An Extension Study to Investigate the Safety and Durability of Clinical Activity of Idelalisib in Subjects With Hematologic Malignancies
Phase: PHASE1
Conditions: Chronic Lymphocytic Leukemia, Lymphoma, Non-Hodgkin
Sponsor: Gilead Sciences

CLINICAL STUDY PROTOCOL
Study Title:
An Extension Study to Investigate the Safety and Durability of 
Clinical Activity of Idelalisib in Subjects with Hematologic 
Malignancies
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
EudraCT Number:
Clinical Trials.gov Identifier:
101254
Not Applicable
NTC01090414
Indication:
Hematologic malignancies
Protocol ID:
101-99
Gilead Medical Monitor:
Name:
Telephone:
Gilead Clinical Program 
Manager:
Name:
Telephone:
Protocol Version/Date:
Original:
22 January 2010
Amendment 1:
12 April 2010
Amendment 2:
28 October 2013
Amendment 3:
25 November 2014
Amendment 4:
25 March 2016
Amendment 5:
07 November 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The information contained in this document, particularly unpublished data, is the property or 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. The information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in the 
protocol. You will 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........................................................................................................................................4
LIST OF IN-TEXT FIGURES ......................................................................................................................................4
PROTOCOL SYNOPSIS ..............................................................................................................................................5
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS......................................................................8
1.
INTRODUCTION ..............................................................................................................................................10
1.1.
Background ............................................................................................................................................10
1.1.1.
General Information .............................................................................................................10
1.1.2.
Nonclinical Pharmacology and Toxicology .........................................................................11
1.1.3.
Clinical Trials of Idelalisib...................................................................................................11
1.2.
Rationale for This Study ........................................................................................................................15
1.3.
Compliance ............................................................................................................................................16
2.
OBJECTIVES.....................................................................................................................................................17
3.
STUDY DESIGN................................................................................................................................................18
3.1.
Primary Endpoint ...................................................................................................................................18
3.2.
Secondary Endpoints..............................................................................................................................18
3.3.
Study Design..........................................................................................................................................18
3.4.
Study Treatments ...................................................................................................................................18
3.5.
Duration of Treatment............................................................................................................................19
3.6.
Study Discontinuation Criteria...............................................................................................................19
4.
SUBJECT POPULATION..................................................................................................................................20
4.1.
Number of Subjects and Subject Selection ............................................................................................20
4.2.
Inclusion Criteria....................................................................................................................................20
4.3.
Exclusion Criteria...................................................................................................................................20
5.
INVESTIGATIONAL MEDICINAL PRODUCT..............................................................................................21
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................21
5.2.
Description and Handling of Idelalisib ..................................................................................................21
5.2.1.
Storage and Handling...........................................................................................................21
5.2.2.
Formulation..........................................................................................................................21
5.2.3.
Packaging and Labeling .......................................................................................................21
5.3.
Dosage and Administration of Idelalisib................................................................................................22
5.4.
Dose Adjustment....................................................................................................................................22
5.5.
Idelalisib Interruption/Dose Modification/Discontinuation ...................................................................22
5.6.
Warnings and Precautions......................................................................................................................24
5.6.1.
Transaminase Elevations......................................................................................................24
5.6.2.
Gastrointestinal Events.........................................................................................................25
5.6.3.
Dermatological Events .........................................................................................................26
5.6.4.
Pulmonary Events ................................................................................................................27
5.6.5.
Hematological and Immunological Events...........................................................................27
5.6.6.
Infectious Events..................................................................................................................28
5.6.7.
Secondary Malignancies.......................................................................................................28
5.6.8.
Ultraviolet Exposure ............................................................................................................29
5.6.9.
Pregnancy, Lactation, and Reproduction..............................................................................29
5.6.10.
Pneumocystis jirovecii Pneumonia Prophylaxis...................................................................29
5.6.11.
Further Safety Information...................................................................................................30
5.7.
Prior and Concomitant Medications.......................................................................................................30

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5.7.1.
Drugs that Alter CYP3A4-Dependent Metabolism..............................................................30
5.7.2.
Drugs that Undergo CYP3A-Dependent Metabolism..........................................................31
5.8.
Accountability for Idelalisib...................................................................................................................31
5.8.1.
Idelalisib Return or Disposal................................................................................................31
5.9.
Treatment Compliance...........................................................................................................................32
6.
STUDY PROCEDURES ....................................................................................................................................33
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................33
6.2.
Study Assessments.................................................................................................................................33
6.3.
Clinical Evaluation.................................................................................................................................34
6.4.
Laboratory Evaluation During the Study ...............................................................................................34
6.4.1.
Evaluation for Gastrointestinal Events/Colitis .....................................................................34
6.4.2.
Immune Monitoring .............................................................................................................35
6.5.
Assessments for Premature Discontinuation from Study.......................................................................35
6.6.
Criteria for Discontinuation of Study Treatment....................................................................................35
6.7.
End of Study Assessments .....................................................................................................................35
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................37
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................37
7.1.1.
Adverse Events.....................................................................................................................37
7.1.2.
Serious Adverse Events........................................................................................................37
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................38
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................38
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................38
7.2.2.
Assessment of Severity ........................................................................................................39
7.2.3.
Assessment of the Outcome of Adverse Events...................................................................39
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead or CRO .........................................................................................................40
7.4.
Gilead Reporting Requirements.............................................................................................................41
7.4.1.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population...........................................................41
7.5.
Special Situations Reports......................................................................................................................42
7.5.1.
Definitions of Special Situations..........................................................................................42
7.5.2.
Instructions for Reporting Special Situations.......................................................................42
8.
STATISTICAL CONSIDERATIONS................................................................................................................44
8.1.
Determination of Sample Size................................................................................................................44
8.2.
Statistical and Analytical Plans..............................................................................................................44
8.2.1.
General Considerations ........................................................................................................44
8.2.2.
Analysis Populations............................................................................................................44
8.2.3.
Subject Disposition ..............................................................................................................44
8.2.4.
Subject Characteristics .........................................................................................................44
8.2.5.
Efficacy Analyses.................................................................................................................45
8.2.6.
Pharmacokinetic and Pharmacodynamic Analyses ..............................................................45
8.2.7.
Safety Analyses....................................................................................................................45
9.
RESPONSIBILITIES..........................................................................................................................................47
9.1.
Investigator Responsibilities ..................................................................................................................47
9.1.1.
Good Clinical Practice..........................................................................................................47
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................47
9.1.3.
Informed Consent.................................................................................................................47
9.1.4.
Confidentiality......................................................................................................................48
9.1.5.
Study Files and Retention of Records ..................................................................................48

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9.1.6.
Case Report Forms...............................................................................................................49
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................50
9.1.8.
Inspections............................................................................................................................50
9.1.9.
Protocol Compliance............................................................................................................50
9.2.
Sponsor Responsibilities ........................................................................................................................50
9.2.1.
Protocol Modifications.........................................................................................................50
9.2.2.
Study Report and Publications .............................................................................................50
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................51
9.3.1.
Access to Information for Monitoring..................................................................................51
9.3.2.
Access to Information for Auditing or Inspections ..............................................................51
9.3.3.
Study Discontinuation..........................................................................................................51
10.
REFERENCES ...................................................................................................................................................52
11.
APPENDICES ....................................................................................................................................................54
Appendix 1.
Investigator Signature Page....................................................................................................55
Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................56
LIST OF IN-TEXT TABLES
Table 5-1.
Requirements and Recommendations for Discontinuation or Modifications of Study 
Treatment in Response to Adverse Events .............................................................................22
Table 5-2.
Known Potent Inducers of CYP3A ........................................................................................31
Table 7-1.
Grading of Adverse Event Severity........................................................................................39
LIST OF IN-TEXT FIGURES
Figure 5-1.
Kaplan-Meier Time to Diarrhea or Colitis .............................................................................26

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title:
An Extension Study to Investigate the Safety and Durability of 
Clinical Activity of Idelalisib in Subjects with Hematologic 
Malignancies
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
101254
Not Applicable
NTC01090414
Study Centers 
Planned:
Approximately 19 centers in the United States
Objectives:
The primary objective of this study is as follows:

To investigate the long-term safety of idelalisib in patients with 
hematologic malignancies

To determine the duration of clinical benefit of idelalisib in 
patients with hematologic malignancies
Study Design:
This is a long-term safety extension study of idelalisib in subjects
with hematologic malignancies who complete other idelalisib studies. 
Subjects will be followed according to the standard of care as 
appropriate for their type of cancer, and will be treated at the dosage 
level received upon completion of their prior idelalisib study. 
Subjects will be withdrawn from the study if they develop progressive 
disease, unacceptable toxicity related to idelalisib, or if they no longer 
derive clinical benefit in the opinion of the investigator.
Number of Subjects 
Planned:
The number of subjects enrolled will be determined by the number of 
subjects completing a prior idelalisib study with a clinical benefit and 
who wish to continue therapy with idelalisib.
Target Population:
Subjects who complete a prior idelalisib study (101-02, 101-07, 
101-08, 101-10) and who are still deriving benefit
Duration of 
Treatment:
Treatment will continue for as long as the subject derives clinical 
benefit and the subject’s benefit-risk profile is deemed positive by the 
investigator.

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Diagnosis and Main 
Eligibility Criteria:
Subjects with hematologic malignancies completing a prior 
idelalisib study (101-02, 101-07, 101-08, 101-10)
Study Procedures/
Frequency:
While on study, the subject will return at regular intervals 
(approximately every 2-3 months) for evaluation of disease status, 
recording of all adverse events (AEs) and serious adverse events 
(SAEs), return of used drug supplies, and dispensing of new drug 
supply.
PJP prophylaxis is required during treatment with idelalisib and for 
2 to 6 months, based on clinical judgment, following treatment 
discontinuation.
While on study, the subject will be followed for disease status 
according to standard of care. Subjects’ disease status will be 
assessed and information will be collected to determine response to 
treatment. If no change in disease status is identified and subject is 
dispensed additional idelalisib, the most recent prior response 
documented for the study will be recorded.
All subjects should have the following laboratory tests approximately 
every 2-3 months : Subjects with CLL will have ALC, PLT, Hgb, 
ANC; subjects with WM will also have IgM, serum M protein. All 
subjects will be monitored for CMV status approximately every 
4 weeks, and for immunologic status approximately every 12 weeks.
All subjects will have CT scan at least once every 12 months and at 
time of initial response (PR or CR after SD, or CR after PR) or 
progression. In addition, for initial CR a bone marrow evaluation is 
required.
Test Product, Dose, 
and Mode of 
Administration:
Idelalisib 100 mg, 150 mg, 200 mg BID, or 100 mg, 200 mg, or 
300 mg once daily Oral
Reference Therapy, 
Dose, and Mode of 
Administration:
Not Applicable
Criteria for 
Evaluation:
Subjects who complete a prior idelalisib study (101-02, 101-07, 
101-08, 101-10) and who are still deriving benefit
Safety:
Safety will be evaluated by assessing all Grade ≥3 AEs and all SAEs.

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Efficacy:
Primary Endpoint

Overall response rate (ORR) – defined as the proportion of 
subjects who achieve CR, PR, or MR (for WM only)
Secondary Endpoints

Duration of Response (DOR) – defined as the interval from the 
first documentation of CR, PR or MR (for WM) to the earlier of 
the first documentation of definitive disease progression or death 
from any cause

Progression-free survival (PFS) – defined as the interval from 
enrollment in the parent study to the earlier of the first 
documentation of definitive disease progression 
(excluding lymphocytosis alone) or death from any cause

Overall survival (OS) – defined as the interval from the start of 
study treatment in the parent study to death from any cause
Pharmacokinetics:
Not Applicable
Statistical Methods:
The intent-to-treat (ITT) analysis set will consist of all subjects
receiving at least 1 dose of study treatment. This analysis set will be 
used for the efficacy and safety analyses.
Subject characteristics and study results will be described and
summarized. Overall response rate based on investigator’s response 
will be calculated along with its 95% confidence intervals (CIs) based 
on exact binomial method.
For the analyses of DOR and PFS, the Kaplan-Meier method will be 
used. For data summaries involving continuous variables, data tables 
will typically contain the following information: sample size, mean, 
standard deviation, standard error, median, minimum and maximum. 
For categorical variables, the following information will typically be 
presented: sample size, proportion, and 95% CIs based on exact 
binomial method.
Safety will be assessed via Grade ≥3 adverse events (AEs). Summary 
of efficacy will be presented by integrating parent study with 101-99 
extension study. All treatment emergent adverse events that are 
observed in the parent studies (101-02, 101-07, 101-08, and 101-10) 
and their extension study will be summarized
Sample Size Calculation:
Not applicable
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
AE
Adverse event
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
AML
Acute myeloid leukemia
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATP
Adenosine triphosphate
AUC
area under the concentration-time curve
B
bendamustine
BID
twice per day
CAL-101
Former name for idelalisib
CFR
Code of Federal Regulations
CI
confidence interval
CLL
chronic lymphocytic leukemia
CMV
Cytomegalovirus
Cmax
maximum concentration
CR
complete response
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
trough concentration
CYP
cytochrome P450 enzyme
DLBCL
diffuse large B-cell lymphoma
DOR
duration of response
DSPH
Gilead Sciences Department of Safety and Public Health
E
everolimus
FL
Follicular lymphoma
GCP
Good Clinical Practice
GS-1101
Former name for idelalisib
Hgb
Hemoglobin
IEC
Independent Ethics Committee
IgM
Immunoglobulin M
IHC
immunohistochemistry
IMP
Investigational medicinal product
iNHL
Indolent non-Hodgkin lymphoma
IRB
Institutional Review Board
ITT
Intent to treat
IWCLL
International Workshop on Chronic Lymphocytic Leukemia
L
lenalidomide

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MCL
Mantle cell lymphoma
MTD
Maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NOAEL
No observed adverse effect levels
ORR
Overall response rate
OS
Overall survival
PFS
Progression-free survival
PI3K
Phosphatidylinositol 3-kinase
PJP
Pneumocystis jirovecii pneumonia
PLT
Platelets
PR
Partial response
R
rituximab
SAE
Serious adverse event
SD
Stable disease
SJS
Stevens-Johnson Syndrome
SLL
Small lymphocytic lymphoma
SOP
Standard Operating Procedure
TEAE
treatment-emergent adverse event
TEN
toxic epidermal necrolysis
TTR
Time to Response
WM
Waldenström’s macroglobulinemia

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1.
INTRODUCTION
1.1.
Background
1.1.1.
General Information
Idelalisib was approved by the United States FDA on July 23, 2014 and in the European Union 
on September 18, 2014. Refer to local labeling for the approved indication statements.
Idelalisib (GS-1101; formerly CAL-101) is a targeted, highly selective competitive inhibitor of 
the adenosine triphosphate (ATP) binding site of the phosphatidylinositol 3-kinase (PI3K) p110
catalytic domain, which has been shown to be prominently expressed in cells of hematopoietic 
origin {Okkenhaug et al 2003, Vanhaesebroeck et al 2005}. PI3Kδ is critical for multiple 
signaling pathways that are hyperactive in B-cell malignancies. Inhibition of PI3Kδ modulates 
B-cell receptor signaling as well as signaling through cytokine and chemokine receptors and 
integrinl. These signaling pathways act via downstream enzymes (most importantly the 
serine/threonine protein kinase, Akt) to regulate proliferation, apoptosis, motility, homing, and 
retention of malignant B-cells in lymphoid tissues and bone marrow compartments. By inhibiting 
PI3Kδ-dependent signaling, idelalisib inhibits proliferation, survival, homing, motility, and 
retention, and promotes apoptosis in many B-cell malignancies.
An essential role of PI3Kδ signaling in the proliferation and survival of hematopoietic cancer 
cells has been demonstrated for several myeloid and B-cell malignancies. Blasts from patients 
with acute myeloid leukemia (AML) have high constitutive PI3K activity, and inhibition of 
PI3Kδ resulted in the inhibition of Akt phosphorylation and cellular proliferation {Sujobert et al 
2005}. Sustained activation of the PI3Kδ pathway has been shown to have a pivotal role in the 
survival of B-cell chronic lymphocytic leukemia (CLL) cells co-cultured with primary or stromal
cell lines {Cuni et al 2004}. The Sponsor has shown that PI3Kδ is expressed in all primary CLL 
patient cells tested and treatment with idelalisib in vitro led to a decrease in viability of most 
CLL patient cells tested. Constitutive activation of Akt has been demonstrated in aggressive 
blastoid variants of mantle cell lymphoma (MCL) as well as cell lines, and treatment of MCL
cell lines with the pan-PI3K inhibitor LY294002 resulted in apoptosis {Rudelius et al 2006}. 
Constitutive activation of AKT has also been reported in diffuse large B-cell lymphoma 
(DLBCL) cell lines and in approximately 50% of DLBCL tissue samples {Uddin et al 2006}. 
Treatment with LY294002 resulted in apoptosis of some DLBCL cell lines. The PI3K/Akt
pathway has also been implicated in survival of follicular lymphoma (FL) cells {Leseux et al 
2006} and Waldenström’s macroglobulinemia (WM) {Leleu et al 2007}. These data provide the 
rationale for targeting the PI3Kδ signaling pathway with idelalisib as a potential new treatment
for hematologic malignancies. In addition, the relative lack of activity of idelalisib against p110α
should minimize the potential for hyperglycemia relative to pan-PI3K inhibitors.
For further information on idelalisib, refer to the current version of the Investigator’s Brochure.

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1.1.2.
Nonclinical Pharmacology and Toxicology
A comprehensive set of nonclinical safety and toxicology studies of idelalisib have been 
completed and have established no observed adverse effect levels (NOAELs) to support clinical 
studies. Lymphoid depletion in lymphoid tissues was observed in these nonclinical studies, 
which is consistent with the expected pharmacological activity of PI3Kinhibition.
Further details on the toxicology of idelalisib can be found in the idelalisib 
Investigator’s Brochure.
1.1.3.
Clinical Trials of Idelalisib
1.1.3.1.
Phase 1 Monotherapy Study in Patients with Hematological Malignancies 
(Study 101-02)
Study 101-02 was a dose ranging study where idelalisib was administered in cohorts of subjects 
across a range of dose levels from 50 mg BID to 350 mg 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}.
Study 101-02 has completed enrollment. A total of 191 subjects were enrolled to the study, 
54 of whom had a diagnosis of CLL. In this cohort, the median age was 63 years (range 37-82).
The disease was considered refractory in 70%, and subjects had a median of 5 prior regimens.
Leukemia cells from 24% of the 54 CLL subjects had del(17p) and/or TP53 mutation and 
91% had an unmutated immunoglobulin heavy chain variable region (IGHV). Pharmacokinetics 
of idelalisib was studied. The multiple-dose Cmax, Ctrough, and AUC of idelalisib increase in a less 
than dose proportional manner, with only modest increase in exposure observed at the dose level 
of 350 mg/dose BID (compared with 150 mg). To assess the pharmacodynamic effect of 
idelalisib, the phosphorylation status of Akt (a direct downstream target of PI3K) in CLL subject 
samples was investigated. Subject sample peripheral blood mononuclear cells (PBMC) were 
screened for levels of phospho-Akt (pAkt) by flow cytometry. At baseline prior to idelalisib 
dosing, a high level of constitutive pAktT308 was noted. Following 8 and 28 days of dosing with 
idelalisib BID, constitutive phosphorylation of Akt in cells from subjects with CLL was reduced 
to the background level observed in healthy volunteers. In the evaluation of the effect of 
idelalisib on cytokine production, plasma concentrations of CLL-derived chemokines, CCL3 and 
CCL4, and of the stroma-derived chemokine, CXCL13, were elevated at baseline and decreased 
significantly during idelalisib administration. Idelalisib treatment was associated with a 
peripheral lymphocytosis in the CLL subjects, with median ALC approximately doubling over 
the first 8 weeks of treatment, and then descending thereafter. This lymphocytosis is considered 
consistent with inhibition of chemokine signaling, with subsequent redistribution of lymphocytes 
from the lymph node to the blood compartment. 
Study 101-02 was completed prior to a revision in the 2013 National Comprehensive Cancer 
Network (NCCN) guidelines for overall response rate (ORR) that no longer considers isolated 
lymphocytosis as a sign of progressive disease (PD). The revision to the standard response 
criteria was driven by the recent recognition that novel agents (including idelalisib) can mobilize 

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CLL cells from tissues into the peripheral blood by interfering with their homing and that this 
represents an expected pharmacologic action rather than an indication of disease progression. 
This effect is especially prominent with monotherapy. These guidelines were modified based on 
a publication by Cheson in 2012 recommending that “persistent lymphocytosis should not 
interfere with the time of designation of a partial response (PR), which should be based more on 
the other measurable aspects of the disease than on lymphocytosis” {Cheson et al 2012}. Based on 
data supplied by investigators in the database, and by applying the 2013 NCCN and Cheson 2012 
criteria, the ORR in CLL subjects was 72.2% with 22% showing stable disease. {Brown et al 
2013}. Amongst the 13 subjects with 17p deletion and/or TP53 mutation, the ORR was 53.8% 
based on investigator response, and amongst the 4 subjects with 17p deletion and/or TP53 
mutation who received twice daily dosing at ≥150 mg BID, the ORR was 75%. The median 
Kaplan-Meier estimate of progression free survival in all CLL subjects is 17.1 months, and in
28 subjects who received twice daily dosing at ≥150 mg per dose, the estimated progression-free 
survival (PFS) is 29 months.
Adverse events (AEs) were usually mild to moderate and not clearly idelalisib-related. The most 
frequently reported AEs, all grades, in the 54 CLL subjects were fatigue (32%), diarrhea (30%), 
pyrexia (30%), cough (24%), back pain (22%), rash (22%), upper respiratory infection (URI) 
(22%), and pneumonia (20%). Elevation of alanine aminotransferase (ALT) and/or 
aspartate aminotransferase (AST) was observed in 28%. There was no clear dose effect for the 
occurrence of transaminase elevation.
Although no maximum tolerated dose (MTD) was identified over the dosing range of 
50 to 350 mg BID, the pharmacokinetic, pharmacodynamic and efficacy results led to a 
determination that 150 mg BID would be the recommended Phase 2 dose, and this has been used 
in all subsequent studies.
1.1.3.2.
Phase 1 Combination Study in Patients with Hematologic Malignancies 
(Study 101-07)
A separate Phase 1 trial (Study 101-07) has evaluated the safety and preliminary activity of 
idelalisib given in combination with an anti-CD20 monoclonal antibody (mAb), a 
chemotherapeutic agent, a mammalian target of rapamycin (mTOR) inhibitor, a proteasome 
inhibitor, an angiogenic agent, and/or an immunomodulatory agent in subjects with relapsed or 
refractory B cell CLL, indolent non-Hodgkin lymphoma (iNHL), or mantle cell lymphoma 
(MCL).
In subjects with relapsed/refractory CLL who had been heavily pretreated, high overall response 
rates (ORR of 80.9%) were achieved, including responses occurring after cessation of the 
combination drugs. Substantial improvements were achieved in all individual response criteria: 
lymph nodes (response rate of 80.9%, mean best percent change in area from baseline of −72.0), 
spleen (response rate of 57.6%), and liver (response rate of 60.0%). Rapid reductions in 
lymphadenopathy (median TTR of 1.9 months) and durable tumor control (median KM estimates 
of DOR and PFS were not reached) were observed. Improvements in hematologic parameters 
were noted in subjects with CLL who had abnormal hematologic parameters at baseline.

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In subjects with relapsed/refractory iNHL who had been heavily pretreated, high overall 
response rates (ORR of 79.1%) were achieved, including responses occurring after cessation of 
the combination drugs. Idelalisib in combination with rituximab (R) and/or bendamustine (B)
induced rapid reductions in lymphadenopathy (median TTR of 1.9 months) and durable tumor 
control (median KM estimates of DOR and PFS were not reached). Improvements in 
hematologic parameters were noted in subjects with iNHL who had abnormal hematologic 
parameters at baseline.
In subjects with relapsed/refractory MCL who were heavily pretreated, high overall response 
rates (ORR of 57.5%) were achieved with idelalisib-based combination therapies, including 
responses occurring after completion of the combination drugs. Idelalisib in combination with 
bendamustine + rituximab (BR) induced rapid reductions in lymphadenopathy (median TTR of 
1.9 months) and durable tumor control (median KM estimates of DOR and PFS were 9.3 and 
11.1 months, respectively). Improvements in hematologic parameters were noted in subjects with 
MCL who had abnormal hematologic parameters at baseline.
Rapid control of B symptoms in symptomatic patients was also demonstrated in all cohorts.
With the exception of the idelalisib+rituximab+lenalidamide (idelalisib+RL) combination, 
idelalisib had a manageable safety profile when administered in combination therapy with agents 
used routinely in clinical practice. The safety data suggest that idelalisib may lead to an increased 
risk of hepatotoxicity when used in combination with R and L at the dose and schedule evaluated 
in this study. Excluding the idelalisib+RL combination, the absence of overlapping toxicities 
allowed the administration of idelalisib and combination therapies at the planned doses of each. 
Diarrhea, neutropenia, pyrexia, rash, and transaminase elevations were similar to what has been 
observed with idelalisib monotherapy. Idelalisib did not exacerbate the known safety profile of 
any of the combination drugs, except possibly for everolimus (E). Everolimus is a CYP3A 
substrate and, after the idelalisib+E treatment cohort completed, it was established that the 
primary idelalisib metabolite is a CYP3A inhibitor, which may account for the comparatively 
high incidence of SAEs (77.8%) and AEs leading to discontinuation of idelalisib (55.6%).
Overall, the AE profile was consistent with that expected for a heavily pretreated, 
relapsed/refractory hematologic cancer population receiving combination immunochemotherapy 
agents. The most frequently reported treatment-emergent AE (TEAE) was pyrexia 
(42.7% of all subjects). The most frequently reported Grade ≥ 3 TEAE was neutropenia 
(32.8% of all subjects). Grade ≥ 3 rash occurred in 5.0% of subjects, including subjects receiving 
bendamustine.
Early transaminase elevations that occurred were generally asymptomatic and transient. 
Overall, a Grade 3 or 4 ALT or AST elevation was reported for 30 subjects (12.4%); 
29 subjects (12.0%) had a dose interruption due to a Grade 3 or 4 ALT or AST elevation. The 
overall median time to onset of Grade 3 or 4 ALT/AST elevation was 6.1 weeks and the overall 
time to resolution of the first Grade 3 or 4 ALT/AST elevation was 2.1 weeks.
There were no clinically meaningful changes in blood pressure, heart rate, or ECG results during 
the study.

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1.1.3.3.
Phase 2 Study of Idelalisib Plus Rituximab in Treatment Naïve Elderly Patients 
with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma 
(Study 101-08)
The primary objective of this study was to evaluate the ORR of idelalisib when combined with 
rituximab in subjects ≥65 years with previously untreated CLL or small lymphocytic lymphoma 
(SLL). Enrollment is complete, and 64 subjects have been followed through at least 48 weeks. 
Eligible subjects received the following treatment regimen: idelalisib 150 mg BID orally on 
Days 1 through 28 of each 28-day cycle (Cycles 1 through 12) + rituximab 375 mg/m2 IV 
weekly for 8 doses (Cycles 1 and 2). Treatment with idelalisib continued until disease 
progression, unacceptable toxicity, or completion of 12 cycles of therapy. Subjects were 
evaluated by the investigators for response after Cycles 2, 4, 6, 9, and 12 according to standard 
International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria.
Of the 64 subjects enrolled in the study 62 (96.9%) completed Cycle 2 of the study, and 
43 subjects (67.2%) completed the study (48 weeks).
At baseline, the subjects (N = 64) were predominantly male, white, with median age of 71 years. 
The majority of subjects (92.2%) were diagnosed with CLL; 7.8% of subjects were diagnosed 
with SLL.
The ORR for all subjects (N = 64) for Study 101-08, including subject participation in 
Study 101-99, was 96.9%; 12 subjects (18.8%) had a CR, and 50 subjects (78.1%) had a PR. 
Two subjects (3.1%) were not evaluable, and no subject had a best response of SD or PD on 
study. The ORR for subjects with the del(17p) and/or TP53 mutation or IgHV mutation was 
100% and 95.7%, respectively.  Of note, 3 of 9 subjects with del(17p)/TP53 mutation achieved 
CR, and the remainder PR. Among evaluable subjects, the lymph node response rate was 98.0%, 
the splenomegaly response rate was 96.4%, the hepatomegaly response rate was 100%, the ALC 
response rate was 100%, the platelet response rate was 94.1%, the hemoglobin response rate was 
100%, and the ANC response rate was 100%.The Kaplan-Meier estimate of PFS at 24 months 
was 93%. The median time to response (TTR) was 1.9 months.
In this study in elderly subjects with previously untreated CLL or SLL, therapy was generally 
well tolerated. The most frequently reported AEs for subjects during either the parent study or 
extension Study 101-99 were diarrhea (55%), pyrexia (42 %), nausea (38%), rash (38%), 
chills (36%), cough (33%), fatigue (31.%), ALT increased (28%), AST increased (27%) and 
pneumonia (27%), dyspnea (23%), headache (23%), vomiting (20%), insomnia (20%),
constipation (17%), pruritus (17%), arthralgia (17%), night sweats (16%), and colitis (16%). 
Eighteen subjects (28.1%) discontinued treatment with idelalisib due to one or more AEs. 
Diarrhea, respiratory disorders, and rash were the most frequently reported AEs leading to 
discontinuation of idelalisib therapy. Four subjects (6.3%) died during Study 101-08. The causes 
of death were pneumonitis, pneumonia and metastatic melanoma, drug induced pneumonitis and 
respiratory failure, and sepsis respiratory failure. An additional subject from 101-08 died during 
the extension Study 101-99 due to acute myocardial infarction. Thirty-seven subjects (48.4%) 
reported a Serious Adverse Event (SAE) during either the parent study or extension 
Study 101-99. The most commonly reported SAEs were diarrhea and pneumonia 
(10 subjects each, 15.6%) and colitis (7 subjects, 10.9%).

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1.1.3.4.
Single-agent Idelalisib for Previously Treated Low-grade Lymphoma: A 
Phase 1/2 Study of Safety, Efficacy, and Flow-cytometric Assessment of 
Tumor-cell Signaling Events (Study 101-10)
Study 101-10 was a Phase 1/2, open-label, single-arm, safety, efficacy, and flow-cytometric 
assessment of tumor cell signaling events study of idelalisib in subjects with previously treated 
low-grade iNHL. Eligible subjects were administered idelalisib 150 mg orally twice daily for
28 days (1 cycle) for up to 12 cycles. Subjects who experienced disease progression while 
receiving idelalisib ≤150 mg twice daily may have been eligible to receive an escalated-dose of 
idelalisib up to a maximum of 300 mg twice daily, per judgment of the investigator.
Idelalisib administration was continued until subjects developed progressive disease while 
receiving idelalisib at a dose of 300 mg twice daily, if they experienced unacceptable toxicity, or 
if in the opinion of the investigator they were no longer deriving clinical benefit
Study 101-10 has completed enrollment. All 18 subjects enrolled in the study received study 
drug. Five subjects (27.8%) completed the study and 13 subjects (72.2%) prematurely 
discontinued the study.
For additional or updated information, please refer to the current version of the idelalisib 
Investigator’s Brochure.
1.2.
Rationale for This Study
This extension study provides the opportunity for subjects with hematologic malignancies who 
have completed a prior study of idelalisib to continue idelalisib treatment for as long as they 
derive clinical benefit.
Subjects with hematologic malignancies who complete one of the following studies are eligible 
for enrollment:

Study 101-02: A Phase 1 Sequential Dose Escalation Study to Investigate the 
Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Idelalisib in Subjects
with Select, Relapsed or Refractory Hematologic Malignancies

Study 101-07: A Phase 1 Study to Investigate the Safety and Clinical Activity of Idelalisib in
Combination with Chemotherapeutic Agents and Anti-CD20 mAb in Subjects with
Relapsed or Refractory Indolent B-cell Non-Hodgkin Lymphoma, Mantle Cell Lymphoma, 
or Chronic Lymphocytic Leukemia

Study 101-08: A Phase 2 Single Arm Study to Investigate the Safety and Clinical Activity of 
Idelalisib in Combination with Rituximab in Elderly Subjects with Previously Untreated 
Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Study 101-10: Single-Agent GS-1101 (CAL-101) for Previously Treated Low-Grade 
Lymphoma: A Phase 1/2 Study of Safety, Efficacy, and Flow-Cytometric Assessment of 
Tumor-Cell Signaling Events

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1.3.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.

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2.
OBJECTIVES
The primary objectives of this study are:

To investigate the long-term safety of idelalisib in subjects with hematologic malignancies

To determine the duration of clinical benefit of idelalisib in subjects with hematologic 
malignancies

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3.
STUDY DESIGN
3.1.
Primary Endpoint
The primary endpoint of this study is:

Safety, assessed using Grade ≥3 adverse events according to the Common Terminology 
Criteria for Adverse Events (CTCAE) v4.03
3.2.
Secondary Endpoints
The secondary endpoints of this study are:

Duration of response (DOR) – defined as the interval from the first documentation of 
CR, PR or MR to the earlier of the first documentation of definitive disease progression or 
death from any cause

Progression-free survival (PFS) – defined as the interval from enrollment to the earlier of the 
first documentation of definitive disease progression excluding lymphocytosis alone or death 
from any cause

Overall survival (OS) – defined as the interval from the start of study treatment to death from 
any cause 

Time to response (TTR) – defined as the interval from first dose to the first documentation of 
CR or PR
3.3.
Study Design
This is a long-term safety extension study of idelalisib in subjects with hematologic malignancies
who complete other idelalisib studies. Subjects will be followed according to the standard of care
as appropriate for their type of cancer, and will be treated at the dosage level received upon 
completion of their prior idelalisib study. Subjects will be withdrawn from the study if they 
develop progressive disease, unacceptable toxicity related to idelalisib, or if they no longer 
derive clinical benefit in the opinion of the investigator.
3.4.
Study Treatments
The Sponsor will provide idelalisib drug product to study sites.
Subjects will be treated at the dose level they were receiving at completion of their prior 
idelalisib trial. Subjects receive idelalisib in the following doses:

100, 150, or 200 mg idelalisib BID

100, 200, or 300 mg idelalisib once daily

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Subjects receive idelalisib in the following formulations:

100- or 150-mg tablets
3.5.
Duration of Treatment
Treatment will continue for as long as the subject derives clinical benefit and the subject’s 
risk-benefit profile is deemed positive by the investigator. See Protocol Section 3.6, 
Study Discontinuation Criteria, for specific discontinuation criteria.
3.6.
Study Discontinuation Criteria
A subject may be withdrawn from the study under the following circumstances:

The subject withdraws consent to participate in the study

The subject permanently discontinues idelalisib treatment for any reason (See Section 6.6)

The subject experiences a toxicity that necessitates permanent discontinuation of idelalisib 
treatment

The subject has progressive disease or whose benefit-risk profile is no longer deemed 
positive by the investigator.

The subject does not comply with the requirements of the protocol

Gilead, a regulatory agency, or an institutional review board (IRB)/
independent ethics committee (IEC) discontinues the study
The reason for withdrawal will be recorded in the Case Report Form (CRF).

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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
A maximum of approximately 250 subjects is anticipated. The number of subjects enrolled will 
be determined by the number of subjects completing a prior idelalisib study with a clinical 
benefit who wish to continue therapy with idelalisib.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.

Subjects with hematologic malignancies completing a prior idelalisib study (101-02, 101-07, 
101-08, 101-10) with a clinical benefit are eligible.

A negative urine pregnancy test is required for female subjects (unless surgically sterile or 
greater than one year post-menopausal).

Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 2.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.

Subjects who are pregnant or nursing will be excluded.

Subjects who are unwilling or unable to comply with the requirements of the protocol will be 
excluded.

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5.
INVESTIGATIONAL MEDICINAL PRODUCT
5.1.
Randomization, Blinding and Treatment Codes
The study is unblinded.
5.2.
Description and Handling of Idelalisib
5.2.1.
Storage and Handling
Idelalisib, the investigational medicinal product (IMP), will be provided in sealed bottles. The 
bottles should be stored at room temperature (ie, 15-30 °C or 59-86 °F). While stability of 
idelalisib 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. Updated stability data will be provided to the sites, as appropriate.
5.2.2.
Formulation
Idelalisib is provided as 100 mg and 150 mg tablets. Idelalisib 100 mg tablets are either 
oval-shaped, film-coated orange tablets, debossed with “GSI” on one side and “100” on the 
other, or plain-faced tablets. Idelalisib 150 mg tablets are either oval-shaped, film-coated
pink tablets, debossed with “GSI” on one side and “150” on the other or plain faced tablets. In 
addition to the active ingredient, idelalisib tablets contain the following inactive ingredients: 
microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch 
glycolate, magnesium stearate, polyethylene glycol, talc, polyvinyl alcohol (PVA), titanium 
dioxide, FD&C Yellow #6/ Sunset Yellow FCF Aluminum Lake (100 mg tablets only), and 
red iron oxide (150 mg only).
5.2.3.
Packaging and Labeling
Idelalisib tablets will be supplied in bottles. A label containing the following information will be 
affixed to the bottle:

Sponsor name and address

Description of contents of package, including dose strength

Caution statement (includes “Keep out of Reach of Children” statement)

Storage conditions

Lot number
The expiry date will be provided in a separate communication and updated as appropriate

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5.3.
Dosage and Administration of Idelalisib
Idelalisib formulated drug product of 100 and 150 mg strengths has been manufactured for 
clinical trials and will be provided to the subject to be taken at home. Subjects will be treated at 
the dose level they were receiving at completion of their prior idelalisib trial. Subjects should be 
instructed to take the doses with water. Idelalisib may be taken with or without food. Missed 
doses should not be taken unless it is within 6 hours of the scheduled dosing and vomited doses 
should be retaken only if the tablet is visible in the vomitus.
5.4.
Dose Adjustment
The idelalisib dose may be increased if the subject has worsening disease but does not meet 
criteria for progressive disease, up to a maximum dose level of 150 mg BID. Recommendations 
and requirements for dose adjustment or discontinuation due to hematologic and 
non-hematologic toxicity are provided in Table 5-1.
Required discontinuation and dose modification instructions provided in Table 5-1 must be 
followed. Recommended actions provided in Table 5-1 comprise 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.
Any planned dose changes should be discussed with the Sponsor prior to implementation.
5.5.
Idelalisib Interruption/Dose Modification/Discontinuation
Requirements and recommendations for discontinuation or modification of study treatment based 
on the type and severity of adverse events or laboratory abnormalities are provided in Table 5-1.
Table 5-1.
Requirements and Recommendations for Discontinuation or 
Modifications of Study Treatment in Response to Adverse Events
NCI CTCAE Grade
Idelalisib
HEMATOLOGICAL ADVERSE EVENTS
Neutropenia
Grade 2
Maintain current dose level and schedule.
Grade 3
Required: Blood counts must be monitored at least weekly until neutropenia is ≤Grade 2.
Recommended: Maintain current dose level and schedule.
Grade 4
(or occurrence of 
neutropenic fever 
or infection)
Required: Interrupt idelalisib. Blood counts must be monitored at least weekly until neutropenia 
Grade 2
Recommended: Idelalisib may be resumed at lower dose when neutropenia is Grade 3. 
Neutropenia should be managed according to established clinical guidelines.
Thrombocytopenia
Grade 3
Maintain current dose level and schedule.
Grade 4
Required: Withhold idelalisib for bruising or bleeding until Grade 3.
Recommended: May resume idelalisib at initial or lower dose level at investigator discretion.

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NCI CTCAE Grade
Idelalisib
NON-HEMATOLOGICAL ADVERSE EVENTS
Rash
Grade ≤ 2
Maintain current dose level and schedule.
Grade ≥3 
Required: Withhold idelalisib until Grade 1.
Recommended: May resume idelalisib at lower dose level or discontinue at investigator 
discretion.
Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis
Any Grade
Required: Discontinue idelalisib. Interrupt coadministered medications potentially associated with 
SJS or TEN. Institute treatment per institutional standards.
Bowel perforation
Any Grade
Required: Discontinue idelalisib.
Diarrhea or Colitis
Any Grade
(in addition see below for 
response to specific 
CTCAE grades)
Required: Obtain history of onset and duration of diarrhea, including description of number of 
stools and stool composition (eg, 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 (ie, evaluate 
for sepsis, bowel obstruction, dehydration)
Recommended: Provide anti-diarrheal and ensure good hydration status. Differentiate between 
small-bowel and large-bowel diarrhea on a clinical basis (Section 5.6.2.2).
Grade 1
Recommended: Provide anti-diarrheal agent (eg, loperamide) and maintain current idelalisib dose 
level and schedule.
Grade ≤ 2
(unless clinical diagnosis is 
established from medical 
history and physical 
examination)
Required: Stool culture for routine pathogens (Salmonella, Shigella, Campylobacter species), 
testing for Clostridium difficile toxin, Rotavirus, Cytomegalovirus (CMV), and Adenovirus. Stool 
for Ova and Parasites (Cryptosporidium parvum, Isospora belli, Enterocytozoon bieneusi, Septata 
intestinalis, Strongyloides, Microsporidia, Entamoeba histolytica, Cyclospora), Giardia antigen 
Grade ≥ 3 diarrhea or 
colitis, or persistent Grade 2 
diarrhea or colitis without 
clear etiology
Required: Withhold idelalisib.  Consider anti-diarrheal (eg, loperamide) and/or addition of 
anti-inflammatory agent (eg, sulfasalazine, budesonide). 
Recommended: Endoscopy with biopsy is strongly recommended to assess by 
immunohistochemistry (IHC) and PCR for CMV, Adenovirus. 
 
 At Grade 1, may resume idelalisib at lower 
dose level or discontinue at investigator discretion.
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)
Recommended: Maintain current dose level and schedule. Monitor ALT, AST, ALP, and bilirubin 
at least 1x per week until all abnormalities are Grade ≤1.
Grade 3
(ALT/AST>5-20 xULN)
(Bilirubin>3-10xULN)
Recommended: 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)
Required: 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, discontinue idelalisib.
Recommended: If bilirubin abnormality was Grade <4, resume idelalisib at lower dose level.
PPD

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NCI CTCAE Grade
Idelalisib
Pneumonitis (new onset or worsening of baseline dyspnea, cough, or hypoxia without obvious infectious cause
Grade 1
(asymptomatic)
Required: Withhold idelalisib until resolution to baseline. May resume at lower dose level or 
discontinue at investigator discretion.
Grade ≥ 2
Required: Discontinue idelalisib permanently in subjects with any severity of symptomatic 
pneumonitis and institute therapy as clinically appropriate.
Pneumocystis jirovecii pneumonia (PJP)
Any Grade
Required: Discontinue idelalisib.
CMV infection/reactivationa
Any Grade
Required: Interrupt idelalisib upon unequivocal clinical or laboratory evidence of CMV infection.
Treat according to established clinical guidelines. If the benefits of resuming idelalisib outweigh 
the risks, consideration should be given to administering preemptive CMV therapy.
Other Nonhematological Adverse Events
Grade 2
Maintain current dose level and schedule.
Grade 3
Recommended: Withhold idelalisib until Grade 1. May resume idelalisib at initial or lower dose 
level or discontinue idelalisib at investigator discretion.
a
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, G-CSF=granulocyte colony-stimulating factor, 
NCI=National Cancer Institute, ULN=upper limit of normal
5.6.
Warnings and Precautions
5.6.1.
Transaminase Elevations
Consistent with observations in a dog toxicology study, reversible asymptomatic ALT/AST
increases were 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 are 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.
In selected subjects who experience more complicated hepatic adverse events, further workup 
may be warranted particularly 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. Hepatic adverse events that require additional workup 
should be discussed with the Gilead Sciences Medical Monitor.

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5.6.2.
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.  Study treatment 
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. 
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.
5.6.2.1.
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-Meier 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}.
5.6.2.2.
Differentiation Between Small-bowel and Large-bowel Diarrhea
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.

Small bowel diarrhea is characterized by large volume diarrhea (more than 1 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 
volumes with gross blood frequently found in the stool. Consider  a colonoscopic evaluation 
and biopsy.
5.6.3.
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 Grade ≥ 3 rash for which another underlying etiology cannot be 
identified (e.g., infection, co-suspect drug), idelalisib must be withheld until the rash is 
Grade ≤1, at which point idelalisib may be discontinued or resumed at a lower dose, at 
investigator discretion.
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, 

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rituximab) and/or other concomitant medications known to be associated with SJS or TEN 
(e.g., allopurinol). If SJS or TEN is suspected, idelalisib must be discontinued, 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.
5.6.4.
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. 
Given the potential for infectious or drug-related pulmonary 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 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.
5.6.5.
Hematological and Immunological Events
In the Phase 1 experience with idelalisib in patients with 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 idelalisib administration were largely 
due to minor fluctuations in these parameters among subjects 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+ 
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Treatment-emergent Grade 3 or 4 neutropenia events including those accompanied by fever or 
infection have occurred in subjects treated with idelalisib. All subjects must have their blood
counts monitored at least every 2 weeks for the first 6 months of idelalisib treatment. At any time 
during the study, subjects who develop Grade 3 neutropenia must have blood counts monitored at 
least weekly until neutropenia is Grade ≤ 2. For subjects who develop Grade 4 neutropenia, idelalisib
must be interrupted and blood counts monitored at least weekly until neutropenia is Grade ≤2
idelalisib may be resumed at a lower dose level once neutropenia is Grade ≤ 3.  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.
5.6.6.
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 for a period of 2 to 
6 months after idelalisib discontinuation and until the CD4+ T-cell count is documented to be 
>200 cells/mcL. The duration of prophylaxis should be based on clinical judgment and may take 
into account risk factors such as concomitant corticosteroid treatment and prolonged neutropenia 
after idelalisib treatment ends.
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.
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.
5.6.7.
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.

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5.6.8.
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.
5.6.9.
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 of idelalisib 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 potential 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 Appendix 2). If a female study 
participant becomes pregnant or decides to breastfeed during the course of the study, all study 
therapy must be discontinued.
5.6.10.
Pneumocystis jirovecii Pneumonia Prophylaxis
Trimethoprim sulfamethoxazole is rated a Pregnancy Category C agent.  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 agent.  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.

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Atovaquone is rated a Pregnancy Category C agent.  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 agent.  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.
5.6.11.
Further Safety Information
Further safety information regarding the study drug may be found in the investigator brochure 
for idelalisib. 
5.7.
Prior and Concomitant Medications
Concomitant treatment as deemed medically necessary by the investigator is allowed.
Prophylaxis against PJP is required during idelalsib treatment and for 2 to 6 months following 
idelalisib treatment discontinuation (see Section5.6.6). 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 with idelalisib. 
Subjects are not allowed to participate concurrently in any other therapeutic clinical study.
5.7.1.
Drugs that Alter CYP3A4-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 an ~80% increase in idelalisib plasma exposures (AUC) {Webb et al 
2010}, which is not considered to be clinically relevant and suggests that idelalisib is a weak 
CYP3A substrate. Preliminary data indicate that when co-administered with rifampin, a highly 
potent inducer of CYP3A, idelalisib exposures are ~75% lower. Co-administration of potent 
inducers of CYP3A with idelalisib should be avoided; a list of strong inducers is provided in 
Table 5-2:

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Table 5-2.
Known Potent 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
5.7.2.
Drugs that Undergo CYP3A-Dependent Metabolism
The major metabolite of idelalisib, GS-563117, is a reversible and time dependent inhibitor of 
CYP3A; accordingly, co-administration of idelalisib with midazolam, a probe CYP3A substrate, 
resulted in ~5-fold increase in midazolam systemic exposure (AUC), indicating that idelalisib is 
a strong inhibitor of CYP3A. Co-administration 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 co-administration of drugs that highly dependent on CYP3A for 
clearance and for which elevated plasma concentrations are associated with serious and/or 
life-threatening events, including narrow therapeutic index CYP3A substrates 
(eg, alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, fentanyl, quinidine, 
ergotamine, dihydroergotamine, astemizole, terfenadine) with idelalisib.
5.8.
Accountability for Idelalisib
The investigator is responsible for ensuring adequate accountability of all used and unused 
idelalisib/supplies. This includes acknowledgement of receipt of each shipment 
(quantity and condition). All unused idelalisib dispensed to subjects must be returned to the site.
Idelalisib accountability records will be provided to each study site to:

Record the date received and quantity of idelalisib

Record the date, subject number, subject initials, and lot number, of the idelalisib dispensed

Record the date, quantity of unused idelalisib returned, along with the initials of the person 
recording the information
All study drug records must be maintained at the site and copies must be submitted to 
Gilead Sciences at the end of the study.
5.8.1.
Idelalisib Return or Disposal
The study monitor will evaluate each site’s study drug disposal procedures and provide 
appropriate instruction for return or destruction of unused idelalisib supplies. If the site has an 
appropriate Standard Operating Procedure (SOP) for drug destruction, the site may destroy 
unused idelalisib and used drug supplies performed in accordance with the site’s 
(hospital/pharmacy) SOP. Where possible, idelalisib will be destroyed at the site. If drug is 
destroyed on site, the Investigator will maintain accurate records for all idelalisib destroyed. 
See Protocol Section 9.1.7, Investigational Medicinal Product Accountability and Return, for 
additional information.

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5.9.
Treatment Compliance
Subject compliance with dosing will be calculated based on return of unused idelalisib by 
subjects. The number of tablets dispensed, days of therapy, and number of tablets returned will 
be recorded.

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6.
STUDY PROCEDURES
The investigator must document any deviation from protocol procedures and notify the 
Sponsor or Sponsor’s representative.
6.1.
Subject Enrollment and Treatment Assignment
Subjects will sign the informed consent document prior to undergoing any study procedures.
The following information will be collected:

Demographics

Hematologic malignancy diagnosis

Prior idelalisib study protocol number

Clinical response status at completion of prior idelalisib study

Dose of idelalisib at completion of prior idelalisib study

Date of Last Subject Visit on prior idelalisib study (may be the same date as enrollment to 
this study)

Recording of all AEs and SAEs
The subject will be dispensed a supply of idelalisib and prescribed an antibiotic for PJP 
prophylaxis.
6.2.
Study Assessments
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all AEs and SAEs on the AE case report form (CRF/eCRF). All other 
untoward medical occurrences observed during the screening period, including exacerbation or 
changes in pre-existing conditions are considered medical history (not collected for this study).
See Section 7 Adverse Events and Toxicity Management for additional details.
While on study, the subject will return at regular intervals (approximately every 2-3 months) for 
the following procedures:

Evaluation of disease status per standard of care

Recording of all  AEs and SAEs, including the following assessments for diarrhea / colitis:
Obtain history of onset and duration of diarrhea, including description of number of 
stools and stool composition (eg, 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 (ie, evaluate for sepsis, bowel obstruction, dehydration)

Return of used drug supplies and dispensing of new idelalisib supply

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6.3.
Clinical Evaluation
While on study, the subject will be followed for disease status according to standard of care. At 
regular intervals (approximately every 2-3 months) the subject’s disease status will be assessed
(disease assessment visits) and information will be collected to determine response to treatment. 
If no change in disease status is identified and the subject is dispensed additional idelalisib, the 
most recent prior response documented for the study will be recorded.
All subjects will have CT scan at least once every 12 months and at time of initial response 
(PR or CR after SD, or CR after PR) or progression. In addition, for initial CR a bone marrow 
evaluation is required.
6.4.
Laboratory Evaluation During the Study
All subjects should have the following laboratory tests  at disease assessment visits: ALC, PLT, 
Hgb, ANC. All subjects with WM should also have the following laboratory tests at disease 
assessment visits: IgM, serum M protein.
All subjects will be monitored for CMV status via quantitative PCR or PP65 antigen
approximately every 4 weeks during idelalisib therapy.
6.4.1.
Evaluation for Gastrointestinal Events/Colitis 
For Grade 2 colitis and diarrhea (unless clinical diagnosis is established from medical history and 
physical examination), the following testing is required:

Stool culture for routine pathogens (Salmonella, Shigella, Campylobacter species, 
Clostridium difficile toxin, Rotavirus, Cytomegalovirus,and Adenovirus)

Stool for Ova and Parasites (Cryptosporidium parvum, Isospora belli, Enterocytozoon 
bieneusi, Septata intestinalis, Strongyloides, Microsporidia, Entamoeba histolytica, 
Cyclospora), Giardia antigen
For Grade ≥ 3  or persistent Grade 2 colitis or diarrhea without clear etiology (eg, Clostridium 
difficile enterocolitis), endoscopy with biopsy is required. All biopsy samples should include 
immunohistochemistry (IHC) and PCR for CMV, and Adenovirus.  
PPD
PPD

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6.4.2.
Immune Monitoring
The following laboratory assessments will be conducted every 12 weeks during idelalisib 
treatment:

Lymphocyte subset panel using flow cytometry (immunophenotyping) 

Quantitative immunoglobulins: IgG, IgM, IgA

Serum CH50 level
6.5.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related 
follow-up and procedures (see Section 6.7). If this is not possible or acceptable to the subject or 
investigator, the subject may be withdrawn from the study.
6.6.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Unacceptable toxicity or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest

Toxicity for which the protocol specifies discontinuation of idelalisib

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 2

Discontinuation of the study at the request of Gilead, a regulatory agency or an IRB/IEC
6.7.
End of Study Assessments
Subjects will be withdrawn from this study if they develop progressive disease, unacceptable 
toxicity related to idelalisib, or if they no longer derive clinical benefit in the opinion of the 
investigator. The following procedures should be performed:

Return of used and unused drug supply

Recording of all AEs and SAEs

CT scan to document progression

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
Laboratory assessments
ALC, PLT, Hgb, ANC. All subjects with WM should have the following laboratory test 
results recorded at each visit: IgM, serum M protein.
Lymphocyte subset panel using flow cytometry (immunophenotyping) 
Quantitative immunoglobulins: IgG, IgM, IgA
Serum CH50 level

Recording of the reason for withdrawal
Deaths occurring within 30 days following the last dose of idelalisib, even if occurring after the 
End of Study Visit, will be captured.

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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
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 the treatment. An AE can therefore be any unfavorable and/or unintended sign, 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:

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 (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.5.1)

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. 
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) is defined as an event that, at any dose, results in the following:

Death

Life-threatening (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

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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 other outcomes constituting SAEs. Medical and scientific judgment must be 
exercised to determine whether such an event is a reportable under expedited reporting rules. 
Examples of medically important events include intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; and development of drug dependency or drug abuse. For the avoidance of doubt, 
infections resulting from contaminated medicinal product will be considered a medically 
important event and subject to expedited reporting requirements.
7.1.3.
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 idelalisib 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 Sections 7.1.1and 7.1.2. If the laboratory abnormality 
is part of a syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result 
(ie, decreased hemoglobin).
7.2.
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.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to 
idelalisib 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)

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7.2.2.
Assessment of Severity
The severity of AEs will be graded according to CTCAE v4.03, available at:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
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 AE. For purposes of consistency with the CTCAE, these 
intensity grades are defined in Table 7-1. 
Table 7-1.
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 AE 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 Section7.1.2.
7.2.3.
Assessment of the Outcome of Adverse Events

Resolved:
The subject has fully recovered from the event with no residual effects 
observable.

Stabilized:
Effects of the event are constant. The likelihood of these effects changing
(improving or worsening) is low.

Ongoing:
Effects of the event are still present and changing. The event is not considered 
stabilized or resolved.
Death is an outcome of an event and not an event per se (sudden death or death of unexplainable 
causes can be reported but follow-up will be required until cause of death is determined).

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7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead or CRO
All SAEs, regardless of cause or relationship, which 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 INC Research Drug Safety 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.
Investigators are not obligated to actively seek SAEs after the 30-day 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.

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 INC Research Drug Safety.
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to INC Research Drug Safety within 24 hours of the investigator’s knowledge of 
the event. Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours as described above.

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
As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.
INC Research Drug Safety:
Fax:
E-mail:

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.
Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
form.
7.4.
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. 
7.4.1.
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, disease progression and death related to disease 
progression should not be reported to Gilead Sciences as adverse events unless it is assessed that 
idelalisib caused or contributed to the disease progression or death related to disease progression 
(ie, by a means other than lack of effect). 
PPD
PPD

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All events of disease progression and death related to disease progression, regardless of 
relationship to idelalisib, 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 on an ongoing basis.
7.5.
Special Situations Reports
7.5.1.
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 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.
7.5.2.
Instructions for Reporting Special Situations
7.5.2.1.
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 idelalisib follow-up period, to INC Drug Safety using the pregnancy report form within 
24 hours of becoming aware of the pregnancy. Refer to Section 7.3 and 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 will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to INC Drug Safety.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported INC Drug Safety 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: 
Refer to Appendix 2 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Recommendations.
7.5.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to INC Drug Safety 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.
Refer to Section 7.3 and the CRF/eCRF completion guidelines for full instructions on the 
mechanism of special situations reporting.
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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8.
STATISTICAL CONSIDERATIONS
8.1.
Determination of Sample Size
The sample size for this study depends on the number of eligible subjects from prior studies 
treated with idelalisib (101-02, 101-07, 101-08 and 101-10). No formal sample size calculation is 
conducted. 
8.2.
Statistical and Analytical Plans
8.2.1.
General Considerations
The baseline value used in each analysis will be the last value before or on the date of 
first dosing in the parent study. 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.
Summary of efficacy will be presented by integrating parent study with this extension study for 
101-02, 101-07, 101-08, and 101-10 respectively
8.2.1.1.
Handling of Missing Data
Analyses will be based upon observed data without imputation.
8.2.2.
Analysis Populations
8.2.2.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will consist of all subjects receiving at least 1 dose of study 
treatment. This analysis set will be used for the efficacy and safety analysis. 
The dose of idelalisib should be the same as the dose that was administered at the end of the 
parent study.
8.2.3.
Subject Disposition
The number and percentage of subjects who received idelalisib, completed parent study, entered 
study 101-99 and discontinued from study 101-99 will be summarized. Summary for the reasons 
of the discontinuation from the study treatment will be provided separately for each individual 
study with 101-99.
8.2.4.
Subject Characteristics
Demographics and baseline characteristics information will be captured from parent study. 
Summary will be provided separately for each individual study with 101-99, but will only 
include subjects who rolled over to 101-99.

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8.2.5.
Efficacy Analyses
Parent studies will be integrated with 101-99 for efficacy analysis. The data will be summarized 
separately for 101-02, 101-07, 101-08 and 101-10 with 101-99 based on subject disease and dose 
categorization as in parent study. The analysis will be performed including all subjects in the 
parent study regardless of their rolling over to 101-99 or not.
8.2.5.1.
Primary Efficacy Analysis
Overall response rate based on investigator’s response will be calculated along with its 
95% confidence intervals (CIs) based on exact method. In the analyses of ORR, subjects who do 
not have sufficient baseline or on-study tumor assessment to characterize response will be 
counted in the denominator
8.2.5.2.
Secondary Efficacy Analyses
For the analyses of DOR, PFS and OS, the Kaplan-Meier method will be used. For categorical 
variables, the following information will typically be presented: sample size, proportion, and 
95% CIs based on exact binomial method.
For the DOR and PFS analyses, subjects who withdraw from the study or are lost to follow-up 
without disease progression or death will be censored on the date of the last visit that lack of 
disease progression was objectively documented. Subjects who start a new antitumor treatment 
other than study treatment before disease progression will be censored on the last visit that lack 
of disease progression was objectively documented before the start of new antitumor treatment. 
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. For subjects without any adequate post-baseline 
disease assessment, PFS will be censored on the date of first study dose.
8.2.6.
Pharmacokinetic and Pharmacodynamic Analyses
Not applicable.
8.2.7.
Safety Analyses
The primary safety endpoint for this study will be the incidence of adverse events. All AEs and 
SAEs encountered by enrolled subjects during the clinical trial from the time the informed 
consent for 101-99 is signed through the end of study visit are required to be recorded on the AE 
CRF page(s). Summary will be provided by including all AEs recorded. 
8.2.7.1.
Extent of Exposure
A subject’s extent of exposure to idelalisib will be generated from the idelalisib administration 
data. Exposure data will be summarized.

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8.2.7.2.
Adverse Events
All adverse events that are observed in the parent studies (101-02, 101-07, 101-08, and 101-10) 
and their extension study will be summarized. 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 occurring from the first dose 
administered on the parent study and throughout subjects’ participation in this extension study 
will be included.
Adverse events will be classified using Medical Dictionary for Regulatory Activities (MedDRA) 
with descriptions by System Organ Class (SOC), High-Level Group Term, High-Level Term 
(HLT), Preferred Term, and Lower-Level Term. The severity of adverse events will be graded by 
the investigator according to the CTCAE, Version 4.03, 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) (see Table 7-1). The relationship of the adverse event to idelalisib will be 
categorized as related or unrelated.
Summaries (number and percentage of subjects) of treatment-emergent adverse events 
(by SOC, HLT, and preferred term) will be provided. A subject who reports multiple 
treatment-emergent adverse events within the same preferred term (or HLT or SOC) is counted 
only once for that preferred term (or HLT or SOC) using the worst severity grade. Adverse event 
descriptions will be presented by decreasing frequency for a given SOC, HLT and preferred 
term.
Separate summaries will be prepared for the following types of treatment-emergent adverse 
events:

idelalisib-related adverse events

Adverse events that are Grade 3 in severity

Adverse events leading to idelalisib discontinuation

By-subject listings will be provided for all AEs collected in 101-99.
8.2.7.3.
Serious Adverse Events
SAEs will be listed and summarized in a similar manner to AEs as described in Section 8.2.7.2.

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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
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), International Conference on Harmonisation (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 in the EU, add: 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 Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, 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) to an IRB/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC approval, with the exception of those necessary to 
reduce immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 

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investigator must use the most current IRB- or IEC-approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB or IEC or 
local requirements.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form submitted to the Sponsor, or IRB.
The investigator agrees that all information received from Gilead, including but not limited to the 
Investigator’s Brochure, this protocol, CRF/eCRF, the IMP, and any other study information, 
remain the sole and exclusive property of Gilead 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. 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.
9.1.5.
Study Files and Retention of Records
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 two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, 
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 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, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number);

Study discussed and date of informed consent;

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
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 IMP, including dates of dispensing and return;

Record of all adverse events and other safety parameters (start and end date, and including 
causality and severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
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 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. Subsequent to data entry, a study monitor will perform source data verification 
within the EDC system. Original entries as well as any changes to data fields will be stored in the 
audit trail of the system. Prior to database lock (or any interim time points as described in the 
clinical data management plan), the investigator will use his/her log in credentials to confirm that 
the forms have been reviewed, and that the entries accurately reflect the information in the 
source documents. The eCRF capture the data required per the protocol schedule of events and 
procedures. System-generated or manual queries will be issued to the investigative site staff as 
data discrepancies are identified by the monitor or internal Gilead staff, who routinely review the 
data for completeness, correctness, and consistency. The site coordinator is responsible for 

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responding to the queries in a timely manner, within the system, either by confirming the data as 
correct or updating the original entry, and providing the reason for the update 
(eg data entry error). At the conclusion of the trial, Gilead will provide the site with a read-only 
archive copy of the data entered by that site. This archive must be stored in accordance with the 
records retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
The study monitor will evaluate each study center’s IMP disposal procedures and provide 
appropriate instruction for destruction of unused IMP supplies. If the site has an appropriate 
standard operating procedure (SOP) for drug destruction as determined by Gilead SOP, the site 
may destroy used (empty or partially empty) and unused IMP supplies in accordance with that
site’s approved SOP. A copy of the site’s approved SOP will be obtained for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs/IECs, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB in 
accordance with local requirements and receive documented IRB/IEC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). 
Gilead will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be 
prepared in certain cases. 

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Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

The results of the study in their entirety have been publicly disclosed by or with the consent 
of Gilead in an abstract, manuscript, or presentation form or the study has been completed at 
all study sites for at least 2 years

The investigator will submit to Gilead 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. 

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).

The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF 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 CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead 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 medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.3.
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 authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.

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10.
REFERENCES
Brown JR, Furman RR, Flinn IW, Coutre SE, Wagner-Johnston ND, Kahl BS, et al. Final 
Results of a Phase 1 Study of Idelalisib (GS-1101) a Selective Inhibitor of 
Phosphatidylinositol 3-Kinase p110 Delta (PI3Kδ) in Patients with Relapsed or 
Refractory CLL [Presentation]. American Society of Clinical Oncology (ASCO) 
Annual Meeting; 2013 May 31-June 4 Chicago, Illinois. 
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.
Coutre SE, Barrientos JC, Brown JR, de Vos S, Furman RR, Keating MJ, et al. Management of 
adverse events associated with idelalisib treatment - expert panel opinion. Leuk 
Lymphoma 2015:1-20.
Cuni S, Perez-Aciego P, Perez-Chacon G, Vargas JA, Sanchez A, Martin-Saavedra FM, et al. A 
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements

PPD
PPD
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Appendix 1. 
Investigator Signature Page 
GILEAD SCffiNCES, INC. 
199 E. BLAJNE STREET 
SEATTLE, WA 98102 
STUDY ACIC'lOWLEDGEMENT 
An Extension Study to Investigate the Safety and Durability of Clinical Activity of ldelalisib in 
Subjects with Hematologic Malignancies 
101-99, Amendment 5, Version 6.0, 07 November 2016 
This protocol has been approveJ by Gilead Scit.:nces, Inc. The following signature documents 
this approval. 
Name (Printed) 
Medical Monitor 
~ IJ (N 
'2.0'\~ 
~----------------
Date 
INVESTIGATOR STATElV.t.ENT 
I have read the protocol, including all appendices, and I agree that it contcrin~ all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outhned herein al)d will make a reasonable effort to oomplete the study within the time 
designated. 
I will provido all study personnd under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I wul discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
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Appendix 2.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.  
Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause. In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
b. Definition of Male Fertility
For the purposes of this study, a male born subject is considered fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
Idelalisib is contraindicated in pregnancy as a malformation effect has been 
demonstrated/suspected or is unknown, taking into consideration class effects, genotoxic 
potential, or a strong suspicion of human teratogenicity/fetotoxicity in early pregnancy based on 
non-clinical data. Idelalisib has demonstrated/suspected or has insufficient data to exclude the 
possibility of a clinically relevant interaction with hormonal contraception that results in reduced 
contraception efficacy.  Therefore, contraceptive steroids are not recommended as a 
contraceptive method either solely or as a part of a contraceptive regimen. Please refer to the 
latest version of the investigator’s brochure for additional information.
b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  They must also not rely on hormone-containing contraceptives as a 
form of birth control during the study.  They must have a negative serum pregnancy test at 
Screening and a negative pregnancy test on the Baseline/Day 1 visit prior to randomization. 
Pregnancy tests will be performed at monthly intervals thereafter.  Female subjects must agree to 
one of the following from Screening until 30 days following the end of relevant systemic 
exposure.

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Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual lifestyle.
Or
Consistent and correct use of 1 of the following methods of birth control listed below.

Intrauterine device (IUD) with a failure rate of <1% per year

Tubal sterilization

Essure micro-insert system (provided confirmation of success 3 months after procedure)

Vasectomy in the male partner (provided that the partner is the sole sexual partner and had 
confirmation of surgical success 3 months after procedure)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the end of relevant systemic exposure.
3) Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid.  Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment and until 90 days after the 
end of relevant systemic exposure.  Additional contraception recommendations should also be 
considered if the female partner is not pregnant.
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
after the end of relevant systemic exposure.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.
5) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days for females or 90 days for female partners 
of male subjects of last study drug dose. Subjects who become pregnant or who suspect that they 
are pregnant during the study must report the information to the investigator and discontinue 
study drug immediately. Subjects whose partner has become pregnant or suspects she is pregnant 
during the study must report the information to the investigator.  Instructions for reporting 
pregnancy, partner pregnancy, and pregnancy outcome are outlined in Section 7.5.2.1.