmacodynamic data sets, as appropriate. Time-to-event 
analyses will be performed with reference to the date of first treatment on 
this study (Study GS-US-312-0117). Similarly, evaluations of on-therapy 
changes will reference the baseline values obtained prior to treatment in 
this study. Analyses will focus on evaluation of outcomes within each 
treatment arm and will be largely descriptive in nature; formal 
comparisons of outcomes in Arm A vs Arm B are not planned. Time-to-
event endpoints will be summarized using Kaplan-Meier methods; 
medians, ranges, and the corresponding 95% CI will be presented. 
Continuous and categorical variables will also be summarized as 
appropriate. Changes from baseline in categorical variables and changes 
from baseline in continuous endpoints will be analyzed using appropriate 
methods. 
Efficacy outcomes among subjects receiving rituximab alone in 
Study GS-US-312-0116 will be evaluated relative to those same 
outcomes among the same subjects receiving standard-dose GS-1101 
alone in Study GS-US-312-0117. More specifically, time-to-event 
endpoints will be compared using the paired Prentice-Wilcoxon test; 
continuous endpoints will be compared using the paired t-test; and 
categorical or non-normal data will be compared using the Wilcoxon 
signed-rank test. 
Based on the safety analysis set, information regarding study treatment 
administration, study drug compliance, safety variables, and post-study 
therapies will be described and summarized. Using data from the 
pharmacokinetic analysis set, GS-1101 plasma concentrations will also 
be described and summarized. 


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Sample Size Calculation 
The sample size for this extension study is not based upon a formal 
statistical hypothesis. The upper bound of the sample size in this study is 
determined by the sample size of the preceding primary clinical trial 
(Study GS-US-312-0116) in which ~160 subjects (~80 per arm) are 
expected to be enrolled. Assuming a ~10% dropout rate during 
Study GS-US-312-0116 and a further ~10% dropout rate in the transition 
from the primary study to the extension study, ~130 subjects are expected 
to be enrolled into Study GS-US-312-0117. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice 
(GCP), including archiving of essential documents. 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS 
β-HCG 
Beta human chorionic gonadotropin 
ABCG2 
adenosine triphosphate-binding cassette sub-family G member 2 (see also BCRP) 
AKT 
AKT (a serine/threonine protein kinase) 
ALC 
absolute lymphocyte count 
ALL 
acute lymphocytic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
ATC 
Anatomical-Therapeutic-Chemical classification system for drugs  
BCRP 
breast cancer resistance protein (see also ABCG2) 
BID 
twice per day 
BTK 
Bruton tyrosine kinase 
CAL-101 
Former name for GS-1101 
CCL 
chemokine (C-C motif) ligand 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIRS 
Cumulative Illness Rating Scale 
CLL 
chronic lymphocytic leukemia 
cGMP 
current Good Manufacturing Practice 
Cmax 
maximum concentration 
CMV 
cytomegalovirus 
CR 
complete response 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
trough concentration 
CXCL 
chemokine (C-X-C motif) ligand 
CYP 
cytochrome P450 enzyme 
DLCO 
diffusing capacity of the lung for carbon monoxide 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSPH 
Gilead Sciences Department of Safety and Public Health 
ECG 
electrocardiogram 
eCCr 
estimated creatinine clearance 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EQ-5D 
EuroQoL Five-Dimension utility measure 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED) 
FACT-Leu 
Functional Assessment of Cancer Therapy: Leukemia questionnaire 
FCεRI 
high-affinity IgE receptor 
FDA 
United States Food and Drug Administration 
FDAMA 
Food and Drug Modernization Act 
FDG 
fluorodeoxyglucose (18F) 
FISH 
fluorescence in-situ hybridization, 
FSH 
follicle-stimulating hormone 
G-CSF 
granulocyte colony-stimulating factor 
GGT 
gamma-glutamyltransferase 
GLP 
Good Laboratory Practice 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HBc antibody 
anti-hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
hERG 
human ether-à-go-go-related gene 
HL 
Hodgkin lymphoma 
HIV 
human immunodeficiency virus 
HRQL 
health-related quality of life 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
Ig 
immunoglobulin (including subtypes A, E, G, and M) 
IgHV 
immunoglobulin heavy chain variable region 
IND 
Investigational New Drug (application) 
iNHL 
indolent non-Hodgkin lymphoma 
INR 
international normalized ratio 
IRB 
institutional review board 
IRC 
independent review committee 
ITT 
intention to treat 
IUD 
intrauterine device 
IWCLL 
International Workshop on CLL 
IWRS 
interactive web response system 
JAK 
Janus kinase 
K2-EDTA 
potassium-ethylenediaminetetraacetic acid 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
LH-RH 
luteinizing hormone-releasing hormone 
LLN 
lower limit of normal 
LPD 
longest perpendicular diameter 
LVD 
longest vertical dimension 
MTD 
maximum tolerated dose 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED) 
mTOR 
mammalian target of rapamycin 
ND 
no disease 
NHL 
non-Hodgkin lymphoma 
NOAEL 
no-observed-adverse effect level 
NOEL 
no-observed-effect level 
OCT 
organic cation transporter 
ORR 
overall response rate 
OS 
overall survival 
pAKT 
phosphorylated AKT 
PD 
progressive disease 
PET 
positron-emission tomography 
PI3K 
phosphatidylinositol 3-kinase 
PI3Kδ 
phosphatidylinositol 3-kinase p110δ isoform 
PFS 
progression-free survival 
PML 
progressive multifocal leukoencephalopathy 
PPD 
product of the perpendicular diameters 
PRO 
patient-reported outcome 
PR 
partial response 
PT 
prothrombin time 
PVA 
polyvinyl alcohol 
PVC/PCTFE 
polyvinyl chloride/polychlorotrifluoroethylene 
QD 
once per day 
QT (interval) 
measure of time between start of Q wave and end of T wave in electrical cycle of heart 
RNA 
ribonucleic acid 
SADR 
serious adverse drug reaction 
SD 
stable disease 
SPD 
sum of the products of the perpendicular diameters of measured lymph nodes 
SSC 
study steering committee 
SUSAR 
suspected, unexpected, serious adverse reaction 
SYK 
spleen tyrosine kinase 
t1/2 
half-life 
Tmax 
time of maximum concentration 
TTF 
time to treatment failure 
TTR 
time to response 
UGT 
uridine 5'-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 
WHODRUG 
World Health Organization Drug Dictionary 
ZAP=70 
zeta-associated protein 70 
 


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1. 
INTRODUCTION 
1.1. 
Chronic Lymphocytic Leukemia 
Chronic lymphocytic leukemia (CLL) is a neoplasia resulting from the progressive 
accumulation of functionally incompetent monoclonal B lymphocytes in blood, bone 
marrow, lymph nodes, spleen, and liver [Dighiero 2008]. CLL constitutes the most 
commonly occurring leukemia in Europe and the United States [Sant 2010, SEER 2011]. 
While some patients never require treatment, many will need therapy for disfiguring or 
obstructing lymphadenopathy, debilitating constitutional B symptoms (fevers, night sweats, 
fatigue, weight loss) [Redaelli 2004], or recurrent cytopenias and infections [Perkins 2002, 
Keating 2002a]. CLL is largely a disease of the elderly; at diagnosis, 70% of patients are 
≥65 years of age and the median age is 72 years [SEER 2011]. 
In younger and relatively healthy patients with CLL, chemoimmunotherapy regimens that 
include the anti-CD20 monoclonal antibody, rituximab, are commonly employed to control 
disease manifestations [Gribben 2011]. Such combination therapies are effective in providing 
durable remissions [Byrd 2005, Hallek 2010, Robak 2010, Fischer 2011, and Iannitto 2011]. 
However, while rituximab is usually well tolerated [Gentile 2010], the chemotherapeutic 
agents (typically fludarabine, cyclophosphamide, or bendamustine) in such regimens are 
acutely cytotoxic, induce permanent bone marrow compromise, and can cause secondary 
malignancies [Kyasa 2004, Tam 2008, Carney 2010]. Furthermore, in elderly patients or in 
those with comorbid conditions, such regimens are associated with less efficacy and greater 
toxicity [Tam 2008, Eichhorst 2009b, Goede 2011]. 
Increasing attention has been paid to the problem of treating patients with CLL who have 
comorbidities. Because of the relatively late age of diagnosis, a large proportion (~90%) of 
patients with CLL have co-morbidities and a substantial proportion (~45%) have major 
chronic conditions such as coronary artery disease, diabetes, or chronic obstructive 
pulmonary disease [Thurmes 2008]. At the time the disease is first identified, ~25% of 
patients with CLL do not meet conventional criteria for participation in clinical studies 
containing cytotoxic agents [Thurmes 2008]. By the time treatment is necessary or during 
treatment for CLL, patients continue to advance in age and have new or worsening chronic 
conditions; as a result, the proportion of patients with comorbidities increases during the 
course of the illness. Such patients have been substantially underrepresented in clinical trials 
due to concerns regarding the ability of such patients to tolerate intensive 
chemoimmunotherapy [Thurmes 2008, Eichhorst 2009a]. Instruments such as the 
Cumulative Illness Rating Scale (CIRS) [Linn 1968] are now being applied in order to 
categorize patient populations as fit or relatively unfit and to evaluate regimens tailored to 
these groups of patients [Eichhorst 2009a, Hallek 2010, Giudice 2011]. 
Health constraints in older or compromised patients have prompted noncytotoxic approaches 
to therapy. Alternative immunotherapeutics, such as the monoclonal antibodies, 
alemtuzumab [Keating 2002b] or ofatumumab [Wierda 2010], have been developed. 
However the therapeutic utility of these drugs is modest; median progression-free survival 
(PFS) values in patients with recurrent CLL have been 4.7 months and 5.8 months, 
respectively. Moreover, these treatments can have clinical liabilities. Alemtuzumab causes 
extreme immunosuppression that leads to frequent opportunistic infection. Administration of 


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the large amounts of protein recommended in ofatumumab product labeling results in 
frequent infusion reactions and cumbersome infusion schedules. 
In view of these issues, repeated use of rituximab monotherapy or rituximab-corticosteroid 
combinations have been advocated in treatment guidelines for older or frail patients with 
recurrent CLL [Eichhorst 2010, Zelenetz 2011]. While single-agent rituximab use can offer 
palliative benefit with good tolerability in some patients with previously treated CLL, tumor 
control is not lasting, especially in patients with bulky adenopathy [Gentile 2010]. Addition 
of high-dose corticosteroids to rituximab can extend median PFS up to 12 months, but this 
combination is commonly associated with severe hyperglycemia and frequent 
life-threatening or fatal infections [Bowen 2007, Dungarwalla 2008]. New, noncytotoxic, 
well-tolerated, and convenient therapies that can successfully be combined with rituximab or 
given as single-agent therapy are needed in order to enhance and prolong tumor control in 
patients with comorbid conditions. 
1.2. 
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies 
Phosphatidylinositol 3-kinases (PI3Ks) are enzymes that regulate several cellular functions 
including motility, proliferation, and survival [Okkenhaug 2003a]. PI3K activation recruits 
and activates numerous intracellular signaling enzymes. The most important of these is the 
serine/threonine kinase, AKT, which mediates a positive pleiotropic effect on cell survival, 
proliferation, growth, and metabolism [Engelman 2006] acting by signaling through 
mammalian target of rapamycin (mTOR) [Hay 2005, Osaki 2004]. 
PI3K signaling is mediated by 4 catalytic isoforms of the p110 subunit of the enzyme – α, β, 
γ, and δ. While potentially important in multiple cell types, PI3K p110δ (PI3Kδ) shows an 
expression pattern that is particularly prominent in cells of hematopoietic origin 
[Vanhaesebroeck 2005]. Mice deficient in PI3Kδ have no gross abnormalities, are fertile, 
fecund, and live a normal life span without an increased susceptibility to infections 
[Okkenhaug 2003b]. However, the B-lymphocyte population in these animals shows a 
decrease in maturation, diminished receptor-induced proliferation, and increased 
susceptibility to apoptotic cell death. Conversely, mice with aberrantly elevated PI3K 
signaling develop lymphadenopathy and have an increased incidence of lymphoma 
[Donahue 2004]. In CLL, sustained activation of the PI3K/AKT/mTOR pathway has been 
shown to promote malignant B-cell survival through mechanisms that are dependent on the 
PI3Kδ isoform [Cuni 2004, Herman 2010, Lannutti 2011]. 
Knowledge of the critical importance of PI3Kδ in B-cell biology and neoplasia has 
encouraged a search for inhibitors of this enzyme that could provide new options in the 
therapy of lymphoid malignancies, including CLL. 
1.3. 
GS-1101 
1.3.1. 
Discovery and Efficacy Pharmacology 
Gilead Sciences, Inc has developed novel drugs that can suppress tumor growth through 
targeting of PI3Kδ activity. High-throughput screening was the basis for the discovery of 
novel agents that selectively inhibit PI3Kδ function but spare other PI3K isoforms and other 
kinases. Chemical optimization, pharmacological characterization, and toxicological 
evaluation have led to identification of GS-1101 (also known as CAL-101), a 415-dalton, 


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orally bioavailable, new chemical entity with potential clinical utility in the treatment of 
cancers [Gilead Sciences 2011]. 
In primary tumor samples and in cell lines derived from patients with CLL, indolent 
non-Hodgkin lymphoma (iNHL), mantle cell lymphoma (MCL), B-cell acute lymphocytic 
leukemia (ALL), or Hodgkin lymphoma (HL), GS-1101 induces dose-dependent reductions 
in AKT phosphorylation [Herman 2010, Meadows 2010, Lannutti 2011]. In addition, 
GS-1101 disrupts the PI3Kδ activation and supportive intercellular signaling observed when 
CLL or HL cells are cocultured with stromal cells [Meadows 2010, Hoellenriegel 2011]. 
These effects have therapeutic consequences. In multiple lymphoid primary tumors and 
malignant cell lines, GS-1101 enhances apoptosis and concentration-dependent cell killing 
when applied as a single agent and increases the therapeutic efficacy of other antineoplastic 
agents when given in combination [Hoellenriegel 2011, Meadows 2011]. In preclinical 
systems, coadministration of GS-1101 with rituximab has not impaired rituximab-mediated 
activity [Herman 2010]. 
1.3.2. 
Safety Pharmacology 
In vitro and in vivo safety pharmacology studies with GS-1101 have demonstrated a 
favorable non-clinical safety profile [Gilead Sciences 2011]. These studies indicate that the 
drug may minimally slow bone marrow progenitor proliferation and differentiation and that it 
has expected inhibitory effects on B-cell response to antigen challenge. However, the data 
indicate that GS-1101 is unlikely to cause serious off-target effects or adverse effects on 
critical organ systems. GS-1101 has no meaningful effect on the human ether-à-go-go-related 
gene (hERG) channel, indicating that GS-1101 would not be expected to induce clinical QT 
prolongation. 
The drug has also proved well tolerated in standard in vivo Good Laboratory Practice (GLP) 
studies of pharmacological safety. A functional observation battery in rats revealed no 
adverse effects on behavior or on autonomic, neuromuscular, or sensorimotor function. In a 
cardiopulmonary function study in awake, telemeterized male beagle dogs, single doses of 
GS-1101 induced no meaningful abnormalities in pulmonary, cardiovascular, arterial blood 
gas, or electrocardiographic (ECG) (including QT interval) parameters. In an assessment of 
bacterial challenge in rats, GS-1101 enhanced, rather than impaired, the phagocytic host 
clearance of staphylococcal bacteria. 
1.3.3. 
Nonclinical Pharmacology and Metabolism 
In rats and dogs, plasma-concentration time profiles of GS-1101 are available following 
single oral and intravenous administration as well as following repeated oral administration 
as part of toxicology studies [Gilead Sciences 2011]. The metabolism of GS-1101 has been 
studied in vitro and in vivo; the major metabolite has been identified and characterized in 
rats, dogs, and humans. No human-specific metabolites have been identified. 
Drug disposition data document GS-1101 oral bioavailability in test species, characterize 
similar plasma protein binding across species, and demonstrate that GS-1101 metabolism is 
dependent upon both hepatic oxidation catalyzed in part by cytochrome P450 (CYP) 3A4 and 
on glucuronidation mediated by uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A4. 
Nonclinical findings show that biliary excretion and hepatic metabolism to renal excretion 


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products are important in GS-1101 elimination. Nonclinical drug-drug interaction data show 
that GS-1101 is unlikely to alter CYP-dependent metabolism of other drugs but could alter 
absorption or disposition of agents that are substrates for P-glycoprotein, the organic cation 
transporter-2 (OCT2), or the adenosine triphosphate-binding cassette sub-family G 
member 2 (ABCG2) transporter (also known as the breast cancer resistance protein [BCRP]). 
1.3.4. 
Toxicology 
In support of clinical development in patients with lymphoid cancers, GS-1101 has 
undergone toxicological evaluation in conformance with the International Conference on 
Harmonisation (ICH) S9 guidance on nonclinical evaluation for anticancer pharmaceuticals 
[FDA 2010]. 
1.3.4.1. 
General Toxicology 
Completed GLP toxicology studies have included 28-day evaluations in both rats and dogs 
and a study evaluating the hematological effects of co-administration of GS-1101 and 
cyclophosphamide [Gilead Sciences 2011]. These studies have shown GS-1101 to be 
tolerated at exposure levels greater than those expected to provide therapeutic activity and 
have identified signals to be monitored in the clinic. Reversible lymphoid depletion in rats 
and dogs was consistent with GS-1101-mediated inhibition of PI3Kδ. In rats, partially 
reversible inflammation of the tongue was noted in GS-1101-treated animals; this may have 
represented an exaggeration of background effects related to gavage-mediated irritation. Mild 
congestion or hemorrhage in the large intestine has been seen in dogs receiving high doses of 
GS-1101. Rats also showed cardiac and hepatic chronic inflammatory infiltrates, although 
attribution to GS-1101 was uncertain because background infiltrates of a similar nature were 
observed in control recovery animals. In dogs, evidence of hepatocellular injury and chronic 
inflammation was accompanied by elevations of serum transaminase values (serum alanine 
aminotransferase [ALT] and serum aspartate aminotransferase [AST]). These hepatic effects 
appeared dose-related, reversible, and monitorable using standard serum chemistry 
laboratory parameters. In both rats and dogs, persistent minimal to mild degeneration of the 
seminiferous tubules and decreased spermatozoa were present in male animals receiving 
GS-1101. When co-administered with cyclophosphamide in rats, GS-1101 did not worsen 
cyclophosphamide-mediated changes in hematological parameters. 
Data from 13-week GLP toxicology studies in rats and dogs are available. These data 
confirm the 28-day toxicology findings. GS-1101 was well tolerated with no notable clinical 
observation or changes in body weight at exposure levels approximating or exceeding those 
observed in subjects at the planned clinical starting dose of 150 mg/dose administered twice 
per day (BID). In both species, dose-dependent lymphoid depletion was observed that was 
consistent with PI3Kδ inhibition by GS-1101. In dogs, expected transient low-level 
elevations of serum ALT in 2 animals receiving the highest GS-1101 dose were observed at 
Day 29 of the study; of note, animals showed spontaneous recovery during continued 
GS-1101 dosing, with no elevations at Day 60 or Day 90. Microscopic review of dog tissues 
indicated no evidence of persistent or residual liver pathology at the conclusion of the study. 
Consistent with previous studies, findings of persistent hypospermatogenesis and decreased 
testicular weight were observed in both species. 


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In an investigative study, a further characterization of the pattern of serum transaminase 
changes associated with administration of high-dose of GS-1101 to dogs confirmed hepatic 
adaptation to the effect. In this study, mean serum ALT/AST values peaked at approximately 
Day 24 to Day 27 and resolved spontaneously as the dogs continued on GS-1101 through the 
end of the study on Day 44. 
1.3.4.2. 
Genotoxicity 
GS-1101 was not genotoxic in a standard battery of assays [Gilead Sciences 2011]. In the 
Ames assay, GS-1101 did not cause mutagenic effects. In human peripheral blood 
lymphocytes, the compound induced no chromosomal aberrations. In a rat micronucleus 
study, GS-1101 did not show evidence of clastogenicity. 
1.3.4.3. 
Reproductive Toxicology 
Data from a non-GLP embryo-fetal developmental toxicity study in rats suggested no 
evidence of maternal toxicity at GS-1101 doses of 25, 50, 75, and 100 mg/kg/day. No 
GS-1101-related findings were observed based on external examination of the fetus at any 
dose level although lower fetal body weights were evident at 100 mg/kg/day and were 
considered related to treatment with GS-1101. Thus, the no-observed-effect level (NOEL) for 
maternal toxicity was 100 mg/kg/day and the NOEL for fetal developmental toxicity was 
75 mg/kg/day. Definitive GLP reproductive toxicology studies in rats and rabbits are 
planned. 
As noted in Section 1.3.4.1, 28-day and 13-week general toxicology studies in rats and dogs 
indicated dose-dependent reductions in testicular weights, with persistent minimal to mild 
degeneration of the seminiferous tubules and decreased spermatozoa in rats and 
hypospermatogenesis in dogs. The no-observed-adverse effect level (NOAEL) was 
50 mg/kg/day for rats and 5 mg/kg/day for dogs. The impact of these testicular changes on 
fertility, if any, has not been assessed. 
1.3.5. 
GS-1101 Clinical Studies 
1.3.5.1. 
Phase 1 Studies in Healthy Subjects and in Patients with Allergic Rhinitis 
Three studies in healthy subjects (Studies 101-01, 101-04, and 101-05) have provided 
information regarding drug safety, pharmacokinetics, food effects, and the potential for drug 
interactions with CYP3A4 inhibitors [Webb 2010, Gilead Sciences 2011]. One of these trials 
also included a preliminary evaluation of absorption, metabolism and excretion in healthy 
volunteers; in this trial, unlabeled GS-1101 was co-administered with a trace amount of 
[14C]GS-1101 given either orally or intravenously and biological samples were assessed by 
accelerator mass spectrometry. 
Safety results from these studies indicated that GS-1101 was well tolerated when 
administered to healthy subjects at single doses through 400 mg (the highest dose level 
tested) and was also generally well tolerated when administered to healthy subjects over 
7 days at dose levels through 200 mg/dose BID (the highest dose level tested). Dosing with 
200 mg/dose BID for 7 days resulted in a skin rash in 3 out of 6 subjects; histological 
findings were consistent with a delayed-type hypersensitivity maculopapular exanthema. 
Rashes have sometimes occurred in patients with hematological malignancies receiving 
GS-1101, but have not typically proved dose- or treatment-limiting. In placebo-controlled 


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single-dose and multiple-dose trials, repeated ECG evaluations performed in tandem with 
pharmacokinetic monitoring showed no evidence of drug-, dose-, or exposure-dependent 
effects on cardiac rhythm or cardiac intervals (eg, QT interval). 
Pharmacokinetic results indicated that increases in plasma GS-1101 maximum concentration 
(Cmax) and area under the concentration-time curve (AUC) values were dose-proportional 
with increasing single-dose administration but less-than-dose-proportional with increasing 
multiple-dose administration. There was only modest accumulation with BID dosing over 
7 days. Consistent with mean half-life (t1/2) values in the range of 6 to 10 hours, steady state 
was achieved within 7 days of repeated dosing. Mean plasma GS-1101 trough concentrations 
(Ctrough) exceeded target values known to be associated with pharmacological activity based 
on nonclinical testing. 
Ingestion of a high-fat, high-calorie meal just prior to administration of GS-1101 moderately 
delayed absorption, increasing the drug’s median time of maximum concentration (Tmax) 
from 0.75 hours to 3 hours without altering mean Cmax. The aggregate effect was an increase 
of 1.4-fold in mean AUC. While the data indicate a food effect, the changes in GS-1101 
pharmacokinetics were modest; thus, GS-1101 may be given with or without food. 
When GS-1101 was administered following 4 days of daily dosing with ketoconazole 
(a potent inhibitor of CYP3A4), increases in mean GS-1101 Cmax and AUC values were 
1.3- and 1.8-fold, respectively. The data indicate that some alterations in GS-1101 
pharmacokinetics occur but that GS-1101 is not a sensitive substrate for CYP3A4. Thus, 
co-administration of CYP3A4 inhibitors and GS-1101 is not contraindicated and does not 
require special monitoring. 
The 14C-labeled GS-1101 results showed that the drug has an oral bioavailability of 56%. 
Hepatic metabolism and biliary excretion appeared to be particularly important in GS-1101 
elimination. Consistent with the metabolism data from animal studies, an oxidation product 
was observed in human plasma and a hydrolyzed product was observed in urine and feces. 
[14C]-GS-1101-derived materials were primarily excreted in feces (>65% of total dose) with 
lesser elimination via urine (<15% of total dose). 
Pharmacodynamic results showed that a GS-1101 dose of 200 mg inhibited ex vivo basophil 
activation via the PI3Kδ-specific, high-affinity immunoglobulin (Ig)E receptor (anti-FCεR1) 
in basophils collected from healthy volunteers. The findings were confirmed when the drug 
was assessed over 7 days in a Phase 1b study in subjects with allergic rhinitis. In this study, 
GS-1101 at a dose level of 100 mg/dose BID showed clinical and pharmacodynamic activity 
(attenuating adverse responses to allergenic challenge and decreasing markers of 
inflammation) and was well tolerated. 
1.3.5.2. 
Phase 1 Studies in Patients with Hematological Malignancies 
1.3.5.2.1. 
Phase 1 Monotherapy Study in Patients with Hematological Malignancies 
A Phase 1 dose-ranging study (Study 101-02) of single-agent GS-1101 extended safety and 
pharmacokinetic observations; documented the clinical and pharmacodynamic activity of 
GS-1101 in subjects with iNHL, MCL, and CLL; and provided dosing information in support 
of further development [Brown 2011, Coutre 2011, Gilead 2011, Kahl 2011]. In this study, 
GS-1101 was administered in cohorts of subjects across a range of dose levels from 


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50 mg/dose BID to 350 mg/dose BID. GS-1101 administration was continued as long as 
individual subjects were safely benefitting from therapy. Subjects were evaluated in 4-week 
cycles; response and progression assessments were based on standard criteria [Hallek 2008]. 
Altogether, 192 subjects were enrolled to the study, including 55 subjects with CLL. As 
expected given the demographics of these diseases, subjects were predominantly male and 
were often elderly, ranging in age to 82 years for the subjects with CLL. The majority (82%) 
of the subjects with CLL had bulky tumors (≥1 lymph node ≥5 cm in diameter) and 31% had 
the adverse prognostic factor of a 17p chromosomal deletion (which commonly confers a 
p53 mutation in the tumors of these subjects). Subjects were heavily pretreated with 
chemoimmunotherapy; the median number of prior therapies by disease was 5 among 
subjects with CLL, but ranged up to 15 prior treatments. Among those with CLL, prior 
rituximab, alkylator, and fludarabine use were nearly universal and 33% had received prior 
alemtuzumab. Considering only rituximab use after initial therapy, 35% had received single-
agent rituximab at least once (some patients up to 3 times) and a total of 51/54 (94%) had 
received rituximab given alone or in combination with other agents. In the estimation of the 
investigators, a substantial proportion (72%) of these subjects had disease that was refractory 
to the last prior therapy. In these subjects, therapy was administered for a median of 9 cycles, 
ranging up to 24 cycles (ie, 96 weeks). 
In this single-agent experience, GS-1101 was generally well tolerated at dose levels through 
350 mg BID (the highest dose tested). No maximum tolerated dose (MTD) was apparent 
within the tested dose range. Furthermore, subjects typically found the drug tolerable over 
periods extending to >2 years; there was no profile suggestive of bothersome chronic events 
such as headache, nausea, diarrhea, or fatigue. No subject had tumor lysis syndrome. No 
overt pattern of myelosuppression was associated with GS-1101 treatment. The data also did 
not suggest drug-related reductions in circulating CD4+ cells or serum Igs. 
Among Grade 3-4 nonhematological adverse events, pneumonia/pneumonitis was observed 
most frequently, occurring in 24% of subjects with CLL. In most instances, these cases were 
considered bacterial in origin, based either on culture results or on response to conventional 
antibiotics. Subjects with CLL have occasionally been diagnosed with Pneumocystis (carinii) 
jiroveci pneumonia; the specific causal role of GS-1101 has been difficult to elucidate 
because infection was sometimes present before starting GS-1101 or the subjects had other 
pre-existing risk factors. Such subjects were not receiving pneumocystis prophylaxis. The 
rate of pneumonia over time (0.045 events/subject/month) with GS-1101 was not worse than 
the expected rate (0.06 events/patient/month) reported historically in comparable patients 
with recurrent CLL [Perkins 2002]. 
Monitorable, reversible elevations of hepatic transaminases were observed in some subjects; 
~5% of subjects with previously treated CLL had Grade 3-4 increases in serum ALT or AST. 
The onset of changes was time-dependent; among those with serum ALT/AST abnormalities, 
onset typically occurred 2 to 8 weeks after GS-1101 initiation. In subjects with Grade 1-2 
events, serum ALT/AST elevations resolved despite continued GS-1101 dosing. In subjects 
with Grade 3-4 events, GS-1101 was temporarily interrupted. Upon resolution of serum 
ALT/AST abnormalities, resumption of GS-1101 at a reduced dose did not result in 
recurrence of serum transaminase increases in the majority (>70%) of subjects who were 
rechallenged. This pattern suggests an adaptation to the effect similar to that observed in 


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dogs receiving GS-1101. Such an adaptive response is commonly observed with other drugs 
that induce transaminase elevations [Tujios 2011]. 
GS-1101 proved highly active in subjects with CLL, iNHL, and MCL. Among subjects with 
CLL, GS-1101 reduced lymphadenopathy in all 51 (100%) of those with ≥1 post-treatment 
tumor assessment. In subjects with CLL tumors having a known 17p chromosomal deletion, 
substantial antitumor activity was observed, although PFS appeared shorter in these subjects 
relative to other trial participants without such a deletion or in whom the 17p chromosomal 
deletion status was unknown. 
The pattern of changes in CLL was particular notable. Rapid and substantial reductions in 
lymph node size were observed in subjects with CLL with >80% of subjects showing a 
lymph node response (≥50% reductions in index nodal lesions). Among subjects who entered 
the trial with baseline thrombocytopenia or anemia, GS-1101 induced sustained increases in 
mean platelet counts and hemoglobin levels. In study participants who entered the study with 
enlarged spleens due to CLL, >70% showed a resolution in splenomegaly. The median PFS 
was 14 months, with some subjects having tumor controlling for durations exceeding 2 years. 
Antitumor activity and tumor control were longest in subjects starting GS-1101 at doses of 
≥150 mg/dose BID. 
A characteristic finding in the single-agent experience was that the majority of subjects had 
an initial increase in peripheral absolute lymphocyte count (ALC) from baseline. The 
increase was maximal during the first 2 cycles and generally decreased thereafter but could 
be persistent in some subjects or could be seen repeatedly in subjects who had interruption 
and resumption of drug therapy (eg, due to intercurrent illness). The characteristics of this 
lymphocytosis indicated a mobilization of CLL cells from tissues rather than a proliferative 
event or a disease flair. The effect was evident within 4 hours of initiating treatment, was 
asymptomatic, and was associated with quiescence of CLL cells as indicated by reductions in 
AKT phosphorylation and decreases in circulating levels of disease-associated chemokines, 
CCL3 and CCL4, and the stroma-derived chemokine, CXCL13. The lymphocyte 
mobilization phenomenon is consistent with in vitro data showing that GS-1101 depresses 
chemokine-mediated signaling between CLL cells and stromal cells [Hoellenriegel 2011]. 
These preclinical data support the concept that drug-mediated PI3Kδ inhibition releases CLL 
cells from sanctuary sites in lymph nodes and bone marrow. This action is not unique to 
GS-1101 alone. Drugs that inhibit spleen tyrosine kinase (SYK) [Friedberg 2010], Bruton 
tyrosine kinase (BTK) [Burger 2010a], or mTOR [Zent 2010] cause a CLL cell redistribution 
from tissue sites to the peripheral blood. Because of the occurrence of this type of pattern, 
investigators working with GS-1101 or inhibitors of these other pathways now rely upon 
measures of disease control other than peripheral blood lymphocyte count in determining 
whether a patient’s disease has progressed. 
An analysis of steady-state GS-1101 plasma concentrations (Day 28 Cmax, AUC0-6h, or Ctrough) 
relative to dose in subjects with both NHL and CLL showed increases in these parameters 
through the dose level of 150 mg/dose BID. At higher doses, flattening of the mean dose-
plasma exposure curve was observed, resulting in smaller incremental increases in exposure. 
Considering all safety, efficacy, and pharmacokinetic findings together, the data supported 
150 mg/dose BID as an appropriate GS-1101 monotherapy starting dose for future studies in 
patients with CLL and other lymphoid malignancies. 


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1.3.5.2.2. 
Phase 1 Combination Study in Patients with Hematological Malignancies 
A separate Phase 1 trial (Study 101-07) has evaluated the safety and preliminary activity of 
GS-1101 given in combination with rituximab to subjects with recurrent iNHL or CLL 
[Brown 2011, Leonard 2011]. 
In this study, rituximab was administered at a standard dose of 375 mg/m2 per infusion 
weekly for 8 weeks in all subjects. GS-1101 was started simultaneously with the rituximab, 
first at a dose level of 100 mg/dose BID (n=13) and then at a dose level of 150 mg/dose BID 
(n=12) and was administered continuously to both subjects with CLL (n=13) and subjects 
with iNHL (n=12) for as long as individual subjects were safely benefiting from therapy. 
Subjects were evaluated in 4-week cycles; response and progression assessments were based 
on standard criteria [Hallek 2008]. 
Among the subjects with CLL, the median age was 63 and ranged to 85 years. Bulky tumors 
(≥1 lymph node ≥5 cm in diameter) were present in 63% of the subjects. The median number 
of prior therapies by disease was 2 and ranged up to 8 prior treatments. All had received prior 
rituximab and the majority had received prior fludarabine or alkylating agents. 
Approximately one-third of subjects had CLL that was refractory to the last prior therapy. At 
the time of data cut-off, therapy had been administered for a median of 5 cycles, ranging up 
to 12 cycles (ie, 48 weeks). 
No GS-1101-related dose-limiting toxicities were observed within the tested subject cohorts. 
Grade 3-4 adverse events largely comprised background events resulting from pre-existing 
disease- or treatment-related conditions or from intercurrent illness. Among subjects with 
CLL, 2 (15%) developed pneumonia. For subjects receiving GS-1101 together with 
rituximab, Grade 3-4 elevations in ALT/AST were not observed in those with CLL, although 
3 subjects (25%) of those with iNHL had such events. 
The GS-1101 plus rituximab combination showed a high level of antitumor activity in both 
subjects with CLL and those with iNHL. Altogether 92% of subjects with CLL receiving the 
combination of GS-1101 and rituximab had reductions in nodal size and 77% showed a 
lymph node response (≥50% reduction in index nodal lesions). Although concomitant 
administration of rituximab did not eliminate the redistribution lymphocytosis that is 
associated with GS-1101, it blunted the magnitude of the change. As a result, the overall 
response rate (ORR) was also 77% among subjects participating in this study. At the time of 
last data analysis, PFS through 48 weeks was 70% and a median PFS had not yet been 
observed. 
Collectively, the emerging data from this study support further evaluation of GS-1101 
together with rituximab in subjects with CLL and indicate that co-administration of GS-1101 
with rituximab is tolerable when using GS-1101 at full dose, ie, at a starting dose level of 
150 mg/dose BID. 
1.4. 
Summary and Justification for the Current Study 
Gilead Sciences is conducting this Phase 3 study program to evaluate the efficacy and safety 
of GS-1101 in patients with previously treated, recurrent CLL. Collectively the data derived 
from the primary clinical trial (Study GS-US-312-0116) and from this extension trial 
(Study GS-US-312-0117) address the activity of GS-1101 together with rituximab, the 


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activity of GS-1101 when given alone, and the potential for dose-dependent restoration of 
drug activity in subjects who have disease that appears to be drug resistant. 
The design and conduct of this clinical trial program is supported by knowledge of the 
demographics of patients with CLL, the natural history and current therapies for the disease, 
and the nonclinical and clinical information regarding GS-1101. The collective data support 
the following conclusions: 
• CLL is a serious, disabling, and potentially life-threatening disorder of older patients that 
requires sequential treatment with agents that provide alternative mechanisms of tumor 
control. Existing cytotoxic agents have serious acute and chronic toxicities, making them 
less suitable for frail or unfit patients. Single-agent rituximab can offer disease palliation 
with good tolerability in some patients with relapsed CLL but tumor control is not 
lasting, especially in patients with bulky adenopathy. Development of a non-cytotoxic 
combination therapy of GS-1101 with rituximab or a monotherapy regimen of GS-1101 
that can address disease pathogenesis with a new mechanism of action and might offer 
complementary nodal and peripheral blood activity would address an unmet medical 
need, particularly when applied in patients with substantial comorbidities or 
myelosuppression from prior chemotherapies. 
• PI3Kδ over-expression plays an important role in CLL biology. Further evaluation of 
GS-1101 as a potential treatment for CLL has sound scientific rationale founded on 
knowledge of the actions of the drug to selectively abrogate PI3Kδ activity and to inhibit 
malignant cell growth and stromal cell signaling in nonclinical models of CLL. These 
data are supported by clinical documentation of GS-1101 inhibition of PI3Kδ signaling in 
patients with CLL. 
• The potential for clinical efficacy of GS-1101 monotherapy or of GS-1101 plus rituximab 
in patients with relapsed or refractory CLL is supported by the observed antitumor 
activity of GS-1101 – given alone or in combination with rituximab – in patients with 
heavily pretreated CLL and iNHL. 
• The safety of advancing development of the GS-1101 monotherapy and of a regimen of 
GS-1101 plus rituximab in this Phase 3 clinical trial program is well supported by safety 
pharmacology and toxicology studies and by Phase 1 single-agent and combination safety 
data obtained in healthy volunteers and in subjects with lymphoid cancers.  
• Dose-safety, dose-exposure, and dose-activity relationships identified in Phase 1 studies 
have established a firm basis for the dosing regimen and dose modification provisions in 
this study. 
• Observations relating to patterns of CLL response among subjects receiving GS-1101 
alone or in combination with rituximab in Phase 1 trials provide the foundation for 
efficacy monitoring in this trial. Of particular note is that GS-1101 mobilizes CLL cells 
from tissues into the peripheral blood. This characteristic pharmacological action is 
prominent early in therapy but can persist over time and should not be confused with 
disease progression in patients who have persistent control of other CLL-related signs 
and symptoms. For this reason, in this Phase 3 study program, subjects will be continued 
on therapy until the occurrence of definitive disease progression, ie, disease progression 


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that is manifest by worsening CLL-related signs or symptoms other than lymphocytosis 
alone.  
• Thorough nonclinical and clinical characterization of the type, severity, manifestations, 
and expected timing of adverse events establish the safety monitoring plan in this trial 
program. 
• The scientific correlative work performed in prior preclinical and clinical studies 
provides strong scientific underpinnings for the companion laboratory studies to be 
performed as a component of this clinical trial program. 
• Given the seriousness of previously treated CLL in patients with substantial comorbidity, 
and the aggregate potential benefits considered in the context of potential risks, further 
development of GS-1101 in this Phase 3 clinical trial program is justified. 
The rationale for specific design features is provided in relevant sections of the protocol, 
including Section 3.2 (Endpoint Selection Rationale), Section 2.2 (Design Rationale), 
Section 4.3 (Enrollment Criteria Rationale), Section 5.9 (Study Treatment Rationale), and 
Section 6.4 (Study Procedure Rationale). 


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2. 
STUDY DESIGN 
2.1. 
Design Overview and Study Schema 
This study is being conducted as part of an overall clinical program that is evaluating the 
efficacy and safety of GS-1101 in the therapy of patients with previously treated CLL (see 
Figure 2-1). Within this program, the primary clinical trial (Study GS-US-312-0116) is a 
Phase 3, multicenter, 2-arm, randomized, double-blind, placebo-controlled, parallel-group 
study. This clinical trial (Study GS-US-312-0117) is a separate, multicenter, 2-arm, double-
blind, parallel-group extension study that is a companion study to the primary study. 
Figure 2-1. 
Study Design 
Randomized
Double-Blind
Initial Therapy
GS-1101, 150 mg BID
Until PD
Placebo BID 
Until PD
Disease 
progression
Double-Blind
Continuing  Therapy
Double-Blind
Extension
Therapy
GS-1101, 150 mg BID
R, 375 mg/m2 Wk 0
R 500 mg/m2 Wk 2,4,6,8,12,16,20
Stratification and 
Randomization
GS-1101, 150 mg BID
Until PD
GS-1101, 300 mg BID
Until PD
Placebo
R, 375 mg/m2 Wk 0
R 500 mg/m2 Wk 2,4,6,8,12,16,20
Screening
Primary Study
Study GS-US-312-0116
Extension Study
Study GS-US-312-0117
Arm A
N=80
Arm B
N=80
 
Candidates for the primary study will be adults with previously treated recurrent CLL who 
have measurable lymphadenopathy, require therapy for CLL, have experienced CLL 
progression <24 months since the completion of the last prior therapy, and are currently not 
sufficiently fit to receive cytotoxic therapy because of chemotherapy-induced bone marrow 
damage or comorbidities. 
Primary study subjects will be stratified based on 17p deletion and/or a p53 mutation status 
(either vs neither), immunoglobulin heavy chain variable region (IgHV) mutation status 
(unmutated vs mutated), and any prior therapy with an anti-CD20 therapeutic monoclonal 
antibody (yes vs no) and randomized in a 1:1 ratio to receive 1 of the 2 treatment arms.  
In the primary study, subjects will be administered rituximab intravenously in the clinic 
starting at a dose of 375 mg/m2 on Day 1 (Week 0) and will continue with a dose of 
500 mg/m2 on Day 15 (Week 2), Day 29 (Week 4), Day 43 (Week 6), Day 57 (Week 8), 
Day 85 (Week 12), Day 113 (Week 16), Day 141 (Week 20) (for a total of 8 infusions). 
Rituximab will be administered until the earliest of subject withdrawal from study, definitive 
progression of CLL, intolerable rituximab-related toxicity, pregnancy, substantial 
noncompliance with study procedures, study discontinuation, or a maximum of 8 infusions. 
GS-1101 or placebo will be taken orally, twice per day continuously while on study 
treatment. GS-1101 or placebo treatment will persist until the earliest of subject withdrawal 
from study, definitive progression of CLL, intolerable study drug-related toxicity, pregnancy, 
substantial noncompliance with study procedures, or study discontinuation. Subjects will be 


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encouraged to continue with protocol-specified therapy for each of the therapeutic agents 
(GS-1101/placebo or rituximab) that continues to be tolerated, even if the other agent needs 
to be discontinued due to drug-specific toxicity. 
Compliant subjects who are tolerating therapy but who develop definitive disease 
progression in the primary clinical trial (Study GS-US-312-0116) can consider enrollment in 
this separate companion extension trial (Study GS-US-312-0117). In the extension trial, 
subjects will take active blinded GS-1101 therapy, either at a higher starting dose or at the 
standard starting dose, with allocation based on the original primary study randomization. 
The primary objective of Study GS-US-312-0116 will be to evaluate the effect of the 
addition of GS-1101 to rituximab on PFS. Secondary objectives will focus on determining 
the effect of the addition of GS-1101 to rituximab on the onset, magnitude, and duration of 
tumor control; overall survival (OS); health-related quality of life (HRQL); changes in 
subject performance status; disease-associated biomarkers and potential mechanisms of 
resistance; treatment administration; safety; and health resource utilization. In Study GS-US-
312-0117, the same endpoints will be assessed as in Study GS-US-312-0116; the focus of the 
analysis will be largely descriptive except for the within-subject assessment of treatment 
effects among subjects receiving first rituximab alone and then GS-1101 alone on Arm B of 
each trial. No formal comparisons of outcomes in Arm A vs Arm B are planned within 
Study GS-US-312-0117. 
2.2. 
Design Rationale 
The randomized, add-on design for the primary trial (Study GS-US-312-0116) is customary 
in the comparative evaluation of new therapies for cancer. While this design provides 
GS-1101 efficacy and safety information only in the context of administration of a 
companion antineoplastic agent, it is appropriate because it documents the incremental 
benefit and toxicity of the investigational therapy in the context of a controlled clinical trial 
while ensuring that all participants receive potentially active treatment. 
This separate extension trial (Study GS-US-312-0117) enhances subject acceptance of 
randomization in the primary study and provides further information regarding GS-1101 
efficacy, resistance, and safety. Among subjects in Arm A, escalation to a higher dose level 
allows evaluation of dose-dependent resistance and a determination if a higher dose can 
reestablish disease control. The safety data obtained in these subjects will add to the overall 
safety database. Among subjects randomized to Arm B in the primary study, evaluation of 
GS-1101 at a starting dose of 150 mg/dose BID in the extension study may permit a within-
subject assessment of the treatment effects with single-agent GS-1101 relative to the effects 
previously observed with rituximab alone. Of importance, the extension study maintains the 
partial blinding of the primary study, thus minimizing the bias that might occur if the overall 
design entailed only a 1-way crossover to open-label GS-1101 among subjects who had 
received placebo on Arm B of the primary study. To ensure confirmation of disease 
progression, tumor size data collected from the primary study will be subjected to  
independent review by an independent review committee (IRC) (see Section 10.4.3); subjects 
will continue with study therapy pending confirmation of progression status by the sponsor 
working in collaboration with the IRC. Subjects must have confirmation that the disease has 


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progressed on the primary study before being permitted to receive secondary GS-1101 
therapy on the extension study. 


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3. 
OBJECTIVES AND ENDPOINTS 
• To determine the effect of GS-1101 on the onset, magnitude, and duration of tumor 
control 
• To compare tumor control in subjects receiving rituximab alone in Study GS-US-312-
0116 to that observed in the same subjects when receiving the standard dose of GS-1101 
alone in Study GS-US-312-0117 
• To assess the effect of GS-1101 on measures of subject well-being, including overall 
survival (OS), health-related quality of life (HRQL), and performance status 
• To assess the effects of GS-1101 on disease-associated biomarkers and to evaluate 
potential mechanisms of resistance to GS-1101 
• To characterize exposure to GS-1101 as determined by treatment administration and 
evaluation of GS-1101 plasma concentrations over time 
• To describe the safety profile observed with GS-1101  
• To estimate health resource utilization associated with administration of GS-1101 
3.1. 
Endpoints 
3.1.1. 
Tumor Control 
• Progression-free survival (PFS) – defined as the interval from the start of study therapy to 
the earlier of the first documentation of definitive disease progression or death from any 
cause; definitive disease progression is CLL progression based on standard criteria and 
occurring for any reason (ie, increasing lymphadenopathy, organomegaly or bone marrow 
involvement; decreasing platelet count, hemoglobin, or neutrophil count; or worsening of 
disease-related symptoms) other than lymphocytosis alone 
• Overall response rate (ORR) – defined as the proportion of subjects who achieve a 
complete response (CR) or partial response (PR)  
• Time to response (TTR) – defined as the interval from start of study therapy to the first 
documentation of CR or PR 
• Duration of response (DOR) – defined as the interval from the first documentation of CR 
or PR to the earlier of the first documentation of definitive disease progression or death 
from any cause 
• Time to treatment failure (TTF) – defined as the interval from start of study therapy to the 
earliest of the first documentation of definitive disease progression, the permanent 
cessation of study drug due to an adverse event, or death from any cause 
• Percent change in lymph node area – defined as the percent change from baseline in the 
sum of the products of the greatest perpendicular diameters (SPD) of index lymph nodes 
• Lymph node response rate – defined as the proportion of subjects who achieve a ≥50% 
decrease from baseline in the SPD of index lymph nodes 


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• Splenomegaly response rate – defined as the proportion of subjects with baseline 
splenomegaly who achieve an on-study normalization or a decrease by ≥50% from 
baseline in the pretreatment enlargement of the splenic longest vertical dimension (LVD) 
(by imaging) or in the pretreatment enlargement of the splenic LVD below the left costal 
margin (by palpation) 
• Hepatomegaly response rate – defined as the proportion of subjects with baseline 
hepatomegaly who achieve an on-study normalization or a decrease by ≥50% from 
baseline in the pretreatment enlargement of the hepatic LVD (by imaging) or in the 
pretreatment enlargement of the hepatic LVD at the right midclavicular line (by 
percussion) 
• Platelet response rate – defined as the proportion of subjects with baseline 
thrombocytopenia (platelet count <100 x 109/L) who achieve an on-study platelet count 
≥100 x 109/L or demonstrate a ≥50% increase in platelet count from baseline 
• Hemoglobin response rate – defined as the proportion of subjects with baseline anemia 
(hemoglobin <110 g/L [11.0 g/dL]) who achieve an on-study hemoglobin ≥110 g/L (11.0 
g/dL) or demonstrate a ≥50% increase in hemoglobin from baseline 
• Neutrophil response rate – defined as the proportion of subjects with baseline neutropenia 
(absolute neutrophil count [ANC] <1 x 109/L) who achieve an ANC ≥1 x 109/L or 
demonstrate a ≥50% increase in ANC from baseline 
3.1.2. 
Patient Well-Being 
• Overall survival (OS) – defined as the interval from start of study therapy to death from 
any cause 
• Change in HRQL domain and symptom scores based on  the Functional Assessment of 
Cancer Therapy: Leukemia (FACT-Leu) (see Appendix 2) – defined as the change from 
baseline and the time to definitive increments or decrements of 10%, 20%, and 40% from 
baseline; time to definitive increment (better than baseline by the specified amount) is the 
interval from start of study therapy to the first timepoint when the HRQL measure is 
consistently better than at baseline (including that timepoint as well as all the subsequent 
timepoints) in a subject whose last HRQL score is better than at baseline; and time to 
definitive HRQL decrement (worse than baseline by the specified amount) is the interval 
from start of study therapy to the earliest of death or the first timepoint when the HRQL 
measure is consistently worse than at baseline (including that timepoint as well as all the 
subsequent timepoints) in a subject whose last performance status score is worse than at 
baseline 
• Changes in Karnofsky performance status – defined as the change from baseline in the 
performance status (see Appendix 3) and the time to definitive performance status 
improvement or worsening; time to definitive performance status improvement (better 
than baseline) is the interval from start of study therapy to the first timepoint when the 
performance status is consistently better than at baseline (including that timepoint as well 
as all the subsequent timepoints) in a subject whose last performance status score is better 
than at baseline; and time to definitive performance status worsening (worse than 


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baseline) is the interval from study therapy until the earliest of death or the first timepoint 
when the performance status is consistently worse than at baseline (including that 
timepoint as well as all the subsequent timepoints) in a subject whose last performance 
status score is worse than at baseline 
3.1.3. 
Pharmacodynamic Markers of Drug Activity and Resistance 
• Changes from baseline in PI3K/AKT/mTOR pathway activation as a measure of PI3Kδ 
pathway activity 
• Changes from baseline in the plasma concentrations of disease-associated chemokines 
and cytokines 
3.1.4. 
Exposure 
• Study drug administration as assessed by prescribing records and compliance as assessed 
by quantification of used and unused drug 
• Trough (pre-dose) and peak (1.5-hour samples) of GS-1101 plasma concentrations as 
assessed by a validated bioanalytical method 
3.1.5. 
Safety 
• Overall safety profile of each study treatment regimen characterized by the type, 
frequency, severity, timing of onset, duration, and relationship to study therapy of any 
adverse events or abnormalities of laboratory tests; serious adverse events; or adverse 
events leading to discontinuation of study treatment 
3.1.6. 
Pharmacoeconomics 
• Change in health status – defined as the change from baseline in overall health and 
single-item dimension scores as assessed using the EuroQoL Five-Dimension (EQ-5D) 
utility measure (Appendix 4) 
• Health resource measures, including resource utilization, total costs, and measures of cost 
per unit of benefit (eg, cost per additional progression-free month, cost per quality-
adjusted life-year) 
3.2. 
Endpoint Selection Rationale 
The proposed endpoints have been chosen based on relevance to the pathophysiology and 
clinical manifestations of CLL, the known pharmacology of GS-1101, and the goals of the 
study in documenting GS-1101 benefit-to-risk ratio. These types of endpoints have been 
employed in prior studies in CLL and can be evaluated with acceptable reliability and 
accuracy. 
3.2.1. 
Tumor Control Endpoints 
Assessments of the magnitude and duration of changes in tumor size are routinely employed 
in registration-directed oncology clinical studies to determine therapeutic effect. Unlike OS, 
these endpoints directly assess the ability of the drug to control the malignancy. Such 
assessments are also integral to treatment decisions; because subjects are being treated until 


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disease progression, repeated tumor assessment must be performed in order to define the 
proper duration of treatment for each study participant. Standard response and progression 
criteria have been established by the International Workshop on CLL (IWCLL) 
[Hallek 2008]; the assessments of treatment effects in this study will be based on these 
criteria, taking into account the specific pharmacology of GS-1101. 
In CLL, disease-related nodal enlargement is a major cause of patient discomfort and can 
cause organ dysfunction [Dighiero 2008]. Extensive lymphadenopathy constitutes a reason to 
treat CLL and controlling the size of pathologically enlarged lymph nodes is an important 
therapeutic goal for improving patient well-being and relieving obstructive symptoms 
[Hallek 2008]. Given that the natural history of recurrent CLL is inexorable nodal growth, 
enhancing tumor shrinkage and prolonging tumor control provides strong evidence of 
pharmacological activity.  
Endpoints of overall tumor control as evaluated in this trial are customarily assessed and 
reported in studies of new therapies in patients with cancer. PFS offers a well established 
outcome measure that directly measures treatment effect, conveys important longitudinal 
information regarding tumor control, can be characterized in all subjects using intention-to-
treat (ITT) principles, and is readily analyzed using statistical methods such as Kaplan-Meier 
techniques. ORR provides an integrated assessment of the magnitude and extent of changes 
in lymphadenopathy, organomegaly, bone marrow infiltration, and bone marrow function 
that conveniently categorizes and describes treatment effects. TTR and DOR are important in 
characterizing the rapidity of achieving tumor shrinkage and the duration of tumor control. 
TTF offers a further characterization of subject outcome that incorporates the added 
dimension of drug tolerability; the degree of correspondence between PFS and TTF provides 
an assessment of how commonly adverse effects are compromising the ability to maintain 
therapy. 
Beyond providing descriptions on overall response assessment using ORR, this protocol will 
also seek to characterize the individual components of response that are important in 
assessment of CLL [Hallek 2008]. Thus, changes in lymph node area and in the proportion of 
subjects having a lymph node response will be analyzed. In addition, among subjects who 
enter the study with splenomegaly, the proportion achieving substantial (≥50%) reductions in 
spleen size will be assessed. Similarly, the proportions of subjects who experience 
improvements in platelets, hemoglobin, and neutrophil counts will be characterized in order 
to provide specific insight into the degree to which therapy alters these individual parameters.  
Because GS-1101 mobilizes CLL cells from tissues into the peripheral blood as part of its 
pharmacological effect, there is a risk of falsely declaring a subject to have experienced 
disease progression if lymphocyte count is considered as the sole basis for potential CLL 
worsening. To account for this potential problem, changes in lymphocyte count will not be 
considered in determining whether a subject has progressive disease, ie, subjects will only be 
declared to have progressive CLL if they meet any of the IWCLL criteria for progressive 
disease other than lymphocytosis alone. Thus, subjects with worsening lymphadenopathy, 
organomegaly, bone marrow involvement, progressive cytopenias, appearance of new 
disease, recurrence of B symptoms, or transformation to an aggressive lymphoid malignancy 
histology (eg, Richter syndrome) will be considered to have progressed. Subjects with 
lymphocytosis without any of these other events will not be considered to have progressed. 


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Given that lymphocytosis has no prognostic significance in patients with relapsed/refractory 
disease [Silverman 2002, Tsimberidou 2007] and is not generally considered a reason to treat 
in patients with CLL [Hallek 2008, Eichhorst 2010, Zelenetz 2011], this approach does not 
jeopardize subject safety or subsequent therapy. Furthermore, it will allow complete 
collection of all response and progression data (both considering lymphocytosis and ignoring 
lymphocytosis) with the intent of providing complete information for regulatory authority 
review. 
The current IWCLL guidelines indicate that physical examination is generally sufficient to 
evaluate nodal response and progression in patients with CLL [Hallek 2008] but that 
radiographic assessments may be appropriate in clinical trials. Computed tomography (CT) is 
considered the preferred imaging method unless patients have contraindications that require 
use of magnetic resonance imaging (MRI). Given the low fluorodeoxyglucose (FDG) avidity 
of CLL, positron- emission tomography (PET) does not have a role in evaluation of this 
disease. The incremental benefits of using radiographic imaging are limited in patients 
undergoing long-term follow-up following first-line therapy [Blum 2007, Eichhorst 2011]. 
However, in the patients with advanced CLL and bulky adenopathy such as those who will 
be enrolled to this trial, it is known that CT scans commonly detect bulky intra-abdominal 
lymphadenopathy and splenomegaly that would be missed by palpation alone and that the 
presence of large-volume, intra-abdominal disease of the nodes and spleen is associated with 
a poor prognosis [Norin 2010]. Thus, while use of CT confers greater radiation exposure, 
subjects have the chance to benefit from radiographic imaging because it will offer more 
accurate information regarding their response to protocol therapy and the appropriate 
duration of protocol treatment. Having this information is particularly important in this trial 
because PI3Kδ inhibition precludes use of lymphocyte counts as evidence for disease 
progression. In addition, the risk is offset by the fact that the trial subjects will primarily be 
patients who have already received more potent mutagens (eg, purine analogs, alkylating 
agents), and all of whom have advanced cancer and limited treatment options at study entry. 
Based on published data [Keating 2002, Wierda 2010], median OS for patients with 
comparably advanced CLL is <18 months, so the long-term secondary malignancy risk from 
CT-related radiation exposure is very low. Finally, in the context of a registration-directed 
pivotal trial of a new drug with a new mechanism of action, radiographic imaging is critically 
important to provide reassurance regarding subject safety and trial validity. In this regard, CT 
evaluations of the lung can be used retrospectively to assess for radiographic evidence of 
drug-induced lung changes [White 2010, Maroto 2011]. Furthermore, CT measurements 
have greater accuracy and reproducibility than palpation, are subject to independent expert 
review, and can be audited against electronic case report form (eCRF) information. 
The timing of radiographic tumor assessments has been carefully considered. To avoid 
duplication, the CT scan documenting CLL progression in Study GS-US-312-0116 will serve 
as the baseline CT scan for Study GS-US-312-0117. Among patients receiving GS-1101 in 
Phase 1b/2 studies who experienced a nodal response (≥50% regression in tumor area), such 
responses were observed with the first 16 week of therapy [Coutre 2011, Leonard 2011]; the 
planned timing of tumor assessments (at Weeks 8, 16, 24, 36, 48 and then every 12 weeks on 
thereafter through 96 weeks) in this study fits with this known timing of changes in lymph 
node size during GS-1101 therapy. Scans at 8-week intervals during the first 24 weeks allow 
initial documentation of response (at Week 8 or 16) and follow-up confirmation of response 


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8 weeks later (at Week 16 or 24) consistent with current response criteria [Hallek 2008]. 
During this period, early documentation of disease progression allows subjects who are not 
benefiting from study therapy to move rapidly to alternative treatments. After 24 weeks on 
study, the reduction in the frequency of CT scans (to 12-week intervals through 96 weeks) 
reduces the overall protocol burden for subjects while still allowing characterization of the 
expected median PFS in this trial. Permitting investigators to omit scans after 96 weeks (ie, 
after ~2 years) further limits the burden on subjects after this period. As outlined in 
Section 7.3, iodine-containing or gadolinium contrast material may be omitted in subjects for 
whom use of a contrast agent would be medically contraindicated. 
3.2.2. 
Measures of Patient Well-Being 
3.2.2.1. 
Overall Survival 
While OS provides an ultimate measure of patient well-being, it has not routinely been used 
as the primary endpoint in CLL clinical trials. Unlike PFS, it does not specifically measure 
drug-mediated tumor control, and thus provides only an indirect assessment of treatment 
effect. Depending upon the treatment setting, long OS times in patients with CLL can 
preclude use of this endpoint as an efficient method for understanding drug benefits. In both 
the front-line and recurrent disease settings, post-study treatments can influence OS in 
unpredictable ways, potentially confounding differences between treatment groups. 
However, given the life-threatening nature of systemic malignancy, documentation of OS is 
customary in oncology therapeutic clinical trials, including those evaluating subjects with 
recurrent CLL [Keating 2002, Wierda 2010]. Evaluation of OS in this study continues the 
survival assessment from the primary study (Study GS-US-312-0116). The study program as 
a whole (considering both the primary randomized trial and secondary extension study) 
offers the potential to better understand OS and causes of death in a frail population of 
patients with both CLL and comorbidities. 
3.2.2.2. 
Health-Related Quality of Life 
Direct patient reporting of outcomes using standardized methods has become an increasingly 
important component of therapeutic assessment. Evaluation of patient-reported outcomes 
(PROs) is particularly relevant in patients who cannot be cured of disease [Fairclough 2002]. 
PRO questionnaires have been previously used in CLL to understand how patients differ 
from the general population in terms of health concerns [Holzner 2004, Eichhorst 2007, 
Shanafelt 2007, Else 2008], to understand differences in perceptions of well-being in younger 
vs older patients [Levin 2007, Else 2008], to determine how treatment affects HRQL 
[Catovksy 2007, Eichhorst 2007, Efficace 2008], and to assess the pharmacoeconomic cost 
of improvements in HRQL [Stephens 2005]. 
Patients with CLL have overtly impaired well-being relative to comparable controls 
[Holzner 2004, Eichhorst 2007, Shanafelt 2007, Else 2008]. Fatigue is cited as a common 
complaint, being present in the substantial majority of patients. Impairment of HRQL prior to 
any treatment is apparent in those with B symptoms or in patients with anemia, supporting 
the concept of initiating treatment when patients experience symptomatic disease. Factors 
associated with lower overall HRQL have included older age, greater fatigue, severity of 
co-morbid health conditions, advanced stage, and ongoing treatment for CLL [Shanafelt 
2007]. Younger patients appear to have worse emotional and social well-being but older 


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patients experience worse physical HRQL [Levin 2007]. In comparative evaluation of 
chemotherapy-containing regimens, differences in HRQL between therapies (eg, fludarabine 
vs fludarabine-cyclophosphamide vs chlorambucil) reflected differences in toxicity while 
improved HRQL was associated with greater efficacy [Catovksy 2007, Eichhorst 2007]. 
In this study, it is postulated that GS-1101-mediated tumor control will be correlated with 
greater positive changes in HRQL and that assessments of the drug’s safety profile will be 
supported by HRQL evaluations. The FACT-Leu (Appendix 2) has been selected to evaluate 
such outcomes for the study. The FACT-Leu comprises a general HRQL measure for patients 
receiving cancer treatment that yields a total score and subscales for physical, functional, 
social/family and emotional well-being [Cella 1993] and a diagnosis-specific measure for 
patients with leukemia [Webster 2002]. The FACT-Leu was developed to assess symptoms 
(eg, fevers, chills, night sweats, nodal swelling, fatigue) specifically relevant to patients with 
leukemia. FACT instruments have documented psychometric properties [Cella 1993, 
Webster 2002, Brucker 2005, Cella 2005, Victorson 2008]. 
The FACT-Leu instrument is available in appropriate languages for this study. FACT-Leu 
data will be obtained at baseline and during each investigational clinic visit during treatment. 
Having FACT-Leu data concurrent with tumor response information will allow an evaluation 
of the potential relationship between tumor response and symptomatic changes as reported by 
patients. To avoid biasing HRQL results, the FACT-Leu will be administered at each visit 
before other procedures are performed and before any study information is conveyed to the 
subject. 
3.2.2.3. 
Changes in Performance Status 
Performance status evaluation provides an integrated assessment of patient well-being 
before, during, and after treatment and, ideally, may indicate how drug efficacy and toxicity 
affect patient functioning. In patients with CLL performance status can be predictive of PFS 
or OS [Sorensen 1997, Hallek 1996, Youngson 1995]. 
In this study, it is hypothesized that GS-1101-mediated tumor control will be correlated with 
changes in performance status and that assessments of the drug’s safety profile might be 
supported by performance status evaluations. The well-established, reliable, and validated 
Karnofsky performance score [Karnofsky 1949, Yates 1980, Schag 1984] (see Appendix 3) 
will be employed in the trial for characterization of the subject population and repeated 
assessment of performance status. 
3.2.3. 
Pharmacodynamic Markers of Drug Activity and Resistance 
In CLL, disease-related perturbations in inflammatory status can be clinically overt; patients 
often develop bothersome B symptoms (fevers, night sweats, and weight loss) that are 
characteristic of excessive systemic inflammation [Redaelli 2004]. Consistent with such 
disease manifestations, the PI3Kδ/AKT/mTOR pathway is constitutively overactive in 
circulating CLL cells [Coutre 2011]. In addition, chemokines and cytokines that are markers 
of aberrant B-cell trafficking or perturbations in inflammation are overexpressed by CLL 
tissues or by stromal cells and circulate in plasma [Burger 2010b, Coutre 2011]. In Phase 1 
studies of GS-1101 it has been confirmed that GS-1101 largely normalizes AKT 


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phosphorylation and induces dose-dependent reductions in plasma concentrations of 
circulating chemokines and cytokines in patients with CLL [Coutre 2011]. 
In this study, it is hypothesized that incremental changes in these biomarkers provide direct 
evidence of mechanism-specific GS-1101 effects on PI3Kδ activity or indirectly document 
drug effects on overall tumor cell volume. In either case, improvements in these 
pharmacodynamic measures provide corroborative evidence in support of GS-1101 
pharmacological activity; conversely, worsening of these biomarkers may indicate 
acquisition of resistance to GS-1101. In addition, it is possible that disease-or 
inflammation-related biomarkers may provide corollary information relating to the adverse 
effects of GS-1101 on the liver; such data might allow better prediction of which subjects 
might be most susceptible to ALT/AST elevations during GS-1101 treatment. Finally, it can 
also be postulated that genetic, protein, or metabolic changes in CLL cells could provide 
signatures that would correlate with drug sensitivity and resistance. 
Based on these considerations, this study will evaluate PI3K/AKT/mTOR pathway activation 
status in CLL cells. For this purpose, blood will be evaluated by flow cytometry using a 
clinically validated assay [Hoellenriegel 2011]. CLL cells will be identified using anti-CD5 
and anti-CD19 antibodies. AKT activation will be determined by quantifying 
phosphorylation at the Ser473 and Thr308 AKT sites using specific anti-pAKT Thr308 and 
anti-pAKT Ser473 antibodies. Additional assessments of PI3K/AKT/mTOR pathway 
signaling (eg, evaluating phosphorylation state for other downstream enzymes) may also be 
explored. 
Plasma will be collected for assessment of circulating concentrations of relevant chemokines 
and cytokines with a particular focus on CCL2, CCL3, CCL4, CXCL12, CXCL13, CCL17, 
CCL19, CCL21, CCL22, sCD40 ligand, tumor necrosis factor-α, and C-reactive protein. In 
addition serum markers of iron metabolism (eg, hepcidin, iron, ferritin, transferrin) that might 
provide markers linking disease-related inflammation with perturbations of liver iron and 
sensitivity to liver injury will be evaluated [Nemeth 2003, Ferrucci 2010]. Clinically 
validated assays (eg, enzyme-linked immunosorbent assays [ELISAs]) will be used to 
measure circulating concentrations of chemokines and cytokines at baseline and during the 
course of GS-1101 therapy. 
CLL cell deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein will be 
collected at baseline and at the conclusion of a subject’s treatment on study. DNA and RNA 
samples will be analyzed using gene array technologies to evaluate for changes in DNA 
mutations or in RNA expression patterns that might be associated with intrinsic or acquired 
resistance to study treatments. Similarly, protein will be evaluated for state-specific changes 
in protein phosphorylation to evaluate for differences in pathway activation at baseline or 
during therapy that might be associated with differences in response or in acquisition of 
resistance to therapy. 
3.2.4. 
Assessments of Exposure 
3.2.4.1. 
Study Drug Administration and Compliance 
Evaluation of study drug administration and compliance provides context for assessments of 
safety, pharmacokinetics, and pharmacological activity. Evaluations of treatment 
administration and modifications from planned therapy document the influence of 


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treatment-emergent adverse events on prescribing practice. Compliance assessment offers a 
general indication of patients’ acceptance of therapy, integrating factors of tolerability, 
palatability, and convenience. 
In this study, information regarding planned treatment and modification from planned 
treatment (eg, dose reductions and interruptions) will be kept. The compliance of the subject 
will be verified by accounting for used and unused drug. 
3.2.4.2. 
Pharmacokinetics 
Given the intent of this protocol to assess longer-term dosing, collection of plasma for 
GS-1101 concentrations is important for evaluating the steady-state maintenance of exposure 
over time. These data may allow correlations of exposure with measures of efficacy, toxicity, 
and resistance, will be important part of exploring exploration of 2 different GS-1101 dose 
levels. Because the GS-1101 pharmacokinetic profile has been well characterized in Phase 1 
studies, limited plasma sampling will be performed in this study. Samples will be collected 
pre-dose and 1.5 hours post-dose relative to the morning administration of GS-1101. This 
approach will provide information regarding plasma Ctrough values and will describe drug 
absorption as characterized by plasma concentrations at the approximate Tmax after the 
morning dose. The 1.5-hour timepoint has been assessed in prior Phase 1 studies, allowing 
across-study correlations of exposure. Based on discussions with investigators, collecting 
more than 2 samples in the morning is not considered reasonable given the need to minimize 
time requirements for study participants and to avoid substantial inconvenience for clinic 
staff. 
Evaluation of GS-1101 plasma concentrations will be performed using liquid 
chromatography with tandem mass spectrometry. The method has been fully validated in the 
context of prior Phase 1 studies. Plasma samples will be retained for potential later analyses 
of GS-1101 metabolites. 
3.2.5. 
Evaluations of Safety 
In defining the therapeutic relevance of a drug in a particular clinical setting, it is imperative 
that its safety profile be fully characterized. As is conventional in all clinical studies, proper 
description of each adverse event or laboratory abnormality requires an understanding of the 
type, incidence, timing, severity, and relatedness to study drug. While information on all 
reported adverse events will be collected, listed, and summarized, particular focus will be 
placed on monitoring and reporting adverse events and laboratory abnormalities that were 
encountered in the prior toxicology studies and clinical experience with GS-1101. Safety 
parameters of specific interest in reporting study results will include those relating to 
infection, pulmonary events (eg, pneumonia/pneumonitis), liver injury, rash, and bone 
marrow dysfunction. Additional scrutiny will be applied to Grade 3-4 adverse events, to 
adverse events causing interruption or discontinuation of GS-1101, and to serious adverse 
events. 
In addition, the protocol will evaluate for potential adverse GS-1101 effects on laboratory 
parameters of immune function; the absolute number of CD4+ and CD8+, CD16/CD56+, 
CD19+, and CD20+ cells will be assessed by flow cytometry. Serum concentrations of IgA, 
IgE, IgG, and IgM will be obtained. 


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For consistency of interpretation, adverse events will be coded using the standard Medical 
Dictionary for Regulatory Activities (MedDRA) [http://www.meddramsso.com]), and the 
severity adverse events and laboratory abnormalities will be graded using the well-defined 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). 
Standard definitions for seriousness will be applied (see Section 8.1.2). 
3.2.6. 
Pharmacoeconomic Measures 
It is increasingly important to understand the potential cost implications of introducing a new 
medication into patient care for CLL [Main 2010, Hornberger 2011]. In order to analyze the 
pharmacoeconomic consequences of GS-1101 administration, data will be collected 
regarding the health status of subjects and regarding health care resource utilization. 
Heath status information will be obtained with the EQ-5D, which is a self-administered, 
generic, indirect utility measure [EuroQoL Group 1990] (Appendix 4). The EQ-5D consists 
of a visual analogue scale on which subjects are asked to rate their current overall health 
status and 5 single-item dimensions which ask subjects to rate their health in terms of 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. For each of the 
5 items, patients must choose between 3 levels of difficulty in accomplishing tasks in that 
dimension. The visual analog scale is then used in combination with the dimension scores to 
generate a health utility score that can be incorporated into analyses of cost effectiveness. 
The EQ-5D has been successfully used in the evaluation of patients with B-cell and other 
cancers [Doorduijn 2005, Witzens-Harig 2009, Yang 2010]. 
The EQ-5D instrument is available in appropriate languages for this study. EQ-5D data will 
be obtained at baseline and during each investigational clinic visit during treatment. The 
EQ-5D will be administered immediately after administration of the FACT-Leu instrument, 
before other procedures are performed and before any study information is conveyed to the 
subject. The EQ-5D instrument takes only 5 minutes to complete. 
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations. 
The basic approach will be to combine the resource utilization data from the trial with data 
on unit prices (collected separately) to estimate total costs. The costs will be described 
relative to the health care findings as measured by duration of tumor control, the symptom-
free survival period, and/or utility outcomes or some other appropriate measure of clinical 
benefits. 


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4. 
SUBJECT POPULATION 
4.1. 
Number of Subjects 
The planned sample size is ~160 subjects but will be bounded by the number of subjects 
enrolled to the primary clinical trial (Study GS-US-312-0116). 
4.2. 
Subject Selection Criteria 
The following eligibility criteria are designed to select subjects for whom study participation 
is considered appropriate. All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether this protocol is suitable for a particular subject. 
Eligibility criteria may not be waived by the investigator and conformance to the eligibility 
criteria is subject to review in the case of a Good Clinical Practice (GCP) or a regulatory 
authority audit. Any questions regarding a subject’s eligibility should be discussed with the 
study sponsor medical monitor prior to enrollment. 
4.2.1. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in 
this study: 
1) Participation in Study GS-US-312-0116. 
2) Occurrence of confirmed, definitive CLL progression while receiving study drug therapy 
(GS-1101/placebo) in Study GS-US-312-0116. Note: Definitive disease progression is 
CLL progression based on standard criteria and occurring for any reason (ie, 
increasing lymphadenopathy, organomegaly, or bone marrow involvement; decreasing 
platelet count, hemoglobin, or neutrophil count; or worsening of disease-related 
symptoms) other than lymphocytosis. Subjects must have confirmation by the sponsor 
working in collaboration with an independent review committee (IRC) that the disease 
has progressed on the clinical trial (Study GS-US-312-0116) before receiving 
secondary GS-1101 therapy on this extension trial (Study GS-US-312-0117). 
3) Presence of radiographically measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures ≥2.0 cm in the longest dimension [LD] and ≥1.0 cm in the 
longest perpendicular dimension [LPD] as assessed by CT or MRI).  
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab and 
GS-1101/placebo) and no intervening or continuing therapy (including radiotherapy, 
chemotherapy, immunotherapy, systemic corticosteroids, or investigational therapy) for 
the treatment of CLL.  
5) The time from permanent cessation of Study GS-US-312-0116 treatment (rituximab 
and/or GS-1101/placebo) and the initiation of Study GS-US-312-0117 therapy is 
≤12 weeks. Note: Study procedures performed as part of Study GS-US-312-0116 need 
not be repeated and can be used as screening procedures for Study GS-US-312-0117 if 
performed within 4 weeks prior to initiation of study drug therapy on Study GS-US-
312-0117. 
6) Karnofsky performance score of ≥40. 


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7) Required baseline laboratory data (within 4 weeks prior to initiation of study treatment) 
as shown in the table below. Note: Confirmation should be considered for out-of-range 
values to determine if the abnormality is real or artifactual. Values should be obtained 
within the screening period and should generally be the most recent measurement 
obtained. Subjects with any degree of neutropenia, thrombocytopenia, or anemia due 
to CLL or prior therapy may enroll. 
Table 4-1. 
Required Screening Laboratory Values 
Organ System 
Parameter 
Required Value 
Serum total bilirubin 
≤1.5 x ULN (unless elevated due to Gilbert’s syndrome) 
Serum ALT 
Hepatic 
Serum AST 
≤2.5 x ULN 
Renal 
eCCr
a 
>30 ml/min 
Pregnancy 
β-HCGb 
Negative  
a 
As calculated by the Cockcroft-Gault formula (see Appendix 5) 
b 
For women of child-bearing potential only; serum β-HCG must be negative during screening and serum β-HCG or 
urine dipstick pregnancy test must be negative at start of study treatment (Visit 2) 
Abbreviations: β-HCG= beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate 
aminotransferase, eCCr=estimated creatinine clearance, ULN=upper limit of normal 
8) For female subjects of childbearing potential, willingness to abstain from heterosexual 
intercourse or use a protocol-recommended method of contraception from the screening 
visit (Visit 1) throughout the study treatment period and for 30 days following the last 
dose of study drug. Note: A female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; 
has medically documented ovarian failure (with serum estradiol and follicle-
stimulating hormone [FSH] levels within the institutional postmenopausal range and a 
negative serum or urine βHCG), or is menopausal (age ≥55 years with amenorrhea for 
≥6 months).  
9) For male subjects of childbearing potential having intercourse with females of 
childbearing potential, willingness to abstain from heterosexual intercourse or use a 
protocol-recommended method of contraception from the start of study therapy (Visit 2) 
throughout the study treatment period and for 90 days following the last dose of study 
drug and to refrain from sperm donation from the start of study treatment (Visit 2) 
throughout the study treatment period and for 90 days following the last dose of study 
drug. Note: A male subject is considered able to father a child unless he has had a 
bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or has 
ongoing testicular suppression with a depot luteinizing hormone- releasing hormone 
(LH-RH) agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate  [Lupron®]), or 
triptorelin pamoate [Trelstar®]). 
10) In the judgment of the investigator, participation in the protocol offers an acceptable 
benefit-to-risk ratio when considering current CLL disease status, medical condition, and 
the potential benefits and risks of alternative treatments for CLL.  
11) Willingness and ability to comply with scheduled visits, drug administration plan, 
imaging studies, laboratory tests, other study procedures, and study restrictions. Note: 
Psychological, social, familial, or geographical factors that might preclude adequate 
study participation should be considered. 


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12) Evidence of a personally signed informed consent indicating that the subject is aware of 
the neoplastic nature of the disease and has been informed of the procedures to be 
followed, the experimental nature of the therapy, alternatives, potential benefits, possible 
side effects, potential risks and discomforts, and other pertinent aspects of study 
participation. 
4.2.2. 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study: 
1) Known histological transformation from CLL to an aggressive lymphoma (ie, Richter 
transformation).  
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of the start 
of study treatment (Visit 2). Note: Subjects with localized fungal infections of skin or 
nails are eligible. Subjects may be receiving prophylactic antiviral or antibacterial 
therapies at the discretion of the investigator; anti-pneumocystis prophylaxis is 
encouraged.  
3) Pregnancy or breastfeeding.  
4) Intentional breaking of the blind in Study GS-US-312-0116 by the investigator or the 
study subject. 
5) Concurrent participation in another therapeutic clinical trial. 
6) Prior or ongoing clinically significant illness, medical condition, surgical history, 
physical finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the 
investigator’s opinion, could adversely affect the safety of the subject or impair the 
assessment of study results. 
4.3. 
Enrollment Criteria Rationale 
The eligibility criteria are designed to limit enrollment to subjects who participated in the 
primary clinical trial (Study GS-US-312-0116), are compliant, have been generally able to 
tolerate study therapy and study procedures, and have experienced definitive CLL 
progression while receiving study treatment (rituximab and/or GS-1101/placebo) in the 
primary study. 
The requirement of measurable lymphadenopathy ensures that subjects have disease that can 
adequately be assessed for evidence of drug activity. Prior therapy provisions are intended to 
ensure that subjects are transitioning directly from Study GS-US-312-0116 to Study GS-US-
312-0117 without receiving intervening treatments. The stipulation of ≤12-week interval 
from Study GS-US-312-0116 treatment until Study GS-US-312-0117 treatment precludes 
excessively protracted intervals between participation in the 2 studies but also permits 
sufficient time for clinicians and subjects to determine whether participation is appropriate.  
To ensure that subjects are not so acutely ill from life-threatening comorbidities that they 
require hospitalization and stabilization, subjects with Karnofsky performance scores <40 (ie, 
those who are bed-bound or hospitalized) will not be enrolled. Baseline laboratory 
evaluations are designed to limit participation to subjects who have not developed serious 
organ compromise that would pose a safety risk or confound the interpretation of adverse 


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effects. Pregnancy testing and restrictions on eligibility relating to reproduction, pregnancy, 
and nursing are important because GS-1101 is a new chemical entity and it is unknown if it 
may have adverse effects on conception, on fetal development, or on the health of a breast-
feeding child. To minimize missing data and premature discontinuations, subjects should 
have sufficient psychological and social resources to comply with study procedures and 
restrictions. Consistent with GCP guidelines, subjects must provide informed consent before 
initiation of any study procedures. 


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5. 
TREATMENT OF SUBJECTS 
5.1. 
Enrollment 
5.1.1. 
Interactive Web Response System 
An interactive web response system (IWRS) will be employed to manage the conduct of the 
trial. The IWRS will be used to maintain a central log documenting enrollment, to manage 
dose modifications, to assess current inventories of study drug, to initiate any necessary 
resupply of study drug, and to document discontinuation of study treatment. 
5.1.2. 
Treatment Assignment 
After a subject has completed the necessary documentation of definitive CLL progression in 
the primary clinical trial (GS-US-312-0116) and has been confirmed to be eligible, the 
subject can be entered into this trial (Study GS-US-312-0117). In order to obtain a treatment 
arm allocation for a subject, a site representative will access the IWRS and supply the system 
with the required information. 
Subjects will be assigned to either of the following treatment assignments with allocation 
based on the original primary study randomization: 
• Arm A: GS-1101 + rituximab (Study GS-US-312-0116) 
⇒high-dose GS-1101 (300 mg BID) (Study GS-US-312-0117) 
• Arm B: Placebo + rituximab (Study GS-US-312-0116) 
⇒standard-dose GS-1101 (150 mg BID) (Study GS-US-312-0117) 
The IWRS will assign blister card numbers and instructions for dispensing of blinded study 
drug (high-dose or standard-dose GS-1101). It is anticipated that subjects will usually begin 
study drug immediately at Visit 2 of the study.  
5.1.3. 
Blinding 
The identity of the treatments will be concealed by central blinding of study drug 
assignments. Blinding will be accomplished through use of a placebo that is well-matched to 
the active drug in appearance, packaging, labeling, and schedule of administration 
(see Section 5.2.1). During the study, subjects, caregivers, investigational site personnel, 
Gilead Sciences study team members, and all other study personnel will remain blinded to 
the identity of the treatment assignments; these assignments will be available only to the 
IWRS, the data monitoring committee (DMC) for the study, an independent bioanalytical 
group that is not part of the study team, and drug safety personnel who are not part of the 
study team. Unblinding during the study will only occur in the case of subject emergencies 
(see Section 5.5) or as requested by the DMC. Where required by local regulation, expedited 
reporting of serious adverse events to specific regulatory authorities will include information 
regarding the study drug treatment assignment (high-dose or standard-dose GS-1101); this 
will be done in such a way that subjects, investigational site personnel, institutional review 
board/independent ethics committees (IRB/IEC), and study team members remain blinded as 
to the treatment assignment for the subject described in the adverse event report. 


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The final unblinded analysis of the study will only be performed when the database is 
completed and locked. While bioanalytical assays to determine GS-1101 concentrations may 
be performed prior to unblinding, pharmacokinetic data that would allow identification of 
treatment assignments for individual subjects will not be available to the study team until 
after the blind is broken and the primary analysis has occurred. Except for emergency 
unblinding, individual subjects, caregivers, and site personnel will not be informed of the 
treatment assignments until the implications of revealing such data for the overall GS-1101 
study program have been determined by the clinical project leader for the GS-1101 
development program. 
5.2. 
Investigational Study Drug (GS-1101/Placebo) 
5.2.1. 
Description 
Subjects allocated to Arm A of the study will be provided with 2 tablets of active GS-1101 
for oral administration at each dose. Each tablet contains 150 mg or 100 mg of active 
GS-1101. The 150-mg tablets will be used for initial therapy; the 100-mg tablets are provided 
for use by those subjects who require a dose reduction (see Table 5-1).  
Subjects allocated to Arm B of the study will be provided with 1 tablet of active GS-1101 
and 1 tablet of placebo for oral administration at each dose. Each active tablet contains 
150 mg or 100 mg of active GS-1101. The 150-mg tablets (and matching placebo) will be 
used for initial therapy; the 100-mg tablets (and matching placebo) are provided for use by 
those subjects who require a dose reduction.  
The 150-mg tablets are pink, film-coated, and include the following inactive excipients: 
microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch 
glycolate, magnesium stearate, red iron oxide, polyethylene glycol, talc, polyvinyl alcohol 
(PVA), and titanium dioxide. The 100-mg tablets are orange, film-coated, and include the 
following inactive excipients: microcrystalline cellulose, hydroxypropyl cellulose, 
croscarmellose sodium, sodium starch glycolate, magnesium stearate, yellow iron oxide, 
polyethylene glycol, talc, PVA, and titanium dioxide. 
The placebo tablets match the active GS-1101 formulations in appearance. The placebo 
tablets matching the 150-mg tablets are pink, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium 
stearate, red iron oxide, polyethylene glycol, talc, PVA, and titanium dioxide. The placebo 
tablets matching the 100-mg tablets are orange, film-coated, and include the following 
inactive ingredients: silicified microcrystalline cellulose, sodium starch glycolate, 
magnesium stearate, yellow iron oxide, polyethylene glycol, talc, PVA and titanium dioxide. 
Details regarding the shape and size of each tablet dosage form will be provided in the 
pharmacy manual for the study. 
5.2.2. 
Source 
Both active GS-1101 and placebo will be supplied free of charge by Gilead Sciences.  
5.2.3. 
Packaging and Labeling 
Study drug (GS-1101 or GS-1101/placebo) will be provided in blister cards. The blister cards 
are made of polyvinyl chloride/polychlorotrifluoroethylene (PVC/PCTFE) film and have 


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aluminum foil lidding materials. Each blister card contains 120 tablets (4-week supply plus a 
modest overage) of one of the relevant dose strengths. The 100-mg or 150-mg and matching 
placebo tablets will be combined in order to obtain the daily doses to be used in this study. 
Thus, in Arm A, the 300-mg GS-1101 dose will be obtained by administering two 150-mg 
tablets and the 200-mg GS-1101 dose will be obtained by administering two 100-mg tablets. 
In Arm B, the 150-mg GS-1101 dose will be obtained by administering one 150-mg tablet 
and one placebo tablet and the 100-mg GS-1101 dose will be obtained by administering one 
100-mg tablet and one placebo tablet.  
Each blister card will have a unique number. Labeling for blister cards dispensed to subjects 
in Arm A will appear identical to blister cards dispensed to subjects in Arm B. All labels for 
study drugs to be distributed to centers in the United States, the EU, and other countries will 
meet all applicable requirements of the United States Food and Drug Administration 
(FDA), the EU Annex 13 of Current Good Manufacturing Practice (cGMP) (Manufacture of 
Investigational Medicinal Products, July 2003), and/or other local regulations as applicable. 
5.2.4. 
Storage and Handling 
Blister cards containing tablets of study drug (GS-1101 or GS-1101/placebo) should be 
stored at controlled room temperature (ie, ~25°C, with a range of 15 to 30°C). While the 
stability of study drug tablets stored at controlled room temperature has been confirmed, brief 
excursions to temperatures as low as 5°C or as high as 40°C (eg, during shipping) will not 
adversely affect the drug. Freezing should be avoided. Updated stability data will be 
provided to the sites, as appropriate. 
5.2.5. 
Dispensing 
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing 
study drug according to the IWRS directions. It is planned that drug will be dispensed at 
4-week intervals through the first 24 weeks of treatment and at 12-week intervals thereafter. 
Sufficient study drug will be provided for each study period at the beginning of the period. 
Multiple blister cards may be dispensed at a single visit. Tablets should be kept in the 
original blister cards provided until they are self-administered by the subject. 
At the time of starting study treatment, the IWRS will provide the clinic staff with the blister 
card numbers designating the blister cards to be dispensed. The clinic staff (eg, pharmacist or 
other qualified person) will write the subject number on each blister card that is dispensed. 
Immediately before dispensing, the clinic staff will write the blister card number for each 
dispensed blister card in the study drug administration record corresponding to the subject 
number. 
5.2.6. 
Return 
The study drug should be retrieved from each subject at the end of each dispensing interval. 
The quantity of study drug and the date returned by the subject should be recorded in the 
study drug accountability records. All study drug returned by the subject should be retained 
for review by the study site monitor prior to return to Gilead Sciences or destruction. 


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5.2.7. 
Accountability 
The disposition of all study drug should be documented from the time of receipt at the site 
through subject dispensing and return. 
Study personnel must ensure that all study drug is kept in a secure locked area with access 
limited to authorized personnel. The study drug must not be used outside the context of this 
protocol. Under no circumstances should the investigator or site personnel supply study drug 
to other investigators or clinics, or allow the study drug to be used other than as directed by 
this protocol. 
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by Gilead Sciences or its designee, including, but not 
limited to, the date received, lot number, amount received, and the disposition of all study 
drug. Upon receipt of a drug shipment, the shipment must be logged into the IWRS. Study 
drug accountability records must also be maintained that include the subject number to whom 
the study drug was dispensed and the date, quantity and lot number of the study drug 
dispensed. 
Depending upon the decision of Gilead Sciences, remaining unused study drug supply will be 
returned to Gilead Sciences or its designee after the study is completed or will be discarded 
or destroyed at the clinical site. If the study drug is discarded or destroyed at the clinical site, 
standard institutional policy should be followed. Records documenting the date of study drug 
shipping or destruction, relevant lot numbers, and amount shipped or destroyed should be 
maintained. 
5.2.8. 
Overdose Precautions 
In Phase 1 studies, an MTD for GS-1101 was not reached when the drug was administered 
continuously at dose levels through 350 mg/dose BID (700 mg per day) [Coutre 2011, Kahl 
2011]. However, in this protocol, an overdose is defined as administration of more than the 
prescribed daily dose (ie, >600 mg in a single day). In a subject who experiences an overdose 
consideration should be given as to whether GS-1101 administration should be temporarily 
interrupted. If the overdose ingestion is recent and substantial, and if there are no medical 
contraindications, use of gastric lavage or induction of emesis may be considered. 
Observation for any symptomatic side effects should be instituted, and biochemical and 
hematological parameters should be followed closely (consistent with the protocol or more 
frequently, as needed). Appropriate supportive management to mitigate adverse effects 
should be initiated. 
The Gilead Sciences medical monitor should be contacted if a study drug overdose occurs. 
Cases of study drug overdose will result in specific reporting requirements (see Section 8.8). 
5.2.9. 
Inadvertent Exposure and Spill Precautions 
Based on available data from nonclinical studies, GS-1101 does not appear to be acutely 
toxic, genotoxic, or irritative at levels that are likely to result from inadvertent exposure to 
the contents of broken tablets. However, personnel handling the drug should use reasonable 
precautions to avoid eye contact, skin contact, inhalation, or ingestion of the study drug 
product. For further information regarding inadvertent exposure and spill precautions, please 
consult the GS-1101 investigator brochure. 


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5.3. 
Study Drug Administration 
5.3.1. 
Premedication 
No specific premedications or supporting medications are required in conjunction with study 
drug administration, although institution of antibiotic prophylaxis for Pneumocystis (carinii) 
jiroveci should be considered in all subjects (see Section 5.6.2). 
5.3.2. 
Administration Instructions 
The prescribed dose of study drug (GS-1101/placebo) should be taken orally. At each dose 
administration, the tablet number corresponding to the appropriate dose of study drug is to be 
swallowed whole with 100 to 200 mL (~ 4 to 8 ounces) of water. In case of breakage of the 
tablets in the oral cavity, additional water should be taken as a rinse.  
Study drug may be taken with or without food. There are no known dietary restrictions 
related to study drug use. 
5.3.3. 
Dosing Schedule 
Study drug should be taken on a BID schedule at approximately the same times each day. 
Ideally, doses should be taken at ~12-hour intervals (eg, at ~7 AM and at ~7 PM). While it is 
realized that variations in dosing schedule may occur in the outpatient setting, the prescribed 
regimen should be followed as closely as possible, especially in the clinic. 
At specified clinic visits, the study drug will be administered in the clinic with dosing 
appropriately timed relative to blood sampling for GS-1101 pharmacokinetics. As detailed in 
Section 6.2, clinic staff should record GS-1101 administration information, including the 
exact clock time of each dose, for doses of study drug administered in the clinic or hospital. 
Thereafter, subjects will be given an adequate supply of tablets to take at home. 
5.3.4. 
Dose Levels 
Study drug dose levels for Arm A and Arm B are described in Table 5-1. The lower dose 
level (Dose Level -1) is provided in case a subject requires a study drug dose modification. 
Table 5-1. 
Study Drug Dose Levels 
Treatment Arm 
Starting Dose 
Dose Level -1 
Arm A 
300 mg/dose BID 
200 mg/dose BID 
Arm B 
150 mg/dose BID 
100 mg/dose BID 
Abbreviation: BID=twice per day 
5.3.5. 
Dose Schedule Interruptions and Vomited Doses 
Subjects who have a delay in administration of a dose of the study drug of <6 hours should 
take the planned dose as soon as possible after the intended time of administration. For 
subjects who have a delay in administration of study drug of ≥6 hours, the dose should not be 
taken. Study drug administration may continue but the missed dose should not be made up 
and the planned timing of subsequent study drug dosing should not be altered. 
Vomited doses may be retaken, but only if the tablet is visible in the vomitus. 


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5.3.6. 
Safety Monitoring and Study Drug Interruption/Dose Modification 
Subjects must be monitored closely for adverse events or laboratory abnormalities during the 
course of the study. Reference should be made to the CTCAE, Version 4.03 for grading the 
severity of adverse events and laboratory abnormalities. 
Based on Phase 1 clinical experience adverse events potentially attributable to GS-1101 in 
patients with CLL have included infrequent hepatic events (manifest primarily as 
asymptomatic and isolated elevations in serum ALT/AST), and instances of pneumonitis, 
gastrointestinal inflammation, or rash. Myelosuppression has not been an overt toxicity of 
GS-1101 in previous experience but provisions for intervention in subjects experiencing very 
protracted treatment-emergent neutropenia or thrombocytopenia are provided as a precaution. 
It is possible that GS-1101 is responsible for other adverse events for which a causal 
relationship has not yet been established. 
If a subject experiences an adverse event that is suspected to be related to study drug and 
requires a dose modification during the course of study therapy, then study drug 
administration should be held, as necessary, until the adverse event resolves or stabilizes to 
an acceptable degree (generally to Grade ≤1). Thereafter, study drug may be reinstituted, but 
the dose should be reduced to Dose Level -1 (see Table 5-1). If the adverse event occurs 
again, one further attempt at reinitiation of therapy at Dose Level -1 may be attempted if the 
investigator feels that a second rechallenge is medically appropriate. If the subject cannot 
tolerate GS-1101 at Dose Level -1 after 2 rechallenges, then the subject should be 
discontinued from study drug therapy. 
After the study drug dose is reduced, the dose need not be re-escalated, even if there is 
minimal or no toxicity with the reduced dose. However, if the subject tolerates the lower 
dose level of study drug for ≥4 weeks then the dose level may be increased to the starting 
dose level (see Table 5-1) at the discretion of the investigator. Such re-escalation may be 
particularly warranted if further evaluation reveals that the adverse event that led to the dose 
reduction was not study-drug-related. The starting dose level should not intentionally be 
exceeded in this study. 
Whenever possible, any dose adjustment of study drug should be discussed between the 
investigator and the Gilead Sciences medical monitor prior to implementation. To implement 
either a dose reduction or a dose reescalation, the investigator/study staff member will call 
the IWRS, enter the subject number, and inform the IWRS of the need for dose titration. The 
IWRS will provide details regarding the blister card to be dispensed to the subject. The 
appropriate clinic staff should instruct the subject/caregiver about the change in dose. 
Recommendations for dose modification based on the type and severity of adverse events or 
laboratory abnormalities are provided in Table 5-2 below. 


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Table 5-2. 
Recommendations for Study Drug Dose Modifications Based on 
Type and Severity of Adverse Events or Laboratory Abnormalities 
Hepatic Study-Drug-Related Event (Elevation in ALT, AST, or Bilirubin) 
CTCAE Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ALT/AST 
>ULN-3 x ULN 
>3-5 x ULN 
>5-20 ULN 
>20 x ULN 
Bilirubin 
>ULN-1.5 x ULN 
>1.5-3 x ULN 
>3-10 x ULN 
>10 x ULN 
GS-1101 Dosing 
Recommendation 
Maintain dose level 
Maintain dose level. 
Monitor ALT, AST, 
ALP, and bilirubin at 
least 1x per week until 
all abnormalities  
are ≤Grade 1 
Withhold study drug and confirm abnormalities 
within 3 days. Monitor ALT, AST, ALP, and 
bilirubin at least 1x per week until all 
abnormalities are Grade ≤1. May resume drug at 
next lower dose level. 
Cutaneous Study-Drug-Related Event  
CTCAE Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
GS-1101 Dosing 
Recommendation 
Withhold study drug until toxicity is Grade 0.  
Resume study drug at current dose level. If 
rechallenge at same dose level results in 
recurrent rash, may resume study drug at next 
lower dose level. 
Withhold study drug until toxicity is Grade 0. 
May resume study drug at next lower dose level.
Hematological Study-Drug-Related Event 
CTCAE Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neutropenia 
(ANC x 109/µL) 
ANC <LLN-1.5 
ANC <1.5-1.0 
ANC <1.0-0.5 
ANC <0.5 
Thrombocytopenia 
(platelets x 109/µL) 
Platelets <LLN-75 
Platelets <75-50 
Platelets<50-25 
Platelets<25 
GS-1101 Dosing 
Recommendation  
Maintain dose level 
Maintain dose level 
Maintain dose level 
For neutropenia 
of Grade 4 for 
≥14 days, consider 
G-CSF support or may 
withhold study drug 
until Grade ≤3. May 
resume study drug at 
next lower dose.  
For Grade 4 
thrombocytopenia with 
bruising or bleeding, 
withhold study drug 
until Grade ≤3. May 
resume study drug at 
next lower dose level. 
Other Study-Drug-Related Event 
CTCAE Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
GS-1101 Dosing 
Recommendation 
Maintain dose level 
Maintain dose level 
Withhold study drug until toxicity is Grade ≤1. 
May resume study drug at next lower dose level 
unless subject has developed a condition 
requiring discontinuation of therapy (see 
Section 5.8). 
Abbreviations:   ALP=alkaline phosphatase, ALT=alanine aminotransferase, ANC=absolute neutrophil count, 
AST=aspartate aminotransferase, CTCAE=Common Terminology Criteria for Adverse Events, G-CSF=granulocyte-colony-
stimulating factor, LLN= lower limit of normal, ULN=upper limit of normal 


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5.4. 
Recommendations for Evaluation, Intervention, and Drug 
Discontinuation for Specific Adverse Events or Conditions 
5.4.1. 
Dermatological Events 
GS-1101 administration has occasionally been associated with the occurrence of a 
maculopapular rash affecting the trunk and extremities [Gilead Sciences 2011]. Based on 
skin biopsy data in several subjects, the findings have been consistent with a delayed-type 
hypersensitivity reaction. Rechallenge with GS-1101 has resulted in recurrence of rash in 
some but not all subjects. 
In subjects who develop a rash while on study drug, causes related to concomitant 
medications, environmental exposures, or infection should be considered and eliminated. 
Depending upon the severity of the initial dermatological event, rechallenge with study drug 
therapy at the same or a lower dose level (see Table 5-2) should be considered if continued 
drug administration offers the potential for clinical benefit. 
5.4.2. 
Gastrointestinal Events 
Inflammation of the tongue has been noted in rats undergoing repeated gavage administration 
of GS-1101; this inflammation may have represented a drug-related exacerbation of 
gavage-mediated irritation. Mild congestion or hemorrhage in the large intestine has been 
seen in dogs receiving high doses of GS-1101. In patients, isolated cases of gastrointestinal 
inflammation (eg, stomatitis, colitis, cecitis) have been noted. Cholangitis manifest as 
hyperbilirubinemia out of proportion to serum transaminase elevations has been observed. 
While disease-related factors, neutropenia, toxicity from prior therapies, effects of ongoing 
supportive care, or pre-existing cholelithiasis may have initiated such events, it is possible 
that GS-1101 played a contributory role due to its immunomodulatory effects 
[Gilead Sciences 2011]. 
For study subjects who develop severe abdominal pain, particularly if early during therapy, 
the possibility of a bowel obstruction or perforation should be considered. Appropriate 
clinical and radiographic examination should be performed and supportive care and surgical 
intervention should be considered. Upon recovery, study therapy may be continued if 
appropriate for the clinical situation. 
For subjects who develop persistent diarrhea, causes related to concomitant medications or 
gastrointestinal infection should be considered and eliminated. Depending upon the clinical 
circumstances, endoscopy and biopsy may be warranted. In such subjects, rechallenge with 
GS-1101 at a lower dose level has resulted in recurrence of symptoms in some but not all 
subjects and has not been associated with other severe adverse events. One patient who 
developed evidence of inflammatory bowel disease during GS-1101 therapy has been treated 
with sulfasalazine (Azulfidine®) and antidiarrheals (eg, loperamide) while continuing on 
GS-1101. 
Thus, depending upon the type and severity of the initial gastrointestinal event, rechallenge 
with study drug at a reduced dose level and with and appropriate support care may be 
warranted if continued drug administration offers the potential for clinical benefit. 


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5.4.3. 
Hepatic Events 
Dogs receiving GS-1101 for 28 days were observed to have dose-related hepatic 
inflammation and cellular necrosis, primarily affecting sinusoids in the centrilobular to 
midzonal regions of the liver [Gilead Sciences 2011]. The changes were associated with 
elevations in serum ALT/AST concentrations. In dogs, serum transaminase elevations 
typically reversed despite continued administration of GS-1101. In some patients with 
lymphoid malignancies, reversible serum ALT/AST elevations have been observed 
[Coutre 2011, Kahl 2011]. In these patients, onset has typically occurred within 2 to 8 weeks 
of starting GS-1101 therapy. Patients with NHL have been affected more commonly than 
those with CLL, suggesting that disease-related factors may alter the sensitivity to 
GS-1101-mediated hepatic effects. While conclusive evidence for a dose-response 
relationship does not exist, higher doses or exposures of GS-1101 may be associated with a 
greater risk of adverse hepatic events. 
Among patients with Grade 1-2 ALT/AST abnormalities, continued dosing has been 
possible; transaminase values commonly resolve despite continued GS-1101 treatment. For 
those with Grade 3-4 ALT/AST elevations, drug interruption has resulted in resolution over 
2 to 6 weeks. Successful rechallenge at lower dose levels of GS-1101 has been achieved in 
the majority of patients. Thus, in subjects with uncomplicated hepatic events, the instructions 
in Table 5-2 should be followed in an attempt to maximize the potential that subjects who 
appear to be benefiting can continue with study drug treatment. 
In selected subjects who experience more complicated hepatic adverse events, further 
work-up may be warranted, as requested by the Gilead Sciences medical monitor. Such an 
evaluation may be particularly warranted in subjects who first experience a serum ALT/AST 
elevation ≥12 weeks from the start of study drug therapy, who have an elevation in serum 
bilirubin concentration or coagulation parameters, or who have other characteristics that 
suggest an atypical change in transaminase values. Further workup may include: obtaining a 
history of recent symptoms/illnesses and of relevant past history (eg, history of hepatitis or of 
hepatitis A or hepatitis B vaccination); obtaining information regarding concomitant drug use 
(prescription and nonprescription medications, dietary supplements, alcohol, illicit drugs, 
special diets); questioning the subject regarding potential exposure to environmental toxins; 
ruling out viral hepatitis A, B, C, D (if hepatitis B is positive), and E, Epstein-Barr virus, 
cytomegalovirus, autoimmune hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis, 
hypoxic/ischemic hepatopathy, and biliary tract disease; obtaining additional tests to evaluate 
liver function (eg, prothrombin time [PT], activated partial thromboplastin time [aPTT], 
international normalized ratio [INR], albumin); and considering gastroenterology or 
hepatology consultation [FDA 2009]. 
Of note, HBV reactivation can occur in patients treated with rituximab with a median time to 
diagnosis of hepatitis among patients with hematologic malignancies of 4 months after the 
initiation of rituximab but such events can occur months after completion of rituximab 
therapy. The risk is very low among patients with negative anti-HBc serology [Matsue 2010]. 
Because subjects with serum anti-HBc antibodies are excluded from the primary study 
(Study GS-US-312-0116), this complication is not anticipated. However, among subjects 
with evidence of Grade ≥3 serum ALT/AST abnormalities, evaluation for HBV reactivation 
(manifest as positivity for serum HBsAg) should be performed as a precautionary measure. 


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In a subject with active HBV, anti-HBV antiviral agents should be initiated. At the discretion 
of the investigators, study drug may be continued if HBV infection can be adequately 
controlled, particularly if the subject is experiencing clinical benefit from study therapy and 
there are few other options for treating the subject’s CLL. 
5.4.4. 
Hematological and Immunological Events 
In the Phase 1 experience with GS-1101 in CLL, patients with Grade≥3 neutropenia, anemia, 
and and/or thrombocytopenia were enrolled to clinical trials. Decreased levels of neutrophil 
counts, hemoglobin, or platelet counts during therapy were largely due to minor fluctuations 
in these parameters among patients with pre-existing hematological abnormalities due to 
disease or prior therapy. Thus, GS-1101 did not appear to induce overt myelosuppression. 
Obvious patterns of drug-mediated reductions in circulating CD4+ lymphocyte counts or 
suppression of serum IgG levels were also not observed. 
Given that patients with CLL commonly have Grade ≥3 hematological abnormalities due to 
underlying disease or prior therapy and that GS-1101 is not associated with substantial 
myelotoxicity or off-target immunosuppression, alterations in study drug dose level for such 
events should only focus on subjects with protracted or symptomatic neutropenia or 
thrombocytopenia, unresponsive to G-CSF supportive care. No modification of GS-1101 for 
changes in circulating CD4+ counts or Ig levels is planned. 
5.4.5. 
Infectious Events 
Patients with CLL receiving GS-1101 have developed serious bacterial, fungal, and viral 
infections during therapy [Gilead Sciences 2011]. Similarly, serious bacterial, fungal, and 
new or reactivated viral infections have also occurred during and for ~1 year following 
rituximab-based therapy [Gea-Banacloche 2010]. New or reactivated viral infections in 
patients receiving rituximab have included cytomegalovirus, herpes simplex virus, 
parvovirus B19, varicella zoster virus, West Nile virus, HBV (see Section 5.4.3) and HCV. 
Because patients with lymphoid malignancies (particularly those with CLL) are susceptible 
to infection due to the underlying disease, neutropenia, and the effects of prior therapy, the 
specific causal role of GS-1101 or rituximab in any of these types of events is unclear. 
Patients with previously treated CLL have developed Pneumocystis (carinii) jiroveci 
pneumonia while receiving GS-1101. While GS-1101 has not specifically been implicated in 
such cases, patients with lymphoid malignancies (particularly those with CLL) may be 
susceptible to pneumocystis infections due to the underlying disease and the effects of prior 
therapy. Pre-existing risk factors of specific concern may include previous pneumocystis 
pneumonia, underlying disease (eg, CLL), prior therapy (eg, alemtuzumab, progenitor cell 
transplantation), or immunocompromised status (low CD4+ lymphocyte counts, HIV 
infection) [Green 2007]. 
Unless there is a contra-indication in a specific study subject, consideration should be given 
to initiation of antibiotic prophylaxis against pneumocystis infection (eg, with trimethoprim-
sulfamethoxazole, dapsone, aerosolized pentamidine, or atovaquone) beginning prior to study 
drug administration. Such support may also offer the benefit of reducing the risk for other 
bacterial infections [Green 2007]. Local practices or guidelines may be followed. 


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For subjects who develop an infection, appropriate medical therapy (with antibiotics, 
antifungals, or antiviral) or other interventions should be instituted. Whenever appropriate, 
subjects should continue with study drug during treatment for the infection. 
5.4.6. 
Progressive Multifocal Leukoencephalopathy 
Progressive multifocal leukoencephalopathy (PML) due to polyomavirus JC has been 
observed in patients who have received rituximab therapy [Carson 2009] for hematologic 
malignancies. The specific causal role of rituximab is unknown because many of these 
patients had other risk factors (eg, low CD4+ counts) and the majority had received 
rituximab in combination with chemotherapy or as part of a hematopoietic stem cell 
transplant. Most cases of PML were diagnosed within 12 months of the last infusion of 
rituximab. 
The diagnosis of PML should be considered in any subject presenting with new-onset 
neurologic manifestations. Evaluation of PML may include consultation with a neurologist, 
brain MRI, and lumbar puncture. In subjects diagnosed with PML, study drug should also be 
permanently discontinued. 
5.4.7. 
Pulmonary Events 
Documented bacterial, fungal, viral, and pneumocystis pneumonias have been observed in 
patients receiving GS-1101, primarily in patients with CLL. Some patients receiving 
GS-1101 alone or in combination have developed evidence of pneumonitis without 
documented lung infection. The specific role of GS-1101 in these events is unclear; 
nonclinical evaluations of pulmonary function and pathology do not indicate a direct toxic 
effect of GS-1101 on the lungs [Gilead Sciences 2011] and disease-related factors or toxicity 
from prior or concomitant therapies may have contributed to these clinical events. 
Rituximab-related noninfectious pneumonitis has been described [Subramanian 2010] with 
an incidence of ~4.3% [Salmasi 2010]. In patients developing rituximab-associated 
pneumonitis, the mean time from the first rituximab infusion to the onset of respiratory 
symptoms was 3 months, with a peak incidence after administration of a mean cumulative 
dosage of 1600 mg/m2 [Lioté 2010]. 
Given the potential for infectious or drug-related adverse events, clinicians should be 
particularly observant for evidence of respiratory events in subjects participating in this trial. 
Subjects should be evaluated who describe pulmonary symptoms (eg, dyspnea on exertion, 
cough, shortness of breath); manifest a decline from baseline of ≥5% in oxygen saturation, or 
demonstrate evidence of pulmonary inflammation (eg, focal or diffuse interstitial pattern or 
ground-glass opacities on chest CT). Potential bacterial, fungal, or viral etiologies should be 
assessed. Pneumocystis (carinii) jiroveci should be considered, especially if the subject is not 
receiving pneumocystis prophylaxis. Depending upon the changes observed and the response 
to antibiotic intervention, recommended diagnostic work-up may include blood and sputum 
cultures; polymerase chain reaction or antigen testing for pneumocystis and respiratory 
viruses (eg, CMV, influenza virus, respiratory syncytial virus, parainfluenza virus, 
rhinovirus); chest X-ray, CT or other imaging methods; pulmonary function testing and 
diffusing capacity of the lung for carbon monoxide (DLCO); bronchoscopic lavage and/or 
biopsy; or open-lung biopsy. Noninfectious etiologies such as pulmonary edema or 
thromboembolism should also be considered. 


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As appropriate for the clinical situation and culture results, subjects should be treated 
empirically or given specific antibiotics, antifungals, or antiviral agents for a cultured 
organism. Supportive care, including oxygen or mechanical ventilation, should be provided 
as necessary.  
For subjects with a symptomatic pneumonitis in the absence of infection (eg, onset of cough 
without fever and lack of response to anti-infective measures), study drug should be 
interrupted and therapy with corticosteroids should be instituted [Lioté 2010]. Resumption of 
study drug at Dose Level -1 should only be considered if the subject is experiencing evidence 
of substantial clinical benefit from therapy and other options for treating the subject’s CLL 
are very limited; reoccurrence of drug-related pneumonitis upon rechallenge should result in 
permanent discontinuation of study treatment. 
5.4.8. 
Tumor Lysis Syndrome 
Patients with tumor lysis syndrome may experience hyperkalemia, hypocalcemia, 
hyperuricemia, hyperphosphatemia, cardiac dysrhythmias, and acute renal failure. 
Tumor lysis syndrome has not been observed with GS-1101 monotherapy. However, if tumor 
lysis were to occur in a subject participating in this study, the subject should receive rapid 
reversal of hyperkalemia, intravenous hydration, antihyperuricemic agents, and appropriate 
cardiac and renal support, including dialysis as indicated. Upon recovery to baseline 
functioning, such subjects should continue study therapy to maintain tumor control. 
5.4.9. 
Pregnancy, Lactation, and Reproduction 
GS-1101 was not overtly teratogenic when administered to pregnant female rats in a 
dose-range-finding study [Gilead Sciences 2011]. However, definitive reproductive 
toxicology studies in animals have not yet been performed and the specific effects of 
GS-1101 on human embryogenesis or fetal development are unknown. Whether GS-1101 is 
excreted in human breast milk is unknown. General toxicology studies in rats and dogs 
indicated dose-dependent reductions in testicular weights, with persistent minimal to mild 
degeneration of the seminiferous tubules and decreased spermatozoa in rats and 
hypospermatogenesis in dogs. The implications of these testicular changes for animal or 
human fertility are unknown. 
Given the preliminary nature of data regarding the risks to a fetus or infant as a result of 
exposure to GS-1101, women of reproductive potential entering this study must have a 
negative serum pregnancy test at baseline and must not be breastfeeding. Males and females 
of childbearing potential should abstain from sexual intercourse or use an effective form of 
contraception (see Section 5.6.4). If a female study participant becomes pregnant or decides 
to breastfeed during the course of the study, all study therapy must be discontinued. Study 
candidates will be informed of the testicular findings through the informed consent process. 
5.5. 
Emergency Unblinding 
Every attempt should be made to preserve the integrity of study drug dose assignment 
blinding. Unblinding in individual subjects who experience adverse events is rarely required 
to provide effective intervention and support. For subjects having adverse events or 
laboratory abnormalities that require drug cessation or medical intervention, the 
investigational staff should strive to provide necessary support to the subject without 


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breaking the blind. In the exceptional circumstance that knowledge of the study drug dose 
assignment appears essential for providing appropriate medical management, the investigator 
should contact the Gilead Sciences medical monitor to discuss the rationale for breaking the 
blind and the adverse consequences of the unblinding for the subject’s continued 
participation in the study. If the investigator still believes that unblinding is warranted, the 
investigator will be able to access the allocation system in order to obtain the treatment 
assignment for that subject. No randomization lists or other unblinding information will be 
provided to the site. After breaking the blind, the investigational site staff should record 
details regarding the reasons for breaking the blind and any adverse events leading to the 
breaking of the blind in the source documents and in the appropriate eCRF. 
If the site breaks the blind, the appropriateness of continued study drug therapy should be 
discussed with the Gilead Sciences medical monitor. Subjects who intentionally subvert the 
blind (eg, through chemical analysis of the drug) should be discontinued from study drug 
therapy.  
5.6. 
Concomitant and Supportive Therapy 
To the extent possible, administration of any prescription or over-the-counter drug products 
other than study medication should be minimized during the study period. Subjects should be 
discouraged from use of street drugs, herbal remedies, self-prescribed drugs, tobacco 
products, or excessive alcohol at any time during the clinical study. 
If considered necessary for the subject’s well-being, drugs for concomitant medical 
conditions or for symptom management may be given at the discretion of the investigator. 
The decision to authorize the use of any drug other than study drug should take into account 
subject safety, the medical need, the potential for drug interactions, the possibility for 
masking symptoms of a more significant underlying event, and whether use of the drug will 
compromise the outcome or integrity of the study 
Subjects should be instructed about the importance of the need to inform the clinic staff of 
the use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and 
during the course of the study. Any concomitant drugs taken by a subject during the course 
of the study and the reason for use should be recorded on the eCRFs. 
Information regarding use or restrictions on specific concomitant medications, dietary 
measures, or other interventions is provided below. 
5.6.1. 
Anticancer or Experimental Therapies Other than Investigational 
Treatments 
No other anticancer therapies (including chemotherapy, radiation, antibody therapy, 
immunotherapy, or other experimental therapies) of any kind are permitted while the subject 
is receiving study treatment. Subjects are not allowed to participate concurrently in any other 
therapeutic clinical study. 
5.6.2. 
Antibiotics 
Except in a subject who has a contra-indication, investigators should consider initiation of 
antibiotic prophylaxis against pneumocystis infection (eg, with trimethoprim-
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drug administration. Such support may also offer the benefit of reducing the risk for other 
bacterial infections [Green 2007]. Investigator discretion and local practices or guidelines 
may be followed. 
For subjects who develop an infection, appropriate medical therapy (with antibiotics, 
antifungals, or antiviral) or other interventions should be instituted. Whenever appropriate, 
subjects may continue with study drug during treatment for the infection. 
5.6.3. 
Antiemetics and Antidiarrheals 
Drug-related nausea and/or vomiting have not been commonly observed with GS-1101 in 
prior studies. However, subjects who experience nausea or vomiting while on study therapy 
may receive antiemetics based on the judgment of the treating physician and local 
institutional practices. At the occurrence of persistent nausea or vomiting of severity 
Grade ≥1, it is suggested that the subject receive an oral or transdermal serotonin antagonist 
(eg, dolasetron, granisetron, ondansetron, tropisetron, palonosetron). The neurokinin receptor 
antagonist, aprepitant, may be considered but is a mild inhibitor of CYP3A4 and so may 
modestly increase GS-1101 plasma exposures. Other classes of antiemetic medications that 
may be employed include dopamine antagonists or benzodiazepines. If possible, systemic 
corticosteroids should be avoided (see Section 5.6.5). 
As needed, subjects may be prescribed loperamide (Imodium® or others) or diphenoxylate 
and atropine (Lomotil®) to control diarrheal symptoms. 
5.6.4. 
Contraception 
In the context of this protocol, a female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, a bilateral tubal ligation, or a bilateral oophorectomy; has 
medically documented ovarian failure (with serum estradiol and FSH levels within the 
institutional postmenopausal range and a negative serum or urine βHCG); or is menopausal 
(age ≥55 years with amenorrhea for ≥6 months). 
Sexually active females of childbearing potential must accept continuous heterosexual 
abstinence as a lifestyle choice or agree to use a protocol-recommended method of 
contraception during heterosexual intercourse throughout the study treatment period and for 
30 days following discontinuation of the study drug. The investigator should counsel subjects 
on the most effective methods for avoiding pregnancy during the trial. Protocol-
recommended contraceptive methods are described in Table 5-3. 


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Table 5-3. 
Protocol-Recommended Contraceptive Methods 
Combination Methods 
Individual Methods 
Hormonal Methods 
(One method to be used 
with a barrier method) 
Barrier Methods 
(Both of these methods to be used OR one of these 
methods to be used with a hormonal method) 
IUD 
Estrogen and progesterone 
Diaphragm with spermicide 
Copper T 380A IUD 
Oral contraceptives 
Male condom (with spermicide) 
LNg 20 IUD 
Transdermal patch 
 
Tubal sterilization 
Vaginal ring 
 
Hysterectomy 
Progesterone 
 
 
Injection 
 
 
Implant 
 
Abbreviation: IUD=intrauterine device 
In the context of this protocol, a male subject is considered able to father a child unless he 
has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or is 
receiving ongoing testicular suppression with a depot luteinizing hormone-releasing hormone 
(LH-RH) agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or 
triptorelin pamoate [Trelstar®]). 
Sexually active male subjects who can father a child must accept continuous heterosexual 
abstinence as a lifestyle choice; limit intercourse to female partners who are surgically sterile, 
post-menopausal, or using effective contraception (as noted in Table 5-3); or agree to use a 
protocol-recommended method of contraception during heterosexual intercourse throughout 
the study treatment period and for 90 days following discontinuation of the study drug (as 
noted in Table 5-3).  
The Gilead Sciences medical monitor should be consulted regarding any questions relating to 
childbearing status or contraception. 
5.6.5. 
Corticosteroids 
Subjects may receive topical, inhaled, or enteric corticosteroids while on study. The use of 
systemic corticosteroids is discouraged because their potential antineoplastic activity in 
patients with CLL may confound interpretation of antitumor effects mediated by study drug 
therapy. However, subjects who develop severe or life-threatening conditions that may be 
alleviated by systemic corticosteroid therapy are permitted to receive such drugs and are not 
required to discontinue study participation. 
5.6.6. 
Granulocyte Colony-Stimulating Factors and Erythropoietin 
Granulocyte-macrophage colony-stimulating factor (GM-CSF) should not be administered 
given the potential for GM-CSF-related inflammatory symptoms. 
G-CSF (filgrastim, PEG-filgrastim, lenograstim) may be administered in response to Grade 4 
neutropenia or neutropenic complications; use should be particularly considered if providing 
hematopoietic support might help to maintain study drug treatment (see Table 5-2). 
While erythropoietic agents (eg, erythropoietin or darbepoetin) may be administered for 
Grade ≥3 anemia, their use in this study is discouraged given the potential to confound 
assessments of improvements in bone marrow function related to study treatment. 


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Reference may be made to the American Society of Clinical Oncology guidelines 
[Rizzo 2008, Smith 2006]. 
5.6.7. 
Drugs that Inhibit CYP3A4-Dependent Metabolism 
GS-1101 is metabolized in part by CYP3A4. However, a clinical drug-drug interaction study 
indicated that administration of a potent CYP3A4 inhibitor together with GS-1101 induced 
only a modest increase in GS-1101 plasma exposure (see Section 1.3.5.1). Thus, 
co-administration of CYP3A4 inhibitors and GS-1101 is not contraindicated and does not 
require special monitoring. 
5.6.8. 
Immunization 
Because of its actions to inhibit PI3Kδ-dependent B-cell function, high doses of GS-1101 can 
impair primary or secondary responses to immunization in animals [Gilead Sciences 2011]. 
The specific clinical relevance of these findings with GS-1101 is unknown. However, for 
subjects who are at substantial risk of an infection (eg, influenza) that might be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of 
study therapy. 
Of note, the safety of immunization with live viral vaccines following GS-1101 therapy has 
not been studied and vaccination with live virus vaccines during study treatment is not 
recommended. 
5.6.9. 
Surgery 
There are no known effects of GS-1101 on coagulation or wound healing. Pending receipt of 
additional information, study drug may be continued in the peri-procedural period in subjects 
who require surgery or invasive procedures. 
5.6.10. 
Diet 
There are no specific dietary restrictions in the study. Study drug may be taken with or 
without food. 
5.7. 
Duration of Study Therapy 
Subjects may continue receiving study drug until the earliest of the inability to tolerate a 
second rechallenge with protocol-described, dose-modified GS-1101 Dose Level –1 (see 
Section 5.3.6) or the occurrence of any events requiring treatment discontinuation as defined 
in Section 5.8. 
5.8. 
Discontinuation of Study Treatment 
All study participants may receive study drug indefinitely; however: 
• Any subject has the right to withdraw from the study at any time. 
• Any subject who has objective evidence of definitive CLL progression while receiving 
study treatment should be withdrawn from the study treatment. 
• Any subject whose medical condition substantially changes after entering the study 
should be carefully evaluated by the investigator in consultation with the Gilead Sciences 


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medical monitor. Such subjects should be withdrawn from study treatment if continuing 
would place them at risk. 
• Any subject who becomes pregnant or begins breastfeeding should be removed from 
study treatment. 
• Any subject who becomes significantly noncompliant with study drug administration, 
study procedures, or study requirements should be withdrawn from study treatment in 
circumstances that increase risk or substantially compromise the interpretation of study 
results. 
• Any subject for whom the blind is intentionally broken by the subject or the study site 
should discontinue study treatment. 
• The investigator, in consultation with the Gilead Sciences medical monitor, may 
withdraw any subject from the study treatment, if, in the investigator’s opinion, it is not 
in the subject’s best interest to continue.  
• Gilead Sciences, relevant regulatory agencies, or IRB/IECs may request discontinuation 
of the study at any time. 
• If allowed by local regulations, Gilead Sciences may transition subjects from study 
treatment to commercial drug supply when GS-1101 becomes commercially available in 
the country where the subject is living. 
The date the subject is withdrawn from study treatment or from the study (including 
long-term follow-up) and the reason for discontinuation will be recorded with the IWRS and 
also should be described on the appropriate eCRF. 
When a subject is withdrawn from study treatment or is permanently removed from study 
treatment (regardless of the reason), all of the evaluations required at the end-of-treatment 
visit should be performed and any additional evaluations should be completed that may be 
necessary to ensure that the subject is free of untoward effects. The subject should be 
encouraged to seek appropriate follow-up for any continuing health problems. 
Subjects who discontinue study treatment may still continue on study follow-up. Thus, all 
subjects receiving ≥1 dose of study drug will be followed during the immediate 
post-treatment and during the long-term follow-up periods unless the subject withdraws 
consent for such follow-up to be conducted. 
5.9. 
Study Treatment Rationale 
Subjects will be assigned to treatment (Arm A or Arm B) in this study based on their 
randomization in the primary study. The 1:1 randomization in the primary trial (GS-US-312-
0116) ensures that sufficient Arm B subjects will cross over from rituximab alone to single-
agent GS-1101 at the 150-mg/dose BID starting dose level in this extension trial (GS-US-
312-0117) to allow an adequate evaluation of efficacy and safety in this trial. The 
randomization and allocation processes will be established and performed through an IWRS; 
the intent is to maximize the integrity and security of the subject disposition and to ensure 
appropriate access and convenience-of-use by the investigational sites. 


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Double blinding is included to provide protection against biased interpretations of efficacy 
and safety data by subjects, caregivers, investigators, Gilead Sciences personnel, or others 
involved in study conduct.  
Selection of the GS-1101 treatment regimen (including starting dose level, dose-
modifications and supportive care, schedule, duration, and conditions of administration) for 
this study program has been based primarily on safety, exposure, and activity profiles from 
previous Phase 1 clinical studies involving healthy volunteers, patients with allergic rhinitis, 
and patients with refractory/relapsed lymphoid malignancies [Webb 2010, Coutre 2011, 
Kahl 2011]. The following information was considered in selecting the study drug dosing 
regimen for the primary study and this companion extension study: 
• GS-1101 was symptomatically well tolerated in patients with lymphoid malignancies 
receiving dose levels of 50 mg/dose BID through 350 mg/dose BID (the highest dose 
level tested). No specific MTD was apparent over the dose range tested. However, 
monitorable, reversible transaminase elevations were observed in some patients and may 
have been more frequent at higher dose levels (~10% rate among patients with CLL 
receiving starting doses of ≥150 mg/dose). Thus, while doses through 350 mg/dose BID 
are tolerable, the starting dose of 150 mg/dose BID appears to appropriately balance 
safety with efficacy in GS-1101-naïve subjects. The starting dose of 300 mg/dose BID in 
this study also appears appropriate for evaluation; it is lower than the dose level of 
350 mg/dose BID that has been tolerable in prior studies and is likely to be suitable in 
subjects who have already been tolerating GS-1101 therapy at ≥100 mg/dose BID.  
• Upon disease progression, permitting escalation from 150 mg/dose BID to 
300 mg/dose BID among subjects allocated to Arm A offers a systematic evaluation of 
higher doses in subjects who are tolerating GS-1101 treatment and might benefit from 
increased PI3Kδ inhibition. The pharmacological basis for considering such an 
intervention is based on the concept that some individuals might have 
lower-than-expected plasma exposures or dose-dependent resistance to the compound at 
150 mg/dose BID and might benefit from a higher dose. The intent is to determine if the 
higher dose can reestablish disease control or whether absolute resistance to PI3Kδ 
inhibition has been acquired. The safety data obtained in these subjects would add to the 
overall safety database. 
• In an allergic rhinitis study, GS-1101 induced statistically significant improvements in 
clinical and pharmacodynamic endpoints when administered at 100 mg/dose BID over 
7 days. These data support the pharmacological relevance of GS-1101-mediated PI3Kδ 
inhibition when administered at the dose-levels to be used in this study. 
• A positive correlation was noted between GS-1101 dose and measures of tumor control 
and chemokine normalization in patients with B-cell malignancies. The majority of 
patients appear to have tumor responses and protracted PFS when receiving starting doses 
of ≥100 mg/dose BID. Thus, treatment with a GS-1101 at a starting dose of 150 mg/dose 
BID appears to offer most patients the potential to benefit from therapy and the dose level 
of 300 mg/dose BID may provide additional benefit in patients with disease resistance as 
systematically evaluated in this trial.  


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• Based on evaluations of GS-1101 steady-state plasma Cmax, AUC, and Ctrough values over 
a range of doses, administration of starting doses of GS-1101 of ≥150 mg/dose BID 
appears appropriate to ensure adequate exposure in the majority of patients.  
• In Phase 1 studies, the mean plasma t1/2 of GS-1101 was ~6.5 to 9.8 hours across all dose 
levels and there was no substantive plasma accumulation over 7 or 28 days. The 
collective data support a study drug administration schedule of BID administration to 
maintain GS-1101 plasma Ctrough values without inducing excessively high plasma Cmax 
values.  
• The changes in exposure observed when administering GS-1101 after a high-fat, 
high-calorie meal are modest (~40% increase in mean AUC with no change in mean 
Cmax). Thus, GS-1101 can be administered with or without food.  
• Clinical evidence suggests that potent inhibitors of CYP3A4 may induce a modest 
increase in GS-1101 plasma concentrations in humans. However, given the fact that 
GS-1101 is well tolerated and appears to be a relatively weak substrate for CYP3A4, 
administration of drugs that inhibit CYP3A4 together with GS-1101 does not appear to 
be contraindicated and special precautionary measures do not appear necessary.  
• The GS-1101 dose modification provisions described in the protocol are designed to 
balance a primary concern for subject safety with the potential for observing 
pharmacological and antitumor activity in circumstances under which a subject 
experiencing an adverse event may still be able to continue on therapy at a lower 
GS-1101 dose level. The enhanced monitoring to be performed and the actions to be 
taken in response to toxicity are based on experience with interruption, dose-
modification, rechallenge, and re-escalation already piloted in GS-1101 Phase 1 trials. In 
addition, GS-1101 antitumor activity has been observed in the Phase 1 studies across all 
dose levels tested, including doses in the range of the modified dose levels planned for 
this protocol. Thus, use of the lower dose level to accommodate individual subject 
tolerability in this protocol is justified because subjects receiving such a GS-1101 dose 
level still have the potential for benefit. 
• In both the primary and extension studies, study treatment will be continued for each 
subject until the occurrence of disease progression. Such a strategy is considered 
appropriate under the assumption that persistent interference with PI3Kδ signaling is 
likely to extend treatment effect. In addition, this design permits collection of further 
single-agent safety information and thus is likely to enhance understanding of the overall 
safety profile of GS-1101.  
• Appropriate disincentives for unblinding of study drug are included in the trial (see 
Section 5.5). Investigational personnel will not have access to information at the site that 
would permit unblinding and must obtain the individual subject treatment assignment 
code only through the treatment allocation system. Clinic staff will be made aware that 
such unblinding may preclude a subject from continuing with study drug administration. 
Unblinding will also involve discussion between the investigator and the Gilead Sciences 
medical monitor; this provision is not intended to prevent an investigator from 
proceeding with unblinding, but to ensure that appropriate consultation is obtained, that 


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the investigator is aware of the consequences of the unblinding for the subject’s 
continued participation in the study, and that appropriate permission is granted to the 
treatment allocation system to release the treatment assignment only for that subject. 


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6. 
STUDY PROCEDURES 
6.1. 
Enrollment and Study Management Procedures 
6.1.1. 
Subject Recruitment 
Study candidates are limited to those subjects who participated in the primary clinical trial 
(Study GS-US-312-0116) and meet the entry criteria for this trial (Study GS-US-312-0117). 
Subjects will be enrolled from investigational sites in the United States and Europe. The site 
principal investigator, designated sub-investigators, or other designees will discuss the 
possibility of participation directly with subjects who participated in the primary study.  
The study sponsor will post a description of the study on the ClinicalTrials.gov website. Any 
promotional information generated by the sponsor or investigational sites will be submitted 
for IRB/IEC review. 
6.1.2. 
Subject Compensation for Participation 
For subjects requesting such assistance, reasonable reimbursements for the costs of travel 
required to participate in this study will be provided by the study sponsor. To receive 
payment for travel, subjects will need to submit the original travel receipts to the research 
study staff at the investigational site. 
However, other than medical care that may be provided, subjects will not be paid for 
participation in the study. Payments for such items as lost wages, disability, discomfort due 
to injury, or meals obtained while waiting at the clinical research center will not be provided. 
Through the informed consent process, study candidates will be notified that their insurance 
company could be charged for standard care that is a component of this research study and 
that subjects may be responsible for co-payments and deductible payments that are typical 
for their insurance coverage. 
6.1.3. 
Screening 
The investigator must inform each prospective subject of the nature of the study, explain the 
potential risks, and obtain written informed consent from the subject and/or a legal guardian 
prior to performing any study-related screening procedures. At the time the study candidate 
signs the informed consent, a site representative should access the IWRS to indicate that a 
study candidate is being screened. The user will need to supply the IWRS with required 
information identifying the site and the subject number as already assigned in Study GS-
US-312-0116. 
Any consented subject who is excluded from the study before initiation of study treatment 
will be considered a screen failure. All screen failures must be documented along with an 
adequate description of the reason the subject was considered a screen failure. If available, 
information should be provided as to why the subject did not meet eligibility criteria, 
withdrew consent, experienced an intercurrent illness, or had other events that precluded 
treatment on this study. 


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6.2. 
Explanation of Study Visits 
The specific study procedures to be conducted for each subject enrolled in the study are 
presented in tabular form in Appendix 7 and are described in the sections that follow. 
Additional information on the study procedures is provided in the study manual. 
For visits at which HRQL and healthy utility data are obtained, it is important that the subject 
be administered the FACT-Leu and the EQ-5D before any other procedures are performed 
and before any study-related information is communicated to the subject; this is necessary to 
avoid biasing the PRO responses provided by the subject. Once the subject has completed the 
FACT-Leu and the EQ-5D assessments, the remaining procedures may be performed. 
At visits involving GS-1101 administration and pharmacokinetic sampling in the clinic, care 
should be taken to perform procedures with the appropriate timing relative to GS-1101 
administration. The actual sample collection times of pharmacokinetic blood specimens 
should be recorded. If a heparinized venous catheter is placed for sample collection in order 
to avoid repeated needle sticks, at least 2 mL of blood should be removed and discarded prior 
to each sample collection in order to avoid heparin contamination of the sample. 
At the visit designated as a laboratory-only visit (Visit 7), subjects will have laboratory 
assessments that may be performed at the investigational site or at an accredited local 
laboratory or clinic that is convenient for the subject/caregiver. If blood is collected at a local 
laboratory, samples are not to be analyzed at the local laboratory. For these visits, subjects 
and/or caregivers will be provided with central laboratory kits that will contain materials 
necessary for the collection and shipment of the laboratory samples by the local laboratory 
clinic to the central laboratory. 
In addition to clinical assessments of tumor status, CT or MRI imaging of the neck, chest, 
abdomen, and pelvis will be performed as a component of tumor assessments during the 
study based on the rationale provided in Section 3.2.1; the same method of assessment (CT 
or MRI) and the same technique should be used to characterize each identified and reported 
lesion at baseline and while on study. 
6.2.1. 
Visit 1 and Screening Period (Clinic Visit) 
The initial screening visit is designated as Visit 1. At Visit 1, the investigator must inform 
each prospective study participant of the nature of the study, explain the potential risks, and 
obtain written informed consent from the study candidate and/or legal guardian prior to 
performing any study-related screening procedures. Once the informed consent document has 
been signed, the subject may undergo the screening procedures. 
In order to optimize scheduling convenience for the subject and for the investigational staff, 
study procedures performed as part of Study GS-US-312-0116 need not be repeated and can 
be used as screening procedures for Study GS-US-312-0117 if performed within 4 weeks 
prior to initiation of study drug therapy on Study GS-US-312-0117. In addition, screening 
procedures may be performed over as many days as necessary provided that screening is 
completed within 4 weeks prior to initiation of study drug therapy on Study GS-US-312-
0117.  
The tests and evaluations outline in Table 6-1 will be performed at Visit 1 or during the 
screening period prior to initiation of study treatment. 


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Table 6-1. 
Procedures and Assessments at Visit 1 (During Screening Period) 
Assessment  
or Procedure 
Explanationa 
Informed consent 
To be obtained before any screening procedures are initiated 
IWRS access 
Access IWRS to document that subject is in screening and provide  the subject number from 
Study GS-US-312-0116 
CIRS assessment 
Recording of current comorbid conditions using the CIRS scoring instrument (see Appendix 6) 
Concomitant 
medications 
Recording of ongoing concomitant medication use 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including height, weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly 
Serum β-HCG 
Women of childbearing potential only 
CLL peripheral blood 
evaluation 
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 12 trisomy; DNA 
mutational analysis for p53, IgHV (including IgHV3-21), and other genes of interest in CLL (eg, 
Notch); flow cytometry for CD5, CD10, CD11c, CD19, CD20, CD23, CD38, CD45, kappa and 
lambda light chains, and ZAP-70; cytology for karyotyping; bone marrow aspirate may be used if 
peripheral blood lymphocyte count is too low 
CLL serology 
Serum β2 microglobulin 
 
 
 
 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Radiology assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis, to be scheduled prior to initiation of study 
treatment at Visit 2; the same method of assessment (CT, MRI) and the same technique should be 
used to characterize each identified and reported lesion at baseline and while on study 
Bone marrow biopsy 
and aspirate 
To be performed at investigator discretion to determine extent of CLL involvement and bone 
marrow cellularity. 
a 
Study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be used as screening 
procedures for Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117. 
Abbreviations: β-HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, CIRS=cumulative illness rating scale, CLL=chronic lymphocytic leukemia, CT=computed 
tomography, DNA=deoxyribonucleic acid, FISH= fluorescence in-situ hybridization, GGT=gamma--glutamyltransferase, 
Ig=immunoglobulin, IgHV=immunoglobulin heavy chain variable region, IWRS=interactive web response system, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, RNA=ribonucleic acid, ZAP-70=zeta-associated 
protein 70 
PPD


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6.2.2. 
Visit 2 (Day 1) (Clinic Visit) 
Subjects will be assessed to determine if they still meet eligibility criteria and can initiate 
study treatment. The procedures outlined in Table 6-2 will be performed at Visit 2 (Day 1). 
Table 6-2. 
Procedures and Assessments at Visit 2 (Day 1) 
Assessment or 
Procedure 
Explanation 
Pre-Dose Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the 
subject 
Adverse events 
Recording of adverse events occurring since the initiation of the screening period 
Concomitant 
medications 
Recording of concomitant medication use since the initiation of the screening period 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
β-HCG 
For women of child-bearing potential only; serum β-HCG or urine dipstick pregnancy test must 
be negative prior to initial study treatment 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
GS-1101 
pharmacokinetics 
Pre-dose collection of plasma sample for GS-1101 pharmacokinetics (with recording of the date 
and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug blister card number 
Study Therapy Administration 
Study drug 
administration 
First dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration) 
Post-Therapy Procedures and Assessments 
GS-1101 
pharmacokinetics 
Post-dose collection of plasma sample for GS-1101 pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
study drug dosing at 
next full clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 3. 
Abbreviations: β-HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web 
response system, LDH=lactate dehydrogenase, RNA=ribonucleic acid 


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6.2.3. 
Visit 3 (Day 15) (Clinic Visit) 
The procedures outlined in Table 6-3 will be performed at Visit 3 (Day 15 [±2 days]).  
Table 6-3. 
Procedures and Assessments at Visit 3 (Day 15) 
Assessment or 
Procedure 
Explanation 
Pre-Dose Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the 
subject 
Adverse events 
Recording of adverse events occurring since the initiation of the screening period 
Concomitant 
medications 
Recording of concomitant medication use since the initiation of the screening period 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
GS-1101 
pharmacokinetics 
Recording of the date and actual clock time of the last prior subject self-administration of study 
drug (should be the prior evening dose)Pre-dose collection of plasma sample for GS-1101 
pharmacokinetics (with recording of the date and actual clock time of the date and actual clock 
time of blood collection) 
IWRS access 
Access of IWRS to document subject visit 
Study Therapy Administration 
Study drug 
administration 
Study drug to be administered to the subject (with recording of the date and actual clock time of 
the study drug administration) 
Post-Therapy Procedures and Assessments 
GS-1101 
pharmacokinetics 
Post-dose collection of plasma sample for GS-1101 pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Instruction regarding 
study drug dosing at 
next full clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 4. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, HRQL=health-
related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, LDH=lactate 
dehydrogenase 


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6.2.4. 
Visit 4 (Day 29) (Clinic Visit) 
The procedures outlined in Table 6-4 will be performed at Visit 4 (Day 29 [±2 days]). 
Table 6-4. 
Procedures and Assessments at Visit 4 (Day 29) 
Assessment or 
Procedure 
Explanation 
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 3 
Concomitant 
medications 
Recording of concomitant medication used since Visit 3 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
GS-1101 
pharmacokinetics 
Pre-dose collection of plasma sample for GS-1101 pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug blister card number 
Study Therapy Administration and Dispensing 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
GS-1101 
pharmacokinetics 
Post-dose collection of plasma sample for GS-1101 pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
dosing at next full 
clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 5. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-
Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging 


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6.2.5. 
Visit 5 (Day 43) (Clinic Visit) 
The procedures outlined in Table 6-5 will be performed at Visit 5 (Day 43 [±2 days]).  
Table 6-5. 
Procedures and Assessments at Visit 5 (Day 43) 
Assessment or 
Procedure 
Explanation 
Pre-Dose Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the 
subject 
Adverse events 
Recording of adverse events occurring since the initiation of the screening period 
Concomitant 
medications 
Recording of concomitant medication use since the initiation of the screening period 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
IWRS access 
Access of IWRS to document subject visit 
Study Therapy Administration 
Study drug 
administration 
Study drug to be administered to the subject (with recording of the date and actual clock time of 
the study drug administration) 
Post-Therapy Procedures and Assessments 
Instruction regarding 
study drug dosing at 
next full clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 6. 
Scheduling of Visit 6 
radiology assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 6; the same 
method of assessment (CT, MRI) should be used as was used at baseline. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, HRQL=health-
related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, LDH=lactate 
dehydrogenase 


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6.2.6. 
Visit 6 (Day 57) (Clinic and Radiology Visit) 
The procedures outlined in Table 6-6 will be performed at Visit 6 (Day 57 [±2 days]).  
Table 6-6. 
Procedures and Assessments at Visit 6 (Day 57) 
Assessment or 
Procedure 
Explanation 
Pre-Visit Tumor Assessment 
Radiology assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the same 
method of assessment (CT or MRI) should be used as was used at baseline and the assessment 
should be done even if study drug has been interrupted.  
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 5 
Concomitant 
medications 
Recording of concomitant medication used since Visit 5 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD5+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Bone marrow biopsy 
and aspirate 
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR. 
GS-1101 
pharmacokinetics 
Pre-dose collection of plasma sample for GS-1101 pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug bottle number 
Study Therapy Administration 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
GS-1101 
pharmacokinetics 
Post-dose collection of plasma sample for GS-1101 pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
dosing at next full 
clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 8. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment 
of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging 


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6.2.7. 
Visit 7 (Day 71) (Laboratory Visit) 
The procedures outlined in Table 6-7 will be performed at Visit 7 (Day 71 [±2 days]). 
Table 6-7. 
Procedures and Assessments at Visit 7 (Day 71) 
Assessment or 
Procedure 
Explanation 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including ALT, AST, ALP, GGT, total bilirubin, LDH 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
GGT=gamma-glutamyltransferase, LDH=lactate dehydrogenase 


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6.2.8. 
Visit 8 (Day 85) (Clinic Visit) 
The procedures outlined in Table 6-8 will be performed at Visit 8 (Day 85 [±2 days]). 
Table 6-8. 
Procedures and Assessments at Visit 8 (Day 85) 
Assessment or 
Procedure 
Explanation 
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 6 
Concomitant 
medications 
Recording of concomitant medication used since Visit 6 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
GS-1101 
pharmacokinetics 
Pre-dose collection of plasma sample for GS-1101 pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug blister card number 
Study Therapy Administration and Dispensing 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
GS-1101 
pharmacokinetics 
Post-dose collection of plasma sample for GS-1101 pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
dosing at next full 
clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 9. 
Scheduling of Visit 9 
radiology assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 9; the same 
method of assessment (CT, MRI) should be used as was used at baseline. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-
Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging 


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6.2.9. 
Visit 9 (Day 113) (Clinic and Radiology Visit) 
The procedures outlined in Table 6-9 will be performed at Visit 9 (Day 113 [±3 days]). 
Table 6-9. 
Procedures and Assessments at Visit 9 (Day 113) 
Assessment or 
Procedure 
Explanation 
Pre-Visit Tumor Assessment 
Radiology assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the same 
method of assessment (CT or MRI) should be used as was used at baseline and the assessment 
should be done even if study drug has been interrupted.  
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 8 
Concomitant 
medications 
Recording of concomitant medication used since Visit 8 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD5+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Bone marrow biopsy 
and aspirate 
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR. 
GS-1101 
pharmacokinetics 
Pre-dose collection of plasma sample for GS-1101 pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug blister card number 
Study Therapy Administration 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
GS-1101 
pharmacokinetics 
Post-dose collection of plasma sample for GS-1101 pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
dosing at next full 
clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 10. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment 
of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging 


GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 80 
23 January 2012 
6.2.10. 
Visit 10 (Day 141) (Clinic Visit) 
The procedures outlined in Table 6-10 will be performed at Visit 10 (Day 141 [±3 days])  
Table 6-10. 
Procedures and Assessments at Visit 10 (Day 141) 
Assessment or 
Procedure 
Explanation 
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 9 
Concomitant 
medications 
Recording of concomitant medication used since Visit 9 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
GS-1101 
pharmacokinetics 
Pre-dose collection of plasma sample for GS-1101 pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug  blister card number 
Study Therapy Administration 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
GS-1101 
pharmacokinetics 
Post-dose collection of plasma sample for GS-1101 pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
dosing at next full 
clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 11. 
Scheduling of 
Visit 11 radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 11; the same 
method of assessment (CT, MRI) should be used as was used at baseline. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-
Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging 


GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 81 
23 January 2012 
6.2.11. 
Visit 11 (Day 169) (Clinic and Radiology Visit) 
The procedures outlined in Table 6-11 will be performed at Visit 11 (Day 169 [±3 days]).  
Table 6-11. 
Procedures and Assessments at Visit 11 (Day 169) 
Assessment or 
Procedure 
Explanation 
Pre-Visit Tumor Assessment 
Radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the same 
method of assessment (CT or MRI) should be used as was used at baseline and the assessment 
should be done even if study drug has been interrupted.  
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 10 
Concomitant 
medications 
Recording of concomitant medication used since Visit 10 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Bone marrow biopsy 
and aspirate 
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR. 
GS-1101 
pharmacokinetics 
Pre-dose collection of plasma sample for GS-1101 pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug blister card numbers 
Study Therapy Administration 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
GS-1101 
pharmacokinetics 
Post-dose collection of plasma sample for GS-1101 pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 12-week supply of study drug to the subject with instructions for self-administration 
at home   
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment 
of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging 


GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 82 
23 January 2012 
6.2.12. 
Visit 12 (Day 211) (Clinic Visit) 
The procedures outlined in Table 6-12 will be performed at Visit 12 (Day 211 [±3 days])  
Table 6-12. 
Procedures and Assessments at Visit 12 (Day 211) 
Assessment or 
Procedure 
Explanation 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 11 
Concomitant 
medications 
Recording of concomitant medication used since Visit 11 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
IWRS access 
Access of IWRS to document subject visit 
Study drug 
administration 
Subject to continue with study drug as prescribed. 
Scheduling of 
Visit 13 radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 13; the same 
method of assessment (CT, MRI) should be used as was used at baseline. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-
Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging 


GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 83 
23 January 2012 
6.2.13. 
Visit 13 (Day 253) (Clinic and Radiology Visit) 
The procedures outlined in Table 6-13 will be performed at Visit 13 (Day 253 [±3 days]).  
Table 6-13. 
Procedures and Assessments at Visit 13 (Day 253) 
Assessment or 
Procedure 
Explanation 
Pre-Visit Tumor Assessment 
Radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the same 
method of assessment (CT or MRI) should be used as was used at baseline and the assessment 
should be done even if study drug has been interrupted.  
During-Visit Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 10 
Concomitant 
medications 
Recording of concomitant medication used since Visit 10 
Study drug 
return/accounting 
Counting returned study drug.  
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Bone marrow biopsy 
and aspirate 
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR. 
IWRS access 
Access of IWRS to obtain study drug blister card numbers 
Study drug 
administration 
Subject to continue with study drug as prescribed. 
Study drug 
dispensing 
Dispensing of 12-week supply of study drug to the subject with instructions for self-administration 
at home   
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment 
of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging 


GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 84 
23 January 2012 
6.2.14. 
Visit 14 (Day 295) (Clinic Visit) 
The procedures outlined in Table 6-14 will be performed at Visit 14 (Day 295 [±3 days])  
Table 6-14. 
Procedures and Assessments at Visit 14 (Day 295) 
Assessment or 
Procedure 
Explanation 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is 
communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 10 
Concomitant 
medications 
Recording of concomitant medication used since Visit 10 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical 
examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, 
total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, 
cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
IWRS access 
Access of IWRS to document subject visit 
Study drug 
administration 
Subject to continue with study drug as prescribed. 
Scheduling of 
Visit 15 radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 15; the 
same method of assessment (CT, MRI) should be used as was used at baseline. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-
Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging 


GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 85 
23 January 2012 
6.2.15. 
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks) (Clinic and 
Radiology Visits) 
The procedures outlined in Table 6-15 will be performed at Visit 15 (Day 337 [±3 days]) and 
every 12 weeks thereafter [±7 Days]). 
Table 6-15. 
Procedures and Assessments at Visit 15 and Subsequent Visits 
(Day 337 and Every 12 Weeks) 
Assessment or 
Procedure 
Explanation 
Pre-Visit Tumor Assessment 
Radiology 
assessmenta 
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the same 
method of assessment (CT or MRI) should be used as was used at baseline and the assessment 
should be done even if study drug has been interrupted.  
During-Visit Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since prior visit 
Concomitant 
medications 
Recording of concomitant medication used since prior visit 
Study drug 
return/accounting 
Counting returned study drug.  
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Bone marrow biopsy 
and aspirate 
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR. 
IWRS access 
Access of IWRS to obtain study drug blister card numbers 
Study drug 
administration 
Subject to continue with study drug as prescribed. 
-Study drug 
dispensing 
Dispensing of 12-week supply of study drug to the subject with instructions for self-administration 
at home   
Scheduling of next 
visit radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for next clinic visit (every 
12 weeks); the same method of assessment (CT, MRI) should be used as was used at baseline. 
a 
For follow-up visits after Week 96, CT or MRI is only required at the end-of-treatment visit (see Table 6-16). 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment 
of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging 


GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 86 
23 January 2012 
6.2.16. 
End-of-Treatment Visit (Clinic Visit) 
At the time of discontinuation from the study, the subject should have the procedures and 
assessments performed as documented in Table 6-16. An end-of-study CT/MRI tumor 
assessment should be performed unless the subject already has radiographic confirmation of 
definitive disease progression ≤4 weeks prior to study drug discontinuation.  
Table 6-16. 
Procedures and Assessments at End-of-Treatment Visit 
Assessment or 
Procedure 
Explanation 
Radiology 
assessmenta 
CT or MRI imaging of neck, chest, abdomen, and pelvis; the same method of assessment (CT or 
MRI) should be used as was used at baseline 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed  
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed 
Adverse events  
Recording of adverse events occurring since prior visit; if a clinically significant adverse event or 
abnormal result is observed that is not resolved by the end-of treatment visit, repeat evaluations 
should be performed to document resolution or stabilization of the abnormality 
Concomitant 
medications 
Recording of concomitant medication used since prior visit 
Study drug 
return/accounting 
Counting returned study drug.  
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical 
examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Serum β-HCG 
Women of childbearing potential only 
CLL peripheral 
blood evaluation 
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 12 trisomy; DNA 
mutational analysis for p53, IgHV (including IgHV3-21), and other genes of interest in CLL (eg, 
Notch); flow cytometry for CD5, CD10, CD11c, CD19, CD20, CD23, CD38, CD45, kappa and 
lambda light chains, and ZAP-70; cytology for karyotyping; bone marrow aspirate may be used if 
peripheral blood lymphocyte count is too low 
CLL serology 
Serum β2 microglobulin 
 
 
 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total protein, 
albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
IWRS 
Access IWRS to document that subject has permanently discontinued study therapy and to indicate 
whether subject agrees to continue to undergo long-term follow-up 
a 
An end-of-treatment CT/MRI tumor assessment should be performed unless the subject already has radiographic 
confirmation of definitive disease progression ≤4 weeks prior to study drug discontinuation. 
Abbreviations: β-HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, CLL=chronic lymphocytic leukemia, CT=computed tomography, FISH= fluorescence in-
situ hybridization, GGT=gamma-glutamyltransferase, IgHV=immunoglobulin heavy-chain variable-region, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, 
RNA=ribonucleic acid, ZAP-70=zeta-associated protein 70 
PPD


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Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 87 
23 January 2012 
6.2.17. 
Immediate Post-Treatment Safety Follow-up 
After the last dose of study treatment subjects should be followed for any drug-related 
adverse events and/or ongoing serious adverse events until those events have resolved or 
become stable, whichever occurs later. Follow-up may be obtained in person or by telephone 
contact. 
6.2.18. 
Long-Term Follow-Up 
Long-term, post-treatment follow-up will be requested of all subjects who withdraw from 
study therapy for any reason. 
The long-term post-treatment follow-up will be conducted (as measured from the last dose of 
study drug) at ~6-month intervals during Year 1 and Year 2, and at ~12-month intervals 
during Years 3, 4, and 5. Data on post-study therapies for CLL, on the occurrence of new 
non-CLL-related health problems (eg, myelodysplasia, Richter’s transformation, chronic 
hepatic abnormalities, etc), and on survival will be collected from all subjects who receive 
≥1 dose of study drug. 
Long-term follow-up information will be gathered during a routine clinic visit or other 
contact with the subject, or via telephone. These data will be collected in the source 
documents (eg, subject medical record) and transcribed into a specific electronic eCRF. Any 
unsuccessful efforts to contact the subject (eg, dates of unanswered phone calls, return of 
certified letter sent to subject’s home, etc) will be documented. 
6.3. 
Blood Collection 
Computations of blood drawing requirements for this study are shown in Table 6-17. The 
maximum amount of blood to be drawn at a visit is 105 mL and the total amount of blood to 
be drawn over the initial 52-week study period (including the 4-week screening period and 
through Week 48 of the study including a possible end-of-therapy visit) is ~551 mL. For a 
40-kg person (the smallest participant expected to enroll in the study), this equates to 
maximum blood volume per body weight per visit of ~2.8 mL/kg and a total blood volume 
per body weight per average 6-week period of ~1.6 mL/kg. These quantities of blood are 
within accepted limits of 3.0 mL/kg of body weight for a single blood draw and 7.0 mL/kg of 
body weight for a 6-week period [National Institutes of Health 2003]. 


PPD
GS-1101 
Protocol GS-US-312-0117 
Gilead Sciences, Inc. 
Table 6-17. 
Blood Drawin2 Requirements Throu2h Visit 15 (Week 48) 
Final 
Original 
Sample 
Tube 
Blood Pel' 
Tubes (n) 
Blood Volume (mL) 
Test 
Tube 
Maximum 
Total in 
Maximum 
Type 
Type 
(mL) 
Pel' Visit 
Study• 
Pet· Visit 
CLL peripheral blood 
Plasma 
Sodimn 
50 
I 
2 
50 
evaluation 
heparin 
Genotyping 
DNA 
Cells 
K2-EDTA 
12 
1 
2 
12 
and 
RNA 
Pax gene 
expression 
Protein 
Cells 
KrEDTA 
8 
1 
2 
8 
analysis 
Coagulation 
Plasma 
Citrate 
4 
1 
1 
4 
Hematology 
Plasma. 
K2-EDTA 
3 
1 
16 
3 
Serum chemistly 
(including 13-HCG and 
Semm 
Clot 
5 
1 
16 
5 
CLL serology) 
Circulating cells for 
PI3K/ AKT /mTOR 
pathway activation 
Cells 
KrEDTA 
4 
1 
13 
4 
and 
immunophenotyping 
Biomarkers 
Plasma 
KrEDTA 
5 
1 
13 
5 
Sermn 
Clot 
5 
1 
13 
5 
Senun Igs 
Sermn 
Clot 
5 
1 
13 
5 
GS-1101 
Plasma 
KrEDTA 
2 
2 
8 
4 
pharmacokinetics 
Total 
105 
0 
0 
0 
a 
Computed for uuttal 52-week penod (constdermg 4 weeks for screenmg and 48 weeks on study) 
Abbreviations: 
human chorionic gonadotropin, AKT =AKT (a serine/threonine protein kinase), 
CLL=chronic lymphocytic leukemia, DNA =deoxyribonucleic acid, Ig=inununoglobulin, KrEDTA=potassituu-
ethylenediaminetetraacetic acid, mTOR=manunalian target of rapamycin, PI3K=phosphatidylinositol3-kinase, 
RNA=ribonucleic acid 
Total in 
Study• 
100 
24 
16 
4 
48 
80 
52 
65 
65 
65 
32 
551 
Specific details regarding blood sample collection and processing requirements will be 
provided separately in the study manual. 
6.4. 
Study Procedure Rationale 
The planned study assessments and timing have been selected as appropriate for screening of 
subjects, for detennination of GS-1 1 0 1-related or disease-related toxicities, for dose 
modification during the study, for characterization of dmg exposure and desired 
phmmacological effects, and for evaluation of dm g activity. The scheduling of testing is 
designed to collect a complete safety and phatmacology data set while maintaining subject 
tolerance of study procedures. The planned schedule of tumor assessments is consistent with 
expected rate of changes and appropriately balances precise measurement of tumor control 
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with the expense and subject inconvenience associated with clinical and radiological 
procedures. For discussion of the rationale for endpoint selection, see Section 3.2. 


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7. 
EFFICACY ASSESSMENTS 
7.1. 
Tumor Status Assessments 
The determination of CLL response and progression will be based on standardized IWCLL 
criteria [Hallek 2008], as specifically modified for this study considering the pharmacology 
of GS-1101 and the methods to be used in evaluation. Treatment decisions by the 
investigator in this study will be based on these assessments. Radiographic and clinical tumor 
assessments will be subject to independent confirmation by the IRC (see Section 10.4.3).  
7.2. 
Method of Assessment 
In addition to clinical examination, imaging-based evaluation will be used in this study in all 
subjects enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI 
scanning may be used at the investigator’s discretion in subjects for whom this may be a 
preferred alternative to CT scanning. Contrast-enhanced scanning is preferred, but iodine-
containing or gadolinium contrast material may be omitted in subjects for whom use of a 
contrast agent would be medically contraindicated. Chest x-ray, ultrasound, endoscopy, 
laparoscopy, PET, radionuclide scans, or tumor markers will not be considered for response 
assessment. 
For radiographic evaluations, the same method of assessment and the same technique (eg, 
scan type, scanner, subject position, dose of contrast, injection/scan interval) should be used 
to characterize each identified and reported lesion at baseline and during study treatment and 
follow-up. CT or MRI of the neck, chest, abdomen, and pelvis should be performed with cuts 
of ≤1.0 cm (ideally ≤0.5 cm) in slice thickness contiguously. 
7.3. 
Timing of Assessments 
All baseline clinical and CT/MRI tumor assessments should be performed within 4 weeks 
prior to the start of treatment. In order to optimize scheduling convenience for the subject and 
for the investigational staff, clinical and CT/MRI tumor assessments performed as part of 
Study GS-US-312-0116 need not be repeated and can be used as baseline tumor assessments 
for Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug 
therapy on Study GS-US-312-0117. Clinical tumor assessments should be performed at each 
clinical visit. On-study CT/MRI tumor assessments should be performed at ~8- to 12-week 
intervals as dictated by the study protocol. For follow-up visits after Week 96, CT or MRI is 
only required at the end-of-treatment visit. An end-of-treatment CT/MRI tumor assessment 
should be performed unless the subject already has radiographic confirmation of disease 
progression ≤4 weeks prior to study drug discontinuation.  
7.4. 
Identification and Measurement of Tumor Lesions and 
Organomegaly 
7.4.1. 
Index Lesions 
At baseline, up to 6 lymph nodes should be selected as index lesions that will be used to 
quantitate the status of the disease during study treatment. Ideally, the index lesions should 
be located in disparate regions of the body. Only peripheral nodes need be selected as index 


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lesions. However, it is optimal if mediastinal and retroperitoneal areas of disease are assessed 
whenever these sites are involved. 
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable 
at baseline. A nodal lesion is considered abnormal and measurable if it has 2 perpendicular 
diameters that can be accurately measured in cross section and each of the perpendicular 
diameters measures ≥1.0 cm. Abnormal, measurable nodal lesions will be subcategorized as 
either large or small. Large nodal lesions have a longest diameter (LD) that is >1.5 cm and a 
longest perpendicular diameter (LPD) that is ≥1.0 cm. Small nodal lesions have an LD that is 
>1.0 cm and ≤1.5 cm and an LDP that is >1.0 cm. Index lesions measuring >1.5 cm in the 
LD, regardless of the measurement of the LPD, will be prioritized during baseline index 
lesion selection. 
Index lesions will be measured and recorded at baseline and at the stipulated intervals during 
treatment. The cross-sectional dimensions (the largest cross-sectional diameter, ie, the LD × 
LPD) will be recorded (in cm) for each index lesion. The product of the perpendicular 
diameters (PPD) (in cm2) will be calculated. The PPDs and the sum of the products (SPDs) 
(in cm2) for all index lesions will be calculated and recorded. The baseline and nadir PPDs 
for individual lesions and the baseline and nadir SPDs will be used as references by which 
tumor response and progression will be characterized during treatment.  
At follow-up time points, the PPDs for individual lesions and the SPD of all nodal index 
lesions will be considered. Because nodal index lesions that have one or both diameters 
>0 cm and <1.0 cm cannot be reliably measured, a default value of 1.0 cm will be assigned 
for each diameter that meets these criteria and the resulting PPD will be used in SPD 
calculations. Based on this convention, a CR may be achieved even if an SPD value is 
>0 cm2. 
New or enlarging nodal lesions that are still ≤1.0 cm by ≤1.0 cm will not be considered to 
represent recurrent or progressive disease. A new node that measures >1.5 cm in any 
diameter or a new node that measures >1.0 cm to ≤1.5 cm in the LD and measures >1.0 cm in 
the LPD will be considered progressive disease. 
In cases in which a large lymph node mass has split into multiple components, only those 
elements that are >1.0 cm in at least 1 diameter will be considered abnormal and used in 
calculating the SPD. Progression of the lesion can only be based on the SPD of abnormal 
sub-components. Lesion sub-components that are considered normal but measurable will 
have the true PPDs calculated, with the result used only for calculating an accurate nadir. 
Similarly, lesion sub-components that are visible but neither abnormal nor measurable will 
have the default PPD of 1.0 cm2 (1.0 cm × 1.0 cm), stored only for the purposes of 
calculating the nadir SPD value. 
7.4.2. 
Spleen and Liver 
Both the spleen and liver will be assessed by CT/MRI scan and by physical examination.  
By imaging, the spleen will be considered enlarged if it is >10 cm in LVD [Bezerra 2005], 
with the LVD being obtained by multiplying the number of sections on which the spleen is 
visualized by the thickness of the sections (eg, if the spleen is seen in 14 contiguous cross-
sectional images with 0.5-cm thickness, the LVD is recorded as 7 cm).  


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Physical examination of the spleen should comprise assessment of its vertical dimension 
below the left costal margin by palpation. By physical examination, the spleen will be 
considered enlarged if it is palpable below the left costal margin. If the spleen is not palpable 
below the left costal margin, it should be assigned a value of 0 cm for physical examination 
assessment.  
By imaging, the liver will be considered enlarged if it is >18 cm in LVD [Erturk 2006], with 
the LVD being obtained by multiplying the number of sections on which the liver is 
visualized by the thickness of the sections (eg, if the liver is seen in 34 contiguous cross-
sectional images with 0.5-cm thickness, the LVD is recorded as 17 cm).  
Physical examination of the liver should comprise assessment of its LVD at the right 
midclavicular line by percussion. The liver will be considered enlarged if it is >15 cm in 
LVD as assessed by percussion [Walker 1990]. 
The spleen and liver should be measured clinically and radiographically at baseline and at the 
stipulated intervals during treatment. The baseline and nadir values will be used as references 
by which tumor response and progression will be characterized during treatment. For 
subjects with splenomegaly at baseline or at the splenic LVD nadir, respective response and 
progression evaluations of the spleen will consider only changes relative to the enlargement 
of the spleen at baseline or nadir, not changes relative to the total splenic LVD. For subjects 
with hepatomegaly at baseline or at the liver LVD nadir, respective response and progression 
evaluations of the liver will consider only changes relative to the enlargement of the liver at 
baseline or nadir, not changes relative to the total hepatic LVD. 
7.4.3. 
Non-Index Lesions 
Any other measurable and abnormal nodal lesions not selected for quantitation as index 
lesions may be considered non-index lesions. In addition, non-measurable evidence of CLL 
such as nodal lesions with both diameters <1.0 cm, extra-nodal lesions, bone lesions, 
leptomeningeal disease, ascites, pleural or pericardial effusions, lymphangitis of the skin or 
lung, abdominal masses that are not confirmed and followed by imaging techniques, cystic 
lesions, previously irradiated lesions, lesions with artifacts, and disease documented by 
indirect evidence only (eg, by laboratory tests such as LDH) may be considered as non-index 
disease. 
The presence or absence of non-index disease should be recorded at baseline and at the 
stipulated intervals during treatment. If present at baseline, up to 6 non-index lesions should 
be recorded. The non-index disease at baseline will be used as a general reference to further 
characterize regression or progression of CLL during assessments of the objective tumor 
response during treatment. Measurements are not required and these lesions should be 
followed as “present” or “absent”. 
7.5. 
Definitions of Tumor Response and Progression  
Responses will be categorized as CR, PR, stable disease (SD), progressive disease (PD). In 
addition, a response category of not evaluable (NE) is provided for situations in which there 
is inadequate information to otherwise categorize response status. While enrollment is 
limited to subjects who have measurable disease, a response category of no disease (ND) is 


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included solely to account for the unexpected situation in which a subject is found to have no 
evidence of tumor either at baseline or on treatment. 
The date of response, date of progression, and best overall response will be determined. The 
best nodal, splenic, hepatic, and peripheral blood counts response will be characterized. The 
best overall response is the best response recorded from the start of treatment until disease 
progression (taking as a reference for disease progression the smallest measurements 
recorded at baseline or post-baseline). All relevant clinical and radiographic information 
required to make each tumor status assessment must be made available for source 
verification and for submission to the IRC (see Section 10.4.3). Where imaging data are 
available, these data will supersede physical examination data in determining tumor status. 
7.5.1. 
Complete Response 
To satisfy criteria for a CR, all of the following criteria must be met and must persist for 
≥8 weeks (minimum of 49 days to allow for CT/MRI scheduling): 
• No evidence of new disease 
• ALC in peripheral blood of <4 x 109/L 
• Regression of all index nodal masses to normal size (ie, ≤1.5 cm in the LD for nodes that 
were considered large at baseline and ≤1.0 cm in the LPD for nodes that were considered 
small at baseline) (see Section 7.4.1 for definitions of large and small nodes)   
• Normal spleen and liver size 
• Regression to normal of all nodal non-index disease and disappearance of all detectable 
non-nodal, non-index disease 
• Morphologically negative bone marrow defined as <30% of nucleated cells being 
lymphoid cells and no lymphoid nodules in a bone marrow sample that is normocellular 
for age 
• No known disease-related constitutional symptoms 
• Peripheral blood counts meeting all of the following criteria: 
o ANC ≥1.5 x 109/L without need for exogenous growth factors (eg, G-CSF) 
o Platelet count ≥100 x 109/L without need for exogenous growth factors 
o Hemoglobin ≥110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (eg, erythropoietin) 
Note: Subjects who fulfill all the criteria for a CR (including bone marrow criteria) but 
who have a persistent anemia, thrombocytopenia, or neutropenia or a hypocellular bone 
marrow that is related to prior or ongoing drug toxicity (and not to CLL) will be 
considered as a CR with incomplete marrow recovery (CRi).  
7.5.2. 
Partial Response 
To satisfy criteria for a PR, all of the following criteria must be met and must persist for 
≥8 weeks (minimum of 49 days to allow for CT/MRI scheduling): 


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• No evidence of new disease 
• A change in disease status meeting ≥2 of the following criteria:  
o Decrease in peripheral blood ALC by ≥50% from baseline 
o A decrease by ≥50% from the baseline in the SPD of the index nodal lesions 
o In a subject with enlargement of the spleen at baseline: normal spleen size or a 
decrease by ≥50% from baseline (minimum 2-cm decrease or reduction in LVD to 
normal) in the pretreatment enlargement of the splenic LVD 
o In a subject with enlargement of the liver at baseline: normal liver size or a decrease 
by ≥50% from baseline (minimum 2-cm decrease or reduction in LVD to normal) in 
the pretreatment enlargement of the liver LVD 
o A decrease by ≥50% from baseline in the CLL marrow infiltrate or in B-lymphoid 
nodules 
• No index, splenic, liver, or non-index disease with worsening that meets the criteria for 
definitive PD 
• Peripheral blood counts meeting ≥1 of the following criteria: 
o ANC ≥1.5 x 109/L or ≥50% increase over baseline without need for exogenous 
growth factors (eg, G-CSF) 
o Platelet count ≥100 x 109/L or ≥50% increase over baseline without need for 
exogenous growth factors 
o Hemoglobin ≥110 g/L (11.0 g/dL) or ≥50% increase over baseline without red blood 
cell transfusions or need for exogenous growth factors (eg, erythropoietin) 
7.5.3. 
Stable Disease 
To satisfy criteria for stable disease (SD), the following criteria must be met: 
• No evidence of new disease 
• There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD 
7.5.4. 
Definitive Progressive Disease 
The occurrence of any of the following events indicates definitive PD:  
• Evidence of any new disease: 
o A new node that measures >1.5 cm in any diameter 
o A new node that measures >1.0 cm to ≤1.5 cm in the LD and >1.0 cm in the LPD 
o New splenomegaly or recurrent splenomegaly (in a subject for whom spleen size had 
normalized) with a splenic LVD that now measures >2 cm larger than the cut-off 
value for the normal splenic LVD 


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o New hepatomegaly or recurrent hepatomegaly (in a subject for whom liver size had 
normalized) with an hepatic LVD that now measures >2 cm larger than the cut-off 
value for the normal hepatic LVD 
o New non-index disease (eg, effusions, ascites, or other organ abnormalities related to 
CLL) 
Note: Isolated new effusions, ascites, or other organ abnormalities are not 
sufficient evidence alone of PD unless histologically confirmed. Thus, a declaration 
of PD should not be made if this is the only manifestation of apparently new 
disease. 
• Evidence of worsening of lymph nodes, spleen or liver, or non-index disease:  
o Increase by ≥50% from the nadir in the SPD of index lesions 
o Evidence of worsening of individual index lymph nodes or nodal masses:  
 Increase from the nadir by ≥50% in the PPD for any individual node if the node 
now has a LD of >1.5 cm and there is an absolute change from the nadir of 
≥0.5 cm in the LD or LPD and to ≥2.0 cm. 
 Increase from the nadir by ≥50% in the LD for any individual node if the node 
now has a LD of >1.5 cm and there is an absolute change from the nadir of 
≥0.5 cm in the LD 
 Increase from the nadir by ≥50% in the LPD for any individual node if the node 
now has a LPD of >1.5 cm and there is an absolute change from the nadir of 
≥0.5 cm in the LPD  
 If a lesion had been classified as a small lymph node, there is an additional 
requirement that the lesion has an LD of >1.0 cm and an LPD of >1.0 cm 
o In a subject with enlargement of the spleen at splenic nadir, there is an increase by 
≥50% from the nadir value (minimum 2-cm increase) in the nadir enlargement of the 
LVD and the splenic LVD now measures >2 cm larger than the cut-off value for the 
normal splenic LVD 
o In a subject with enlargement of the liver at hepatic nadir, there is an increase by 
≥50% from the nadir value (minimum 2-cm increase) in the nadir enlargement of the 
LVD with an hepatic LVD that now measures >2 cm larger than the cut-off value for 
the normal hepatic LVD 
o Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or other 
organ abnormalities related to CLL)  
o Transformation to a more aggressive histology (eg, Richter syndrome) as established 
by lymph node biopsy 
• Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to 
an autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an 
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o The current platelet count is <100 x 109/L and there has been a decrease by >50% 
from the highest on-study platelet count  
o The current hemoglobin is <110 g/L (11.0 g/dL) and there has been a decrease by 
>20 g/L (2 g/dL) from the highest on-study hemoglobin  
7.5.5. 
Non-Evaluable 
Subjects have a status of NE if any of the following conditions occur:  
• No data or the data are inadequate or missing such that a response determination cannot 
be made 
7.5.6. 
No Disease 
Subjects have a status of ND if all of the following conditions occur:  
• No index disease noted at baseline or on-treatment  
• No non-index disease noted at baseline or on-treatment. 
• No enlargement of the liver or spleen at baseline or on-treatment 
• No abnormalities of peripheral blood counts (elevated ALC or abnormally low ANC, 
platelet count, or hemoglobin) and no evidence of CLL in bone marrow (if available) at 
baseline or on treatment 
7.5.7. 
Lymphocytosis During Therapy 
GS-1101 can mobilize CLL cells from tissues into the peripheral blood. This characteristic 
pharmacological action can be prominent early in therapy but can persist over time and 
should not be confused with disease progression in subjects who have persistent control of 
other CLL-related signs and symptoms. In the absence of other objective evidence of 
disease progression, lymphocytosis alone will not be considered evidence of disease 
progression. Subjects with lymphocytosis should be continued on study therapy until the 
occurrence of definitive disease progression (ie, disease progression that is manifest by 
worsening CLL-related signs other than lymphocytosis alone), or the occurrence of another 
reason to discontinue study therapy as described in Section 5.8. In particular, worsening of 
constitutional symptoms in the absence of objective evidence of worsening CLL will not be 
considered definitive disease progression. In such subjects, both CLL-related and 
non-CLL-related causes for the constitutional symptoms should be considered. If disease 
progression is suspected, CT/MRI and peripheral blood counts should be obtained and bone 
marrow biopsy should be considered in order to provide objective evidence of CLL status. 
7.5.8. 
Documentation of Definitive CLL Progression 
Of importance, tumor size data collected from the primary study will be subjected to IRC 
review (see Section 10.4.3). Subjects must have confirmation by the sponsor working in 
collaboration with the IRC that the disease has progressed on the primary clinical trial 
(Study GS-US-312-0116) before being permitted to receive secondary GS-1101 therapy on 
this extension trial ( GS-US-312-0117). If there is uncertainty regarding whether there is 
definitive progression, the subject should continue study treatment and remain under close 
observation (eg, evaluated at 4-week intervals) pending confirmation of progression status. 
CT/MRI should be attempted in order to document definitive disease progression. If obtained 


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within the specified screening period for the extension study, this scan can serve as the 
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8. 
SAFETY ASSESSMENTS 
8.1. 
Adverse Event Definitions 
8.1.1. 
Adverse Event 
An adverse event (adverse event) is any untoward medical occurrence in a clinical 
investigation subject administered a medicinal product; the event does not necessarily have a 
causal relationship with study drug administration or usage. An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. 
In this study, any of the following events will be considered an adverse event: 
• Any complication that occurs as a result of a protocol-mandated procedure (eg, 
venipuncture, biopsy) in the screening, on-treatment, or post-treatment periods. 
• Any pre-existing condition that increases in severity or changes in nature during or as a 
consequence of study drug administration. Worsening manifestations of the underlying 
cancer (eg, increase in pain, tumor flare reaction, tumor lysis syndrome) may be 
considered adverse events in this study. 
• Any injury or accident occurring during the screening, on-treatment, or post-treatment 
periods. If a medical condition is known to have caused the injury or accident (eg, a fall 
secondary to dizziness), the medical condition (dizziness) and the accident (fall) should 
be reported as 2 separate adverse events.  
• Any abnormality in physiological testing or a physical examination finding that requires 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test). 
• Any laboratory (eg, clinical chemistry, hematology, urinalysis) or investigational  
abnormality (eg, ECG, X-ray) independent of the underlying medical condition that 
requires clinical intervention, results in further investigation (beyond ordering a repeat 
[confirmatory] test), or leads to investigational medicinal product interruption or 
discontinuation unless it is associated with an already reported clinical event. If the 
laboratory abnormality is part of a syndrome, the syndrome or diagnosis (eg, anemia) not 
the laboratory result (eg, decreased hemoglobin) should be recorded.  
• A complication related to pregnancy or termination of a pregnancy (see Section 8.9 for 
additional information). 
None of the following events is considered an adverse event: 
• Lymphocytosis 
• Laboratory abnormalities not requiring clinical intervention or further investigation. Such 
abnormalities will be captured as part of overall laboratory monitoring. 
• A diagnostic, medical or surgical procedure (eg, surgery, endoscopy, tooth extraction, 
transfusion). However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an adverse event. For example, an acute 


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appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event and the resulting appendectomy should be recorded in the source 
documents.  
• A pre-existing disease or condition or laboratory abnormality present or detected before 
the initial screening visit and that does not worsen. 
• An intervention not associated with an untoward medical occurrence (eg, hospitalization 
for elective surgery or for social and/or convenience reasons). 
8.1.2. 
Serious Adverse Event 
A serious adverse event is defined is an untoward medical occurrence that results in any of 
the following outcomes: 
• Death (ie, all deaths occurring between signing of the consent form to within 30 days 
after last study drug administration), including deaths due to disease progression. Deaths 
that occur as a result of an adverse event that started during the study period should be 
reported. The reported adverse event should be the event that caused the death. Death is 
the outcome of this serious adverse event. 
• Life-threatening situation (ie, with an immediate risk of death from the event as it 
occurred but not including an event that, had it occurred in a more serious form, might 
have caused death). 
• In-patient hospitalization or prolongation of existing hospitalization. Of note, an 
untoward medical occurrence that occurs during hospitalization is an adverse event but a 
complication that prolongs hospitalization is a serious adverse event. In-patient 
hospitalization comprises formal admission to a hospital for medical reasons, for any 
length of time, whether or not hospitalization extends overnight. However, hospital 
admissions for administration of the study drug, procedures required by the study 
protocol, or tumor-related diagnostic procedures are not considered serious.  
• Persistent or significant disability/incapacity. 
• Congenital anomaly/birth defect in the offspring of a subject who received the 
investigational medicinal product. 
• Other medically significant event. Such events may not be immediately life-threatening 
or result in death or hospitalization, but based upon appropriate medical and scientific 
judgment, may jeopardize the subject or may require medical or surgical intervention to 
prevent one of the outcomes listed above. Examples of such events might include: 
o Allergic bronchospasm requiring intensive treatment in an emergency room or at 
home 
o New cancers or blood dyscrasias 
o Convulsions that do not result in hospitalization 
o Development of drug dependency or drug abuse 


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8.1.3. 
Unexpected Adverse Event 
An unexpected adverse event is defined as an event that has a nature or severity, or 
specificity that is not consistent with the applicable investigator brochure or that is 
symptomatically and pathophysiologically related to a known toxicity but differs because of 
greater severity or specificity. For example, under this definition, hepatic necrosis would be 
unexpected (by virtue of greater severity) if the investigator brochure only referred to 
elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure 
only listed cerebral vascular accidents. “Unexpected,” as used in this definition, refers to an 
adverse drug experience that has not been previously observed and reported rather than an 
experience that has not been anticipated based on the pharmacological properties of the study 
drug.  
8.2. 
Eliciting Adverse Event Information 
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study subject. In addition, each study subject will be 
questioned about adverse events at each scheduled clinic visit or during each telephone 
contact with the subject following initiation of study treatment. The type of question asked 
should be open-ended, eg, "Have you had any new health problems?” or a similar type of 
query.  
8.3. 
Recording Adverse Events 
All adverse events will be assessed by the investigator or qualified designee and recorded in 
the eCRFs. The investigator should attempt to establish a diagnosis of the event on the basis 
of signs, symptoms and/or other clinical information. In such cases, the diagnosis should be 
documented as the adverse event and/or serious adverse event and not described as the 
individual signs or symptoms. The following information should be recorded: 
• Description of the adverse event using concise medical terminology 
• Description as to whether or not the adverse event is serious (see Section 8.1.2) 
• The start date (date of adverse event onset) 
• The stop date (date of adverse event resolution) 
• The severity of the adverse event (see Section 8.4) 
• A description of the potential relatedness of the adverse event to study drug or a study 
procedure (see Section 8.5)  
• The action taken due to the adverse event 
• The outcome of the adverse event 
8.4. 
Grading of the Severity of an Adverse Event 
The severity of adverse events will be graded using the CTCAE, Version 4.03 (provided in 
study manual and available at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-


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14_QuickReference_8.5x11.pdf). For each episode, the highest severity grade attained should 
be reported.  
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 
(fatal) to describe the maximum intensity of the adverse event. For purposes of consistency 
with the CTCAE, these intensity grades are defined in Table 8-1. 
Table 8-1. 
Grading of Adverse Event Severity 
Grade 
Adjective 
Description 
Grade 1 
Mild 
Sign or symptom is present, but it is easily tolerated, is not expected to have a 
clinically significant effect on the subject’s overall health and well-being, does not 
interfere with the subject’s usual function, and is not likely to require medical 
attention. 
Grade 2 
Moderate 
Sign or symptom causes interference with usual activity or affect clinical status, 
and may require medical intervention. 
Grade 3 
Severe 
Sign or symptom is incapacitating or significantly affects clinical status and likely 
requires medical intervention and/or close follow-up. 
Grade 4 
Life-threatening Sign or symptom results in a potential threat to life. 
Grade 5 
Fatal 
Sign or symptom results in death. 
 
The distinction between the seriousness and the severity of an adverse event should be noted. 
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. 
For example, a headache may be severe in intensity, but would not be classified as serious 
unless it met one of the criteria for serious events listed in Section 8.1.2 above. 
8.5. 
Describing Adverse Event Relationship to Study Drug and Study 
Procedures 
The relationship of an adverse event to study drug should be assessed using clinical 
judgment, describing the event as either unrelated (no) or related (yes) consistent with the 
following definitions: 
• No: Evidence exists that the adverse event had an etiology other than the study drug. For 
serious adverse events, an alternative causality must be provided (eg, pre-existing 
condition, underlying disease, intercurrent illness, or concomitant medication). 
• Yes:  A temporal relationship exists between the adverse event onset and administration 
of the investigational medicinal product that cannot be readily explained by the subject’s 
clinical state or concomitant therapies. Furthermore, the adverse event appears with some 
degree of certainty to be related to the study drug based on the known therapeutic and 
pharmacologic actions or adverse event profile of the investigational medicinal product. 
In case of cessation or reduction of the dose, the adverse event abates or resolves. In case 
of interruption and rechallenge, the event reappears upon rechallenge. 
Of note, even in circumstances when the study drug is given intermittently or is interrupted 
temporarily before the onset of the adverse event, consideration should be given as to 
whether the study drug may have contributed to the event.  


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As noted in Section 5.5, unblinding should be avoided unless absolutely necessary for a 
subject’s well-being; breaking the blind should not be performed merely to obtain enhanced 
certainty regarding the relationship of an adverse event to study drug.  
The relationship to protocol-mandated study procedures (eg, procedures such as venipuncture 
or biopsy) should be assessed using the following considerations: 
• No: Evidence exists that the adverse event has an etiology other than the study procedure. 
• Yes: The adverse event occurred as a result of a protocol-mandated procedure.  
8.6. 
Adverse Event Reporting Period 
The start of the adverse event reporting for a study subject will coincide with signing of the 
informed consent for Study GS-US-312-0117. Any new adverse events occurring thereafter 
should not be reported within Study GS-US-312-0116, but instead should be reported within 
Study GS-US-312-0117. The end of the adverse-event-reporting period for Study GS-US-
312-0117 occurs 30 days after the completion of study treatment or when any ongoing drug-
related adverse events and/or serious adverse events have resolved or become stable. A 
subject withdrawn from the study because of an adverse event must be followed until the 
clinical outcome from the adverse event is determined. The investigator should use 
appropriate judgment in ordering additional tests as necessary to monitor the resolution of 
events ongoing at the completion of study treatment. Gilead Sciences may request that 
certain adverse events be followed longer. A longer reporting period applies in the case of 
pregnancy (see Section 8.9).  
8.7. 
Adverse Event Reporting Requirements 
8.7.1. 
Site Reporting Requirements 
Classification of an event as serious or nonserious (see Section 8.1.2) determines the 
reporting procedures to be followed by the site.  
Site reporting requirements for adverse events are summarized in Table 8-2, below. 


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Table 8-2. 
Site Reporting Requirements for Adverse Events 
Classification 
Reporting Time 
Reporting Action 
Within 24 hours 
Fax report on designated serious adverse event report form to 
PPD Pharmacovigilancea, and to the site IRB/IEC, as per 
local IRB/IEC requirements; include copies of relevant 
source documentsb (eg, progress notes, autopsy reports, 
laboratory and diagnostic test results, discharge summaries) 
in communication to PPD Pharmacovigilancea 
Serious 
Per eCRF submission 
procedurec 
Record and submit information on appropriate eCRFs 
Nonserious 
Per eCRF submission 
procedure 
Record and submit information on appropriate eCRFs 
a 
See contact information in Table 8-3 below. 
b 
Subject name, address, and other personal identifiers should be obscured but without losing the traceability of a 
document to the study subject identifiers. 
c 
CLL progression or death due to CLL progression should be reported by the investigator as a serious adverse event 
only if it is assessed that the study drugs caused or contributed to the CLL progression (ie, by a means other than lack 
of effect). Unrelated events of CLL progression should be captured on the appropriate eCRF.  
Abbreviations: CLL = chronic lymphocytic leukemia, eCRF=case report form, IRB/IEC= Institutional Review 
Board/Independent Ethics Committee 
For serious adverse events, in addition to completing the adverse event portion of the eCRF, 
the serious adverse event report form must also be completed. The information in the adverse 
event portion of the eCRF page and the serious adverse event report form(s) must match or 
be reconciled. Where the same data are collected, the forms must be completed in a 
consistent manner. For example, the same adverse event term should be used on both forms. 
Particularly for fatal or life-threatening events, copies of progress notes, autopsy reports, 
laboratory and diagnostic test results, discharge summaries, and other relevant documents 
should be faxed when requested and applicable. Follow-up information to the serious adverse 
event should be clearly documented as “follow up” in the serious adverse event report form 
and must be faxed to these same parties. Gilead Sciences may request additional information 
from the investigator to ensure the timely completion of accurate safety reports. 
The subject’s name, address, and other personal identity information should be obscured on 
any source documents (eg, progress notes, nurses’ notes, laboratory and diagnostic test 
results, discharge summaries). Only the subject’s study number, initials, or date of birth are 
to be provided. 
The serious adverse event report form must be communicated to PPD Pharmacovigilance and 
to the site IRB/IEC (if required by local regulations) within 24 hours. In the rare event that 
the investigator does not become aware of the occurrence of a serious adverse event 
immediately (for example, if a subject initially seeks treatment elsewhere), the investigator is 
to report the event within 24 hours after learning of it and to document his/her first awareness 
of the adverse event. 
Contact details for PPD Pharmacovigilance and for the Gilead study medical monitor are 
provided in Table 8-3: 


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Table 8-3. 
Contact Information for Reporting Serious Adverse Events 
Function 
Contact Information 
PPD Pharmacovigilance 
(US) 
Facsimile: 
  
PPD Pharmacovigilance 
(International) 
Facsimile: 
 
 
Name: 
 
 
Title: 
Associate Director, Clinical Research 
Office Telephone: 
 
Mobile Telephone: 
 
Facsimile: 
 
Gilead Sciences Medical 
Monitor 
E-mail: 
 
 
8.7.2. 
Gilead Sciences Reporting Requirements 
Gilead Sciences is required to expedite reports to regulatory authorities worldwide relating to 
serious adverse events including events related to study procedures; serious adverse drug 
reactions (SADRs); or suspected, unexpected, serious adverse reactions (SUSARs) consistent 
with relevant legislation or regulations, including the applicable US FDA Code of Federal 
Regulations (CFR), the European Commission Clinical Trials Directive (2001/20/EC, and 
revisions), and other country-specific legislation or regulations.  
Each serious adverse event report received from the investigator through PPD 
Pharmacovigilance will be evaluated by Gilead Sciences Drug Safety and Public Health 
(DSPH). Gilead Sciences DSPH will assess the seriousness of the event (see Section 8.1.2), 
the expectedness of the event (see Section 8.1.3), and the relationship to participation in the 
study (see Section 8.5). For regulatory reporting purposes, expectedness will be determined 
by Gilead Sciences using reference safety information specified in the investigator brochure 
and the event will be classified as related if either the investigator or Gilead Sciences 
determines that the event may be related to the study drug (see Section 8.5). 
Gilead Sciences or its designee will also provide all investigators and the DMC with a safety 
letter e-mail, fax, or overnight mail notifying them of a SUSAR. Investigators will be 
requested to provide written notification of the SUSAR to the IRB/IEC as soon as is 
practical, consistent with local regulatory requirements and local institutional policy. 
8.7.3. 
Reporting of Adverse Events Relating to the Primary Endpoint and 
Other Anticipated Medical Events in the Study Population 
To maintain the integrity of the study, serious adverse events that are associated with the 
following disease-related effects, and that are assessed as unrelated to study treatment, will 
not be reported in an expedited fashion by Gilead Sciences: 
• Progression of CLL 
• Death related to progression of CLL 
These events will be exempt from global expedited reporting requirements for the duration of 
the study because they define the primary efficacy endpoint for this study. They will be 
reported, as appropriate, in the final clinical study report and in any relevant aggregate safety 
reports.  
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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The safety information from this study will also be reviewed by an independent DMC on an 
ongoing basis. The DMC can have access to partially blinded or unblinded data in order to 
determine if it is safe to continue the study according to the protocol. 
8.8. 
Study Drug Overdose 
An overdose is ingestion or administration of an amount of study drug that exceeds the dose 
mandated by the protocol (see Sections 5.2.8), any misuse or abuse of study drug, or any 
misuse or abuse of any other product taken as a concomitant medication. An overdose is 
considered to have occurred if this definition is met, whether or not the administration is 
accidental or intentional, is suspected or confirmed, and whether or not the overdose is 
associated with an adverse experience. 
An overdose must be reported using the Gilead Sciences DSPH Clinical Overdose form. The 
completed DSPH Clinical Overdose form must be forwarded within 24 hours to DSPH or if 
applicable, to the CRO. Any questions or concerns should be discussed with the 
Gilead Sciences medical monitor. 
Along with information regarding the circumstances of the overdose, any clinical sequelae in 
association with the overdose should be reported as an adverse event or serious adverse event 
according to the reporting requirements for those events (see Section 8.6). Overdose will be 
considered a serious adverse event only if any of the seriousness criteria are met (see 
Section 8.1.2). Details of signs or symptoms, clinical management and outcome should be 
reported, if available. 
8.9. 
Pregnancy Requirements 
Each female subject should be instructed to discontinue further study therapy and inform the 
investigator immediately if she becomes pregnant at any time between the initiation of study 
drug until 30 days after the last ingestion of study drug. 
The investigator must report any pregnancy to PPD Pharmacovigilance within 24 hours of 
the time the investigator becomes aware of the pregnancy.  
The investigator should counsel the subject regarding the possible effects of prior 
investigational medicinal product exposure on the fetus and the need to inform the study site 
of the outcome of the pregnancy. 
All pregnancies of study subjects and female partners of male subjects that occur during the 
study should be reported using the Pregnancy Report eCRF. Monitoring of the pregnancy in 
both female study subjects and female partner of male study subjects should continue until 
the conclusion of the pregnancy. The outcome of the pregnancy should be reported on the 
Pregnancy Outcome Report eCRF within 5 days of the conclusion of the pregnancy. If the 
end of the pregnancy occurs after the study has been completed, the outcome should be 
reported directly to Gilead Sciences DSPH (facsimile: 
 e-mail: 
  
Neither the pregnancy itself nor an induced elective abortion to terminate the pregnancy 
without medical reasons is considered an adverse event; such occurrences should be reported 
on the appropriate pregnancy report forms. However, if the outcome of the pregnancy meets 
the criteria for classification as a serious adverse event (ie, spontaneous abortion, induced 
PPD
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abortion due to complications, stillbirth, neonatal death, or congenital anomaly [including 
that in an aborted fetus]), the investigator should follow the procedures for reporting serious 
adverse events, ie, report the event to PPD Pharmacovigilance by telephone and follow up by 
submission of the appropriate adverse event eCRFs (see Section 8.7.1). 
Additional information about pregnancy outcomes that are classified as serious adverse 
events includes:  
• Any spontaneous abortion, including miscarriage and missed abortion will be reported as 
an serious adverse event. 
• A induced therapeutic abortion to terminate any pregnancy due to complications or other 
medical reasons will be recorded as an serious adverse event. The underlying medical 
reason for this procedure should be recorded as the adverse event term. 
• All neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as serious adverse events. In addition, any infant death after 1 month that the 
investigator assesses as possibly related to the in utero exposure to the study drug should 
also be reported. 
• In the case of a live birth, the “normality” of the newborn can be assessed at time of birth 
(ie, there is no required minimum follow-up of a presumably normal infant before the 
Pregnancy Outcome Report eCRF can be completed). 
• The “normality” of an aborted fetus can be assessed by gross visual inspection unless 
there are pre-abortion laboratory findings suggestive of a congenital anomaly, in which 
case pathologic examination should be requested.  


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Analysis Conventions 
9.1.1. 
Analysis Sets 
9.1.1.1. 
Full Analysis Set 
The full-analysis set includes all subjects who receive ≥1 dose of any study treatment 
(high-dose GS-1101 or standard-dose GS-1101). In the full-analysis set, study drug 
assignment will be designated according to initial allocation in this study, regardless of 
whether subjects receive a different study therapy from that to which they were allocated.  
This analysis set will be used in the analyses of subject characteristics, PFS, ORR, TTF, and 
OS. Subjects in the full-analysis set who do not have sufficient baseline or on-study tumor 
status information to be adequately assessed for ORR will be counted as failures in the 
analysis of ORR.  
9.1.1.2. 
Responding Analysis Set 
The responding analysis set includes subjects in the full-analysis set who have measurable 
nodal disease, who can be evaluated for tumor response with both baseline and on-study 
tumor evaluations, and who achieve a CR or PR. The subjects will be grouped for analyses 
with treatment assignments designated according to the actual study drug received.  
This analysis set will be used in the analyses of TTR and DOR. 
9.1.1.3. 
Evaluable Analysis Sets 
The evaluable analysis sets include subjects in the full-analysis set who have the necessary 
baseline and on-study measurements to provide interpretable results for specific parameters 
of interest.  
These analysis sets will be used in the analyses of percent changes in lymph node area, 
lymph node response rate, splenomegaly response rate, hepatomegaly response rate, platelet 
response rate, hemoglobin response rate, neutrophil response rate, changes in HRQL, and 
changes in performance status.  
9.1.1.4. 
Safety Analysis Set 
A safety analysis set will include subjects in the full-analysis set grouped for analyses with 
treatment assignments designated according to the actual study drug received.  
This analysis set will be used in the analyses of safety variables as well as study treatment 
administration, post-study therapy, and health economic variables. 
9.1.1.5. 
Pharmacodynamic/Pharmacokinetic Analysis Sets 
The pharmacodynamic/pharmacokinetic analysis sets include subjects in the safety analysis 
set who have the necessary baseline and on-study measurements to provide interpretable 
results for specific parameters of interest.  
These analysis sets will be used in the analyses of AKT phosphorylation, 
chemokines/cytokines, and GS-1101 plasma concentrations. 


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9.1.2. 
Data Handling Conventions 
9.1.2.1. 
General Methods  
By-subject listings will be created for important variables from each eCRF module. 
Summary tables for continuous variables will contain the following statistics: N (number in 
population), n (number with data), mean, standard deviation, 95% confidence intervals (CIs) 
on the mean, median, minimum, and maximum. Summary tables for categorical variables 
will include: N, n, percentage, and 95% CIs on the percentage. Unless otherwise indicated, 
95% CIs for binary variables will be calculated using the binomial distribution (exact 
method) and will be 2-sided. Data will be described and summarized by relevant treatment 
arm, analysis set, and timepoint. As appropriate, changes from baseline to each subsequent 
timepoint will be described and summarized by treatment arm. Similarly, as appropriate, the 
best change from baseline during the study will also be described and summarized by 
treatment arm. Graphical techniques (eg, waterfall plots, Kaplan-Meier curves, line plots) 
may be used when such methods are appropriate and informative.  
Time-to-event analyses will be performed with reference to the date of first treatment on this 
clinical trial (Study GS-US-312-0117). Similarly, evaluations of on-therapy changes will 
reference the baseline values obtained prior to treatment in this study. The baseline value 
used in each analysis will be the last (most recent) pre-treatment value. Data from all sites 
will be pooled for all analyses. Analyses will be based upon the observed data unless 
methods for handling missing data are specified. If there is a significant degree of non-
normality, analyses may be performed on log-transformed data or nonparametric tests may 
be applied, as appropriate.  
Analyses will generally focus on evaluation of outcomes within each treatment arm; formal 
analyses comparing outcomes in Arm A to those in Arm B are not planned. Unless otherwise 
specified, all analyses will be 2-sided at the 0.05 level of significance.  
9.1.2.2. 
Calculation of Tumor Control and Patient Well-Being Variables 
Tumor control assessments will be based on standardized IWCLL criteria [Hallek 2008], as 
specifically modified for this study considering the pharmacology of GS-1101. The 
individual and composite endpoints of response and progression (considering changes in 
lymph node area, liver and spleen size, bone marrow, platelet counts, hemoglobin, neutrophil 
counts, and peripheral blood lymphocyte counts) will be determined. Tumor control will be 
documented at each assessment by response category (eg, CR, PR, SD, definitive PD, NE, 
ND) as defined for each response parameter, SPD value, percentage change in SPD values 
from baseline or nadir, date that response is first documented, date that response is 
confirmed, and date of definitive CLL progression.  
The date of definitive CLL progression will be the timepoint at which progression is first 
identified by CT/MRI, physical examination, or by worsening platelet count or hemoglobin. 
However, where imaging data are available, these data will supersede physical examination 
data in determining tumor status. For purposes of analysis, subjects who have only physical 
examination evidence of definitive disease progression that is not confirmed by CT/MRI will 
be considered to have progressed at the time of the physical examination finding. Because of 
the characteristic redistribution lymphocytosis that expected with PI3Kδ inhibition, 


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lymphocyte count will be ignored in the evaluation of progression. Calculations of 
progression considering lymphocyte count will be described but not analyzed.  
Changes in tumor status as provided by the investigator and changes in tumor status as 
adjudicated by the IRC (see Section 10.4.3) will be described and compared. The findings of 
the IRC will be considered primary for analyses of all tumor control endpoints. 
For time-to-event endpoints other than OS, only events occurring ≤30 days following the 
permanent discontinuation of study treatment will be considered as events; for subjects with 
events occurring >30 days following the permanent discontinuation of study treatment, the 
data will be censored. The following censoring conventions will be applied: 
• PFS: Data from surviving, non-progressing subjects will be censored at the earliest of the 
time of initiation of antitumor treatment other than the study treatment or the last time 
that lack of definitive CLL progression was objectively documented while on study 
treatment. 
• DOR: Data from surviving, non-progressing subjects will be censored at the earliest of 
the time of initiation of antitumor treatment other than the study treatment or the last time 
that lack of definitive CLL progression was objectively documented while on study 
treatment. 
• TTF: Data from surviving subjects who do not have treatment failure will be censored at 
the earliest of the time of initiation of antitumor treatment other than the study treatment 
or the last on-therapy time that lack of treatment failure was objectively documented. 
• OS: Data from surviving subjects will be censored at the last time that the subject was 
known to be alive.  
• Time to definitive increment in HRQL: Data from subjects who do not have definitive 
HRQL increment by the specified amount (10%, 20%, or 40%) will be censored at the 
earliest of the time of initiation of antitumor treatment other than the study treatment or 
the last HRQL assessment while on study treatment. 
• Time to definitive decrement in HRQL: Data from surviving subjects who do not have 
definitive HRQL decrement by the specified amount (10%, 20% or 40%) will be 
censored at the earliest of the time of initiation of antitumor treatment other than the 
study treatment or the last HRQL assessment while on study treatment. 
• Time to definitive performance status improvement: Data from subjects who do not have 
definitive performance status improvement will be censored at the earliest of the time of 
initiation of antitumor treatment other than the study treatment or the last performance 
status assessment while on study treatment.  
• Time to definitive performance status worsening: Data from surviving subjects who do 
not have definitive performance status worsening will be censored at the earliest of the 
time of initiation of antitumor treatment other than the study treatment or the last 
performance status assessment while on study treatment. 


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9.2. 
Analysis Plan 
9.2.1. 
Subject Disposition and Baseline Characteristics 
A listing of all full-analysis subjects will be generated to describe site, subject number, first 
screening date, first treatment date, allocated study drug assignment, actual study drug 
assignment, the longest duration of study drug treatment, and the reason for discontinuing 
study treatment. Available information on subjects who were screened or registered but not 
treated will be listed separately. A table will be created summarizing these categories in 
terms of number and percent for the full-analysis set. 
Subject baseline characteristics will be listed and summarized by treatment arm for the full-
analysis and responding analysis sets. As appropriate for the specific variable, subject 
baseline characteristics acquired in Study GS-US-312-0116 will be referenced in Study GS-
US-312-0117. Subject characteristics between Arm A and Arm B may be compared using the 
Wilcoxon rank-sum test for continuous variables and the Fisher’s exact test for categorical 
variables. Similarly, within each arm, subject characteristics between GS-US-312-0116 and 
GS-US-312-0117 may also be compared. 
9.2.2. 
Efficacy Analyses 
9.2.2.1. 
Time-to-Event Tumor Control and Survival Endpoints 
PFS, TTR, DOR, TTF, and OS will be described in the appropriate analysis set using 
Kaplan-Meier methods by treatment group. Medians, ranges, and corresponding 95% CIs  
will be presented.  
The Cox regression approach will be used to explore the influence of the primary study 
stratification factors and other baseline characteristics on PFS and OS. The stratification 
variables from the primary study and additional baseline subject characteristics may be 
included as covariates, focusing on those with expected prognostic significance. For the Cox 
regression modeling, a stepwise selection process will be applied to these variables to 
identify the final subset of relevant factors. Each prognostic factor will be preliminarily 
evaluated in the Cox regression model. Only the variables significant at the 0.20 level will be 
considered to build the multivariate model. A forward selection process will be applied to 
these variables to identify the final subset of relevant factors. .  
9.2.2.2. 
Categorical Endpoints  
ORR, CR and PR rates, nodal response rate, splenomegaly response rate, hepatomegaly 
response rate, platelet response rate, hemoglobin response rate, and neutrophil response rate 
will be described. In the analyses of ORR, subjects who do not have sufficient baseline or on-
study tumor assessment to characterize response will be counted as failures. For all analyses, 
the corresponding 95% CIs will be presented. 
The potential influence of subject baseline characteristics on response rates will be explored 
with multiple logistic regression modeling. 
9.2.2.3. 
Continuous Endpoints 
Changes in lymph node area and changes in performance status, PI3K/AKT/mTOR pathway 
activation, and plasma chemokines/cytokines will be assessed by treatment group. Both 


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changes from baseline to each subsequent timepoint and best overall on-study changes will 
be analyzed using appropriate methods (eg, analysis of covariance [ANCOVA] or paired 
t-tests). Means and standard errors will be presented. 
9.2.2.4. 
Health-Related Quality of Life and Performance Status 
The FACT-Leu questionnaire data will be scored, processed, and standardized (ranging from 
0-100) according to the user manual. Missing items in a subscale will be imputed consistent 
with the user manual instructions. Data collected from the FACT-Leu instrument will not be 
reconciled with adverse event or laboratory data or with EQ-D5 findings. 
Because a significant portion of the study subjects will have CLL disease progression during 
the course of the study and no HRQL or performance status data will be collected after 
disease progression, the duration of data collection for these variables will vary among the 
study subjects. Hence, at each HRQL or performance status assessment timepoint, changes 
from baseline in HRQL parameters or in performance status in the 2 treatment groups will be 
described by treatment group. considering both: 1) all subjects in the evaluable analysis sets 
for HRQL or performance status with the worst score assigned to those subjects who have 
progressed at the time of the analysis, and 2) all subjects in the evaluable analysis sets for 
HRQL or performance status who have not progressed at the time of the analysis. Subjects 
who are lost-to-follow-up without disease progression will be excluded, ie, missing data will 
not be imputed. In addition, Kaplan-Meier methods will be used for each of the FACT-Leu 
subscale scores, assessing time to changes in each variable by increments or decrements of 
10%, 20%, and 40% from baseline. Similarly Kaplan-Meier methods will be used assessing 
time to definitive performance status improvement or worsening from baseline. For these 
analyses, medians, ranges, and corresponding 95% CIs for each treatment group will be 
presented. In the analyses of FACT-Leu data, particular focus will be placed on changes in 
subject reports relating to CLL (focusing specifically on fever, chills, night sweats, 
lymphadenopathy, and fatigue).  
9.2.3. 
Exposure and Safety Analyses 
9.2.3.1. 
Treatment Administration and Study Drug Compliance 
Descriptive information will be provided by treatment arm regarding the number of doses of 
study therapy prescribed, the total number of doses taken, the percent of expected doses 
taken, the number of days of treatment, and the number and timing of prescribed dose 
reductions and interruptions. 
Study drug compliance will be described by treatment arm in terms of the proportion of study 
drug actually taken based on returned pill count relative to the amount that was dispensed 
(taking into account physician-prescribed reductions and interruptions). 
9.2.3.2. 
GS-1101 Plasma Concentrations 
Bioanalytical analyses will performed independently so that the study team and investigators 
will not have knowledge of data from individual subjects. GS-1101 plasma concentrations 
immediately pre-dose and at 1.5 hours after administration of the dose of study drug at each 
relevant clinic visit will be summarized by treatment and visit using descriptive statistics. 


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9.2.3.3. 
Prior, Concomitant, and Post-Treatment Medication Use 
Prior, concomitant, and post-treatment medications will be coded by means of the World 
Health Organization Drug Dictionary (WHODRUG) dictionary into 
Anatomical-Therapeutic-Chemical classification (ATC) codes. 
Descriptions of prior medication use will be focused on drugs and regimens used as 
treatments for CLL. Information regarding CLL therapy that was administered prior to 
Study GS-US-312-0116 will be referenced in reporting the results of Study GS-US-312-
0117. In addition, relevant treatment administration information collected during 
Study GS-US-312-0116 will be referenced in reporting the results of this study. As 
appropriate and if available, information on the sequencing, type, dose, schedule, timing, 
duration of use, and efficacy of prior regimens will be provided, focusing particularly on 
findings observed in Study GS-US-312-0116. 
The type and timing of use of concomitant medications will be listed and summarized by 
type and treatment arm. Information regarding the type and use of specific supportive 
medications (eg, pneumocystis prophylaxis, hematopoietic growth factors, corticosteroids) 
during study treatment will be described. 
The number, type, and timing of post-study-treatment regimens for CLL will be summarized 
by treatment arm, characterizing the disposition of all subjects who were eligible for 
post-study treatment and also those who were not eligible for post-study treatment (eg, 
subjects who are never treated at all, die while on study treatment, are still on study, are lost 
to follow-up, etc). 
9.2.3.4. 
Adverse Events 
All adverse events will be listed. The focus of adverse event summarization will be on 
treatment-emergent adverse events. A treatment-emergent adverse event is defined as an 
adverse event that occurs or worsens in the period from the first dose of study treatment to 
30 days after the last dose of study treatment. Adverse events that occur before the first dose 
of study treatment or >30 days after the subject has been discontinued from study treatment 
will be included in data listings. 
Adverse events will be classified using MedDRA (http://www.meddramsso.com) with 
descriptions by System Organ Class, High-Level Group Term, High-Level Term, Preferred 
Term, and Lower-Level Term. The severity of adverse events will be graded by the 
investigator according to the CTCAE, Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf), 
whenever possible. If a CTCAE criterion does not exist for a specific type of adverse event, 
the grade corresponding to the appropriate adjective will be used by the investigator to 
describe the maximum intensity of the adverse event: Grade 1 (mild), Grade 2 (moderate), 
Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the 
adverse event to the study drug will be categorized as related or unrelated. 
Treatment-emergent adverse events will be summarized by treatment arm and by visit. 
Summary tables will be presented to show the number of subjects reporting treatment-
emergent adverse events by severity grade and corresponding percentages. A subject who 
reports multiple treatment-emergent adverse events within the same Preferred Term (or 


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System Organ Class) is counted only once for that Preferred Term (or System Organ Class) 
using the worst severity grade. Adverse event descriptions will be presented in alphabetical 
order of System Organ Class, then by decreasing frequency in the “overall” column for a 
given Preferred Term. 
Separate listings and summaries will be prepared for the following types of treatment-
emergent adverse events: 
• Study-drug-related adverse events 
• Adverse events that are Grade ≥3 in severity 
• Adverse events leading to study drug interruption and/or dose modification 
• Adverse events leading to study drug discontinuation 
• Serious adverse events (with categorization of the primary reason that the adverse event 
is considered serious, eg, death, hospitalization, etc) 
Separate listings and summaries will be prepared for long-term follow-up safety data (see 
Section 6.2.18). 
9.2.3.5. 
Laboratory Evaluations 
All laboratory data will be listed. Summaries of laboratory data will be based on observed 
data and will be reported using conventional units. The focus of laboratory data 
summarization will be on treatment-emergent laboratory abnormalities. A treatment-
emergent laboratory abnormality is defined as an abnormality that, compared to baseline, 
worsens by ≥1 grade in the period from the first dose of study treatment to 30 days after the 
last dose of study treatment. If baseline data are missing, then any graded abnormality (ie, an 
abnormality that is Grade ≥1 in severity) will be considered treatment emergent. Laboratory 
abnormalities that occur before the first dose of study treatment or >30 days after the subject 
has been discontinued from study treatment will be included in data listings. 
Hematological, serum biochemistry, and urine data will be programmatically graded 
according to CTCAE severity grade, when applicable. For parameters for which a CTCAE 
scale does not exist, reference ranges from the central laboratory will be used to determine 
programmatically if a laboratory parameter is below, within, or above the normal range for 
the subject’s age, sex, etc. 
Hematological and serum biochemistry and their changes from baseline will be summarized 
by treatment arm and by visit. Summary tables will be presented for each relevant assay to 
show the number of subjects by CTCAE severity grade with corresponding percentages. For 
parameters for which a CTCAE scale does not exist, the frequency of subjects with values 
below, within, and above the normal ranges will be summarized. Subjects will be 
characterized only once for a given assay, based on their worst severity grade observed 
during a period of interest (eg, during the study or from baseline to a particular visit). 
Shift tables for hematology and serum biochemistry will also be presented by showing 
change in CTCAE severity grade from baseline to each visit. For parameters for which a 
CTCAE scale does not exist, shift tables will be presented showing change in results from 
baseline (normal, low and high [or abnormal]) to each visit (normal, low and high [or 


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abnormal]). Tables will be prepared to show frequencies adjusted for baseline values; for this 
frequency, subjects with the same or worse toxicity grade at baseline are not considered. 
Separate listings and summaries will be prepared for laboratory abnormalities that are 
Grade ≥3 in severity. 
9.2.3.6. 
Oxygen Saturation Values 
All oxygen saturation data will be listed. Summaries of oxygen saturation data will be based 
on observed data and will be reported as % saturation. Data and changes from baseline will 
be summarized by treatment arm and by visit. Summary tables will be presented for values 
below 92% and for declines from baseline of ≥5% to show the number of subjects with 
corresponding percentages. Subjects will be characterized only once for each of these 
categorizations, based on their lowest value observed during a period of interest (eg, during 
the study or from baseline to a particular visit). 
9.2.4. 
Other Analyses 
9.2.4.1. 
Between-Study Comparisons 
It is expected that  patients with a progressive malignancy like CLL will normally fare better 
with an earlier therapy than with a later therapy. However, if the converse situation proves 
true – eg, if an investigational treatment (GS-1101) administered later shows similar or 
greater benefit than a standard treatment (rituximab) administered earlier – strong evidence 
of investigational drug effect is demonstrated. Evaluating data derived from the same study 
subjects during their sequential participation in 2 clinical trials offers unique analytical 
challenges. However, in this integrated Phase 3 study program, it is likely that comparing 
baseline characteristics and outcomes among Arm B subjects participating in Study GS-US-
312-0116 and Study GS-US-312-0117 will be informative. Such an evaluation characterizes 
how the subjects and the CLL disease process change with time and treatment. In addition, 
such an analysis provides relevant supporting information documenting the benefits of 
single-agent GS-1101 relative to single-agent rituximab in the same subjects. 
Accordingly, the subject baseline characteristics at the start of Study GS-US-312-0116 
relative to those at the start of Study GS-US-312-0117 will be evaluated. Subject baseline 
characteristics between the studies may be compared using the Wilcoxon rank-sum test for 
continuous variables and the Fisher’s exact test for categorical variables.  
Time-to-event efficacy variables (eg, PFS, TTR, DOR, TTF, time to performance status, or 
HRQL changes) will be evaluated using the paired Prentice-Wilcoxon test, comparing results 
in Study GS-US-312-0116 to those in Study GS-US-312-0117 among subjects who 
participate in Arm B of both studies. Within each study period, medians, ranges, hazard 
ratios and corresponding 95% CIs will be presented using Kaplan Meier methods. As 
appropriate, Cox regression techniques may be used to explore the influence of baseline 
characteristics on treatment differences when comparing these outcomes between the studies. 
For categorical variables (eg, ORR, lymph node response rate, splenomegaly response rate, 
hepatomegaly response rate), the Wilcoxon signed-rank test will be employed to compare 
outcomes between Study GS-US-312-0116 and Study GS-US-312-0117 for Arm B subjects. 
For all analyses, odds ratios and the corresponding 95% CIs will be presented. Differences 
between studies for Arm B subjects relating to continuous variables (eg, percentage changes 


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in lymph node area; changes in performance status, PI3K/AKT/mTOR pathway activation 
and plasma chemokines/cytokines) will be analyzed using appropriate methods (eg, analysis 
of covariance [ANCOVA] or paired t-tests). Means and standard errors will be presented. As 
appropriate, the potential influence of subject baseline characteristics on treatment effects 
may be explored with multiple logistic regression techniques. 
9.2.4.2. 
Health Care Resource Utilization 
The EQ-D5 questionnaire data will be scored, processed, and standardized according to the 
user manual. As for the FACT-Leu, data will be analyzed using appropriate methods to 
account for incomplete completion of questionnaires. Data collected from the EQ-D5 will not 
be reconciled with adverse event or laboratory data or with FACT-Leu findings. 
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations. 
The basic approach to the health economic analysis will be to combine the resource 
utilization data from the trial with data on unit prices (collected separately) to estimate total 
costs.  
The perspective of this analysis will be that of the third-party payer(s) and the hospital over a 
lifetime horizon in the base case. The costs will be described relative to the health care 
findings as measured by duration of tumor control, the symptom-free survival period, life-
years, utility outcomes, or other measure of appropriate clinical benefits. In order to facilitate 
the calculation of utilities for use in the cost effectiveness analyses, the health status of 
subjects will be evaluated using PFS, Karnofsky performance status, FACT-Leu, and EQ-5D. 
9.2.4.3. 
Data Explorations  
Changes in biomarkers during acquisition of resistance will be evaluated descriptively. Data 
explorations may be performed to evaluate potential associations between subject 
characteristics and outcome measures. Explorations may be performed to assess the potential 
associations between different outcomes measures (eg, relationships between HRQL changes 
and clinical/radiographic endpoints of tumor control). 
9.3. 
Sample Size 
The sample size for this extension study is not based upon a formal statistical hypothesis. The 
upper bound of the sample size in this study is determined by the sample size of the 
preceding primary study (Study GS-US-312-0116) in which ~160 subjects (~80 per arm) are 
expected to be enrolled. It is estimated that this extension study (Study GS-US-312-0117) 
will have a total GS-1101-treated N~130 (assuming a ~10% dropout rate during 
Study GS-US-312-0116 and a further ~10% dropout rate in the transition from the primary 
study to the extension study). 


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9.4. 
Timing of Analyses 
9.4.1. 
Interim Analysis 
The DMC will have access to serious adverse events requiring expedited reporting and will 
be provided with accumulating safety data on a regular basis. Interim safety reviews will be 
conducted by the DMC in conjunction with safety reviews of the primary clinical trial 
(Study GS-US-312-0116). Thus, interim safety reviews will be performed by the DMC at 
intervals of ~6 months; the specific frequency of these reviews will depend upon the rate at 
which the trials are enrolled, the nature of any emerging safety signals, and monitoring 
recommendations from the DMC. At each review, all available safety data will be 
summarized and evaluated.  
An interim efficacy analysis of this clinical trial (Study GS-US-312-0117) is planned that 
take place at the time of the final analysis of the primary study (Study GS-US-312-0116). 
The intent is to provide the data from this extension study in support of regulatory review of 
data from the primary study. The blind will be broken to the study team at Gilead Sciences 
for analysis purposes. However, the study will be continued to obtain further follow-up 
efficacy and safety information; individual subjects, caregivers, and site personnel will not be 
informed of the treatment assignments until the implications of revealing such data for the 
overall GS-1101 study program have been determined. 
9.4.2. 
Final Analysis 
An additional, final analysis of efficacy and safety may be performed to satisfy regulatory 
requirements and to perform long-term efficacy, safety and OS follow-up. The timing of this 
analysis is expected to occur within 36 months of accrual of the final subject to 
Study GS-US-312-0117. 


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10. 
RESPONSIBILITIES 
10.1. 
Investigator Responsibilities 
10.1.1. 
Compliance with Ethical and Regulatory Guidelines 
The investigator will ensure that this study is conducted in accordance with the principles of 
the “Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), with ICH guidelines, or with the laws and regulations of the country in which 
the research is conducted, whichever affords the greater protection to the study subject. For 
studies conducted under a United States Investigational New Drug (IND) application, the 
investigator will ensure adherence to the basic principles of GCP as outlined in 21 CFR 312, 
subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 1998, and 
21 CFR, part 56, 1998. 
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 
1993, “Retention of Bioavailability and Bioequivalence Testing Samples.” 
Because this is a “covered” clinical trial, the investigator will ensure adherence to 21 CFR, 
Part 54, 1998; a covered clinical trial is any “study of a drug or device in humans submitted 
in a marketing application or reclassification petition subject to this part that the applicant or 
FDA relies on to establish that the product is effective (including studies that show 
equivalence to an effective product) or that make a significant contribution to the 
demonstration of safety.” This requires that investigators and all sub-investigators must 
provide documentation of their financial interest or arrangements with Gilead Sciences, or 
proprietary interests in the drug being studied. This documentation must be provided before 
participation of the investigator and any subinvestigator in the trial. The investigator or 
subinvestigator agrees to notify Gilead Sciences of any change in reportable financial 
interests during the study and for 1 year following completion of the study. Study completion 
is defined as the date that the last subject has completed the protocol-defined activities. 
10.1.2. 
Institutional Review Board/Independent Ethics Committee 
This protocol and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) will be submitted by the investigator to an IRB (for sites enrolling in the 
United States) and to an IEC for sites enrolling outside of the United States). Approval from 
the IRB/IEC must be obtained before starting the study and should be documented in a letter 
to the investigator specifying the protocol number, protocol version, protocol date, 
documents reviewed, and date on which the committee met and granted the approval. 
Any modifications or amendments made to the protocol after receipt of the initial IRB/IEC 
approval must also be submitted to the IRB/IEC for approval before implementation. Only 
changes necessary to eliminate apparent immediate hazards to the subjects may be initiated 
prior to IRB/IEC approval. In that event, the investigator must notify the IRB/IEC and 
Gilead Sciences in writing within 5 working days after implementation. 
The investigator shall submit a progress report, at least once yearly, to the IRB/IEC, and must 
provide a copy to Gilead Sciences. As soon as possible after completion or termination of the 
study, the investigator will submit a final report to the IRB/IEC and to Gilead Sciences. This 


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report should include the dates of initiation and completion of the trial, a description of any 
changes in study procedures or amendments to the protocol, any deviations from the 
protocol, the number and type of subjects evaluated, the number of subjects who 
discontinued (and the reasons for discontinuation), the number of subjects who completed the 
trial, and the results of the trial, including a description of any adverse events. 
Gilead Sciences will assist the investigator in the preparation of this report, as needed. 
10.1.3. 
Informed Consent 
After adequately, explaining the aims, methods, objectives, and potential hazards of the study 
and before undertaking any study-related procedures, the investigator is responsible for 
obtaining written informed consent from each individual participating in this study. The 
investigator must utilize an IRB/IEC-approved consent form for documenting written 
informed consent. Each informed consent will be appropriately signed and dated by the 
subject or the subject’s legally authorized representative and the person obtaining consent. 
The approved informed consent must not be changed without prior approval by 
Gilead Sciences and the IRB/IEC. 
10.1.4. 
Confidentiality 
The investigator must assure that each subject’s anonymity will be strictly maintained and 
that each subject’s identity is protected from unauthorized parties. Only subject initials, date 
of birth, and an identification code (but no subject names) should be recorded on any form or 
biological sample submitted to the Gilead Sciences or designees (eg, laboratories), or to the 
IRB/IEC. However, sufficient information must be retained at the site to permit sample data 
and data in the database to be connected with the unique subject number assigned to each 
study participant. 
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the GS-1101 investigator brochure, this protocol, eCRFs, the investigational new 
drug, and any other study information, remain the sole and exclusive property of 
Gilead Sciences during the conduct of the study and thereafter. This information is not to be 
disclosed to any third party (except employees or agents directly involved in the conduct of 
the study or as required by law) without prior written consent from Gilead Sciences. The 
investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain. 
10.1.5. 
Study Files and Retention of Records and Biological Samples 
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into at least the following 2 categories: (1) investigator’s 
study file, and (2) subject clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
the IRB/IEC and governmental approval with correspondence, informed consent, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 


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The required source data referenced in the monitoring plan for the study, and should include 
sequential notes containing at least the following information for each subject: 
• Subject identification (name, date of birth, gender) 
• Documentation that subject meets eligibility criteria, eg, history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria) 
• Participation in trial (including trial number) 
• Trial discussed and date of informed consent 
• Dates of all visits 
• Documentation that protocol-specific procedures were performed 
• Results of efficacy parameters, as required by the protocol 
• Start and end date (including dose regimen) of trial medication (including relevant drug 
dispensing and return information) 
• Record of all adverse events and other safety parameters (including start and end date, 
causality and intensity) 
• Concomitant medication (including start and end date and dose if relevant dose changes 
occur) 
• Date of trial completion and reason for discontinuation, if applicable 
All clinical study documents must be retained by the investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (ie, the United States, Europe, 
or Japan) and until there are no pending or contemplated marketing applications in an ICH 
region; or, if no application is filed or if the application is not approved for such indication, 
until 2 years after the investigation is discontinued and regulatory authorities have been 
notified. Investigators may be required to retain documents longer if required by applicable 
regulatory requirements, by local regulations, or by an agreement with Gilead Sciences. The 
investigator must notify Gilead Sciences before destroying any clinical study records. The 
investigator will promptly notify Gilead Sciences in the event of accidental loss or 
destruction of any study records.  
Should the investigator wish to assign the study records to another party or move them to 
another location, Gilead Sciences must be notified in advance. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all 
of the documents, special arrangements must be made between the investigator and 
Gilead Sciences to store these in sealed containers outside of the site so that they can be 
returned sealed to the investigator in case of a regulatory audit. When source documents are 
required for the continued care of the subject, appropriate copies should be made for storage 
outside of the site. 
Biological samples retained by the investigator will be stored and maintained by the 
investigator until notification is received from Gilead Sciences that the retained samples and 
records no longer need to be retained. The investigator must obtain written permission from 


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Gilead Sciences before disposing of any retained samples. The investigator should promptly 
notify Gilead Sciences in the event of accidental loss or destruction of any study samples. 
With the permission of Gilead Sciences, the retained samples may be transferred to an 
acceptable designee, such as another investigator, another institution, a contract storage site, 
or to Gilead Sciences. 
10.1.6. 
Case Report Forms 
An eCRF is required and must be completed for each enrolled subject, with all required study 
data accurately recorded such that the information matches the data contained in medical 
records (eg, physicians’ notes, nurses’ notes, clinic charts, or other study-specific source 
documents). As required by the protocol, eCRFs should also be completed for those subjects 
who fail to complete the study (even during the screening period). If a subject withdraws 
from the study, the reason must be noted on the eCRF. If a subject is withdrawn from the 
study because of a treatment-limiting adverse event, thorough efforts should be made to 
clearly document the outcome.  
The eCRFs for this study will exist within a Web-based electronic data capture (EDC) 
system. After the investigator or the investigator’s designees (eg, research coordinators) have 
been appropriately trained, they will be given access to the EDC system and will enter the 
data required by the protocol into the EDC system. Any change of data will be made via the 
EDC system, with all changes tracked by the system to provide an audit trail. 
The eCRF must be completed and signed by the principal investigator or subinvestigator (as 
appropriate) within a reasonable time period after data collection. This signature serves to 
attest that the information contained in the eCRF is true. 
10.1.7. 
Drug Accountability  
As described in the relevant section (see Section 5.2.7), the investigator is responsible for 
ensuring adequate accountability of all used and unused investigational medicinal product, 
placebos, and comparators. This responsibility includes acknowledgment of receipt of each 
shipment of study product (quantity and condition), subject dispensing records, and returned 
or destroyed study product. Dispensing records will document quantities received from 
Gilead Sciences and quantities dispensed to subjects, including lot number, date dispensed, 
subject identifier number, subject initials, and the initials of the person dispensing the 
medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during 
the study if appropriate. At the end of the study, following final drug inventory reconciliation 
by the monitor, the study site will dispose of and/or destroy all unused investigational 
medicinal product supplies, including empty containers, according to these procedures. If the 
site cannot meet Gilead Sciences’ requirements for disposal, arrangements will be made 
between the site and Gilead Sciences or its representative for destruction or return of unused 
investigational medicinal product supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by 
the study monitor over the course of the study. 


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10.1.8. 
Inspections 
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from Gilead Sciences or its representatives, to 
IRB/IECs, and to regulatory authority or health authority inspectors. It is important that the 
investigator and relevant institutional personnel are available during monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process. 
10.1.9. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
10.2. 
Sponsor Responsibilities 
10.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, will 
be made only by Gilead Sciences. All protocol modifications must be submitted to the 
IRB/IEC in accordance with local requirements. Except as noted in Section 10.1.2, IRB/IEC 
approval must be obtained before changes can be implemented. 
10.2.2. 
Communications with Regulatory Authorities 
Gilead Sciences, working either directly or through designees, will assume responsibility for 
regulatory interactions with relevant regulatory authorities. Gilead Sciences will maintain an 
IND for GS-1101 in support of the study in the United States and will maintain similar 
regulatory applications with other regulatory authorities, as required for conduct of the study. 
In fulfilling this responsibility, Gilead Sciences (or a designee) will collect, assemble, and 
communicate all required regulatory documents (eg, Form FDA 1572, investigator financial 
disclosure forms, protocol and protocol amendments, investigator brochures, informed 
consent documents, annual reports) as required by regulation. Gilead Sciences (or a designee) 
will also assume responsibility for adverse event reporting to regulatory authorities as 
described in Section 8.7.2. 
10.2.3. 
Data Management 
Electronic data capture will be used to enter study data eCRFs and to transfer the data into a 
study-specific electronic database. During the data collection process, automated quality 
assurance programs will be used to identify missing data, selected protocol violations, out-of-
range data, and other data inconsistencies. Requests for data clarification or correction will 
be forwarded to the investigative site for resolution. As appropriate, eCRFs, listings, tables, 
and SAS datasets will be provided to the investigational sites for review. 
Quality assurance and quality control systems will be implemented and maintained according 
to written standard operating procedures to ensure that the data are generated, recorded, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements. Data 
collection and storage systems will provide audit trail, security mechanisms, and electronic 
signature capabilities that meet the requirements of FDA Title 21 of CFR Part 11 regarding 
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Data security will be controlled through appropriate and specific restriction of access only to 
data and systems required by individual users to accomplish their roles in the data 
management process. Individual login and password protections will be employed at study 
sites and at Gilead Sciences or its designee. The database will exist on physically secured 
servers. Data backups will be done regularly and will be stored in separate facilities. Printed 
documents relating to the study will be secured when not under review.  
10.2.4. 
Study Reporting and Publication 
Gilead Sciences may make information obtained during this study available in order to 
further the scientific or business needs of the company or as required by law or regulation. In 
this regard, Gilead Sciences may provide study information to private or public organizations 
(eg, business partners, collaborators, consultants, CROs, investors, other physicians who are 
conducting similar studies, funding organizations, regulatory authorities, or other government 
authorities).  
Gilead Sciences will prepare a clinical study report for submission to relevant regulatory 
agencies. Gilead Sciences will ensure that the report meets the standards set out in the ICH 
Guideline for Structure and Content of Clinical Study Reports (ICH E3). An abbreviated 
report may be prepared in certain cases, as appropriate. 
Gilead Sciences intends that the data from this study will be presented and published. The 
Gilead Sciences study director will work in collaboration with the principal investigators in 
preparing presentations and writing manuscripts for publication.  
Investigators should not present or publish the data from the individual sites of this study 
without agreement among the principal investigators and Gilead Sciences. However, after 
conclusion of the study and without prior written approval from Gilead Sciences, 
investigators in this study may communicate, orally present, or publish in scientific journals 
or other scholarly media the results of the trial if either of the following conditions is met: 
• The results of the study in their entirety have been publicly disclosed in an abstract, 
manuscript, or presentation form by Gilead Sciences or with the consent of 
Gilead Sciences; or 
• The primary clinical trial (Study GS-US-312-0116) and this companion extension trial 
(Study GS-US-312-0117) have been closed at all study sites for ≥2 years. 
No such communication, presentation, or publication will include Gilead Sciences’ 
confidential information (see Section 10.1.4). 
The investigator will submit to Gilead Sciences any proposed publication or presentation 
along with the respective scientific journal or presentation forum at least 30 days before 
submission of the publication or presentation. The investigator will comply with 
Gilead Sciences’ request to delete references to its confidential information (other than the 
study results) in any paper or presentation. If deemed necessary by Gilead Sciences, the 
investigator also agrees to withhold publication or presentation for an additional 60 days in 
order to obtain patent protection. 


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10.3. 
Joint Investigator/Sponsor Responsibilities 
10.3.1. 
Access to Information for Monitoring 
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor 
must have direct access to the investigator’s source documentation in order to verify the data 
recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy 
of the data being entered on them. The monitor should have access to any subject records 
needed to verify the entries on the eCRFs. The investigator agrees to cooperate with the 
monitor to ensure that any problems detected in the course of these monitoring visits are 
resolved. 
10.3.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of Gilead Sciences may conduct inspections or 
audits of the clinical study. If the investigator is notified of an inspection by a regulatory 
authority the investigator agrees to notify the Gilead Sciences medical monitor immediately. 
The investigator agrees to provide to representatives of a regulatory agency or 
Gilead Sciences access to records, facilities, and personnel for the effective conduct of any 
inspection or audit. 
10.3.3. 
Public Notification of Study Conduct 
Consistent with Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and 
with requirements of the International Committee of Medical Journal Editors (ICMJE) as a 
condition of consideration for publication of study results, Gilead Sciences will be 
responsible for ensuring that this protocol is listed at the ClinicalTrials.gov website (or 
equivalent) and that information at the website relating to study design and conduct is 
appropriately updated during the course of the study. In order to facilitate this process, 
investigators will need to supply Gilead Sciences with appropriate contact information for 
study site personnel. 
10.3.4. 
Study Discontinuation 
Both the sponsor and the investigator reserve the right to terminate the study at any time. 
Should this be necessary, both parties will arrange discontinuation procedures and notify the 
appropriate regulatory authorities and IRB/IECs. In terminating the study, Gilead Sciences 
and the investigator will assure that adequate consideration is given to the protection of the 
subjects’ interests.  
10.4. 
Study Committees 
10.4.1. 
Study Steering Committee 
A study steering committee (SSC) will be responsible for assisting Gilead Sciences with 
protocol development, review of any study amendments, coordination of study conduct, 
interpretation of data, and presentation and publication of study results. The SSC comprises 
the Gilead Sciences medical monitor for the study, the Gilead Sciences study director, and 
several clinicians with expertise in the care of subjects with CLL. Other specialists may be 


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invited to participate as members of the SSC at any time if additional expertise is desired. 
Academic SSC members may be involved in accruing subjects to the study. The 
Gilead Sciences study director serves as the chair of the SSC. It is expected that the members 
of the SSC will be the same as those for the SSC of the primary clinical trial 
(Study GS-US-312-0116).  
10.4.2. 
Data Monitoring Committee 
A DMC, operating autonomously from Gilead Sciences, the clinical investigators, and the 
SSC, will be responsible for providing independent recommendations to Gilead Sciences 
about evolving risk-benefit observed in the course of the study and any modifications 
required during the course of the study. The DMC will consist of a biostatistician and 
≥2 physicians experienced in treating patients with lymphoid malignancies. The DMC will 
be chaired by one of these individuals. DMC members must not be actively involved in study 
design, conduct, or subject accrual and must not have financial, proprietary, professional, or 
other interests that may affect impartial, independent decision-making. Specialists may be 
invited to participate as non-voting members at any time if additional expertise is desired. 
The DMC will formally interact with the external SSC members through the sharing of 
meeting minutes. Informal interactions between the DMC and external SSC members will be 
limited. The DMC will operate under a charter developed as a collaborative document 
between Gilead Sciences and the DMC. It is expected that the members of the DMC will be 
the same as those for the primary study (Study GS-US-312-0116).  
The primary responsibility of the DMC is to protect the safety and welfare of subjects 
participating in this clinical trial and to ensure the integrity of the clinical trial. In general, the 
DMC will be responsible for: 
• Reviewing the general progress of the study as regards subject accrual, study conduct, 
and protocol violations 
• Examining accumulated safety, efficacy, and other relevant data at prespecified points 
during the course of the study  
• Reviewing major study design modifications prior to implementation of those 
modifications 
• Making recommendations concerning continuation, modification, interruption, or 
termination of each study 
• Advising the company on changes to informed consent documents 
• Proposing updates to the DMC monitoring plan, changes in the DMC membership, 
actions to be taken relating to conflict of interest or confidentiality breaches, the need for 
additional expertise during DMC deliberations, revisions to the DMC charter, or 
alterations in the support provided to the DMC 
• Providing expert advice to the Gilead Science medical monitor on an ad hoc basis 
regarding matters such as safety concerns or diagnostic evaluations in individual subjects 
 


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Based on the results of its deliberations during the course of the study, the DMC can 
recommend appropriate actions (eg, continuation of the study unchanged, continuation of the 
study with modifications in design or monitoring plan, interruption of study accrual, study 
termination). 
10.4.3. 
Independent Review Committee 
An IRC will be established to provide a blinded review of radiographic data and pertinent 
clinical data in order to provide expert interpretation of changes in tumor status. The IRC will 
include ≥1 independent board-certified radiologist and ≥1 independent board-certified 
hematologist or oncologist, and will be managed by a CRO selected by Gilead Sciences. The 
review of radiographic and clinical data by the IRC will be performed on an ongoing basis. 
The specifics of the IRC’s processes and reading methods will be described in an 
independent review charter developed by the contracted imaging facility in conjunction with 
Gilead Sciences. The same organization that is providing IRC services for 
Study GS-US-312-0116 will provide IRC services for this study.  


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11. 
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12. 
APPENDICES 
Appendix 1. 
Investigator Signature Page 
Appendix 2. 
Functional Assessment of Cancer Therapy: Leukemia 
(FACT-Leu) 
Appendix 3. 
Performance Status Scoring System 
Appendix 4. 
EuroQoL-5 Dimensions (EQ-5D) 
Appendix 5. 
Cockcroft-Gault Method for Estimating Creatinine Clearance 
Appendix 6. 
Cumulative Illness Rating Scale (CIRS) 
Appendix 7. 
Schedule of Study Procedures 
 


PPD
PPD
GS-1 101 
Protocol GS-US-312-01 I 7 
Final 
Gilead Sciences, Inc. 
Original 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
199 EAST BLAINE STREET 
SEATTLE, WA 98102 
STUDY ACKNOWLEDGEMENT 
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and Safety of 
Two Different Dose Levels of Single-Agent GS-1101 (CAL-101) as Therapy 
for Patients with Previously Treated Chronic Lymphocytic Leukemia 
GS-US-312-0117 Original Protocol, 23 January 2012 
This protocol has been approved by Gilead Sciences, Inc. The followi 
this am::>_r_ov.;..a;;,;l.;... ------------. 
Gilead Sciences Study Director 
2..0 I 2._ 
Date 
INVESTIGATOR STATEMENT 
J have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. 1 will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to 
all information provided by Gilead Sciences, Inc. I will discuss this material with them to 
ensure that they are fully informed about the drugs and the study. 
Principal Investigator 
Printed Name 
Date 
CONFIDENTIAL 
Page 139 
Signature 
Site Number 
23 January 2012 


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Appendix 2. 
Functional Assessment of Cancer Therapy: Leukemia 
(FACT-Leu) 
 
FACT-Leu (Version 4) 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 davs. 
PHYSICA 
ot 
at all 
PI 
I have a lack of energy ............................................ 
0 
GP2 
I have nausea ...................................................................... 
0 
Because of my physical condition, I have trouble 
meeting the needs of my famiJy .... ........................... 
0 
GP,1 
I have pain ................................................................ 
0 
GPS 
I am bothered by side effects of treatment.. ....................... 
0 
01'6 
I feel ill ' ......... ' ........................................................... '' ....... 
0 
GP7 
I am forced to spend time in bed ......................................... 
0 
OCIAL/F AMlL Y WELLwBEI G 
ot 
at all 
GS I 
I feel close to my friends .................................................... 
0 
GSl 
I get emotional suppo.tt from my family ............................ 
0 
GS3 
[get upport from my friends........ .................................. .. 
0 
My family has accepted my illness............................. .. 
0 
GS5 
I am satisfied with family communication about. my 
il ness...... ................................................................. 
0 
I feel close to my partner (or the person who is my majn 
support) ............................................................................... 
0 
Ql 
Regardle . ofvour current level of exual aclivily. plea e 
Si 
an 
er the following que lion. Ifyou prefa 1101 to an wer il, 
please mark thi box 0 and go to rhe next ection. 
I am ati fied with my sex life . . ........ ..... . . ... .. .. .. .. .. .............. 
0 
Efll!lisb(Univ« I) 
c.,nsJ•• 1 gg7, 1997 
A Jittle 
Some-
bat 
what 
2 
2 
2 
2 
2 
2 
2 
A little 
Some-
bit 
what 
2 
2 
2 
2 
2 
2 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
Very 
1nuch 
4 
4 
4 
4 
4 
4 
4 
Very 
nmch 
4 
4 
4 
4 
4 
4 
4 
P•I'J' I of3 


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FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
ot 
at all 
GEl 
I feel sad ............................................................................... 
0 
GE2 
I am satisfied with how I am coping with my illness .......... 
0 
Gill 
I am losing hope in the fight against my illness ................... 
0 
Gil-l 
I feel I ervous ............................... ..... .................. .................. 
0 
I worry about dying . ........................................................... 
0 
I worry that my condition will get worse ............................ 
0 
F NCTIONAL WELL-BEING 
ot 
at aU 
OF ! 
I am abl.e to work (include work at home) .......................... 
0 
0F2 
My work (include work at home) .is fulfilling ..................... 
0 
GFl 
I am able to enjoy life ........................................................... 
0 
GFII 
I have accepted my illness .. ............. .................. .. ... .. " ........ 
0 
I am sleeping well ... 
, ... ... ... ............ ....... ............ ..... ... ............. 
0 
GF6 
I am enjoying the things I usuaJly do for fun ...................... 
0 
01'7 
I am content with the quality of my life right now ............... 
0 
A little 
Some-
bit 
what 
2 
2 
2 
2 
2 
2 
A little 
Some-
bit 
what 
2 
2 
2 
2 
2 
2 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
Quite 
a bit 
3 
3 
.., 
.) 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
19 November 2007 
Page 2 of3 


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FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
BR..\11 
I.EUI 
llH 
THl 
Htl2 
BMT6 
C6 
An7 
LF.tJS 
!.EU6 
I.EU 
ADDITIONA CONCERNS 
ot 
A little 
Some-
at all 
bit 
what 
I am bothered by fevers ( epi ode of high body 
temperature) ........................................................................ 
0 
I have certain parts of my body where I experience pain.... 
0 
I am bothered by the chills ...... .......................... .................. 
0 
I have night sweats ........................ ...................................... 
0 
I am bothered by lumps or swelling in certain parts of 
my body (e.g. neck armpits or groin) ................ .............. 
0 
I bleed easily ....................................................................... 
0 
I bruise easily .................................. .................................... 
0 
I feel weak all over.......................... ..................................... 
0 
I get tired easily __ ................................................................ 
0 
I an1losing weight ................................................................ 
0 
I have a good appetite .. ...................................................... . 
0 
I am able to do my usual activities ...................................... 
0 
I worry about getting infections . .. ...................................... 
0 
I feel uncertain about my future health ............................... 
0 
I worry that I might get new symptoms of my illness......... 
0 
I have ernotiona] ups and downs......................................... 
0 
I feel isolated from others because of my illness or 
treatment . . 
. . . . . .. . . . . . 
. . . . . . .. .. .. . .. 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Vety 
much 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
19 November 2007 
Page 3 of3 


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Appendix 3. 
Performance Status Scoring System 
Karnofsky Performance Status 
General Description 
Score 
Specific Description 
100 
Normal; no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of 
disease. 
Able to carry on normal 
activity and to work; no 
special care needed. 
80 
Normal activity with effort; some signs or symptoms of 
disease. 
70 
Cares for self; unable to carry on normal activity or to do 
active work. 
60 
Requires occasional assistance, but is able to care for most of 
personal needs. 
Unable to work; able to live 
at home and care for most 
personal needs; varying 
amount of assistance needed. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is indicated although 
death not imminent. 
20 
Very sick; hospital admission necessary; active supportive 
treatment necessary. 
10 
Moribund; fatal processes progressing rapidly. 
Unable to care for self; 
requires equivalent of 
institutional or hospital care; 
disease may be progressing 
rapidly. 
0 
Dead 
 


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Appendix 4. 
EuroQoL-5 Dimensions (EQ-5D) 
EuroQoL-5 Dimensions (EQ-5D) 
 
Sample 
By placing a checkmark in one-box in each group below, please indicate which 
best de.scribe. your own health state. today. 
lolobility 
I ha•:e no prol*ms in walking about 
I ha .. ·e some problems in walking about 
I am con:ined to bed 
Self-Care 
I have no problems with 
I have so.-ne prob'.ems. washing or dressi'lg myself 
I am unable to wash or dress myself 
Usual Activities 
work, study, housework, famity, or leisure activities) 
I ha ... e no problems with performing my usual activities 
I have some problems with performing my usual acti\Jlties 
I am unable to petform my usual activities 
Pain/Discomfort 
I have no pain ot discomfort 
I have moderate pai-l or discomfort 
I ha'le extreme pai\ or discomfort 
Anxiety/De1>ression 
I am no1 anxious ot deFNessed 
I am moderately anxious ot dep1essed 
I am extremely anxious or depressed 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 


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Sample 
To help people say how good or bad a health state i;, 
we h.aw drawn a scale (rather like a thennometer) on 
which the best state you can imagine is marked 100 
and the worst state you cau imagine is marked 0. 
We would like you to indicate on Ibis scale how good 
or bad your own healrh is today, in your opinion. 
Please do this by drawing a line from the box below 
to whichever point on the scale indicates how good or 
bad yonr health stare is today. 
Your own 
health state 
today 
100 
t 
f. f 
l r 
f I 
t• o t 
I 
0 
"'"""' 


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Original 
 
CONFIDENTIAL 
Page 146 
23 January 2012 
Appendix 5. 
Cockcroft-Gault Method for Estimating Creatinine Clearance  
Formulas for calculating the estimated creatinine clearance (eCcr) are provided in the table 
below. The formula appropriate to the units in which serum creatinine was measured and the 
subject’s gender should be used. 
Cockcroft-Gault Formulas for Calculating Estimated Creatinine Clearance 
Serum  
Creatinine Units Gender 
Formula 
 
 
 
 
 
(140-subject age [years]) × subject weight [kilograms] × 1
Males 
eCcr 
[mL/min] 
= 
72 × subject serum creatinine [mg/dl] 
 
 
 
 
 
 
 
 
(140-subject age [years]) × subject weight [kilograms] × 
0.85 
mg/dL 
Females 
eCcr 
[mL/min] 
= 
72 × subject serum creatinine [mg/dl] 
 
 
 
 
 
 
 
 
 
 
(140-subject age [years]) × subject weight [kilograms] × 
1.23 
Males 
eCcr 
[mL/min] 
= 
Subject serum creatinine [mg/dl] 
 
 
 
 
 
 
 
 
(140-subject age [years]) × subject weight [kilograms] × 
1.04 
µM/dL 
Females 
eCcr 
[mL/min] 
= 
Subject serum creatinine [mg/dl] 
 
 
 
 
 
 
Abbreviation: eCcr=estimated creatinine clearance 


GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 147 
23 January 2012 
Appendix 6. 
Cumulative Illness Rating Scale (CIRS) 
The CIRS used in this protocol is designed to provide an assessment of recurrent or ongoing 
chronic comorbid conditions, classified by 14 organ systems. Using the drop-down lists of 
organ-specific diagnoses, please select any conditions present in the study subject. If the 
subject has a recurrent or ongoing chronic conditions that are not described in the list for a 
given organ system, please indicate the name of the conditions under “other chronic 
condition” for that organ system. Please take into account that CLL-induced discomfort, 
symptoms, or disability should not be considered. If additional explanation would be helpful, 
text comments may be inserted.  
CIRS List of Comorbid Conditions 
Organ System 
Diagnosis 
Comment 
Chronic heart failure 
 
Angina pectoris 
 
Medically relevant arrhythmia 
 
Valve dysfunction 
 
Congenital heart disease 
 
Cardiomyopathy 
 
Myocarditis 
 
Chronic pericarditis 
 
Endocarditis 
 
Other chronic cardiac condition: 
 
Cardiac 
Other chronic cardiac condition: 
 
Hypertension 
 
Thrombosis 
 
Peripheral diabetic microvascular disease 
 
Peripheral artery disease 
 
Aortic aneurysm 
 
Aortitis 
 
Raynaud disease 
 
Vasculitis 
 
Other chronic vascular condition: 
 
Vascular 
Other chronic vascular condition 
 
Sickle cell anemia 
 
Hemoglobinopathy 
 
Polycythemia 
 
Thrombocythemia 
 
Hemophilia 
 
Paroxysmal nocturnal hemoglobinuria 
 
Thrombotic thrombocytopenic purpura 
 
Dysfibrinogenemia 
 
HIV 
 
Other chronic hematological or immunological 
condition: 
 
Hematological/ 
immunological 
Other chronic hematological or immunological condition 
 


GS-1101 
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Gilead Sciences, Inc. 
Original 
 
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Organ System 
Diagnosis 
Comment 
Asthma 
 
Chronic obstructive pulmonary disease 
 
Cystic fibrosis 
 
Emphysema 
 
Chronic bronchitis 
 
Chronic pleural effusions 
 
Pulmonary fibrosis 
 
Sarcoidosis 
 
Pulmonary embolism 
 
Pulmonary arterial hypertension 
 
Lung cancer 
 
Other chronic respiratory condition: 
 
Respiratory  
Other chronic respiratory condition 
 
Loss of vision  
 
Glaucoma 
 
Cataract 
 
Macular degeneration 
 
Diabetic retinopathy 
 
Loss of hearing 
 
Otitis/chronic otitis 
 
Vestibular impairment 
 
Vertigo 
 
Temporomandibular disorder 
 
Sialolithiasis  
 
Chronic sinusitis 
 
Laryngeal/pharyngeal disorders 
 
Ophthalmological/ 
otolaryngological 
Other chronic ophthalmological or otolaryngological 
condition: 
 
Chronic esophagitis 
 
Dysphagia 
 
Achalasia 
 
Gastroduodenal ulceration 
 
Celiac disease 
 
Irritable bowel syndrome 
 
Short bowel syndrome 
 
Malnutrition 
 
Malabsorption 
 
Small bowel obstruction 
 
Hernia 
 
Pseudomyxoma peritonei 
 
Upper gastrointestinal cancer 
 
Other chronic upper gastrointestinal condition: 
 
Upper  
gastrointestinal 
Other chronic upper gastrointestinal condition: 
 
Diverticulitis 
 
Inflammatory Hernia bowel disease 
 
Volvulus 
 
Colon cancer 
 
Other chronic lower gastrointestinal condition: 
 
Lower 
gastrointestinal 
Other chronic lower gastrointestinal condition: 
 
Chronic hepatitis or hepatic cirrhosis 
 
Biliary obstructive disorders 
 
Pancreatitis 
 
Hepatic, biliary, or pancreatic cancer 
 
Other chronic hepatic or pancreatic condition: 
 
Hepatic/ 
pancreatic 
Other chronic hepatic or pancreatic condition: 
 


GS-1101 
Protocol GS-US-312-0117 
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Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
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Organ System 
Diagnosis 
Comment 
Chronic kidney disease 
 
Diabetic nephropathy 
 
Pyelonephritis 
 
Renal cancer 
 
Other chronic renal condition: 
 
Renal  
Other chronic renal condition 
 
Recurrent/chronic urinary tract infection 
 
Nephrolithiasis 
 
Bladder dysfunction 
 
Vaginal/vulvar disease 
 
Uterine/ovarian disease 
 
Prostatitis 
 
Bladder, uterine, ovarian, prostate, or other cancer 
 
Prostate hypertrophy 
 
Other chronic gynecological or urological condition: 
 
Gynecological/ 
urological 
Other chronic gynecological or urological condition: 
 
Dermatitis 
 
Dermatomyositis 
 
Myopathy 
 
Gout 
 
Psoriasis 
 
Keratosis 
 
Urticaria 
 
Scleroderma 
 
Basal cell carcinoma 
 
Squamous cell carcinoma 
 
Melanoma 
 
Osteomyelitis 
 
Osteoarthritis 
 
Rheumatoid arthritis 
 
Spondyloarthritis 
 
Temporal arteritis/polymyalgia rheumatica 
 
Polychondritis 
 
Fibromyalgia 
 
Osteoporosis 
 
Systemic lupus erythematosus 
 
Dermatomyositis 
 
Sjögren syndrome 
 
Other chronic dermatological or musculoskeletal 
condition: 
 
Dermatologic/ 
musculoskeletal 
Other chronic dermatological or musculoskeletal 
condition: 
 


GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 150 
23 January 2012 
Organ System 
Diagnosis 
Comment 
Cerebrovascular disease (transient ischemic 
attack/stroke/hemorrhage) 
 
Dementia 
 
Parkinson disease 
 
Non-Parkinsonian movement disorder (eg, ataxia/chorea)
 
Leukodystrophic disorders 
 
Amyotrophic lateral sclerosis 
 
Multiple sclerosis 
 
Demyelinating disease 
 
Guillain-Barré syndrome 
 
Paralysis (eg, paraplegia/quadriplegia/hemiplegia) 
 
Myelopathy 
 
Cranial nerve disorder 
 
Degenerative disk disease with nerve root compression 
 
Migraine headaches 
 
Seizure disorder 
 
Secondary neuropathy (eg, 
diabetic/alcoholic/autoimmune) 
 
Neurofibromatosis/tuberous sclerosis 
 
Benign or malignant central nervous system tumor 
 
Other chronic neurological condition: 
 
Neurological 
Other chronic neurological condition: 
 
Diabetes 
 
Adrenal disorder 
 
Thyroid disorder 
 
Parathyroid disorder 
 
Pheochromocytoma 
 
Pituitary disorder 
 
Hemochromatosis 
 
Porphyria 
 
Paget's disease 
 
Endocrine or neuroendocrine tumor 
 
Other chronic endocrine or metabolic condition: 
 
Endocrine/ 
metabolic 
Other chronic endocrine or metabolic condition: 
 
Depression 
 
Anxiety 
 
Bipolar disorder 
 
Paranoia 
 
Schizophrenia 
 
Neurosis 
 
Personality disorder 
 
Substance addiction/abuse 
 
Posttraumatic stress disorder 
 
Chronic fatigue syndrome 
 
Other chronic psychiatric condition: 
 
Psychiatric 
Other chronic psychiatric condition: 
 
Abbreviation:  CIRS=Cumulative Illness Rating Scale 


GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 151 
23 January 2012 
For each condition selected from the CIRS List of Comorbid Conditions, please rate the 
severity of that condition. For the severity rating, please use the scoring guidelines shown in 
the table below, considering the magnitude of symptoms, how manageable the condition is, 
and the extent of intervention required: 
CIRS Rating Scale 
Score 
Severity 
Findings 
1 
Mild 
Mild discomfort, symptoms or disability 
Easy to control 
Requiring either no therapy/medication or only as needed 
2 
Moderate 
Moderate  discomfort, symptoms or disability 
Manageable 
Requiring daily treatment or first-line therapy 
3 
Severe 
Severe discomfort, symptoms or disability 
Hard to control 
Requiring second-line therapy or multiple medications 
4 
Extremely 
severe 
Life threatening, permanently disabling disability, causing organ 
failure 
Poorly manageable 
Requiring urgent intervention or resistant to therapy 
Abbreviation:  CIRS=Cumulative Illness Rating Scale 
 


PPD
GS-1101 
Protocol GS-US-312-0117 
Gilead Sciences, Inc. 
A 
d' 7 
IX . 
S h d I 
c e u eo f S d P 
tu ly roce 
Pel'iod 
Screen 
Visit 
1 
2 
3 
Week 
-4 
0 
2 
Within 
Study Day 
-28 
1 
15 
Davs 
Visit Window 
±2 
Informed consent 
X 
CIR.S assessment 
X 
(women of childbearing potential) 
X 
X 
CLL peripheral blood evaluation 
X 
CLL serology 
X 
IWRS 
X 
X 
X 
I 
HRQL/healthy utility - FACT-Leu/EQ-50 
X 
X 
Adverse events 
X 
X 
Concomitant medications 
X 
X 
X 
Performance status 
X 
X 
X 
Physical exam (includes nodes, liver, spleen) 
X 
X 
Oxygen saturation (by pulse oximetry) 
X 
X 
X 
Hematology 
X 
X 
X 
Serum chemistry 
X 
X 
X 
Circulating cells 
X 
X 
Biomarkers 
X 
X 
Serumlgs 
X 
X 
Study drug administration in clinic 
X 
X 
GS-1101 pharmacokinetics 
X 
X 
Study drug dispensing/accounting 
X 
Radiology assessment (CTIMRJ) 
X 
Bone marrow biopsy/aspirate 
X 
Post-treatment CLL therapy 
Long-term follow-up 
d ures 
4 
5 
6 
7 
4 
6 
8 
10 
29 
43 
57 
71 
±2 
±2 
±2 
±2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x" 
a 
For follow-up Vlstts after Week 96, CT or MRI ts only requtred at the end-of-treatment VlStt. 
Treatment 
8 
9 
10 
11 
12 
13 
14 
12 
16 
20 
24 
30 
36 
42 
85 
113 
141 
169 
211 
253 
295 
±2 
±3 
±3 
±3 
±3 
±3 
±3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x" 
x" 
x" 
15 
16+ 
48 
Q12 
End of 
337 Weeks treatment 
±3 
±7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x" 
x• 
x" 
x" 
x" 
Final 
Original 
Follow-up 
Post-
Long-
therapy term 
Within 
To 
+30 
+5 
days 
years 
l 
I 
X 
X 
X 
X 
b 
At baseline, to be performed at investigator discretion to determine extent of CLL involvement and bone marrow cellularity. Post-baseline, to be performed to confirm response category in 
subjects with potential CR by physical examination and radiological assesstnents. 
Abbre"iations: 13-HCG=beta human chorionic gonadotropin, CIR.S=chronic illness rating scale, CLL=chronic lymphocytic leukemia, CR=complete response, CT=computed tomography, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assesstnent of Cancer Therapy- Leukemia, HRQL= health-related quality of life, lg=intmunoglobulin, IWRS=interactive web response 
system, MRI= magnetic resonance intaging. 
CONFIDENTIAL 
Page 152 
23 Januaty 2011 

Prot_011.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and 
Safety of Two Different Dose Levels of Single-Agent Idelalisib
(GS-1101) for Previously Treated Chronic Lymphocytic Leukemia
A Companion Trial to Study GS-US-312-0116: A Phase 3, Randomized, 
Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of Idelalisib (GS-1101) in Combination with Rituximab for 
Previously Treated Chronic Lymphocytic Leukemia
Sponsor:
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102
USA
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
EudraCT Number:
101254
2011-006293-72
Indication:
Chronic Lymphocytic Leukemia 
Protocol ID:
GS-US-312-0117
Gilead Sciences
Medical Monitor:
Name:
Telephone:
Office Fax:
Mobile Telephone:
E-mail:
Protocol Version/Date:
Version 1.0 (Original)
23 January 2012
Version 2.0 (Amendment 1)
23 January 2013
Version 3.0 (Amendment 2)
10 September 2013
Version 4.0 (Amendment 3)
16 December 2013
Version 5.0 (Amendment 4)
27 May 2014
Version 6.0 (Amendment 5)
10 October 2014
Version 7.0 (Amendment 6)
28 March 2016
Version 8.0 (Amendment 7)
05 August 2016
Version 9.0 (Amendment 8)
24 October 2016
Version 10.0 (Amendment 9)
21 September 2017
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or under 
control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, potential 
investigator, or consultant, for review by you, your staff, and an applicable institutional review board 
or independent ethics committee. This information is only to be used by you in connection with 
authorized clinical studies of the investigational drug described in the protocol. You must not 
disclose any of the information to others without written authorization from Gilead Sciences, Inc., 
except to the extent necessary to obtain informed consent from those persons to whom the drug may 
be administered.
PPD
PPD
PPD
PPD
PPD


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 10.0
CONFIDENTIAL
Page 2
21 September 2017
TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................6
LIST OF IN-TEXT FIGURES ......................................................................................................................................6
PROTOCOL SYNOPSIS ..............................................................................................................................................7
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................19
1.
INTRODUCTION ..............................................................................................................................................23
1.1.
Chronic Lymphocytic Leukemia............................................................................................................23
1.2.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies....................................................................24
1.3.
Idelalisib (formerly GS-1101)................................................................................................................25
1.3.1.
General Information .............................................................................................................25
1.3.2.
Safety Pharmacology............................................................................................................25
1.3.3.
Nonclinical Pharmacology and Metabolism.........................................................................26
1.3.4.
Toxicology ...........................................................................................................................27
1.3.5.
Idelalisib Clinical Studies.....................................................................................................27
1.4.
Summary and Justification for the Current Study ..................................................................................31
2.
STUDY DESIGN................................................................................................................................................34
2.1.
Design Overview and Study Schema .....................................................................................................34
2.2.
Design Rationale ....................................................................................................................................35
3.
OBJECTIVES AND ENDPOINTS ....................................................................................................................37
3.1.
Endpoints ...............................................................................................................................................37
3.1.1.
Tumor Control......................................................................................................................37
3.1.2.
Patient Well-Being ...............................................................................................................38
3.1.3.
Pharmacodynamic Markers of Drug Activity and Resistance..............................................39
3.1.4.
Exposure...............................................................................................................................39
3.1.5.
Safety....................................................................................................................................39
3.1.6.
Pharmacoeconomics.............................................................................................................39
3.2.
Endpoint Selection Rationale.................................................................................................................39
3.2.1.
Tumor Control Endpoints.....................................................................................................39
3.2.2.
Measures of Patient Well-Being...........................................................................................42
3.2.3.
Pharmacodynamic Markers of Drug Activity and Resistance..............................................43
3.2.4.
Assessments of Exposure .....................................................................................................45
3.2.5.
Evaluations of Safety............................................................................................................45
3.2.6.
Pharmacoeconomic Measures ..............................................................................................46
4.
SUBJECT POPULATION..................................................................................................................................47
4.1.
Number of Subjects................................................................................................................................47
4.2.
Subject Selection Criteria.......................................................................................................................47
4.2.1.
Inclusion Criteria..................................................................................................................47
4.2.2.
Exclusion Criteria.................................................................................................................49
4.3.
Enrollment Criteria Rationale ................................................................................................................50
5.
TREATMENT OF SUBJECTS ..........................................................................................................................51
5.1.
Enrollment..............................................................................................................................................51
5.1.1.
Interactive Web Response System .......................................................................................51
5.1.2.
Treatment Assignment .........................................................................................................51
5.1.3.
Blinding................................................................................................................................52


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 10.0
CONFIDENTIAL
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21 September 2017
5.2.
Investigational Study Drug (Idelalisib/Placebo) ....................................................................................53
5.2.1.
Description ...........................................................................................................................53
5.2.2.
Source...................................................................................................................................53
5.2.3.
Packaging and Labeling .......................................................................................................53
5.2.4.
Storage and Handling...........................................................................................................54
5.2.5.
Dispensing............................................................................................................................54
5.2.6.
Return...................................................................................................................................55
5.2.7.
Accountability......................................................................................................................55
5.2.8.
Overdose Precautions...........................................................................................................55
5.2.9.
Inadvertent Exposure and Spill Precautions.........................................................................56
5.3.
Study Drug Administration....................................................................................................................56
5.3.1.
Premedication.......................................................................................................................56
5.3.2.
Administration Instructions..................................................................................................56
5.3.3.
Dosing Schedule...................................................................................................................56
5.3.4.
Dose Levels..........................................................................................................................56
5.3.5.
Dose Schedule Interruptions and Vomited Doses ................................................................57
5.3.6.
Safety Monitoring and Study Drug Interruption/Dose Modification ...................................57
5.4.
Evaluation, Intervention, and Drug Discontinuation for Specific Adverse Events or 
Conditions ..............................................................................................................................................61
5.4.1.
Dermatological Events .........................................................................................................61
5.4.2.
Gastrointestinal Events.........................................................................................................62
5.4.3.
Hepatic Events......................................................................................................................64
5.4.4.
Hematological and Immunological Events...........................................................................65
5.4.5.
Infectious Events..................................................................................................................65
5.4.6.
Progressive Multifocal Leukoencephalopathy .....................................................................66
5.4.7.
Pulmonary Events ................................................................................................................66
5.4.8.
Secondary Malignancies.......................................................................................................67
5.4.9.
Tumor Lysis Syndrome........................................................................................................67
5.4.10.
Pregnancy, Lactation, and Reproduction..............................................................................67
5.4.11.
Ultraviolet Exposure ............................................................................................................69
5.4.12.
Further Safety Information...................................................................................................69
5.5.
Emergency Unblinding ..........................................................................................................................69
5.6.
Concomitant and Supportive Therapy....................................................................................................69
5.6.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments............................................................................................................................70
5.6.2.
Antibiotics............................................................................................................................70
5.6.3.
Antiemetics and Antidiarrheals............................................................................................70
5.6.4.
Contraception .......................................................................................................................71
5.6.5.
Corticosteroids .....................................................................................................................72
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin..............................................72
5.6.7.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism..................................................72
5.6.8.
Drugs that undergo CYP3A-Dependent Metabolism...........................................................73
5.6.9.
Immunization .......................................................................................................................73
5.6.10.
Surgery .................................................................................................................................73
5.6.11.
Diet.......................................................................................................................................73
5.7.
Duration of Study Drug..........................................................................................................................73
5.8.
Discontinuation of Study Drug ..............................................................................................................73
5.9.
Discontinuation from Study ...................................................................................................................74
5.10.
Study Treatment Rationale.....................................................................................................................75
6.
STUDY PROCEDURES ....................................................................................................................................77
6.1.
Enrollment and Study Management Procedures ....................................................................................77
6.1.1.
Subject Recruitment .............................................................................................................77
6.1.2.
Subject Compensation for Participation...............................................................................77


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 10.0
CONFIDENTIAL
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6.1.3.
Screening..............................................................................................................................77
6.2.
Explanation of Study Visits....................................................................................................................78
6.2.1.
Visit 1 and Screening Period (Clinic Visit)..........................................................................79
6.2.2.
Visit 2 (Day 1) (Clinic Visit)................................................................................................81
6.2.3.
Visit 3 (Day 15) (Clinic Visit)..............................................................................................82
6.2.4.
Visit 4 (Day 29) (Clinic Visit)..............................................................................................83
6.2.5.
Visit 5 (Day 43) (Clinic Visit)..............................................................................................85
6.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit) .....................................................................86
6.2.7.
Visit 7 (Day 71) (Laboratory Visit)......................................................................................87
6.2.8.
Visit 8 (Day 85) (Clinic Visit)..............................................................................................88
6.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit) ...................................................................90
6.2.10.
Visit 10 (Day 141) (Clinic Visit)..........................................................................................92
6.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit) .................................................................94
6.2.12.
Visit 12 (Day 211) (Clinic Visit)..........................................................................................96
6.2.13.
Visit 13 (Day 253) (Clinic and Radiology Visit) .................................................................97
6.2.14.
Visit 14 (Day 295) (Clinic Visit)..........................................................................................98
6.2.15.
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks) (Clinic 
and Radiology Visits)...........................................................................................................99
6.2.16.
End-of-Study Visit (Clinic Visit) .......................................................................................101
6.2.17.
30 Day and Long-Term Follow-up.....................................................................................102
6.3.
Sample Storage.....................................................................................................................................102
6.4.
Blood Collection ..................................................................................................................................103
6.5.
Study Procedure Rationale...................................................................................................................103
7.
EFFICACY ASSESSMENTS...........................................................................................................................104
7.1.
Tumor Status Assessments...................................................................................................................104
7.2.
Method of Assessment .........................................................................................................................104
7.3.
Timing of Assessments ........................................................................................................................104
7.4.
Identification and Measurement of Tumor Lesions and Organomegaly ..............................................105
7.4.1.
Index Lesions .....................................................................................................................105
7.4.2.
Spleen and Liver.................................................................................................................106
7.4.3.
Non-Index Lesions .............................................................................................................106
7.5.
Definitions of Tumor Response and Progression.................................................................................106
7.5.1.
Complete Response............................................................................................................107
7.5.2.
Partial Response .................................................................................................................107
7.5.3.
Stable Disease ....................................................................................................................108
7.5.4.
Definitive Progressive Disease...........................................................................................108
7.5.5.
Non-Evaluable....................................................................................................................110
7.5.6.
No Disease .........................................................................................................................110
7.5.7.
Lymphocytosis During Therapy.........................................................................................111
7.5.8.
Documentation of Definitive CLL Progression..................................................................111
8.
SAFETY ASSESSMENTS...............................................................................................................................112
8.1.
Adverse Event Definitions ...................................................................................................................112
8.1.1.
Adverse Event ....................................................................................................................112
8.1.2.
Serious Adverse Event .......................................................................................................113
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .......................................................................114
8.2.
Assessment of Adverse Events and Serious Adverse Events...............................................................114
8.2.1.
Assessment of Causality for Study Drugs and Procedures.................................................115
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.....................................................................................................................115
8.4.
Gilead Reporting Requirements...........................................................................................................116
8.5.
Grading of the Severity of an Adverse Event.......................................................................................116


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 10.0
CONFIDENTIAL
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8.6.
Adverse Event Reporting Period..........................................................................................................117
8.7.
Adverse Event Reporting Requirements ..............................................................................................117
8.7.1.
Site Reporting Requirements..............................................................................................117
8.7.2.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population.........................................................119
8.8.
Special Situations Reporting Requirements.........................................................................................119
8.8.1.
Definitions of Special Situations........................................................................................119
8.9.
Instructions for Reporting Special Situations.......................................................................................120
8.9.1.
Instructions for Reporting Pregnancies ..............................................................................120
8.9.2.
Reporting Other Special Situations ....................................................................................121
9.
STATISTICAL CONSIDERATIONS..............................................................................................................122
9.1.
Analysis Objectives..............................................................................................................................122
9.2.
Analysis Endpoints...............................................................................................................................122
9.3.
Analysis Conventions...........................................................................................................................122
9.3.1.
Analysis Sets ......................................................................................................................122
9.3.2.
Data Handling Conventions ...............................................................................................123
9.4.
Analysis Plan........................................................................................................................................125
9.4.1.
Subject Disposition and Baseline Characteristics...............................................................125
9.4.2.
Efficacy Analyses...............................................................................................................126
9.4.3.
Exposure and Safety Analyses ...........................................................................................127
9.4.4.
Other Analyses ...................................................................................................................129
9.5.
Sample Size..........................................................................................................................................130
9.6.
Timing of Analyses..............................................................................................................................131
10.
RESPONSIBILITIES........................................................................................................................................132
10.1.
Investigator Responsibilities ................................................................................................................132
10.1.1.
Compliance with Ethical and Regulatory Guidelines.........................................................132
10.1.2.
Institutional Review Board/Independent Ethics Committee ..............................................132
10.1.3.
Informed Consent...............................................................................................................133
10.1.4.
Confidentiality....................................................................................................................133
10.1.5.
Study Files and Retention of Records and Biological Samples..........................................133
10.1.6.
Case Report Forms.............................................................................................................135
10.1.7.
Drug Accountability...........................................................................................................135
10.1.8.
Inspections..........................................................................................................................136
10.1.9.
Protocol Compliance..........................................................................................................136
10.2.
Sponsor Responsibilities ......................................................................................................................136
10.2.1.
Protocol Modifications.......................................................................................................136
10.2.2.
Communications with Regulatory Authorities...................................................................136
10.2.3.
Data Management ..............................................................................................................137
10.2.4.
Study Reporting and Publication........................................................................................137
10.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................138
10.3.1.
Access to Information for Monitoring................................................................................138
10.3.2.
Access to Information for Auditing or Inspections ............................................................138
10.3.3.
Public Notification of Study Conduct ................................................................................138
10.3.4.
Study Discontinuation........................................................................................................138
10.4.
Study Committees ................................................................................................................................139
10.4.1.
Data Monitoring Committee ..............................................................................................139
10.4.2.
Independent Review Committee ........................................................................................140
11.
REFERENCES .................................................................................................................................................141


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12.
APPENDICES ..................................................................................................................................................151
Appendix 1.
Investigator Signature Page..................................................................................................152
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) ...................................153
Appendix 3.
Performance Status Scoring System.....................................................................................156
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D) ........................................................................................157
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance ............................................159
Appendix 6.
Cumulative Illness Rating Scale (CIRS) ..............................................................................160
Appendix 7.
Schedule of Study Procedures..............................................................................................162
LIST OF IN-TEXT TABLES
Table 4-1.
Required Screening Laboratory Values..................................................................................48
Table 5-1.
Study Drug Dose Levels.........................................................................................................57
Table 5-2.
Recommendations and Requirements for Study Drug Dose Modifications Based on 
Type and Severity of Treatment-Related Adverse Events or Laboratory 
Abnormalities .........................................................................................................................58
Table 5-3.
Protocol-Recommended Contraceptive Methods ...................................................................71
Table 5-4.
Known Strong Inducers of CYP3A........................................................................................72
Table 6-1.
Procedures and Assessments at Visit 1 (During Screening Period)........................................80
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1) .....................................................................81
Table 6-3.
Procedures and Assessments at Visit 3 (Day 15) ...................................................................82
Table 6-4.
Procedures and Assessments at Visit 4 (Day 29) ...................................................................83
Table 6-5.
Procedures and Assessments at Visit 5 (Day 43) ...................................................................85
Table 6-6.
Procedures and Assessments at Visit 6 (Day 57) ...................................................................86
Table 6-7.
Procedures and Assessments at Visit 7 (Day 71) ...................................................................87
Table 6-8.
Procedures and Assessments at Visit 8 (Day 85) ...................................................................88
Table 6-9.
Procedures and Assessments at Visit 9 (Day 113) .................................................................90
Table 6-10.
Procedures and Assessments at Visit 10 (Day 141) ...............................................................92
Table 6-11.
Procedures and Assessments at Visit 11 (Day 169) ...............................................................94
Table 6-12.
Procedures and Assessments at Visit 12 (Day 211) ...............................................................96
Table 6-13.
Procedures and Assessments at Visit 13 (Day 253) ...............................................................97
Table 6-14.
Procedures and Assessments at Visit 14 (Day 295) ...............................................................98
Table 6-15.
Procedures and Assessments at Visit 15 and Subsequent Visits (Day 337 and Every 
12 Weeks)...............................................................................................................................99
Table 6-16.
Procedures and Assessments at End-of-Study Visit.............................................................101
Table 8-1.
Grading of Adverse Event Severity......................................................................................117
Table 8-2.
Site Reporting Requirements for Adverse Events ................................................................118
Table 8-3.
Contact Information for Reporting Serious Adverse Events ................................................119
LIST OF IN-TEXT FIGURES
Figure 2-1.
Study Design ..........................................................................................................................34
Figure 5-1.
Kaplan-Meler Time to Diarrhea or Colitis .............................................................................63


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
199 East Blaine Street
Seattle, WA 98102, USA
Study Title:
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and 
Safety of Two Different Dose Levels of Single-Agent Idelalisib
(GS-1101) as Therapy for Patients with Previously Treated Chronic 
Lymphocytic Leukemia
A Companion Study to Study GS-US-312-0116: A Phase 3, Randomized, 
Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of Idelalisib (GS-1101) in Combination with Rituximab as 
Therapy for Patients with Previously Treated Chronic Lymphocytic 
Leukemia
Study Centers 
Planned:
Approximately 90 centers in the United States and in Europe
IND Number:
EudraCT Number:
101254
2011-006293-72
Objectives:

To evaluate the effect of idelalisib (formerly GS-1101) on the onset, 
magnitude, and duration of tumor control

To compare tumor control in subjects receiving rituximab alone in 
Study GS-US-312-0116 to that observed in the same subjects when 
receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject well-being, 
including overall survival (OS), health-related quality of life 
(HRQL), and performance status

To assess the effects of idelalisib on disease-associated biomarkers 
and to evaluate potential mechanisms of resistance to idelalisib

To characterize exposure to idelalisib as determined by treatment 
administration and evaluation of idelalisib plasma concentrations 
over time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with 
administration of idelalisib


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Study Design:
This study is being conducted as part of an overall clinical program 
evaluating the efficacy and safety of idelalisib in the therapy of patients 
with previously treated chronic lymphocytic leukemia (CLL).
Within this program, the primary clinical trial (Study GS-US-312-0116)
is a Phase 3, multicenter, 2-arm, randomized, double-blind, 
placebo-controlled, parallel-group study.
This clinical trial (Study GS-US-312-0117) is a separate, multicenter, 
2-arm, double-blind, parallel-group extension study that is a companion 
trial to Study GS-US-312-0116; in this trial, compliant subjects from 
GS-US-312-0116 who are tolerating primary study therapy but 
experience definitive CLL progression are eligible to receive active 
blinded idelalisib therapy at the standard dose or a higher dose, with 
allocation based on the original primary study randomization. In the 
event GS-US-312-0116 is stopped early due to overwhelming efficacy 
following an interim analysis or at the final analysis, subjects who are on 
Study GS-US-312-0116 at that time may transition to GS-US-312-0117. 
Additionally, GS-US-312-0117 will become an open-label study
offering idelalisib 150 mg BID to GS-US-312-0116 subjects who were
randomized to placebo, and subjects randomized to idelalisib will 
continue idelalisib at 150 mg BID.
Study Schema:
Treatment Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117)


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Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID
Treatment Assignment

Assignment to Arm A or Arm B with allocation based on the 
original primary study randomization

Implementation through an interactive web response system (IWRS)
Stratification
Not applicable for Study GS-US-312-0117
Number of 
Subjects Planned:
Total of up to ~180 subjects (up to ~90 subjects per treatment arm)
Target 
Population:
Subjects in the primary Phase 3 study (GS-US-312-0116) who are 
compliant, are tolerating primary study therapy, and 1) have definitive 
progression of CLL while receiving primary study drug therapy 
(idelalisib/placebo) or 2) are actively participating in 
Study GS-US-312-0116 at the time the study is stopped, including if 
stopped early due to overwhelming efficacy following an interim analysis.
Duration of 
Treatment:
Study drug will be taken continuously until the earliest of subject 
withdrawal from study drug, definitive progression of CLL, intolerable 
study drug-related toxicity, pregnancy, substantial noncompliance with 
study procedures, or study discontinuation. Idelalisib administration will
be continued only in subjects whose benefit-risk profile is deemed 
positive by the investigator.
Diagnosis and 
Main Eligibility 
Criteria:
Inclusion Criteria
Subjects must meet all of the following conditions to be eligible for 
enrollment into the study:
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while 
receiving study drug therapy (idelalisib /placebo) in 
Study GS-US-312-0116. Note: Definitive disease progression is 
CLL progression based on standard criteria and occurring for any 
reason (ie, increasing lymphadenopathy, organomegaly, or bone 
marrow involvement; decreasing platelet count, hemoglobin, or 
neutrophil count; or worsening of disease-related symptoms) other 
than lymphocytosis. Subjects must have confirmation by the 
sponsor working in collaboration with an independent review 
committee (IRC) that the disease has progressed on the primary 
clinical trial (Study GS-US-312-0116) before receiving secondary 
idelalisib therapy on this extension trial (Study GS-US-312-0117).


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3) Presence of measurable lymphadenopathy (defined as the presence 
of ≥1 nodal lesion that measures 2.0 cm in the longest diameter 
[LD] and 1.0 cm in the longest perpendicular diameter [LPD] as 
assessed by computed tomography [CT] or magnetic resonance 
imaging [MRI]).
4) Permanent cessation of Study GS-US-312-0116 treatment 
(rituximab and/or idelalisib/placebo) and no intervening or 
continuing therapy (including radiotherapy, chemotherapy, 
immunotherapy, or investigational therapy) for the treatment of 
CLL. Note: Subjects may receive corticosteroids to manage CLL 
manifestations.
5) The time from permanent cessation of Study GS-US-312-0116 
treatment (rituximab and/or idelalisib/placebo) and the initiation of 
Study GS-US-312-0117 therapy is 12 weeks. Note: Study 
procedures performed as part of Study GS-US-312-0116 need not 
be repeated and can be used as screening procedures for 
Study GS-US-312-0117 if performed within 4 weeks prior to 
initiation of study drug therapy on Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation 
of study treatment) as shown in the table below. Note: Confirmation 
should be considered for out-of-range values to determine if the 
abnormality is real or artifactual. Values should be obtained within 
the screening period and should generally be the most recent 
measurement obtained. Subjects with any degree of neutropenia, 
thrombocytopenia, or anemia due to CLL or prior therapy may 
enroll.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCr
a
>30 ml/min
Pregnancy
-HCGb
Negative
a
As calculated by the Cockcroft-Gault formula {Cockcroft 1976}
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or 
urine dipstick pregnancy test must be negative at randomization (Visit 2)
Abbreviations: -HCG=beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
eCCr=estimated creatinine clearance, ULN=upper limit of normal


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8) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening 
visit (Visit 1) throughout the study and for 30 days from the last dose 
of study drug. Note: A female subject is considered to be of 
childbearing potential unless she has had a hysterectomy, bilateral 
tubal ligation, or bilateral oophorectomy; has medically 
documented ovarian failure (with serum estradiol and 
follicle-stimulating hormone [FSH] levels within the institutional 
postmenopausal range and a negative serum or urine -HCG), or 
is menopausal (defined as age ≥54 years with amenorrhea for 
>12 months or amenorrhea for >6 months with serum estradiol 
and FSH levels within the institutional postmenopausal range).
9) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of 
study drug (Visit 2) throughout the study and for 90 days following 
the last dose of study drug and to refrain from sperm donation from 
the start of study drug (Visit 2) throughout the study and for 90 days 
following the last dose of study drug. Note: A male subject is 
considered able to father a child unless he has had a bilateral 
vasectomy with documented aspermia or a bilateral orchiectomy, 
or has ongoing testicular suppression with a depot luteinizing 
hormone- releasing hormone (LH-RH) agonist 
(eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), 
or triptorelin pamoate [Trelstar®]).
10) In the judgment of the investigator, participation in the protocol 
offers an acceptable benefit-to-risk ratio when considering current 
CLL disease status, medical condition, and the potential benefits and 
risks of alternative treatments for CLL.
11) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, 
familial, or geographical factors that might preclude adequate 
study participation should be considered.
12) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study 
participation.


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Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be 
enrolled in this study:
1) Known histological transformation from CLL to an aggressive 
lymphoma (ie, Richter transformation). 
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at 
the time of the start of study treatment (Visit 2). Note: Subjects with 
localized fungal infections of skin or nails are eligible. Subjects 
may be receiving prophylactic antiviral or antibacterial therapies at 
the discretion of the investigator; anti-pneumocystis prophylaxis is 
encouraged. 
3) Pregnancy or breastfeeding.
4) Intentional breaking of the blind in Study GS-US-312-0116 by the 
investigator or the study subject.
5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical condition, 
surgical history, physical finding, electrocardiogram (ECG) finding, 
or laboratory abnormality that, in the investigator’s opinion, could 
adversely affect the safety of the subject or impair the assessment of 
study results.
In the event Study GS-US-312-0116 is stopped early, subjects who are 
actively participating in Study GS-US-312-0116 will become eligible for 
this study, provided the following inclusion are met:
1) Participation in Study GS-US-312-0116 within 12 weeks of 
enrollment onto GS-US-312-0117.
2) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the screening 
visit (Visit 1) throughout the study and for 30 days from the last dose 
of study drug. 
3) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the start of
study drug (Visit 2) throughout the study and for 90 days following 
the last dose of study drug and to refrain from sperm donation from 
the start of study drug (Visit 2) throughout the study and for 90 days 
following the last dose of study drug.
4) In the judgment of the investigator, participation in the protocol 
offers an acceptable benefit-to-risk ratio when considering current 
CLL disease status, medical condition, and the potential benefits and 
risks of alternative treatments for CLL.


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5) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, 
familial, or geographical factors that might preclude adequate 
study participation should be considered.
6) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature 
of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study 
participation.
Study Procedures/
Frequency:
Clinic/laboratory visits will occur every 2 weeks for the first 12 weeks, 
every 4 weeks between Weeks 12 and 24, and every 6 weeks between 
Weeks 24 and 48. Subjects continuing on study drug past Week 48 will 
have clinic visits every 12 weeks. Subjects will be assessed for safety at 
each visit. Subjects will be assessed for CLL disease status by physical 
and laboratory examinations at each visit and by CT or MRI at 
Weeks 8, 16, 24, 36, and 48 and every 12 weeks thereafter. As of 
Amendment 9, Version 10, CT/MRI assessments will no longer be 
performed at the every 12 week scheduled visits, and will only be 
performed at the time of clinically-suspected disease progression or at 
study discontinuation.
Following unblinding of the study:

Subjects who were randomized to idelalisib on 
Study GS-US-312-0116 and who received ≥24 weeks idelalisib will 
complete Visit 16+ twelve weeks from the date of their last 
radiology assessment (CT/MRI) and study visits will continue every 
12 weeks thereafter. Visits 3 through 15 will not be required.

Subjects who have received < 24 weeks idelalisib will have all 
Study GS-US-312-0117 assessments completed per the 
Schedule of Procedures until they have received idelalisib for 
24 weeks cumulative across both studies. After completion of 
24 weeks of cumulative idelalisib treatment, Visit 16+ will be 
conducted 12 weeks from the date of their last radiology assessment 
(CT/MRI), after which time study visits will occur every 12 weeks.
Test Therapy, Dose, 
and Mode of 
Administration:
Blinded Portion

Arm A: Idelalisib, 300 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be provided 
as 2 tablets of active idelalisib for oral administration

Arm B: Idelalisib, 150 mg/dose BID starting on Day 1 and administered 
continuously thereafter; the study drug will be provided as 1 tablet of
active idelalisib and 1 tablet of placebo for oral administration


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Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly 
enrolled subjects will receive 150 mg BID
Note: At the Investigator’s discretion, subjects who were randomized 
to placebo on study GS-US-312-0116 may delay initiation of idelalisib 
following enrollment on Study GS-US-312-0117 until the time of 
disease progression or until the investigator determines that the 
subject would benefit from initiation of idelalisib treatment
Reference Therapy, 
Dose, and Mode of 
Administration:
Not applicable
Criteria for 
Evaluation:
Tumor Control

Progression-free survival (PFS) – defined as the interval from the 
start of study therapy to the earlier of the first documentation of 
definitive disease progression or death from any cause; definitive 
disease progression is CLL progression based on standard criteria 
other than lymphocytosis alone

Overall response rate (ORR) – defined as the proportion of subjects 
who achieve a complete response (CR) or partial response (PR)

Lymph node response rate – defined as the proportion of subjects 
who achieve a 50% decrease from baseline in the sum of the 
products of the greatest perpendicular diameters (SPD) of index 
lesions

CR rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from start of study 
therapy to the first documentation of CR or PR

Duration of response (DOR) – defined as the interval from the 
first documentation of CR or PR to the earlier of the first 
documentation of definitive disease progression or death from any 
cause

Percent change in lymph node area – defined as the percent change 
from baseline in the SPD of index lymph nodes

Splenomegaly response rate – defined as the proportion of subjects 
with baseline splenomegaly who achieve an on-study normalization 
or a 50% decrease (minimum 2 cm) from baseline in the 
enlargement of the splenic LVD (by imaging)


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
Hepatomegaly response rate – defined as the proportion of subjects 
with baseline hepatomegaly who achieve an on-study normalization 
or a 50% decrease (minimum 2 cm) from baseline the hepatic 
longest vertical dimension (LVD) (by imaging)

ALC response rate – defined as the proportion of subjects with 
baseline lymphocytosis (ALC4 x 109/L) who achieve an on-study 
ALC <4 x 109/L or demonstrate a 50% decrease in ALC from 
baseline (ALC values within 4 weeks post-baseline will be excluded 
from the ALC response rate evaluation)

Platelet response rate – defined as the proportion of subjects with 
baseline thrombocytopenia (platelet count <100 x 109/L) who 
achieve an on-study platelet count 100 x 109/L or demonstrate a 
50% increase in platelet count from baseline without need for 
exogenous growth factors (Platelet values within 4 weeks 
post-baseline or within 8 days post transfusion will be excluded from 
the platelet response rate evaluation)

Hemoglobin response rate – defined as the proportion of subjects 
with baseline anemia (hemoglobin <110 g/L [11.0 g/dL]) who 
achieve an on-study hemoglobin 110 g/L (11.0 g/dL) or 
demonstrate a 50% increase in hemoglobin from baseline without 
red blood cell transfusions or need for exogenous growth factors 
(eg erythropoietin)

Neutrophil response rate – defined as the proportion of subjects with 
baseline neutropenia (absolute neutrophil count [ANC] ≤1.5 x 109/L) 
who achieve an ANC >1.5 x 109/L or demonstrate a 50% increase 
in ANC from baseline without need for exogenous growth factors 
(eg, G-CSF)
Patient Well-Being

Overall survival (OS) – defined as the interval from start of study 
therapy to death from any cause

Change from baseline in HRQL domain and symptom scores based 
on the Functional Assessment of Cancer Therapy: 
Leukemia (FACT-Leu) (See Appendix 2)

Changes from baseline in Karnofsky performance status 
(See Appendix 3)
Pharmacodynamic Markers of Drug Activity and Resistance

Changes from baseline in PI3K/AKT/mTOR pathway activation as a 
measure of PI3Kpathway activity

Changes from baseline in the plasma concentrations of 
disease-associated chemokines and cytokines


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Exposure

Study drug administration as assessed by prescribing records and 
compliance as assessed by quantification of used and unused drug

Trough (pre-dose) and peak (~1.5-hour samples) of idelalisib plasma 
concentrations as assessed by a validated bioanalytical method
Safety

Overall safety profile of each regimen characterized by the type, 
frequency, severity, timing of onset, duration, and relationship to 
study therapy of any adverse events or abnormalities of laboratory 
tests; serious adverse events; or adverse events leading to 
discontinuation of study drug
Pharmacoeconomics

Change in health status – defined as the change from baseline in 
overall health and single-item dimension scores as assessed using the 
EuroQoL Five-Dimension (EQ-5D) utility measure

Health resource measures, including resource utilization, total costs, 
and measures of cost per unit of benefit (eg, cost per additional 
progression-free month, cost per quality-adjusted life-year)
Statistical Methods:
Appropriate data analysis sets will be defined. The intent-to-treat (ITT) 
analysis set will include data from all subjects who receive 1 dose of 
any study therapy on this study; in this data set, study drug assignment 
(high-dose or standard-dose idelalisib) will be designated according to 
the planned allocation to this study. A safety analysis set will comprise 
data from subjects in the ITT analysis set with treatment assignments 
designated according to the actual study drug (high-dose or 
standard-dose idelalisib) received. Other analysis sets [per-protocol (PP) 
and pharmacodynamic/pharmacokinetic analysis sets] will be used for 
certain analyses as well.
Subject characteristics and study results will be described and 
summarized by treatment arm and assessment for the relevant analysis 
sets. Descriptive summaries will be prepared to show sample size, mean, 
standard deviation, 95% confidence intervals (CIs) on the mean, median, 
minimum, and maximum for continuous variables and counts, 
percentages, and 95% CIs on the percentage for categorical variables.
An independent review committee (IRC) will review radiographic data 
and pertinent clinical data in order to provide expert evaluation of tumor 
status. The findings of the IRC will be considered primary for analyses 
of PFS and other tumor control endpoints.


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For endpoints relating to tumor control, patient well-being, and 
biomarkers, analyses will be done based on ITT, PP or 
pharmacodynamic data sets, as appropriate. Blinded portion of the study 
analyses will be presented in the following two groups:

IDELA 300 mg BID: Subjects who have PD per IRC confirmation in 
Arm A of Study GS-US-312-0116 and subsequently enroll into 
Study GS-US-312-0117 to receive IDELA 300 mg BID during the 
double-blind portion of the study

Placebo in GS-US-312-0116 + IDELA 150 mg BID in 
GS-US-312-0117: Subjects who have PD per IRC confirmation in 
Arm B of Study GS-US-312-0116 and subsequently enroll in 
Study GS-US-312-0117 to receive IDELA 150 mg BID during the 
double-blind portion of the study.
After unblinding, open-label extension study analyses will be presented 
in the following 4 groups:

IDELA 150 mg BID: Subjects who are randomized to Arm A in 
Study GS-US-312-0116 and transition to Study GS-US-312-0117 
during the open-label portion of the study to continue IDELA 
150 mg BID

Placebo in GS-US-312-0116 + IDELA 150 mg BID (open-label): 
Subjects who are randomized to Arm B in Study GS-US-312-0116 
and transition to receive IDELA 150 mg BID during the open-label 
portion of the study

IDELA 300 mg BID: Subjects who have PD per IRC confirmation in 
Arm A of Study GS-US-312-0116 and subsequently enroll 
Study GS-US-312-0117 to receive IDELA 300 mg BID during the 
double-blind portion of the study

Placebo in GS-US-312-0116 + IDELA 150 mg BID in 
GS-US-312-0117: Subjects who have PD per IRC confirmation in 
Arm B of Study GS-US-312-0116 and subsequently enroll 
Study GS-US-312-0117 to receive IDELA 150 mg BID during the 
double-blind portion of the study. Analyses will focus on evaluation 
of outcomes within each treatment arm and will be descriptive in 
nature; formal comparisons of outcomes between arms are not 
planned. Time-to-event endpoints will be summarized using 
Kaplan-Meier methods; medians, ranges, and the corresponding 
95% CI will be presented. Continuous and categorical variables will 
also be summarized as appropriate. Changes from baseline in 
categorical variables and changes from baseline in continuous 
endpoints will be analyzed using appropriate methods.


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Efficacy outcomes among subjects receiving rituximab alone in 
Study GS-US-312-0116 will be evaluated relative to those same 
outcomes among the same subjects receiving standard-dose idelalisib 
alone in Study GS-US-312-0117. 
Based on the safety analysis set, information regarding study drug 
administration, study drug compliance, safety variables, and post-study 
therapies will be described and summarized. Using data from the 
pharmacokinetic analysis set, idelalisib plasma concentrations will also 
be described and summarized.
Sample Size Calculation
The sample size for this extension study is not based upon a formal 
statistical hypothesis. The upper bound of the sample size in this study is 
determined by the sample size of the preceding primary clinical trial
(Study GS-US-312-0116) in which ~180 subjects (~90 per arm) are 
expected to be enrolled. Assuming a ~10% dropout rate during 
Study GS-US-312-0116 and a further ~10% dropout rate in the 
transition from the primary study to the extension study, ~180 subjects 
are expected to be enrolled into Study GS-US-312-0117.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP), 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
-HCG
Beta human chorionic gonadotropin
ABCG2
adenosine triphosphate-binding cassette sub-family G member 2 (see also BCRP)
AKT
AKT (a serine/threonine protein kinase)
ALC
absolute lymphocyte count
ALL
acute lymphocytic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
ATC
Anatomical-Therapeutic-Chemical classification system for drugs 
BCRP
breast cancer resistance protein (see also ABCG2)
BID
twice per day
BTK
Bruton tyrosine kinase
CAL-101
Former name for GS-1101
CCL
chemokine (C-C motif) ligand
CFR
Code of Federal Regulations
CI
confidence interval
CIRS
Cumulative Illness Rating Scale
CLL
chronic lymphocytic leukemia
cGMP
current Good Manufacturing Practice
Cmax
maximum concentration
CMV
cytomegalovirus
CR
complete response
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough concentration
CXCL
chemokine (C-X-C motif) ligand
CYP
cytochrome P450 enzyme
DLCO
diffusing capacity of the lung for carbon monoxide
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DOR
duration of response
DSPH
Gilead Sciences Department of Safety and Public Health
ECG
electrocardiogram


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eCCr
estimated creatinine clearance
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EQ-5D
EuroQoL Five-Dimension utility measure
FACT-Leu
Functional Assessment of Cancer Therapy: Leukemia questionnaire
FCεRI
high-affinity IgE receptor
FDA
United States Food and Drug Administration
FDAMA
Food and Drug Modernization Act
FDG
fluorodeoxyglucose (18F)
FISH
fluorescence in-situ hybridization,
FSH
follicle-stimulating hormone
G-CSF
granulocyte colony-stimulating factor
GGT
gamma-glutamyltransferase
GLP
Good Laboratory Practice
GM-CSF
granulocyte-macrophage colony-stimulating factor
HBc antibody
anti-hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
hERG
human ether-à-go-go-related gene
HL
Hodgkin lymphoma
HIV
human immunodeficiency virus
HRQL
health-related quality of life
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
idelalisib
formerly CAL-101 and GS-1101
IEC
independent ethics committee
Ig
immunoglobulin (including subtypes A, E, G, and M)
IgHV
immunoglobulin heavy chain variable region
IND
Investigational New Drug (application)
iNHL
indolent non-Hodgkin lymphoma
INR
international normalized ratio
IRB
institutional review board
IRC
independent review committee
ITT
intention to treat
IUD
intrauterine device
IWCLL
International Workshop on CLL
IWRS
interactive web response system
JAK
Janus kinase


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K2-EDTA
potassium-ethylenediaminetetraacetic acid
LD
longest diameter
LDH
lactate dehydrogenase
LH-RH
luteinizing hormone-releasing hormone
LLN
lower limit of normal
LPD
longest perpendicular diameter
LVD
longest vertical dimension
MTD
maximum tolerated dose
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mTOR
mammalian target of rapamycin
ND
no disease
NHL
non-Hodgkin lymphoma
NOAEL
no-observed-adverse effect level
NOEL
no-observed-effect level
OCT
organic cation transporter
ORR
overall response rate
OS
overall survival
pAKT
phosphorylated AKT
PCR
polymerase chain reaction
PD
progressive disease
PET
positron-emission tomography
PFS
progression-free survival
PI3K
phosphatidylinositol 3-kinase
PI3K
phosphatidylinositol 3-kinase p110isoform
PJP
Pneumocystis jiroveci pneumonia
PML
progressive multifocal leukoencephalopathy
PP
per-protocol
PPD
product of the perpendicular diameters
PRO
patient-reported outcome
PR
partial response
PT
prothrombin time
PVA
polyvinyl alcohol
PVC/PCTFE
polyvinyl chloride/polychlorotrifluoroethylene
QD
once per day
QT (interval)
measure of time between start of Q wave and end of T wave in electrical cycle of heart
RNA
ribonucleic acid
SADR
serious adverse drug reaction
SD
stable disease


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SPD
sum of the products of the perpendicular diameters of measured lymph nodes
SSC
study steering committee
SJS
Stevens-Johnson Syndrome
SUSAR
suspected, unexpected, serious adverse reaction
SYK
spleen tyrosine kinase
t1/2
half-life
TEN
Toxic Epidermal Necrolysis
Tmax
time of maximum concentration
TTR
time to response
UGT
uridine 5'-diphospho-glucuronosyltransferase
ULN
upper limit of normal
WHODRUG
World Health Organization Drug Dictionary
ZAP-70
zeta-associated protein 70


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1.
INTRODUCTION
1.1.
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is a neoplasia resulting from the progressive accumulation 
of functionally incompetent monoclonal B lymphocytes in blood, bone marrow, lymph nodes, 
spleen, and liver {Dighiero 2008}. CLL constitutes the most commonly occurring leukemia in 
Europe and the United States {Sant 2010, Surveillance Epidemiology and End Results (SEER) 
Program 2011}. While some patients never require treatment, many will need therapy for
disfiguring or obstructing lymphadenopathy, debilitating constitutional B symptoms 
(fevers, night sweats, fatigue, weight loss) {Redaelli 2004}, or recurrent cytopenias and 
infections {Keating 2002b, Perkins 2002}. CLL is largely a disease of the elderly; at diagnosis, 
70% of patients are 65 years of age and the median age is 72 years {Surveillance Epidemiology 
and End Results (SEER) Program 2011}.
In younger and relatively healthy patients with CLL, chemoimmunotherapy regimens that 
include the anti-CD20 monoclonal antibody, rituximab, are commonly employed to control 
disease manifestations {Gribben 2011}. Such combination therapies are effective in providing 
durable remissions {Byrd 2005, Fischer 2011, Hallek 2010, Iannitto 2011, Robak 2010}. 
However, while rituximab is usually well tolerated {Gentile 2010}, the chemotherapeutic agents 
(typically fludarabine, cyclophosphamide, or bendamustine) in such regimens are acutely 
cytotoxic, induce permanent bone marrow compromise, and can cause secondary malignancies 
{Carney 2010, Kyasa 2004, Tam 2008}. Furthermore, in elderly patients or in those with 
comorbid conditions, such regimens are associated with less efficacy and greater toxicity 
{Eichhorst 2009b, Goede 2011, Tam 2008}.
Increasing attention has been paid to the problem of treating patients with CLL who have 
comorbidities. Because of the relatively late age of diagnosis, a large proportion (~90%) of 
patients with CLL have co-morbidities and a substantial proportion (~45%) have major chronic 
conditions such as coronary artery disease, diabetes, or chronic obstructive pulmonary disease 
{Thurmes 2008}. At the time the disease is first identified, ~25% of patients with CLL do not 
meet conventional criteria for participation in clinical studies containing cytotoxic agents 
{Thurmes 2008}. By the time treatment is necessary or during treatment for CLL, patients 
continue to advance in age and have new or worsening chronic conditions; as a result, the 
proportion of patients with comorbidities increases during the course of the illness. Such patients 
have been substantially underrepresented in clinical trials due to concerns regarding the ability of 
such patients to tolerate intensive chemoimmunotherapy {Eichhorst 2009a, Thurmes 2008}. 
Instruments such as the Cumulative Illness Rating Scale (CIRS) {Linn 1968} are now being 
applied in order to categorize patient populations as fit or relatively unfit and to evaluate 
regimens tailored to these groups of patients {Del Giudice 2011, Eichhorst 2009a, Hallek 2010}.
Health constraints in older or compromised patients have prompted noncytotoxic approaches to 
therapy. Alternative immunotherapeutics, such as the monoclonal antibodies, alemtuzumab
{Keating 2002a} or ofatumumab {Wierda 2010}, have been developed. However the therapeutic 


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utility of these drugs is modest; median progression-free survival (PFS) values in patients with 
recurrent CLL have been 4.7 months and 5.8 months, respectively. Moreover, these treatments 
can have clinical liabilities. Alemtuzumab causes extreme immunosuppression that leads to 
frequent opportunistic infection. Administration of the large amounts of protein recommended in 
ofatumumab product labeling results in frequent infusion reactions and cumbersome infusion 
schedules.
In view of these issues, repeated use of rituximab monotherapy or rituximab-corticosteroid 
combinations have been advocated in treatment guidelines for older or frail patients with 
recurrent CLL {Eichhorst 2010, Zelenetz 2011}. While single-agent rituximab use can offer 
palliative benefit with good tolerability in some patients with previously treated CLL, tumor 
control is not lasting, especially in patients with bulky adenopathy {Gentile 2010}. Addition of 
high-dose corticosteroids to rituximab can extend median PFS up to 12 months, but this 
combination is commonly associated with severe hyperglycemia and frequent life-threatening or 
fatal infections {Bowen 2007, Dungarwalla 2008}. New, noncytotoxic, well-tolerated, and 
convenient therapies that can successfully be combined with rituximab or given as single-agent 
therapy are needed in order to enhance and prolong tumor control in patients with comorbid 
conditions.
1.2.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies
Phosphatidylinositol 3-kinases (PI3Ks) are enzymes that regulate several cellular functions 
including motility, proliferation, and survival {Okkenhaug 2003b}. PI3K activation recruits and 
activates numerous intracellular signaling enzymes. The most important of these is the 
serine/threonine kinase, AKT, which mediates a positive pleiotropic effect on cell survival, 
proliferation, growth, and metabolism {Engelman 2006} acting by signaling through mammalian 
target of rapamycin (mTOR) {Hay 2005, Osaki 2004}.
PI3K signaling is mediated by 4 catalytic isoforms of the p110 subunit of the enzyme - , , , 
and . While potentially important in multiple cell types, PI3K p110(PI3K) shows an 
expression pattern that is particularly prominent in cells of hematopoietic origin 
{Vanhaesebroeck 2005}. Mice deficient in PI3Khave no gross abnormalities, are fertile, 
fecund, and live a normal life span without an increased susceptibility to infections {Okkenhaug 
2003a}. However, the B-lymphocyte population in these animals shows a decrease in maturation, 
diminished receptor-induced proliferation, and increased susceptibility to apoptotic cell death.
Conversely, mice with aberrantly elevated PI3K signaling develop lymphadenopathy and have 
an increased incidence of lymphoma {Donahue 2004}. In CLL, sustained activation of the 
PI3K/AKT/mTOR pathway has been shown to promote malignant B-cell survival through 
mechanisms that are dependent on the PI3Kisoform {Cuni 2004, Herman 2010, Lannutti 
2011}.
Knowledge of the critical importance of PI3Kδ in B-cell biology and neoplasia has encouraged a 
search for inhibitors of this enzyme that could provide new options in the therapy of lymphoid 
malignancies, including CLL.


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1.3.
Idelalisib (formerly GS-1101)
1.3.1.
General Information
Idelalisib was approved in the US on July 23, 2014 and in the European Union on 
September 18, 2014. Refer to local labeling for the approved indication statements and dosing 
recommendations.
Gilead Sciences, Inc has developed novel drugs that can suppress tumor growth through 
targeting of PI3Kδ activity. High-throughput screening was the basis for the discovery of novel 
agents that selectively inhibit PI3Kfunction but spare other PI3K isoforms and other kinases. 
Chemical optimization, pharmacological characterization, and toxicological evaluation have led 
to identification of idelalisib (also known as GS-1101), a 415-dalton, orally bioavailable, 
new chemical entity with potential clinical utility in the treatment of cancers.
In primary tumor samples and in cell lines derived from patients with CLL, indolent 
non-Hodgkin lymphoma (iNHL), mantle cell lymphoma (MCL), B-cell acute lymphocytic 
leukemia (ALL), or Hodgkin lymphoma (HL), idelalisib induces dose-dependent reductions in 
AKT phosphorylation {Herman 2010, Lannutti 2011, Meadows 2010}. In addition, idelalisib
disrupts the PI3Kactivation and supportive intercellular signaling observed when CLL or HL 
cells are cocultured with stromal cells {Hoellenriegel 2011, Meadows 2010}. These effects have 
therapeutic consequences. In multiple lymphoid primary tumors and malignant cell lines, 
idelalisib enhances apoptosis and concentration-dependent cell killing when applied as a single 
agent and increases the therapeutic efficacy of other antineoplastic agents when given in 
combination {Hoellenriegel 2011, Meadows 2011}. In preclinical systems, coadministration of 
idelalisib with rituximab has not impaired rituximab-mediated activity {Herman 2010}.
1.3.2.
Safety Pharmacology
In vitro and in vivo safety pharmacology studies with idelalisib have demonstrated a favorable 
non-clinical safety profile. These studies indicate that the drug may minimally slow bone marrow 
progenitor proliferation and differentiation and that it has expected inhibitory effects on 
B-cell response to antigen challenge. However, the data indicate that idelalisib is unlikely to 
cause serious off-target effects or adverse effects on critical organ systems. Idelalisib has no 
meaningful effect on the human ether-à-go-go-related gene (hERG) channel, indicating that 
idelalisib would not be expected to induce clinical QT prolongation.
The drug has also proved well tolerated in standard in vivo Good Laboratory Practice (GLP) 
studies of pharmacological safety. A functional observation battery in rats revealed no adverse 
effects on behavior or on autonomic, neuromuscular, or sensorimotor function. In a 
cardiopulmonary function study in awake, telemeterized male beagle dogs, single doses of 
idelalisib induced no meaningful abnormalities in pulmonary, cardiovascular, arterial blood gas, 
or electrocardiographic (ECG) (including QT interval) parameters. In an assessment of bacterial 
challenge in rats, idelalisib enhanced, rather than impaired, the phagocytic host clearance of 
staphylococcal bacteria.


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1.3.3.
Nonclinical Pharmacology and Metabolism
Consistent with the moderate to high bioavailability seen in nonclinical species, idelalisib shows 
high permeability across human Caco-2 cell monolayers.  At lower concentrations, the reverse 
permeability at low concentration exceeds forward permeability, indicating efflux driven by 
transporters (eg, human P-glycoprotein (MDR1) and breast cancer resistance protein [BCRP]); 
idelalisib is a substrate for the efflux transporters MDR1 and BCRP; however, the permeability 
increases in a concentration-dependent manner, resulting in a lower efflux ratio at higher, 
clinically relevant concentrations of idelalisib.
Idelalisib exhibits moderately high plasma protein binding in mouse, rat, dog, and human. In dog 
and human plasma, the protein binding is concentration-independent between 1 and 20 µM. 
Protein binding in human plasma is slightly higher than in mouse, rat, and dog plasma, which 
have comparable free fractions.  In human plasma, idelalisib and GS-563117 
(the major metabolite of idelalisib) have an average free fraction of ~16% and ~12%, respectively.
After oral administration of 14C-idelalisib to rats and dogs, radioactivity is widely distributed, but 
relatively excluded from bone, brain, spinal cord, and eye lens in rats and from brain and eyes in 
dogs. In rats, the radioactivity declines steadily and most tissues have undetectable levels by 
72 hours post dose.  In bile duct-cannulated rats and dogs, ≥69% of radioactivity is recovered in 
bile and urine, indicating high absorption of idelalisib in vivo.
In hepatic tissues from nonclinical species, idelalisib is primarily metabolized by 
aldehyde oxidase, CYP3A, and UGT1A4.  In vitro metabolism in dog and human yields 
3 primary oxidative metabolites and 5 primary glucuronides. Of these, the oxidative product 
GS-563117 is the predominant metabolite in vitro and in vivo. In preclinical species, plasma 
levels of GS-563117 are below those of idelalisib. In humans, GS-563117 
(only circulating metabolite and formed via aldehyde oxidase) plasma levels significantly exceed 
those of idelalisib. After oral administration of 14C-idelalisib to rats and dogs, biliary excretion 
appears to be the major route of elimination of idelalisib and its metabolites as the majority of 
radioactivity is found in feces or bile and little in urine.
Idelalisib is not a substrate for the renal transporters OCT2, OAT1, and OAT3 or the 
hepatic uptake transporters OATP1B1 and OATP1B3.  GS-563117 is not a substrate for 
OATP1B1 and OATP1B3.
Idelalisib is not an inhibitor of CYP1A, CYP2B6, CYP2C9, and CYP2D6, and at concentrations 
above those observed clinically, is an inhibitor of CYP2C8 (IC50 = 13 µM), CYP2C19 
(IC50 = 76 µM), and CYP3A (IC50 = 44 µM). GS-563117 is not an inhibitor of CYP1A, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and a competitive and time dependent 
inhibitor of CYP3A (IC50 = 3.1 µM), (KI = 0.18 µM, kinact = 0.033 min-1 with midazolam as 
the probe substrate).
In vitro, idelalisib is not an inhibitor of the transporters BCRP, OCT2, OAT1, and OAT3, and is 
an inhibitor of MDR1 (IC50 = 7.7 µM), OATP1B1 (IC50 = 10.1 µM), OATP1B3 (IC50 = 7.0 µM),
and, at concentrations above those observed clinically, of glucuronosyltransferase UGT1A1 


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(IC50 = 42.0 µM). GS-563117 is not an inhibitor of MDR1, BCRP, OATP1B1, OATP1B3, 
OAT1, OAT3, and OCT2, and at concentrations above those observed clinically, an inhibitor of 
UGT1A1 (IC50 = 16.8 µM).
Any potential clinical implications of these metabolism studies were evaluated in a formal 
drug-drug interaction study (GS-US-313-0130) which evaluated the effect of idelalisib on 
cytochrome P450 3A and the drug transporters P-gp, OATP1B1, and OATP1B3. 
Study GS-US-313-0130 also evaluated the impact of an inducer of metabolizing enzymes and 
transporters (rifampin) on the PK of idelalisib in healthy human subjects. Findings from this 
study are presented in Section 1.3.5.1.
1.3.4.
Toxicology
The toxicological profile of idelalisib was well characterized through the conduct of single dose, 
repeat dose, developmental and reproductive, and genetic toxicology and local tolerance studies. 
The primary target organ toxicities following repeated dosing include the lymphoid, hepatic, 
male reproductive systems in rats and dogs, and gastrointestinal system in dogs. Adverse effects 
in the lymphoid system were primarily the result of on target pharmacology resulting in 
decreased lymphocytes in multiple lymphoid organs, primarily involving B-cell regions. Liver 
effects were transient and reversible with continued dosing and did not result in chronic liver 
injury. Reduction in sperm numbers in males were reversible and did not impact fertility or 
reproductive performance.  Gastrointestinal effects in dogs were minor, superficial, and 
considered secondary to effects on lymphocytes in Peyer’s Patches. Idelalisib was shown to be 
teratogenic and associated with embryo-fetal lethality. Effects on the reproductive system have 
been reported for inhibitors which target other isoforms of PI3K. The dose-dependence and 
potential of idelalisib to selectively inhibit additional PI3K isoforms may be responsible for the 
off-target toxicity. Additionally, the drug may have the potential to produce phototoxic reactions 
in humans. These findings represent toxicities that can be monitored, are considered clinically 
manageable, or are considered acceptable risks in the intended patient population.
Further details on the toxicology of idelalisib can be found in the Idelalisib 
Investigator’s Brochure (IB).
1.3.5.
Idelalisib Clinical Studies
1.3.5.1.
Phase 1 Studies in Healthy Subjects and in Patients with Allergic Rhinitis
Various studies in healthy subjects have evaluated safety, pharmacokinetics, food effect, and the 
potential for drug interactions of idelalisib with CYP3A4 inhibitors {Webb 2010}.
Safety results from these studies indicated that idelalisib was well tolerated when administered to 
healthy subjects at single doses through 400 mg (the highest dose level tested) and was also 
generally well tolerated when administered to healthy subjects over 7 days at dose levels through 
200 mg/dose BID (the highest dose level tested). Dosing with 200 mg/dose BID for 7 days 
resulted in a skin rash in 3 out of 6 subjects; histological findings were consistent with a 
delayed-type hypersensitivity maculopapular exanthema. Rashes have sometimes occurred in 


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patients with hematological malignancies receiving idelalisib, but have not typically proved 
dose- or treatment-limiting. In placebo-controlled single-dose and multiple-dose trials, repeated 
ECG evaluations performed in tandem with pharmacokinetic monitoring showed no evidence of 
drug-, dose-, or exposure-dependent effects on cardiac rhythm or cardiac intervals 
(eg, QT interval). Pharmacokinetic results indicated that idelalisib appeared rapidly in plasma 
with a median Tmax of 1 to 1.5 hours. Cmax and AUC increased in a less-than-dose-proportional 
manner and mean t1/2 values were across the dose range were 6.5 to 9.8 hours.
Idelalisib dosing after a high-fat, high-calorie meal delayed median time of 
maximum concentration (Tmax) from 0.75 hours to 3 hours; mean Cmax was unaffected and 
mean AUC was ~40% higher. These changes in idelalisib exposures are considered 
modest/clinically non-relevant; thus, idelalisib may be given with or without food.
Idelalisib is metabolized in humans primarily by aldehyde oxidase, with some involvement of 
CYP3A4 and UGT1A4. Accordingly, when idelalisib was administered following 4 days of daily 
dosing with ketoconazole (a potent inhibitor of CYP3A4), modest/moderate increases in mean 
idelalisib Cmax and AUC values of ~30% and ~80% higher, respectively, which is not considered 
to be clinically relevant and suggesting that idelalisib is a weak CYP3A substrate. GS-563117 is 
formed from idelalisib primarily via aldehyde oxidase.
The 14C-labeled idelalisib human mass balance results showed that the drug has moderate to high 
oral bioavailability. Idelalisib is eliminated mainly via hepatic metabolism and biliary excretion 
in the feces (~78% of dose); recovery in urine was < 15%. GS-563117, the only circulating 
metabolite observed in human plasma, was also observed in urine and feces.
Results from the drug interaction/probe Study GS-US-313-0130 indicate that idelalisib does not 
affect the pharmacokinetics of substrates of Pgp, BCRP, OATP1B1 or OATP1B3 transporters. 
Idelalisib is not expected to affect the exposures of coadministered agents via transporter 
mediated interactions.
The exposures (AUC) of probe CYP3A substrate, midazolam, increased ~5-fold upon 
coadministration with idelalisib, driven by competitive and time-dependent CYP3A inhibition by
GS-563117, the only circulating metabolite of idelalisib. Coadministration of the highly potent 
CYP3A inducer rifampin resulted in a ~75% reduction in idelalisib systemic exposures, likely 
driven by a higher relative contribution of CYP3A to overall idelalisib clearance under the 
induced state.
Pharmacodynamic results showed that a idelalisib dose of 200 mg inhibited ex vivo basophil 
activation via the PI3K-specific, high-affinity immunoglobulin (Ig)E receptor (anti-FCR1) in 
basophils collected from healthy volunteers. The findings were confirmed when the drug was 
assessed over 7 days in a Phase 1b study in subjects with allergic rhinitis. In this study, idelalisib
at a dose level of 100 mg/dose BID showed clinical and pharmacodynamic activity 
(attenuating adverse responses to allergenic challenge and decreasing markers of inflammation) 
and was well tolerated.


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1.3.5.2.
Phase 1 Studies in Patients with Hematological Malignancies
1.3.5.2.1.
Phase 1 Monotherapy Study in Patients with Hematological Malignancies
A Phase 1 dose-ranging study (Study 101-02) of single-agent idelalisib extended safety and 
pharmacokinetic observations; documented the clinical and pharmacodynamic activity of 
idelalisib in subjects with iNHL, MCL, and CLL; and provided dosing information in support of
further development {Brown 2011, Coutre 2011, Kahl 2011}. In this study, idelalisib was 
administered in cohorts of subjects across a range of dose levels from 50 mg/dose BID to 
350 mg/dose BID. Idelalisib administration was continued as long as individual subjects were 
safely benefitting from therapy. Subjects were evaluated in 4-week cycles; response and 
progression assessments were based on standard criteria {Hallek 2008}.
A total of 191 subjects were enrolled to the study at dose levels of 50 mg BID (n=17), 
150 mg QD (n=16), 100 mg BID (n=25), 150 mg BID (n=45), 200 mg BID (n=35), 
350 mg BID (n=17), and 300 mg QD (n=19). An additional cohort was also enrolled to receive 
idelalisib 150 mg BID in 28 day cycles (21 days on idelalisib/7 days off [n=17]). Subject
characteristics were as follows: males/females n=139 (73%)/52 (27%) with median age of 
64.5 (range 32-91) years. Diagnoses included: CLL, n=54 (28%); iNHL, n=64 (34%); aggressive 
NHL (MCL and DLBCL), n=49 (26%); AML, n=12 (6%); and MM, n=12 (6%). Categorization 
of disease by response to the last prior therapy included: refractory, n=111 (58%); 
relapsed, n=79 (42%); and unknown, n=1 (1%).  The median (range) number of prior therapies 
was 5 (1-14). Among subjects with iNHL and CLL, the majority had received prior rituximab 
and prior alkylating agent therapy.
Adverse events were usually mild to moderate and not clearly idelalisib-related. Among 
Grade ≥3 adverse events, pneumonias and diarrhea were notable. Pneumonia was observed in 
23 (12%) subjects, primarily in subjects with CLL. In most instances, these findings were 
considered bacterial in origin, based either on culture results or on response to conventional 
antibiotics. Grade ≥3 adverse events of diarrhea were seen in 11 subjects (5.8%). Other 
Grade ≥3 events included rash in 3 (1.6%) subjects. The relative contributions of disease-related 
factors, toxicity from prior therapies or ongoing supportive care, and idelalisib to these events 
was not clear.
Grade ≥3 hematological laboratory abnormalities have included neutropenia, n=46 (24%); 
thrombocytopenia, n=27 (14%), anemia, n=14 (7.3%), and lymphopenia 13 (6.8%); with 
12 subjects (6.3%) having febrile neutropenia.  The occurrence of these events was greater in 
subjects with leukemia, particularly in those with pre-existing hematological abnormalities due 
to disease or prior therapy, commonly making attribution of these events to idelalisib uncertain.
Consistent with the observations in the 28-day dog toxicology study, reversible Grade ≥3 
ALT/AST elevations occurred in 28 (15%) subjects and have been attributed to idelalisib. Onset 
generally occurred between 2 to 16 weeks after idelalisib initiation and resolution was usually 
seen 2 to 6 weeks after idelalisib interruption.  After resolution of ALT/AST increases, 
14 subjects were rechallenged at the same or a reduced dose of idelalisib and 9 (64%) of these 
subjects were able to resume treatment without recurrence of transaminase elevations.
Two (1.0%) subjects had ≥ 2 x ULN elevations in bilirubin in the context of Grade ≥3 


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elevated AST/ALT, both of whom had confounding factors (recent history of biliary obstruction 
or concomitant use of potentially hepatotoxic medications) so that a definitive causal relationship 
to idelalisib could not be established.
Pharmacokinetic analyses indicated that the increase in Cmax and AUC0-6h with dose was less 
than dose-proportional, with modest increases above the dose level of 150 mg BID.
Pharmacodynamic data supported drug activity.  In subjects with NHL, plasma concentrations of 
chemokines CCL22 and CCL17 were elevated at baseline and showed significant decreases 
within 1 cycle of idelalisib treatment (p<0.001 for both comparisons). Flow cytometry of CLL 
cells from subjects showed that idelalisib reduced constitutive expression of phosphorylated 
AKT to background levels when measured after 1 week of treatment (p<0.0001), demonstrating 
pharmacodynamic inhibition of activated PI3K signaling.  Plasma concentrations of 
chemokines CCL3, CCL4, and CXCL13 were elevated in CLL subjects at baseline and 
decreased significantly within 1 cycle of idelalisib administration (p<0.001 for all comparisons).
Tumor reductions meeting antitumor response criteria were not observed in subjects with AML 
or MM. One of 11 subjects with DLBCL achieved a PR.  In 104 subjects with iNHL and MCL, 
idelalisib induced PRs at all dose levels, with respective ORRs in enrolled subjects of 
29/64 (45%) for iNHL and 16/40 (40%) for MCL. The median DOR has not been reached in 
subjects with iNHL; 19 subjects continued to receive idelalisib in a long-term extension study. 
The median [range] DOR was 2.7 months [1 month to 8 months] in subjects with MCL; 
6 MCL subjects continued to receive idelalisib in a long-term extension study.
In subjects with CLL, idelalisib reduced lymphadenopathy in almost all subjects; 
44/54 (81.5%) achieved a lymph node response (≥50% reduction in target nodal lesions). An 
initial increase in peripheral absolute lymphocyte counts of >50% from baseline was observed in 
some subjects; increases were maximal during the first 2 cycles and decreased thereafter; the 
pattern suggested drug-mediated lymphocyte redistribution.  In 54 subjects with CLL, 
39/54 (72%) achieved a PR (includes PR with lymphocytosis).  The median DOR was not 
reached; 23 subjects continued to receive idelalisib in a long-term extension study.
1.3.5.2.2.
Phase 1 Combination Study in Patients with Hematological Malignancies
A separate Phase 1 trial (Study 101-07) has evaluated the safety and preliminary activity of 
idelalisib given in combination with rituximab to subjects with recurrent iNHL or CLL {Brown 
2011, Leonard 2011}.
In this study, rituximab was administered at a standard dose of 375 mg/m2 per infusion weekly 
for 8 weeks in all subjects. Idelalisib was started simultaneously with the rituximab, first at a 
dose level of 100 mg/dose BID (n=13) and then at a dose level of 150 mg/dose BID (n=12) and 
was administered continuously to both subjects with CLL (n=13) and subjects with iNHL (n=12)
for as long as individual subjects were safely benefiting from therapy. Subjects were evaluated in 
4-week cycles; response and progression assessments were based on standard criteria {Hallek 
2008}.


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Among the subjects with CLL, the median age was 63 and ranged to 85 years. Bulky tumors 
(1 lymph node 5 cm in diameter) were present in 63% of the subjects. The median number of 
prior therapies by disease was 2 and ranged up to 8 prior treatments. All had received prior 
rituximab and the majority had received prior fludarabine or alkylating agents. Approximately 
one-third of subjects had CLL that was refractory to the last prior therapy. At the time of data 
cut-off, therapy had been administered for a median of 5 cycles, ranging up to 12 cycles 
(ie, 48 weeks).
No idelalisib-related dose-limiting toxicities were observed within the tested subject cohorts. 
Grade 3-4 adverse events largely comprised background events resulting from pre-existing 
disease- or treatment-related conditions or from intercurrent illness. Among subjects with CLL, 
2 (15%) developed pneumonia. For subjects receiving idelalisib together with rituximab, 
Grade 3-4 elevations in ALT/AST were not observed in those with CLL, although 
3 subjects (25%) of those with iNHL had such events.
The idelalisib plus rituximab combination showed a high level of antitumor activity in both 
subjects with CLL and those with iNHL. Altogether 92% of subjects with CLL receiving the 
combination of idelalisib and rituximab had reductions in nodal size and 77% showed a 
lymph node response (50% reduction in index nodal lesions). Although concomitant 
administration of rituximab did not eliminate the redistribution lymphocytosis that is associated 
with idelalisib, it blunted the magnitude of the change. As a result, the overall response rate 
(ORR) was also 77% among subjects participating in this study. At the time of last data analysis, 
PFS through 48 weeks was 70% and a median PFS had not yet been observed.
Collectively, the emerging data from this study support further evaluation of idelalisib together 
with rituximab in subjects with CLL and indicate that co-administration of idelalisib with 
rituximab is tolerable when using idelalisib at full dose, ie, at a starting dose level of 
150 mg/dose BID.
For additional or updated information, please refer to the current version of the IB.
1.4.
Summary and Justification for the Current Study
Gilead Sciences is conducting this Phase 3 study program to evaluate the efficacy and safety of 
idelalisib in patients with previously treated, recurrent CLL. Collectively the data derived from 
the primary clinical trial (Study GS-US-312-0116) and from this extension trial 
(Study GS-US-312-0117) address the activity of idelalisib together with rituximab, the activity 
of idelalisib when given alone, and the potential for dose-dependent restoration of drug activity 
in subjects who have disease that appears to be drug resistant.
The design and conduct of this clinical trial program is supported by knowledge of the 
demographics of patients with CLL, the natural history and current therapies for the disease, and 
the nonclinical and clinical information regarding idelalisib. The collective data support the 
following conclusions:


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
CLL is a serious, disabling, and potentially life-threatening disorder of older patients that 
requires sequential treatment with agents that provide alternative mechanisms of tumor 
control. Existing cytotoxic agents have serious acute and chronic toxicities, making them less 
suitable for frail or unfit patients. Single-agent rituximab can offer disease palliation with 
good tolerability in some patients with relapsed CLL but tumor control is not lasting, 
especially in patients with bulky adenopathy. Development of a non-cytotoxic combination 
therapy of idelalisib with rituximab or a monotherapy regimen of idelalisib that can address 
disease pathogenesis with a new mechanism of action and might offer complementary 
nodal and peripheral blood activity would address an unmet medical need, particularly when 
applied in patients with substantial comorbidities or myelosuppression from prior 
chemotherapies.

PI3Kδ over-expression plays an important role in CLL biology. Further evaluation of 
idelalisib as a potential treatment for CLL has sound scientific rationale founded on 
knowledge of the actions of the drug to selectively abrogate PI3Kδ activity and to inhibit 
malignant cell growth and stromal cell signaling in nonclinical models of CLL. These data 
are supported by clinical documentation of idelalisib inhibition of PI3Kδ signaling in patients 
with CLL.

The potential for clinical efficacy of idelalisib monotherapy or of idelalisib plus rituximab in 
patients with relapsed or refractory CLL is supported by the observed antitumor activity of 
idelalisib - given alone or in combination with rituximab - in patients with heavily pretreated 
CLL and iNHL.

The safety of advancing development of the idelalisib monotherapy and of a regimen of 
idelalisib plus rituximab in this Phase 3 clinical trial program is well supported by safety 
pharmacology and toxicology studies and by Phase 1 single-agent and combination safety 
data obtained in healthy volunteers and in subjects with lymphoid cancers.

Dose-safety, dose-exposure, and dose-activity relationships identified in Phase 1 studies
support the dosing regimen and dose modification provisions in this study.

Observations relating to patterns of CLL response among subjects receiving idelalisib alone 
or in combination with rituximab in Phase 1 trials provide the foundation for efficacy
monitoring in this trial. Of particular note is that idelalisib mobilizes CLL cells from tissues 
into the peripheral blood. This characteristic pharmacological action is prominent early in 
therapy but can persist over time and should not be confused with disease progression in 
patients who have persistent control of other CLL-related signs and symptoms. For this 
reason, in this Phase 3 study program, subjects will be continued on therapy until the 
occurrence of definitive disease progression, ie, disease progression that is manifest by 
worsening CLL-related signs or symptoms other than lymphocytosis alone. 

Thorough nonclinical and clinical characterization of the type, severity, manifestations, and 
expected timing of adverse events establish the safety monitoring plan in this trial program.


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
The scientific correlative work performed in prior preclinical and clinical studies provides 
strong scientific underpinnings for the companion laboratory studies to be performed as a 
component of this clinical trial program.

Given the seriousness of previously treated CLL in patients with substantial comorbidity, and 
the aggregate potential benefits considered in the context of potential risks, further 
development of idelalisib in this Phase 3 clinical trial program is justified.
The rationale for specific design features is provided in relevant sections of the protocol, 
including Section 3.2 (Endpoint Selection Rationale), Section 2.2 (Design Rationale), 
Section 4.3 (Enrollment Criteria Rationale), Section 5.10 (Study Treatment Rationale), and 
Section 6.5 (Study Procedure Rationale).


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2.
STUDY DESIGN
2.1.
Design Overview and Study Schema
This study is being conducted as part of an overall clinical program that is evaluating the efficacy 
and safety of idelalisib in the therapy of patients with previously treated CLL (see Figure 2-1). 
Within this program, the primary clinical trial (Study GS-US-312-0116) is a Phase 3, 
multicenter, 2-arm, randomized, double-blind, placebo-controlled, parallel-group study. This 
clinical trial (Study GS-US-312-0117) is a separate, multicenter, 2-arm, double-blind, 
parallel-group extension study that is a companion study to the primary study.
Figure 2-1.
Study Design
Candidates for the primary study will be adults with previously treated recurrent CLL who have 
measurable lymphadenopathy, require therapy for CLL, have experienced CLL progression 
<24 months since the completion of the last prior therapy, and are currently not sufficiently fit to 
receive cytotoxic therapy because of chemotherapy-induced bone marrow damage or 
comorbidities.
Primary study subjects will be stratified based on 17p deletion and/or a p53 mutation status 
(either vs neither), immunoglobulin heavy chain variable region (IgHV) mutation status 
(unmutated vs mutated), and any prior therapy with an anti-CD20 therapeutic monoclonal 
antibody (yes vs no) and randomized in a 1:1 ratio to receive 1 of the 2 treatment arms.
In the primary study, subjects will be administered rituximab intravenously in the clinic starting 
at a dose of 375 mg/m2 on Day 1 (Week 0) and will continue with a dose of 500 mg/m2 on 
Day 15 (Week 2), Day 29 (Week 4), Day 43 (Week 6), Day 57 (Week 8), Day 85 (Week 12), 
Day 113 (Week 16), Day 141 (Week 20) (for a total of 8 infusions). Rituximab will be
administered until the earliest of subject withdrawal from study, definitive progression of CLL, 
intolerable rituximab-related toxicity, pregnancy, substantial noncompliance with study 
procedures, study discontinuation, or a maximum of 8 infusions.


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Idelalisib or placebo will be taken orally, BID continuously. Subjects will continue whichever 
study drug (idelalisib/placebo or rituximab) continues to be tolerated, even if the other drug has 
been discontinued due to toxicity.
If permanent discontinuation of study drug, occurs prior to definitive progression of CLL, 
subjects shall remain on study until definitive progression of CLL or withdrawal from the study 
for reasons specified in Section 5.7.
Compliant subjects who are tolerating therapy but who develop definitive disease progression in 
the primary clinical trial (Study GS-US-312-0116) can consider enrollment in this separate 
companion extension trial (Study GS-US-312-0117). In the extension trial, subjects will take 
active blinded idelalisib therapy, either at a higher starting dose or at the standard starting dose, 
with allocation based on the original primary study randomization. Following unblinding of 
Study GS-US-312-0116, subjects will be allowed to enter Study GS-US-312-0117 in the absence 
of evidence of disease progression and will take 150 mg BID idelalisib regardless of treatment 
assignment in Study GS-US-312-0116.
The primary objective of Study GS-US-312-0116 will be to evaluate the effect of the addition of 
idelalisib to rituximab on PFS. Secondary and tertiary objectives will focus on determining the 
effect of the addition of idelalisib to rituximab on the onset, magnitude, and duration of tumor 
control; overall survival (OS); health-related quality of life (HRQL); changes in subject 
performance status; disease-associated biomarkers and potential mechanisms of resistance; 
treatment administration; safety; and health resource utilization. In Study GS-US-312-0117, the 
same endpoints will be assessed as in Study GS-US-312-0116; the focus of the analysis will be 
largely descriptive except for the within-subject assessment of treatment effects among subjects 
receiving first rituximab alone and then idelalisib alone on Arm B of each trial. No formal 
comparisons of outcomes in Arm A vs Arm B are planned within Study GS-US-312-0117.
2.2.
Design Rationale
The randomized, add-on design for the primary trial (Study GS-US-312-0116) is customary in 
the comparative evaluation of new therapies for cancer. While this design provides idelalisib
efficacy and safety information only in the context of administration of a companion 
antineoplastic agent, it is appropriate because it documents the incremental benefit and toxicity 
of the investigational therapy in the context of a controlled clinical trial while ensuring that all 
participants receive potentially active treatment.
This separate extension trial (Study GS-US-312-0117) enhances subject acceptance of 
randomization in the primary study and provides further information regarding idelalisib
efficacy, resistance, and safety. Among subjects in Arm A, escalation to a higher dose level 
allows evaluation of dose-dependent resistance and a determination if a higher dose can 
reestablish disease control. The safety data obtained in these subjects will add to the overall 
safety database. Among subjects randomized to Arm B in the primary study, evaluation of 
idelalisib at a starting dose of 150 mg/dose BID in the extension study may permit a 
within-subject assessment of the treatment effects with single-agent idelalisib relative to the 
effects previously observed with rituximab alone. Of importance, the extension study maintains 


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the partial blinding of the primary study, thus minimizing the bias that might occur if the overall 
design entailed only a 1-way crossover to open-label idelalisib among subjects who had received 
placebo on Arm B of the primary study. To ensure confirmation of disease progression, tumor 
size data collected from the primary study will be subjected to independent review by an 
independent review committee (IRC) (see Section 10.4.2); subjects will continue with study 
therapy pending confirmation of progression status by the sponsor working in collaboration with 
the IRC. Subjects must have confirmation that the disease has progressed on the primary study 
before being permitted to receive secondary idelalisib therapy on the extension study, or in the 
event the primary study is stopped, subjects who have not yet progressed may enroll on the 
extension study to receive 150 mg BID idelalisib.


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3.
OBJECTIVES AND ENDPOINTS

To evaluate the effect of idelalisib on the onset, magnitude, and duration of tumor control

To compare tumor control in subjects receiving rituximab alone in Study GS-US-312-0116 to 
that observed in the same subjects when receiving the standard dose of idelalisib alone in 
Study GS-US-312-0117

To assess the effect of idelalisib on measures of subject well-being, including overall survival 
(OS), health-related quality of life (HRQL), and performance status

To assess the effects of idelalisib on disease-associated biomarkers and to evaluate potential 
mechanisms of resistance to idelalisib

To characterize exposure to idelalisib as determined by treatment administration and 
evaluation of idelalisib plasma concentrations over time

To describe the safety profile observed with idelalisib

To estimate health resource utilization associated with administration of idelalisib
3.1.
Endpoints
3.1.1.
Tumor Control

Progression-free survival (PFS) – defined as the interval from the start of study therapy to the 
earlier of the first documentation of definitive disease progression or death from any cause; 
definitive disease progression is CLL progression based on standard criteria other than 
lymphocytosis alone

ORR – defined as the proportion of subjects who achieve a CR or partial response (PR) 

Lymph node response rate – defined as the proportion of subjects who achieve a 
50% decrease from baseline in the SPD of index lymph nodes

CR rate – defined as the proportion of subjects who achieve a CR

Time to response (TTR) – defined as the interval from start of study therapy to the first 
documentation of CR or PR

Duration of response (DOR) – defined as the interval from the first documentation of 
CR or PR to the earlier of the first documentation of definitive disease progression or death 
from any cause


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
Percent change in lymph node area – defined as the percent change from baseline in the sum 
of the products of the greatest perpendicular diameters (SPD) of index lymph nodes

Splenomegaly response rate – defined as the proportion of subjects with baseline 
splenomegaly who achieve an on-study normalization or a 50% decrease (minimum 2 cm) 
from baseline in the enlargement of the splenic LVD (by imaging)

Hepatomegaly response rate – defined as the proportion of subjects with baseline 
hepatomegaly who achieve an on-study normalization or a 50% decrease (minimum 2 cm) 
from baseline in the hepatic longest vertical dimension (LVD) (by imaging)

ALC response rate – defined as the proportion of subjects with baseline lymphocytosis 
(ALC4 x 109/L) who achieve an on-study ALC <4 x 109/L or demonstrate a 50% decrease 
in ALC from baseline; ALC values within 4 weeks post-baseline will be excluded from the 
ALC response rate evaluation

Platelet response rate – defined as the proportion of subjects with baseline thrombocytopenia 
(platelet count <100 x 109/L) who achieve an on-study platelet count 100 x 109/L or 
demonstrate a 50% increase in platelet count from baseline; platelet values within 4 weeks 
post-baseline or after 8 days post transfusion will be excluded from the platelet response rate 
evaluation

Hemoglobin response rate – defined as the proportion of subjects with baseline anemia 
(hemoglobin <110 g/L [11.0 g/dL]) who achieve an on-study hemoglobin 110 g/L 
(11.0 g/dL) or demonstrate a 50% increase in hemoglobin from baseline; hemoglobin 
values within 4 weeks post-baseline or after 4 weeks of receiving packed cell/whole blood 
transfusion or after 6 weeks of receiving exogenous growth factors (e.g., Darbepoetin alfa) 
will be excluded for the hemoglobin response evaluation

Neutrophil response rate – defined as the proportion of subjects with baseline neutropenia 
(absolute neutrophil count [ANC] ≤1.5 x 109/L) who achieve an ANC >1.5 x 109/L or 
demonstrate a 50% increase in ANC from baseline; ANC values within 4 weeks of 
post-baseline or after 2 weeks of receiving exogenous growth factors 
(e.g., Filgrastim, G-CSF, Lenograstim) or after 4 weeks of receiving Neulasta were excluded 
for response evaluation
3.1.2.
Patient Well-Being

Overall survival (OS) – defined as the interval from start of study therapy to death from any 
cause

Change from baseline in HRQL domain and symptom scores based on the 
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) (see Appendix 2)

Changes from baseline in Karnofsky performance status – defined as the change from 
baseline in the performance status (see Appendix 3)


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3.1.3.
Pharmacodynamic Markers of Drug Activity and Resistance

Changes from baseline in PI3K/AKT/mTOR pathway activation as a measure of PI3K
pathway activity

Changes from baseline in the plasma concentrations of disease-associated chemokines and 
cytokines
3.1.4.
Exposure

Study drug administration as assessed by prescribing records and compliance as assessed by 
quantification of used and unused drug

Trough (pre-dose) and peak (1.5-hour samples) of idelalisib plasma concentrations as 
assessed by a validated bioanalytical method
3.1.5.
Safety

Overall safety profile of each study treatment regimen characterized by the type, frequency, 
severity, timing of onset, duration, and relationship to study therapy of any adverse events or 
abnormalities of laboratory tests; serious adverse events; or adverse events leading to 
discontinuation of study drug
3.1.6.
Pharmacoeconomics

Change in health status – defined as the change from baseline in overall health and 
single-item dimension scores as assessed using the EuroQoL Five-Dimension (EQ-5D) utility 
measure (Appendix 4)

Health resource measures, including resource utilization, total costs, and measures of 
cost per unit of benefit (eg, cost per additional progression-free month, 
cost per quality-adjusted life-year)
3.2.
Endpoint Selection Rationale
The proposed endpoints have been chosen based on relevance to the pathophysiology and 
clinical manifestations of CLL, the known pharmacology of idelalisib, and the goals of the study 
in documenting idelalisib benefit-to-risk ratio. These types of endpoints have been employed in 
prior studies in CLL and can be evaluated with acceptable reliability and accuracy.
3.2.1.
Tumor Control Endpoints
Assessments of the magnitude and duration of changes in tumor size are routinely employed in 
registration-directed oncology clinical studies to determine therapeutic effect. Unlike OS, these 
endpoints directly assess the ability of the drug to control the malignancy. Such assessments are 
also integral to treatment decisions; because subjects are being treated until disease progression, 


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repeated tumor assessment must be performed in order to define the proper duration of treatment 
for each study participant. Standard response and progression criteria have been established by 
the International Workshop on CLL (IWCLL) {Hallek 2008}; the assessments of treatment 
effects in this study will be based on these criteria, taking into account the specific pharmacology 
of idelalisib.
In CLL, disease-related nodal enlargement is a major cause of patient discomfort and can cause 
organ dysfunction {Dighiero 2008}. Extensive lymphadenopathy constitutes a reason to treat 
CLL and controlling the size of pathologically enlarged lymph nodes is an important therapeutic 
goal for improving patient well-being and relieving obstructive symptoms {Hallek 2008}. Given 
that the natural history of recurrent CLL is inexorable nodal growth, enhancing tumor shrinkage 
and prolonging tumor control provides strong evidence of pharmacological activity.
Endpoints of overall tumor control as evaluated in this trial are customarily assessed and reported 
in studies of new therapies in patients with cancer. PFS offers a well established outcome 
measure that directly measures treatment effect, conveys important longitudinal information 
regarding tumor control, can be characterized in all subjects using intention-to-treat (ITT) 
principles, and is readily analyzed using statistical methods such as Kaplan-Meier techniques. 
ORR provides an integrated assessment of the magnitude and extent of changes in 
lymphadenopathy, organomegaly, bone marrow infiltration, and bone marrow function that 
conveniently categorizes and describes treatment effects. TTR and DOR are important in 
characterizing the rapidity of achieving tumor shrinkage and the duration of tumor control. 
Beyond providing descriptions on overall response assessment using ORR, this protocol will also 
seek to characterize the individual components of response that are important in assessment of 
CLL {Hallek 2008}. Thus, changes in lymph node area and in the proportion of subjects having 
a lymph node response will be analyzed. In addition, among subjects who enter the study with 
splenomegaly or hepatomegaly, the proportion of subjects who achieve substantial (50%) 
reductions in spleen or liver size will be assessed. Similarly, the proportions of subjects who 
experience improvements in ALC, platelets, hemoglobin, and neutrophil counts will be 
characterized in order to provide specific insight into the degree to which therapy alters these 
individual parameters.
Because idelalisib mobilizes CLL cells from tissues into the peripheral blood as part of its 
pharmacological effect, there is a risk of falsely declaring a subject to have experienced disease 
progression if lymphocyte count is considered as the sole basis for potential CLL worsening. To 
account for this potential problem, changes in lymphocyte count will not be considered in 
determining whether a subject has progressive disease, ie, subjects will only be declared to have 
progressive CLL if they meet any of the IWCLL criteria for progressive disease other than 
lymphocytosis alone. Thus, subjects with worsening lymphadenopathy, organomegaly, bone 
marrow involvement, progressive cytopenias, appearance of new disease, or transformation to an 
aggressive lymphoid malignancy histology (eg, Richter syndrome) will be considered to have 
progressed. Subjects with lymphocytosis without any of these other events will not be considered 
to have progressed. Given that lymphocytosis has no prognostic significance in patients with 
relapsed/refractory disease {Silverman 2002, Tsimberidou 2007} and is not generally considered 
a reason to treat in patients with CLL {Eichhorst 2010, Hallek 2008, Zelenetz 2011}, this 


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approach does not jeopardize subject safety or subsequent therapy. Furthermore, it will allow 
complete collection of all response and progression data (both considering lymphocytosis and 
ignoring lymphocytosis) with the intent of providing complete information for regulatory 
authority review.
The current IWCLL guidelines indicate that physical examination is generally sufficient to 
evaluate nodal response and progression in patients with CLL {Hallek 2008} but that 
radiographic assessments may be appropriate in clinical trials. Computed tomography (CT) is 
considered the preferred imaging method unless patients have contraindications that require use 
of magnetic resonance imaging (MRI). Given the low fluorodeoxyglucose (FDG) avidity of 
CLL, positron- emission tomography (PET) does not have a role in evaluation of this disease. 
The incremental benefits of using radiographic imaging are limited in patients undergoing 
long-term follow-up following first-line therapy {Blum 2007, Eichhorst 2011}. However, in the 
patients with advanced CLL and bulky adenopathy such as those who will be enrolled to this 
trial, it is known that CT scans commonly detect bulky intra-abdominal lymphadenopathy and 
splenomegaly that would be missed by palpation alone and that the presence of large-volume, 
intra-abdominal disease of the nodes and spleen is associated with a poor prognosis {Norin 
2010}. Thus, while use of CT confers greater radiation exposure, subjects have the chance to 
benefit from radiographic imaging because it will offer more accurate information regarding 
their response to protocol therapy and the appropriate duration of protocol treatment. Having this 
information is particularly important in this trial because PI3Kinhibition precludes use of 
lymphocyte counts as evidence for disease progression. In addition, the risk is offset by the fact 
that the trial subjects will primarily be patients who have already received more potent mutagens 
(eg, purine analogs, alkylating agents), and all of whom have advanced cancer and limited 
treatment options at study entry. Based on published data {Keating 2002a, Wierda 2010}, 
median OS for patients with comparably advanced CLL is <18 months, so the long-term 
secondary malignancy risk from CT-related radiation exposure is very low. Finally, in the 
context of a registration-directed pivotal trial of a new drug with a new mechanism of action, 
radiographic imaging is critically important to provide reassurance regarding subject safety and 
trial validity. In this regard, CT evaluations of the lung can be used retrospectively to assess for
radiographic evidence of drug-induced lung changes {Maroto 2011, White 2010}. Furthermore, 
CT measurements have greater accuracy and reproducibility than palpation, are subject to 
independent expert review, and can be audited against electronic case report form (eCRF) 
information.
The timing of radiographic tumor assessments has been carefully considered. To avoid 
duplication, the CT scan documenting CLL progression in Study GS-US-312-0116 will serve as 
the baseline CT scan for Study GS-US-312-0117. Among patients receiving idelalisib in 
Phase 1b/2 studies who experienced a nodal response (50% regression in tumor area), such 
responses were observed with the first 16 week of therapy {Coutre 2011, Leonard 2011}; the 
planned timing of tumor assessments (at Weeks 8, 16, 24, 36, 48 and then every 12 weeks 
thereafter) in this study fits with this known timing of changes in lymph node size during 
idelalisib therapy. Scans at 8-week intervals during the first 24 weeks allow efficient 
documentation of response. During this period, early documentation of disease progression 
allows subjects who are not benefiting from study therapy to move rapidly to alternative 


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treatments. After 24 weeks on study or after 24 weeks cumulative treatment with idelalisib 
across Study GS-US-312-0116 and Study GS-US-312-0117, the reduction in the frequency of 
CT scans (to 12-week intervals) reduces the overall protocol burden for subjects while still 
allowing characterization of the expected median PFS in this trial. As outlined in Section 7.3, 
iodine-containing or gadolinium contrast material may be omitted in subjects for whom use of a 
contrast agent would be medically contraindicated.
3.2.2.
Measures of Patient Well-Being
3.2.2.1.
Overall Survival
While OS provides an ultimate measure of patient well-being, it has not routinely been used as 
the primary endpoint in CLL clinical trials. Unlike PFS, it does not specifically measure 
drug-mediated tumor control, and thus provides only an indirect assessment of treatment effect. 
Depending upon the treatment setting, long OS times in patients with CLL can preclude use of 
this endpoint as an efficient method for understanding drug benefits. In both the front-line and 
recurrent disease settings, post-study treatments can influence OS in unpredictable ways, 
potentially confounding differences between treatment groups.
However, given the life-threatening nature of systemic malignancy, documentation of OS is 
customary in oncology therapeutic clinical trials, including those evaluating subjects with 
recurrent CLL {Keating 2002a, Wierda 2010}. Evaluation of OS in this study continues the 
survival assessment from the primary study (Study GS-US-312-0116). The study program as a 
whole (considering both the primary randomized trial and secondary extension study) offers the 
potential to better understand OS and causes of death in a frail population of patients with both 
CLL, considering the consequences of the disease and comorbidities.
3.2.2.2.
Health-Related Quality of Life
Direct patient reporting of outcomes using standardized methods has become an increasingly 
important component of therapeutic assessment. Evaluation of patient-reported outcomes (PROs) 
is particularly relevant in patients who cannot be cured of disease {Reeve 2007}. PRO 
questionnaires have been previously used in CLL to understand how patients differ from the 
general population in terms of health concerns {Eichhorst 2007, Else 2008, Holzner 2004, 
Shanafelt 2007}, to understand differences in perceptions of well-being in younger vs older 
patients {Else 2008, Levin 2007}, to determine how treatment affects HRQL {Catovsky 2007, 
Efficace 2008, Eichhorst 2007}, and to assess the pharmacoeconomic cost of improvements in 
HRQL {Stephens 2005}.
Patients with CLL have overtly impaired well-being relative to comparable controls {Eichhorst 
2007, Else 2008, Holzner 2004, Shanafelt 2007}. Fatigue is cited as a common complaint, being 
present in the substantial majority of patients. Impairment of HRQL prior to any treatment is 
apparent in those with B symptoms or in patients with anemia, supporting the concept of 
initiating treatment when patients experience symptomatic disease. Factors associated with lower 
overall HRQL have included older age, greater fatigue, severity of co-morbid health conditions, 
advanced stage, and ongoing treatment for CLL {Shanafelt 2007}. Younger patients appear to 


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have worse emotional and social well-being but older patients experience worse physical HRQL 
{Levin 2007}. In comparative evaluation of chemotherapy-containing regimens, differences in 
HRQL between therapies (eg, fludarabine vs fludarabine-cyclophosphamide vs chlorambucil) 
reflected differences in toxicity while improved HRQL was associated with greater efficacy 
{Catovsky 2007, Eichhorst 2007}.
In this study, it is postulated that idelalisib-mediated tumor control will be correlated with greater 
positive changes in HRQL and that assessments of the drug’s safety profile will be supported by 
HRQL evaluations. The FACT-Leu (Appendix 2) has been selected to evaluate such outcomes 
for the study. The FACT-Leu comprises a general HRQL measure for patients receiving cancer 
treatment that yields a total score and subscales for physical, functional, social/family and 
emotional well-being {Cella 1993} and a diagnosis-specific measure for patients with leukemia 
{Webster 2002}. The FACT-Leu was developed to assess symptoms (eg, fevers, chills, 
night sweats, nodal swelling, fatigue) specifically relevant to patients with leukemia. FACT 
instruments have documented psychometric properties {Brucker 2005, Cella 2005, Cella 1993, 
Victorson 2008, Webster 2002}.
The FACT-Leu instrument is available in appropriate languages for this study. FACT-Leu data 
will be obtained at baseline and during each investigational clinic visit during treatment. Having 
FACT-Leu data concurrent with tumor response information will allow an evaluation of the 
potential relationship between tumor response and symptomatic changes as reported by patients. 
To avoid biasing HRQL results, the FACT-Leu will be administered at each visit before other 
procedures are performed and before any study information is conveyed to the subject.
3.2.2.3.
Changes in Performance Status
Performance status evaluation provides an integrated assessment of patient well-being before, 
during, and after treatment and, ideally, may indicate how drug efficacy and toxicity affect 
patient functioning. In patients with CLL performance status can be predictive of PFS or OS 
{Hallek 1996, Sorensen 1997, Youngson 1995}.
In this study, it is hypothesized that idelalisib-mediated tumor control will be correlated with 
changes in performance status and that assessments of the drug’s safety profile might be 
supported by performance status evaluations. The well-established, reliable, and validated 
Karnofsky performance score {Karnofsky 1949, Schag 1984, Yates 1980} (see Appendix 3) will 
be employed in the trial for characterization of the subject population and repeated assessment of 
performance status.
3.2.3.
Pharmacodynamic Markers of Drug Activity and Resistance
In CLL, disease-related perturbations in inflammatory status can be clinically overt; patients 
often develop bothersome B symptoms (fevers, night sweats, and weight loss) that are 
characteristic of excessive systemic inflammation {Redaelli 2004}. Consistent with such disease 
manifestations, the PI3K/AKT/mTOR pathway is constitutively overactive in circulating CLL 
cells {Coutre 2011}. In addition, chemokines and cytokines that are markers of aberrant B-cell 
trafficking or perturbations in inflammation are overexpressed by CLL tissues or by stromal cells 


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and circulate in plasma {Burger 2010, Coutre 2011}. In Phase 1 studies of idelalisib it has been 
confirmed that idelalisib largely normalizes AKT phosphorylation and induces dose-dependent 
reductions in plasma concentrations of circulating chemokines and cytokines in patients with 
CLL {Coutre 2011}.
In this study, it is hypothesized that incremental changes in these biomarkers provide direct 
evidence of mechanism-specific idelalisib effects on PI3Kδ activity or indirectly document drug 
effects on overall tumor cell volume. In either case, improvements in these pharmacodynamic 
measures provide corroborative evidence in support of idelalisib pharmacological activity; 
conversely, worsening of these biomarkers may indicate acquisition of resistance to idelalisib. In 
addition, it is possible that disease-or inflammation-related biomarkers may provide corollary 
information relating to the adverse effects of idelalisib on the liver; such data might allow better 
prediction of which subjects might be most susceptible to ALT/AST elevations during idelalisib
treatment. Finally, it can also be postulated that genetic, protein, or metabolic changes in CLL 
cells could provide signatures that would correlate with drug sensitivity and resistance.
Based on these considerations, this study will evaluate PI3K/AKT/mTOR pathway activation 
status in CLL cells. For this purpose, blood will be evaluated by flow cytometry using a 
clinically validated assay {Hoellenriegel 2011}. CLL cells will be identified using anti-CD5 and 
anti-CD19 antibodies. AKT activation will be determined by quantifying phosphorylation at the 
Ser473 and Thr308 AKT sites using specific anti-pAKT Thr308 and anti-pAKT
Ser473 antibodies. Additional assessments of PI3K/AKT/mTOR pathway signaling 
(eg, evaluating phosphorylation state for other downstream enzymes) may also be explored.
Plasma will be collected for assessment of circulating concentrations of relevant chemokines and
cytokines with a particular focus on CCL2, CCL3, CCL4, CXCL12, CXCL13, CCL17, CCL19, 
CCL21, CCL22, sCD40 ligand, tumor necrosis factor-α, and C-reactive protein. In addition 
serum markers of iron metabolism (eg, hepcidin, iron, ferritin, transferrin) that might provide 
markers linking disease-related inflammation with perturbations of liver iron and sensitivity to 
liver injury will be evaluated {Ferrucci 2010, Nemeth 2003}. Clinically validated assays 
(eg, enzyme-linked immunosorbent assays [ELISAs]) will be used to measure circulating 
concentrations of chemokines and cytokines at baseline and during the course of idelalisib
therapy.
CLL cell deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein will be collected at 
baseline and at the conclusion of a subject’s treatment on study. DNA and RNA samples will be 
analyzed using gene array technologies to evaluate for changes in DNA mutations or in 
RNA expression patterns that might be associated with intrinsic or acquired resistance to study 
treatments. Similarly, protein will be evaluated for state-specific changes in protein 
phosphorylation to evaluate for differences in pathway activation at baseline or during therapy 
that might be associated with differences in response or in acquisition of resistance to therapy.


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3.2.4.
Assessments of Exposure
3.2.4.1.
Study Drug Administration and Compliance
Evaluation of study drug administration and compliance provides context for assessments of 
safety, pharmacokinetics, and pharmacological activity. Evaluations of treatment administration 
and modifications from planned therapy document the influence of treatment-emergent adverse 
events on prescribing practice. Compliance assessment offers a general indication of patients’ 
acceptance of therapy, integrating factors of tolerability, palatability, and convenience.
In this study, information regarding planned treatment and modification from planned treatment 
(eg, dose reductions and interruptions) will be kept. The compliance of the subject will be 
verified by accounting for used and unused drug.
3.2.4.2.
Pharmacokinetics
Given the intent of this protocol to assess longer-term dosing, collection of plasma for idelalisib
concentrations is important for evaluating exposure over time. These data may allow correlations 
of exposure with measures of efficacy, toxicity, and resistance. Because the idelalisib
pharmacokinetic profile has been well characterized in Phase 1 studies, limited plasma sampling 
will be performed in this study. Samples will be collected pre-dose and 1.5 hours post-dose 
relative to the morning administration of idelalisib. Based on discussions with investigators, 
collecting more than 2 samples in the morning is not considered reasonable given the need to 
minimize time requirements for study participants and to avoid substantial inconvenience for 
clinic staff.
Evaluation of idelalisib plasma concentrations will be performed using liquid chromatography 
with tandem mass spectrometry. The method has been fully validated in the context of prior 
Phase 1 studies. Plasma samples will be retained for potential later analyses of idelalisib
metabolites.
3.2.5.
Evaluations of Safety
In defining the therapeutic relevance of a drug in a particular clinical setting, it is imperative that 
its safety profile be fully characterized. As is conventional in all clinical studies, proper 
description of each adverse event or laboratory abnormality requires an understanding of the 
type, incidence, timing, severity, and relatedness to study drug. While information on all reported 
adverse events will be collected, listed, and summarized, particular focus will be placed on 
monitoring and reporting adverse events and laboratory abnormalities that were encountered in 
the prior toxicology studies and clinical experience with idelalisib. Safety parameters of specific 
interest in reporting study results will include those relating to bone marrow function, 
dermatological events, gastrointestinal inflammation, infection, pulmonary events 
(eg, pneumonia/pneumonitis), and liver injury. Additional scrutiny will be applied to 
Grade 3-4 adverse events, to adverse events causing interruption or discontinuation of idelalisib, 
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In addition, the protocol will evaluate for potential adverse idelalisib effects on laboratory 
parameters of immune function; the absolute number of CD4+, CD5+,CD8+, CD16/CD56+, 
CD19+, and CD20+ cells will be assessed by flow cytometry. Serum concentrations of IgA, IgE, 
IgG, and IgM will be obtained.
For consistency of interpretation, adverse events will be coded using the standard 
Medical Dictionary for Regulatory Activities (MedDRA) [http://www.meddramsso.com]), and 
the severity adverse events and laboratory abnormalities will be graded using the well-defined 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). 
Standard definitions for seriousness will be applied (see Section 8.1.2).
3.2.6.
Pharmacoeconomic Measures
It is increasingly important to understand the potential cost implications of introducing a new 
medication into patient care for CLL {Hornberger 2012, Main 2010}. In order to analyze the 
pharmacoeconomic consequences of idelalisib administration, data will be collected regarding 
the health status of subjects and regarding health care resource utilization.
Heath status information will be obtained with the EQ-5D, which is a self-administered, generic, 
indirect utility measure {The EuroQol Group 1990} (Appendix 4). The EQ-5D consists of a 
visual analogue scale on which subjects are asked to rate their current overall health status and 
5 single-item dimensions which ask subjects to rate their health in terms of mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression. For each of the 5 items, patients must 
choose between 3 levels of difficulty in accomplishing tasks in that dimension. The visual analog 
scale is then used in combination with the dimension scores to generate a health utility score that 
can be incorporated into analyses of cost effectiveness. The EQ-5D has been successfully used in 
the evaluation of patients with B-cell and other cancers {Doorduijn 2005, Witzens-Harig 2009, 
Yang 2010}.
The EQ-5D instrument is available in appropriate languages for this study. EQ-5D data will be 
obtained at baseline and during each investigational clinic visit during treatment. The EQ-5D 
will be administered immediately after administration of the FACT-Leu instrument, before other 
procedures are performed and before any study information is conveyed to the subject. The 
EQ-5D instrument takes only 5 minutes to complete.
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach will be to combine the resource utilization data from the trial with data on 
unit prices (collected separately) to estimate total costs. The costs will be described relative to 
the health care findings as measured by duration of tumor control, the symptom-free survival 
period, and/or utility outcomes or some other appropriate measure of clinical benefits.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects
The planned sample size is ~160 subjects but will be bounded by the number of subjects enrolled 
to the primary clinical trial (Study GS-US-312-0116).
4.2.
Subject Selection Criteria
Subjects in the primary Phase 3 study (GS-US-312-0116) who are compliant, are tolerating 
primary study therapy, and 1) have definitive progression of CLL while receiving primary study 
drug therapy (idelalisib /placebo) or 2) are actively participating in Study GS-US-312-0116 at 
the time the study is stopped, including if stopped early due to overwhelming efficacy following 
an interim analysis are eligible to enroll in the extension study. Eligibility criteria may not be 
waived by the investigator and conformance to the eligibility criteria is subject to review in the 
case of a Good Clinical Practice (GCP) or a regulatory authority audit. Any questions regarding a 
subject’s eligibility should be discussed with the study sponsor medical monitor prior to 
enrollment.
4.2.1.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while receiving study drug therapy 
(idelalisib/placebo) in Study GS-US-312-0116. Note: Definitive disease progression is CLL 
progression based on standard criteria and occurring for any reason 
(ie, increasing lymphadenopathy, organomegaly, or bone marrow involvement; 
decreasing platelet count, hemoglobin, or neutrophil count; or worsening of 
disease-related symptoms) other than lymphocytosis. Subjects must have confirmation by 
the sponsor working in collaboration with an independent review committee (IRC) that the 
disease has progressed on the clinical trial (Study GS-US-312-0116) before receiving
secondary idelalisib therapy on this extension trial (Study GS-US-312-0117).
3) Presence of radiographically measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures 2.0 cm in the longest diameter [LD] and 1.0 cm in the 
longest perpendicular diameter [LPD] as assessed by CT or MRI).
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab and idelalisib/placebo) 
and no intervening or continuing therapy (including radiotherapy, chemotherapy, 
immunotherapy, or investigational therapy) for the treatment of CLL. Note: Subjects may 
receive corticosteroids to manage CLL manifestations.


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5) The time from permanent cessation of Study GS-US-312-0116 treatment (rituximab and/or
idelalisib/placebo) and the initiation of Study GS-US-312-0117 therapy is 12 weeks. 
Note: Study procedures performed as part of Study GS-US-312-0116 need not be repeated 
and can be used as screening procedures for Study GS-US-312-0117 if performed within 
4 weeks prior to initiation of study drug therapy on Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation of study treatment) as 
shown in the table below. Note: Confirmation should be considered for out-of-range values 
to determine if the abnormality is real or artifactual. Values should be obtained within the 
screening period and should generally be the most recent measurement obtained. Subjects 
with any degree of neutropenia, thrombocytopenia, or anemia due to CLL or prior therapy 
may enroll.
Table 4-1.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCra
>30 ml/min
Pregnancy
-HCGb
Negative
a
As calculated by the Cockcroft-Gault formula (see Appendix 5) {Cockcroft 1976}
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or 
urine dipstick pregnancy test must be negative at start of study treatment (Visit 2)
Abbreviations: -HCG= beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
eCCr=estimated creatinine clearance, ULN=upper limit of normal
8) For female subjects of childbearing potential, willingness to use a protocol-recommended 
method of contraception (as outlined in Section 5.6.4) from the screening visit (Visit 1) 
throughout the study and for 30 days following the last dose of study drug.
Note: A female subject is considered to be of childbearing potential unless she has had a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically 
documented ovarian failure (with serum estradiol and follicle-stimulating hormone [FSH] 
levels within the institutional postmenopausal range and a negative serum or 
urine HCG), or is menopausal (age ≥54 with amenorrhea for >12 months or 
amenorrhea for >6 months with serum estradiol and FSH levels within the institutional 
postmenopausal range).
9) For male subjects of childbearing potential having intercourse with females of childbearing 
potential, willingness to use a protocol-recommended method of contraception 
(as outlined in Section 5.6.4) from the start of study drug (Visit 2) throughout the study and 
for 90 days following the last dose of study drug and to refrain from sperm donation from the 
start of study drug (Visit 2) throughout the study and for 90 days following the last dose of 
study drug. Note: A male subject is considered able to father a child unless he has had a 


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bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or has ongoing
testicular suppression with a depot luteinizing hormone- releasing hormone (LH-RH) 
agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate  [Lupron®]), or 
triptorelin pamoate [Trelstar®]).
10) In the judgment of the investigator, participation in the protocol offers an acceptable 
benefit-to-risk ratio when considering current CLL disease status, medical condition, and the 
potential benefits and risks of alternative treatments for CLL. 
11) Willingness and ability to comply with scheduled visits, drug administration plan, imaging 
studies, laboratory tests, other study procedures, and study restrictions. 
Note: Psychological, social, familial, or geographical factors that might preclude adequate 
study participation should be considered.
12) Evidence of a personally signed informed consent indicating that the subject is aware of the 
neoplastic nature of the disease and has been informed of the procedures to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study participation.
4.2.2.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
1) Known histological transformation from CLL to an aggressive lymphoma 
(ie, Richter transformation). Note: Biopsy documentation of the absence or presence of 
transformation is not required.
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of the start of 
study treatment (Visit 2). Note: Subjects with localized fungal infections of skin or nails are 
eligible. Subjects may be receiving prophylactic antiviral or antibacterial therapies at the 
discretion of the investigator; anti-pneumocystis prophylaxis is encouraged. For subjects 
who are at substantial risk of an infection (eg, influenza) that may be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of 
protocol therapy.
3) Pregnancy or breastfeeding. 
4) Intentional breaking of the blind in Study GS-US-312-0116 by the investigator or the study 
subject.
5) Concurrent participation in another therapeutic clinical trial.
6) Prior or ongoing clinically significant illness, medical condition, surgical history, physical 
finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the 
investigator’s opinion, could adversely affect the safety of the subject or impair the
assessment of study results.


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4.3.
Enrollment Criteria Rationale
The eligibility criteria are designed to limit enrollment to subjects who participated in the 
primary clinical trial (Study GS-US-312-0116), are compliant, have been generally able to 
tolerate study therapy and study procedures, and have experienced definitive CLL progression 
while receiving study treatment (rituximab and/or idelalisib/placebo) in the primary study or who 
are actively participating in Study GS-US-312-0116 at the time the study is stopped, including if 
stopped early due to overwhelming efficacy.
The requirement of measurable lymphadenopathy to enter the blinded portion of the study 
ensures that subjects have disease that can adequately be assessed for evidence of drug activity. 
Prior therapy provisions are intended to ensure that subjects are transitioning directly from 
Study GS-US-312-0116 to Study GS-US-312-0117 without receiving intervening treatments. 
The stipulation of 12-week interval from Study GS-US-312-0116 treatment until 
Study GS-US-312-0117 treatment precludes excessively protracted intervals between 
participation in the 2 studies but also permits sufficient time for clinicians and subjects to 
determine whether participation is appropriate. 
In the blinded portion of the study, to ensure that subjects are not so acutely ill from 
life-threatening comorbidities that they require hospitalization and stabilization, subjects with 
Karnofsky performance scores <40 (ie, those who are bed-bound or hospitalized) will not be 
enrolled. Baseline laboratory evaluations are designed to limit participation to subjects who have 
not developed serious organ compromise that would pose a safety risk or confound the 
interpretation of adverse effects. Pregnancy testing and restrictions on eligibility relating to 
reproduction, pregnancy, and nursing are important because idelalisib is a new chemical entity 
with teratogenic effects in rats and it is unknown if it may have adverse effects on conception, on 
fetal development, or on the health of a breast-feeding child. To minimize missing data and 
premature discontinuations, subjects should have sufficient psychological and social resources to 
comply with study procedures and restrictions. Consistent with GCP guidelines, subjects must 
provide informed consent before initiation of any study procedures.


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5.
TREATMENT OF SUBJECTS
5.1.
Enrollment
5.1.1.
Interactive Web Response System
An IWRS will be employed to manage the conduct of the trial. The IWRS will be used to 
maintain a central log documenting enrollment, to manage dose modifications, to assess current 
inventories of study drug, to initiate any necessary resupply of study drug, and to document 
discontinuation of study.
5.1.2.
Treatment Assignment
After a subject has completed the necessary documentation of definitive CLL progression in the 
primary clinical trial (GS-US-312-0116) and has been confirmed to be eligible, the subject can 
be entered into this trial (Study GS-US-312-0117). In order to obtain a treatment arm allocation 
for a subject, a site representative will access the IWRS and supply the system with the required 
information.
Subjects will be assigned to either of the following treatment assignments with allocation based 
on the original primary study randomization:
Treatment Groups
Blinded Portion

Arm A: Idelalisib + rituximab (Study GS-US-312-0116)
high-dose idelalisib (300 mg BID) (Study GS-US-312-0117)

Arm B: Placebo + rituximab (Study GS-US-312-0116)
standard-dose idelalisib (150 mg BID) (Study GS-US-312-0117)
Open-Label Extension Portion (following unblinding)

Arm A: subjects already on 300 mg BID will continue, and newly enrolled subjects will 
receive 150 mg BID

Arm B: subjects already on 150 mg BID will continue, and newly enrolled subjects will 
receive 150 mg BID
Note: At the Investigator’s discretion, subjects who were randomized to placebo on 
Study GS-US-312-0116 may delay initiation of idelalisib following enrollment on 
Study GS-US-312-0117 until the time of disease progression or until the investigator 
determines that the subject would benefit from initiation of idelalisib treatment.


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Treatment Assignment

Assignment to Arm A or Arm B with allocation based on the original primary study 
randomization

Implementation through an interactive web response system (IWRS)
The IWRS will assign blister card, or bottle numbers and instructions for dispensing of blinded 
study drug (high-dose or standard-dose idelalisib). It is anticipated that subjects will usually 
begin study drug immediately at Visit 2 of the study.
5.1.3.
Blinding
During the blinded portion of the study, the identity of the treatments will be concealed by 
central blinding of study drug assignments. Blinding will be accomplished through use of a 
placebo that is well-matched to the active drug in appearance, packaging, labeling, and schedule 
of administration (see Section 5.2.1). During the study, subjects, caregivers, investigational site 
personnel, Gilead Sciences study team members, and all other study personnel will remain 
blinded to the identity of the treatment assignments; these assignments will be available only to 
the IWRS, the data monitoring committee (DMC) for the study, an independent bioanalytical 
group that supports the DMC, and drug safety personnel who are not part of the study team.
Unblinding an individual subject’s treatment assignment during the study will only occur in the 
case of subject emergencies (see Section 5.5) or in the event the study is discontinued by the
Sponsor, a Regulatory Agency, or an IRB or EC (see Section 5.9). Where required by local 
regulation, expedited reporting of serious adverse events to specific regulatory authorities will 
include information regarding the study drug treatment assignment 
(high-dose or standard-dose idelalisib); this will be done in such a way that subjects, 
investigational site personnel, institutional review board/independent ethics committees 
(IRB/IEC), and study team members remain blinded as to the treatment assignment for the 
subject described in the adverse event report.
The unblinded analysis of the study will be performed when the database is completed and 
locked following unblinding of Study GS-US-312-0116 and Study GS-US-312-0117. The final 
analysis of the open label portion of the study will occur once the open label portion is stopped.
While bioanalytical assays to determine idelalisib concentrations may be performed prior to 
unblinding, pharmacokinetic data that would allow identification of treatment assignments for 
individual subjects will not be available to the study team until after the blind is broken and the 
primary analysis has occurred. Except for emergency unblinding, individual subjects, caregivers, 
and site personnel will not be informed of the treatment assignments until the implications of 
revealing such data for the overall idelalisib study program have been determined by the clinical 
project leader for the idelalisib development program.


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5.2.
Investigational Study Drug (Idelalisib/Placebo)
5.2.1.
Description
Subjects allocated to Arm A in the blinded portion of the study will be provided with 2 tablets of 
active idelalisib for oral administration at each dose. Each tablet contains 150 mg or 100 mg of 
active idelalisib. The 150-mg tablets will be used for initial therapy; the 100-mg tablets are 
provided for use by those subjects who require a dose reduction (see Table 5-1).
Subjects allocated to Arm B in the blinded portion of the study will be provided with 1 tablet of 
active idelalisib and 1 tablet of placebo for oral administration at each dose. Each active tablet 
contains 150 mg or 100 mg of active idelalisib. The 150-mg tablets (and matching placebo) will 
be used for initial therapy; the 100-mg tablets (and matching placebo) are provided for use by 
those subjects who require a dose reduction.
In the open-label portion of the study, subjects will be provided with 150 mg tablets of idelalisib.
The 150-mg tablets are pink, oval-shaped film-coated, and include the following inactive 
excipients: microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, 
sodium starch glycolate, magnesium stearate, red iron oxide, polyethylene glycol, talc, 
polyvinyl alcohol (PVA), and titanium dioxide. The 100-mg tablets are orange, oval shaped film-
coated, and include the following inactive excipients: microcrystalline cellulose, hydroxypropyl 
cellulose, croscarmellose sodium, sodium starch glycolate, magnesium stearate, FD&C Yellow 
#6/Sunset Yellow FCF aluminum lake, polyethylene glycol, talc, PVA, and titanium dioxide.
The placebo tablets match the active idelalisib formulations in appearance. The placebo tablets 
matching the 150-mg tablets are pink, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium stearate, 
red iron oxide, polyethylene glycol, talc, PVA, and titanium dioxide. The placebo tablets 
matching the 100-mg tablets are orange, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium stearate, 
FD&C Yellow #6/Sunset Yellow FCF aluminum lake, polyethylene glycol, talc, PVA and 
titanium dioxide.
5.2.2.
Source
Both active idelalisib and placebo will be supplied free of charge by Gilead Sciences.
5.2.3.
Packaging and Labeling
During the blinded portion of the study, study drug (idelalisib or idelalisib/placebo) will be 
provided in blister cards. The blister cards are made of polyvinyl chloride/
polychlorotrifluoroethylene (PVC/PCTFE) film and have aluminum foil lidding materials. Each 
blister card contains 120 tablets (4-week supply plus a modest overage) of one of the relevant 
dose strengths. The 100-mg or 150-mg and matching placebo tablets will be combined in order 
to obtain the daily doses to be used in this study. Thus, in Arm A, the 300-mg idelalisib dose will 


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be obtained by administering two 150-mg tablets and the 200-mg idelalisib dose will be obtained 
by administering two 100-mg tablets. In Arm B, the 150-mg idelalisib dose will be obtained by 
administering one 150-mg tablet and one placebo tablet and the 100-mg idelalisib dose will be 
obtained by administering one 100-mg tablet and one placebo tablet.
Each blister card will have a unique number. Labeling for blister cards dispensed to subjects in 
Arm A will appear identical to blister cards dispensed to subjects in Arm B, and may include 
either idelalisib or placebo.
When the primary study (GS-US-312-0116) is stopped including if early after an 
interim analysis, GS-US-312-0116 active study subjects will become eligible for participation on 
Study GS-US-312-0117. Active GS-US-312-0117 study subjects will be transitioned to 
open-label idelalisib at this time. Each bottle contains 60 tablets 
(4 week supply plus a modest overage) of one of the relevant dose strengths (150 mg, 100 mg) 
and a polyester coil. Bottles are white and are made of high-density polyethylene. Each bottle is 
closed with a white, continuous-thread, child-resistant, polypropylene screw cap fitted with an 
induction-sealed, aluminum-faced liner.
All labels for study drugs to be distributed to centers in the United States, the EU, and other 
countries will meet all applicable requirements of the United States Food and Drug 
Administration (FDA), the EU Annex 13 of Current Good Manufacturing Practice (cGMP) 
(Manufacture of Investigational Medicinal Products, July 2010), and/or other local regulations as 
applicable.
5.2.4.
Storage and Handling
Blister cards or bottles containing tablets of study drug (idelalisib or idelalisib/placebo) should
be stored at controlled room temperature (ie, ~25 °C, with a range of 15 to 30 °C). While the 
stability of study drug tablets stored at controlled room temperature has been confirmed, brief 
excursions to temperatures as low as -20 °C or as high as 40 °C (eg, during shipping) will not 
adversely affect the drug. Updated stability data will be provided to the sites, as appropriate.
5.2.5.
Dispensing
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing 
study drug according to the IWRS directions. It is planned that drug will be dispensed at 4-week 
intervals through the first 24 weeks of treatment and at 12-week intervals thereafter, or on a 
frequency consistent with the subject’s visit schedule. Sufficient study drug will be provided for 
each study period at the beginning of the period. Multiple blister cards or bottles may be 
dispensed at a single visit. Tablets should be kept in the original blister cards or bottles provided
until they are self-administered by the subject.
At the time of starting study treatment, the IWRS will provide the clinic staff with the blister 
card numbers designating the blister cards to be dispensed, or the quantity of open-label bottles 
to be dispensed. The clinic staff (eg, pharmacist or other qualified person) will write the subject 
number on each blister card or bottle that is dispensed. Immediately before dispensing, the clinic 
staff will write the blister card or bottle number in the study drug administration record 
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5.2.6.
Return
The study drug should be retrieved from each subject at the end of each dispensing interval. The 
quantity of study drug and the date returned by the subject should be recorded in the study drug 
accountability records. When possible, all study drug returned by the subject should be retained 
for review by the study site monitor prior to return to Gilead Sciences or destruction.
5.2.7.
Accountability
The disposition of all study drug should be documented from the time of receipt at the site 
through subject dispensing and return.
Study personnel must ensure that all study drug is kept in a secure locked area with access 
limited to authorized personnel. The study drug must not be used outside the context of this 
protocol. Under no circumstances should the investigator or site personnel supply study drug to 
other investigators or clinics, or allow the study drug to be used other than as directed by this 
protocol.
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by Gilead Sciences or its designee, including, but not limited to, 
the date received, lot number, amount received, and the disposition of all study drug. Upon 
receipt of a drug shipment, the shipment must be logged into the IWRS. Study drug 
accountability records must also be maintained that include the subject number to whom the 
study drug was dispensed and the date, quantity and lot number of the study drug dispensed.
Depending upon the decision of Gilead Sciences, remaining unused study drug supply will be 
returned to Gilead Sciences or its designee after the study is completed or will be discarded or 
destroyed at the clinical site. If the study drug is discarded or destroyed at the clinical site, 
standard institutional policy should be followed. Records documenting the date of study drug 
shipping or destruction, relevant lot numbers, and amount shipped or destroyed should be 
maintained.
5.2.8.
Overdose Precautions
In Phase 1 studies, an MTD for idelalisib was not reached when the drug was administered 
continuously at dose levels through 350 mg/dose BID (700 mg per day) {Coutre 2011, Kahl 
2011}. However, in this protocol, an overdose is defined as administration of more than the 
prescribed daily dose (ie, >600 mg in a single day). In a subject who experiences an overdose 
consideration should be given as to whether idelalisib administration should be temporarily 
interrupted. If the overdose ingestion is recent and substantial, and if there are no medical 
contraindications, use of gastric lavage or induction of emesis may be considered. Observation 
for any symptomatic side effects should be instituted, and biochemical and hematological 
parameters should be followed closely (consistent with the protocol or more frequently, as 
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The Gilead Sciences medical monitor should be contacted if a study drug overdose occurs. Cases 
of study drug overdose will result in specific reporting requirements (see Section 8.8).
5.2.9.
Inadvertent Exposure and Spill Precautions
Based on available data from nonclinical studies, idelalisib does not appear to be acutely toxic, 
genotoxic, or irritative at levels that are likely to result from inadvertent exposure to the contents 
of broken tablets. However, personnel handling the drug should use reasonable precautions to 
avoid eye contact, skin contact, inhalation, or ingestion of the study drug product. For further 
information regarding inadvertent exposure and spill precautions, please consult the idelalisib
investigator brochure.
5.3.
Study Drug Administration
5.3.1.
Premedication
No specific premedications or supporting medications are required in conjunction with study 
drug administration.
5.3.2.
Administration Instructions
The prescribed dose of study drug (idelalisib/placebo) should be taken orally. At each dose 
administration, the tablet number corresponding to the appropriate dose of study drug is to be 
swallowed whole with 100 to 200 mL (~ 4 to 8 ounces) of water. In case of breakage of the 
tablets in the oral cavity, additional water should be taken as a rinse. 
Study drug may be taken with or without food. There are no known dietary restrictions related to 
study drug use.
5.3.3.
Dosing Schedule
Study drug should be taken on a BID schedule at approximately the same times each day. Ideally,
doses should be taken at ~12-hour intervals (eg, at ~7 AM and at ~7 PM). While it is realized 
that variations in dosing schedule may occur in the outpatient setting, the prescribed regimen 
should be followed as closely as possible, especially in the clinic.
At specified clinic visits, the study drug will be administered in the clinic with dosing 
appropriately timed relative to blood sampling for idelalisib pharmacokinetics. As detailed in 
Section 6.2, clinic staff should record idelalisib administration information, including the exact 
clock time of each dose, for doses of study drug administered in the clinic or hospital. Thereafter, 
subjects will be given an adequate supply of tablets to take at home.
5.3.4.
Dose Levels
Study drug dose levels for Arm A and Arm B are described in Table 5-1. The lower dose level
(Dose Level -1) is provided in case a subject requires a study drug dose modification.


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Table 5-1.
Study Drug Dose Levels
Treatment Arm
Starting Dose
Dose Level -1
Arm A
300 mg/dose BID
200 mg/dose BID
Arm B
150 mg/dose BID
100 mg/dose BID
Abbreviation: BID=twice per day
When the primary study (GS-US-312-0116) is stopped, and GS-US-312-0116 active study 
subjects become eligible for participation on Study GS-US-312-0117 subjects will be enrolled 
into Study GS-US-312-0117 at open label 150 mg BID. Subjects already participating in 
Study GS-US-312-0117 will remain on the same dose.
5.3.5.
Dose Schedule Interruptions and Vomited Doses
Subjects who have a delay in administration of a dose of the study drug of <6 hours should take 
the planned dose as soon as possible after the intended time of administration. For subjects who 
have a delay in administration of study drug of 6 hours, the dose should not be taken. Study 
drug administration may continue but the missed dose should not be made up and the planned 
timing of subsequent study drug dosing should not be altered.
Vomited doses may be retaken, but only if the tablet is visible in the vomitus.
5.3.6.
Safety Monitoring and Study Drug Interruption/Dose Modification
Subjects must be monitored closely for adverse events or laboratory abnormalities during the
course of the study. Reference should be made to the CTCAE, Version 4.03 for grading the 
severity of adverse events and laboratory abnormalities.
Recommendations and requirements for modifications of the dosing regimens based on the drug 
and the type and severity of adverse events or laboratory abnormalities are provided in Table 5-2
below. The dose modification instructions focus on the types of events most commonly 
attributed to each of the study agents. Required dose modifications and actions provided in 
Table 5-2 must be followed based on the type and severity of adverse avent. The 
recommendations provided in Table 5-2 comprise only guidelines; variations from these 
recommendations may be warranted based on an investigator’s individual judgment in 
considering potential risks, benefits, and therapeutic alternatives available to each subject.
Consistent with Table 5-2, if a subject experiences an adverse event that is suspected to be 
related to study drug and requires a dose modification during the course of study therapy, then 
study drug administration should be held, as necessary, until the adverse event resolves or 
stabilizes to an acceptable degree Thereafter, study drug may be reinstituted, but the dose should 
be modified per(Table 5-1 and Table 5-2). If the adverse event occurs again, reinitiation of 
therapy may be attempted if the investigator feels that a second rechallenge is medically 
appropriate. If the subject cannot tolerate idelalisib at Dose Level -1 after 2 rechallenges, then 
the subject should be discontinued from study drug therapy unless continued therapy is discussed 
with the Gilead Sciences medical monitor.


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After the study drug dose is reduced, the dose need not be re-escalated, even if there is minimal 
or no toxicity with the reduced dose. However, if the subject tolerates the lower dose level of 
study drug for ≥4 weeks then the dose level may be increased to the starting dose level 
(see Table 5-1) at the discretion of the investigator. Such re-escalation may be particularly 
warranted if further evaluation reveals that the adverse event that led to the dose reduction was 
not study-drug-related. The starting dose level should not intentionally be exceeded in this study.
Whenever possible, any dose adjustment of study drug should be discussed between the 
investigator and the Gilead Sciences medical monitor prior to implementation. To implement 
either a dose reduction or a dose reescalation, the investigator/study staff member will call the 
IWRS, enter the subject number, and inform the IWRS of the need for dose titration. The IWRS 
will provide details regarding the study drug to be dispensed to the subject. The appropriate 
clinic staff should instruct the subject/caregiver about the change in dose.
Recommendations for dose modification based on the type and severity of adverse events or 
laboratory abnormalities are provided in Table 5-2 below.
Table 5-2.
Recommendations and Requirements for Study Drug Dose 
Modifications Based on Type and Severity of Treatment-Related 
Adverse Events or Laboratory Abnormalities
NCI CTCAE Gradea
Recommendation
Idelalisib
HEMATOLOGICAL ADVERSE EVENTS
Neutropenia
Grade 2 neutropenia
Recommended Action: Maintain current dose level and schedule.
Grade 3 neutropenia
Required Action: Blood counts should be monitored at least weekly until ANC < Grade 2.
Recommended Action: Maintain current idelalisib dose level and schedule.
Grade 4 neutropenia
(or occurrence of 
neutropenic fever 
or infection)
Required Action: Withhold idelalisib.
Required Action:Monitor blood counts at least weekly until ANC < Grade 2 
Recommended Action: May resume idelalisib at lower dose level at investigator discretion.
Neutropenia should be managed according to established clinical guidelines.
Thrombocytopenia
Grade 3
Recommended Action: Maintain current dose level and schedule.
Grade 4
Required Action: Withhold idelalisib for bruising or bleeding until Grade 3. 
Recommended Action: May resume idelalisib at initial or lower dose level at investigator 
discretion.
NON-HEMATOLOGICAL ADVERSE EVENTS
Rash
Grade 1
Recommended Action: Maintain current dose level and schedule.
Grade 2
Recommended Action: Maintain current dose level and schedule.


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NCI CTCAE Gradea
Recommendation
Idelalisib
Grade ≥3 
Required Action: Withhold idelalisib until Grade 1. 
Recommended Action: Resume at lower dose level or discontinue idelalisib at 
investigator discretion.
Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN)
Any Grade
Required Action: Discontinue idelalisib. Interrupt coadministered medications potentially 
associated with SJS/TEN.  Institute treatment per institutional standards.
Gastrointestinal Inflammation/Diarrhea
Grade 1
Required Action: Obtain history of onset and duration of diarrhea, including description,
number of stools, stool composition (e.g., watery, bloody, nocturnal), travel history, 
dietary changes and a medication review to identify possible diarrheogenic agents.
Required Action: Perform physical examination including assessment for fever, dizziness, 
abdominal pain/cramping, and weakness (e.g., evaluate for sepsis, bowel obstruction, 
dehydration).
Recommended Action: Provide anti-diarrheal (eg, loperamide) and maintain current 
idelalisib dose level and schedule.
Grade 2 diarrhea or 
colitis (unless clinical 
diagnosis is 
established from 
medical history and 
physical examination)
Required Action: Obtain history of onset and duration of diarrhea, including description,
number of stools, and stool composition (e.g., watery, bloody, nocturnal), travel history, 
dietary changes and a medication review to identify possible diarrheogenic agents.
Required Action: Perform physical examination including assessment for fever, dizziness, 
abdominal pain/cramping, and weakness (e.g., evaluate for sepsis, bowel obstruction, 
dehydration).
Required Action: For Grade 2 colitis or diarrhea (unless clinical diagnosis is established 
from medical history and physical examination), perform stool culture for routine 
pathogens (Salmonella, Shigella, Campylobacter species, Clostridium difficile toxin, 
Rotavirus, Cytomegalovirus, Adenovirus), ova and parasites (Cryptosporidium parvum, 
Isospora belli, Enterocytozoon bieneusi, Septata intestinalis, Strongyloides, Microsporidia, 
Entamoeba histolytica, Cyclospora), and Giardia antigen.
Recommended Action: For persistent Grade 2 colitis or diarrhea without clear etiology 
(clostridium difficile enterocolitis), endoscopy with biopsyb is strongly recommended to 
assess by immunohistochemistry (IHC) and PCR for CMV, Adenovirus.  (Optional: If 
ileal biopsy is performed, consider Acid Fast Bacillus staining.)
Recommended Action: Provide anti-diarrheal (eg, loperamide). Consider addition of anti-
inflammatory agent (eg, sulfasalazine, budesonide). Maintain current idelalisib dose level 
and schedule.


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NCI CTCAE Gradea
Recommendation
Idelalisib
Grade ≥ 3 diarrhea or 
colitis or persistent 
grade 2 diarrhea or 
colitis without clear 
etiology
Required Action: Withhold idelalisib. 
Required Action: Obtain history of onset and duration of diarrhea, including description,
number of stools, stool composition (e.g., watery, bloody, nocturnal), travel history, 
dietary changes and a medication review to identify possible diarrheogenic agents.
Required Action: Perform physical examination including assessment for fever, dizziness, 
abdominal pain/cramping, and weakness (e.g., evaluate for sepsis, bowel obstruction, 
dehydration).
Required Action: For Grade 3 colitis or diarrhea (unless clinical diagnosis is established 
from medical history and physical examination), perform stool culture for routine 
pathogens (Salmonella, Shigella, Campylobacter species, Clostridium difficile toxin, 
Rotavirus, Cytomegalovirus, Adenovirus), ova and parasites (Cryptosporidium parvum, 
Isospora belli, Enterocytozoon bieneusi, Septata intestinalis, Strongyloides, Microsporidia, 
Entamoeba histolytica, Cyclospora), and Giardia antigen.
Recommended Action: For Grade 3 colitis or diarrhea without clear etiology (eg, 
clostridium difficile enterocolitis), endoscopy with biopsyb isstrongly recommended to 
assess by immunohistochemistry (IHC) and PCR for CMV, Adenovirus. . (Optional: If 
ileal biopsy is performed, consider Acid Fast Bacillus staining.)
Recommended Action: At Grade 1, may resume idelalisib at lower dose level or 
discontinue at investigator discretion.
Recommended Action: Provide anti-diarrheal (eg, loperamide) and/or addition of 
anti-inflammatory agent (eg, sulfasalazine, budesonide).
Hepatic Adverse Events (elevations in ALT, AST, or bilirubin)
Grade 1
(ALT/AST3xULN)
(Bilirubin1.5xULN)
Recommended Action: Maintain current dose level and schedule.
Grade 2
(ALT/AST>3-5xULN)
(Bilirubin>1.5-
3xULN)
Recommended Action: Monitor ALT, AST, ALP, and bilirubin at least 1x per week until 
all abnormalities are Grade ≤ 1; thereafter maintain current dose level.
Grade 3
(ALT/AST>5-20xUL
N)
(Bilirubin>3-10xULN)
Recommended Action: Withhold idelalisib. Monitor ALT, AST, ALP, and bilirubin at 
least 1x per week until all abnormalities are Grade 1. 
Recommended Action: If bilirubin abnormality was Grade <3, resume idelalisib at same 
dose level. If bilirubin abnormality was Grade >3, resume at lower dose level.
Grade 4
(ALT/AST>20xULN)
(Bilirubin>10xULN)
Required Action: Withhold idelalisib. 
Required Action: Monitor ALT, AST, ALP, and bilirubin at least 1x per week until all 
abnormalities are Grade 1. 
Required Action: If bilirubin abnormality was Grade 4, discontinue idelalisib.
Required Action: If bilirubin abnormality was Grade <4, if drug is restarted then resume 
idelalisib at lower dose level. 


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NCI CTCAE Gradea
Recommendation
Idelalisib
Pneumonitis (with new onset or worsening baseline dyspnea, cough, or hypoxia without obvious infectious cause)
Grade 1  
(asymptomatic)
Required Action: Withhold idelalisib until resolution to baseline.
May resume at lower dose level or discontinue idelalisib at investigator discretion.
Grade ≥ 2
Required Action: Discontinue idelalisib permanently in subjects with any severity of 
symptomatic pneumonitis and institute therapy as clinically appropriate.
Pneumocystis jirovecci pneumonia (PJP)
Any Grade
Required Action: Discontinue idelalisib
Organizing Pneumonia
Any Grade
Required Action: Discontinue idelalisib permanently
Unequivocal CMV infectionc
Any Grade
Required Action: Interrupt idelalisib upon unequivocal clinical or laboratory evidence of 
CMV infection.
Required Action: Treat according to established clinical guidelines.
Required Action: If the benefits of resuming idelalisib are judged to outweigh the risks, 
consideration should be given to administering pre-emptive CMV therapy.
Other Nonhematological Adverse Events
Grade 2
Recommended Action: Maintain current dose level and schedule.
Grade 3
Recommended Action: Withhold idelalisib until Grade 1. May resume idelalisib at initial 
or lower dose level or discontinue idelalisib at investigator discretion.
a
CTCAE, Version 4.03.
b
Refer to 5.4.2.2 for recommendations if the differentiation between small-bowel and large-bowel diarrhea is unclear
c
CMV should be diagnosed using clinical or laboratory criteria per established institutional standard
Abbreviations:  ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST= aspartate aminotransferase, 
CTCAE=Common Terminology Criteria for Adverse Events, CMV=cytomegalovirus, G-CSF=granulocyte colony-stimulating 
factor, NCI=National Cancer Institute, ULN=upper limit of normal
5.4.
Evaluation, Intervention, and Drug Discontinuation for Specific Adverse 
Events or Conditions
5.4.1.
Dermatological Events
Subjects receiving idelalisib with ≥ Grade 3 rash have generally presented with a maculopapular 
rash on the trunk and extremities that is occasionally associated with fever and/or pruritus and 
responded to treatment with diphenhydramine and/or topical or oral corticosteroids. 
For subjects who develop Grade ≥3 rash for which an underlying etiology cannot be identified 
(e.g., infection, co suspect drug), study drug must be interrupted. 
Severe cutaneous reactions, including fatal events of Stevens-Johnson syndrome (SJS) and toxic 
epidermal necrolysis (TEN), have been reported in subjects receiving idelalisib. Assessment of 
potential causal association between idelalisib and the occurrence of SJS or TEN has been 


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confounded by the coadministration of antineoplastic agents (e.g., bendamustine, rituximab) 
and/or other concomitant medications known to be associated with SJS or TEN (e.g., allopurinol).
If SJS or TEN is suspected, idelalisib and all coadministered medications associated with SJS or 
TEN should be interrupted and the subject treated accordingly. 
Subjects should be monitored for the development of SJS, TEN, or other severe cutaneous 
reactions and idelalisib treatment should be discontinued if such events occur.
Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab. 
These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid 
dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis {Genentech Inc 2011}. 
The onset of these reactions has varied from 1 to 13 weeks following initiation of rituximab 
exposure. The safety of readministration of rituximab to patients with severe mucocutaneous 
reactions has not been determined; thus, for subjects experiencing a severe mucocutaneous 
reaction, rituximab should be discontinued.
Among patients receiving bendamustine, skin reactions have been reported in clinical trials and 
post-marketing safety reports {Cephalon 2012}. These events have included rash, toxic skin 
reactions, bullous exanthema, and purpura {Gavini 2012}. Cases of Stevens-Johnson syndrome 
and toxic epidermal necrolysis have been reported when bendamustine was administered 
concomitantly with allopurinol and other medications known to cause these syndromes. There 
may be an increased risk of skin toxicity in subjects receiving bendamustine together with 
trimethoprim-sulfamethoxazole. Because of coadministration of other agents, the precise 
relationship of cutaneous adverse events to bendamustine has often been uncertain. Where skin 
reactions to bendamustine do occur, they may be progressive and increase in severity with 
further treatment. Therefore, patients with skin reactions should be monitored closely. If skin 
reactions are severe or progressive, bendamustine should be discontinued.
5.4.2.
Gastrointestinal Events
Isolated cases of gastrointestinal inflammation (eg, stomatitis, colitis, cecitis) have been noted in 
subjects receiving idelalisib. Rare cases of gastrointestinal perforation have occurred, generally 
in the setting of occult carcinoma, mesenteric embolus or diverticular disease.  Idelalisib must be 
discontinued in subjects who experience bowel perforation.
Cholangitis manifest as hyperbilirubinemia out of proportion to serum transaminase elevations 
has been observed. While disease related factors, neutropenia, toxicity from prior therapies, 
effects of ongoing supportive care, or pre existing cholelithiasis may have initiated such events, 
it is possible that idelalisib played a contributory role. In such subjects, rechallenge with 
idelalisib has been possible and has not been associated with other severe adverse events. 
Subjects who have developed evidence of enteritis during idelalisib therapy have been 
successfully treated with antidiarrheals (eg, loperamide) and with enteric steroidal (eg, budesonide)
or non steroidal (eg sulfasalazine [Azulfidine®]) anti-inflammatory agents and have been able to 
continue or resume idelalisib.


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For study subjects who develop severe abdominal pain the possibility of a bowel obstruction or 
perforation should be considered. Appropriate clinical and radiographic examination should be 
performed and supportive care or surgical intervention should be considered. Upon recovery, 
rituximab may be resumed. 
Among patients receiving rituximab in combination with chemotherapy, rare instances of 
life-threatening bowel obstruction or perforation has been observed {Ram 2009}, primarily in 
patients with NHL. In post-marketing reports, the mean time to documented gastrointestinal 
perforation was 6 (range 1–77) days from start of chemoimmunotherapy. It is hard to draw a 
definite conclusion regarding the role of rituximab in these cases, as the affected patients had 
multiple risk factors including lymphomatous involvement of the gastrointestinal tract, other 
gastrointestinal disorders, and/or the risk of concomitant treatments with chemoradiotherapy and 
corticosteroids. Very isolated instances of inflammatory bowel disease have been seen in patients 
receiving rituximab {Ardelean 2010}.
5.4.2.1.
Investigation for Idelalisib Late Onset or Severe Diarrhea/Colitis
See CTCAE Version 4.03 for definitions of colitis and diarrhea.
Among idelalisib-treated patients who reported diarrhea or colitis, the median time to onset of 
any grade diarrhea or colitis was 1.9 months (range, 0.0–29.8), of grade 1 or 2 was 1.5 months 
(range, 0.0–15.2) and of grade 3 or 4 was 7.1 months (range, 0.5–29.8). Kaplan–Meier curves of 
time to onset of diarrhea or colitis are shown for all idelalisib- treated patients in Figure 5-1
{Coutre 2015}.
Figure 5-1.
Kaplan-Meler Time to Diarrhea or Colitis
Idelalisib-associated severe diarrhea responds poorly to antimotility agents however, median 
time to resolution ranged between 1 week and 1 month across trials following interruption of 
idelalisib treatment and, in some instances, initiation of corticosteroid treatment 
{Gilead Sciences Inc 2014}.


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5.4.2.2.
Differentiation Between Small-bowel and Large-bowel Diarrhea 
Differentiate between small-bowel and large-bowel diarrhea on a clinical basis if recommended.  
If unclear, consider upper and lower tract endoscopy with biopsy.

Small bowel diarrhea is characterized by large volume diarrhea (more than one per day), 
possibly associated dehydration, weight loss, and paraumbilical pain.   Consider an 
endoscopic small-bowel biopsy and evaluate other etiologies such as celiac disease.

Large-bowel diarrhea may present with lower pelvic pain, tenesmus, generally smaller stool 
volumes with gross blood frequently found in the stool. Consider a colonoscopic evaluation 
and biopsy.
5.4.3.
Hepatic Events
Transaminase Elevations: Consistent with observations in a dog toxicology study, reversible 
asymptomatic ALT/AST increases were also observed early in the idelalisib program in phase 1 
studies (101-02 and 101-07) in subjects with hematologic malignancies. Transaminase elevations 
generally occurred within 4 to 12 weeks of drug initiation, and resolved spontaneously over a 
period of 2 to 4 weeks with drug being continued for Grade 1 and 2 elevations and drug withheld 
for Grade 3 or 4 elevations until resolution. These early observations have been consistent with 
the ongoing experience with idelalisib treatment and transaminase elevations are now well 
characterized as most frequently asymptomatic, transient and occurring within the first 3 months 
of treatment.
Grade 1 or 2 elevations commonly resolve despite continued idelalisib treatment and Grade 3 or 
4 elevations can be managed by withholding idelalisib. Successful rechallenge after resolution at 
either the same or lower dose level of idelalisib has been achieved in the majority of subjects. 
There has been no evidence of impaired synthetic function. Close monitoring of hepatic 
laboratory tests during therapy is important to allow for appropriate idelalisib interruption and 
reinstitution so that subjects may continue with study drug treatment.
HBV Reactivation: HBV reactivation can occur in patients treated with anti-CD20 antibodies.  
Subjects who are HBc antibody positive/HBV DNA PCR negative at screening will be 
monitored for potential HBV reactivation (manifest as detectable HBV DNA by quantitative 
PCR). Although some subjects who are HBc antibody positive with negative PCR may have had 
passive transfer of antibody from intravenous IgG, it cannot be known for certain that any such 
subject did not have natural HBV infection. Therefore, all subjects will be tested monthly for the 
duration of anti-CD20 therapy and every 3 months for 1 year following the last dose of rituximab 
during study participation. Following the completion of study participation, monitoring for HBV 
reactivation will be conducted per standard of care at the discretion of the investigator. If there is 
evidence of HBV reactivation, immediately discontinue anti-CD20 and start appropriate 
treatment for HBV.  In the event of HBV reactivation, please contact the Medical Monitor 
regarding continuation of idelalisib.


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5.4.4.
Hematological and Immunological Events
In the Phase 1 experience with idelalisib in NHL and CLL, subjects with Grade3 neutropenia, 
anemia, and/or thrombocytopenia were enrolled to clinical trials. Decreased levels of neutrophil 
counts, hemoglobin, or platelet counts during therapy were largely due to minor fluctuations in 
these parameters among patients with pre-existing hematological abnormalities due to disease or 
prior therapy. Thus, idelalisib did not appear to induce overt myelosuppression. Obvious patterns 
of drug-mediated reductions in circulating CD4+ lymphocyte counts or suppression of serum 
IgG levels were also not observed.
Treatment-emergent Grade 3 or 4 neutropenia events, including febrile neutropenia, have 
occurred in subjects treated with idelalisib. For subjects who develop Grade 3 neutropenia, blood 
counts must be monitored weekly. For subjects who develop Grade 4 neutropenia , idelalisib 
must be interrupted and blood counts monitored weekly until ANC is ≥ 0.5 Gi/L, at which point, 
idelalisib dosing may be resumed at 100 mg BID.  Neutropenia should be managed according to 
established clinical guidelines.
No modification of any drug for changes in circulating CD4+ counts or Ig levels is planned.
5.4.5.
Infectious Events
Patients with lymphoid cancers receiving idelalisib have developed serious and fatal infections 
during therapy. Opportunistic infections, most notably Pneumocystis jirovecii pneumonia (PJP) 
and CMV infection, have most frequently occurred within the first 6 months of treatment with 
idelalisib and are increased in the context of concurrent myelosuppressive therapy such as 
bendamustine.
Subjects must receive trimethoprim-sulfamethoxazole or other established prophylaxis for PJP 
throughout the course of idelalisib treatment, and must continue for 2 to 6 months after the last 
dose of idelalisib.  Prophylaxis must continue until the CD4+ T-cell count is documented to be 
>200 cells/mcL after idelalisib treatment ends. Subjects must permanently discontinue idelalisib 
upon diagnosis of PJP.
CMV surveillance for active disease (quantitative PCR or PP65 antigen) must be conducted 
approximately every 4 weeks throughout the course of idelalisib treatment. CMV viral load 
testing should be performed from the same specimen type whenever possible and caution should 
be exercised when comparing CMV viral load results across different testing centers. If 
unequivocal clinical or laboratory evidence of CMV infection is present, the subject must 
interrupt idelalisib treatment and undergo effective antiviral treatment according to established 
clinical guidelines. If the benefits of resuming idelalisib are judged to outweigh the risks, 
consideration should be given to administering pre-emptive CMV therapy.
Serious bacterial, fungal, and new or reactivated viral infections have occurred during and for 
~1 year following rituximab-based therapy {Gea-Banacloche 2010}. New or reactivated viral 
infections in patients receiving rituximab have included CMV, herpes simplex virus, parvovirus 
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In high-risk subjects (history of recurrent infection, allogeneic transplant, treatment with 
alemtuzumab, hypogammaglobulinemia) other infection prophylaxis should be considered per 
consensus guidelines. Administration of intravenous immunoglobulin is permitted per standard 
institutional practice {Raanani 2009}. For subjects who develop an infection, appropriate 
medical therapy should be instituted in a timely manner.
5.4.6.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) due to polyomavirus JC has been observed 
in patients who have received rituximab therapy {Carson 2009} for hematologic malignancies.
The specific causal role of rituximab is unknown because many of these patients had other risk 
factors (eg, low CD4+ counts) and the majority had received rituximab in combination with 
chemotherapy or as part of a hematopoietic stem cell transplant. Most cases of PML were 
diagnosed within 12 months of the last infusion of rituximab.
The diagnosis of PML should be considered in any subject presenting with new-onset or 
worsening neurologic manifestations, especially weakness or paralysis, vision loss, impaired 
speech, or cognitive deterioration. Evaluation of PML should include consultation with a 
neurologist, brain MRI, and lumbar puncture. In subjects diagnosed with PML, study drug 
should also be permanently discontinued.
5.4.7.
Pulmonary Events
Documented bacterial, fungal, viral, and pneumocystis pneumonias have been observed in 
patients receiving idelalisib, primarily in patients with CLL. Some study subjects receiving 
idelalisib alone or in combination have developed evidence of pneumonitis and organizing 
pneumonia, respectively, without documented pulmonary infection.
Rituximab-related noninfectious pneumonitis has been described {Subramanian 2010} with an 
incidence of ~4.3% {Salmasi 2010}. In patients developing rituximab-associated pneumonitis, 
the mean time from the first rituximab infusion to the onset of respiratory symptoms was 
3 months, with a peak incidence after administration of a mean cumulative dosage of 
1600 mg/m2 {Liote 2010}.
Given the potential for infectious or drug-related adverse events, clinicians should be particularly 
observant for evidence of respiratory events in subjects participating in this trial. Subjects who 
describe pulmonary symptoms (eg, dyspnea on exertion, cough, shortness of breath); manifest a 
decline from baseline of 5% in oxygen saturation, or demonstrate evidence of pulmonary 
inflammation (eg, focal or diffuse interstitial pattern or ground-glass opacities on chest CT)
should be evaluated. Potential bacterial, fungal, or viral etiologies should be assessed. 
Noninfectious etiologies such as pulmonary edema or thromboembolism should also be 
considered.
As appropriate for the clinical situation and culture results, subjects should be treated empirically 
or given specific antibiotics, antifungals, or antiviral agents for a cultured organism. Supportive 
care, including oxygen or mechanical ventilation, should be provided as necessary.


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For subjects with suspected Grade 1 pneumonitis, withhold idelalisib until resolution to baseline. 
Upon resolution to baseline, idelalisib may be resumed at lower dose level or discontinued at 
investigator discretion. For subjects with suspected Grade ≥ 2 pneumonitis (eg, new onset or 
worsening of baseline cough, dyspnea, hypoxia and/or a diffuse interstitial pattern or ground-
glass opacities on chest imaging without obvious infectious etiology), idelalisib must be 
discontinued permanently and therapy initiated as clinically appropriate.
Cases of organizing pneumonia, some with fatal outcome, have occurred with idelalisib. In 
subjects presenting with serious lung events, idelalisib should be interrupted and the subject 
assessed for an explanatory etiology. If organizing pneumonia is diagnosed, treatment with 
idelalisib should be permanently discontinued and the subject treated accordingly.
5.4.8.
Secondary Malignancies
Subjects receiving idelalisib for CLL or iNHL have developed pre-malignant and secondary 
malignant diseases, such as basal cell carcinoma, myelodysplastic syndrome, myeloproliferative 
disorders, and more aggressive lymphoid malignancies (eg, have had Richter transformation). 
Generally this has occurred in subjects who have received multiple previous lines of therapy and 
when idelalisib is combined with other therapies such as rituximab or bendamustine. The specific 
association of the therapeutic agents with these types of events has not been determined.
There are reports of pre-malignant and malignant diseases that have developed in subjects who 
have been treated with bendamustine, including myelodysplastic syndrome, myeloproliferative 
disorders, acute myeloid leukemia, and bronchial carcinoma. The specific association of the 
therapeutic agents with these types of events has not been determined.
5.4.9.
Tumor Lysis Syndrome
Tumor lysis syndrome has not been observed with idelalisib monotherapy. 
Subjects with tumor lysis syndrome should receive rapid reversal of hyperkalemia, intravenous 
hydration, antihyperuricemic agents, and appropriate cardiac and renal support, including
dialysis as indicated. Upon recovery to baseline functioning, such subjects should continue study 
treatment.
5.4.10.
Pregnancy, Lactation, and Reproduction
Idelalisib has induced embryo lethality and teratogenicity when administered to pregnant female 
rats at maternally toxic doses. However, definitive reproductive toxicology studies in animals 
have not yet been performed and the specific effects of idelalisib on human embryogenesis or 
fetal development are unknown. Whether idelalisib is excreted in human breast milk is unknown. 
General toxicology studies in rats and dogs indicated dose-dependent reductions in testicular 
weights, with persistent minimal to mild degeneration of the seminiferous tubules and decreased 
spermatozoa in rats and hypospermatogenesis in dogs. The implications of these testicular 
changes for animal or human fertility are unknown.


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Given the preliminary nature of data regarding the risks to a fetus or infant as a result of 
exposure to idelalisib, women of reproductive potential entering this study must have a negative 
serum pregnancy test at baseline and must not be breastfeeding. Males and females of 
childbearing potential should abstain from sexual intercourse or use an effective form of 
contraception (see Section 5.6.4). If a female study participant becomes pregnant or decides to 
breastfeed during the course of the study, all study therapy must be discontinued.
5.4.10.1.
PJP Prophylaxis
Trimethoprim sulfamethoxazole is rated a Pregnancy category C.  In rats, oral doses of 
533 mg/kg or 200 mg/kg produced teratologic effects manifested mainly as cleft palates. 
One survey found no congenital abnormalities in 35 children whose mothers had received oral 
sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter. Because 
sulfamethoxazole and trimethoprim may interfere with folic acid metabolism it should be used 
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Dapsone is rated a Pregnancy Category C.  Extensive, but uncontrolled experience and 
two published surveys on the use of Dapsone in pregnant women have not shown that Dapsone 
increases the risk of fetal abnormalities if administered during all trimesters of pregnancy or can 
affect reproduction capacity. Because of the lack of animal studies or controlled human 
experience, Dapsone should be given to a pregnant woman only if clearly needed. Dapsone is 
excreted in breast milk in substantial amounts. Hemolytic reactions can occur in neonates. 
Because of the potential for tumorgenicity shown for Dapsone in animal studies a decision 
should be made whether to discontinue nursing or discontinue the drug taking into account the 
importance of drug to the mother.
Atovaquone is rated a Pregnancy Category C.  Atovaquone is teratogenic and did not cause 
reproductive toxicity in rats at plasma concentrations up to 2 to 3 times the estimated human 
exposure. Atovaquone can cause maternal toxicity in rabbits at plasma concentrations that were 
approximately one half the estimated human exposure. Mean fetal body lengths and weights 
were decreased and there were higher numbers of early resorption and post-implantation loss per 
dam. It is not clear whether these effects are caused by atovaquone directly or are secondary to 
maternal toxicity. Concentrations of atovaquone in rabbit fetuses averaged 30% of the concurrent 
maternal plasma concentrations.  There are no adequate and well-controlled studies in pregnant 
women. Atovaquone should be used during pregnancy only if the potential benefit justifies the 
potential risk to the fetus. It is not known whether atovaquone is excreted into human milk. 
Because many drugs are excreted into human milk, caution should be exercised when 
Atovaquone is administered to a nursing woman. In a rat study, atovaquone concentrations in the 
milk were 30% of the concurrent atovaquone concentrations in the maternal plasma.
Aerosolized Pentamidine (NebuPent) is a Pregnancy Category C.  There are no adequate and 
well controlled studies of NebuPent in pregnant women. One literature report indicated that 
intravenously administered pentamidine in pregnant rats at 4 mg/kg/day was embryolethal; 
teratogenicity was not observed in this study. It is unknown whether pentamidine administered 
via the aerosolized route crosses the placenta at clinically significant concentrations. It is not 
known whether NebuPent can cause fetal harm when administered to a pregnant woman. 


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NebuPent should be given to a pregnant woman only if clearly needed.  It is not known whether 
NebuPent is excreted in human milk.  NebuPent should not be given to a nursing mother unless 
the potential benefits are judged to outweigh the unknown risks.
5.4.11.
Ultraviolet Exposure
In vitro studies indicate enhanced cytotoxicity when embryonic murine fibroblasts treated with 
GS-563117 (the major metabolite of idelalisib) are simultaneously exposed to ultraviolet light. 
While nonclinical findings suggest the hypothetical potential for phototoxicity in humans, 
available clinical data do not reveal a photosafety concern. Although specific clinical correlates 
for these nonclinical data are not available, investigators and study subjects should be observant 
for the possibility that study participants may have exaggerated sunburn reactions 
(eg, burning, erythema, exudation, vesicles, blistering, edema) involving areas of skin exposed to 
ultraviolet light.
5.4.12.
Further Safety Information
Further safety information regarding the study drug may be found in the investigator brochure 
for idelalisib. 
5.5.
Emergency Unblinding
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IWRS system 
for that subject. Gilead recommends but does not require that the investigator contact the 
Gilead medical monitor before breaking the blind. Treatment assignment should remain blinded 
unless that knowledge is necessary to determine subject emergency medical care. The rationale 
for unblinding must be clearly explained in source documentation and on the case report 
form/ electronic case report form (CRF/eCRF), along with the date on which the treatment 
assignment was obtained. The investigator is requested to contact the Gilead medical monitor 
promptly in case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).
5.6.
Concomitant and Supportive Therapy
To the extent possible, administration of any prescription or over-the-counter drug products other 
than study medication should be minimized during the study period. Subjects should be 
discouraged from use of street drugs, herbal remedies, self-prescribed drugs, tobacco products, or 
excessive alcohol at any time during the clinical study.


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If considered necessary for the subject’s well-being, drugs for concomitant medical conditions or 
for symptom management may be given at the discretion of the investigator. The decision to 
authorize the use of any drug other than study drug should take into account subject safety, the 
medical need, the potential for drug interactions, the possibility for masking symptoms of a more 
significant underlying event, and whether use of the drug will compromise the outcome or 
integrity of the study
Subjects should be instructed about the importance of the need to inform the clinic staff of the 
use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and during 
the course of the study. Any concomitant drugs taken by a subject during the course of the study 
and the reason for use should be recorded on the eCRFs.
Information regarding use or restrictions on specific concomitant medications, dietary measures, 
or other interventions is provided below.
5.6.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments
Except for corticosteroids (see Section 5.6.5), no other systemic anticancer therapies (including 
but not limited to chemotherapy, radiation, antibody therapy, immunotherapy, or other 
experimental therapies) of any kind are permitted. Subjects are not allowed to participate 
concurrently in any other therapeutic clinical study.
5.6.2.
Antibiotics
Investigators must initiate antibiotic prophylaxis against pneumocystis infection 
(eg, with trimethoprim-sulfamethoxazole, dapsone, aerosolized pentamidine, or atovaquone)
beginning prior to study drug administration. Such support may also offer the benefit of reducing 
the risk for other bacterial infections {Green 2007}. Investigator discretion and local practices or 
guidelines may be followed.
For subjects who develop an infection, appropriate medical therapy (with antibiotics, antifungals, 
or antiviral) or other interventions should be instituted. Whenever appropriate, subjects may 
continue with study drug during treatment for the infection; however, subjects who develop PJP
must permanently discontinue study drug.
5.6.3.
Antiemetics and Antidiarrheals
Drug-related nausea and/or vomiting have not been commonly observed with idelalisib in prior 
studies. However, subjects who experience nausea or vomiting while on study therapy may 
receive antiemetics based on the judgment of the treating physician and local institutional 
practices. At the occurrence of persistent nausea or vomiting of severity Grade 1, it is suggested 
that the subject receive an oral or transdermal serotonin antagonist (eg, dolasetron, granisetron, 
ondansetron, tropisetron, palonosetron). Other classes of antiemetic medications that may be 
employed include dopamine antagonists or benzodiazepines. As needed, subjects may be 
prescribed loperamide (Imodium® or others) or diphenoxylate and atropine (Lomotil®) to control 
diarrheal symptoms.


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5.6.4.
Contraception
In the context of this protocol, a female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, a bilateral tubal ligation, or a bilateral oophorectomy; has 
medically documented ovarian failure (with serum estradiol and FSH levels within the 
institutional postmenopausal range and a negative serum or urine HCG); or is menopausal 
(age ≥54 years with amenorrhea for >12 months or amenorrhea for >6 months with serum 
estradiol and FSH levels within the institutional postmenopausal range).
Sexually active females of childbearing potential must agree to use a protocol-recommended 
method of contraception during heterosexual intercourse throughout the study treatment period 
and for 30 days following the last dose of the study drug. The investigator should counsel 
subjects on the most effective methods for avoiding pregnancy during the trial. 
Protocol-recommended contraceptive methods are described in Table 5-3.
Table 5-3.
Protocol-Recommended Contraceptive Methods
Individual Methods
Combination Methods
Hormonal Methods
(One method to be used
with a barrier method)
Barrier Methods
(Both of these methods to be used OR
one of these methods to be used
with a hormonal method)
IUD

Copper T 380A IUD

LNg 20 IUD
Tubal sterilization
Hysterectomy
Estrogen and progesterone

Oral contraceptives

Transdermal patch

Vaginal ring
Progesterone

Injection

Implant

Diaphragm with spermicidea

Male condom(with spermicidea)
a
If available/approved for use in the specific country
Abbreviation: IUD=intrauterine device
In the context of this protocol, a male subject is considered able to father a child unless he has 
had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or is receiving
ongoing testicular suppression with a depot luteinizing hormone-releasing hormone (LH-RH) 
agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or 
triptorelin pamoate [Trelstar®]).
Sexually active male subjects who can father a child must accept continuous heterosexual 
abstinence as a lifestyle choice; limit intercourse to female partners who are surgically sterile, 
post-menopausal, or using effective contraception (as noted in Table 5-3); or agree to use a 
protocol-recommended method of contraception during heterosexual intercourse throughout the 
study treatment period and for 90 days following discontinuation of the study drug
(as noted in Table 5-3). 


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The Gilead Sciences medical monitor should be consulted regarding any questions relating to 
childbearing status or contraception.
5.6.5.
Corticosteroids
Subjects may receive topical, inhaled, enteric, or systemic corticosteroids while on study. It 
should be realized that the use of systemic corticosteroids in patients with CLL may confound 
interpretation of antitumor effects mediated by study drug therapy. However, subjects who 
develop conditions that may be alleviated by systemic corticosteroid therapy are permitted to 
receive such drugs and are not required to discontinue study participation.
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin
Granulocyte-macrophage colony-stimulating factor (GM-CSF) should not be administered given 
the potential for GM-CSF-related inflammatory symptoms.
G-CSF (filgrastim, PEG-filgrastim, lenograstim) may be administered in response to 
Grade 4 neutropenia or neutropenic complications; use should be particularly considered if 
providing hematopoietic support might help to maintain study drug treatment (see Table 5-2).
While erythropoietic agents (eg, erythropoietin or darbepoetin) may be administered for 
Grade 3 anemia, their use in this study is discouraged given the potential to confound 
assessments of improvements in bone marrow function related to study drug.
Reference may be made to the American Society of Clinical Oncology guidelines {Rizzo 2008, 
Smith 2006}.
5.6.7.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism
Idelalisib is metabolized primarily via aldehyde oxidase and in part by CYP3A. A clinical 
drug-drug interaction study indicated that administration of a potent CYP3A inhibitor together 
with idelalisib resulted in a ~80% increase in idelalisib plasma exposures (AUC) 
(see Section 1.3.5.1), which is not considered to be clinically relevant and suggesting that 
idelalisib is a weak CYP3A substrate. Preliminary data indicate when coadministered with 
rifampin, a highly potent inducer of CYP3A, idelalisib exposures are ~75% lower. 
Coadministration of potent inducers of CYP3A with idelalisib should be avoided; a list of strong 
inducers is provided in Table 5-4:
Table 5-4.
Known Strong Inducers of CYP3A
Effect on CYP3A
Drug Class
Medications
Strong CYP3A Inducers
Antimycobacterial
Rifampin
Anticonvulsants
carbamazepine, phenytoin
Foods/herbs
St. John’s wort
Abbreviation: CYP=cytochrome P450 enzyme


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5.6.8.
Drugs that undergo CYP3A-Dependent Metabolism
The major metabolite of idelalisib, GS-563117, is a reversible and time dependent inhibitor of 
CYP3A; accordingly coadministration of idelalisib with midazolam, a probe CYP3A substrate, 
resulted in a ~5-fold increase in midazolam systemic exposure (AUC), indicating that idelalisib 
is a strong inhibitor of CYP3A. Coadministration of CYP3A substrates with idelalisib may result 
in an increase in their systemic exposures (eg, antiarrhythmics, calcium channel blockers, 
benzodiazepines, certain HMG-CoA reductase inhibitors, phosphodiesterase-5 (PDE5) 
inhibitors, warfarin). Avoid coadministration of drugs that are narrow therapeutic index CYP3A 
substrates (eg, alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, fentanyl, 
quinidine, ergotamine, dihydroergotamine, astemizole, terfenadine) with idelalisib.
5.6.9.
Immunization
Because of its actions to inhibit PI3Kδ-dependent B-cell function, high doses of idelalisib can 
impair primary or secondary responses to immunization in animals.
The specific clinical relevance of these findings with idelalisib is unknown. However, for 
subjects who are at substantial risk of an infection (eg, influenza) that might be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of study 
therapy.
Of note, the safety of immunization with live viral vaccines following idelalisib therapy has not 
been studied and vaccination with live virus vaccines during study treatment is not 
recommended.
5.6.10.
Surgery
There are no known effects of idelalisib on coagulation or wound healing. Pending receipt of 
additional information, study drug may be continued in the peri-procedural period in subjects 
who require surgery or invasive procedures.
5.6.11.
Diet
There are no specific dietary restrictions in the study. Study drug may be taken with or without food.
5.7.
Duration of Study Drug
Subjects may continue receiving study drug until the occurrence of any events requiring study 
drug discontinuation as defined in Section 5.8.
5.8.
Discontinuation of Study Drug
All study participants may receive study drug indefinitely; however:

Any subject has the right to discontinue study drug at any time.

Any subject who has objective evidence based on IRC review of definitive CLL progression
will discontinue study drug.


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
Any subject unable to tolerate a second rechallenge with protocol-described, dose-modified 
idelalisib at Dose Level –1 (see Section 5.2) should discontinue study drug.

Any subject who becomes pregnant or begins breastfeeding should discontinue study drug.

Any subject who becomes significantly noncompliant with study drug administration, study 
procedures, or study requirements should discontinue study drug.

Any subject for whom the blind is intentionally broken by the subject or the study site should 
discontinue study drug (only applicable to the blinded portion of the study).

The investigator, in consultation with the Gilead Sciences medical monitor, may discontinue
study drug, if, it is not in the subject’s best interest to continue.

If allowed by local regulations, Gilead Sciences may transition subjects from study drug to 
commercial drug supply when idelalisib becomes commercially available in the country 
where the subject is living.

Any subject who is diagnosed with any grade of SJS, TEN, PJP, or organizing pneumonia, or 
any subject diagnosed with Grade ≥2 pneumonitis should discontinue study drug.
Any subject whose benefit-risk profile is not deemed positive by the investigator should 
discontinue study drug.
Subjects who permanently discontinue study drug for a reason other than disease progression 
(as determined by the IRC) shall continue with assessments per the schedule of procedures until 
disease progression or until another anticancer or experimental therapy is initiated.
5.9.
Discontinuation from Study
Subject study participation will be ended due to any of the following reasons:

Adverse event.

Disease progression.

Withdrawal of consent.

Significant subject noncompliance with study drug administration, study procedures, or study 
requirements.

Initiation of any additional systemic anticancer therapies (other than corticosteroids, 
see Section 5.6.5) including chemotherapy, radiation, antibody therapy, immunotherapy, or 
other experimental treatment.

Physician’s decision to remove the subject from the study.

Pregnancy.

The subject is lost to follow-up.


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
Death.

Discontinuation of study by the Sponsor, a Regulatory Agency, or an IRB or EC.
5.10.
Study Treatment Rationale
Subjects will be assigned to treatment (Arm A or Arm B) in this study based on their 
randomization in the primary study. The 1:1 randomization in the primary trial
(GS-US-312-0116) ensures that sufficient Arm B subjects will cross over from 
rituximab alone to single-agent idelalisib at the 150-mg/dose BID starting dose level in this 
extension trial (GS-US-312-0117) to allow an adequate evaluation of efficacy and safety in this 
trial. The randomization and allocation processes will be established and performed through an 
IWRS; the intent is to maximize the integrity and security of the subject disposition and to ensure 
appropriate access and convenience-of-use by the investigational sites.
Double blinding is included to provide protection against biased interpretations of efficacy and 
safety data by subjects, caregivers, investigators, Gilead Sciences personnel, or others involved 
in study conduct.
Selection of the idelalisib treatment regimen (including starting dose level, dose-modifications 
and supportive care, schedule, duration, and conditions of administration) for this study program 
has been based primarily on safety, exposure, and activity profiles from previous Phase 1 clinical 
studies involving healthy volunteers, patients with allergic rhinitis, and patients with 
refractory/relapsed lymphoid malignancies {Coutre 2011, Kahl 2011, Webb 2010}. The 
following information was considered in selecting the study drug dosing regimen for the primary 
study and this companion extension study:

Idelalisib was symptomatically well tolerated in patients with lymphoid malignancies receiving 
dose levels of 50 mg/dose BID through 350 mg/dose BID (the highest dose level tested). No
specific MTD was apparent over the dose range tested. However, monitorable, reversible 
transaminase elevations were observed in some patients and may have been more frequent at 
higher dose levels (~10% rate among patients with CLL receiving starting doses of 
150 mg/dose). Thus, while doses through 350 mg/dose BID are tolerable, the starting dose 
of 150 mg/dose BID appears to appropriately balance safety with efficacy in idelalisib-naïve 
subjects. The starting dose of 300 mg/dose BID in this study also appears appropriate for 
evaluation; it is lower than the dose level of 350 mg/dose BID that has been tolerable in prior 
studies and is likely to be suitable in subjects who have already been tolerating idelalisib
therapy at 100 mg/dose BID. 

Upon disease progression, permitting escalation from 150 mg/dose BID to 300 mg/dose BID 
among subjects allocated to Arm A offers a systematic evaluation of higher doses in subjects 
who are tolerating idelalisib treatment and might benefit from increased PI3Kinhibition. 
The pharmacological basis for considering such an intervention is based on the concept that 
some individuals might have lower-than-expected plasma exposures or dose-dependent 
resistance to the compound at 150 mg/dose BID and might benefit from a higher dose. 


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The intent is to determine if the higher dose can reestablish disease control or whether 
absolute resistance to PI3Kinhibition has been acquired. The safety data obtained in these 
subjects would add to the overall safety database.

In an allergic rhinitis study, idelalisib induced statistically significant improvements in 
clinical and pharmacodynamic endpoints when administered at 100 mg/dose BID over 
7 days. These data support the pharmacological relevance of idelalisib-mediated 
PI3Kδ inhibition when administered at the dose-levels to be used in this study.

A positive correlation was noted between idelalisib dose and measures of tumor control and 
chemokine normalization in patients with B-cell malignancies. The majority of patients 
appear to have tumor responses and protracted PFS when receiving starting doses of 
100 mg/dose BID. Thus, treatment with a idelalisib at a starting dose of 150 mg/dose BID 
appears to offer most patients the potential to benefit from therapy and the dose level of 
300 mg/dose BID may provide additional benefit in patients with disease resistance as 
systematically evaluated in this trial. 

Increases in idelalisib plasma Cmax, AUC, and Ctrough values were less than dose-proportional 
in subjects with lymphoid malignancies; the dose-exposure evaluation indicated modest 
increases in plasma exposure at dose levels >150 mg BID.  Thus, administration of starting 
doses of idelalisib of 150 mg/dose BID appears appropriate to ensure adequate exposure in 
the majority of patients. 

In Phase 1 studies, the mean plasma t1/2 of idelalisib was ~6.5 to 9.8 hours across all dose 
levels and there was no substantive plasma accumulation over 7 or 28 days.

The changes in exposure observed when administering idelalisib after a high-fat, high-calorie 
meal are modest (~40% increase in mean AUC with no change in mean Cmax). 
Thus, idelalisib can be administered with or without food. 

The idelalisib dose modification provisions described in the protocol are designed to balance 
a primary concern for subject safety with the potential for observing pharmacological and 
antitumor activity in circumstances under which a subject experiencing an adverse event may 
still be able to continue on therapy at a lower idelalisib dose level. The enhanced monitoring 
to be performed and the actions to be taken in response to toxicity are based on experience 
with interruption, dose-modification, rechallenge, and re-escalation already piloted in 
idelalisib Phase 1 trials. In addition, idelalisib antitumor activity has been observed in the 
Phase 1 studies across all dose levels tested, including doses in the range of the modified 
dose levels planned for this protocol. Thus, use of the lower dose level to accommodate 
individual subject tolerability in this protocol is justified because subjects receiving such an
idelalisib dose level still have the potential for benefit.

In both the primary and extension studies, study treatment will be continued for each subject
until the occurrence of disease progression. Such a strategy is considered appropriate under 
the assumption that persistent interference with PI3Ksignaling is likely to extend treatment 
effect. In addition, this design permits collection of further single-agent safety information 
and thus is likely to enhance understanding of the overall safety profile of idelalisib. 


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6.
STUDY PROCEDURES
6.1.
Enrollment and Study Management Procedures
6.1.1.
Subject Recruitment
Study candidates are limited to those subjects who participated in the primary clinical trial
(Study GS-US-312-0116) and meet the entry criteria for this trial (Study GS-US-312-0117).
Subjects will be enrolled from investigational sites in the United States and Europe. The site 
principal investigator, designated sub-investigators, or other designees will discuss the possibility 
of participation directly with subjects who participated in the primary study.
The study sponsor will post a description of the study on the ClinicalTrials.gov website. Any 
promotional information generated by the sponsor or investigational sites will be submitted for 
IRB/IEC review.
6.1.2.
Subject Compensation for Participation
For subjects requesting such assistance, reasonable reimbursements for the costs of travel 
required to participate in this study will be provided by the study sponsor. To receive payment 
for travel, subjects will need to submit the original travel receipts to the research study staff at 
the investigational site.
However, other than medical care that may be provided, subjects will not be paid for 
participation in the study. Payments for such items as lost wages, disability, discomfort due to 
injury, or meals obtained while waiting at the clinical research center will not be provided. 
Through the informed consent process, study candidates will be notified that their insurance 
company could be charged for standard care that is a component of this research study and that 
subjects may be responsible for co-payments and deductible payments that are typical for their 
insurance coverage.
6.1.3.
Screening
The investigator must inform each prospective subject of the nature of the study, explain the 
potential risks, and obtain written informed consent from the subject and/or a legal guardian 
prior to performing any study-related screening procedures. At the time the study candidate signs 
the informed consent, a site representative should access the IWRS to indicate that a study 
candidate is being screened. The user will need to supply the IWRS with required information 
identifying the site and the subject number as already assigned in Study GS-US-312-0116.
Any consented subject who is excluded from the study before initiation of study treatment will 
be considered a screen failure. All screen failures must be documented along with an adequate 
description of the reason the subject was considered a screen failure. If available, information 
should be provided as to why the subject did not meet eligibility criteria, withdrew consent, 
experienced an intercurrent illness, or had other events that precluded treatment on this study.


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6.2.
Explanation of Study Visits
The specific study procedures to be conducted for each subject enrolled in the study are 
presented in tabular form in Appendix 7 and are described in the sections that follow. Additional 
information on the study procedures is provided in the study manual.
For visits at which HRQL and healthy utility data are obtained, it is important that the subject be 
administered the FACT-Leu and the EQ-5D before any other procedures are performed and 
before any study-related information is communicated to the subject; this is necessary to avoid 
biasing the PRO responses provided by the subject. Once the subject has completed the 
FACT-Leu and the EQ-5D assessments, the remaining procedures may be performed.
At visits involving idelalisib administration and pharmacokinetic sampling in the clinic, care 
should be taken to perform procedures with the appropriate timing relative to idelalisib
administration. The actual sample collection times of pharmacokinetic blood specimens should 
be recorded. If a heparinized venous catheter is placed for sample collection in order to avoid 
repeated needle sticks, at least 2 mL of blood should be removed and discarded prior to each 
sample collection in order to avoid heparin contamination of the sample.
At the visit designated as a laboratory-only visit (Visit 7), subjects will have laboratory 
assessments that may be performed at the investigational site or at an accredited local laboratory 
or clinic that is convenient for the subject/caregiver. If blood is collected at a local laboratory, 
samples are not to be analyzed at the local laboratory. For these visits, subjects and/or caregivers 
will be provided with central laboratory kits that will contain materials necessary for the 
collection and shipment of the laboratory samples by the local laboratory clinic to the central 
laboratory.
Local lab results may be requested in the event central laboratory results are not available for 
assessment of disease response, progression, or the evaluation of a significant event. In addition 
to clinical assessments of tumor status, CT or MRI imaging of the neck, chest, abdomen, and 
pelvis will be performed as a component of tumor assessments during the study based on the 
rationale provided in Section 3.2.1.
Following unblinding of the study:

Subjects who were randomized to idelalisib on Study GS-US-312-0116 and who received 
≥24 weeks idelalisib will complete Visit 16+ twelve weeks from the date of their last 
radiology assessment (CT/MRI) and study visits will continue every 12 weeks thereafter.
Visits 3 through 15 will not be required.

Subjects who have received < 24 weeks of idelalisib will have all Study GS-US-312-0117 
assessments completed per the Schedule of Procedures until they have received idelalisib for 
24 weeks cumulative across both studies. After completion of 24 weeks of cumulative 
idelalisib treatment, Visit 16+ will be conducted 12 weeks from the date of their last 
radiology assessment (CT/MRI), after which time study visits will occur every 12 weeks.


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6.2.1.
Visit 1 and Screening Period (Clinic Visit)
The initial screening visit is designated as Visit 1. At Visit 1, the investigator must inform each 
prospective study participant of the nature of the study, explain the potential risks, and obtain 
written informed consent from the study candidate and/or legal guardian prior to performing any 
study-related screening procedures. Once the informed consent document has been signed, the 
subject may undergo the screening procedures.
In order to optimize scheduling convenience for the subject and for the investigational staff, 
study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be 
used as screening procedures for Study GS-US-312-0117 if performed within 4 weeks prior to 
initiation of study drug therapy on Study GS-US-312-0117. In addition, screening procedures 
may be performed over as many days as necessary provided that screening is completed within 
4 weeks prior to initiation of study drug therapy on Study GS-US-312-0117.
The tests and evaluations outline in Table 6-1 will be performed at Visit 1 or during the 
screening period prior to initiation of study treatment.


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Table 6-1.
Procedures and Assessments at Visit 1 (During Screening Period)
Assessment or Procedure
Explanationa
Informed consent
To be obtained before any screening procedures are initiated
IWRS access
Access IWRS to document that subject is in screening and provide the subject number
from Study GS-US-312-0116
CIRS assessment
Recording of current comorbid conditions using the CIRS scoring instrument
(see Appendix 6)
Concomitant medications
Recording of ongoing concomitant medication use
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including height, weight, evidence of palpable lymphadenopathy, hepatomegaly, 
and/or splenomegaly
Serum β-HCG
Women of childbearing potential only
CLL peripheral blood 
evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 
12 trisomy; DNA mutational analysis for p53, IgHV (including IgHV3-21), and other 
genes of interest in CLL (eg, Notch); flow cytometry for CD5, CD10, CD11c, CD19, 
CD20, CD23, CD38, CD45, kappa and lambda light chains, and ZAP-70; 
cytology for karyotyping.
CLL serology
Serum 2 microglobulin
 
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis, to be scheduled with 
4 weeks prior to initiation of study treatment at Visit 2
Bone marrow biopsy and 
aspirate
To be performed at investigator discretion to determine extent of CLL involvement 
and bone marrow cellularity.
a
Study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be used as screening 
procedures for Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117.
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase,
AST=aspartate aminotransferase, CIRS=cumulative illness rating scale, CLL=chronic lymphocytic leukemia, CT=computed 
tomography, DNA=deoxyribonucleic acid, FISH= fluorescence in-situ hybridization, GGT=gamma--glutamyltransferase, 
Ig=immunoglobulin, IgHV=immunoglobulin heavy chain variable region, IWRS=interactive web response system, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging, RNA=ribonucleic acid, ZAP-70=zeta-associated protein 70
PPD
PPD


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6.2.2.
Visit 2 (Day 1) (Clinic Visit)
Subjects will be assessed to determine if they still meet eligibility criteria and can initiate study 
treatment. Study drug holds from primary study GS-US-312-0116 may continue as medically 
appropriate. The procedures outlined in Table 6-2 will be performed at Visit 2 (Day 1).
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
β-HCG
For women of child-bearing potential only; serum -HCG or urine dipstick pregnancy 
test must be negative prior to initial study treatment
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics
(with recording of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration
Study drug administrationa
First dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib
pharmacokineticsa
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensinga
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding study 
drug dosing at next full 
clinic visita
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 3.
a
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll on Study GS-US-312-0117 following 
unblinding may have idelalisib treatment (and associated PK testing) delayed at the Investigator’s discretion until the time of 
disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib treatment
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response 
system, LDH=lactate dehydrogenase, RNA=ribonucleic acid


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6.2.3.
Visit 3 (Day 15) (Clinic Visit)
The procedures outlined in Table 6-3 will be performed at Visit 3 (Day 15 [±2 days]).
Table 6-3.
Procedures and Assessments at Visit 3 (Day 15)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib pharmacokinetics
Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose). Pre-dose 
collection of plasma sample for idelalisib pharmacokinetics (with recording of the 
date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to document subject visit
Study Therapy Administration
Study drug administration
Study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Instruction regarding study 
drug dosing at next full 
clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 4.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase,
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, HRQL=health-related 
quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, LDH=lactate dehydrogenase


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6.2.4.
Visit 4 (Day 29) (Clinic Visit)
The procedures outlined in Table 6-4 will be performed at Visit 4 (Day 29 [±2 days]).
Table 6-4.
Procedures and Assessments at Visit 4 (Day 29)
Assessment or Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 3
Concomitant medications
Recording of concomitant medication used since Visit 3
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, IgM
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics
(with recording of the date and actual clock time of the date and actual clock time of 
blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration and Dispensing
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)


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Assessment or Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 5.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.5.
Visit 5 (Day 43) (Clinic Visit)
The procedures outlined in Table 6-5 will be performed at Visit 5 (Day 43 [±2 days]).
Table 6-5.
Procedures and Assessments at Visit 5 (Day 43)
Assessment or Procedure
Explanation
Pre-Dose Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the initiation of the screening period
Concomitant medications
Recording of concomitant medication use since the initiation of the screening period
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
IWRS access
Access of IWRS to document subject visit
Post-Therapy Procedures and Assessments
Instruction regarding study 
drug dosing at next full 
clinic visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 6.
Scheduling of Visit 6 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 6.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, 
LDH=lactate dehydrogenase


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6.2.6.
Visit 6 (Day 57) (Clinic and Radiology Visit)
The procedures outlined in Table 6-6 will be performed at Visit 6 (Day 57 [±2 days]).
Table 6-6.
Procedures and Assessments at Visit 6 (Day 57)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted.
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 5
Concomitant medications
Recording of concomitant medication used since Visit 5
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and 
CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug bottle number


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Assessment or Procedure
Explanation
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 8.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging
6.2.7.
Visit 7 (Day 71) (Laboratory Visit)
The procedures outlined in Table 6-7 will be performed at Visit 7 (Day 71 [±2 days]).
Table 6-7.
Procedures and Assessments at Visit 7 (Day 71)
Assessment or Procedure
Explanation
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including ALT, AST, ALP, GGT, total bilirubin, LDH
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
GGT=gamma-glutamyltransferase, LDH=lactate dehydrogenase


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6.2.8.
Visit 8 (Day 85) (Clinic Visit)
The procedures outlined in Table 6-8 will be performed at Visit 8 (Day 85 [±2 days]).
Table 6-8.
Procedures and Assessments at Visit 8 (Day 85)
Assessment or Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 6
Concomitant medications
Recording of concomitant medication used since Visit 6
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM, 
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number
Study Therapy Administration and Dispensing
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)


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Assessment or Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 9.
Scheduling of Visit 9 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 9.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.9.
Visit 9 (Day 113) (Clinic and Radiology Visit)
The procedures outlined in Table 6-9 will be performed at Visit 9 (Day 113 [±3 days]).
Table 6-9.
Procedures and Assessments at Visit 9 (Day 113)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit the assessment should be done even if study drug has been interrupted.
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 8
Concomitant medications
Recording of concomitant medication used since Visit 8
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD5+, CD19+, and 
CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card number


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Assessment or Procedure
Explanation
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 10.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.10.
Visit 10 (Day 141) (Clinic Visit)
The procedures outlined in Table 6-10 will be performed at Visit 10 (Day 141 [±3 days]).
Table 6-10.
Procedures and Assessments at Visit 10 (Day 141)
Assessment or Procedure
Explanation
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 9
Concomitant medications
Recording of concomitant medication used since Visit 9
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug  blister card number
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)


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Assessment or Procedure
Explanation
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 4-week supply of study drug to the subject with instructions for 
self-administration at home
Instruction regarding 
dosing at next full clinic 
visit
Instruction to the subject that the morning dose of study drug should not be taken on 
the day of Visit 11.
Scheduling of Visit 11 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 11.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.11.
Visit 11 (Day 169) (Clinic and Radiology Visit)
The procedures outlined in Table 6-11 will be performed at Visit 11 (Day 169 [±3 days]). 
Table 6-11.
Procedures and Assessments at Visit 11 (Day 169)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted. 
Pre-Therapy Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant medications
Recording of concomitant medication used since Visit 10
Study drug return/
accounting
Counting returned study drug. Recording of the date and actual clock time of the last 
prior subject self-administration of study drug (should be the prior evening dose)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics (with recording 
of the date and actual clock time of the date and actual clock time of blood collection)
IWRS access
Access of IWRS to obtain study drug blister card numbers


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Assessment or Procedure
Explanation
Study Therapy Administration
Study drug administration
Dose of study drug to be administered to the subject
(with recording of the date and actual clock time of the study drug administration)
Post-Therapy Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours ± 15 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for 
self-administration at home.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.12.
Visit 12 (Day 211) (Clinic Visit)
The procedures outlined in Table 6-12 will be performed at Visit 12 (Day 211 [±3 days]).
Table 6-12.
Procedures and Assessments at Visit 12 (Day 211)
Assessment or Procedure
Explanation
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 11
Concomitant medications
Recording of concomitant medication used since Visit 11
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit
Study drug administration
Subject to continue with study drug as prescribed.
Scheduling of Visit 13 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 13.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.13.
Visit 13 (Day 253) (Clinic and Radiology Visit)
The procedures outlined in Table 6-13 will be performed at Visit 13 (Day 253 [±3 days]).
Table 6-13.
Procedures and Assessments at Visit 13 (Day 253)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted.
During-Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant medications
Recording of concomitant medication used since Visit 10
Study drug return/
accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study drug administration
Subject to continue with study drug as prescribed.
Study drug dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for 
self-administration at home.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of 
Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.14.
Visit 14 (Day 295) (Clinic Visit)
The procedures outlined in Table 6-14 will be performed at Visit 14 (Day 295 [±3 days]).
Table 6-14.
Procedures and Assessments at Visit 14 (Day 295)
Assessment or Procedure
Explanation
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since Visit 10
Concomitant medications
Recording of concomitant medication used since Visit 10
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
Circulating cells 
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
IWRS access
Access of IWRS to document subject visit
Study drug administration
Subject to continue with study drug as prescribed.
Scheduling of Visit 15 
radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 15.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging


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6.2.15.
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks)
(Clinic and Radiology Visits)
The procedures outlined in Table 6-15 will be performed at Visit 15 (Day 337 [±3 days]) and 
every 12 weeks thereafter [±7 Days]).
Table 6-15.
Procedures and Assessments at Visit 15 and Subsequent Visits
(Day 337 and Every 12 Weeks)
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessmenta
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the 
visit; the assessment should be done even if study drug has been interrupted.
During-Visit Procedures and Assessments
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed and before any study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since prior visit
Concomitant medications
Recording of concomitant medication used since prior visit
Study drug return/
accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Urine β-HCG dipstick
For women of child-bearing potential only
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
CMV viral load
CMV viral load testing approximately every 4 weeks throughout the course of 
idelalisib treatment
Circulating cells
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Immune monitoring
Lymphocyte subset panel using flow cytometry (immunophenotyping), 
serum CH50 level
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines


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Assessment or Procedure
Explanation
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for 
CR, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish 
CR.
IWRS access
Access of IWRS to obtain study drug blister card numbers
Study drug administration
Subject to continue with study drug as prescribed.
Study drug dispensing
Dispensing of 12-week supply of study drug to the subject with instructions for 
self-administration at home
PJP prophylaxis
Subjects must receive trimethoprim-sulfamethoxazole or other established 
prophylaxis for PJP throughout the course of idelalisib treatment.  Subjects must 
permanently discontinue idelalisib upon diagnosis of PJP.
Scheduling of next visit 
radiology assessmenta
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for next 
clinic visit (every 12 weeks).
a
As of Amendment 9, Version 10, CT/MRI assessments will no longer be performed at the every 12 week scheduled visits, 
and will only be performed at the time of clinically-suspected disease progression or at study discontinuation.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CMV=cytomegalovirus, CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, 
FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related 
quality of life, Ig=immunoglobulin, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, PJP= Pneumocystis 
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6.2.16.
End-of-Study Visit (Clinic Visit)
At the time of discontinuation from the study, the subject should have the procedures and 
assessments performed as documented in Table 6-16. An end-of-study CT/MRI tumor 
assessment should be performed unless the subject already has radiographic confirmation of 
definitive disease progression or a CT/MRI has been performed within 4 weeks prior to the 
end-of-study visit.
Table 6-16.
Procedures and Assessments at End-of-Study Visit
Assessment or Procedure
Explanation
Radiology assessmenta
CT or MRI imaging of neck, chest, abdomen, and pelvis
FACT-Leu
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed
EQ-5D
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before 
any other procedures are performed
Adverse events 
Recording of adverse events occurring since prior visit; if a clinically significant 
adverse event or abnormal result is observed that is not resolved by the 
end-of-treatment visit, repeat evaluations should be performed to document resolution 
or stabilization of the abnormality
Concomitant medications
Recording of concomitant medication used since prior visit
Study drug return/
accounting
Counting returned study drug.
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air
Physical examination
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly
Serum β-HCG
Women of childbearing potential only
CLL peripheral blood 
evaluation
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 
12 trisomy; DNA mutational analysis for p53, IgHV (including IgHV3-21), and other 
genes of interest in CLL (eg, Notch); flow cytometry for CD5, CD10, CD11c, CD19, 
CD20, CD23, CD38, CD45, kappa and lambda light chains, and ZAP-70; 
cytology for karyotyping
CLL serology
Serum 2 microglobulin
 
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistry
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, 
phosphorus, total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, 
uric acid, cholesterol, triglycerides
PPD
PPD


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Assessment or Procedure
Explanation
Circulating cells
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation 
of absolute number of CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells 
by flow cytometry
Immune monitoring
Lymphocyte subset panel using flow cytometry (immunophenotyping), serum CH50 
level
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
PJP prophylaxis
Subjects must receive trimethoprim-sulfamethoxazole or other established 
prophylaxis for PJP after completion of idelalisib treatment until the CD4+ T-cell 
count is > 200 cells/mcL, at which point PJP prophylaxis may be discontinued.
IWRS
Access IWRS to document that subject has permanently discontinued study therapy
and to indicate whether subject agrees to continue to undergo long-term follow-up
a
An end-of-study CT/MRI tumor assessment should be performed unless the subject has had a CT/MRI assessment 4 weeks 
prior to end-of-study discontinuation.
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, CLL=chronic lymphocytic leukemia, CT=computed tomography, FISH= fluorescence in-situ 
hybridization, GGT=gamma-glutamyltransferase, IgHV=immunoglobulin heavy-chain variable-region, IWRS=interactive web 
response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, PJP= Pneumocystis jirovecii pneumonia,
RNA=ribonucleic acid, ZAP-70=zeta-associated protein 70
6.2.17.
30 Day and Long-Term Follow-up
A 30 Day follow-up visit will be performed 30 (+ 5) days following the end-of-study visit; 
however, it may be waived for subjects who have permanently discontinued study drug and have 
had a study visit >30 days after the last dose of study drug.
Long-term, follow-up will be requested of all subjects who withdraw from study for any reason.
The long-term follow-up for survival will be conducted at ~6-month intervals for 5 years, 
starting at the end-of-study visit. Information may be gathered during a routine clinic visit or 
other contact with the subject, or via telephone. Information gathered will include medical status, 
anti-tumor treatments, secondary malignancies, and survival.
6.3.
Sample Storage
 
 
 
 
 
PPD


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6.4.
Blood Collection
The maximum amount of blood to be drawn at a visit ~115 mL and the total amount of blood to 
be drawn over the initial 52-week study period (including the 4-week screening period and 
through Week 48 of the study including a possible end-of-therapy visit) is ~560 mL. For a 
40-kg person (the smallest participant expected to enroll in the study), this equates to 
maximum blood volume per body weight per visit of ~2.8 mL/kg and a total blood volume 
per body weight per average 6-week period of ~1.6 mL/kg. These quantities of blood are within 
accepted limits of 3.0 mL/kg of body weight for a single blood draw and 7.0 mL/kg of 
body weight for a 6-week period.
Specific details regarding blood sample collection and processing requirements will be provided 
separately in the study manual.
 
 
 
6.5.
Study Procedure Rationale
The planned study assessments and timing have been selected as appropriate for screening of 
subjects, for determination of idelalisib-related or disease-related toxicities, for dose 
modification during the study, for characterization of drug exposure and desired pharmacological 
effects, and for evaluation of drug activity. The scheduling of testing is designed to collect a 
complete safety and pharmacology data set while maintaining subject tolerance of study 
procedures. The planned schedule of tumor assessments is consistent with expected rate of 
changes and appropriately balances precise measurement of tumor control with the expense and 
subject inconvenience associated with clinical and radiological procedures. For discussion of the 
rationale for endpoint selection, see Section 3.2.
PPD


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7.
EFFICACY ASSESSMENTS
7.1.
Tumor Status Assessments
The determination of CLL response and progression will be based on standardized IWCLL
criteria {Hallek 2008}, as specifically modified for this study to reflect current recommendations 
which consider the mechanism of action of idelalisib and similar drugs {Cheson 2012}. 
Treatment decisions by the investigator in this study will be based on these assessments. 
Radiographic and clinical tumor assessments will be subject to independent confirmation by the 
IRC (see Section 10.4.2).
7.2.
Method of Assessment
In addition to clinical examination, imaging-based evaluation will be used in this study in all 
subjects enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI 
scanning may be used at the investigator’s discretion in subjects for whom this may be a 
preferred alternative to CT scanning; however, if MRI is performed, a non-contrast CT of the 
chest should be performed. Contrast-enhanced scanning is preferred, but iodine-containing or 
gadolinium contrast material may be omitted in subjects for whom use of a contrast agent would 
be medically contraindicated. Chest x-ray, ultrasound, endoscopy, laparoscopy, PET, 
radionuclide scans, or tumor markers will not be considered for response assessment.
For radiographic evaluations, the same method of assessment and the same technique 
(eg, scan type, scanner, subject position, dose of contrast, injection/scan interval) should be used 
to characterize each identified and reported lesion at baseline and during study treatment and 
follow-up.
All relevant clinical and radiographic information required to make each tumor status assessment 
must be made available for source verification and for submission to the IRC 
(see Section 10.4.2).
7.3.
Timing of Assessments
All baseline clinical and CT/MRI tumor assessments should be performed within 4 weeks prior 
to initiation of study drug therapy. In order to optimize scheduling convenience for the subject 
and for the investigational staff, clinical and CT/MRI tumor assessments performed as part of 
Study GS-US-312-0116 need not be repeated and can be used as baseline tumor assessments for 
Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117. Clinical tumor assessments should be performed at each clinical visit. 
On-study CT/MRI tumor assessments should be performed at ~8- to 12-week intervals as 
dictated by the study protocol. As of Amendment 9, Version 10, CT/MRI assessments will no 
longer be performed at the every 12 week scheduled visits, and will only be performed at the 
time of clinically-suspected disease progression or at study discontinuation.  An end-of-study 
CT/MRI tumor assessment should be performed unless the subject has had a CT/MRI assessment 
4 weeks prior.


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7.4.
Identification and Measurement of Tumor Lesions and Organomegaly
7.4.1.
Index Lesions
At baseline, up to 6 lymph nodes should be selected as index lesions that will be used to 
quantitate the status of the disease during study treatment. Ideally, the index lesions should be 
located in disparate regions of the body. Only peripheral nodes need be selected as index lesions. 
However, it is optimal if mediastinal and retroperitoneal areas of disease are assessed whenever 
these sites are involved.
Index lesions will be measured and recorded at baseline and at the stipulated intervals. The 
cross-sectional dimensions (the largest cross-sectional diameter, ie, the LD × LPD) will be 
recorded (in cm) for each index lesion. The product of the perpendicular diameters (PPD) 
(in cm2) for each index lesion and the sum of the products (SPDs) (in cm2) for all index lesions 
will be calculated and recorded. The baseline SPDs will be used as references by which tumor 
response will be characterized during treatment. The nadir LD of individual lesions and the nadir 
SPD will be used as references by which CLL progression will be characterized. All LD and 
LPD diameters will be reported in centimenters and all PPDs and SPDs will be reported in 
centimeters squared.
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable at 
baseline. A lymph node lesion is considered abnormal if it has a single diameter that is 1.5 cm 
and is considered measurable if it has 2 perpendicular diameters that can be accurately measured 
in cross section with the LD being 1.0 cm and the LPD also being 1.0 cm.
At follow-up time points, the LDs for individual lesions and the SPD of all nodal index lesions 
will be considered. Because nodal index lesions that have one or both diameters 
>0 cm and 1.0 cm cannot be reliably measured, a default value of 1.0 cm will be assigned for 
each diameter that meets these criteria and the resulting PPD will be used in SPD calculations. 
Based on this convention, a CR may be achieved even if an SPD value is >0 cm2, 
(ie, if all lymph nodes measure <1.0 cm2).
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD will be considered 
progressive disease.
In cases in which a large lymph node mass has split into multiple components, all 
subcomponents regardless of size will be used in calculating the SPD. Progression of the lesion 
will be based on the SPD of sub-components. Lesion sub-components will have the true PPDs 
calculated. Similarly, lesion sub-components that are visible but neither abnormal nor 
measurable will have the default PPD of 1.0 cm2 (1.0 cm 1.0 cm) used in calculating the SPD.
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer 
be separated by this boundary, the newly merged lesion will be measured bi-dimensionally.


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7.4.2.
Spleen and Liver
Both the spleen and liver will be assessed by CT/MRI scan at baseline and at the stipulated 
intervals during treatment. The baseline and nadir values for the longest vertical dimension 
(LVD) of each organ will be used as reference to further characterize the objective tumor 
response of the measurable dimensions of the CLL during treatment. All spleen and liver LVD 
measurements should be recorded in centimeters.
By imaging, the spleen will be considered enlarged if it is >12 cm in LVD {Asghar 2011, 
Bezerra 2005}.
For subjects with splenomegaly at baseline or at the splenic LVD nadir, respective response and 
progression evaluations of the spleen will consider only changes relative to the enlargement of 
the spleen at baseline or nadir, not changes relative to the total splenic LVD.
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen in its LVD or 
decrease to ≤12 cm in the LVD, is required for declaration of a splenomegaly response. 
Conversely, an increase in splenic enlargement by ≥50% from nadir 
(with a minimum 2 cm increase) is required for declaration of splenic progression.
By imaging, the liver will be considered enlarged if it is >18 cm in LVD {Erturk 2006}.
A 50% decrease (minimum 2 cm) from baseline in the enlargement of the liver in its LVD or 
decrease to ≤ 18 cm in the LVD is required for declaration of a hepatomegaly response. 
Conversely, an increase in liver enlargement by ≥50% from nadir 
(with a minimum 2 cm increase) is required for declaration of hepatic progression.
7.4.3.
Non-Index Lesions
Any other measurable and abnormal nodal lesions not selected for quantitation as index lesions 
may be considered non-index lesions. In addition, non-measurable evidence of CLL such as 
nodal lesions with both diameters <1.0 cm, extra-nodal lesions, bone lesions, leptomeningeal 
disease, ascites, pleural or pericardial effusions, lymphangitis of the skin or lung, abdominal 
masses that are not confirmed and followed by imaging techniques, cystic lesions, previously 
irradiated lesions, lesions with artifacts, and may be considered as non-index disease.
The presence or absence of non-index disease should be recorded at baseline and at the stipulated 
intervals during treatment. If present at baseline, up to 6 non-index lesions should be recorded. 
The non-index disease at baseline will be used as a general reference to further characterize 
regression or progression of CLL during assessments of the objective tumor response during 
treatment. Measurements are not required and these lesions should be followed as 
“present” or “absent”.
7.5.
Definitions of Tumor Response and Progression
Responses will be categorized by the IRC as CR, PR, SD, or PD. In addition, a response category 
of not evaluable (NE) is provided for situations in which there is inadequate information to 
otherwise categorize response status. A response category of no disease (ND) is included for 
situations in which there is absence of tumor both at baseline and on treatment.


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The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until disease/recurrence progression (taking as a reference 
for disease progression the smallest measurements recorded since treatment started). Subjects 
with a best overall response of NE or ND will be counted in the denominators in calculations of 
tumor response rates.
7.5.1.
Complete Response
To satisfy criteria for a CR, all of the following criteria must be met:

No evidence of new disease

ALC in peripheral blood of <4 x 109/L

Regression of all index nodal masses to normal size (1.5 cm in the LD)

Normal spleen and liver size

Regression to normal of all nodal non-index disease and disappearance of all detectable 
non-nodal, non-index disease

Morphologically negative bone marrow defined as <30% of nucleated cells being lymphoid 
cells and no lymphoid nodules in a bone marrow sample that is normocellular for age

Peripheral blood counts meeting all of the following criteria:
ANC >1.5 x 109/L without need for exogenous growth factors (eg, G-CSF)
Platelet count 100 x 109/L without need for exogenous growth factors or transfusions
Hemoglobin 110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (eg, erythropoietin)
Note: Subjects who fulfill all the criteria for a CR (including bone marrow criteria) but who 
have a persistent anemia, thrombocytopenia, or neutropenia or a hypocellular bone marrow 
that is related to prior or ongoing drug toxicity (and not to CLL) will be considered as a CR 
with incomplete marrow recovery (CRi).
7.5.2.
Partial Response
To satisfy criteria for a PR, all of the following criteria must be met:

No evidence of new disease

A change in disease status meeting 2 of the following criteria, with 2 exceptions in which 
only 1 criterion is needed: (1) Only lymphadenopathy is present at baseline; 
(2) Only lymphadenopathy and lymphocytosis are present at baseline. In these 2 cases, only 
lymphadenopathy must improve to the extent specified below:


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In a subject with baseline lymphocytosis (ALC4 x 109/L), a decrease in 
peripheral blood ALC by 50% from baseline or a decrease to <4 x 109/L
A decrease by 50% from the baseline in the SPD of the index nodal lesions
In a subject with enlargement of the spleen at baseline, a splenomegaly response, defined 
as a ≥50% decrease (minimum 2 cm) from baseline in the enlargement of the spleen or 
decrease to ≤12 cm in the LVD by imaging
In a subject with enlargement of the liver at baseline, a hepatomegaly response, defined 
as a ≥50% decrease (minimum 2 cm) from baseline in the enlargement of the liver or 
decrease to ≤18 cm in the LVD by imaging
A decrease by 50% from baseline in the CLL marrow infiltrate or in 
B-lymphoid nodules

No index, splenic, liver, or non-index disease with worsening that meets the criteria for 
definitive PD

Peripheral blood counts meeting 1 of the following criteria:
ANC >1.5 x 109/L or 50% increase over baseline without need for exogenous growth 
factors (eg, G-CSF)
Platelet count 100 x 109/L or 50% increase over baseline without need for 
exogenous growth factors or transfusions
Hemoglobin 110 g/L (11.0 g/dL) or 50% increase over baseline without red blood cell 
transfusions or need for exogenous growth factors (eg, erythropoietin)
7.5.3.
Stable Disease
To satisfy criteria for stable disease (SD), the following criteria must be met:

No evidence of new disease

There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD
7.5.4.
Definitive Progressive Disease
The occurrence of any of the following events indicates definitive PD:

Evidence of any new disease:
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD


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New or recurrent splenomegaly, with a minimum LVD of 14 cm
New or recurrent hepatomegaly, with a minimum LVD of 20 cm
Unequivocal reappearance of an extra-nodal lesion that had resolved
A new unequivocal extra-nodal lesion of any size
New non-index disease (eg, effusions, ascites, or other organ abnormalities 
related to CLL)
Note: Isolated new effusions, ascites, or other organ abnormalities are not sufficient evidence 
alone of PD unless histologically confirmed. Thus, a declaration of PD should not be made if 
this is the only manifestation of apparently new disease.

Evidence of worsening of index lesions, spleen or liver, or non-index disease:
Increase by 50% from the nadir in the SPD of index lesions
Increase from the nadir by 50% in the LD of an individual node or extra-nodal mass that 
now has an LD of >1.5 cm and an LPD of > 1.0 cm
Splenic progression, defined as an increase in splenic enlargement by 50% from nadir 
(with a minimum 2 cm increase and a minimum LVD of 14 cm)
Hepatic progression, defined as an increase in hepatic enlargement by 50% from nadir 
(with a minimum 2 cm increase and minimum LVD of 20 cm)
Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or other 
organ abnormalities related to CLL) 
Transformation to a more aggressive histology (eg, Richter syndrome) as established by 
lymph node or other tissue biopsy, or fluid cytology (with the biopsy or fluid cytology 
date being considered the date of CLL progression if the subject has no earlier objective 
documentation of CLL progression).

Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to an 
autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an infiltrate of 
clonal CLL cells
The current platelet count is <100 x 109/L and there has been a decrease by >50% from 
the highest on-study platelet count
The current hemoglobin is <110 g/L (11.0 g/dL) and there has been a 
decrease by >20 g/L (2 g/dL) from the highest on-study hemoglobin


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Note: If there is uncertainty regarding whether there is true progression, the subject should 
continue study treatment and remain under close observation 
(eg, evaluated at 4-week intervals) pending confirmation of progression status by the IRC. In 
particular, worsening of constitutional symptoms in the absence of objective evidence of 
worsening CLL will not be considered definitive disease progression; in such subjects, both 
CLL-related and non-CLL-related causes for the constitutional symptoms should be 
considered. Worsening of disease during temporary interruption of study treatment 
(eg, for intercurrent illness) is not necessarily indicative of resistance to study treatment. In 
these instances, CT/MRI or other relevant evaluations should be considered in order to 
document whether definitive disease progression has occurred. If subsequent evaluations 
suggest that the subject has experienced persistent definitive CLL progression, then the date of 
progression should be the timepoint at which progression was first objectively documented.
7.5.5.
Non-Evaluable
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE:

There are no images or inadequate or missing images

Images of the liver and spleen are missing at that time point (with the exception that absence 
of splenic images will not result in an NE designation in a subject known to have 
undergone splenectomy).
Note: A time-point will be considered to have a response of NE if any index lesion is missing. 
PD may be assigned at any time point regardless of the extent of missing index or 
non-index lesions. Missing non-index lesions will not impact the ability to assess for response 
or disease progression.
7.5.6.
No Disease
Subjects have a status of ND if all of the following conditions occur:

No index disease noted at baseline or on-treatment 

No non-index disease noted at baseline or on-treatment.

No enlargement of the liver or spleen at baseline or on-treatment

No abnormalities of peripheral blood counts (elevated ALC or abnormally low ANC, 
platelet count, or hemoglobin) and no evidence of CLL in bone marrow (if available) at 
baseline or on treatment


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7.5.7.
Lymphocytosis During Therapy
Idelalisib can mobilize CLL cells from tissues into the peripheral blood. This characteristic 
pharmacological action can be prominent early in therapy but can persist over time and should 
not be confused with disease progression in subjects who have persistent control of other 
CLL-related signs and symptoms. In the absence of other objective evidence of disease 
progression, lymphocytosis alone will not preclude subjects from meeting the criteria for PR if 
other criteria for PR are met and will not be considered evidence of disease progression if 
occurring in isolation. Subjects with lymphocytosis should be continued on study drug until the 
occurrence of definitive disease progression (ie, disease progression that is manifest by 
worsening CLL-related signs other than lymphocytosis alone), or the occurrence of another 
reason to discontinue study therapy as described in Section 5.8.
7.5.8.
Documentation of Definitive CLL Progression
Of importance, CLL response and progression data collected from the primary study will be 
subjected to IRC review (see Section 10.4.2). Subjects must have confirmation by the sponsor 
working in collaboration with the IRC that the disease has progressed on the primary clinical 
trial (Study GS-US-312-0116) before being permitted to receive secondary idelalisib therapy 
on this extension trial (GS-US-312-0117). Subjects should continue study drug pending 
confirmation of progression status. CT/MRI should be attempted in order to document definitive 
disease progression by the IRC. The end-of study scan from the primary study can serve as the 
baseline scan for the extension study if obtained within the specific screening period for the 
extension study. If obtained within the specified screening period for the extension study, this 
scan can serve as the baseline scan for the extension study.


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8.
SAFETY ASSESSMENTS
8.1.
Adverse Event Definitions
8.1.1.
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical product which; does not necessarily have a causal relationship 
with study drug administration or usage. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Lymphocytosis

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an adverse event and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 5.2.8)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
In this study, any of the following events will be considered an adverse event:

Any complication that occurs as a result of a protocol-mandated procedure 
(eg, venipuncture, biopsy) in the screening, on-treatment, or post-treatment periods.

Any pre-existing condition that increases in severity or changes in nature during or as a 
consequence of study drug administration. Worsening manifestations of the underlying 
cancer (eg, increase in pain, tumor flare reaction, tumor lysis syndrome) may be considered 
adverse events in this study.


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
Any injury or accident occurring during the screening, on-treatment, or post-treatment 
periods. If a medical condition is known to have caused the injury or accident 
(eg, a fall secondary to dizziness), the medical condition (dizziness) and the accident (fall) 
should be reported as 2 separate adverse events. 

Any abnormality in physiological testing or a physical examination finding that requires 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test).

Any laboratory (eg, clinical chemistry, hematology, urinalysis) or investigational abnormality 
(eg, ECG, X-ray) independent of the underlying medical condition that requires clinical
intervention, results in further investigation (beyond ordering a repeat [confirmatory] test), or 
leads to investigational medicinal product interruption or discontinuation unless it is
associated with an already reported clinical event. If the laboratory abnormality is part of a 
syndrome, the syndrome or diagnosis (eg, anemia) not the laboratory result 
(eg, decreased hemoglobin) should be recorded. 

A complication related to pregnancy or termination of a pregnancy (see Section 5.4.10 for 
additional information).
8.1.2.
Serious Adverse Event
A serious adverse event (SAE) is defined as an event that results in any of the following:

Death

Life-threatening situation (Note: The term “life-threatening” in the definition of “serious” 
refers to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization.

Persistent or significant disability/incapacity.

A congenital anomaly/birth defect

A medically important event or reaction. Such events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention to prevent one of the outcomes listed above. Examples of such events 
might include:
Allergic bronchospasm requiring intensive treatment in an emergency room or at home
New cancers or blood dyscrasias
Convulsions that do not result in hospitalization
Development of drug dependency or drug abuse


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Medical and scientific judgment must be exercised to determine whether such an event is 
reportable under expedited reporting rules.
Infections resulting from contaminated medicinal product will be considered a medically 
important event and subject to expedited reporting requirements.
Given the endpoints of the study, in order to maintain the integrity of the study the following 
events that are assessed as unrelated to IMP will not be considered SAEs:

Progression of CLL

Death related to progression of CLL
Disease progression and death from disease progression should be reported as SAEs by the 
investigator only if it is assessed that the IMPs caused or contributed to the disease progression 
(i.e., by a means other than lack of effect). Unrelated disease progression and death due to 
disease progression should be captured on the eCRF.
These events will be reported, as appropriate, in the final clinical study report and in any relevant 
aggregate safety reports. The safety information from this study will also be reviewed by an 
independent DMC on an ongoing basis. The DMC can have access to partially blinded or 
unblinded data in order to determine if it is safe to continue the study according to the protocol.
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to IMP interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, electrocardiogram, x-rays, vital signs) that are 
associated with signs and/or symptoms must be recorded as an AE or SAE if they meet the 
definition of an AE or SAE as described in Section 8.5. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result 
(ie, decreased hemoglobin).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 5.4.
8.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.


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8.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP 
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event has an etiology other than the IMP. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event reporting.
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed from screening 
onwards.
All AEs, regardless of cause or relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP must be reported to the CRF/eCRF database as 
instructed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported.
All AEs should be followed up until resolution if possible. If by the last day on study 
(including the off-study medication follow-up period) the AE has not resolved, then the AE will 
be followed up until the investigator and/or Gilead Sciences determine that the subject's 
condition is stable. However, Gilead Sciences may request that certain AEs be followed until 
resolution.


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Investigators are not obligated to actively seek SAEs after the above period. However, if the 
investigator learns of any SAEs that occur after study participation has concluded and the event 
is deemed relevant to the use of IMP, he/she should promptly document and report the event to 
Gilead DSPH.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.

At the time of study start, SAEs will be reported using a paper serious adverse event 
reporting form. During the study conduct, sites may transition to an electronic SAE (eSAE) 
system. Gilead will notify sites in writing and provide training and account information prior 
to implementing an eSAE system.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by faxing 
the report form within 24 hours of the investigator’s knowledge of the event to the attention 
of Gilead DSPH or to the designated CRO.
8.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to expedite 
to worldwide regulatory agencies reports of SAEs, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the 
EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide 
regulatory agencies and the relevant IEC in concerned Member States of applicable SUSARs as 
outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the IRB or IEC of SUSAR reports as soon as is practical, where this is 
required by local regulatory agencies, and in accordance with the local institutional policy.
8.5.
Grading of the Severity of an Adverse Event
The severity of adverse events will be graded using the CTCAE, Version 4.03 (provided in 
study manual and available at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). For 
each episode, the highest severity grade attained should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or 
Grade 5 (fatal) to describe the maximum intensity of the adverse event. For purposes of 
consistency with the CTCAE, these intensity grades are defined in Table 8-1.


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Table 8-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Sign or symptom is present, but it is easily tolerated, is not expected to have a 
clinically significant effect on the subject’s overall health and well-being, does not 
interfere with the subject’s usual function, and is not likely to require medical 
attention.
Grade 2
Moderate
Sign or symptom causes interference with usual activity or affect clinical status, and 
may require medical intervention.
Grade 3
Severe
Sign or symptom is incapacitating or significantly affects clinical status and likely 
requires medical intervention and/or close follow-up.
Grade 4
Life-threatening
Sign or symptom results in a potential threat to life.
Grade 5
Fatal
Sign or symptom results in death.
The distinction between the seriousness and the severity of an adverse event should be noted. 
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For 
example, a headache may be severe in intensity, but would not be classified as serious unless it 
met one of the criteria for serious events listed in Section 8.1.2 above.
8.6.
Adverse Event Reporting Period
The start of the adverse event reporting for a study subject will coincide with signing of the 
informed consent for Study GS-US-312-0117. Any new adverse events occurring thereafter 
should not be reported within Study GS-US-312-0116, but instead should be reported within
Study GS-US-312-0117. The end of the adverse-event-reporting period for 
Study GS-US-312-0117 occurs 30 days after the discontinuation from study drug or when any 
ongoing drug-related adverse events and/or serious adverse events have resolved or become 
stable. A subject withdrawn from the study because of an adverse event must be followed until 
the clinical outcome from the adverse event is determined. The investigator should use
appropriate judgment in ordering additional tests as necessary to monitor the resolution of events 
ongoing at the completion of study treatment. Gilead Sciences may request that certain adverse 
events be followed longer.
Investigators are not obligated to actively seek information regarding the occurrence of new 
serious adverse events beginning after the 30-day post-study period. However, if the investigator 
learns of such a serious adverse event and that event is deemed relevant to the use of the study 
drug, he/she should promptly document and report the event. A longer reporting period applies in 
the case of pregnancy (see Section 8.9.1)
8.7.
Adverse Event Reporting Requirements
8.7.1.
Site Reporting Requirements
Classification of an event as serious or nonserious (see Section 8.1.2) determines the reporting 
procedures to be followed by the site.


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Site reporting requirements for adverse events are summarized in Table 8-2, below.
Table 8-2.
Site Reporting Requirements for Adverse Events
Classification
Reporting Time
Reporting Action
Serious
Within 24 hours
Fax report on designated serious adverse event report form 
to PPD Pharmacovigilancea, and to the site IRB/IEC, 
as per local IRB/IEC requirements; include copies of 
relevant source documentsb (eg, progress notes, 
autopsy reports, laboratory and diagnostic test results, 
discharge summaries) in communication to 
PPD Pharmacovigilancea
Per eCRF submission procedurec
Record and submit information on appropriate eCRFs
Nonserious
Per eCRF submission procedure
Record and submit information on appropriate eCRFs
a
See contact information in Table 8-3 below.
b
Subject name, address, and other personal identifiers should be obscured but without losing the traceability of a document to 
the study subject identifiers.
c
CLL progression or death due to CLL progression should be reported by the investigator as a serious adverse event only if it 
is assessed that the study drugs caused or contributed to the CLL progression (ie, by a means other than lack of effect). 
Unrelated events of CLL progression should be captured on the appropriate eCRF. 
Abbreviations: CLL = chronic lymphocytic leukemia, eCRF=case report form, IRB/IEC= Institutional Review Board/
Independent Ethics Committee
For serious adverse events, in addition to completing the adverse event portion of the eCRF, the 
serious adverse event report form must also be completed. The information in the adverse event 
portion of the eCRF page and the serious adverse event report form(s) must match or be 
reconciled. Where the same data are collected, the forms must be completed in a consistent 
manner. For example, the same adverse event term should be used on both forms. Particularly for 
fatal or life-threatening events, copies of progress notes, autopsy reports, laboratory and 
diagnostic test results, discharge summaries, and other relevant documents should be faxed when 
requested and applicable. Follow-up information to the serious adverse event should be clearly 
documented as “follow up” in the serious adverse event report form and must be faxed to these 
same parties. Gilead Sciences may request additional information from the investigator to ensure 
the timely completion of accurate safety reports.
The subject’s name, address, and other personal identity information should be obscured on any 
source documents (eg, progress notes, nurses’ notes, laboratory and diagnostic test results, 
discharge summaries). Only the subject’s study number, initials, or date of birth are to be 
provided.
The serious adverse event report form must be communicated to PPD Pharmacovigilance and to 
the site IRB/IEC (if required by local regulations) within 24 hours. In the rare event that the 
investigator does not become aware of the occurrence of a serious adverse event immediately 
(for example, if a subject initially seeks treatment elsewhere), the investigator is to report the 
event within 24 hours after learning of it and to document his/her first awareness of the adverse 
event.


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Contact details for PPD Pharmacovigilance and for the Gilead study medical monitor are 
provided in Table 8-3:
Table 8-3.
Contact Information for Reporting Serious Adverse Events
Function
Contact Information
PPD Pharmacovigilance
(US)
Facsimile:
PPD Pharmacovigilance
(International)
Facsimile:
Gilead Sciences
Medical Monitor
Name:
Title: 
Medical Monitor, Clinical Research
Telephone:
Facsimile:
E-mail:
8.7.2.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population
To maintain the integrity of the study, progression of CLL and death related to progression of 
CLL will not be reported to Gilead Sciences as serious adverse events unless it is assessed that 
the study drug caused or contributed to CLL progression or death related to CLL progression 
(ie, by a means other than lack of effect). These events will be exempt from global expedited 
reporting requirements for the duration of the study because they define the primary efficacy 
endpoint for this study. All events of progression of CLL and death related to progression of 
CLL, regardless of relationship to study drug, will be reported in the eCRFs and, as appropriate, 
in the final clinical study report and in any relevant aggregate safety reports. Disease progression 
information from this study will be reviewed by an independent DMC on an ongoing basis.
8.8.
Special Situations Reporting Requirements
8.8.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, lack of 
effect reports and pregnancy reports regardless of an associated AE. Also includes reports of 
adverse reactions in infants following exposure from breastfeeding, and reports of adverse 
reactions associated with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following possible maternal or paternal 
exposure to the medicinal product.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Lack of effect is defined as a situation where there is apparent failure of the medicinal product or 
medical technology to bring about the intended beneficial effect on the individual in a defined 
population with a given medical problem, under ideal conditions of use.
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
8.9.
Instructions for Reporting Special Situations
8.9.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (ie, signs the informed consent) and throughout the study, including the 
post study drug follow-up period, to the  or Gilead DSPH ] using the pregnancy report form 
within 24 hours of becoming aware of the pregnancy. Refer to the CRF/eCRF completion 
guidelines for full instructions on the mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE, and therefore should be reported as 
such. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must be 
reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to PPD Pharmacovigilance or Gilead DSPH using 
the pregnancy outcome report form. If the end of the pregnancy occurs after the study has been 
completed, the outcome should be reported directly to Gilead DSPH. Gilead DSPH 
contact information is as follows: Email:
 and Fax:
PPD
PPD


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Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to PPD Pharmacovigilance 
or Gilead DSPH using the pregnancy and pregnancy outcome forms within 24 hours. Monitoring 
of the subject should continue until the conclusion of the pregnancy. If the end of the pregnancy 
occurs after the study has been completed, the outcome should be reported directly to 
Gilead DSPH, fax number
 or email 
8.9.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to PPD Pharmacovigilance or Gilead DSPH within 24 hours of the investigator 
becoming aware of the situation. These reports must consist of situations that involve study IMP, 
but do not apply to concomitant medications. Except for situations that result in AEs, special 
situations involving concomitant medications will not be reported. Any inappropriate use of 
medications prohibited by this protocol should not be reported as “misuse,” but may be more 
appropriately documented as a protocol deviation.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.
PPD
PPD


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9.
STATISTICAL CONSIDERATIONS
9.1.
Analysis Objectives
As described in Section 3, the objectives of this clinical trial will focus on determining the effect 
of idelalisib on the onset, magnitude, and duration of tumor control; measures of patient 
well-being (including OS, HRQL; and changes in subject performance status); disease-associated 
biomarkers and potential mechanisms of resistance; treatment administration; safety; and health 
resource utilization.
9.2.
Analysis Endpoints
The endpoints of the study are defined in Section 3.1, grouped in categories relating to tumor 
control, patient well-being, pharmacodynamic markers of drug activity and resistance, exposure, 
safety, and pharmacoeconomics.
9.3.
Analysis Conventions
9.3.1.
Analysis Sets
9.3.1.1.
Intent-to-Treat Analysis Set
The ITT analysis set includes all subjects who receive 1 dose of any study treatment 
(high-dose idelalisib or standard-dose idelalisib). In the ITT analysis set, study drug assignment 
will be designated according to planned allocation in this study, regardless of whether subjects 
receive a different study therapy from that to which they were allocated.
This analysis set will be used in the analyses of subject characteristics and all the tumor control 
and patient well-being endpoints. Subjects in the ITT analysis set who do not have sufficient 
baseline or on-study tumor status information to be adequately assessed for response status will 
be included in the denominators in the calculation of response rates.
9.3.1.2.
Per-Protocol Analysis Set
The PP analysis set includes data from subjects in the ITT analysis set who meet the general 
criteria defining the target population for this study, are adherent to the protocol, are compliant 
with study drug treatment, and are evaluable for relevant efficacy endpoints. Treatment 
assignment will be designated according to the actual treatment received. The specific 
classification of subjects to be included in the PP analysis set will be included in the statisticial 
analysis plan which will be finalized prior to the database lock.
The PP analysis set will be used in sensitivity analyses of these tumor control and patient 
well-being endpoints: PFS, ORR, lymph node response rate, OS and CR rate.


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9.3.1.3.
Safety Analysis Set
A safety analysis set will include subjects in the ITT analysis set grouped for analyses with 
treatment assignments designated according to the actual study drug received.
This analysis set will be used in the analyses of safety variables as well as study treatment 
administration, and health economic variables.
9.3.1.4.
Pharmacodynamic and/or Pharmacokinetic Analysis Sets
The pharmacodynamic and/or pharmacokinetic analysis sets include data from subjects in the 
safety analysis set who have the necessary baseline and on-study measurements to provide 
interpretable results for the specific parameters of interest. 
These analysis sets will be used in the analyses of AKT phosphorylation, chemokines/cytokines, 
and idelalisib plasma concentrations.
9.3.2.
Data Handling Conventions
9.3.2.1.
General Methods 
By-subject listings will be created for important variables from each eCRF module. 
Summary tables for continuous variables will contain the following statistics: 
N (number in population), n (number with data), mean, standard deviation, 
95% confidence intervals (CIs) on the mean, median, minimum, and maximum. Summary tables 
for categorical variables will include: N, n, percentage, and 95% CIs on the percentage. Unless 
otherwise indicated, 95% CIs for binary variables will be calculated using the binomial 
distribution (exact method) and will be 2-sided. Data will be described and summarized by 
relevant treatment arm, analysis set, and timepoint. As appropriate, changes from baseline to 
each subsequent timepoint will be described and summarized by treatment arm. Similarly, as 
appropriate, the best change from baseline during the study will also be described and 
summarized by treatment arm. Graphical techniques (eg, waterfall plots, 
Kaplan-Meier curves, line plots) may be used when such methods are appropriate and 
informative.
Data from all sites will be pooled for all analyses. Analyses will be based upon the observed data 
unless methods for handling missing data are specified. If there is a significant degree of 
non-normality, analyses may be performed on log-transformed data or nonparametric tests may 
be applied, as appropriate.
9.3.2.2.
Double-Blinded Portion of the Study Analyses
Efficacy and safety data collected during the blinded portion of Study GS-US-312-0117 will be 
presented in the following 2 groups:


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
IDELA 300 mg BID: Subjects who have PD per IRC confirmation in Arm A of 
Study GS-US-312-0116 and subsequently enroll into Study GS-US-312-0117 to receive 
IDELA 300 mg BID during the double-blind portion of the study

Placebo in Study GS-US-312-0116 + IDELA 150 mg BID in Study GS-US-312-0117: 
Subjects who have PD per IRC confirmation in Arm B of Study GS-US-312-0116 and 
subsequently enroll Study GS-US-312-0117 to receive IDELA 150 mg BID during the 
double-blind portion of the study
All analyses will be performed based on the data collected during the blinded-portion of the 
extension study. Time-to-event analyses will reference to the date of first treatment on this 
clinical trial (Study GS-US-312-0117). Similarly, evaluations of on-therapy changes will 
reference the baseline values obtained prior to treatment in this study. The baseline value used in 
each analysis will be the last (most recent) pre-treatment value. Analyses will be descriptive in 
nature and formal comparisons of outcomes in the 2 groups are not planned.
9.3.2.3.
Open-Label Extension Study Analyses
GS-US-312-0117 will become an open-label study offering idelalisib 150 mg BID to 
GS-US-312-0116 subjects who were randomized to Arm B. Subjects randomized to Arm A will 
continue idelalisib at 150 mg BID. Efficacy and safety data collected during the primary and 
open-label extension studies will be presented in the following 4 groups:

IDELA 150 mg BID: Subjects who are randomized to Arm A in Study GS-US-312-0116 and 
transition to Study GS-US-312-0117 during the open-label portion of the study to continue 
IDELA 150 mg BID

Placebo in GS-US-312-0116 + IDELA 150 mg BID (open-label): Subjects who are 
randomized to Arm B in Study GS-US-312-0116 and transition to receive 
IDELA 150 mg BID during the open-label portion of the study

IDELA 300 mg BID: Subjects who have PD per IRC confirmation in Arm A of 
Study GS-US-312-0116 and subsequently enroll Study GSUS-312-0117 to receive 
IDELA 300 mg BID during double-blind portion of the study

Placebo in GS-US-312-0116 + IDELA 150 mg BID in GS-US-312-0117: Subjects who have 
PD per IRC confirmation in Arm B of Study GS-US-312-0116 and subsequently enroll 
Study GS-US-312-0117 to receive IDELA 150 mg BID during double-blind portion of the 
study.
Depending on the endpoints, analyses may be based on the combined data from both primary and 
extension studies or data from the extension study alone. Analyses will be descriptive in nature 
and formal comparisons of outcomes in the 4 groups are not planned. A separate statistical 
analysis plan will be created for the open-label portion of the study.


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9.3.2.4.
Calculation of Tumor Control and Patient Well-Being Variables
Tumor control assessments will be based on standardized IWCLL criteria {Cheson 2012, Hallek 
2008}, as specifically modified for this study considering the pharmacology of idelalisib. The 
individual and composite endpoints of response and progression (considering changes in lymph 
node area, liver and spleen size, bone marrow, platelet counts, hemoglobin, neutrophil counts, 
and peripheral blood lymphocyte counts) will be determined. Tumor control will be documented 
at each assessment by response category (eg, CR, PR, SD, definitive PD, NE, ND) as defined for 
each response parameter, SPD value, percentage change in SPD values from baseline or nadir, 
date that response is first documented and date of definitive CLL progression.
The date of definitive CLL progression will be the timepoint at which progression is 
first identified by relevant objective radiographic or laboratory data. Because of the characteristic 
redistribution lymphocytosis that is expected with PI3Kinhibition, lymphocyte count will be 
ignored in the evaluation of progression. Changes in tumor status as provided by the investigator 
and changes in tumor status as adjudicated by the IRC (see Section 10.4.2) will be described. 
The findings of the IRC will be considered primary for analyses of all tumor control endpoints.
The following censoring conventions will be applied:

PFS and DOR: Data from surviving, non-progressing subjects will be censored at the earliest 
of the time of initiation of antitumor treatment other than the study treatment or the last time 
that lack of definitive CLL progression was objectively documented. Data from subjects who 
have CLL progression or die after 2 consecutive missing tumor assessments will be 
censored at the last time prior to the missing assessments that lack of definitive CLL 
progression was objectively documented.

OS: Data from surviving subjects will be censored at the last time that the subject was known 
to be alive.
9.4.
Analysis Plan
9.4.1.
Subject Disposition and Baseline Characteristics
A listing of all ITT analysis subjects will be generated to describe site, subject number, 
first screening date, first treatment date, allocated study drug assignment, actual study drug 
assignment, the longest duration of study drug treatment, and the reason for discontinuing study 
treatment. Available information on subjects who were screened or registered but not treated will 
be listed separately. A table will be created summarizing these categories in terms of number and 
percent for the ITT analysis set.
Subject baseline characteristics will be listed and summarized by treatment arm for the 
ITT analysis set. As appropriate for the specific variable, subject baseline characteristics
acquired in Study GS-US-312-0116 will be referenced in Study GS-US-312-0117.


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9.4.2.
Efficacy Analyses
9.4.2.1.
Time-to-Event Tumor Control and Survival Endpoints
PFS, DOR and OS will be described in the ITT analysis set using Kaplan-Meier methods by 
treatment group. Medians, ranges, and corresponding 95% CIs will be presented.
The Cox regression approach may be used to explore the influence of the primary study 
stratification factors and other baseline characteristics on PFS and OS. The stratification 
variables from the primary study and additional baseline subject characteristics may be included 
as covariates, focusing on those with expected prognostic significance.
9.4.2.2.
Categorical Endpoints
Response rates, lymph node response rate, splenomegaly response rate, 
hepatomegaly response rate, ALC response rate, platelet response rate, hemoglobin response 
rate, and neutrophil response rate will be described. In the calculation of response rates, subjects 
who do not have sufficient baseline or on-study tumor assessment to characterize response will 
be included in the denominator. For all analyses, the corresponding 95% CIs will be presented.
The potential influence of subject baseline characteristics on response rates may be explored
with multiple logistic regression modeling.
9.4.2.3.
Continuous Endpoints
Changes in lymph node area and changes in performance status, PI3K/AKT/mTOR pathway 
activation, and plasma chemokines/cytokines will be assessed by treatment group. Both changes 
from baseline to each subsequent timepoint and best overall on-study changes will be analyzed 
using appropriate methods (eg, analysis of covariance [ANCOVA] or paired t-tests). Means and 
standard errors will be presented.
9.4.2.4.
Health-Related Quality of Life and Performance Status
The FACT-Leu questionnaire data will be scored and processed according to the user manual. 
Missing items in a subscale will be imputed consistent with the user manual instructions. Data 
collected from the FACT-Leu instrument will not be reconciled with adverse event or laboratory 
data or with EQ-D5 findings.
As a baseline, the last value obtained prior to receiving the first idelalisib dose of 
150 mg and 300 mg will be used, depending on the treatment group assigned.
The mean and change from baseline in mean scores to each subsequent assessment will be 
summarized for the FACT-Lym subscale and composite scores. The best change from baseline 
during the study, defined as the highest positive value among all post-baseline visits minus 
the baseline value, will also be summarized.


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9.4.3.
Exposure and Safety Analyses
9.4.3.1.
Treatment Administration and Study Drug Compliance
Descriptive information will be provided by treatment arm regarding the number of doses of 
study therapy prescribed, the total number of doses taken, the percent of expected doses taken, 
the number of days of treatment, and the number and timing of prescribed dose reductions and 
interruptions.
Study drug compliance will be described by treatment arm in terms of the proportion of study 
drug actually taken based on returned pill count relative to the amount that was dispensed 
(taking into account physician-prescribed reductions and interruptions).
9.4.3.2.
Idelalisib Plasma Concentrations
Bioanalytical analyses will performed independently so that the study team and investigators will 
not have knowledge of data from individual subjects. Idelalisib plasma concentrations 
immediately pre-dose and at 1.5 hours after administration of the dose of study drug at each 
relevant clinic visit will be summarized by treatment and visit using descriptive statistics.
9.4.3.3.
Prior, Concomitant, and Post-Treatment Medication Use
Prior, concomitant, and post-treatment medications will be coded by means of the 
World Health Organization Drug Dictionary (WHODRUG) dictionary into 
Anatomical-Therapeutic-Chemical classification (ATC) codes.
Descriptions of prior medication use will be focused on drugs and regimens used as treatments 
for CLL. Information regarding CLL therapy that was administered prior to 
Study GS-US-312-0116 will be referenced in reporting the results of Study GS-US-312-0117. In 
addition, relevant treatment administration information collected during Study GS-US-312-0116 
will be referenced in reporting the results of this study. As appropriate and if available, 
information on the sequencing, type, dose, schedule, timing, duration of use, and efficacy of 
prior regimens will be provided, focusing particularly on findings observed in 
Study GS-US-312-0116.
The type and timing of use of concomitant medications will be listed and summarized by type 
and treatment arm. Information regarding the type and use of specific supportive medications 
(eg, pneumocystis prophylaxis, hematopoietic growth factors, corticosteroids) during study 
treatment will be described.
The number, type, and timing of post-study-treatment regimens for CLL will be summarized by 
treatment arm, characterizing the disposition of all subjects who were eligible for post-study 
treatment and also those who were not eligible for post-study treatment (eg, subjects who are 
never treated at all, die while on study treatment, are still on study, are lost to follow-up, etc).


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9.4.3.4.
Adverse Events
All adverse events will be listed. The focus of adverse event summarization will be on 
treatment-emergent adverse events. A treatment-emergent adverse event is defined as an adverse 
event that occurs or worsens in the period from the first dose of study treatment to 30 days after 
the last dose of study treatment.
Adverse events will be classified using MedDRA (http://www.meddramsso.com) with 
descriptions by System Organ Class, High-Level Group Term, High-Level Term, 
Preferred Term, and Lower-Level Term. The severity of adverse events will be graded by the 
investigator according to the CTCAE, Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf), 
whenever possible. If a CTCAE criterion does not exist for a specific type of adverse event, the 
grade corresponding to the appropriate adjective will be used by the investigator to describe the 
maximum intensity of the adverse event: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), 
Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the adverse event to the study 
drug will be categorized as related or unrelated.
Treatment-emergent adverse events will be summarized by treatment arm and by visit. 
Summary tables will be presented to show the number of subjects reporting treatment-emergent 
adverse events by severity grade and corresponding percentages. A subject who reports multiple 
treatment-emergent adverse events within the same Preferred Term (or System Organ Class) is 
counted only once for that Preferred Term (or System Organ Class) using the worst severity 
grade. Adverse event descriptions will be presented by decreasing frequency for a given 
System Organ Class and Preferred Term.
Separate listings and summaries will be prepared for the following types of treatment-emergent 
adverse events:

Study-drug-related adverse events

Adverse events that are Grade 3 in severity

Adverse events leading to study drug interruption and/or dose modification

Adverse events leading to study drug discontinuation

Serious adverse events (with categorization of the primary reason that the adverse event is 
considered serious, eg, death, hospitalization, etc)
Separate listings and summaries will be prepared for long-term follow-up safety data 
(see Section 6.2.17).
9.4.3.5.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed data. 
The focus of laboratory data summarization will be on treatment-emergent laboratory 
abnormalities. A treatment-emergent laboratory abnormality is defined as an abnormality that, 


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compared to baseline, worsens by 1 grade in the period from the first dose of study drug to
30 days after the last dose of study drug. If baseline data are missing, then any graded 
abnormality (ie, an abnormality that is Grade 1 in severity) will be considered treatment 
emergent. Hematological, serum biochemistry, and urine data will be programmatically graded 
according to CTCAE severity grade, when applicable. For parameters for which a CTCAE scale 
does not exist, reference ranges from the central laboratory will be used to determine 
programmatically if a laboratory parameter is below, within, or above the normal range for the 
subject’s age, sex, etc.
Hematological and serum biochemistry and their changes from baseline will be summarized by 
treatment arm and by visit. Summary tables will be presented for each relevant assay to show the 
number of subjects by CTCAE severity grade with corresponding percentages. For parameters 
for which a CTCAE scale does not exist, the frequency of subjects with values below, within, 
and above the normal ranges will be summarized. Subjects will be characterized only once for a 
given assay, based on their worst severity grade observed during a period of interest 
(eg, during the study or from baseline to a particular visit).
Shift tables for hematology and serum biochemistry will also be presented by showing change in 
CTCAE severity grade from baseline to the worst grade post baseline. Separate listings and 
summaries will be prepared for laboratory abnormalities that are Grade 3 in severity.
9.4.3.6.
Oxygen Saturation Values
All oxygen saturation data will be listed. Summaries of oxygen saturation data will be based on 
observed data and will be reported as % saturation. Data and changes from baseline will be 
summarized by treatment arm and by visit. Summary tables will be presented for values 
below 92% and for declines from baseline of 5% to show the number of subjects with 
corresponding percentages. Subjects will be characterized only once for each of these 
categorizations, based on their lowest value observed during a period of interest 
(eg, during the study or from baseline to a particular visit).
9.4.4.
Other Analyses
9.4.4.1.
Between-Study Comparisons
It is expected that patients with a progressive malignancy like CLL will normally fare better with 
an earlier therapy than with a later therapy. However, if the converse situation proves true –
eg, if an investigational treatment (idelalisib) administered later shows similar or greater benefit 
than a standard treatment (rituximab) administered earlier – strong evidence of investigational 
drug effect is demonstrated. Evaluating data derived from the same study subjects during their 
sequential participation in 2 clinical trials offers unique analytical challenges. However, in this 
integrated Phase 3 study program, it is likely that comparing baseline characteristics and 
outcomes among Arm B subjects participating in Study GS-US-312-0116 and 
Study GS-US-312-0117 will be informative. Such an evaluation characterizes how the subjects
and the CLL disease process change with time and treatment. In addition, such an analysis 
provides relevant supporting information documenting the benefits of single-agent idelalisib
relative to single-agent rituximab in the same subjects.


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Accordingly, baseline characteristics, time-to-event efficacy variables (eg, PFS, TTR, DOR), 
categorical variables (eg, ORR, lymph node response rate, splenomegaly response rate, 
hepatomegaly response rate), and continuous variables (eg, percentage changes in 
lymph node area; changes in performance status, PI3K/AKT/mTOR pathway activation and 
plasma chemokines/cytokines)  may be evaluated between Study GS-US-312-0116 and 
Study GS-US-312-0117 for Arm B subjects.
9.4.4.2.
Health Care Resource Utilization
The EQ-D5 questionnaire data will be scored, processed, and standardized according to the user 
manual. Change from baseline in EQ-5D visual analogue scale and EQ-5D index will be 
summarized. As for the FACT-Leu, data will be analyzed using appropriate methods to account 
for incomplete completion of questionnaires. Data collected from the EQ-D5 will not be 
reconciled with adverse event or laboratory data or with FACT-Leu findings.
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach to the health economic analysis will be to combine the resource utilization 
data from the trial with data on unit prices (collected separately) to estimate total costs.
The perspective of this analysis will be that of the third-party payer(s) and the hospital over a 
lifetime horizon in the base case. The costs will be described relative to the health care findings 
as measured by duration of tumor control, the symptom-free survival period, life-years, utility 
outcomes, or other measure of appropriate clinical benefits. In order to facilitate the calculation 
of utilities for use in the cost effectiveness analyses, the health status of subjects will be 
evaluated using PFS, Karnofsky performance status, FACT-Leu, and EQ-5D.
9.4.4.3.
Data Explorations
Changes in biomarkers during acquisition of resistance will be evaluated descriptively. Data 
explorations may be performed to evaluate potential associations between subject characteristics 
and outcome measures. Explorations may be performed to assess the potential associations 
between different outcomes measures (eg, relationships between HRQL changes and 
clinical/radiographic endpoints of tumor control).
9.5.
Sample Size
The sample size for this extension study is not based upon a formal statistical hypothesis. The 
upper bound of the sample size in this study is determined by the sample size of the preceding 
primary study (Study GS-US-312-0116) in which ~220 subjects (~110 per arm) are expected to 
be enrolled. It is estimated that this extension study (Study GS-US-312-0117) will have a total 
idelalisib-treated N~180 (assuming a ~10% dropout rate during Study GS-US-312-0116 and a 
further ~10% dropout rate in the transition from the primary study to the extension study).


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9.6.
Timing of Analyses
The DMC will have access to serious adverse events requiring expedited reporting and will be 
provided with accumulating safety data on a regular basis. Interim safety reviews will be 
conducted by the DMC in conjunction with safety reviews of the primary clinical trial
(Study GS-US-312-0116) if applicable. Thus, interim safety reviews will be performed by the 
DMC at intervals of ~6 months; the specific frequency of these reviews will depend upon the 
rate at which the trials are enrolled, the nature of any emerging safety signals, and monitoring 
recommendations from the DMC. At each review, all available safety data will be summarized 
and evaluated.
An interim efficacy analysis of this clinical trial (Study GS-US-312-0117) is planned to take 
place at the time of the final blinded analysis of the primary study (GS-US-312-0116). The intent 
is to provide the data from this extension study in support of regulatory review of data from the 
primary study. An analysis of efficacy and safety may be performed to satisfy regulatory 
requirements and to perform long-term efficacy, safety and OS follow-up. The timing of the final 
analysis is expected to occur within 48 months of accrual of the final subject to 
Study GS-US-312-0117.


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10.
RESPONSIBILITIES
10.1.
Investigator Responsibilities
10.1.1.
Compliance with Ethical and Regulatory Guidelines
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), with ICH guidelines, or with the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the study subject. These 
standards are consistent with the European Union Clinical Trials Directive 2001/20/EC and 
Good Clinical Practice Directive 2005/28/EC. The investigator will ensure adherence to the 
basic principles of GCP as outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and 
Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
This study is also subject to and will be conducted in accordance with 21 CFR, part 320, 1993, 
“Retention of Bioavailability and Bioequivalence Testing Samples.”
Because this is a “covered” clinical trial, the investigator will ensure adherence to 
21 CFR, Part 54, 1998; a covered clinical trial is any “study of a drug or device in humans 
submitted in a marketing application or reclassification petition subject to this part that the 
applicant or FDA relies on to establish that the product is effective (including studies that show 
equivalence to an effective product) or that make a significant contribution to the demonstration 
of safety.” This requires that investigators and all sub-investigators must provide documentation 
of their financial interest or arrangements with Gilead Sciences, or proprietary interests in the 
drug being studied. This documentation must be provided before participation of the investigator 
and any subinvestigator in the trial. The investigator or subinvestigator agrees to notify 
Gilead Sciences of any change in reportable financial interests during the study and for 1 year 
following completion of the study. Study completion is defined as the date that the last subject 
has completed the protocol-defined activities.
10.1.2.
Institutional Review Board/Independent Ethics Committee
This protocol and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) will be submitted by the investigator to an IRB (for sites enrolling in 
the United States) and to an IEC for sites enrolling outside of the United States). Approval from 
the IRB/IEC must be obtained before starting the study and should be documented in a letter to 
the investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval.
Any modifications or amendments made to the protocol after receipt of the initial IRB/IEC
approval must also be submitted to the IRB/IEC for approval before implementation. Only 
changes necessary to eliminate apparent immediate hazards to the subjects may be initiated prior 
to IRB/IEC approval. In that event, the investigator must notify the IRB/IEC and Gilead Sciences
in writing within 5 working days after implementation.


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The investigator shall submit a progress report, at least once yearly, to the IRB/IEC, and must 
provide a copy to Gilead Sciences. As soon as possible after completion or termination of the 
study, the investigator will submit a final report to the IRB/IEC and to Gilead Sciences. This 
report should include the dates of initiation and completion of the trial, a description of any 
changes in study procedures or amendments to the protocol, any deviations from the protocol, 
the number and type of subjects evaluated, the number of subjects who discontinued 
(and the reasons for discontinuation), the number of subjects who completed the trial, and the 
results of the trial, including a description of any adverse events. Gilead Sciences will assist the 
investigator in the preparation of this report, as needed.
10.1.3.
Informed Consent
After adequately, explaining the aims, methods, objectives, and potential hazards of the study 
and before undertaking any study-related procedures, the investigator is responsible for obtaining 
written informed consent from each individual participating in this study. The investigator must 
utilize an IRB/IEC-approved consent form for documenting written informed consent. Each 
informed consent will be appropriately signed and dated by the subject or the subject’s legally 
authorized representative and the person obtaining consent.
The approved informed consent must not be changed without prior approval by Gilead Sciences
and the IRB/IEC.
10.1.4.
Confidentiality
The investigator must assure that each subject’s anonymity will be strictly maintained and that 
each subject’s identity is protected from unauthorized parties. Only subject initials, date of birth, 
and an identification code (but no subject names) should be recorded on any form or biological 
sample submitted to the Gilead Sciences or designees (eg, laboratories), or to the IRB/IEC.
However, sufficient information must be retained at the site to permit sample data and data in the 
database to be connected with the unique subject number assigned to each study participant.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the idelalisib investigator brochure, this protocol, eCRFs, the investigational new drug, 
and any other study information, remain the sole and exclusive property of Gilead Sciences
during the conduct of the study and thereafter. This information is not to be disclosed to any 
third party (except employees or agents directly involved in the conduct of the study or 
as required by law) without prior written consent from Gilead Sciences. The investigator further 
agrees to take all reasonable precautions to prevent the disclosure by any employee or agent of 
the study site to any third party or otherwise into the public domain.
10.1.5.
Study Files and Retention of Records and Biological Samples
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator’s study file, and 
(2) subject clinical source documents.


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The investigator’s study file will contain the protocol/amendments, eCRF and query forms, the 
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data referenced in the monitoring plan for the study, and should include 
sequential notes containing at least the following information for each subject:

Subject identification (name, date of birth, gender)

Documentation that subject meets eligibility criteria, eg, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria)

Participation in trial (including trial number)

Trial discussed and date of informed consent

Dates of all visits

Documentation that protocol-specific procedures were performed

Results of efficacy parameters, as required by the protocol

Start and end date (including dose regimen) of trial medication (including relevant drug 
dispensing and return information)

Record of all adverse events and other safety parameters (including start and end date, 
causality and intensity)

Concomitant medication (including start and end date and dose if relevant dose changes 
occur)

Date of trial completion and reason for discontinuation, if applicable
All clinical study documents must be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (ie, the United States, Europe, 
or Japan) and until there are no pending or contemplated marketing applications in an 
ICH region; or, if no application is filed or if the application is not approved for such indication, 
until 2 years after the investigation is discontinued and regulatory authorities have been notified. 
Investigators may be required to retain documents longer if required by applicable regulatory 
requirements, by local regulations, or by an agreement with Gilead Sciences. The investigator 
must notify Gilead Sciences before destroying any clinical study records. The investigator will 
promptly notify Gilead Sciences in the event of accidental loss or destruction of any study 
records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead Sciences must be notified in advance.


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If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead Sciences
to store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site.
Biological samples including tissue and blood samples collected as a study procedure or as 
standard of care during study participation will be stored and maintained by the investigator until 
notification is received from Gilead Sciences that the retained samples and records no longer 
required. The investigator must obtain written permission from Gilead Sciences before disposing 
of any retained samples. The investigator should promptly notify Gilead Sciences in the event of 
accidental loss or destruction of any study samples. With the permission of Gilead Sciences, the 
retained samples may be transferred to an acceptable designee, such as another investigator, 
another institution, a contract storage site, or to Gilead Sciences.
10.1.6.
Case Report Forms
An eCRF is required and must be completed for each enrolled subject, with all required study 
data accurately recorded such that the information matches the data contained in medical records 
(eg, physicians’ notes, nurses’ notes, clinic charts, or other study-specific source documents). As 
required by the protocol, eCRFs should also be completed for those subjects who fail to complete 
the study (even during the screening period). If a subject withdraws from the study, the reason 
must be noted on the eCRF. If a subject is withdrawn from the study because of a 
treatment-limiting adverse event, thorough efforts should be made to clearly document the 
outcome.
The eCRFs for this study will exist within a Web-based electronic data capture (EDC) system. 
After the investigator or the investigator’s designees (eg, research coordinators) have been 
appropriately trained, they will be given access to the EDC system and will enter the data 
required by the protocol into the EDC system. Any change of data will be made via the 
EDC system, with all changes tracked by the system to provide an audit trail.
The eCRF must be completed and signed by the principal investigator or subinvestigator 
(as appropriate) within a reasonable time period after data collection. This signature serves to 
attest that the information contained in the eCRF is true.
10.1.7.
Drug Accountability
As described in the relevant section (see Section 5.2.7), the investigator is responsible for 
ensuring adequate accountability of all used and unused investigational medicinal product, 
placebos, and comparators. This responsibility includes acknowledgment of receipt of each 
shipment of study product (quantity and condition), subject dispensing records, and returned or 
destroyed study product. Dispensing records will document quantities received from 
Gilead Sciences and quantities dispensed to subjects, including lot number, date dispensed, 
subject identifier number, subject initials, and the initials of the person dispensing the 
medication.


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At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during the 
study if appropriate. At the end of the study, following final drug inventory reconciliation by the 
monitor, the study site will dispose of and/or destroy all unused investigational medicinal 
product supplies, including empty containers, according to these procedures. If the site cannot 
meet Gilead Sciences’ requirements for disposal, arrangements will be made between the site 
and Gilead Sciences or its representative for destruction or return of unused investigational 
medicinal product supplies.
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study.
10.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRB/IECs, 
and to regulatory authority or health authority inspectors. It is important that the investigator and 
relevant institutional personnel are available during monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process.
10.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
10.2.
Sponsor Responsibilities
10.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, will be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB/IEC in 
accordance with local requirements. Except as noted in Section 10.1.2, IRB/IEC approval must 
be obtained before changes can be implemented.
10.2.2.
Communications with Regulatory Authorities
Gilead Sciences, working either directly or through designees, will assume responsibility for 
regulatory interactions with relevant regulatory authorities. Gilead Sciences will maintain an 
IND for idelalisib in support of the study in the United States and will maintain similar 
regulatory applications with other regulatory authorities, as required for conduct of the study. In 
fulfilling this responsibility, Gilead Sciences (or a designee) will collect, assemble, and 
communicate all required regulatory documents (eg, Form FDA 1572, investigator financial 
disclosure forms, protocol and protocol amendments, investigator brochures, informed consent 
documents, annual reports) as required by regulation. Gilead Sciences (or a designee) will also 
assume responsibility for adverse event reporting to regulatory authorities as described in 
Section 8.7.2.


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10.2.3.
Data Management
Electronic data capture will be used to enter study data eCRFs and to transfer the data into a 
study-specific electronic database. During the data collection process, automated quality 
assurance programs will be used to identify missing data, selected protocol violations, 
out-of-range data, and other data inconsistencies. Requests for data clarification or correction 
will be forwarded to the investigative site for resolution. As appropriate, eCRFs, listings, tables, 
and SAS datasets will be provided to the investigational sites for review.
Quality assurance and quality control systems will be implemented and maintained according to 
written standard operating procedures to ensure that the data are generated, recorded, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements. Data 
collection and storage systems will provide audit trail, security mechanisms, and electronic 
signature capabilities that meet the requirements of FDA Title 21 of CFR Part 11 regarding 
electronic records and electronic signatures.
Data security will be controlled through appropriate and specific restriction of access only to data 
and systems required by individual users to accomplish their roles in the data management 
process. Individual login and password protections will be employed at study sites and at 
Gilead Sciences or its designee. The database will exist on physically secured servers. Data 
backups will be done regularly and will be stored in separate facilities. Printed documents 
relating to the study will be secured when not under review.
10.2.4.
Study Reporting and Publication
Gilead Sciences may make information obtained during this study available in order to further 
the scientific or business needs of the company or as required by law or regulation. In this 
regard, Gilead Sciences may provide study information to private or public organizations 
(eg, business partners, collaborators, consultants, CROs, investors, other physicians who are 
conducting similar studies, funding organizations, regulatory authorities, or other 
government authorities).
Gilead Sciences will prepare a clinical study report for submission to relevant regulatory 
agencies. Gilead Sciences will ensure that the report meets the standards set out in the 
ICH Guideline for Structure and Content of Clinical Study Reports (ICH E3). An abbreviated 
report may be prepared in certain cases, as appropriate.
Gilead Sciences intends that the data from this study will be presented and published. 
Gilead Sciences will work in collaboration with the principal investigators in preparing 
presentations and writing manuscripts for publication.

Investigators may publish or present the results of the study generated by their individual site 
either with the advanced written consent of Gilead or > 2 years after the completion of this 
extension study (GS-US-312-0117) at all participating institutions.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information (see Section 10.1.4).


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The investigator will submit to Gilead Sciences any proposed publication or presentation along 
with the respective scientific journal or presentation forum prior to submission of the publication 
(at least 30 days prior to manuscripts and 15 days prior for abstracts and oral presentations). The 
investigator will comply with Gilead Sciences’ request to delete references to its confidential 
information (other than the study results) in any paper or presentation. If deemed necessary by 
Gilead Sciences, the investigator also agrees to withhold publication or presentation for an 
additional 60 days in order to obtain patent protection.
10.3.
Joint Investigator/Sponsor Responsibilities
10.3.1.
Access to Information for Monitoring
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor must 
have direct access to the investigator’s source documentation in order to verify the data recorded 
in the eCRFs for consistency.
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.
10.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead Sciences may conduct inspections or audits 
of the clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead Sciences medical monitor immediately. The investigator 
agrees to provide to representatives of a regulatory agency or Gilead Sciences access to records, 
facilities, and personnel for the effective conduct of any inspection or audit.
10.3.3.
Public Notification of Study Conduct
Consistent with Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and 
with requirements of the International Committee of Medical Journal Editors (ICMJE) as a 
condition of consideration for publication of study results, Gilead Sciences will be responsible 
for ensuring that this protocol is listed at the ClinicalTrials.gov website (or equivalent) and that 
information at the website relating to study design and conduct is appropriately updated during 
the course of the study. In order to facilitate this process, investigators will need to supply 
Gilead Sciences with appropriate contact information for study site personnel.
10.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authorities and IRB/IECs. In terminating the study, Gilead Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.


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10.4.
Study Committees
10.4.1.
Data Monitoring Committee
A DMC, operating autonomously from Gilead Sciences, the clinical investigators, and the SSC, 
will be responsible for providing independent recommendations to Gilead Sciences about 
evolving risk-benefit observed in the course of the study and any modifications required during 
the course of the study. The DMC will consist of a biostatistician and 2 physicians experienced 
in treating patients with lymphoid malignancies. The DMC will be chaired by one of these 
individuals. DMC members must not be actively involved in study design, conduct, or subject
accrual and must not have financial, proprietary, professional, or other interests that may affect 
impartial, independent decision-making. Specialists may be invited to participate as non-voting 
members at any time if additional expertise is desired. The DMC will formally interact with the 
external SSC members through the sharing of meeting minutes. Informal interactions between 
the DMC and external SSC members will be limited. The DMC will operate under a charter 
developed as a collaborative document between Gilead Sciences and the DMC. It is expected 
that the members of the DMC will be the same as those for the primary study 
(Study GS-US-312-0116). 
The primary responsibility of the DMC is to protect the safety and welfare of subjects 
participating in this clinical trial and to ensure the integrity of the clinical trial. In general, the 
DMC will be responsible for:

Reviewing the general progress of the study as regards subject accrual, study conduct, and 
protocol violations

Examining accumulated safety, efficacy, and other relevant data at prespecified points during 
the course of the study 

Reviewing major study design modifications prior to implementation of those modifications

Making recommendations concerning continuation, modification, interruption, or termination 
of each study

Advising the company on changes to informed consent documents

Proposing updates to the DMC monitoring plan, changes in the DMC membership, actions to 
be taken relating to conflict of interest or confidentiality breaches, the need for additional 
expertise during DMC deliberations, revisions to the DMC charter, or alterations in the 
support provided to the DMC

Providing expert advice to the Gilead Science medical monitor on an ad hoc basis regarding 
matters such as safety concerns or diagnostic evaluations in individual subjects
Based on the results of its deliberations during the course of the study, the DMC can recommend 
appropriate actions (eg, continuation of the study unchanged, continuation of the study with 
modifications in design or monitoring plan, interruption of study accrual, study termination).


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10.4.2.
Independent Review Committee
An IRC will be established to provide a blinded review of radiographic data and pertinent 
clinical data in order to provide expert interpretation of changes in tumor status. The IRC will 
include 1 independent board-certified radiologist and 1 independent board-certified 
hematologist or oncologist, and will be managed by a CRO selected by Gilead Sciences. The 
review of radiographic and clinical data by the IRC will be performed on an ongoing basis until 
the primary analysis . The specifics of the IRC’s processes and reading methods will be 
described in an independent review charter developed by the contracted imaging facility in 
conjunction with Gilead Sciences. The same organization that is providing IRC services for 
Study GS-US-312-0116 will provide IRC services for this study.


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11.
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Apoptosis 2004;9 (6):667-76.
Perkins JG, Flynn JM, Howard RS, Byrd JC. Frequency and type of serious infections in 
fludarabine-refractory B-cell chronic lymphocytic leukemia and small 
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Stephens JM, Gramegna P, Laskin B, Botteman MF, Pashos CL. Chronic lymphocytic leukemia: 
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12.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
Appendix 3.
Performance Status Scoring System
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D)
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Appendix 6.
Cumulative Illness Rating Scale (CIRS)
Appendix 7.
Schedule of Study Procedures


PPD
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Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
199 EAST BLAINE STREET 
SEATTLE, WA 98102 
STUDY ACKNOWLEDGEMENT 
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and Safety of 
Two Different Dose Levels of Single-Agent Idelalisib (GS-1101) for Previously Treated 
Chronic Lymphocytic Leukemia 
GS-US-312-0117, Version 10 (Amendment 9), 21 September 2017 
This protocol has been approved by Gilead Sciences, Inc. The following_ggnature documents 
this approval. 
~~-:-----~10 
Gilead Sciences Medical Monitor 
Date 
~STIGATORSTATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
informa6on provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator 
Printed Name 
Date 
CONFIDENTIAL 
Page 152 
Signature 
Site Number 
21 September 2017 


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Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
FACT-Leu (Version 4) 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days. 
PHYSICAL WELL-BEING 
GPI 
I have a lack of energy . . . . . . . . . . . . . . . 
GPl 
l have nausea 
.... ............ 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
GP4 
I have pain ...... ..... , 
......... ......................... 
GP5 
l am bothered by side effects of treatment 
01'6 
I feel ill . 
. ···················· 
GP7 
1 am forced to spend time in bed 
SOCIAL/FAMILY WELL-BEING 
OS! 
I feel close to my friends ...... 
.................. 
GS1 
I get emotional support from my family 
GS3 
1 get support from my friends .... 
GS4 
My family has accepted my illness 
GS5 
1 am satisfied with family communication about my 
illness .................... 
GS6 
I feel close to my partner (or the person who is my main 
support) . 
QI 
Regardless o_fyour current level of sexual activity. please 
answer the following question. ffyou prefer not to answer it, 
please mark this box 0 and go to the next section. 
GS7 
I am satisfied with my sex life ......................................... 
Engh !l.h (Universal) 
C~nglu 1987, 1997 
Not 
A little 
Some-
Quite 
at all 
bit 
what 
a bit 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
Not 
A little 
Some-
Quite 
at all 
bit 
what 
a bit 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
0 
2 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
19 Novcmlx:r 1007 
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FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
EMOTIONAL WELL-BEING 
GEl 
I feel sad ..... ................................ , 
GE2 
I am satisfied with how I am coping with my illness .... 
GE3 
I am losing hope in the fight against my illness 
GE4 
I feel nervous 
................... , 
GE5 
I worry about dying . . . . . . . . . . . . . . . . . . . . . . . . 
GE6 
I worry that my condition will get worse 
FUNCTIONAL WELL-BEING 
GFI 
I am able to work (include work at home) 
GF2 
My work (include work at home) is fulfilling ... 
GF3 
I am able to enjoy life ...... 
................. , ...... 
GF4 
1 have accepted my illness ... ................. 
GF5 
1 am sleeping well 
................................. 
GF6 
I am enjoying the things 1 usually do for fun 
GF7 
I am content with the quality of my life right now 
Enghsh (Universal) 
Cop}'right 1987, 1997 
Not 
A little 
Some-
at all 
bit 
what 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Not 
A little 
Some-
at all 
bit 
what 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
19 November 1007 
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FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
ADDITIONAL CONCERNS 
Not 
A little 
Some-
at all 
bit 
what 
BRM3 
I am bothered by fevers (episodes of high body 
temperature) 
...... ........ . 
0 
2 
Pl 
I have certai n parts of my body where I experience pain.... 
0 
2 
BRMl 
ES3 
LEU I 
THI 
Till 
Hll2 
BMT6 
Cl 
C6 
An7 
N3 
LEm 
LEU6 
BRM9 
I am bothered by the chills .. .......... ... . 
I have night sweats .............................. .. 
I am bothered by lumps or swelling in certain parts of 
my body (e.g., neck, armpits, or groin) 
I bleed easily . 
1 bruise easily . 
I feel weak all over. 
I get tired easily 
I am losing weight 
I have a good appetite .......... ............ .. 
I am able to do my usual activities 
I worry about getting infections ......................... . 
I feel uncertain about my future health .................... .. 
1 worry that I might get new symptoms of my illness 
I have emotional ups and downs 
LEU7 
I feel isolated from others because of my illness or 
treatment 
Enghsh (Universal) 
Cop}'right 1987, 1997 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
19 November 1007 
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Appendix 3.
Performance Status Scoring System
Karnofsky Performance Status
General Description
Score
Specific Description
Able to carry on normal activity and 
to work; no special care needed.
100
Normal; no complaints;
no evidence of disease.
90
Able to carry on normal activity;
minor signs or symptoms of disease.
80
Normal activity with effort;
some signs or symptoms of disease.
Unable to work; able to live at home 
and care for most personal needs; 
varying amount of assistance 
needed.
70
Cares for self;
unable to carry on normal activity or to do active work.
60
Requires occasional assistance,
but is able to care for most of personal needs.
50
Requires considerable assistance and frequent medical care.
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly.
40
Disabled; requires special care and assistance.
30
Severely disabled;
hospital admission is indicated although death not imminent.
20
Very sick; hospital admission necessary;
active supportive treatment necessary.
10
Moribund; fatal processes progressing rapidly.
0
Dead


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Appendix 4.
EuroQoL-5 Dimensions (EQ-5D)
Sample


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Sample


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Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance
Formulas for calculating the estimated creatinine clearance (eCcr) are provided in the table 
below. The formula appropriate to the units in which serum creatinine was measured and the 
subject’s gender should be used.
Cockcroft-Gault Formulas for Calculating Estimated Creatinine Clearance
Serum
Creatinine Units
Gender
Formula
mg/dL
Males
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1
72 subject serum creatinine [mg/dl]
Females
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 0.85
72 subject serum creatinine [mg/dl]
M/dL
Males
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.23
Subject serum creatinine [mg/dl]
Females
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.04
Subject serum creatinine [mg/dl]
Abbreviation: eCcr=estimated creatinine clearance


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Appendix 6.
Cumulative Illness Rating Scale (CIRS)
The CIRS used in this protocol is designed to provide an assessment of recurrent or ongoing 
chronic comorbid conditions, classified by 14 organ systems. Using the drop-down lists of 
organ-specific diagnoses, please select any conditions present in the study subject. If the subject
has a recurrent or ongoing chronic conditions that are not described in the list for a given organ 
system, please indicate the name of the conditions under “other chronic condition” for that organ 
system. Please take into account that CLL-induced discomfort, symptoms, or disability should 
not be considered. If additional explanation would be helpful, text comments may be inserted.
CIRS List of Comorbid Conditions
Organ System
Diagnosis
Comment
Cardiac
Chronic heart failure
Angina pectoris
Medically relevant arrhythmia
Valve dysfunction
Congenital heart disease
Cardiomyopathy
Myocarditis
Chronic pericarditis
Endocarditis
Other chronic cardiac condition:
Other chronic cardiac condition:
Vascular
Hypertension
Thrombosis
Peripheral diabetic microvascular disease
Peripheral artery disease
Aortic aneurysm
Aortitis
Raynaud disease
Vasculitis
Other chronic vascular condition:
Other chronic vascular condition


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Organ System
Diagnosis
Comment
Hematological/
immunological
Sickle cell anemia
Hemoglobinopathy
Polycythemia
Thrombocythemia
Hemophilia
Paroxysmal nocturnal hemoglobinuria
Thrombotic thrombocytopenic purpura
Dysfibrinogenemia
HIV
Other chronic hematological or 
immunological condition:
Other chronic hematological or 
immunological condition
Abbreviation: CIRS=Cumulative Illness Rating Scale
For each condition selected from the CIRS List of Comorbid Conditions, please rate the severity 
of that condition. For the severity rating, please use the scoring guidelines shown in the table 
below, considering the magnitude of symptoms, how manageable the condition is, and the extent 
of intervention required:
CIRS Rating Scale
Score
Severity
Findings
1
Mild
Mild discomfort, symptoms or disability
Easy to control
Requiring either no therapy/medication or only as needed
2
Moderate
Moderate  discomfort, symptoms or disability
Manageable
Requiring daily treatment or first-line therapy
3
Severe
Severe discomfort, symptoms or disability
Hard to control
Requiring second-line therapy or multiple medications
4
Extremely severe
Life threatening, permanently disabling disability, causing organ failure
Poorly manageable
Requiring urgent intervention or resistant to therapy
Abbreviation: CIRS=Cumulative Illness Rating Scale


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Appendix 7.
Schedule of Study Procedures
Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4 a
5a
6 a
7a
8 a
9 a
10 a
11 a
12 a
13 a
14 a
15 a
16+e
End
of
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28 Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30 days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Informed consent
X
CIRS assessment
X
β-HCG
(women of 
childbearing 
potential)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CLL peripheral 
blood evaluation
X
X
CLL serology
X
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HRQL/
healthy utility –
FACT-Leu/EQ-5D
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exam
(includes nodes, 
liver, spleen)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PPD


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Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4 a
5a
6 a
7a
8 a
9 a
10 a
11 a
12 a
13 a
14 a
15 a
16+e
End
of
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28 Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30 days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
Oxygen saturation
(by pulse 
oximetry)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Circulating cells/
Immune 
monitoringb
X
X
X
X
X
X
X
X
X
X
X
X
X
Xb
Biomarkers
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum Igsb
X
X
X
X
X
X
X
X
X
X
X
X
X
Xb
Study drug
administration in 
clinic
X
X
X
X
X
X
X
X
Idelalisib
pharmacokinetics c
X
X
X
X
X
X
X
X
Study drug
dispensing/
accounting c
X
X
X
X
X
X
X
X
X
X
X
Radiology 
assessment 
(CT/MRI)
X
Xf
Xf
Xf
Xf
Xf
Xf, k
X f,g
Bone marrow 
biopsy/
aspirate d
X
X
X
X
X
X
X
X
CMV viral loadh
X
PJP prophylaxisi, j
Xi
Xj


Idelalisib
Protocol GS-US-312-0117
Final
Gilead Sciences, Inc.
Version 10.0
CONFIDENTIAL
Page 164
21 September 2017
Period
Screen
Treatment
Follow-up
Visit
1
2
3a
4 a
5a
6 a
7a
8 a
9 a
10 a
11 a
12 a
13 a
14 a
15 a
16+e
End
of
Study
30 days
Long-term
Week
-4
0
2
4
6
8
10
12
16
20
24
30
36
42
48
Q12
Weeks
Study Day
Within
-28 Days
1
15
29
43
57
71
85
113
141
169
211
253
295
337
Within
+30 days
To
+5
years
Visit Window
±2
±2
±2
±2
±2
±2
±3
±3
±3
±3
±3
±3
±3
±7
CD4+ T-cell countj
(related to PJP 
prophylaxis)
Xj
Post-treatment 
CLL therapy
X
Long-term 
follow-up 
X
a
Following unblinding of the study, the visit schedule will be modified per Section 6.2 and Visits 3 – 15 may not be applicable for subjects who were randomized to idelalisib 
on Study GS-US-312-0116 or who were randomized to placebo on GS-US-312-0116 and have received 24 weeks cumulative treatment with idelalisib
b
Circulating cells/Immune monitoring  and Serum Igs should be performed at the the End of Study visit
c
Subjects who were randomized to placebo on Study GS-US-312-0116 and enroll following unblinding, may have idelalisib treatment (and associated PK testing) delayed at 
the Investigator’s discretion until the time of disease progression or until the investigator determines the subject may benefit by the initiation of idelalisib treatment
d
At screening, to be performed at investigator discretion to determine extent of CLL involvement and bone marrow cellularity. Post-screening, to be performed to confirm 
response category in subjects with potential CR or to confirm a hematologically-based disease progression; if the subject does not otherwise meet criteria for CR or if the 
nature of PD does not require bone marrow confirmations, it is not necessary to obtain a follow-up bone marrow biopsy/aspirate
e
Following unblinding, Visit 16+ may be completed prior to 48 weeks as subjects transition to a Q12 week visit schedule 
f
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the assessment should be done even if study drug has been interrupted
g
An end-of-study CT/MRI tumor assessment should be performed unless the subject already has radiographic confirmation of definitive disease progression < 4 weeks prior to 
study discontinuation
h
CMV viral load should be performed approximately every 4 weeks throughout idelalisib treatment.  If unequivocal clinical or laboratory evidence of CMV infection is 
present, the subject must interrupt idelalisib treatment and undergo effective antiviral treatment according to established clinical guidelines.
i
PJP prophylaxis:  subjects must receive trimethoprim-sulfamethoxazole or other established prophylaxis for PJP throughout the course of idelalisib treatment and for 2 to 6 
months after the last dose of idelalisib.  Subjects must permanently discontinue idelalisib upon diagnosis of PJP. Prophylaxis will continue for 2 to 6 months after the last dose of 
idelalisib and until the CD4+ T-cell count is documented to be >200 cells/mcL after idelalisib treatment ends. 
j
CD4+ T-cell countl (related to PJP prophylaxis):  PJP prophylaxis will continue until the CD4+ T-cell count is documented to be >200 cells/mcL after idelalisib treatment ends.
k
As of Amendment 9, Version 10, CT/MRI assessments will no longer be performed at the every 12 week scheduled visits, and will only be performed at the time of clinically-
suspected disease progression or at study discontinuation.
Abbreviations: -HCG=beta human chorionic gonadotropin, CIRS=chronic illness rating scale, CLL=chronic lymphocytic leukemia, CMV=cytomegalovirus, CR=complete 
response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy- Leukemia, HRQL= health-related quality of life, 
Ig=immunoglobulin, IWRS=interactive web response system, MRI= magnetic resonance imaging, PJP= Pneumocystis jirovecii pneumonia.