A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and Safety of Two Different Dose Levels of Single-Agent Idelalisib (GS-1101) for Previously Treated Chronic Lymphocytic Leukemia A Companion Trial to Study GS-US-312-0116: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in Combination With Rituximab for Previously Treated Chronic Lymphocytic Leukemia
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia
Sponsor: Gilead Sciences

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The information contained in this document, particularly unpublished data, is the property or under 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Knowledge of the critical importance of PI3Kδ in B-cell biology and neoplasia has encouraged a 
search for inhibitors of this enzyme that could provide new options in the therapy of lymphoid 
malignancies, including CLL.
1.3.
Idelalisib (formerly GS-1101)
1.3.1.
General Information
Idelalisib was approved in the US on July 23, 2014 and in the European Union on 
September 18, 2014. Refer to local labeling for the approved indication statements and dosing 
recommendations.
Gilead Sciences, Inc has developed novel drugs that can suppress tumor growth through 
targeting of PI3Kδ activity. High-throughput screening was the basis for the discovery of novel 
agents that selectively inhibit PI3Kfunction but spare other PI3K isoforms and other kinases. 
Chemical optimization, pharmacological characterization, and toxicological evaluation have led 
to identification of idelalisib (also known as GS-1101), a 415-dalton, orally bioavailable, 
new chemical entity with potential clinical utility in the treatment of cancers.
In primary tumor samples and in cell lines derived from patients with CLL, indolent 
non-Hodgkin lymphoma (iNHL), mantle cell lymphoma (MCL), B-cell acute lymphocytic 
leukemia (ALL), or Hodgkin lymphoma (HL), idelalisib induces dose-dependent reductions in 
AKT phosphorylation {Herman et al 2010}, {Meadows et al 2010}, {Lannutti et al 2011}. In 
addition, idelalisib disrupts the PI3Kactivation and supportive intercellular signaling observed 
when CLL or HL cells are cocultured with stromal cells {Meadows et al 2010}, {Hoellenriegel 
et al 2011}. These effects have therapeutic consequences. In multiple lymphoid primary tumors
and malignant cell lines, idelalisib enhances apoptosis and concentration-dependent cell killing 
when applied as a single agent and increases the therapeutic efficacy of other antineoplastic 
agents when given in combination {Hoellenriegel et al 2011}, {Meadows et al 2011}. In 
preclinical systems, coadministration of idelalisib with rituximab has not impaired 
rituximab-mediated activity {Herman et al 2010}.
1.3.2.
Safety Pharmacology
In vitro and in vivo safety pharmacology studies with idelalisib have demonstrated a favorable 
non-clinical safety profile. These studies indicate that the drug may minimally slow bone marrow 
progenitor proliferation and differentiation and that it has expected inhibitory effects on 
B-cell response to antigen challenge. However, the data indicate that idelalisib is unlikely to 
cause serious off-target effects or adverse effects on critical organ systems. Idelalisib has no 
meaningful effect on the human ether-à-go-go-related gene (hERG) channel, indicating that 
idelalisib would not be expected to induce clinical QT prolongation.
The drug has also proved well tolerated in standard in vivo Good Laboratory Practice (GLP) 
studies of pharmacological safety. A functional observation battery in rats revealed no adverse 
effects on behavior or on autonomic, neuromuscular, or sensorimotor function. In a 
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idelalisib induced no meaningful abnormalities in pulmonary, cardiovascular, arterial blood gas, 
or electrocardiographic (ECG) (including QT interval) parameters. In an assessment of bacterial 
challenge in rats, idelalisib enhanced, rather than impaired, the phagocytic host clearance of 
staphylococcal bacteria.
1.3.3.
Nonclinical Pharmacology and Metabolism
Consistent with the moderate to high bioavailability seen in nonclinical species, idelalisib shows 
high permeability across human Caco-2 cell monolayers.  At lower concentrations, the reverse 
permeability at low concentration exceeds forward permeability, indicating efflux driven by 
transporters (eg, human P-glycoprotein (MDR1) and breast cancer resistance protein [BCRP]); 
idelalisib is a substrate for the efflux transporters MDR1 and BCRP; however, the permeability 
increases in a concentration-dependent manner, resulting in a lower efflux ratio at higher, 
clinically relevant concentrations of idelalisib.
Idelalisib exhibits moderately high plasma protein binding in mouse, rat, dog, and human. In dog 
and human plasma, the protein binding is concentration-independent between 1 and 20 µM. 
Protein binding in human plasma is slightly higher than in mouse, rat, and dog plasma, which 
have comparable free fractions.  In human plasma, idelalisib and GS-563117 
(the major metabolite of idelalisib) have an average free fraction of ~16% and ~12%, respectively.
After oral administration of 14C-idelalisib to rats and dogs, radioactivity is widely distributed, but 
relatively excluded from bone, brain, spinal cord, and eye lens in rats and from brain and eyes in 
dogs. In rats, the radioactivity declines steadily and most tissues have undetectable levels by 
72 hours post dose.  In bile duct-cannulated rats and dogs, ≥69% of radioactivity is recovered in 
bile and urine, indicating high absorption of idelalisib in vivo.
In hepatic tissues from nonclinical species, idelalisib is primarily metabolized by 
aldehyde oxidase, CYP3A, and UGT1A4.  In vitro metabolism in dog and human yields 
3 primary oxidative metabolites and 5 primary glucuronides. Of these, the oxidative product 
GS-563117 is the predominant metabolite in vitro and in vivo. In preclinical species, plasma 
levels of GS-563117 are below those of idelalisib. In humans, GS-563117 
(only circulating metabolite and formed via aldehyde oxidase) plasma levels significantly exceed 
those of idelalisib. After oral administration of 14C-idelalisib to rats and dogs, biliary excretion 
appears to be the major route of elimination of idelalisib and its metabolites as the majority of 
radioactivity is found in feces or bile and little in urine.
Idelalisib is not a substrate for the renal transporters OCT2, OAT1, and OAT3 or the 
hepatic uptake transporters OATP1B1 and OATP1B3.  GS-563117 is not a substrate for 
OATP1B1 and OATP1B3.
Idelalisib is not an inhibitor of CYP1A, CYP2B6, CYP2C9, and CYP2D6, and at concentrations 
above those observed clinically, is an inhibitor of CYP2C8 (IC50 = 13 µM), CYP2C19 
(IC50 = 76 µM), and CYP3A (IC50 = 44 µM). GS-563117 is not an inhibitor of CYP1A, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and a competitive and time dependent 
inhibitor of CYP3A (IC50 = 3.1 µM), (KI = 0.18 µM, kinact = 0.033 min-1 with midazolam as 
the probe substrate).

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

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

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Pharmacodynamic results showed that a idelalisib dose of 200 mg inhibited ex vivo basophil 
activation via the PI3K-specific, high-affinity immunoglobulin (Ig)E receptor (anti-FCR1) in 
basophils collected from healthy volunteers. The findings were confirmed when the drug was 
assessed over 7 days in a Phase 1b study in subjects with allergic rhinitis. In this study, idelalisib
at a dose level of 100 mg/dose BID showed clinical and pharmacodynamic activity 
(attenuating adverse responses to allergenic challenge and decreasing markers of inflammation) 
and was well tolerated.
1.3.5.2.
Phase 1 Studies in Patients with Hematological Malignancies
1.3.5.2.1.
Phase 1 Monotherapy Study in Patients with Hematological Malignancies
A Phase 1 dose-ranging study (Study 101-02) of single-agent idelalisib extended safety and 
pharmacokinetic observations; documented the clinical and pharmacodynamic activity of 
idelalisib in subjects with iNHL, MCL, and CLL; and provided dosing information in support of 
further development {Brown et al 2011}, {Coutre et al 2011}, {Kahl et al 2011}. In this study, 
idelalisib was administered in cohorts of subjects across a range of dose levels from 50 mg/dose 
BID to 350 mg/dose BID. Idelalisib administration was continued as long as individual subjects 
were safely benefitting from therapy. Subjects were evaluated in 4-week cycles; response and 
progression assessments were based on standard criteria {Hallek et al 2008}.
A total of 191 subjects were enrolled to the study at dose levels of 50 mg BID (n=17), 
150 mg QD (n=16), 100 mg BID (n=25), 150 mg BID (n=45), 200 mg BID (n=35), 
350 mg BID (n=17), and 300 mg QD (n=19). An additional cohort was also enrolled to receive 
idelalisib 150 mg BID in 28 day cycles (21 days on idelalisib/7 days off [n=17]). Subject
characteristics were as follows: males/females n=139 (73%)/52 (27%) with median age of 
64.5 (range 32-91) years. Diagnoses included: CLL, n=54 (28%); iNHL, n=64 (34%); aggressive 
NHL (MCL and DLBCL), n=49 (26%); AML, n=12 (6%); and MM, n=12 (6%). Categorization 
of disease by response to the last prior therapy included: refractory, n=111 (58%); 
relapsed, n=79 (42%); and unknown, n=1 (1%).  The median (range) number of prior therapies 
was 5 (1-14). Among subjects with iNHL and CLL, the majority had received prior rituximab 
and prior alkylating agent therapy.
Adverse events were usually mild to moderate and not clearly idelalisib-related. Among 
Grade ≥3 adverse events, pneumonias and diarrhea were notable. Pneumonia was observed in 
23 (12%) subjects, primarily in subjects with CLL. In most instances, these findings were 
considered bacterial in origin, based either on culture results or on response to conventional 
antibiotics. Grade ≥3 adverse events of diarrhea were seen in 11 subjects (5.8%). Other 
Grade ≥3 events included rash in 3 (1.6%) subjects. The relative contributions of disease-related 
factors, toxicity from prior therapies or ongoing supportive care, and idelalisib to these events 
was not clear.
Grade ≥3 hematological laboratory abnormalities have included neutropenia, n=46 (24%); 
thrombocytopenia, n=27 (14%), anemia, n=14 (7.3%), and lymphopenia 13 (6.8%); with 
12 subjects (6.3%) having febrile neutropenia.  The occurrence of these events was greater in 
subjects with leukemia, particularly in those with pre-existing hematological abnormalities due 
to disease or prior therapy, commonly making attribution of these events to idelalisib uncertain.

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Consistent with the observations in the 28-day dog toxicology study, reversible Grade ≥3 
ALT/AST elevations occurred in 28 (15%) subjects and have been attributed to idelalisib. Onset 
generally occurred between 2 to 16 weeks after idelalisib initiation and resolution was usually 
seen 2 to 6 weeks after idelalisib interruption.  After resolution of ALT/AST increases, 
14 subjects were rechallenged at the same or a reduced dose of idelalisib and 9 (64%) of these 
subjects were able to resume treatment without recurrence of transaminase elevations.
Two (1.0%) subjects had ≥ 2 x ULN elevations in bilirubin in the context of Grade ≥3 
elevated AST/ALT, both of whom had confounding factors (recent history of biliary obstruction 
or concomitant use of potentially hepatotoxic medications) so that a definitive causal relationship 
to idelalisib could not be established.
Pharmacokinetic analyses indicated that the increase in Cmax and AUC0-6h with dose was less 
than dose-proportional, with modest increases above the dose level of 150 mg BID.
Pharmacodynamic data supported drug activity.  In subjects with NHL, plasma concentrations of 
chemokines CCL22 and CCL17 were elevated at baseline and showed significant decreases 
within 1 cycle of idelalisib treatment (p<0.001 for both comparisons). Flow cytometry of CLL 
cells from subjects showed that idelalisib reduced constitutive expression of phosphorylated 
AKT to background levels when measured after 1 week of treatment (p<0.0001), demonstrating 
pharmacodynamic inhibition of activated PI3K signaling.  Plasma concentrations of 
chemokines CCL3, CCL4, and CXCL13 were elevated in CLL subjects at baseline and 
decreased significantly within 1 cycle of idelalisib administration (p<0.001 for all comparisons).
Tumor reductions meeting antitumor response criteria were not observed in subjects with AML 
or MM. One of 11 subjects with DLBCL achieved a PR.  In 104 subjects with iNHL and MCL, 
idelalisib induced PRs at all dose levels, with respective ORRs in enrolled subjects of 
29/64 (45%) for iNHL and 16/40 (40%) for MCL. The median DOR has not been reached in 
subjects with iNHL; 19 subjects continued to receive idelalisib in a long-term extension study. 
The median [range] DOR was 2.7 months [1 month to 8 months] in subjects with MCL; 
6 MCL subjects continued to receive idelalisib in a long-term extension study.
In subjects with CLL, idelalisib reduced lymphadenopathy in almost all subjects; 
44/54 (81.5%) achieved a lymph node response (≥50% reduction in target nodal lesions). An 
initial increase in peripheral absolute lymphocyte counts of >50% from baseline was observed in 
some subjects; increases were maximal during the first 2 cycles and decreased thereafter; the 
pattern suggested drug-mediated lymphocyte redistribution.  In 54 subjects with CLL, 
39/54 (72%) achieved a PR (includes PR with lymphocytosis).  The median DOR was not 
reached; 23 subjects continued to receive idelalisib in a long-term extension study.
1.3.5.2.2.
Phase 1 Combination Study in Patients with Hematological Malignancies
A separate Phase 1 trial (Study 101-07) has evaluated the safety and preliminary activity of 
idelalisib given in combination with rituximab to subjects with recurrent iNHL or CLL {Brown 
et al 2011}, {Leonard et al 2011}.

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

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

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

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

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

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

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

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

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

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

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

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

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

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3.2.4.
Assessments of Exposure
3.2.4.1.
Study Drug Administration and Compliance
Evaluation of study drug administration and compliance provides context for assessments of 
safety, pharmacokinetics, and pharmacological activity. Evaluations of treatment administration 
and modifications from planned therapy document the influence of treatment-emergent adverse 
events on prescribing practice. Compliance assessment offers a general indication of patients’ 
acceptance of therapy, integrating factors of tolerability, palatability, and convenience.
In this study, information regarding planned treatment and modification from planned treatment 
(eg, dose reductions and interruptions) will be kept. The compliance of the subject will be 
verified by accounting for used and unused drug.
3.2.4.2.
Pharmacokinetics
Given the intent of this protocol to assess longer-term dosing, collection of plasma for idelalisib
concentrations is important for evaluating exposure over time. These data may allow correlations 
of exposure with measures of efficacy, toxicity, and resistance. Because the idelalisib
pharmacokinetic profile has been well characterized in Phase 1 studies, limited plasma sampling 
will be performed in this study. Samples will be collected pre-dose and 1.5 hours post-dose 
relative to the morning administration of idelalisib. Based on discussions with investigators, 
collecting more than 2 samples in the morning is not considered reasonable given the need to 
minimize time requirements for study participants and to avoid substantial inconvenience for 
clinic staff.
Evaluation of idelalisib plasma concentrations will be performed using liquid chromatography 
with tandem mass spectrometry. The method has been fully validated in the context of prior 
Phase 1 studies. Plasma samples will be retained for potential later analyses of idelalisib
metabolites.
3.2.5.
Evaluations of Safety
In defining the therapeutic relevance of a drug in a particular clinical setting, it is imperative that 
its safety profile be fully characterized. As is conventional in all clinical studies, proper 
description of each adverse event or laboratory abnormality requires an understanding of the 
type, incidence, timing, severity, and relatedness to study drug. While information on all reported 
adverse events will be collected, listed, and summarized, particular focus will be placed on 
monitoring and reporting adverse events and laboratory abnormalities that were encountered in 
the prior toxicology studies and clinical experience with idelalisib. Safety parameters of specific 
interest in reporting study results will include those relating to bone marrow function, 
dermatological events, gastrointestinal inflammation, infection, pulmonary events 
(eg, pneumonia/pneumonitis), and liver injury. Additional scrutiny will be applied to 
Grade 3-4 adverse events, to adverse events causing interruption or discontinuation of idelalisib, 
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In addition, the protocol will evaluate for potential adverse idelalisib effects on laboratory 
parameters of immune function; the absolute number of CD4+, CD5+,CD8+, CD16/CD56+, 
CD19+, and CD20+ cells will be assessed by flow cytometry. Serum concentrations of IgA, IgE, 
IgG, and IgM will be obtained.
For consistency of interpretation, adverse events will be coded using the standard 
Medical Dictionary for Regulatory Activities (MedDRA) [http://www.meddramsso.com]), and 
the severity adverse events and laboratory abnormalities will be graded using the well-defined 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). 
Standard definitions for seriousness will be applied (see Section 8.1.2).
3.2.6.
Pharmacoeconomic Measures
It is increasingly important to understand the potential cost implications of introducing a new 
medication into patient care for CLL {Main et al 2010}, {Hornberger et al 2012}. In order to 
analyze the pharmacoeconomic consequences of idelalisib administration, data will be collected 
regarding the health status of subjects and regarding health care resource utilization.
Heath status information will be obtained with the EQ-5D, which is a self-administered, generic, 
indirect utility measure {The EuroQol Group 1990} (Appendix 4). The EQ-5D consists of a 
visual analogue scale on which subjects are asked to rate their current overall health status and 
5 single-item dimensions which ask subjects to rate their health in terms of mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression. For each of the 5 items, patients must 
choose between 3 levels of difficulty in accomplishing tasks in that dimension. The visual analog 
scale is then used in combination with the dimension scores to generate a health utility score that 
can be incorporated into analyses of cost effectiveness. The EQ-5D has been successfully used in 
the evaluation of patients with B-cell and other cancers {Doorduijn et al 2005}, {Witzens-Harig 
et al 2009}, {Yang et al 2010}.
The EQ-5D instrument is available in appropriate languages for this study. EQ-5D data will be 
obtained at baseline and during each investigational clinic visit during treatment. The EQ-5D 
will be administered immediately after administration of the FACT-Leu instrument, before other 
procedures are performed and before any study information is conveyed to the subject. The 
EQ-5D instrument takes only 5 minutes to complete.
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach will be to combine the resource utilization data from the trial with data on 
unit prices (collected separately) to estimate total costs. The costs will be described relative to 
the health care findings as measured by duration of tumor control, the symptom-free survival 
period, and/or utility outcomes or some other appropriate measure of clinical benefits.

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4.
SUBJECT POPULATION
4.1.
Number of Subjects
The planned sample size is ~160 subjects but will be bounded by the number of subjects enrolled 
to the primary clinical trial (Study GS-US-312-0116).
4.2.
Subject Selection Criteria
Subjects in the primary Phase 3 study (GS-US-312-0116) who are compliant, are tolerating 
primary study therapy, and 1) have definitive progression of CLL while receiving primary study 
drug therapy (idelalisib /placebo) or 2) are actively participating in Study GS-US-312-0116 at 
the time the study is stopped, including if stopped early due to overwhelming efficacy following 
an interim analysis are eligible to enroll in the extension study. Eligibility criteria may not be 
waived by the investigator and conformance to the eligibility criteria is subject to review in the 
case of a Good Clinical Practice (GCP) or a regulatory authority audit. Any questions regarding a 
subject’s eligibility should be discussed with the study sponsor medical monitor prior to 
enrollment.
4.2.1.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Participation in Study GS-US-312-0116.
2) Occurrence of confirmed, definitive CLL progression while receiving study drug therapy 
(idelalisib/placebo) in Study GS-US-312-0116. Note: Definitive disease progression is CLL 
progression based on standard criteria and occurring for any reason 
(ie, increasing lymphadenopathy, organomegaly, or bone marrow involvement; 
decreasing platelet count, hemoglobin, or neutrophil count; or worsening of 
disease-related symptoms) other than lymphocytosis. Subjects must have confirmation by 
the sponsor working in collaboration with an independent review committee (IRC) that the 
disease has progressed on the clinical trial (Study GS-US-312-0116) before receiving
secondary idelalisib therapy on this extension trial (Study GS-US-312-0117).
3) Presence of radiographically measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures 2.0 cm in the longest diameter [LD] and 1.0 cm in the 
longest perpendicular diameter [LPD] as assessed by CT or MRI).
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab and idelalisib/placebo) 
and no intervening or continuing therapy (including radiotherapy, chemotherapy, 
immunotherapy, or investigational therapy) for the treatment of CLL. Note: Subjects may 
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5) The time from permanent cessation of Study GS-US-312-0116 treatment (rituximab and/or
idelalisib/placebo) and the initiation of Study GS-US-312-0117 therapy is 12 weeks. 
Note: Study procedures performed as part of Study GS-US-312-0116 need not be repeated 
and can be used as screening procedures for Study GS-US-312-0117 if performed within 
4 weeks prior to initiation of study drug therapy on Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation of study treatment) as 
shown in the table below. Note: Confirmation should be considered for out-of-range values 
to determine if the abnormality is real or artifactual. Values should be obtained within the 
screening period and should generally be the most recent measurement obtained. Subjects 
with any degree of neutropenia, thrombocytopenia, or anemia due to CLL or prior therapy 
may enroll.
Table 4-1.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCra
>30 ml/min
Pregnancy
-HCGb
Negative
a
As calculated by the Cockcroft-Gault formula (see Appendix 5) {Cockcroft et al 1976}
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or 
urine dipstick pregnancy test must be negative at start of study treatment (Visit 2)
Abbreviations: -HCG= beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
eCCr=estimated creatinine clearance, ULN=upper limit of normal
8) For female subjects of childbearing potential, willingness to use a protocol-recommended 
method of contraception (as outlined in Section 5.6.4) from the screening visit (Visit 1) 
throughout the study and for 30 days following the last dose of study drug.
Note: A female subject is considered to be of childbearing potential unless she has had a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically 
documented ovarian failure (with serum estradiol and follicle-stimulating hormone [FSH] 
levels within the institutional postmenopausal range and a negative serum or 
urine HCG), or is menopausal (age ≥54 with amenorrhea for >12 months or 
amenorrhea for >6 months with serum estradiol and FSH levels within the institutional 
postmenopausal range).
9) For male subjects of childbearing potential having intercourse with females of childbearing 
potential, willingness to use a protocol-recommended method of contraception 
(as outlined in Section 5.6.4) from the start of study drug (Visit 2) throughout the study and 
for 90 days following the last dose of study drug and to refrain from sperm donation from the 
start of study drug (Visit 2) throughout the study and for 90 days following the last dose of 
study drug. Note: A male subject is considered able to father a child unless he has had a 

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

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

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

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

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

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

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5.2.6.
Return
The study drug should be retrieved from each subject at the end of each dispensing interval. The 
quantity of study drug and the date returned by the subject should be recorded in the study drug 
accountability records. When possible, all study drug returned by the subject should be retained 
for review by the study site monitor prior to return to Gilead Sciences or destruction.
5.2.7.
Accountability
The disposition of all study drug should be documented from the time of receipt at the site 
through subject dispensing and return.
Study personnel must ensure that all study drug is kept in a secure locked area with access 
limited to authorized personnel. The study drug must not be used outside the context of this 
protocol. Under no circumstances should the investigator or site personnel supply study drug to 
other investigators or clinics, or allow the study drug to be used other than as directed by this 
protocol.
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by Gilead Sciences or its designee, including, but not limited to, 
the date received, lot number, amount received, and the disposition of all study drug. Upon 
receipt of a drug shipment, the shipment must be logged into the IWRS. Study drug 
accountability records must also be maintained that include the subject number to whom the 
study drug was dispensed and the date, quantity and lot number of the study drug dispensed.
Depending upon the decision of Gilead Sciences, remaining unused study drug supply will be 
returned to Gilead Sciences or its designee after the study is completed or will be discarded or 
destroyed at the clinical site. If the study drug is discarded or destroyed at the clinical site, 
standard institutional policy should be followed. Records documenting the date of study drug 
shipping or destruction, relevant lot numbers, and amount shipped or destroyed should be 
maintained.
5.2.8.
Overdose Precautions
In Phase 1 studies, an MTD for idelalisib was not reached when the drug was administered 
continuously at dose levels through 350 mg/dose BID (700 mg per day) {Coutre et al 2011}, 
{Kahl et al 2011}. However, in this protocol, an overdose is defined as administration of more 
than the prescribed daily dose (ie, >600 mg in a single day). In a subject who experiences an 
overdose consideration should be given as to whether idelalisib administration should be 
temporarily interrupted. If the overdose ingestion is recent and substantial, and if there are no 
medical contraindications, use of gastric lavage or induction of emesis may be considered. 
Observation for any symptomatic side effects should be instituted, and biochemical and 
hematological parameters should be followed closely (consistent with the protocol or more 
frequently, as needed). Appropriate supportive management to mitigate adverse effects should be 
initiated.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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6.4.
Blood Collection
The maximum amount of blood to be drawn at a visit ~115 mL and the total amount of blood to 
be drawn over the initial 52-week study period (including the 4-week screening period and 
through Week 48 of the study including a possible end-of-therapy visit) is ~560 mL. For a 
40-kg person (the smallest participant expected to enroll in the study), this equates to 
maximum blood volume per body weight per visit of ~2.8 mL/kg and a total blood volume 
per body weight per average 6-week period of ~1.6 mL/kg. These quantities of blood are within 
accepted limits of 3.0 mL/kg of body weight for a single blood draw and 7.0 mL/kg of 
body weight for a 6-week period.
Specific details regarding blood sample collection and processing requirements will be provided 
separately in the study manual.
 
 
 
6.5.
Study Procedure Rationale
The planned study assessments and timing have been selected as appropriate for screening of 
subjects, for determination of idelalisib-related or disease-related toxicities, for dose 
modification during the study, for characterization of drug exposure and desired pharmacological 
effects, and for evaluation of drug activity. The scheduling of testing is designed to collect a 
complete safety and pharmacology data set while maintaining subject tolerance of study 
procedures. The planned schedule of tumor assessments is consistent with expected rate of 
changes and appropriately balances precise measurement of tumor control with the expense and 
subject inconvenience associated with clinical and radiological procedures. For discussion of the 
rationale for endpoint selection, see Section 3.2.
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7.
EFFICACY ASSESSMENTS
7.1.
Tumor Status Assessments
The determination of CLL response and progression will be based on standardized IWCLL
criteria {Hallek et al 2008}, as specifically modified for this study to reflect current 
recommendations which consider the mechanism of action of idelalisib and similar drugs 
{Cheson et al 2012}. Treatment decisions by the investigator in this study will be based on these 
assessments. Radiographic and clinical tumor assessments will be subject to independent 
confirmation by the IRC (see Section 10.4.2).
7.2.
Method of Assessment
In addition to clinical examination, imaging-based evaluation will be used in this study in all 
subjects enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI 
scanning may be used at the investigator’s discretion in subjects for whom this may be a 
preferred alternative to CT scanning; however, if MRI is performed, a non-contrast CT of the 
chest should be performed. Contrast-enhanced scanning is preferred, but iodine-containing or 
gadolinium contrast material may be omitted in subjects for whom use of a contrast agent would 
be medically contraindicated. Chest x-ray, ultrasound, endoscopy, laparoscopy, PET, 
radionuclide scans, or tumor markers will not be considered for response assessment.
For radiographic evaluations, the same method of assessment and the same technique 
(eg, scan type, scanner, subject position, dose of contrast, injection/scan interval) should be used 
to characterize each identified and reported lesion at baseline and during study treatment and 
follow-up.
All relevant clinical and radiographic information required to make each tumor status assessment 
must be made available for source verification and for submission to the IRC 
(see Section 10.4.2).
7.3.
Timing of Assessments
All baseline clinical and CT/MRI tumor assessments should be performed within 4 weeks prior 
to initiation of study drug therapy. In order to optimize scheduling convenience for the subject 
and for the investigational staff, clinical and CT/MRI tumor assessments performed as part of 
Study GS-US-312-0116 need not be repeated and can be used as baseline tumor assessments for 
Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117. Clinical tumor assessments should be performed at each clinical visit. 
On-study CT/MRI tumor assessments should be performed at ~8- to 12-week intervals as 
dictated by the study protocol. An end-of-study CT/MRI tumor assessment should be performed 
unless the subject has per-protocol CT/MRI assessments 4 weeks prior. If a subject 
permanently discontinues study drug prior to objective documentation of CLL progression, 
investigators should continue further follow-up at ~12-week intervals until CLL progression is 
documented by the central IRC.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PPD
PPD
ldclalisib 
Protocol GS-US-312-0117 
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Version 8.0 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
199 EAST BLAINE STREET 
SEATTLE, WA 98102 
STUDY ACKNOWLEDGEMENT 
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and Safety of 
Two Different Dose Levels of Single-Agent Idelalisib (GS-1101) for Previously Treated 
Chronic Lymphocytic Leukemia 
GS-US-312-0117, Version 8 (Amendment 7), 05 August 2016 
This protocol has been approved b} Gilead Sciences, Inc. The following signature documents 
this approvaL 
~--:-::--:-------~·· 
Gilead Sciences Medical Monitor 
INVESTIGATOR STATEMENT 
1 have read the protocol, including all appendices, and 1 agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies ofthe protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator 
Printed Name 
Date 
CONFlDENTIAL 
Page 153 
Signature 
Site Number 
05 August 2016 

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

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

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

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

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Gilead Sciences, Inc. 
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Appendix 4. 
EuroQoL-5 Dimensions (EQ-SD) 
By placmg a clleckmark m one box in each group below. please ind.t~ate wbJch 
stat~mems b~1 describe your own health sEate today. 
Mobility 
I have no proWems in •11alking about 
I ha1:e some p oblems r walking about 
I am corrlir.ed to bed 
Self-Care 
I ~ve no problems wim self-care 
I have some probrems washing o dress g- myself 
I am unabla to ~'ash or dress myseli 
Usual Activities (e.g., work, study, housework, family, or leisure activities) 
I have no problems with perorming my usual ac1ivlties 
I hiwe some prob ems •1f'i1h perlormiJ'Ig my usua( activities 
I am unable to ~erform my usuaJ actvites 
Pain/Discomfort 
I have no pain o: discomfon 
I ha'o·e moderate pail or discorrrott 
I h.ave eldreme pa.n or rLsoomfort 
Anxiety!Oe pression 
I am n~ anxious ot de~ressed 
I am moderately anxi01.1s or depressed 
I am extremely anxious or depressed 
CONFIDENTIAL 
Page 158 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
05 August 2016 

Idelalisib 
Protocol GS-US-312-0117 
Gilead Sciences, Inc. 
To help people say bow good or bad a health state LS, 
we have drawn a scale (rather bke a thennometer) on 
which the best stare you can un.agine 1S marked 100 
and the worsr stare you can imagine is marked 0. 
We \Vould like you to mdicate on this scale how good 
or bad your own health is today. in your opinion. 
Please do this by drawmg a line from the box below 
to wlllcbever pomt on the scale indicates how good or 
bad your health state is today. 
CONFIDENTIAL 
Yow· own 
hPalth statl' 
toda~· 
Page 159 
B~ 
imagmable 
health SUll! 
tOO 
T 
0 
\Vm"t 
ima:inab!e 
huhh:;ute 
Final 
Version 8.0 
05 August 2016 

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

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

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

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

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

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