Conditions: Chronic Lymphocytic Leukemia
Keywords: Zydelig CLL CAL-101 GS 1101 GS-1101 PI3K Rituxan Rituximab Bendamustine Leukemia idelalisib
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 416
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the effect of the addition of idelalisib (formerly GS-1101) to bendamustine + rituximab (BR) on progression-free survival (PFS) in participants with previously treated chronic lymphocytic leukemia (CLL)

Detailed description:

Arms:
arm 1: Participants will receive idelalisib plus bendamustine and rituximab arm 2: Participants will receive placebo to match idelalisib plus bendamustine and rituximab

Interventions: intervention 1: Idelalisib intervention 2: Rituximab intervention 3: Bendamustine intervention 4: Placebo to match idelalisib
Intervention descriptions: intervention 1: Idelalisib 150 mg administered orally twice daily intervention 2: Rituximab 375 mg/m\^2 on Day 1, then 500 mg/m\^2 every 28 days administered intravenously for a maximum of 6 infusions intervention 3: Bendamustine 70 mg/mg\^2/day on 2 consecutive days every 28 days administered intravenously for a maximum of 12 infusions intervention 4: Placebo to match idelalisib administered orally twice daily

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in 
Combination with Bendamustine and Rituximab for Previously Treated 
Chronic Lymphocytic Leukemia
Sponsor:
333 Lakeside Drive
Foster City, CA 94404
USA
IND Number:
EudraCT Number:
101254
2011-006292-20
Indication:
Chronic Lymphocytic Leukemia
Gilead Protocol ID:
GS-US-312-0115
Gilead Sciences
Medical Monitor:
Name:
Office Telephone:
Mobile Telephone:
E-mail:
Protocol 
Version/Date:
Version 1.0 (Original)
16 March 2012
Version 2.0 (Amendment 1)
19 December 2012
Version 3.0 (Amendment 2)
01 May 2013
Version 4.0 (Amendment 3)
06 November 2013
Version 5.0 (Amendment 4)
25 April 2014
Version 6.0 (Amendment 5)
10 October 2014
Version 7.0 (Amendment 6)
15 December 2015
Version 8.0 (Amendment 7)
25 March 2016
Version 9.0 (Amendment 8)
03 August 2016
Version 10.0 (Amendment 9)
24 October 2016
Version 11.0 (Amendment 10) 21 September 2017
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
institutional review board or independent ethics committee. This information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in the 
protocol. You must not disclose any of the information to others without written authorization
from Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
PPD
PPD
(rJ GILEAU 


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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....................................................................20
1.
INTRODUCTION ..............................................................................................................................................24
1.1.
Chronic Lymphocytic Leukemia............................................................................................................24
1.2.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies....................................................................25
1.3.
Idelalisib (formerly GS-1101)................................................................................................................26
1.3.1.
General Information .............................................................................................................26
1.3.2.
Safety Pharmacology............................................................................................................26
1.3.3.
Nonclinical Pharmacology and Metabolism.........................................................................27
1.3.4.
Toxicology ...........................................................................................................................28
1.3.5.
Idelalisib Clinical Studies.....................................................................................................29
1.4.
Summary and Justification for the Current Study ..................................................................................33
2.
STUDY DESIGN................................................................................................................................................35
2.1.
Design Overview and Study Schema .....................................................................................................35
2.2.
Design Rationale ....................................................................................................................................36
3.
OBJECTIVES AND ENDPOINTS ....................................................................................................................38
3.1.
Primary Objective ..................................................................................................................................38
3.2.
Secondary Objectives.............................................................................................................................38
3.3.
Primary Endpoint ...................................................................................................................................38
3.4.
Secondary and Tertiary Endpoints .........................................................................................................38
3.4.1.
Tumor Control......................................................................................................................39
3.4.2.
Patient Well-Being ...............................................................................................................40
3.4.3.
Pharmacodynamic Markers of Drug Activity and Resistance..............................................40
3.4.4.
Exposure...............................................................................................................................40
3.4.5.
Safety....................................................................................................................................40
3.4.6.
Pharmacoeconomics.............................................................................................................40
3.5.
Endpoint Selection Rationale.................................................................................................................41
3.5.1.
Tumor Control Endpoints.....................................................................................................41
3.5.2.
Measures of Patient Well-Being...........................................................................................43
3.5.3.
Pharmacodynamic Markers of Drug Activity and Resistance..............................................45
3.5.4.
Assessments of Exposure .....................................................................................................46
3.5.5.
Evaluations of Safety............................................................................................................46
3.5.6.
Pharmacoeconomic Measures ..............................................................................................47
4.
SUBJECT POPULATION..................................................................................................................................49
4.1.
Number of Subjects................................................................................................................................49
4.2.
Subject Selection Criteria.......................................................................................................................49
4.2.1.
Inclusion Criteria..................................................................................................................49
4.2.2.
Exclusion Criteria.................................................................................................................52
4.3.
Enrollment Criteria Rationale ................................................................................................................54
5.
TREATMENT OF SUBJECTS ..........................................................................................................................56
5.1.
Randomization and Blinding..................................................................................................................56


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5.1.1.
Interactive Web Response System .......................................................................................56
5.1.2.
Randomization and Stratification.........................................................................................56
5.1.3.
Blinding................................................................................................................................56
5.2.
Investigational and Reference Study Drugs ...........................................................................................57
5.2.1.
Investigational Study Drug (Idelalisib/Placebo)...................................................................57
5.2.2.
Reference Drug (Rituximab)................................................................................................60
5.2.3.
Reference Drug (Bendamustine)..........................................................................................62
5.3.
Study Drug Administration ....................................................................................................................65
5.3.1.
Combination Dosing Regimen .............................................................................................65
5.3.2.
Premedications .....................................................................................................................68
5.3.3.
Study Drug (Idelalisib/Placebo) Administration ..................................................................68
5.3.4.
Reference Drug (Bendamustine/Rituximab) Administration ...............................................69
5.3.5.
Safety Monitoring and Study Treatment Interruption/Dose Modification ...........................70
5.4.
Evaluation, Intervention, and Drug Discontinuation for Specific Adverse Events or 
Conditions ..............................................................................................................................................81
5.4.1.
Dermatological Events .........................................................................................................81
5.4.2.
Gastrointestinal Events.........................................................................................................82
5.4.3.
Hepatic Events......................................................................................................................83
5.4.4.
Hematological and Immunological Events...........................................................................84
5.4.5.
Infectious Events..................................................................................................................85
5.4.6.
Infusion Reactions................................................................................................................86
5.4.7.
Progressive Multifocal Leukoencephalopathy .....................................................................87
5.4.8.
Pulmonary Events ................................................................................................................87
5.4.9.
Secondary Malignancies.......................................................................................................88
5.4.10.
Tumor Lysis Syndrome........................................................................................................89
5.4.11.
Cardiac Disorders.................................................................................................................89
5.4.12.
Pregnancy, Lactation, and Reproduction..............................................................................89
5.4.13.
PJP Prophylaxis....................................................................................................................90
5.4.14.
Ultraviolet Exposure ............................................................................................................91
5.4.15.
Further Safety Information...................................................................................................91
5.5.
Emergency Unblinding ..........................................................................................................................91
5.6.
Concomitant and Supportive Therapy....................................................................................................92
5.6.1.
Anticancer or Experimental Therapies Other than Investigational 
Treatments............................................................................................................................92
5.6.2.
Antibiotics............................................................................................................................92
5.6.3.
Antiemetics and Antidiarrheals............................................................................................93
5.6.4.
Contraception .......................................................................................................................93
5.6.5.
Corticosteroids .....................................................................................................................94
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin..............................................94
5.6.7.
Drugs that Inhibit/Induce CYP3A-Dependent Metabolism..................................................95
5.6.8.
Drugs that undergo CYP3-A-Dependent Metabolism..........................................................95
5.6.9.
Immunization .......................................................................................................................95
5.6.10.
Surgery .................................................................................................................................96
5.6.11.
Diet.......................................................................................................................................96
5.7.
Duration of Study Drug..........................................................................................................................96
5.8.
Discontinuation of Study Drug ..............................................................................................................96
5.9.
Discontinuation from Study ...................................................................................................................97
5.10.
Study Treatment Rationale.....................................................................................................................98
6.
STUDY PROCEDURES ..................................................................................................................................101
6.1.
Enrollment and Study Management Procedures ..................................................................................101
6.1.1.
Subject Recruitment ...........................................................................................................101
6.1.2.
Subject Compensation for Participation.............................................................................101
6.1.3.
Screening............................................................................................................................101


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6.2.
Explanation of Study Visits..................................................................................................................102
6.2.1.
Visit 1 and Screening Period (Clinic Visit)........................................................................103
6.2.2.
Visit 2 (Clinic Visit – Randomization and Treatment Start) ..............................................105
6.2.3.
Visits 3, 6, 9, 12, 15, and 18 (Clinic Visit –Bendamustine Administration) ......................106
6.2.4.
Visits 4, 7, 10, 13, 16, and 19 (Laboratory Visits) .............................................................107
6.2.5.
Visit 5 (Clinic Visit)...........................................................................................................107
6.2.6.
Visits 8, 14, and 17 (Clinic Visits – Rituximab and Bendamustine 
Administration) ..................................................................................................................109
6.2.7.
Visit 11 (Radiology and Clinic Visit – Rituximab and Bendamustine 
Administration) ..................................................................................................................111
6.2.8.
Visit 20 (Radiology and Clinic Visit).................................................................................113
6.2.9.
Visits 21 and 23 (Clinic Visits) ..........................................................................................115
6.2.10.
Visits 22 and 24 (Radiology and Clinic Visits)..................................................................116
6.2.11.
Visit 25 and Subsequent Visits (Every 12 Weeks) 
(Radiology and Clinic Visits).............................................................................................117
6.2.12.
End-of-Study Visit (Clinic Visit) .......................................................................................118
6.2.13.
30-Day and Long-Term Follow-up ....................................................................................119
6.3.
Sample Storage.....................................................................................................................................120
6.4.
Blood Collection ..................................................................................................................................120
6.5.
Study Procedure Rationale...................................................................................................................120
7.
EFFICACY ASSESSMENTS...........................................................................................................................121
7.1.
Tumor Status Assessments...................................................................................................................121
7.2.
Method of Assessment .........................................................................................................................121
7.3.
Timing of Assessments ........................................................................................................................121
7.4.
Identification and Follow-up of Tumor Lesions and Organomegaly ...................................................122
7.4.1.
Index Lesions .....................................................................................................................122
7.4.2.
Spleen and Liver.................................................................................................................123
7.4.3.
Non-Index Lesions .............................................................................................................123
7.5.
Definitions of Tumor Response and Progression.................................................................................124
7.5.1.
Complete Response............................................................................................................124
7.5.2.
Partial Response .................................................................................................................125
7.5.3.
Stable Disease ....................................................................................................................125
7.5.4.
Definitive Progressive Disease...........................................................................................126
7.5.5.
Non-Evaluable....................................................................................................................127
7.5.6.
No Disease .........................................................................................................................127
7.6.
Lymphocytosis During Therapy...........................................................................................................128
7.7.
Documentation of Definitive CLL Progression ...................................................................................128
8.
SAFETY ASSESSMENTS...............................................................................................................................129
8.1.
Adverse Event Definitions ...................................................................................................................129
8.1.1.
Adverse Event ....................................................................................................................129
8.1.2.
Serious Adverse Event .......................................................................................................130
8.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .......................................................................131
8.2.
Assessment of Adverse Events and Serious Adverse Events...............................................................131
8.2.1.
Assessment of Causality for Study Drugs and Procedures.................................................132
8.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.....................................................................................................................132
8.4.
Gilead Reporting Requirements...........................................................................................................133
8.5.
Grading of the Severity of an Adverse Event.......................................................................................133
8.6.
Adverse Event Reporting Period..........................................................................................................134
8.7.
Adverse Event Reporting Requirements ..............................................................................................134
8.7.1.
Site Reporting Requirements..............................................................................................134


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8.7.2.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population.........................................................136
8.8.
Special Situations Reporting Requirements.........................................................................................136
8.8.1.
Definitions of Special Situations........................................................................................136
8.9.
Instructions for Reporting Special Situations.......................................................................................137
8.9.1.
Instructions for Reporting Pregnancies ..............................................................................137
8.9.2.
Reporting Other Special Situations ....................................................................................138
9.
STATISTICAL CONSIDERATIONS..............................................................................................................139
9.1.
Analyis Objectives ...............................................................................................................................139
9.2.
Analysis Endpoints...............................................................................................................................139
9.2.1.
Primary Endpoint ...............................................................................................................139
9.2.2.
Secondary and Tertiary Endpoints .....................................................................................139
9.3.
Analysis Conventions...........................................................................................................................139
9.3.1.
Analysis Sets ......................................................................................................................139
9.3.2.
Data Handling Conventions ...............................................................................................140
9.3.3.
Subject Disposition and Baseline Characteristics...............................................................142
9.3.4.
Efficacy Analyses...............................................................................................................142
9.3.5.
Exposure and Safety Analyses ...........................................................................................145
9.3.6.
Other Analyses ...................................................................................................................147
9.4.
Sample Size..........................................................................................................................................148
9.4.1.
Sample Size Calculation.....................................................................................................148
9.4.2.
Blinded Sample Size Re-estimation...................................................................................149
9.5.
Timing of Analyses..............................................................................................................................149
9.5.1.
Interim Analysis .................................................................................................................149
9.5.2.
Final Efficacy Analysis ......................................................................................................150
9.5.3.
Follow-up Analyses............................................................................................................150
10.
RESPONSIBILITIES........................................................................................................................................151
10.1.
Investigator Responsibilities ................................................................................................................151
10.1.1.
Compliance with Ethical and Regulatory Guidelines.........................................................151
10.1.2.
Institutional Review Board/Independent Ethics Committee ..............................................151
10.1.3.
Informed Consent...............................................................................................................152
10.1.4.
Confidentiality....................................................................................................................152
10.1.5.
Study Files and Retention of Records and Biological Samples..........................................152
10.1.6.
Case Report Forms.............................................................................................................154
10.1.7.
Drug Accountability...........................................................................................................154
10.1.8.
Inspections..........................................................................................................................155
10.1.9.
Protocol Compliance..........................................................................................................155
10.2.
Sponsor Responsibilities ......................................................................................................................155
10.2.1.
Protocol Modifications.......................................................................................................155
10.2.2.
Communications with Regulatory Authorities...................................................................155
10.2.3.
Data Management ..............................................................................................................156
10.2.4.
Study Reporting and Publication........................................................................................156
10.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................157
10.3.1.
Access to Information for Monitoring................................................................................157
10.3.2.
Access to Information for Auditing or Inspections ............................................................157
10.3.3.
Public Notification of Study Conduct ................................................................................157
10.3.4.
Study Discontinuation........................................................................................................157
10.4.
Study Committees ................................................................................................................................158
10.4.1.
Study Steering Committees................................................................................................158
10.4.2.
Data Monitoring Committee ..............................................................................................158
10.4.3.
Independent Review Committee ........................................................................................159


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11.
REFERENCES .................................................................................................................................................160
12.
APPENDICES ..................................................................................................................................................171
Appendix 1.
Investigator Signature Page..................................................................................................172
Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia ........................................................173
Appendix 3.
Performance Status Scoring System.....................................................................................176
Appendix 4.
EuroQoL-5 Dimensions (EQ-5D) ........................................................................................177
Appendix 5.
Cockcroft-Gault Method for Estimating Creatinine Clearance ............................................179
Appendix 6.
CIRS List of Comorbid Conditions......................................................................................180
Appendix 7.
Schedule of Study Procedures..............................................................................................187
LIST OF IN-TEXT TABLES
Table 4-1.
Required Screening Laboratory Values..................................................................................51
Table 5-1.
Planned Dosing Regimen During the Randomized Double-Blind Combination 
Therapy Portion of the Study..................................................................................................66
Table 5-2.
Planned Sequence of Drug Administration on Day 1 and Day 2 of Each Cycle....................67
Table 5-3.
Study Drug (Idelalisib/Placebo) Dose Levels.........................................................................68
Table 5-4.
Reference Drug (Rituximab) Dose Levels .............................................................................69
Table 5-5.
Reference Drug (Bendamustine) Dose Levels........................................................................70
Table 5-6.
Modifications of Study Treatments for Subsequent Cycle Based on Worst Drug-
Related Adverse Events Observed in the Prior Cycle ............................................................72
Table 5-7.
Protocol-Recommended Contraceptive Methods ...................................................................93
Table 5-8.
Known strong inducers of CYP3A.........................................................................................95
Table 6-1.
Procedures and Assessments at Visit 1 (Screening Period)..................................................104
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1) ...................................................................105
Table 6-3.
Procedures and Assessments at Visits 3, 6, 9, 12, 15, and 18 (+1 Day) ...............................106
Table 6-4.
Procedures and Assessments at Visits 4, 7, 10, 13, 16, and 19 (2 Days)............................107
Table 6-5.
Procedures and Assessments at Visit 5 (2 Days)................................................................107
Table 6-6.
Procedures and Assessments at Visits 8, 14, and 17 (2 Days)............................................109
Table 6-7.
Procedures and Assessments at Visit 11 (3 Days)..............................................................111
Table 6-8.
Procedures and Assessments at Visit 20 (3 Days)..............................................................113
Table 6-9.
Procedures and Assessments at Visits 21 and 23 (3 Days) ................................................115
Table 6-10.
Procedures and Assessments at Visits 22 and 24 (3 Days) ................................................116
Table 6-11.
Procedures and Assessments at Visit 25 and Subsequent Visits (Every 12 Weeks 
[7 Days]).............................................................................................................................117
Table 6-12.
Procedures and Assessments at End-of-Study Visit.............................................................118
Table 8-1.
Grading of Adverse Event Severity......................................................................................134
Table 8-2.
Site Reporting Requirements for Adverse Events ................................................................135
Table 8-3.
Contact Information for Reporting Serious Adverse Events ................................................136
Table 9-1.
Boundary-Crossing Probabilities at Interim and Final Analyses Based on the 
Assumptions of the Study.....................................................................................................150
LIST OF IN-TEXT FIGURES
Figure 2-1.
Study Design ..........................................................................................................................35
Figure 5-1.
Kaplan-Meier Time to Diarrhea or Colitis .............................................................................83


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404 USA
Study Title:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Efficacy and Safety of Idelalisib (GS-1101) in Combination 
with Bendamustine and Rituximab for Previously Treated Chronic 
Lymphocytic Leukemia
Study Centers 
Planned:
Approximately 180 centers in North America, South America, 
Australia Pacific and in Europe
IND Number:
EudraCT 
Number:
101254
2011-006292-20
Primary 
Objective:

To evaluate the effect of the addition of idelalisib (formerly GS-1101) to 
bendamustine/rituximab on progression-free survival (PFS) in subjects 
with previously treated chronic lymphocytic leukemia (CLL)
Secondary
Objectives:

To evaluate the effect of the addition of idelalisib to 
bendamustine/rituximab on the onset, magnitude, and duration of tumor 
control

To assess the effect of the addition of idelalisib to 
bendamustine/rituximab on measures of subject well-being, including 
overall survival (OS), health-related quality of life (HRQL), and 
performance status

To assess the effects of the addition of idelalisib to 
bendamustine/rituximab on disease-associated biomarkers and to 
evaluate potential mechanisms of resistance to idelalisib

To characterize the effect of bendamustine/rituximab on idelalisib
exposure through evaluations of idelalisib plasma concentrations over 
time

To describe the safety profile observed with the addition of idelalisib to 
bendamustine/rituximab

To estimate health resource utilization associated with the addition of 
idelalisib to bendamustine/rituximab


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Study Design:
Study GS-US-312-0115 is a Phase 3, multicenter, 2-arm, randomized, 
double-blind, placebo-controlled, parallel-group clinical trial.
Study Schema
Subjects are randomized to double-blind treatment with idelalisib + 
bendamustine/rituximab or placebo + bendamustine/rituximab for 24 weeks, 
and then receive double-blind continuing therapy with idelalisib or placebo 
until disease progression. Following a decision to unblind the study based on 
the interim analysis results and DMC recommendation, subjects randomized 
to Arm A (idelalisib + bendamustine/rituximab) may continue study 
treatment with idelalisib, whereas subjects randomized to Arm B (placebo + 
bendamustine/rituximab) should discontinue placebo tablets.
Treatment Groups

Arm A: Idelalisib + bendamustine/rituximab

Arm B: Placebo + bendamustine/rituximab
Randomization and Stratification

1:1 allocation to Arm A vs Arm B with implementation through an 
interactive web response system (IWRS)

Fixed-block centralized randomization with allocation of subjects within 
the 8 strata as defined by the intersection of 3 binary stratification 
factors:
17p deletion and/or p53 mutation in CLL cells:
either vs neither (or indeterminate)
Immunoglobulin heavy chain variable region (IgHV) mutation:
unmutated (or IgHV3-21) vs mutated (or indeterminate)
Disease status: refractory (CLL progression <6 months from 
completion of prior therapy) vs relapsed (CLL progression 
6 months from completion of prior therapy)
screening 
ArmB 
Study 
St•dy GS-US-312-0115 
Randomlz~d 
Double-Blind 
Initial Therapy 
Double-Blind 
Continuing Therapy 
Off-Study Survival 
Follow-up 
Post~Study 
Th.,rapy 
lnvestlpte,r,' dlOlcei 
of comrNrdal or 
lnwstlpdon•I th.,.PV 
Stratification and 
Randomization 
Abbrevl'1fon$: S=bondamus.lin e-, BIO= twice P4)rd;ty, C=-cycle, R=rituximab 
• Followine ii diedsion to unblind the study based on the interim ;analysis. results, subjects randoml-zed to Arm 8 should 
discontinue placebo tablets and cont inue with study procedures per protocol 


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Number of
Subjects 
Planned:
Total of ~390 subjects (~195 subjects per treatment arm)
Target 
Population:
Adult subjects with previously treated recurrent CLL who have measurable 
lymphadenopathy; require therapy for CLL; have received prior therapy 
containing a purine analog or bendamustine and an anti-CD20 monoclonal 
antibody; are not refractory to bendamustine; have experienced CLL 
progression <36 months since the completion of the last prior therapy; and 
are currently sufficiently fit to receive cytotoxic therapy.
Duration of 
Treatment:
Study drug (idelalisib/placebo) 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. Subjects 
who are tolerating study drug (idelalisib/placebo) should continue study 
drug even if bendamustine or rituximab must be discontinued due to 
bendamustine- or rituximab-related toxicities. Idelalisib administration 
should be continued in subjects without disease progression and in those 
with a positive benefit-risk profile assessment as per the investigator.
Rituximab will be administered until the earliest of a maximum of 
6 infusions, subject withdrawal from study, definitive progression of CLL, 
intolerable rituximab-related toxicity, pregnancy, substantial noncompliance 
with study procedures, or study discontinuation.
Bendamustine will be administered until the earliest of a maximum of 
12 infusions, subject withdrawal from study, definitive progression of CLL, 
intolerable bendamustine-related toxicity, pregnancy, substantial 
noncompliance with study procedures, or study discontinuation.
Following a decision to unblind the study based on the interim analysis 
results and DMC recommendation, treatment assignments will be unblinded. 
Subjects randomized to Arm A (idelalisib +bendamustine/rituximab) may 
continue study treatment with idelalisib, whereas subjects randomized to 
Arm B (placebo + bendamustine/rituximab) should discontinue placebo 
tablets and continue with study procedures per protocol.
Diagnosis and 
Main 
Eligibility 
Criteria:
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for 
participation in this study:
1) Male or female 18 years of age.
2) Diagnosis of B-cell CLL, with diagnosis established according to 
International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 
criteria and documented within medical records.


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3) CLL that warrants treatment (consistent with accepted IWCLL criteria 
for initiation of therapy). Any of the following conditions constitute CLL 
that warrants treatment:
a) Evidence of progressive marrow failure as manifested by the onset or 
worsening of anemia and/or thrombocytopenia, or
b) Massive (ie, lower edge of spleen 6 cm below the left
costal margin), progressive, or symptomatic splenomegaly, or
c) Massive (ie, 10 cm in the longest diameter), progressive, or 
symptomatic lymphadenopathy, or
d) Progressive lymphocytosis in the absence of infection, with an 
increase in blood absolute lymphocyte count (ALC) 50% over a 
2-month period or lymphocyte doubling time of <6 months (as long 
as initial ALC was 30,000/µL), or
e) Autoimmune anemia and/or thrombocytopenia that is poorly 
responsive to corticosteroids or other standard therapy, or
f)
Constitutional symptoms, defined as any one or more of the 
following disease-related symptoms or signs occurring in the absence 
of evidence of infection:
i)
Unintentional weight loss of 10% within the previous 6 months, 
or
ii) Significant fatigue (Grade 2), or
iii) Fevers >100.5°F or 38.0°C for 2 weeks, or
iv) Night sweats for >1 month.
4) 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]).
5) Prior treatment for CLL comprising:
a) 2 cycles of a regimen containing a purine analog (eg, fludarabine, 
pentostatin, cladribine) or bendamustine, and
b) 2 doses with a regimen containing an anti-CD20 monoclonal
antibody (eg, rituximab, ofatumumab, GA-101) Note: Prior 
cytotoxic drugs or anti-CD20 antibodies may have been 
administered as single agents or as components of combination 
therapies. Subjects may also have received other commercially 
available therapies (eg, alemtuzumab, lenalidomide, 
corticosteroids, or others) or non-excluded investigational 
therapies. Each repeated but separated therapeutic application of 
the same single-agent or combination is considered an independent 
regimen.


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6) Documentation of CLL progression <36 months since the completion of 
the last prior therapy for CLL.
7) Discontinuation of all therapy (including radiotherapy, chemotherapy, 
immunotherapy, or investigational therapy) for the treatment of CLL 
3 weeks before randomization. Note: Subjects may receive 
corticosteroids to manage CLL manifestations.
8) All acute toxic effects of any prior antitumor therapy resolved to 
Grade 1 before randomization (with the exception of alopecia [Grade 1 
or 2 permitted], neurotoxicity [Grade 1 or 2 permitted], or bone marrow 
parameters [Grades 1 or 2 permitted]). 
9) Karnofsky performance score of ≥60.
10) Required baseline laboratory data (within 4 weeks prior to randomization) 
as shown in the following table. 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.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hematopoietic
ANC
1.5 x 109/La
Platelets
75 x 109/La
Hemoglobin
100 g/L (10.0 g/dL or 6.2 mmol/L)a
Hepatic
Serum total bilirubin
1.5 x ULN
(unless elevated due to
Gilbert’s syndrome or hemolysis)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCr
b
40 ml/min
Pregnancy
-HCGc
Negative
Infection
HIV
Negative HIV antibody
HBV
Negative HBsAg and negative HBc antibody 
or positive HBc and negative for HBV DNA 
by quantative PCR
HCV
Negative viral RNA
(if HCV antibody is positive)
a
Grade 2 neutropenia, thrombocytopenia, or anemia is permitted if abnormality is related to bone 
marrow involvement with CLL (as documented by bone marrow biopsy/aspirate obtained since 
the last prior therapy).
b
As calculated by the Cockcroft-Gault formula {Cockcroft 1976}
c
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, 
ANC=absolute neutrophil count, AST=aspartate aminotransferase, DNA=deoxyribonucleic acid, 
eCCr=estimated creatinine clearance, HBc antibody=anti-hepatitis B core antibody, HBsAg=hepatitis 
B surface antigen, HBV=hepatitis B virus, HCV=hepatitis C virus, HIV=human immunodeficiency 
virus, Ig=immunoglobulin, PCR=polymerase chain reaction, RNA=ribonucleic acid, 
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11) 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 or >12 months from the last dose of rituximab (whichever is later).
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 with amenorrhea for 
>12 months or amenorrhea for >6 months with serum estradiol and 
FSH levels within the institutional postmenopausal range).
12) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the randomization 
visit (Visit 2) throughout the study and until >6 months following the 
last dose of bendamustine or >90 days following the last dose of study 
drug (whichever is later) and to refrain from sperm donation from 
randomization (Visit 2) throughout the study and until >6 months 
following the last dose of bendamustine or >90 days following the 
last dose of study drug (whichever is later). 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®]).
13) In the judgment of the investigator, participation in the protocol offers an 
acceptable benefit-to-risk ratio when considering current CLL disease 
status, prior treatment history, medical condition, and the potential 
benefits and risks of alternative treatments for CLL. Note: Investigators 
should consider whether a study subject is an appropriate candidate 
for bendamustine-containing therapy based on the number and 
severity of comorbid conditions; subjects with a baseline Cumulative 
Illness Rating Scale (CIRS) score of 6 may be particularly 
appropriate candidates for this trial.
14) Willingness and ability to comply with scheduled visits, drug 
administration plan, imaging studies, laboratory tests, other study 
procedures, and study restrictions. Note: Psychological, social, familial, 
or geographical factors that might preclude adequate study 
participation should be considered.


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15) Evidence of a personally signed informed consent indicating that the 
subject is aware of the neoplastic nature of the disease and has been 
informed of the procedures to be followed, the experimental nature of 
the therapy, alternatives, potential benefits, possible side effects, 
potential risks and discomforts, and other pertinent aspects of study 
participation.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be 
enrolled in this study:
1) Known histological transformation from CLL to an aggressive 
lymphoma (ie, Richter transformation). Note: Biopsy documentation of 
the absence or presence of transformation is not required.
2) Known presence of intermediate- or high-grade myelodysplastic 
syndrome (ie, subjects are excluded who have 5% bone marrow blasts; 
karotypic abnormalities other than normal, Y deletion, 5q deletion, 
or 20q deletion; or 2 lineages of cytopenias due to myelodysplasia).
3) History of a non-CLL malignancy except for the following: adequately 
treated local basal cell or squamous cell carcinoma of the skin, cervical 
carcinoma in situ, superficial bladder cancer, asymptomatic prostate 
cancer without known metastatic disease and with no requirement for 
therapy or requiring only hormonal therapy and with normal 
prostate-specific antigen for 1 year prior to randomization, other 
adequately treated Stage 1 or 2 cancer currently in complete remission, 
or any other cancer that has been in complete remission for ≥5 years. 
4) Evidence of ongoing systemic bacterial, fungal, or viral infection at the 
time of randomization (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. 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.
5) Ongoing drug-induced liver injury, chronic active hepatitis C (HCV), 
chronic active hepatitis B (HBV), alcoholic liver disease, non-alcoholic 
steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused 
by cholelithiasis, cirrhosis of the liver, or portal hypertension.
6) Ongoing drug-induced pneumonitis.
7) Ongoing inflammatory bowel disease.


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8) Ongoing alcohol or drug addiction.
9) Pregnancy or breastfeeding.
10) History of prior allogeneic bone marrow progenitor cell or solid organ 
transplantation.
11) Ongoing immunosuppressive therapy other than corticosteroids. 
Note: Subjects may use topical, enteric, inhaled, or systemic 
corticosteroids as therapy for manifestations of CLL, comorbid 
conditions, or autoimmune anemia and/or thrombocytopenia. During 
study participation, subjects may receive systemic or other 
corticosteroids as pretreatment for rituximab infusions or as needed 
for treatment-emergent comorbid conditions.
12) In a subject with a history of prior bendamustine therapy, a time interval
from the last dose of bendamustine to the subsequent CLL progression 
of <6 months.
13) History of prior therapy with any inhibitor of AKT, Bruton tyrosine 
kinase (BTK), Janus kinase (JAK), mammalian target of rapamycin 
(mTOR), phosphatidylinositol 3-kinase (PI3K) (including idelalisib), 
or spleen tyrosine kinase (SYK).
14) History of anaphylaxis in association with previous administration of 
monoclonal antibodies.
15) Concurrent participation in another therapeutic clinical trial.
16) Prior or ongoing clinically significant illness, medical condition, surgical 
history, physical finding, electrocardiogram (ECG) finding, or laboratory 
abnormality that, in the investigator’s opinion, could adversely affect the 
safety of the subject or impair the assessment of study results.
Study 
Procedures/
Frequency:
Subjects will be randomized with a 1:1 ratio into 1 of the 2 treatment arms. 
Idelalisib or placebo will be taken orally, BID continuously. After 
study-wide unblinding, placebo will no longer be administered.
Subjects will be administered rituximab in the clinic on Day 1 of each 
28-day cycle through Cycle 6. Subjects will be administered bendamustine 
on Days 1 and 2 of each 28-day cycle through Cycle 6.
Clinic/laboratory visits will occur every 2 weeks through Week 24 and every 
6 weeks between Weeks 24 and 48. Subjects who continue on study drug
past Week 48 will have clinic visits every 12 weeks (as well as CMV testing 
approximately every 4 weeks). Subjects will be assessed for safety at each 
clinic visit. Subjects will be assessed for CLL disease status by physical and 
laboratory examinations at each clinic visit and by CT or MRI at Weeks 12, 
24, 36, and 48 and every 12 weeks thereafter. As of Amendment 10, 
Version 11, CT/MRI assessments will no longer be performed at the every 
12 week scheduled visits, and will only be performed at the time of 
clinically-suspected disease progression or at study discontinuation.


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Test Therapy, 
Dose, and 
Mode of 
Administration:

Idelalisib: 150 mg/dose or placebo taken orally BID starting on Day 1 
and administered continuously thereafter. After study-wide unblinding, 
placebo will no longer be administered. 
Reference 
Therapy, Dose, 
and Mode of 
Administration:

Rituximab: 375 mg/m2 intravenously on Day 1 of the first 28-day cycle 
of treatment; followed by 500 mg/m2 intravenously on Day 1 of each of 
5 further 28-day cycles of treatment (up to 6 total cycles as tolerated)

Bendamustine: 70 mg/m2/dose intravenously on Day 1 and Day 2 of 
each 28-day cycle (up to 6 total cycles as tolerated)
Criteria for 
Evaluation:
Primary Endpoint

Progression-free survival (PFS) – defined as the interval from 
randomization 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.
Secondary and Tertiary Endpoints
Four endpoints are designated as secondary endpoints for which sequential 
testing will be performed to control Type 1 error rate. Secondary endpoints 
will be ORR, lymph node response rate, OS, and CR rate. All other 
endpoints will be considered tertiary.
Tumor Control

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
CCI


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Patient Well-Being

Overall survival (OS) – defined as the interval from randomization to 
death from any cause 
CCI
CCI


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Statistical 
Methods:
Analysis Methods
Appropriate data analysis sets will be defined. The intent-to-treat (ITT) 
analysis set will be used in the analyses of the primary efficacy endpoint, 
PFS. The ITT analysis set will include data from all subjects who are 
randomized with study drug (idelalisib/placebo) assignment designated 
according to initial randomization. A safety analysis set will comprise data 
from subjects who receive 1 dose of study drug. Other analysis sets 
[per-protocol and pharmacodynamic/pharmacokinetic data analysis] 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.
CCI


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An IRC will review radiographic data and pertinent clinical data in order to 
provide expert evaluation of tumor status. The findings of the IRC will be 
considered primary for analyses of PFS and other tumor control endpoints.
For the primary efficacy analysis, the difference in PFS between the 
treatment arms will be assessed in the ITT analysis set using Kaplan-Meier 
methods and the stratified log-rank test. Medians, ranges, the proportion of 
subjects who are progression-free at 24 and 48 weeks from randomization 
(based on Kaplan-Meier estimates), hazard ratios, and the corresponding 
95% confidence intervals (CIs) (as calculated using a Cox proportional 
hazards regression model) will be presented.
Secondary endpoints will be ORR, lymph node response rate, CR rate, and 
OS. The primary efficacy hypothesis relating to PFS must be rejected at the 
2-sided 0.05 significance level before the efficacy hypotheses for these 
secondary efficacy endpoints are tested. These 4 secondary endpoints will be 
tested at the 2-sided 0.032 significance level in the order listed. If a null 
hypothesis is not rejected, formal sequential testing will be stopped and only 
nominal significance will be cited for the remaining secondary endpoints.
For secondary or tertiary endpoints relating to tumor control, patient 
well-being, and biomarkers, analyses will be done based on the ITT, PP, or 
pharmacodynamic data sets, as appropriate. Time-to-event efficacy 
endpoints will be analyzed in a similar manner as PFS.
Categorical variables will be compared using the Cochran-Mantel-Haenszel 
test adjusted for stratification factors. Continuous endpoints will be assessed 
using analysis of covariance (ANCOVA) with baseline values and 
stratification factors as covariates. Changes from baseline in HRQL 
parameters and in performance status will be compared between the 
treatment groups using the Wilcoxon rank-sum test.
Information from the safety analysis set 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
Based on data from prior studies, it is reasonable to assume that 
administration of bendamustine/rituximab to subjects with previously treated 
CLL in Arm B of this trial will result in a median PFS of ~15 months. An 
improvement in median PFS from 15 months to 22.5 months due to the 
addition of idelalisib to bendamustine/rituximab in Arm A of the study 
would correspond to a benefit ratio of 1.5 (hazard ratio 0.67).
It is assumed that PFS times are exponentially distributed in each of the 
2 arms. With a hazard ratio equal to 1 under the null hypothesis of no 
difference between the 2 treatment arms and a hazard ratio of 0.67 under the 


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alternative hypothesis of superiority of the idelalisib-containing 
combination, 260 events (definitive CLL progressions or deaths) are 
required to achieve a power of 0.90 based on a stratified log-rank test with a 
2-sided significance level of 0.05. Further assuming a planned accrual period 
of 18 months (with approximately half of the subjects enrolled during the 
initial 60% of the accrual period, and the remaining half of the subjects 
enrolled during the last 40% of the accrual period), a minimum follow-up 
period of 24 months, and an expectation that 15% of subjects will be lost to 
follow-up (7% during the accrual period and 8% during the follow-up 
period), ~195 subjects per treatment arm (~390 total) are to be enrolled in 
order to achieve the expected number of events by the end of the planned 
minimum 24-month follow-up period.
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
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 Drug Safety and Public Health
ECG
electrocardiogram
eCCr
estimated creatinine clearance


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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
K2-EDTA
potassium-ethylenediaminetetraacetic acid


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LD
longest diameter
LDH
lactate dehydrogenase
LH-RH
luteinizing hormone-releasing hormone
LLN
lower limit of normal
LPD
longest perpendicular diameter
LVD
longest vertical dimension
MTD
maximum tolerated dose
MCL
mantle cell lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mTOR
mammalian target of rapamycin
ND
no disease
NHL
non-Hodgkin lymphoma
NOAEL
no-observed-adverse effect level
NOEL
no-observed-effect level
OCT
organic cation transporter
ORR
overall response rate
OS
overall survival
pAKT
phosphorylated AKT
PCR
polymerase chain reaction
PD
progressive disease
PET
positron-emission tomography
PI3K
phosphatidylinositol 3-kinase
PI3K
phosphatidylinositol 3-kinase p110isoform
PFS
progression-free survival
PJP
Pneumocystis jirovecii 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
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
SJS
Steven’s- Johnson Syndrome
SPD
sum of the products of the perpendicular diameters of measured lymph nodes


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SSC
Study Steering Committee
SUSAR
suspected, unexpected, serious adverse reaction
SYK
spleen tyrosine kinase
t1/2
half-life
Tmax
time of maximum concentration
TEN
toxic epidermal necrolysis
TTR
time to response
UGT
uridine 5'-diphospho-glucuronosyltransferase
ULN
upper limit of normal
US
United States
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 neoplastic condition resulting from the progressive 
accumulation of functionally incompetent monoclonal B lymphocytes in blood, bone marrow, 
lymph nodes, spleen, and liver {Dighiero 2008}. CLL constitutes the most commonly occurring 
leukemia in the United States (US) and Europe {Sant 2010, Surveillance Epidemiology and End 
Results (SEER) Program 2011}. While some patients never require treatment, many will need 
therapy for disfiguring or obstructing lymphadenopathy, debilitating constitutional B symptoms 
(fevers, night sweats, fatigue, weight loss) {Redaelli 2004}, or recurrent cytopenias and 
infections {Keating 2002b, Perkins 2002}. CLL is largely a disease of the elderly; at diagnosis, 
70% of patients are 65 years of age and the median age is 72 years {Surveillance Epidemiology 
and End Results (SEER) Program 2011}.
In patients with treatment-naive CLL, chemotherapy or chemoimmunotherapy are commonly 
employed to control disease manifestations {Gribben 2011}. Such therapies typically contain 
some combination of a purine analog, an alkylating agent, and an anti-CD20 monoclonal 
antibody (eg, rituximab) and can be effective in providing durable remissions {Byrd 2005, 
Catovsky 2007, Hallek 2010, Robak 2010}. However, these treatments are not curative; the 
disease will eventually relapse and further intervention is required to obtain and maintain tumor 
control. If the interval from prior therapy to disease progression has been long (24 to 36 months),
retreatment with the previous regimen is advocated {Eichhorst 2010, Zelenetz 2011}. However, 
if the interval from prior therapy has been shorter (<24 to 36 months), it is presumed that 
resistance to the previously administered cytotoxic agent is likely and that a change in therapy is 
warranted.
Bendamustine is an alkylating agent with a unique chemical structure that has seen increasing 
use in the therapy of lymphoid malignancies {Kalaycio 2009}. The drug was approved for the 
treatment of CLL in Europe and in the US based on positive results of randomized Phase 3 trial 
showing substantially improved tumor control with bendamustine alone compared with 
chlorambucil alone in previously untreated patients {Knauf 2009}. However, the 
pharmacological profile of bendamustine suggested that it might also be useful in patients with 
disease that had become resistant to other cytotoxic agents {Jamshed 2009}. Preclinical data 
indicated that bendamustine has distinctive activity in cell lines resistant to other alkylators 
{Kalaycio 2009} and clinical findings showing substantial activity in patients with indolent 
non-Hodgkin lymphoma (iNHL) refractory to alkylating agents or purine analogs {Friedberg 
2008}.
Application of bendamustine in patients with previously treated CLL was explored in a Phase 1 
dose-ranging study that included patients who had received prior fludarabine {Lissitchkov 
2006}. The starting dose regimen of 100 mg/m2 on Days 1 and 2 of each 4-week treatment cycle
was the same as had been employed in the Phase 3 registration trial in previously untreated 
patients {Knauf 2009}. In the Phase 1 study in previously treated patients it was found that the
planned starting dose of 100 mg/m2 was intolerable due to myelotoxicity and infection. 


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Sequential dose-de-escalation was performed in 10-mg/m2 decrements (with dose levels 
including 100, 90, 80, and 70 mg/m2). The data confirmed a maximum tolerated dose (MTD) of 
70 mg/m2 but showed that this starting dose level was still associated with antitumor activity in 
the majority of patients.
These findings led to efforts to combine bendamustine with rituximab as therapy for previously 
treated CLL. In a prospective Phase 2 study of the German CLL Study Group, 78 patients 
received bendamustine 70 mg/m2on Day1 and 2 in 6 planned 4-week cycles. Study participants 
also received rituximab at the beginning of each cycle, with planned doses of 375 mg/m2 in the 
first cycle and 500 mg/m2 in the 5 subsequent cycles {Fischer 2011}. The overall response rate 
(ORR) was 59% and progression-free survival (PFS) was 15.2 months. The best positive 
predictors of improved tumor control were absence of a 17p deletion and mutated 
immunoglobulin heavy chain variable region (IgHV) in malignant cells. The clinical data from 
this trial were supported by an Italian retrospective analysis of 109 patients with previously 
treated CLL receiving bendamustine/rituximab (N=87) or bendamustine monotherapy (N=22)
{Iannitto 2011}. Among those administered bendamustine/rituximab, 63% ORR was observed.
Median PFS was reported at 16 months. The results indicated that patients with relapsed disease 
had substantially better outcomes than those with refractory CLL. Myelotoxicity was the major 
reported adverse event reported in both series and was more prominent among patients with 
comorbidities such as renal dysfunction {Fischer 2011}.
These data have supported adoption of bendamustine/rituximab therapy in current treatment 
guidelines as a standard of care for previously treated patients who are sufficiently fit to receive 
cytotoxic therapy {Eichhorst 2010, Zelenetz 2011}. Based on the deliberations of an 
international panel of expert hematologists, a bendamustine starting dose of 70 mg/m2 has been 
considered appropriate when the drug is coadministered with rituximab in patients who had 
received prior therapy {Cheson 2010}
However, while the bendamustine/rituximab combination offers benefit, tumor response is not 
universal and progressive disease eventually develops in all patients. New non-myelosuppressive, 
well-tolerated, and convenient therapies that can be successfully combined with 
bendamustine/rituximab are needed in order to enhance and prolong tumor control.
1.2.
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies
Phosphatidylinositol 3-kinases (PI3Ks) are enzymes that regulate several cellular functions 
including motility, proliferation, and survival {Okkenhaug 2003b}. PI3K activation recruits and 
activates numerous intracellular signaling enzymes. The most important of these is the 
serine/threonine kinase, AKT, which mediates a positive pleiotropic effect on cell survival, 
proliferation, growth, and metabolism {Engelman 2006} acting by signaling through mammalian 
target of rapamycin (mTOR) {Hay 2005, Osaki 2004}.
PI3K signaling is mediated by 4 catalytic isoforms of the p110 subunit of the enzyme –
, , , and . While potentially important in multiple cell types, PI3K p110(PI3K) shows an 
expression pattern that is particularly prominent in cells of hematopoietic origin 
{Vanhaesebroeck 2005}. Mice deficient in PI3Khave no gross abnormalities, are fertile, 


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fecund, and live a normal life span without an increased susceptibility to infections {Okkenhaug 
2003a}. However, the B-lymphocyte population in these animals shows a decrease in maturation, 
diminished receptor-induced proliferation, and increased susceptibility to apoptotic cell death.
Conversely, mice with aberrantly elevated PI3K signaling develop lymphadenopathy and have 
an increased incidence of lymphoma {Donahue 2004}. In CLL, sustained activation of the 
PI3K/AKT pathway has been shown to promote malignant B-cell survival through mechanisms 
that are dependent on the PI3Kisoform {Cuni 2004, Herman 2010, Lannutti 2011}.
Knowledge of the critical importance of PI3Kδ in B-cell biology and neoplasia has encouraged a 
search for inhibitors of this enzyme that could provide new options in the therapy of lymphoid 
malignancies, including CLL.
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, a 415-dalton, orally bioavailable, new chemical entity with 
potential clinical utility in the treatment of cancers.
In primary tumor samples and in cell lines derived from patients with CLL, indolent
non-Hodgkin lymphoma (iNHL), mantle cell lymphoma (MCL), B-cell acute lymphocytic 
leukemia (ALL), or Hodgkin lymphoma (HL), idelalisib induces dose-dependent reductions in 
AKT phosphorylation {Herman 2010, Lannutti 2011, Meadows 2010}. In addition, idelalisib
disrupts the PI3Kactivation and supportive intercellular signaling observed when CLL or HL 
cells are cocultured with stromal cells {Hoellenriegel 2011, Meadows 2010}. These effects have 
therapeutic consequences. In multiple lymphoid primary tumors and malignant cell lines, 
idelalisib enhances apoptosis and concentration-dependent cell killing when applied as a 
single agent and increases the therapeutic efficacy of other antineoplastic agents when given in 
combination {Hoellenriegel 2011, Meadows 2011}. In preclinical systems, coadministration of 
idelalisib with rituximab has not impaired rituximab-mediated activity {Herman 2010}.
1.3.2.
Safety Pharmacology
In vitro and in vivo safety pharmacology studies with idelalisib have demonstrated a favorable 
non-clinical safety profile. These studies indicate that the drug may minimally slow bone marrow 
progenitor proliferation and differentiation and that it has expected inhibitory effects on B-cell
response to antigen challenge. However, the data indicate that idelalisib is unlikely to cause 
serious off-target effects or adverse effects on critical organ systems. Idelalisib has no 
meaningful effect on the human ether-à-go-go-related gene (hERG) channel, indicating that 
idelalisib would not be expected to induce clinical QT prolongation.


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The drug has also proved well tolerated in standard in vivo Good Laboratory Practice (GLP) 
studies of pharmacological safety. A functional observation battery in rats revealed no adverse 
effects on behavior or on autonomic, neuromuscular, or sensorimotor function. In a 
cardiopulmonary function study in awake, telemeterized male beagle dogs, single doses of 
idelalisib induced no meaningful abnormalities in pulmonary, cardiovascular, arterial blood gas, 
or electrocardiographic (ECG) (including QT interval) parameters. In an assessment of bacterial 
challenge in rats, idelalisib enhanced, rather than impaired, the phagocytic host clearance of 
staphylococcal bacteria.
1.3.3.
Nonclinical Pharmacology and Metabolism
Consistent with the moderate to high bioavailability seen in nonclinical species, idelalisib shows 
high permeability across human Caco-2 cell monolayers.  At lower concentrations, the reverse 
permeability at low concentration exceeds forward permeability, indicating efflux driven by 
transporters (for 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 
(a 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 (the only circulating metabolite,
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 
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Idelalisib is not an inhibitor of CYP1A, CYP2B6, CYP2C9, and CYP2D6, and at concentrations 
above those observed clinically, is an inhibitor of CYP2C8 (IC50 = 13 µM), CYP2C19 
(IC50 = 76 µM), and CYP3A (IC50 = 44 µM). GS-563117 is not an inhibitor of CYP1A, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and a competitive and time dependent 
inhibitor of CYP3A (IC50 = 3.1 µM), (KI = 0.18 µM, kinact = 0.033 min-1 with midazolam as the 
probe substrate).
In vitro, idelalisib is not an inhibitor of the transporters BCRP, OCT2, OAT1, and OAT3, and is 
an inhibitor of MDR1 (IC50 = 7.7 µM), OATP1B1 (IC50 = 10.1 µM), OATP1B3 (IC50 = 7.0 µM), 
and, at concentrations above those observed clinically, of glucuronosyltransferase UGT1A1 
(IC50 = 42.0 µM). GS-563117 is not an inhibitor of MDR1, BCRP, OATP1B1, OATP1B3, 
OAT1, OAT3, and OCT2, and at concentrations above those observed clinically, an inhibitor of 
UGT1A1 (IC50 = 16.8 µM).
Idelalisib does not activate human AhR or induce CYP1A2 [messenger RNA (mRNA) or 
activity] at clinically relevant concentrations. Idelalisib is a weak activator of human PXR 
(EC50 = 18 µM) and shows similarly weak potency as an inducer of CYP3A4, CYP2C8, 
CYP2C9, UGT1A1, and MDR1 (by mRNA). Approximately 2-fold weaker induction of 
CYP2B6 activity and mRNA suggests weak activation of CAR.  GS-563117 shows no induction 
of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP3A, UGT1A1, UGT1A4, MDR1, and 
aldehyde oxidase at clinically relevant concentrations.
Any potential clinical implications of these metabolism studies are being evaluated in a formal 
drug-drug interaction study (GS-US-313-0130) which is evaluating the effect of idelalisib on 
cytochrome P450 3A and the drug transporters P-gp, OATP1B1, and OATP1B3. Study
GS-US-313-0130 will also evaluate the impact of an inducer of metabolizing enzymes and 
transporters (rifampin) on the PK of idelalisib in healthy human subjects. Preliminary 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.


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Further details on the toxicology of idelalisib can be found in the Idelalisib Investigator’s
Brochure (IB).
1.3.5.
Idelalisib Clinical Studies
1.3.5.1.
Phase 1 Studies in Healthy Subjects and in Patients with Allergic Rhinitis
Various studies in healthy subjects have evaluated safety, pharmacokinetics, food effect, and the 
potential for drug interactions of idelalisib with CYP3A4 inhibitors {Webb 2010}. Safety results 
from these studies indicated that idelalisib was well tolerated when administered to healthy 
subjects at single doses through 400 mg (the highest dose level tested) and was also generally 
well tolerated when administered to healthy subjects over 7 days at dose levels through 
200 mg/dose BID (the highest dose level tested). Dosing with 200 mg/dose BID for 7 days 
resulted in a skin rash in 3 out of 6 subjects; histological findings were consistent with a 
delayed-type hypersensitivity maculopapular exanthema. Rashes have sometimes occurred in 
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 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 primarily metabolized in humans 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, were observed, 
indicating that idelalisib is not a sensitive substrate for CYP3A4. Thus, coadministration of 
CYP3A4 inhibitors and idelalisib is not contraindicated and does not require special monitoring.
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, was the primary/only 
circulating metabolite observed in human plasma, and 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 
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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 to CYP3A to overall idelalisib clearance under the 
induced state.
Pharmacodynamic results showed that a idelalisib dose of 200 mg inhibited ex vivo basophil 
activation via the PI3K-specific, high-affinity immunoglobulin (Ig)E receptor (anti-FCR1) in 
basophils collected from healthy volunteers. The findings were confirmed when the drug was 
assessed over 7 days in a Phase 1b study in subjects with allergic rhinitis. In this study, idelalisib
at a dose level of 100 mg/dose BID showed clinical and pharmacodynamic activity 
(attenuating adverse responses to allergenic challenge and decreasing markers of inflammation) 
and was well tolerated.
1.3.5.2.
Phase 1 Studies in Patients with Hematological Malignancies
1.3.5.2.1.
Phase 1 Monotherapy Study in Patients with Hematological Malignancies
(Study 101-02)
A Phase 1 dose-ranging study (Study 101-02) of single-agent idelalisib extended safety and 
pharmacokinetic observations; documented the clinical and pharmacodynamic activity of 
idelalisib in subjects with iNHL, MCL, and CLL; and provided dosing information in support of 
further development {Brown 2011, Coutre 2011, Kahl 2011}. In this study, idelalisib was 
administered in cohorts of subjects across a range of dose levels from 50 mg/dose BID to 
350 mg/dose BID. Idelalisib administration was continued as long as individual subjects were 
safely benefitting from therapy. Subjects were evaluated in 4-week cycles; response and 
progression assessments were based on standard criteria {Hallek 2008}.
A total of 191 subjects were enrolled to the study at dose levels of 50 mg BID (n=17), 
150 mg QD (n=16), 100 mg BID (n=25), 150 mg BID (n=45), 200 mg BID (n=35), 
350 mg BID (n=17), and 300 mg QD (n=19). An additional cohort was also enrolled to receive 
idelalisib 150 mg BID in 28 day cycles (21 days on idelalisib/7 days off [n=17]), Patients 
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 
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Other Grade ≥3 events included rash in 3 (1.6%) subjects. The relative contributions of 
disease-related factors, toxicity from prior therapies or ongoing supportive care, and idelalisib to 
these events was not clear.
Grade ≥3 hematological laboratory abnormalities have included neutropenia, n=46 (24%); 
thrombocytopenia, n=27, (14%), anemia, n=14 (7.3%), and lymphopenia 13 (6.8%); with 
12 subjects (6.3%) having febrile neutropenia. The occurrence of these events was greater in 
subjects with leukemia, particularly in those with pre-existing hematological abnormalities due 
to disease or prior therapy, commonly making attribution of these events to idelalisib uncertain.
Consistent with the observations in the 28-day dog toxicology study, reversible Grade ≥3 
ALT/AST elevations occurred in 28 (15%) subjects and have been attributed to idelalisib. Onset 
generally occurred between 2 to 16 weeks after idelalisib initiation and resolution was usually 
seen 2 to 6 weeks after idelalisib interruption.  After resolution of ALT/AST increases, 
14 subjects were rechallenged at the same or a reduced dose of idelalisib and 9 (64%) of these 
subjects were able to resume treatment without recurrence of transaminase elevations. 
Two (1.0%) subjects had ≥ 2 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 parameters computed from plasma samples collected on Days 1 and 28
demonstrated that there was no appreciable accumulation or loss of exposure with repeated 
dosing. At both Days 1 and 28, the increase in Cmax and AUC0-6h with dose was less than 
dose-proportional, with minimal incremental 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 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.
 
 
In subjects with CLL, idelalisib reduced lymphadenopathy in the majority of 54 subjects with 
≥1 post-treatment tumor assessment; 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 some subjects; increases were maximal during the 
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first 2 cycles and decreased thereafter; the pattern suggested drug-mediated lymphocyte 
redistribution. The ORR was 53.7% (all PR). 
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 bendamustine or bendamustine-rituximab to subjects with 
recurrent iNHL or CLL {de Vos 2011, Sharman 2011}.
In this study, 28 patients with CLL received idelalisib with bendamustine alone (n=14) or with 
bendamustine/rituximab (n=14). Bendamustine doses were 70 or 90 mg/m2 on Days 1 and 2 of 
each of 6 planned 4-week cycles. Rituximab was infused at a dose of 375 mg/m2 on Day 1 of 
each of the 6 planned 4-week cycles. Idelalisib was first evaluated at a dose level of 
100 mg/dose BID (n=4) and then at a dose level of 150 mg/dose BID (n=24) and was 
administered continuously for as long as individual subjects were safely benefiting from therapy. 
Subjects were evaluated in 4-week cycles; response and progression assessments were based on 
standard criteria {Hallek 2008}.
Among the subjects with CLL, the median age was 65 and ranged to 86 years. Bulky tumors 
(1 lymph node 5 cm in diameter) were present in 64% of the subjects. The median number of 
prior therapies 3 and ranged up to 9 prior treatments. The substantial majority (>90%) had 
received prior purine analogs, alkylating agents, and rituximab and 36% had received prior 
bendamustine. Approximately half 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 6 cycles, 
ranging up to 17 cycles (ie, 68 weeks).
No idelalisib-related dose-limiting toxicities were observed within the tested subject cohorts. 
Grade 3 neutropenia was observed in 11 (40%) of patients and only 1 (4%) patient had febrile 
neutropenia. Grade 3-4 non-myelosuppressive adverse events largely comprised background 
events resulting from pre-existing disease- or treatment-related conditions or from intercurrent 
illness. Among these subjects with CLL, 4 (15%) developed pneumonia. For subjects receiving 
idelalisib together with bendamustine or bendamustine/rituximab, Grade 3-4 elevations in 
ALT/AST were observed in 3 (11%) of subjects.
When idelalisib was coadministered with bendamustine or bendamustine/rituximab, combination 
therapy showed a high level of antitumor activity. The intention-to-treat (ITT) ORR was 
11/14 (79%) for the idelalisib plus bendamustine regimen and 12/14 (86%) among patients 
receiving idelalisib with bendamustine/rituximab. Concomitant administration of bendamustine 
appeared to largely eliminate the redistribution lymphocytosis that is associated with idelalisib
monotherapy. At the time of the data analysis, overall PFS through 48 weeks was >80% and a 
median PFS had not yet been observed.
Collectively, the emerging data from this study support further evaluation of idelalisib together 
with bendamustine/rituximab in subjects with CLL and indicate that co-administration of 
idelalisib with bendamustine/rituximab is tolerable when using idelalisib at full dose, ie, at a 
starting dose level of 150 mg/dose BID.
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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 to evaluate the efficacy and safety of adding 
idelalisib to bendamustine/rituximab in patients with previously treated, recurrent CLL.
The design and conduct of this study 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 that requires sequential 
treatment with agents that provide alternative mechanisms of tumor control.
Bendamustine/rituximab can offer disease palliation in fit patients with previously treated 
CLL but tumor control is not lasting. Development of a combination therapy of idelalisib
with bendamustine/rituximab that can address disease pathogenesis with a new mechanism of 
action and might offer complementary nodal and peripheral blood activity would address a
persistent unmet medical need.

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 plus bendamustine/rituximab in patients with 
relapsed or refractory CLL is supported by the observed antitumor activity of 
idelalisib - given alone or in combination with bendamustine-containing therapy – in patients 
with heavily pretreated CLL and iNHL.

The safety of advancing development of the regimen of idelalisib plus 
bendamustine/rituximab in this Phase 3 study 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 bendamustine/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, subjects will be continued on therapy until 
the occurrence of definitive disease progression, ie, disease progression that is manifest by 
worsening CLL-related signs 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.

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.

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 is justified.
The rationale for specific design features is provided in relevant sections of the protocol, 
including Section 3.5 (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
Study GS-US-312-0115 is a Phase 3, multicenter, 2-arm, randomized, double-blind, 
placebo-controlled, parallel-group clinical trial (see Figure 2-1) that will be conducted at centers 
in the United States, Canada, Australia, New Zealand, Russia, Turkey, and in Europe.
Figure 2-1.
Study Design
Study candidates will be adults with previously treated recurrent CLL who have measurable 
lymphadenopathy (as confirmed by the IRC); require therapy for CLL; have received prior 
therapy containing a purine analog or bendamustine and an anti-CD20 monoclonal antibody; are 
not refractory to bendamustine; have experienced CLL progression <36 months since the 
completion of the last prior therapy; and are currently sufficiently fit to receive cytotoxic 
therapy.
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 disease status (refractory vs relapsed) and randomized in a 1:1 ratio to receive 
1 of the 2 treatment arms. 
All subjects will receive rituximab with a planned dosing regimen of 375 mg/m2 intravenously 
on Day 1 in the first cycle and 500 mg/m2 intravenously on Day 1 of each of the subsequent 
5 cycles (6 cycles total). All subjects will also be administered bendamustine intravenously at a 
starting dose of 70 mg/m2/infusion; bendamustine will be given on Days 1 and 2 of each of the 
6 planned 4-week treatment cycles. Bendamustine and rituximab will be administered until the 
earliest of subject withdrawal from study, definitive progression of CLL, intolerable 
Screening 
Arm A 
N=195 
N=195 
Study 
Study GS-US-312-011S 
Randomized 
Double-Blind 
Initial Therapy 
ldelalisib, 150 mg BID 
B, 70 mg/m2 D1,2 Q4 weeks Cl-6 
R, 375 mg/m2 Cl, 500 mg/m 2 CZ-6 
24 weeks 
Placebo BID 
B, 70 mg/m2 D1,2 Q4 weeks Cl-6 
R, 375 mg/m2 Cl, 500 mg/m2 CZ-6 
24weeks 
Double-Blind 
Continuing Therapy 
Off-Study Survival 
Follow-up 
Post-Study 
Therapy 
Stratification and 
Randomization 
Abbreviations: B=bemdamustin@, BID= twice p@r- day, C=cycle, R=r-ituximab 
• Following a decision to unblind the study based on the interi m analysis re sults, subjects randomized to Arm B should 
d iscontinue placebo tablet s and continue with study procedures per protocol 


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bendamustine-or rituximab-related toxicity, pregnancy, substantial noncompliance with study 
procedures, study discontinuation, or a maximum of 6 cycles. Bendamustine or rituximab may be 
continued even if the other agent is discontinued due to drug-specific toxicity.
Study drug (idelalisib/placebo) will be taken orally, BID continuously. Subjects will continue 
whichever study drug (idelalisib/placebo or rituximab or bendamustine) continues to be 
tolerated, even if one or both the other drugs must be discontinued due to toxicity. After 
study-wide unblinding, placebo will no longer be administered.
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.
Clinic/laboratory visits will occur every 2 weeks through Week 24 and every 6 weeks between 
Weeks 24 and 48. Subjects who continue on study treatment past Week 48 will have clinic visits 
every 12 weeks. Subjects will be assessed for safety at each clinic visit. Subjects will be assessed 
for CLL disease status by physical and laboratory examinations at each clinic visit and by 
CT or MRI at Weeks 12, 24, 36, and 48 and every 12 weeks thereafter. As of Amendment 10, 
Version 11, CT/MRI assessments will no longer be performed at the every 12 week scheduled 
visits, and will only be performed at the time of clinically-suspected disease progression or at 
study discontinuation.
The primary objective of Study GS-US-312-0115 will be to evaluate the effect of the addition of 
idelalisib to bendamustine/rituximab on PFS. Secondary and tertiary objectives will focus on 
determining the effect of the addition of idelalisib to bendamustine/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.
2.2.
Design Rationale
The randomized, add-on design for GS-US-312-0115 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 companion antineoplastic agents, 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.
Randomization is an accepted means to reduce bias and allows for the highest standard of 
evidence in documenting a treatment effect. Given the 2-arm, 3-stratification-factor design, a 
standard block randomization should be sufficient to preclude site personnel from making 
inferences regarding treatment assignments based on known block sizes. A 1:1 randomization of 
idelalisib: placebo is planned in order to avoid the loss of statistical power associated with an 
unbalanced randomization. The randomization process will be established and performed 
through an IWRS; the intent is to maximize the integrity and security of the randomization and 
ensure appropriate access and convenience-of-use by the investigational sites.


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Stratification will be used to balance allocation by potentially important parameters. The selected 
stratification factors are those that are likely to have a substantial influence on prognosis based 
on historical information regarding the therapy of CLL {Cramer 2011, Gonzalez 2011}, 
considering published data regarding use of bendamustine/rituximab in patients with CLL 
{Fischer 2011, Iannitto 2011}, or based on information derived from the Phase 1 experience 
involving the idelalisib treatment of CLL {Coutre 2011}. Available data suggest that each of the 
selected stratification factors may divide the population relatively evenly, with >30% of the 
subjects have each of the levels of the strata. Further stratification factors could be considered, 
but it is problematic to overstratify a trial of this size given the potential loss of statistical power 
associated with expenditure of further degrees of freedom in the analysis.
Double blinding is included to provide protection against biased interpretations of efficacy and 
safety data by subjects, caregivers, investigators, Gilead Sciences personnel, or others involved 
in study conduct.


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3.
OBJECTIVES AND ENDPOINTS
3.1.
Primary Objective

To evaluate the effect of the addition of idelalisib to bendamustine/rituximab on PFS in 
subjects with previously treated CLL
3.2.
Secondary Objectives

To evaluate the effect of the addition of idelalisib to bendamustine/rituximab on the onset, 
magnitude, and duration of tumor control 

To assess the effect of the addition of idelalisib to bendamustine/rituximab on measures of 
subject well-being, including OS, HRQL, and performance status

To assess the effects of the addition of idelalisib to bendamustine/rituximab on disease 
associated biomarkers and to evaluate potential mechanisms of resistance to idelalisib

To characterize the effect of bendamustine/rituximab on idelalisib exposure through 
evaluations of idelalisib plasma concentrations over time

To describe the safety profile observed with the addition of idelalisib to 
bendamustine/rituximab

To estimate health resource utilization associated with the addition of idelalisib to 
bendamustine/rituximab
3.3.
Primary Endpoint

Progression-free survival (PFS) – defined as the interval from randomization 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.
3.4.
Secondary and Tertiary Endpoints
The following secondary and tertiary endpoints will be defined and analyzed in this study. 
Four endpoints are designated as secondary endpoints for which sequential testing will be 
performed to control Type 1 error (see Section 9.3.4.6). Secondary endpoints will be overall 
response rate (ORR), lymph node response rate, complete response (CR) rate, and OS. All other 
endpoints will be considered tertiary.


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3.4.1.
Tumor Control

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 lesions

CR rate – defined as the proportion of subjects who achieve a CR
CCI


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3.4.2.
Patient Well-Being

Overall survival (OS) – defined as the interval from randomization to death from any cause
3.4.3.
Pharmacodynamic Markers of Drug Activity and Resistance
3.4.4.
Exposure
3.4.5.
Safety
3.4.6.
Pharmacoeconomics
CCI
CCI
CCI
CCI
CCI
CCI


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3.5.
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.
3.5.1.
Tumor Control Endpoints
Assessments of the magnitude and duration of changes in tumor size are routinely employed in 
registration-directed oncology clinical studies to determine therapeutic effect. Unlike OS, these 
endpoints directly assess the ability of the drug to control the malignancy. Such assessments are 
also integral to treatment decisions; because subjects are being treated until disease progression, 
repeated tumor assessment must be performed in order to define the proper duration of treatment 
for each study participant. Standard response and progression criteria have been established by 
the International Workshop on CLL (IWCLL) {Hallek 2008}; the assessments of treatment 
effects in this study will be based on these criteria, taking into account the specific pharmacology 
of idelalisib.
In CLL, disease-related nodal enlargement is a major cause of patient discomfort and can cause 
organ dysfunction {Dighiero 2008}. Extensive lymphadenopathy constitutes a reason to treat 
CLL and controlling the size of pathologically enlarged lymph nodes is an important therapeutic 
goal for improving patient well-being and relieving obstructive symptoms {Hallek 2008}. Given 
that the natural history of recurrent CLL is inexorable nodal growth, enhancing tumor shrinkage 
and prolonging tumor control provides strong evidence of pharmacological activity. In assessing 
PFS as the primary outcome measure, this study builds on a past precedent in randomized, 
pivotal trials supporting the approval of rituximab or bendamustine in CLL {Hallek 2010, Knauf 
2009, Robak 2010}. PFS offers a well-established primary outcome measure that directly 
measures treatment effect, conveys important longitudinal information regarding tumor control, 
can be characterized in all subjects using ITT principles, and is readily analyzed using statistical 
methods such as Kaplan-Meier techniques, log-rank tests, and Cox regression models.
Other endpoints of overall tumor control as evaluated in this trial are customarily assessed and 
reported in studies of new therapies in patients with cancer. In CLL, 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. 
 
Beyond providing descriptions on overall response 
assessment using ORR, this protocol will also seek to characterize the individual components of 
response that are important in assessment of CLL {Hallek 2008}. 
 
CCI
CCI


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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, worsening post-chemotherapy cytopenias, appearance of new disease, or 
transformation to a more aggressive lymphoid malignancy histology (eg, Richter syndrome) will 
be considered to have progressed. Subjects with lymphocytosis without any of these other events 
will not be considered to have progressed. Given that lymphocytosis has no prognostic 
significance in patients with relapsed/refractory disease {Silverman 2002, Tsimberidou 2007}
and is not generally considered a reason to treat in patients with CLL {Eichhorst 2010, Hallek 
2008, Zelenetz 2011}, this approach does not jeopardize subject safety or subsequent therapy. 
Furthermore, it will allow complete collection of all response and progression data (both 
considering lymphocytosis and ignoring lymphocytosis) with the intent of providing complete 
information for regulatory authority review.
The current IWCLL guidelines indicate that physical examination is generally sufficient to 
evaluate nodal response and progression in patients with CLL {Hallek 2008} but that 
radiographic assessments may be appropriate in clinical trials. Computed tomography (CT) is 
considered the preferred imaging method unless patients have contraindications that require use 
of magnetic resonance imaging (MRI). Given the low fluorodeoxyglucose (FDG) avidity of 
CLL, positron- emission tomography (PET) does not have a role in evaluation of this disease. 
The incremental benefits of using radiographic imaging is limited in patients undergoing 
long-term follow-up following first-line therapy {Blum 2007, Eichhorst 2011}. However, in the 
patients with advanced CLL and bulky adenopathy such as those who will be enrolled to this 
trial, it is known that CT scans commonly detect bulky intra-abdominal lymphadenopathy and 
splenomegaly that would be missed by palpation alone and that the presence of large-volume, 
intra-abdominal disease of the nodes and spleen is associated with a poor prognosis {Norin 
2010}. Thus, while use of CT confers greater radiation exposure, subjects have the chance to 
benefit from radiographic imaging because it will offer more accurate information regarding 
their response to protocol therapy and the appropriate duration of protocol treatment. Having this 
information is particularly important in this trial because PI3Kinhibition precludes use of 
lymphocyte counts as evidence for disease progression. Based on published data {Fischer 2011, 
Iannitto 2011}, median OS for patients with comparably advanced CLL is ~1.5 to 3 years, 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 compare 
the treatment arms for radiographic evidence of drug-induced lung changes {Maroto 2011, White 
2010}. Furthermore, CT measurements have greater accuracy and reproducibility than palpation, 
are subject to independent expert review, and can be audited against electronic case report form 
(eCRF) information.


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The timing of radiographic tumor assessments has been carefully considered. Among subjects 
receiving idelalisib in Phase 1b/2 studies who experienced a nodal response (50% regression
in tumor area), such responses were observed with the first 24 week of therapy {Coutre 2011, 
Sharman 2011}; the planned timing of tumor assessments (at Weeks 12, 24, 36, and 48 and every 
12 weeks thereafter) in this study fits with this known timing of changes in lymph node size 
during idelalisib therapy. Scans at 12-week intervals during the first 24 weeks allow efficient
documentation of response. During this period, early documentation of disease progression 
allows subjects who are not benefiting from study therapy to move rapidly to alternative 
treatments. After 24 weeks on study, the frequency of CT scans (at 12-week intervals) reduces 
the overall protocol burden for subjects while still allowing detection of the incremental 
7.5-month improvement in PFS (from a median of 15 months to 22.5 months) that is targeted in 
this comparative trial. As outlined in Section 7.2, iodine-containing or gadolinium contrast 
material may be omitted in subjects for whom use of a contrast agent would be medically 
contraindicated.
3.5.2.
Measures of Patient Well-Being
3.5.2.1.
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 {Fischer 2011, Iannitto 2011, Keating 2002a, Wierda 2010}. Evaluation of OS in 
this study has the potential to ensure that no unexpected, early adverse effect on the likelihood of 
death occurs as a consequence of the addition of idelalisib to rituximab and bendamustine.
3.5.2.2.
Health-Related Quality of Life
Direct patient reporting of outcomes using standardized methods has become an increasingly 
important component of therapeutic assessment. Evaluation of patient-reported outcomes (PROs) 
is particularly relevant in patients who cannot be cured of disease {Reeve 2007}. PRO 
questionnaires have been previously used in CLL to understand how patients differ from the 
general population in terms of health concerns {Eichhorst 2007, Else 2008, Holzner 2004, 
Shanafelt 2007}, to understand differences in perceptions of well-being in younger vs older 
patients {Else 2008, Levin 2007}, to determine how treatment affects HRQL {Catovsky 2007, 
Efficace 2008, Eichhorst 2007}, and to assess the pharmacoeconomic cost of improvements in 
HRQL {Stephens 2005}.


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Patients with CLL have overtly impaired well-being relative to comparable controls {Eichhorst 
2007, Else 2008, Holzner 2004, Shanafelt 2007}. Fatigue is cited as a common complaint, being 
present in the substantial majority of patients. Impairment of HRQL prior to any treatment is 
apparent in those with B symptoms or in patients with anemia, supporting the concept of 
initiating treatment when patients experience symptomatic disease. Factors associated with lower 
overall HRQL have included older age, greater fatigue, severity of co-morbid health conditions, 
advanced stage, and ongoing treatment for CLL {Shanafelt 2007}. Younger patients appear to 
have worse emotional and social well-being but older patients experience worse physical HRQL 
{Levin 2007}. In comparative evaluation of chemotherapy-containing regimens, differences in 
HRQL between therapies (eg, fludarabine vs fludarabine-cyclophosphamide vs chlorambucil) 
reflected differences in toxicity while improved HRQL was associated with greater efficacy 
{Catovsky 2007, Eichhorst 2007}.
In this Phase 3 study of idelalisib plus bendamustine/rituximab, it is postulated that incremental 
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 (see Appendix 2) has been selected to evaluate such outcomes for the study. The 
FACT-Leu comprises a general HRQL measure for patients receiving cancer treatment that 
yields a total score and subscales for physical, functional, social/family and emotional well-being 
{Cella 1993} and a diagnosis-specific measure for patients with leukemia {Webster 2002}. The 
FACT-Leu was developed to assess symptoms (eg, fevers, chills, night sweats, nodal 
swelling, fatigue) specifically relevant to patients with leukemia. FACT instruments have 
documented psychometric properties {Brucker 2005, Cella 2005, Cella 1993, Victorson 2008, 
Webster 2002}.
The FACT-Leu instrument is available in appropriate languages for this study. FACT-Leu data 
will be obtained at baseline and during each investigational clinic visit during treatment. Having 
FACT-Leu data concurrent with tumor response information will allow an evaluation of the 
potential relationship between tumor response and symptomatic changes as reported by patients. 
To avoid biasing HRQL results, the FACT-Leu will be administered at each visit before other 
procedures are performed and before any study information is conveyed to the subject.
3.5.2.3.
Changes in Performance Status
Performance status evaluation provides an integrated assessment of patient well-being before, 
during, and after treatment and, ideally, may indicate how drug efficacy and toxicity affect 
patient functioning. In patients with CLL performance status can be predictive of PFS or OS 
{Hallek 1996, Sorensen 1997, Youngson 1995}.
In this study, it is hypothesized that idelalisib-mediated tumor control will be correlated with 
changes in performance status and that assessments of the drug’s safety profile might be 
supported by performance status evaluations. The well-established, reliable, and validated 
Karnofsky performance score {Karnofsky 1949, Schag 1984, Yates 1980} (see Appendix 3) will 
be employed in the trial for characterization of the subject population and repeated assessment of 
performance status.


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3.5.3.
Pharmacodynamic Markers of Drug Activity and Resistance
In CLL, disease-related perturbations in inflammatory status can be clinically overt; patients 
often develop bothersome B symptoms (fevers, night sweats, and weight loss) that are 
characteristic of excessive systemic inflammation {Redaelli 2004}. Consistent with such disease 
manifestations, the PI3K/AKT/mTOR pathway is constitutively overactive in circulating CLL 
cells {Coutre 2011}. In addition, chemokines and cytokines that are markers of aberrant B-cell 
trafficking or perturbations in inflammation are overexpressed by CLL tissues or by stromal cells 
and circulate in plasma {Burger 2010, Coutre 2011}. In Phase 1 studies of idelalisib it has been 
confirmed that idelalisib largely normalizes AKT phosphorylation and induces dose-dependent 
reductions in plasma concentrations of circulating chemokines and cytokines in patients with 
CLL {Coutre 2011}.
In this study, it is hypothesized that incremental changes in these biomarkers provide direct 
evidence of mechanism-specific idelalisib effects on PI3Kδ activity or indirectly document drug 
effects on overall tumor cell volume. In either case, improvements in these pharmacodynamic 
measures provide corroborative evidence in support of idelalisib pharmacological activity; 
conversely, worsening of these biomarkers may indicate acquisition of resistance to idelalisib. In 
addition, it is possible that disease-or inflammation-related biomarkers may provide corollary 
information relating to the adverse effects of idelalisib on the liver; such data might allow better 
prediction of which subjects might be most susceptible to ALT/AST elevations during idelalisib
treatment. Finally, it can also be postulated that genetic, protein, or metabolic changes in CLL 
cells could provide signatures that would correlate with drug sensitivity and resistance.
Based on these considerations, this study will evaluate PI3K/AKT/mTOR pathway activation 
status in CLL cells. For this purpose, blood will be evaluated by flow cytometry {Hoellenriegel 
2011}. CLL cells will be identified using anti-CD5 and anti-CD19 antibodies. AKT activation
will be determined by quantifying phosphorylation at the Ser473 and Thr308 AKT sites using 
specific anti-pAKT Thr308 and anti-pAKT Ser473 antibodies. Additional assessments of 
PI3K/AKT/mTOR pathway signaling (eg, evaluating phosphorylation state for other downstream 
enzymes) may also be explored.
Plasma will be collected for assessment of circulating concentrations of relevant chemokines and 
cytokines with a particular focus on CCL2, CCL3, CCL4, CXCL12, CXCL13, CCL17, CCL19, 
CCL21, CCL22, sCD40 ligand, tumor necrosis factor-α, and C-reactive protein. In addition 
serum markers of iron metabolism (eg, hepcidin, iron, ferritin, transferrin) that might provide 
markers linking disease-related inflammation with perturbations of liver iron and sensitivity to 
liver injury will be evaluated {Ferrucci 2010, Nemeth 2003}. Circulating concentrations of
chemokines and cytokines will be measured 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 


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treatments. Similarly, protein will be evaluated for state-specific changes in protein 
phosphorylation to evaluate for differences in pathway activation at baseline or during therapy 
that might be associated with differences in response or in acquisition of resistance to therapy.
3.5.4.
Assessments of Exposure
3.5.4.1.
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 collected. The compliance of the subject will be 
verified by accounting for used and unused drug.
3.5.4.2.
Pharmacokinetics
Given the intent of this protocol to assess longer-term dosing, collection of plasma for idelalisib
concentrations is important for evaluating exposures 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 {Webb 2010}. Plasma samples will be retained for potential later analyses of
idelalisib metabolites.
3.5.5.
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 


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(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 the 
therapeutic agents, and to serious adverse events.
Rituximab commonly causes infusion reactions that are mediated via release of cytokines or are 
induced by activation of mast cells or basophils; such reactions are most common during the 
first two infusions of the monoclonal antibody and are commonly managed by slowing the rate 
of infusion {Chung 2008}. Because idelalisib reduces cytokine release by B-cells and decreases
mast cell and basophil activation, it is possible that idelalisib pretreatment may have a 
modulating effect on rituximab-induced infusion reactions and may permit more rapid 
administration of rituximab. To evaluate this hypothesis, the maximum severity of rituximab 
infusion reactions and the duration of the rituximab infusion will be recorded during rituximab 
infusions.
In addition, the protocol may evaluate for potential adverse idelalisib effects on laboratory 
parameters of immune function including: circulating cells (CD4+, CD5+, CD8+, CD16/CD56+, 
CD19+, and CD20+ cells), a lymphocyte subset panel using flow cytometry 
(immunophenotyping), quantitative immunoglobulins IgG, IgM, IgA, and serum CH50 level.
For consistency of interpretation, adverse events will be coded using the standard 
Medical Dictionary for Regulatory Activities (MedDRA), 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. Standard definitions for seriousness will be applied 
(see Section 8.1.2).
3.5.6.
Pharmacoeconomic Measures
It is increasingly important to understand the potential cost implications of introducing a new 
medication into patient care for CLL {Hornberger 2012, Main 2010}. In order to analyze the 
pharmacoeconomic consequences of adding idelalisib to bendamustine/rituximab, 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} (see Appendix 4). The EQ-5D consists of a
visual analogue scale on which subjects are asked to rate their current overall health status and 
5 single-item dimensions which ask subjects to rate their health in terms of mobility, self-care, 
usual activities, pain/discomfort and anxiety/depression. For each of the 5 items patients must 
choose between 3 levels of difficulty in accomplishing tasks in that dimension. The visual analog 
scale is then used in combination with the dimension scores to generate a health utility score that 
can be incorporated into analyses of cost effectiveness. The EQ-5D has been successfully used in 
the evaluation of patients with B-cell and other cancers {Doorduijn 2005, Witzens-Harig 2009, 
Yang 2010}.


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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 in preparation for a full-cost analysis.
Based on the degree to which the addition of idelalisib to rituximab increases costs overall, the 
incremental costs will be compared relative to the health care gains as measured by duration of 
tumor control, the symptom-free survival period, and/or utility gains 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 ~390 subjects (~195 subjects per treatment arm). However, as many 
as 420 subjects may be enrolled in order to permit study participation by eligible subjects who 
have already signed the informed consent document and entered screening at the time that study 
enrollment is closed. The total accrual may be increased if a blinded analysis of the event rate 
indicates that an upward sample size adjustment is warranted (see Section 9.4.2).
4.2.
Subject Selection Criteria
This clinical trial can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select subjects for whom study participation is 
considered appropriate. All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject. Eligibility 
criteria may not be waived by the investigator and conformance to the eligibility criteria is 
subject to review in the case of a Good Clinical Practice (GCP) or a regulatory authority audit. 
Any questions regarding a subject’s eligibility should be discussed with the study sponsor 
medical monitor prior to enrollment.
4.2.1.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study:
1) Male or female 18 years of age.
2) Diagnosis of B-cell CLL, with diagnosis established according IWCLL criteria and 
documented within medical records. 
3) CLL that warrants treatment (consistent with accepted IWCLL criteria for initiation of 
therapy). Any of the following conditions constitute CLL that warrants treatment:
a) Evidence of progressive marrow failure as manifested by the onset or worsening of 
anemia and/or thrombocytopenia, or
b) Massive (ie, lower edge of spleen 6 cm below the left costal margin), progressive, 
or symptomatic splenomegaly, or
c) Massive (ie, 10 cm in the longest diameter), progressive, or symptomatic 
lymphadenopathy, or
d) Progressive lymphocytosis in the absence of infection, with an increase in blood absolute 
lymphocyte count (ALC) 50% over a 2-month period or lymphocyte doubling time of 
<6 months (as long as initial ALC was 30,000/µL), or


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e) Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids 
or other standard therapy, or
f)
Constitutional symptoms, defined as any one or more of the following disease-related 
symptoms or signs occurring in the absence of evidence of infection:
i)
Unintentional weight loss of 10% within the previous 6 months, or
ii) Significant fatigue (Grade 2), or
iii) Fevers >100.5°F or 38.0°C for 2 weeks, or
iv) Night sweats for >1 month.
4) 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 CT or MRI). 
5) Prior treatment for CLL comprising:
a) 2 cycles of a regimen containing a purine analog (eg, fludarabine, pentostatin, 
cladribine) or bendamustine, and 
b) 2 doses with a regimen containing an anti-CD20 monoclonal antibody 
(eg, rituximab, ofatumumab, GA-101) Note: Prior cytotoxic drugs or anti-CD20 
antibodies may have been administered as single agents or as components of 
combination therapies. Subjects may also have received other commercially available 
therapies (eg, alemtuzumab, lenalidomide, corticosteroids, or others) or non-excluded 
investigational therapies. Each repeated but separated therapeutic application of the 
same single-agent or combination is considered an independent regimen.
6) Documentation of CLL progression <36 months since the completion of the last prior therapy 
for CLL.
7) Discontinuation of all therapy (including radiotherapy, chemotherapy, immunotherapy, 
or investigational therapy) for the treatment of CLL 3 weeks before randomization. 
Note: Subjects may receive corticosteroids to manage CLL manifestations.
8) All acute toxic effects of any prior antitumor therapy resolved to Grade 1 before 
randomization (with the exception of alopecia [Grade 1 or 2 permitted], neurotoxicity 
[Grade 1 or 2 permitted], or bone marrow parameters [Grades 1 or 2 permitted]).
9) Karnofsky performance score of ≥60 (see Appendix 3).
10) Required baseline laboratory data (within 4 weeks prior to randomization) as shown in the 
following table. 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.


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Table 4-1.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hematopoietic
ANC
1.5 x 109/La
Platelets
75 x 109/La
Hemoglobin
100 g/L (10.0 g/dL or 6.2 mmol/L)a
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome or hemolysis)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCr
b
40 ml/min
Pregnancy
-HCGc
Negative
Infection
HIV
Negative HIV antibody
HBV
Negative HBsAg and negative HBc antibody or positive HBc and 
negative for HBV DNA by quantitative PCR
HCV
Negative viral RNA (if HCV antibody is positive)
a
Grade 2 neutropenia, thrombocytopenia, or anemia is permitted if abnormality is related to bone marrow involvement with 
CLL (as documented by bone marrow biopsy/aspirate obtained since the last prior therapy).
b
As calculated by the Cockcroft-Gault formula (see Appendix 5) {Cockcroft 1976}
c
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, ANC=absolute neutrophil count, 
AST=aspartate aminotransferase, DNA=deoxyribonucleic acid, eCCr=estimated creatinine clearance, 
HBc antibody=anti-hepatitis B core antibody, HBsAg=hepatitis B surface antigen, HBV=hepatitis B virus, HCV=hepatitis C 
virus, HIV=human immunodeficiency virus, Ig=immunoglobulin, PCR=polymerase chain reaction, RNA=ribonucleic acid, 
ULN=upper limit of normal
11) 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 or >12 months from the last dose of rituximab 
(whichever is later). 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 with amenorrhea for >12 months
or amenorrhea for >6 months with serum estradiol and FSH levels within the institutional 
postmenopausal range).
12) For male subjects of childbearing potential having intercourse with females of childbearing 
potential, willingness to use a protocol-recommended method of contraception from the 
randomization visit (Visit 2) throughout the study treatment period and until >6 months 
following the last dose of bendamustine or > 90 days following the last dose of study drug
(whichever is later) and to refrain from sperm donation from randomization (Visit 2) 
throughout the study treatment period and until >6 months following the last dose of 
bendamustine or >90 days following the last dose of study drug (whichever is later). 


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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®]).
13) In the judgment of the investigator, participation in the protocol offers an acceptable 
benefit-to-risk ratio when considering current CLL disease status, prior treatment history, 
medical condition, and the potential benefits and risks of alternative treatments for CLL. 
Note: Investigators should consider whether a study subject is an appropriate candidate 
for bendamustine-containing therapy based on the number and severity of comorbid 
conditions; subjects with a baseline Cumulative Illness Rating Scale (CIRS) score 
of 6 (see Appendix 6) may be particularly appropriate candidates for this trial.
14) 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.
15) 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) Known presence of intermediate- or high-grade myelodysplastic syndrome (ie, subjects are 
excluded who have 5% bone marrow blasts; karotypic abnormalities other than normal, 
Y deletion, 5q deletion, or 20q deletion; or 2 lineages of cytopenias due to myelodysplasia).
3) History of a non-CLL malignancy except for the following: adequately treated local basal 
cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder 
cancer, asymptomatic prostate cancer without known metastatic disease and with no 
requirement for therapy or requiring only hormonal therapy and with normal 
prostate-specific antigen for 1 year prior to randomization, other adequately treated 
Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in 
complete remission for ≥5 years. 


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4) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of 
randomization (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. 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.
5) Ongoing drug-induced liver injury, chronic active hepatitis C (HCV), chronic active 
hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary 
cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal 
hypertension.
6) Ongoing drug-induced pneumonitis.
7) Ongoing inflammatory bowel disease.
8) Ongoing alcohol or drug addiction.
9) Pregnancy or breastfeeding. 
10) History of prior allogeneic bone marrow progenitor cell or solid organ transplantation.
11) Ongoing immunosuppressive therapy other than corticosteroids Note: Subjects may use 
topical, enteric, inhaled, or systemic corticosteroids as therapy for manifestations of CLL, 
comorbid conditions, or autoimmune anemia and/or thrombocytopenia during study 
participation, subjects may receive systemic or other corticosteroids as pretreatment for 
rituximab infusions or as needed for treatment-emergent comorbid conditions.
12) In a subject with a history of prior bendamustine therapy, a time interval from the last dose of 
bendamustine to the subsequent CLL progression of <6 months.
13) History of prior therapy with any inhibitor of AKT, Bruton tyrosine kinase (BTK), 
Janus kinase (JAK), mammalian target of rapamycin (mTOR), phosphatidylinositol 3 kinase 
(PI3K) (including idelalisib), or spleen tyrosine kinase (SYK). 
14) History of anaphylaxis in association with previous administration of monoclonal antibodies.
15) Concurrent participation in another therapeutic clinical trial.
16) 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
In general, the eligibility criteria are designed to limit enrollment to subjects who clearly have 
CLL, are able to tolerate study procedures, and will provide interpretable results.
To maximize the likelihood that therapeutic intervention is appropriately matched to disease risk, 
subjects must have CLL that is sufficiently severe to justify therapy as determined by accepted 
criteria {Hallek 2008}. The requirement of measurable lymphadenopathy ensures that subjects 
have disease that can adequately be assessed for evidence of drug activity. Prior therapy 
provisions are intended to identify subjects who have already received appropriate therapies with 
well-defined activity. Exclusion of patients who have experienced CLL progression within
6 months of prior bendamustine therapy avoids treating those with disease known to be 
refractory to this agent. Ensuring participation of only patients who are <36 months from prior 
therapy limits enrollment to subjects who might benefit from a change in therapy (including the 
addition of study drug) based on current guidelines {Eichhorst 2010, Zelenetz 2011}. Extending
this interval to as long as 36 months acknowledges that patients who had received and tolerated 
bendamustine-based therapy in the past and have now relapsed after a protracted period (eg, after 
18-36 months) might wish to consider bendamustine-based therapy again.
This protocol focuses on establishing a combination chemoimmunotherapy that will be suitable 
for patients who are likely to tolerate a regimen containing a potently myelosuppressive 
cytotoxic agent. Thus, while any degree of cytopenias are permitted if due to CLL, the trial 
requires that study candidates not have Grade 3 neutropenia, thrombocytopenia, or anemia 
attributable to cumulative myelotoxicity. Given that bendamustine-related myelotoxicity is 
substantially more likely in patients with severe renal dysfunction {Fischer 2011}, subjects must 
have a baseline eCCr value 40 mL/minute.
To ensure that subjects are able to perform basic self-care functions and are not so ill from 
life-threatening comorbidities that they require hospitalization and stabilization, subjects with 
Karnofsky performance scores <60 will not be enrolled. To preserve subject safety and trial 
integrity, subjects must not have other serious prior or concomitant conditions or therapies that 
would compromise safety, compliance, or evaluation. Severe comorbid conditions 
(eg, myelodysplasia, other cancers {Luciani 2009}, active hepatitis, hepatic dysfunction, ongoing
of drug-induced pneumonitis) may mask, exacerbate, or confound the interpretation of adverse 
effects or efficacy of idelalisib and therefore subjects with such medical disorders are excluded.
Pregnancy testing and restrictions on eligibility relating to reproduction, pregnancy, and nursing
are important. Rituximab is known to have effects on the immune system in the developing 
fetuses of drug-exposed female animals and humans; such effects can persist in infants for 
several months following in utero exposure. Bendamustine is known to be embryotoxic and 
teratogenic in laboratory animals {Cephalon 2012}. Idelalisib is a new chemical entity and it is 
unknown if it may have adverse effects on conception, on fetal development, or on the health of
a breast-feeding child.


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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.
While it will not be used to determine eligibility in this trial, the general health status of study 
subjects will be characterized at baseline using the Cumulative Illness Rating Scale (CIRS) 
instrument (see Appendix 6). The CIRS has a well-established history as a clinical tool for 
classifying patient comorbidities {Linn 1968}. Its utility is based on its validation as a predictor 
of clinical outcomes in older patient populations {Boulos 2006, Castle 2005, Conwell 1993, de 
Groot 2003, Extermann 2000, Extermann 1998, Miller 1992, Parmelee 1995, Salvi 2008, Zekry 
2010}; its utility in predicting prognosis, appropriate patient selection, and treatment tolerability 
in patients with cancer {Firat 2006, Monfardini 2005, Ngeow 2010, Wedding 2007a, Wedding 
2007b}, and its increasing use to categorize treatable fit (“GO-GO”) vs treatable frail
(“SLOW-GO”) patients with CLL {Eichhorst 2009, Hallek 2010}.


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5.
TREATMENT OF SUBJECTS
5.1.
Randomization and Blinding
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 screening, to implement stratification and randomization, 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.
Randomization and Stratification
After a subject has completed the necessary screening assessments and has been confirmed to be 
eligible, the subject can be randomized into the study. In order to obtain a treatment arm 
assignment for a subject, a site representative will access the IWRS and supply the system with 
the required information.
Subjects will be randomized in a 1:1 ratio to either of the following treatment assignments:

Arm A: Idelalisib + bendamustine/rituximab

Arm B: Placebo + bendamustine/rituximab
In order to balance treatment allocation by potentially important predictive factors, a fixed-block 
centralized randomization will allocate subjects within the 8 strata as defined by the intersection 
of the following 3 binary stratification factors:

17p deletion and/or p53 mutation in CLL cells: either vs neither (or indeterminate)

Immunoglobulin heavy chain variable region (IgHV) mutation:
unmutated (or IgHV3-21) vs mutated (or indeterminate)

Disease status: refractory (CLL progression <6 months from completion of prior therapy) 
vs relapsed (CLL progression 6 months from completion of prior therapy)
The IWRS will assign bottle numbers and instructions for dispensing of blinded study drug 
(idelalisib or placebo). It is anticipated that subjects will usually begin study drug immediately 
after randomization at Visit 2 of the study. In case of administrative delays, every attempt should 
be made to initiate study drug as soon as possible, but no more than 7 days from randomization.
5.1.3.
Blinding
The identity of the treatments will be concealed by central blinding of study drug assignments. 
Blinding will be accomplished through use of a placebo that is well-matched to the active drug in 
appearance, packaging, labeling, and schedule of administration (see Section 5.2.1.1). 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; 


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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). Where 
required by local regulation, expedited reporting of serious adverse events to specific regulatory 
authorities will include information regarding the study drug treatment assignment 
(idelalisib or placebo); this will be done in such a way that subjects, investigational site 
personnel, institutional review board/independent ethics committees (IRB/IEC), and study team 
members remain blinded as to the treatment assignment for the subject described in the adverse 
event report.
The final unblinded analysis of the study will only be performed when the database is completed 
and locked, unless the DMC recommends unblinding the study following an interim analysis of
unblinded data. 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 randomized 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.
In the event that treatment is unblinded, subjects randomized to Arm A will be informed of their 
treatment assignment, and continue to receive idelalisib and be followed for progression free 
survival. Subjects randomized to Arm B should continue with study procedures per protocol, but 
must discontinue from placebo.  Subjects should remain on study until definitive progression of 
CLL or discontinuation from the study for reasons specified in Section 5.9.
5.2.
Investigational and Reference Study Drugs
5.2.1.
Investigational Study Drug (Idelalisib/Placebo)
5.2.1.1.
Description
For subjects allocated to Arm A of the study, idelalisib will be provided in tablets intended for 
oral administration. 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 Section 5.3.3). The 150-mg tablets are either pink, 
oval-shaped, film-coated tablets with “GSI” on one side and “150” on the other side or plain 
faced tablets, 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 either orange, oval-shaped, film-coated, tablets with “GSI” on one side and 
“100” on the other side or plain-faced tablets, 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.


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For subjects allocated to Arm B of the study, an inactive placebo formulation will be provided in 
tablets intended for oral administration. 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.
5.2.1.2.
Source
Both active idelalisib and placebo will be supplied free of charge by Gilead Sciences.
5.2.1.3.
Packaging and Labeling
Study drug (idelalisib/placebo) will be provided in bottles. Each bottle contains 60 tablets 
(4-week supply plus a modest overage) of one of the relevant dose strengths (150 mg, 100 mg, 
or matching placebos) and a polyester packing material. 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.
Each bottle will have a unique number. Labeling for active idelalisib (GS-1101) and placebo will 
be identical, and may include either idelalisib or GS-1101. All labels for study drugs to be 
distributed to centers in the US and other countries will meet all applicable requirements of the 
United States Food and Drug Administration (FDA), Annex 13 of Current Good Manufacturing 
Practice (cGMP) (Manufacture of Investigational Medicinal Products, July 2010), and/or other 
local regulations as applicable.
5.2.1.4.
Storage and Handling
Bottles containing tablets of study drug (idelalisib/placebo) should be stored at controlled room 
temperature of 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).  
Storage conditions are specified on the label.  Until the study drugs are dispensed to the subjects, 
all bottles should be stored in a securely locked area, accessible only to authorized site personnel.
To ensure stability and proper identification, study drug(s) should not be stored in a container 
other than the container in which they were supplied. Consideration should be given to handling, 
preparation, and disposal through measures that minimize drug contact with the body. 
Appropriate precautions should be followed to avoid direct eye contact or exposure when 
handling idelalisib.
5.2.1.5.
Dispensing
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing 
study drug (idelalisib/placebo) according to the IWRS directions. It is planned that drug will be 
dispensed at 12-week intervals Multiple bottles will be dispensed at a single visit. Tablets should 
be dispensed in the original bottles provided.


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At the time of randomization, the IWRS will provide the clinic staff with the bottle numbers 
designating the bottles to be dispensed. The clinic staff (eg, pharmacist or other qualified person) 
will write the subject number on each bottle that is dispensed. Immediately before dispensing,
the clinic staff will write the bottle number for each dispensed bottle in the study drug 
administration record corresponding to the subject number.
5.2.1.6.
Return
The study drug (idelalisib/placebo) should be retrieved from each subject at the end of each 
dispensing interval. The quantity of study drug and the date returned by the subject should be 
recorded in the study drug accountability records. All study drug returned by the subject should 
be retained for review by the study site monitor prior to return to Gilead Sciences or destruction.
5.2.1.7.
Accountability
The disposition of all study drug (idelalisib/placebo) 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.
5.2.1.8.
Overdose Precautions
In Phase 1 studies, an MTD for idelalisib was not reached when administering the drug 
continuously at dose levels of 350 mg/dose BID (700 mg per day) {Coutre 2011, Kahl 2011}. 
However, in this protocol, an overdose is defined as administration of more than the prescribed 
daily dose (ie, >300 mg in a single day).


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In a subject who experiences an overdose, consideration should be given as to whether idelalisib
administration should be temporarily interrupted. If the overdose ingestion is recent and 
substantial, and if there are no medical contraindications, use of gastric lavage or induction of 
emesis may be considered. Observation for any symptomatic side effects should be instituted, 
and biochemical and hematological parameters should be followed closely (consistent with the 
protocol or more frequently, as needed). Appropriate supportive management to mitigate adverse 
effects should be initiated.
The Gilead Sciences medical monitor should be contacted if a study drug overdose occurs. Cases 
of study drug (idelalisib/placebo) overdose will result in specific reporting requirements 
(see Section 8.8).
5.2.1.9.
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.
5.2.2.
Reference Drug (Rituximab)
5.2.2.1.
Description
Rituximab (Rituxan) is a genetically engineered chimeric murine/human monoclonal 
IgG1 kappa antibody directed against the CD20 antigen found on pre-B and mature B cells
{Genentech Inc 2011}. Rituximab is produced by mammalian Chinese hamster ovary cells. The
protein has an approximate molecular weight of 145 kD.
The drug is provided as a clear, colorless, preservative-free liquid concentrate containing 
10 mg/mL of rituximab. The product is formulated in 9 mg/mL sodium chloride, 7.35 mg/mL 
sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and water for injection with a pH of 6.5.
5.2.2.2.
Packaging
Rituximab is supplied in 100-mg (10-mL) or 500-mg (50-mL) single-use vials.
5.2.2.3.
Source – Commercial Supply
Unless otherwise instructed by the sponsor, the rituximab to be used in this study may be 
obtained from available commercial supplies. As applicable for a specific subject, costs for 
rituximab should be submitted for insurance reimbursement; if such costs are not covered by the 
medical insurance for the subject, these expenses can be submitted to Gilead Sciences for 
reimbursement.


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5.2.2.4.
Source – Non-Commercial Supply
If rituximab is obtained from a source other than available commercial source, the disposition of 
all rituximab should be documented from the time of receipt at the site through subject 
dispensing and infusion.
Study personnel must ensure that all rituximab is kept in a secure locked area with access limited 
to authorized personnel. Rituximab must not be used outside the context of 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 rituximab. Rituximab
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 rituximab dispensed.
Depending upon the decision of Gilead Sciences, remaining unused rituximab 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 rituximab is discarded or destroyed at the clinical site, 
standard institutional policy should be followed and be readily available for review by 
Gilead Sciences and/or its designee. Records documenting the date of rituximab shipping or 
destruction, relevant lot numbers, and amount shipped or destroyed should be maintained.
5.2.2.5.
Storage and Stability
Rituximab vials are stable at 2 °C–8 °C (36 °F–46 °F). Vials should be protected from direct 
sunlight and should not be frozen or shaken.
Diluted rituximab solutions for infusion may be stored at 2 °C–8 °C (36 °F–46 °F) for 24 hours 
and are known to be stable for an additional 24 hours at room temperature. However, since 
rituximab solutions do not contain a preservative, diluted solutions should be stored refrigerated 
(2 °C-8 °C).
No incompatibilities between rituximab and polyvinylchloride or polyethylene bags have been 
observed. The storage and stability data is provided as guidelines, local standard practice may 
also be followed.
5.2.2.6.
Solution Preparation and Dispensing
Before use, the rituximab vials should be inspected for particulate matter or discoloration. Any 
vial with evidence of particulates or discoloration should not be used.
Using aseptic technique, the necessary amount of rituximab should be withdrawn from the vial 
and diluted to a final concentration of 1 to 4 mg/mL in an infusion bag containing either 
0.9% Sodium Chloride, USP or 5% Dextrose in Water, USP. The bag should be gently inverted 
to mix the solution. The infusion solution should not be mixed or diluted with other drugs. Any 
unused portion of rituximab remaining in the vial should be discarded.


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The intravenous solution should be prepared and dispensed by the clinical research center 
pharmacist and should be infused by a qualified nurse with experience in monitoring the 
administration of chemotherapeutic agents.
5.2.2.7.
Accountability
Acquisition, storage, control, and disposal of rituximab used in the study should be performed 
according to institutional procedures and policies.
The investigator and/or the responsible site personnel must maintain accurate records of the 
source, dates of administration, quantities of administration, and lot numbers of the rituximab 
dispensed for this study.
5.2.2.8.
Overdose Precautions
Rituximab doses as high as 2000 mg/m2 have been administered without inducing excessive 
toxicity {O'Brien 2001}. However, for this protocol, an overdose is defined as infusion of
>500 mg/m2 of rituximab in a single day.
In a subject who experiences an overdose, any further rituximab infusion on that day should be 
interrupted. 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, as necessary.
The Gilead Sciences medical monitor should be contacted if a rituximab overdose occurs. Cases 
of rituximab overdose may result in specific reporting requirements (see Section 8.6).
5.2.2.9.
Exposure and Spill Precautions
Based on available data, rituximab does not appear to be irritative, acutely toxic, or genotoxic at 
levels that are likely to result from inadvertent exposure to the drug. No special precautions 
relating to exposure are required.
5.2.3.
Reference Drug (Bendamustine)
5.2.3.1.
Description
Bendamustine (Treanda) is a bifunctional mechlorethamine derivative containing a purine-like 
benzimidazole ring {Cephalon 2012}. The chemical name of bendamustine hydrochloride is
1H-benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]-1 methyl-, monohydrochloride. 
Its empirical molecular formula is C16H21Cl2N3O2 HCl, and its molecular weight is 394.7 daltons.
Mechlorethamine and its derivatives form electrophilic alkyl groups. These groups form 
covalent bonds with electron-rich nucleophilic moieties, resulting in interstrand DNA crosslinks. 
The bifunctional covalent linkage can lead to cell death via several pathways. Bendamustine is 
cytotoxic in both quiescent and dividing cells.


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Bendamustine hydrochloride for injection is provided as a sterile non-pyrogenic white to 
off-white lyophilized powder mixed with mannitol.
5.2.3.2.
Packaging
Bendamustine hydrochloride for injection is provided in individual cartons containing amber 
8-mL or 20-mL single-use vials. The 8-mL vial contains 25 mg of bendamustine and 42.5 mg of 
mannitol powder. The 20-mL vial contains 100 mg of bendamustine and 170 mg of 
mannitol powder.
5.2.3.3.
Source – Commercial Supply
Unless otherwise instructed by the sponsor, the bendamustine to be used in this study may be 
obtained from available commercial supplies. As applicable for a specific subject, costs for 
bendamustine should be submitted for insurance reimbursement; if such costs are not covered by 
the medical insurance for the subject, these expenses can be submitted to Gilead Sciences for 
reimbursement.
5.2.3.4.
Source – Non-Commercial Supply
If bendamustine is obtained from a source other than available commercial source, the 
disposition of all bendamustine should be documented from the time of receipt at the site through 
subject dispensing and infusion.
Study personnel must ensure that all bendamustine 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.
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. 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 bendamustine 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 bendamustine is discarded or destroyed at the clinical site, 
standard institutional policy should be followed and be readily available for review by 
Gilead Sciences and/or its designee. Records documenting the date of study drug shipping or 
destruction, relevant lot numbers, and amount shipped or destroyed should be maintained.
5.2.3.5.
Storage and Stability
Bendamustine vials are stable when stored at room temperatures up to 25 °C (77 °F). 
Temperature excursions are permitted up to 30 °C (86 °F). Bendamustine should be stored in the 
original containers until the time of use in order to protect the drug from light.


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Bendamustine contains no antimicrobial preservative. The admixture should be prepared as close 
as possible to the time of patient administration. Once diluted with either 
0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, 
USP, the final admixture is stable for 24 hours when stored refrigerated (2-8 °C or 36-47 °F) or 
for 3 hours when stored at room temperature (15-30 °C or 59-86 °F) in room light. Drug 
administration should be completed within the established periods of stability for the admixed 
solution. The storage and stability data is provided as guidelines, local standard practice may also 
be followed.
5.2.3.6.
Solution Preparation and Dispensing
Bendamustine hydrochloride for injection is intended for intravenous infusion only after 
reconstitution with Sterile Water for Injection, USP, and after further dilution with either 
0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, 
USP. No other diluents have been shown to be compatible.
Vials of bendamustine should be inspected visually for particulate matter and discoloration prior 
to administration. Vials should be aseptically reconstituted as follows:

25 mg bendamustine vial to be mixed with 5 mL of Sterile Water for Injection, USP.

100 mg bendamustine vial to be mixed with 20 mL of Sterile Water for Injection, USP.
With shaking, the lyophilized powder should completely dissolve in 5 minutes, yielding a clear, 
colorless to pale yellow solution with a bendamustine hydrochloride concentration of 5 mg/mL. 
The pH of the reconstituted solution is 2.5 - 3.5. If particulate matter is observed, the 
reconstituted product should not be used.
Within 30 minutes of reconstitution, the volume needed for the required dose (based on a 
5-mg/mL concentration) should be transferred to a 500-mL infusion bag of 
0.9% Sodium Chloride Injection, USP (normal saline) As an alternative to 
0.9% Sodium Chloride Injection, USP, a 500-mL infusion bag of 2.5% Dextrose/
0.45% Sodium Chloride Injection, USP, may be used. After transferring, thoroughly mix the 
contents of the infusion bag. The resulting admixture should be a clear and colorless to slightly 
yellow solution with a final concentration of bendamustine hydrochloride in the infusion bag of
0.2-0.6 mg/mL.
5.2.3.7.
Accountability
Acquisition, storage, control, and disposal of bendamustine used in the study should be 
performed according to institutional procedures and policies.
The investigator and/or the responsible site personnel must maintain accurate records of the 
source, dates of administration, quantities of administration, and lot numbers of the 
bendamustine dispensed for this study.


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5.2.3.8.
Overdose Precautions
The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities 
included sedation, tremor, ataxia, convulsions, and respiratory distress. Across all clinical 
experience, the reported maximum single dose received was 280 mg/m2. Three of four patients 
treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. 
These changes included QT prolongation (one patient), sinus tachycardia (one patient), 
ST and T wave deviations (two patients) and left anterior fascicular block (one patient). Cardiac 
enzymes and ejection fractions remained normal in all patients. In this protocol, an overdose is 
defined as administration of more than the prescribed dose (ie, >70 mg/m2 in a single day).
No specific antidote for bendamustine overdose is known. Management of overdosage should 
include general supportive measures, including monitoring of hematologic parameters and 
ECGs.
The Gilead Sciences medical monitor should be contacted if a bendamustine overdose occurs. 
Cases of bendamustine overdose may result in specific reporting requirements (see Section 8.6).
5.2.3.9.
Exposure and Spill Precautions
As with other potentially toxic anticancer agents, care should be exercised in the handling and 
preparation of solutions prepared from bendamustine. The use of gloves and safety glasses is 
recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a 
solution of bendamustine contacts the skin, wash the skin immediately and thoroughly with soap 
and water. If bendamustine contacts the mucous membranes, flush thoroughly with water.
5.3.
Study Drug Administration
5.3.1.
Combination Dosing Regimen
Table 5-1 provides information regarding the planned study drug (idelalisib/placebo), 
bendamustine, and rituximab dosing regimen.


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Table 5-1.
Planned Dosing Regimen During the Randomized Double-Blind Combination Therapy Portion of the 
Study
Period
Screen
Combination Therapya
Further
Therapya
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Week
-4
0
2
4
6
8
10
12
14
16
18
20
22
24
Day
-28
1
2
15
29
30
43
57
58
71
85
86
99
113
114
127
141
142
155
169
Purpose
Screening
Clinic
Visits
Lab
Visit
Clinic
Visit
Lab
Visit
Clinic
Visit
Lab
Visit
Clinic
Visit
Lab
Visit
Clinic
Visit
Lab
Visit
Clinic
Visit
Lab
Visit
Clinic
Visit
Study Drug
(idelalisib/placebo)
150 mg/dose BID,a taken continuously
Premedication
X
X
X
X
X
X
X
X
X
X
X
X
Rituximab Dose,
mg/m2
375
-
500
-
500
-
500
-
500
-
500
-
Bendamustine Dose,
mg/m2
70
70
70
70
70
70
70
70
70
70
70
70
a
Intended dose levels and schedules of administration are shown. However, individual study subjects may require dose modifications or delays in therapy to accommodate 
drug-related, dose-limiting toxicities (see Section 5.3.5).
Abbreviation: BID=2 times per day


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Table 5-2 indicates the planned sequence of drug administration that should be followed on the 
first day and second day of each treatment cycle. As noted in the table, the sequence of drug 
administration may be prolonged to 3 days in subjects for whom the investigator believes such 
an extension is medically warranted.
Table 5-2.
Planned Sequence of Drug Administration on Day 1 and Day 2 of 
Each Cycle
Day
Drug
Sequencing and Instructions
1
Study drug
(see also Section 5.3.3)
Morning dose of study drug (idelalisib/placebo) to be 
administered orally to the subject in the clinic (with recording of 
the date and actual clock time of the study drug administration).
Pretreatment
(see also Section 5.3.2)
Antipyretic and antihistamine to be administered orally to the 
subject at the same time as study drug (idelalisib/placebo) and 
~30 minutes prior to rituximab infusion. An intravenous 
corticosteroid may also be administered per local practices as a 
premedication to minimize rituximab infusion reactions. 
Antiemetics may be given to minimize bendamustine-related 
nausea.
Prophylaxis for tumor lysis syndrome may be considered per 
local practices. Prophylaxis for Pneumocystis (carinii) jiroveci
should also be considered.
Rituximab
(see also Section 5.3.4.1)
Cycle 1 dose
(375 mg/m2)a
Rituximab intravenous infusion to be started ~30 minutes after 
pretreatment administration at initial infusion rate of 50 mg/hr; 
in the absence of infusion toxicity, the infusion rate can be 
increased in 50-mg/hr increments every 30 minutes, to a 
maximum of 400 mg/hr.
Cycle 2-6
doses
(500 mg/m2)
Rituximab intravenous infusion to be started ~30 minutes after 
pretreatment administration at initiation infusion rate of 
100 mg/hr; in the absence of infusion toxicity, the infusion rate 
can be increased in 100-mg/hr increments every 30 minutes, to a 
maximum of 400 mg/hr.
Bendamustineb
(Section 5.3.4.2)
Bendamustine intravenous infusion to be started at completion of 
rituximab; bendamustine to be administered over ~60 minutes.
2
Study drug
(see also Section 5.3.3)
Morning dose of study drug (idelalisib/placebo) to be taken 
orally by the subject at home.
Pretreatmentc
(see also Section 5.3.2)
Antiemetics may be given to minimize bendamustine-related 
nausea.
Bendamustine
(see also Section 5.3.4.2)
Bendamustine intravenous infusion to be administered over 
~60 minutes.
a
For a subject with a greater risk of infusion reactions due to a pretreatment ALC of 25 x 109/L, the Day 1 rituximab 
infusion may be limited to 100 mg total drug (ie, 1 vial of rituximab) and the remainder of the planned total rituximab dose 
may be administered prior to bendamustine on Day 2.
b
Bendamustine infusions may be deferred and administered on Days 2 and 3 for subjects in whom a more extended drug 
administration sequence is warranted (eg, due to the occurrence of a rituximab-related infusion reaction or a protracted 
rituximab infusion time on Day 1).
c
For a subject who appears to be prone to bendamustine-related infusion reactions, premedication with an antipyretic, an 
antihistamine, and a corticosteroid should also be considered prior to administration of bendamustine on Day 2.
Abbreviations: ALC=absolute lymphocyte count


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5.3.2.
Premedications
No specific premedication is required for study drug (idelalisib/placebo) administration.
In accordance with rituximab prescribing information {Genentech Inc 2011}, subjects should be
premedicated with an antipyretic and an antihistamine to reduce the incidence and severity of 
infusion reactions. A recommended regimen is diphenhydramine, 25 mg orally, and 
acetaminophen (paracetamol), 650 mg orally, both given ~30 minutes prior to each rituximab 
administration. An intravenous corticosteroid may also be administered as a premedication. 
Local practices and guidelines may be followed.
Bendamustine administration has been associated with nausea and/or vomiting in 
~15 to 20% of patients. Investigators may wish to provide prophylactic antiemetics according to 
local practices.
In the absence of concomitant cytotoxic administration, tumor lysis syndrome is uncommon with 
either idelalisib or rituximab. Tumor lysis syndrome has occurred in ~5% of patients when 
idelalisib had been combined with bendamustine or bendamustine/rituximab. Investigators may 
wish to institute prophylaxis and monitoring for tumor lysis syndrome according to local 
practices.
5.3.3.
Study Drug (Idelalisib/Placebo) Administration
Study drug (idelalisib/placebo) dose levels are shown in Table 5-3 below. The starting dose level 
will be 150 mg/dose BID. The lower dose level (Dose Level -1) is provided in case a subject 
requires a study drug dose modification (see Section 5.3.5).
Table 5-3.
Study Drug (Idelalisib/Placebo) Dose Levels
Dose Level
Dosing Regimen
Starting
150 mg/dose BID
-1
100 mg/dose BID
Abbreviation: BID=twice per day
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.
Study drug will be started on a BID schedule beginning ~30 minutes prior to the initial rituximab 
infusion. At this first treatment visit and at specific follow-up clinic visits, the morning dose of 
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 
study drug administration information, including the exact clock time of each dose, for doses of 
study drug administered in the clinic or hospital. Thereafter, subjects will be given an adequate 
supply of tablets to take at home.


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Subjects should be instructed to take study drug 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.
Subjects who have a delay in administration of 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.
5.3.4.
Reference Drug (Bendamustine/Rituximab) Administration
5.3.4.1.
Rituximab
Rituximab dose levels for the initial cycle and subsequent cycles of study treatment are shown in 
Table 5-4 below. Dosing will be based on mg/m2 of body surface area. The dose calculation of 
body surface area will be based on the subject’s pretreatment height and actual body weight. The 
total doses of rituximab throughout therapy should be based on the pretreatment body surface 
area without consideration of fluctuations in body weight during treatment. Escalations or
reductions in rituximab dosing are not planned.
Table 5-4.
Reference Drug (Rituximab) Dose Levels
Cycle 1
Cycles 2-6
Rituximab dose
375 mg/m2
500 mg/m2
Rituximab will be administered intravenously in the clinic according to the dosing regimen and 
administration sequence described in Table 5-1 and Table 5-2. Unless drug-specific toxicities 
preclude its further administration, rituximab should always be administered at the beginning of 
each cycle in synchrony with bendamustine. Thus, if bendamustine administration must be 
delayed due to bendamustine-related toxicities, rituximab should also be delayed. Information 
regarding delays or discontinuations of rituximab therapy for specific adverse events is provided 
in Section 5.4.
5.3.4.2.
Bendamustine
Bendamustine dose levels are shown in Table 5-5 below. Dosing will be based on mg/m2 of body 
surface area. The dose calculation of body surface area will be based on the subject’s 
pretreatment height and actual body weight. The total doses of bendamustine throughout therapy 
should be based on the pretreatment body surface area without consideration of fluctuations in 
body weight during treatment. The starting dose level will be 70 mg/m2. The lower dose levels
(Dose Level -1 and Dose Level -2) are provided in case a subject requires a bendamustine dose 
modification (see Section 5.3.5)


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Table 5-5.
Reference Drug (Bendamustine) Dose Levels
Dose Level
Dosing Regimen
Starting
70 mg/m2 on Days 1 and 2
-1
50 mg/m2 on Days 1 and 2
-2
25 mg/m2 on Days 1 and 2
Bendamustine will be administered intravenously in the clinic according to the schedule and 
administration sequence described in Table 5-1 and Table 5-2. Unless drug-specific toxicities 
preclude its further administration, bendamustine administration must be delayed due to 
bendamustine-related toxicities. Information regarding delays or discontinuations of 
bendamustine therapy for specific adverse events is provided in Section 5.4.
5.3.5.
Safety Monitoring and Study Treatment 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.
Modifications of the dosing regimen based on the drug and the type and severity of adverse 
events or laboratory abnormalities are provided in Table 5-6. The dose modification instructions 
focus on the types of events most commonly attributed to the study agent(s). The idelalisib 
modifications in Table 5-6 include both recommended as well as required actions. When a 
modification is indicated as a recommendation it only serves as a guideline; variations from the 
recommendation 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 5-6, if a subject experiences an adverse event that is suspected to be 
related to study drug (idelalisib/placebo) during the course of study treatment, then study drug 
administration may be held, as necessary, until the adverse event resolves or stabilizes to an 
acceptable degree (as described in Table 5-6). If permanent discontinuation is not required per 
Table 5-6, study drug may be reinstituted at either the starting dose level (150 mg/dose BID) or 
at Dose Level -1 (100 mg/dose BID) consistent with the instructions in Table 5-6. A further 
attempt at reinitiation of therapy at Dose Level -1 (100 mg/dose BID) may be attempted if the 
investigator feels that a rechallenge at that dose level is medically appropriate. After a study drug 
dose reduction, 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 may be increased to 150 mg/dose BID, 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 (150 mg/dose 
BID) should not be exceeded in this study.


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Investigators should contact the Gilead Sciences medical monitor with any questions regarding 
dose modification. To implement either a dose reduction or a dose reescalation, the
investigator/study staff member will access the IWRS, enter the subject randomization number, 
and inform the IWRS of the need for dose titration. The IWRS will provide details regarding the 
bottles to be dispensed to the subject. The appropriate clinic staff should instruct the 
subject/caregiver about the change in dose.
Rituximab doses will not be modified during the study. As shown in Table 5-6, the scheduling of 
rituximab should be synchronized with that for bendamustine.
Bendamustine administration should follow the recommendations in Table 5-6. If a subject 
experiences an adverse event that is suspected to be bendamustine-related and requires a dose 
modification during the course of study therapy, then the bendamustine dose should be reduced 
by 1 dose level. Successive adjustments to progressively lower dose levels can be made. If the 
patient cannot tolerate bendamustine at Dose Level -2 (25 mg/m2/dose on Days 1 and 2), then the 
patient should be discontinued from bendamustine therapy. After a bendamustine dose reduction, 
the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. 
However, if the patient tolerates a reduced dose of bendamustine then the bendamustine may be 
increased to the next higher dose level, 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 bendamustine-related. Successive adjustments to progressively higher 
dose levels can be made at 4-week intervals. The starting dose level 
(70 mg/m2/dose on Days 1 and 2) should not be intentionally exceeded.
Investigators should contact the Gilead Sciences medical monitor with any questions regarding 
dose modification. 


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Table 5-6.
Modifications of Study Treatments for Subsequent Cycle Based on Worst Drug-Related Adverse Events
Observed in the Prior Cycle
NCI CTCAE Gradea
Idelalisib
Rituximab
Bendamustine
HEMATOLOGICAL ADVERSE EVENTS
Neutropenia
Grade 2
Recommended Action: Maintain current dose level and 
schedule.
Maintain 500-mg/m2 dose level and 
schedule.
Maintain current dose level and 
schedule.
Grade 3
Required Action: Monitor blood counts at least weekly 
until ANC < Grade 2.
Recommended Action: Maintain current dose level and 
schedule.  
Delay rituximab until Grade 2 
(ANC ≥1 x 109/L); thereafter, 
resume at 500-mg/m2 dose level. If 
delay of rituximab is >4 weeks, 
discontinue bendamustine.
Delay until Grade 2 
(ANC ≥1 x 109/L); if delay is 
2-4 weeks, reduce by 1 dose level 
and consider G-CSF support. If 
delay is >4 weeks, discontinue 
bendamustine.
Grade 4
(or occurrence of 
neutropenic fever or 
infection)
Dosing:

Required Action: Withhold idelalisib.  

Recommended Action:  May resume idelalisib at 
lower dose level when ANC < Grade 3.
Required Action: Monitor blood counts at least weekly 
until ANC < Grade 2.
Recommended Action: Neutropenia should be managed 
according to established clinical guidelines.
Delay rituximab until Grade 2 
(ANC ≥1 x 109/L); thereafter, 
resume at 500-mg/m2 dose level. If 
delay of rituximab is >4 weeks, 
discontinue bendamustine.
Delay until Grade 2 
(ANC ≥0.5 x 109/L); reduce by 
1 dose level and consider G-CSF 
support. If delay is >4 weeks, 
discontinue bendamustine.
Thrombocytopenia
Grade 2
Recommended Action: Maintain current dose level and 
schedule.
Maintain 500-mg/m2 dose level and 
schedule
Maintain current dose level and 
schedule
Grade 3
Recommended Action: Maintain current dose level and 
schedule.
Delay rituximab until Grade 1
(platelets ≥75 x 109/L); thereafter,
resume at 500-mg/m2 dose level. If 
delay of rituximab is >4 weeks, 
discontinue bendamustine.
Delay until Grade 1
(platelets ≥75 x 109/L); if delay is 
2-4 weeks reduce by 1 dose level. 
If delay is >4 weeks, discontinue 
bendamustine.


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NCI CTCAE Gradea
Idelalisib
Rituximab
Bendamustine
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.
Delay rituximab until Grade 1
(platelets ≥75 x 109/L); thereafter, 
resume at 500-mg/m2 dose level. If 
delayof rituximab is >4 weeks, 
discontinue bendamustine.
Delay until Grade 1
(platelets ≥75 x 109/L); reduce by 
1 dose level. If delay is >4 weeks, 
discontinue bendamustine.
NON-HEMATOLOGICAL ADVERSE EVENT
Rash
Grade 1
Recommended Action: Maintain current dose level and 
schedule.
Maintain 500-mg/m2 dose level and 
schedule
Maintain current dose level and 
schedule
Grade 2
Recommended Action: Maintain current dose level and 
schedule.
Delay bendamustine and rituximab 
until Grade 1; thereafter, resume 
at 500-mg/m2 dose level.
Delay bendamustine and rituximab 
until Grade 1. Resume 
bendamustine at current dose level. If 
rechallenge at same dose level results 
in recurrence, may resume
bendamustine at next lower dose 
level.
Grade > 3
Required Action: Withhold idelalisib until Grade 1.
Recommended Action: Resume at lower dose level or 
discontinue idelalisib at investigator discretion.
Delay bendamustine and rituximab 
until Grade 1; thereafter, resume 
at 500-mg/m2 dose level or 
discontinue rituximab at 
investigator discretion.
Delay bendamustine and rituximab 
until Grade 1. Thereafter, resume 
at next lower dose level or 
discontinue bendamustine at 
investigator discretion.
Grade 4
Required Action: Withhold idelalisib until Grade 1. 
Recommended Action: Resume at lower dose level or 
discontinue idelalisib at investigator discretion.
Discontinue rituximab.
Discontinue bendamustine.
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.


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NCI CTCAE Gradea
Idelalisib
Rituximab
Bendamustine
Gastrointestinal Inflammation/Diarrhea
Grade 1
Required Action: Obtain history of onset and duration of 
diarrhea, including description of number of stools, stool 
composition (eg, 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 (eg, evaluate for sepsis, bowel obstruction, 
dehydration).
Recommended Action: Differentiate between small-
bowel and large-bowel diarrhea on a clinical basisb. 
Provide anti-diarrheal (eg, loperamide) and maintain 
current idelalisib dose level and schedule; ensure good 
hydration status.
Maintain 500-mg/m2 dose level and 
schedule
Maintain current dose level and 
schedule
Grade 2
Required Action: Obtain history of onset and duration of 
diarrhea, including description of number of stools, stool 
composition (eg, 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 (eg, evaluate for sepsis, 
bowel obstruction, dehydration).
Dosing:

For persistent Grade 2 Colitis or Diarrhea (without 
clear etiology):
o
Required Action: Withhold idelalisib.
o
Recommended Action: At Grade <1 may 
resume idelalisib at lower dose or discontinue 
at investigator discretion.
Maintain 500-mg/m2 dose level and 
schedule
Maintain current dose level and 
schedule


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NCI CTCAE Gradea
Idelalisib
Rituximab
Bendamustine

For Grade 2 Colitis or Diarrhea (without clear 
etiology):
o
Recommended Action: Maintain current 
idelalisib dose level and schedule.
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), testing for Clostridium difficile toxin, 
Rotavirus, Cytomegalovirus (CMV), 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 (eg, clostridium difficile 
enterocolitis) endoscopy with biopsy is strongly 
recommended to assess by immunohistochemistry (IHC) 
and PCR for CMV, Adenovirus.
 
Recommended Action: Differentiate between 
small-bowel and large-bowel diarrhea on a clinical 
basisb. Provide anti-diarrheal (eg, loperamide). Consider 
addition of anti-inflammatory agent (eg, sulfasalazine, 
budesonide). Ensure good hydration status.
CCI


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NCI CTCAE Gradea
Idelalisib
Rituximab
Bendamustine
Grade 3
Required Action: Obtain history of onset and duration of 
diarrhea, including description of number of stools, stool 
composition (eg, 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 (eg, evaluate for sepsis, 
bowel obstruction, dehydration).
Dosing:

Required Action: Withhold idelalisib.

Recommended Action: At grade <1, may resume at 
lower dose level or discontinue idelalisib at 
investigator discretion.
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), testing for Clostridium difficile toxin, 
Rotavirus, Cytomegalovirus (CMV), Adenovirus, ova 
and parasites (Cryptosporidium parvum, Isospora belli, 
Enterocytozoon bieneusi, Septata intestinalis, 
Strongyloides, Microsporidia, Entamoeba histolytica, 
Cyclospora), and Giardia antigen.
Recommended Action: Endoscopy with biopsy is 
strongly recommended to assess by 
immunohistochemistry (IHC) and PCR for CMV, 
Adenovirus.
 
 
 
 
 
Delay as necessary to ensure 
subject is sufficiently stable to 
receive further treatment; maintain 
500-mg/m2 dose level and schedule
Delay as necessary to ensure 
subject is sufficiently stable to 
receive further treatment; maintain 
current dose level and schedule
CCI


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NCI CTCAE Gradea
Idelalisib
Rituximab
Bendamustine
Grade 4
Required Action: Obtain history of onset and duration of 
diarrhea, including description, number of stools, stool 
composition (eg, 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 (eg, evaluate for sepsis, bowel obstruction, 
dehydration).
Dosing:

Required Action: Withhold idelalisib.

Recommended Action: At Grade <1, may resume at 
lower dose level or discontinue idelalisib at 
investigator discretion.
Required Action: For Grade 4 colitis or diarrhea (unless 
clinical diagnosis is established from medical history and 
physical examination), perform stool culture for routine 
pathogens (Salmonella, Shigella, Campylobacter 
species), testing for Clostridium difficile toxin, 
Rotavirus, Cytomegalovirus (CMV), Adenovirus, ova 
and parasites (Cryptosporidium parvum, Isospora belli, 
Enterocytozoon bieneusi, Septata intestinalis, 
Strongyloides, Microsporidia, Entamoeba histolytica, 
Cyclospora), and Giardia antigen.
Recommended Action: Endoscopy with biopsy is 
strongly recommended to assess by 
immunohistochemistry (IHC) and PCR for CMV, 
Adenovirus.
 
 
 
 
 
Delay as necessary to ensure 
subject is sufficiently stable to 
receive further treatment; maintain 
500-mg/m2 dose level and schedule 
or discontinue rituximab at 
investigator discretion.
Delay as necessary to ensure 
subject is sufficiently stable to 
receive further treatment; maintain 
current dose level and schedule
CCI


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NCI CTCAE Gradea
Idelalisib
Rituximab
Bendamustine
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.
Maintain 500-mg/m2 dose level and 
schedule
Maintain current dose level and 
schedule
Grade 2
(ALT/AST > 3-5xULN)
(Bilirubin > 1.5- 
3xULN)
Recommended Action: Maintain current dose level and 
schedule. Monitor ALT, AST, ALP, and bilirubin at least 
1x per week until all abnormalities are Grade <1.
Maintain 500-mg/m2 dose level and 
schedule.
Maintain current dose level and 
schedule.
Grade 3
(ALT/AST>5-20xULN)
(Bilirubin > 3-10xULN)
Recommended Action: Withhold idelalisib until ALT, 
AST, ALP, and bilirubin are Grade <1.

If bilirubin abnormality was Grade <3, resume 
idelalisib at same dose level. 

If bilirubin abnormality was Grade 3, resume 
idelalisib at lower dose level. 
Recommended Action: Monitor ALT, AST, ALP, and 
bilirubin at least 1x per week until all abnormalities are 
Grade 1. 
Delay and monitor ALT, AST, 
ALP, and bilirubin at least 1x per 
week until all abnormalities are 
Grade 1; thereafter maintain 
500-mg/m2 dose level.
Delay and monitor ALT, AST, 
ALP, and bilirubin at least 1x per 
week until all abnormalities are 
Grade 1. If bilirubin abnormality 
is Grade <3 may resume study 
drug at same dose level. If 
bilirubin abnormality is Grade 3, 
resume at next lower dose level.
Grade 4
(ALT/AST>20xULN)
(Bilirubin > 10xULN)
Required Action: Withhold idelalisib until ALT, AST, 
ALP, and bilirubin are Grade <1.

Required Action:  If bilirubin abnormality was 
Grade 4, discontinue idelalisib. 

Recommended Action:  If bilirubin abnormality 
was Grade < 4, resume idelalisib at lower dose 
level.
Required Action: Monitor ALT, AST, ALP, and 
bilirubin at least 1x per week until all abnormalities are 
Grade 1. 
Delay and monitor ALT, AST, 
ALP, and bilirubin at least 1x per 
week until all abnormalities are 
Grade 1; thereafter maintain 
500-mg/m2 dose level.
Delay and monitor ALT, AST, 
ALP, and bilirubin at least 1x per 
week until all abnormalities are 
Grade 1. If bilirubin abnormality 
is Grade <3 may resume study 
drug at same dose level. If 
bilirubin abnormality is Grade 3, 
resume at next lower dose level.


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NCI CTCAE Gradea
Idelalisib
Rituximab
Bendamustine
Pneumonitis (with new onset or worsening of baseline dyspnea, cough, or hypoxia without obvious infectious cause)
Grade 1 (asymptomatic)
Required Action: Withhold idelalisib until resolution to 
baseline. May resume at lower dose level or discontinue 
at investigator discretion.
Maintain 500- mg/m2 dose level 
and schedule.
Maintain current dose level and 
schedule.
Grade > 2
Required Action: Discontinue idelalisib permanently in 
subjects with any severity of symptomatic pneumonitis 
and institute therapy as clinically appropriate.
Grade 2: Maintain 500- mg/m2
dose level and schedule.
Grade 3: Delay as necessary to 
ensure subject is sufficiently stable 
to receive further treatment; 
maintain 500-mg/m2 dose level and 
schedule or discontinue rituximab 
at investigator discretion.
Grade 4: Discontinue rituximab.
Grade 2: Maintain current dose 
level and schedule.
Grade 3 and Grade 4: Delay as 
necessary to ensure subject is 
sufficiently stable to receive 
further treatment; maintain current 
dose level, reduce dose, or 
discontinue bendamustine at 
investigator discretion.
Pneumocystis Pneumonia
Any Grade
Required Action: Discontinue idelalisib permanently.
Organizing Pneumonia
Any Grade
Required Action: Discontinue idelalisib permanently.
Unequivocal CMV infectionc or Reactivation
Any Grade
Required Action: Interrupt idelalisib upon unequivocal clinical or laboratory evidence of CMV infection. Treat 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.
Other Nonhematological Adverse Events
Grade 2
Recommended Action: Maintain current dose level and 
schedule.
Maintain 500- mg/m2 dose level 
and schedule
Maintain current dose level and 
schedule


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NCI CTCAE Gradea
Idelalisib
Rituximab
Bendamustine
Grade 3
Recommended Action: Withhold idelalisib until 
Grade 1. May resume at lower dose level or discontinue 
idelalisib at investigator discretion.
Delay as necessary to ensure 
subject is sufficiently stable to 
receive further treatment; maintain 
500-mg/m2 dose level and schedule 
or discontinue rituximab at 
investigator discretion.
Delay as necessary to ensure 
subject is sufficiently stable to 
receive further treatment; reduce 
dose or discontinue bendamustine 
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, ANC=absolute neutrophil count, AST=aspartate aminotransferase, CMV=cytomegalovirus, 
CTCAE=Common Terminology Criteria for Adverse Events, G-CSF=granulocyte-colony-stimulating factor, NCI=National Cancer Institute, ULN=upper limit of normal


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5.4.
Evaluation, Intervention, and Drug Discontinuation for Specific Adverse 
Events or Conditions
5.4.1.
Dermatological Events
5.4.1.1.
Dermatological Events (Idelalisib)
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 pruritis and 
responded to treatment with diphenhydramine and/or topical or oral corticosteroids.
For subjects who develop a Grade >3 rash for which an underlying etiology cannot be identified 
(eg, infection, co-suspect drug), study drug must be interrupted until Grade <1; idelalisib can 
then be resumed at a lower dose level or discontinued at the investigator’s discretion.
Severe cutaneous reactions, including fatal events of Stevens-Johnson syndrome (SJS) and 
toxic epidermal necrolysis (TEN), have been reported in subjects receiving idelalisib. 
Assessment of potential causal association between idelalisib and the occurrence of SJS or TEN 
has been confounded by the coadministration of antineoplastic agents (eg, bendamustine, 
rituximab) and/or other concomitant medications known to be associated with SJS or TEN 
(eg, 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 must be discontinued if such events occur.
Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab. 
These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid 
dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis {Genentech Inc 2011}. 
The onset of these reactions has varied from 1 to 13 weeks following initiation of rituximab 
exposure. The safety of readministration of rituximab to patients with severe mucocutaneous 
reactions has not been determined; thus, for subjects experiencing a severe mucocutaneous 
reaction, rituximab should be discontinued.
Among patients receiving bendamustine, skin reactions have been reported in clinical trials and 
post-marketing safety reports {Cephalon 2012}. These events have included rash, toxic skin 
reactions, bullous exanthema, and purpura {Gavini 2012}. Cases of Stevens-Johnson syndrome 
and toxic epidermal necrolysis have been reported when bendamustine was administered 
concomitantly with allopurinol and other medications known to cause these syndromes. There 
may be an increased risk of skin toxicity in subjects receiving bendamustine together with 
trimethoprim-sulfamethoxazole. Because of coadministration of other agents, the precise 
relationship of cutaneous adverse events to bendamustine has often been uncertain. Where skin 
reactions to bendamustine do occur, they may be progressive and increase in severity with 
further treatment. Therefore, patients with skin reactions should be monitored closely. If skin 
reactions are severe or progressive, bendamustine should be discontinued.


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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.
Among patients receiving rituximab in combination with chemotherapy, rare instances of 
life-threatening bowel obstruction or perforation has been observed {Ram 2009}, primarily in 
patients with NHL. In post-marketing reports, the mean time to documented gastrointestinal 
perforation was 6 (range 1–77) days from start of chemoimmunotherapy. It is hard to draw a 
definite conclusion regarding the role of rituximab in these cases, as the affected patients had 
multiple risk factors including lymphomatous involvement of the gastrointestinal tract, other 
gastrointestinal disorders, and/or the risk of concomitant treatments with chemoradiotherapy and 
corticosteroids. Very isolated instances of inflammatory bowel disease have been seen in patients 
receiving rituximab {Ardelean 2010}.
5.4.2.1.
Investigation for Idelalisib Late Onset or Severe Diarrhea/Colitis
See CTCAE Version 4.03 for definitions of colitis and diarrhea.
Among idelalisib-treated patients who reported diarrhea or colitis, the median time to onset of 
any grade diarrhea or colitis was 1.9 months (range, 0.0–29.8), of grade 1 or 2 was 1.5 months 
(range, 0.0–15.2) and of grade 3 or 4 was 7.1 months (range, 0.5–29.8). Kaplan–Meier curves of 
time to onset of diarrhea or colitis are shown for all idelalisib- treated patients in Figure 5-1
{Coutre 2015}.


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Figure 5-1.
Kaplan-Meier Time to Diarrhea or Colitis
Idelalisib-associated severe diarrhea responds poorly to antimotility agents however, median 
time to resolution ranged between 1 week and 1 month across trials following interruption of 
idelalisib treatment and, in some instances, initiation of corticosteroid treatment
{Gilead Sciences Inc 2014}.
5.4.2.2.
Differentiation Between Small-bowel and Large-bowel Diarrhea
Differentiation between small-bowel and large-bowel diarrhea may be possible on a clinical 
basis.  If unclear, consider upper and lower tract endoscopy with biopsy.

Small bowel diarrhea is characterized by large volume diarrhea (more than 1 per day), 
possible associated dehydration, weight loss, and paraumbilical pain. Consider an endoscopic 
small-bowel biopsy and evaluate other etiologies such as celiac disease.

Large-bowel diarrhea may present with lower pelvic pain, tenesmus, generally smaller stool 
volumes with gross blood frequently found in the stool. Consider  a colonoscopic evaluation 
and biopsy.
5.4.3.
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 
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for Grade 3 or 4 elevations until resolution. These early observations have been consistent with 
the ongoing experience with idelalisib treatment and transaminase elevations are now well 
characterized as most frequently asymptomatic, transient and occurring within the first 3 months 
of treatment.
Grade 1 or 2 elevations commonly resolve despite continued idelalisib treatment and Grade 3 or 
4 elevations can be managed by withholding idelalisib. Successful rechallenge after resolution at 
either the same or lower dose level of idelalisib has been achieved in the majority of subjects. 
There has been no evidence of impaired synthetic function. Close monitoring of hepatic 
laboratory tests during therapy is important to allow for appropriate idelalisib interruption and 
reinstitution so that subjects may continue with study drug treatment.
HBV Reactivation: HBV reactivation can occur in patients treated with anti-CD20 antibodies.  
Subjects who are HBc antibody positive/HBV DNA PCR negative at screening will be 
monitored for potential HBV reactivation (manifest as detectable HBV DNA by quantitative 
PCR). Although some subjects who are HBc antibody positive with negative PCR may have had 
passive transfer of antibody from intravenous IgG, it cannot be known for certain that any such 
subject did not have natural HBV infection. Therefore, all subjects will be tested monthly for the 
duration of anti-CD20 therapy and every 3 months for 1 year following the last dose of rituximab 
during study participation. Following the completion of study participation, monitoring for HBV 
reactivation will be conducted per standard of care at the discretion of the investigator. If there is 
evidence of HBV reactivation, immediately discontinue anti-CD20 therapy and start appropriate 
treatment for HBV. In the event of HBV reactivation, please contact the Medical Monitor 
regarding continuation of idelalisib.
Product labeling for bendamustine indicates that the drug should be used with caution in patients 
with hepatic impairment of Grade 2 {Cephalon 2012}. As indicated in Table 5-6, bendamustine
administration should be delayed until any abnormalities of ALT, AST, or bilirubin are 
Grade 1. Dose modifications of bendamustine for Grade 3 bilirubin elevations appear 
warranted.
5.4.4.
Hematological and Immunological Events
In the Phase 1 experience with idelalisib in patients with NHL and CLL, subjects with Grade 3 
neutropenia, anemia, and or thrombocytopenia were enrolled to clinical trials. Decreased levels 
of neutrophil counts, hemoglobin, or platelet counts during idelalisib administration were largely 
due to minor fluctuations in these parameters among subjects with pre-existing hematological 
abnormalities due to disease or prior therapy. Thus, idelalisib did not appear to induce overt 
myelosuppression. Obvious patterns of drug-mediated reductions in circulating CD4+ 
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 at least weekly until ANC < Grade 2. For subjects who develop 
Grade 4 neutropenia, idelalisib must be interrupted and blood counts monitored at least weekly 
until ANC is Grade < 2. Idelalisib may be resumed at a lower dose when ANC < Grade 3.  
Neutropenia should be managed according to established clinical guidelines.


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Rituximab-induced B-cell depletion occurred in 70% to 80% of patients with NHL {Genentech 
Inc 2011}.  Frequencies of Grade 3 cytopenias have included lymphopenia (40%), neutropenia 
(6%), leucopenia (4%), anemia (3%), and thrombocytopenia (2%). Suppression of CD4+ counts 
has not been evident. Decreased IgM and IgG serum levels occurred in 14% of patients with 
NHL. Rituximab has not commonly been associated with bone marrow suppression; thus, 
alterations in rituximab for such events during combination therapy are not planned unless 
neutropenia is prolonged and refractory to standard of care growth factor support. In subjects 
with persistent neutropenia despite G-CSF administration, rituximab doses may be delayed for as 
long as 4 weeks to allow recovery of neutrophil counts to Grade ≤3 (see Table 5-6).
Almost all patients treated with bendamustine/rituximab have experienced myelosuppression
{Fischer 2011, Iannitto 2011}. Reductions in ANC, lymphocytes (including prolonged 
lymphocytopenia [< 600/μl] and low CD4-positive T-cell counts [< 200/μl]), platelets, and 
hemoglobin have been observed. Hematological nadirs are commonly observed several weeks 
after drug administration and may be observed for at least 7-9 months after the completion of 
treatment. Serious and fatal infections have occurred with bendamustine hydrochloride, 
including bacterial (sepsis, pneumonia) and opportunistic infections such as Pneumocystis 
jirovecii pneumonia (PJP), varicella zoster virus (VZV), and cytomegalovirus (CMV). 
Lymphocytopenia and CD4-positive T-cell depletion are more pronounced when bendamustine 
is combined with rituximab. Patients with lymphocytopenia and low CD4-positive T-cell count 
following treatment with bendamustine hydrochloride are more susceptible to (opportunistic) 
infections. Therefore, patients should be monitored for respiratory signs and symptoms 
throughout treatment. Patients should be advised to report new signs of infection, including fever 
or respiratory symptoms, promptly. Discontinuation of bendamustine hydrochloride should be 
considered if there are signs of (opportunistic) infections. Among patients with an eCCr of 
<70 mL/minute, substantially higher rates of myelosuppression and neutropenic infection were 
observed among patients with CLL receiving bendamustine/rituximab {Fischer 2011}.
Because bendamustine commonly causes severe myelosuppression, dose modification provisions 
during combination therapy will modify the bendamustine dose. At the conclusion of 
chemoimmunotherapy, subjects with protracted or symptomatic neutropenia or 
thrombocytopenia during continuing single-agent study drug therapy (idelalisib/placebo) may 
warrant a study drug dose modification if myelosuppression is unresponsive to G-CSF
supportive care or is symptomatic. 
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 
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Subjects must receive trimethoprim-sulfamethoxazole or other established prophylaxis for PJP 
throughout the course of idelalisib treatment. Prophylaxis must continue for a period of 2 to 
6 months after the last dose of idelalisib and until the CD4+ T-cell count is documented to be 
>200 cells/mcL. The duration of prophylaxis should be based on clinical judgment and may take 
into account risk factors such as concomitant corticosteroid treatment and prolonged neutropenia 
after idelalisib treatment ends. 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. 
Infection, including pneumonia and sepsis, has been reported in patients taking bendamustine in 
clinical trials and in post-marketing reports. Infection has been associated with hospitalization, 
septic shock and death. Patients with myelosuppression following treatment with bendamustine 
are more susceptible to infections. There may be an increased risk of skin toxicity when 
bendamustine is given together with trimethoprim-sulfamethoxazole.
In high-risk subjects (history of recurrent infection, allogeneic transplant, treatment with 
alemtuzumab, hypogammaglobulinemia) other infection prophylaxis should be considered per 
consensus guidelines. Administration of intravenous immunoglobulin is permitted per standard 
institutional practice {Raanani 2009}. For subjects who develop an infection, appropriate
medical therapy should be instituted in a timely manner.
5.4.6.
Infusion Reactions
Rituximab can cause severe, including fatal, infusion reactions {Genentech Inc 2011}. Patients
with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary 
adverse reactions to rituximab, and those with high numbers of circulating malignant cells 
(25 x 109/L) may be at particular risk. Severe reactions typically occur during the first infusion 
and are generally less frequent and less severe with subsequent infusions. The time to onset of 
infusion toxicity ranges from 30 to 120 minutes. Rituximab-induced infusion reactions and 
sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary 
infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, 
cardiogenic shock, and/or anaphylactoid events.


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For a subject who is experiencing a Grade 3 rituximab-related infusion reaction, the rituximab 
infusion should be interrupted and the infusion rate decreased. Medical management 
(eg, oxygen, epinephrine, bronchodilators, and/or glucocorticoids) should be instituted, as 
needed. Upon improvement of symptoms, the infusion may be continued at 50% of the previous 
rate. At the discretion of the investigator, rituximab therapy may be permanently discontinued in 
subjects with Grade 4 infusion reactions or with reactions requiring substantial intervention.
For a subject with a greater risk of infusion reactions due to a pretreatment ALC of 25 x 109/L, 
the Day 1 rituximab infusion may be limited to 100 mg total drug (ie, 1 vial of rituximab) and the 
remainder of the planned total rituximab dose may be administered prior to bendamustine on 
Day 2.
Infusion reactions attributed to bendamustine have occurred in clinical trials. Symptoms have 
included fever, chills, pruritus, and rash. In rare instances severe anaphylactic and anaphylactoid 
reactions have occurred, particularly in the second and subsequent cycles of therapy. There are 
postmarketing reports of bendamustine extravasations resulting in hospitalizations from 
erythema, marked swelling, and pain. Precautions should be taken to avoid extravasation, 
including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and 
necrosis during and after administration of bendamustine.
Measures to prevent severe bendamustine infusions reactions, including antihistamines, 
antipyretics, and corticosteroids can be considered in subsequent cycles in patients who have 
previously experienced Grade 1 or 2 bendamustine-induced infusion reactions. Discontinuation 
of bendamustine should be considered in patients with Grade 3 bendamustine-related infusion 
reactions.
5.4.7.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) due to polyomavirus JC has been observed 
in patients who have received rituximab therapy {Carson 2009} for hematologic malignancies.
The specific causal role of rituximab is unknown because many of these patients had other risk 
factors (eg, low CD4+ counts) and the majority had received rituximab in combination with 
chemotherapy or as part of a hematopoietic stem cell transplant. Most cases of PML were 
diagnosed within 12 months of the last infusion of rituximab.
The diagnosis of PML should be considered in any subject presenting with new-onset neurologic 
manifestations. Evaluation of PML may include consultation with a neurologist, brain MRI, and
lumbar puncture with quantitative PCR assays targeting the DNAs of JC, VZV, CMV and 
HHV-6. Subjects diagnosed with PML should receive no further rituximab. Study drug 
(idelalisib/placebo) should also be permanently discontinued.
5.4.8.
Pulmonary Events
Documented bacterial, fungal, viral, and pneumocystis pneumonias have been observed in 
patients receiving idelalisib, primarily in patients with CLL. Some study subjects receiving 
idelalisib alone or in combination have developed evidence of pneumonitis and organizing 
pneumonia, respectively, without documented pulmonary infection. 


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Rituximab-related noninfectious pneumonitis has been described {Subramanian 2010} with an 
incidence of ~4.3% {Salmasi 2010}. In patients developing rituximab-associated pneumonitis, 
the mean time from the first rituximab infusion to the onset of respiratory symptoms was 
3 months, with a peak incidence after administration of a mean cumulative dosage of 
1600 mg/m2 {Liote 2010}. 
Pneumonias and pulmonary fibrosis have occurred in patients receiving bendamustine 
{Cephalon 2012}.
Given the potential for infectious or drug-related pulmonary adverse events, clinicians should be 
particularly observant for evidence of respiratory events in subjects participating in this trial. 
Subjects who describe pulmonary symptoms (eg, dyspnea on exertion, cough, shortness 
of breath); manifest a decline from baseline of 5% in oxygen saturation, or demonstrate 
evidence of pulmonary inflammation (eg, focal or diffuse interstitial pattern or ground-glass 
opacities on chest CT) should be evaluated. Potential bacterial, fungal, or viral etiologies should 
be assessed. Noninfectious etiologies such as pulmonary edema or thromboembolism should also 
be considered.
As appropriate for the clinical situation and culture results, subjects should be treated empirically 
or given specific antibiotics, antifungals, or antiviral agents for a cultured organism.
For subjects with suspected Grade 1 pneumonitis, withhold idelalisib/placebo until resolution to 
baseline. Upon resolution to baseline, idelalisib/placebo may be resumed at a lower dose level or 
discontinued at investigator discretion. For subjects with suspected Grade > 2 pneumonitis 
(eg, new onset or worsening of baseline cough, dyspnea, hypoxia and/or a diffuse interstitial 
pattern or ground-glass opacities on chest imaging without obvious infectious etiology),
idelalisib/placebo must be discontinued permanently and therapy initiated as clinically 
appropriate.
Cases of organizing pneumonia, some with fatal outcome, have occurred with idelalisib. In 
subjects presenting with serious lung events, idelalisib should be interrupted and the subject 
assessed for an explanatory etiology. If organizing pneumonia is diagnosed, treatment with 
idelalisib should be permanently discontinued and the subject treated accordingly.
5.4.9.
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.


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5.4.10.
Tumor Lysis Syndrome
Tumor lysis syndrome has not been observed with idelalisib monotherapy.
When idelalisib is combined with other agents known to induce tumor lysis syndrome, 
prophylaxis with agents such as allopurinol may be considered. The benefit versus risk of 
prophylactic agents must be carefully considered given a potential of increased risk of severe 
skin toxicity.
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 including study drug (idelalisib/placebo).
5.4.11.
Cardiac Disorders
Fatal cases of myocardial infarction and cardiac failure have been reported with bendamustine 
hydrochloride treatment. Subjects with concurrent or history of cardiac disease should be 
observed closely.  
5.4.12.
Pregnancy, Lactation, and Reproduction
Idelalisib has induced embryo lethality and teratogenicity when administered to pregnant female 
rats at maternally toxic doses. However, definitive reproductive toxicology studies in animals 
have not yet been performed and the specific effects of idelalisib on human embryogenesis or 
fetal development are unknown. Whether idelalisib is excreted in human breast milk is unknown.
General toxicology studies of idelalisib in rats and dogs indicated dose-dependent reductions in 
testicular weights, with persistent minimal to mild degeneration of the seminiferous tubules and 
decreased spermatozoa in rats and hypospermatogenesis in dogs. The implications of these 
testicular changes for animal or human fertility are unknown.
Reproduction studies of rituximab in cynomolgus monkeys at maternal exposures similar to 
human therapeutic exposures have shown no teratogenic effects {Genentech Inc 2011}. 
However, B-cell lymphoid tissue was reduced in the offspring of these animals; B-cell counts 
returned to normal levels and immunologic function was restored within 6 months of birth. In 
humans, B-cell lymphocytopenia generally lasting <6 months can occur postnatally in infants 
exposed to rituximab in utero. Rituximab is secreted in the milk of lactating 
cynomolgus monkeys, and IgG is excreted in human milk {Genentech Inc 2011}. However, 
antibodies in breast milk do not enter the neonatal infant circulations in substantial amounts. It is 
not known whether rituximab is secreted into human milk.
Bendamustine is a mutagen and clastogen. Single intraperitoneal doses of bendamustine in mice 
and rats administered during organogenesis caused an increase in resorptions, skeletal and 
visceral malformations, and decreased fetal body weights. It is not known whether bendamustine 
is excreted in human milk. Impaired spermatogenesis, azoospermia, and total germinal aplasia 
have been reported in male patients treated with alkylating agents, especially in combination 


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with other drugs. In some instances spermatogenesis may return in patients in remission, but this 
may occur only several years after intensive chemotherapy has been discontinued.
Given the potential the risks to a fetus or infant as a result of exposure to idelalisib, women of 
reproductive potential entering this study must have a negative serum pregnancy test at baseline 
and must not be breastfeeding. Males and females of childbearing potential should abstain from 
sexual intercourse or use an effective form of contraception (see Section 5.6.4). If a female study 
participant becomes pregnant or decides to breastfeed during the course of the study, all study 
therapy (idelalisib/placebo, rituximab and bendamustine) must be discontinued.
5.4.13.
PJP Prophylaxis
Trimethoprim sulfamethoxazole is rated a Pregnancy category C agent.  In rats, oral doses of 
533 mg/kg or 200 mg/kg produced teratologic effects manifested mainly as cleft palates. 
One survey found no congenital abnormalities in 35 children whose mothers had received oral 
sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter. Because 
sulfamethoxazole and trimethoprim may interfere with folic acid metabolism it should be used 
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Dapsone is rated a Pregnancy Category C agent.  Extensive, but uncontrolled experience and 
two published surveys on the use of Dapsone in pregnant women have not shown that Dapsone 
increases the risk of fetal abnormalities if administered during all trimesters of pregnancy or can 
affect reproduction capacity. Because of the lack of animal studies or controlled human 
experience, Dapsone should be given to a pregnant woman only if clearly needed. Dapsone is 
excreted in breast milk in substantial amounts. Hemolytic reactions can occur in neonates. 
Because of the potential for tumorgenicity shown for Dapsone in animal studies a decision 
should be made whether to discontinue nursing or discontinue the drug taking into account the 
importance of drug to the mother.
Atovaquone is rated a Pregnancy Category C agent.  Atovaquone is teratogenic and did not cause 
reproductive toxicity in rats at plasma concentrations up to 2 to 3 times the estimated human 
exposure. Atovaquone can cause maternal toxicity in rabbits at plasma concentrations that were 
approximately one half the estimated human exposure. Mean fetal body lengths and weights were 
decreased and there were higher numbers of early resorption and post-implantation loss per dam. It is 
not clear whether these effects are caused by atovaquone directly or are secondary to maternal 
toxicity. Concentrations of atovaquone in rabbit fetuses averaged 30% of the concurrent maternal 
plasma concentrations.  There are no adequate and well-controlled studies in pregnant women. 
Atovaquone should be used during pregnancy only if the potential benefit justifies the potential risk 
to the fetus. It is not known whether atovaquone is excreted into human milk. Because many drugs 
are excreted into human milk, caution should be exercised when Atovaquone is administered to a 
nursing woman. In a rat study, atovaquone concentrations in the milk were 30% of the concurrent 
atovaquone concentrations in the maternal plasma.
Aerosolized Pentamidine (NebuPent) is a Pregnancy Category C agent.  There are no adequate and 
well controlled studies of NebuPent in pregnant women. One literature report indicated that 
intravenously administered pentamidine in pregnant rats at 4 mg/kg/day was embryolethal; 
teratogenicity was not observed in this study. It is unknown whether pentamidine administered via 


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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.
5.4.14.
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.
5.4.15.
Further Safety Information
Further safety information regarding the study drug may be found in the investigator brochure 
for idelalisib. Further information regarding bendamustine and rituximab can be found in the 
respective product information.
5.5.
Emergency Unblinding
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IWRS system 
for that subject. Gilead recommends but does not require that the investigator contact the 
Gilead medical monitor before breaking the blind. Treatment assignment should remain blinded 
unless that knowledge is necessary to determine subject emergency medical care. The rationale 
for unblinding must be clearly explained in source documentation and on the 
case report form/electronic case report form (CRF/eCRF), along with the date on which the 
treatment assignment was obtained. The investigator is requested to contact the 
Gilead medical monitor promptly in case of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).


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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 corticosterioids (see Section 5.6.5), no other systemic anticancer therapies (including 
chemotherapy, radiation, antibody therapy, immunotherapy, or other experimental therapies) of 
any kind are permitted while the subject is receiving study treatment with idelalisib. Discuss the 
use of topical anticancer agents (eg, topical 5-FU) with the medical monitor.  Subjects are not 
allowed to participate concurrently in any other therapeutic clinical study.
5.6.2.
Antibiotics
Investigators must initiate antibiotic prophylaxis against pneumocystis infection (eg, with 
trimethoprim-sulfamethoxazole, dapsone, aerosolized pentamidine, or atovaquone) beginning 
prior to study drug administration. Such support may also offer the benefit of reducing the risk 
for other bacterial infections {Green 2007}. Investigator discretion and local practices or
guidelines may be followed. It should be realized that there may be an increased risk of skin 
toxicity in subjects receiving bendamustine together with trimethoprim-sulfamethoxazole.
For subjects who develop an infection, appropriate medical therapy (with antibiotics, antifungals, 
or antiviral) or other interventions should be instituted. When appropriate, subjects may continue 
with study drug (idelalisib/placebo) and bendamustine/rituximab during treatment for the 
infection; however, subjects who develop PJP must permanently discontinue study drug.


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5.6.3.
Antiemetics and Antidiarrheals
Drug-related nausea and/or vomiting have not been commonly observed with idelalisib or 
rituximab. Bendamustine is moderately emetogenic. 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 
(defined as age ≥54with 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 throughout the study and for 30 days from the last dose of study drug 
(idelalisib/placebo) or >12 months from the last dose of rituximab (whichever is later). The 
investigator should counsel subjects on the most effective methods for avoiding pregnancy 
during the trial. Protocol-recommended contraceptive methods are described in Table 5-7.
Table 5-7.
Protocol-Recommended Contraceptive Methods
Individual Methods
Combination Methods
Hormonal Methods
(One method to be used
with a barrier method)
Barrier Methods
(Both of these methods to be used OR 
one of these methods to be used
with a hormonal method)
IUD

Copper T 380A IUD

LNg 20 IUD
Tubal sterilization
Hysterectomy
Estrogen and progesterone
Oral contraceptives
Transdermal patch
Vaginal ring
Progesterone
Injection
Implant
Diaphragm with spermicide
Male condom
(with spermicide)
Abbreviation: IUD=intrauterine device


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In the context of this protocol, a male subject is considered able to father a child unless he has 
had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or is receiving
ongoing testicular suppression with a depot luteinizing hormone-releasing hormone (LH-RH) 
agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or 
triptorelin pamoate [Trelstar®]).
Sexually active male subjects who can father a child must limit intercourse to female partners 
who are surgically sterile, post-menopausal, or using effective contraception 
(as noted in Table 5-7); or agree to use a protocol-recommended method of contraception during 
heterosexual intercourse throughout the study and until >6 months following the last dose of 
bendamustine or >90 days following the last dose of study drug (whichever is later)
(as noted in Table 5-7). 
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 treatment (idelalisib/placebo or 
rituximab). However, systemic corticosteroids should be used to prevent rituximab infusion 
reactions. Low-dose corticosteroids for treatment of rheumatological conditions are permitted. In 
addition, subjects who develop conditions that may be alleviated by systemic corticosteroid 
therapy are permitted to receive such drugs and are not required to discontinue study 
participation.
5.6.6.
Granulocyte Colony-Stimulating Factors and Erythropoietin
Granulocyte-macrophage colony-stimulating factor (GM-CSF) should not be administered given 
the potential for GM-CSF-related inflammatory symptoms.
G-CSF (filgrastim, PEG-filgrastim, lenograstim) may be administered in response to Grade 4
neutropenia or neutropenic complications; use should be particularly considered if providing 
hematopoietic support might help to maintain study drug treatment (see Table 5-6).
While erythropoietic agents (eg, erythropoietin or darbepoetin) may be administered for 
Grade 3 anemia, their use in this study is discouraged given the potential to confound 
assessments of improvements in bone marrow function related to study drug.
Reference may be made to the American Society of Clinical Oncology guidelines {Rizzo 2008, 
Smith 2006}.


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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 an ~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 5-8:
Table 5-8.
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 CYP3-A-Dependent Metabolism
The major metabolite of idelalisib, GS-563117, is a reversible and time dependent inhibitor of 
CYP3A; accordingly, coadministration of idelalisib with midazolam, a probe CYP3A substrate, 
resulted in a ~5-fold increase in midazolam systemic exposure (AUC), indicating that idelalisib 
is a strong inhibitor of CYP3A. Coadministration of CYP3A substrates with idelalisib may result 
in an increase in their systemic exposures (eg, antiarrhythmics, calcium channel blockers, 
benzodiazepines, certain HMG-CoA reductase inhibitors, phosphodiesterase-5 [PDE5]
inhibitors, warfarin). Avoid coadministration of drugs that are narrow therapeutic index CYP3A 
substrates (eg, alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, fentanyl, 
quinidine, ergotamine, dihydroergotamine, astemizole, terfenadine) with idelalisib.
5.6.9.
Immunization
Because of its actions to inhibit PI3Kδ-dependent B-cell function, high doses of idelalisib can 
impair primary or secondary responses to immunization in animals.
In randomized clinical trials, rituximab has been shown to reduce the antibody response to 
pneumococcal vaccination (a T-cell-independent antigen) or to anti-keyhole limpet hemocyanin 
antibodies (a novel protein antigen) {Genentech Inc 2011}. Response to tetanus toxoid vaccine
(a T-cell-dependent antigen with existing immunity) or maintenance of a positive 
Candida skin test (as a measure of T-cell-mediated delayed-type hypersensitivity) was not 
altered.


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The specific clinical relevance of these findings with idelalisib or rituximab 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 or rituximab 
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 (idelalisib/placebo) 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 (idelalisib/placebo) may be 
taken with or without food.
5.7.
Duration of Study Drug
Subjects may continue receiving study drug (idelalisib/placebo) until the occurrence of any 
events requiring study drug discontinuation as defined in Section 5.8.
Subjects may continue to receive rituximab until the earliest of a maximum of 6 infusions or the 
occurrence of any events requiring rituximab discontinuation as defined in Section 5.8.
Subjects may continue to receive bendamustine until the earliest of a maximum of 12 infusions 
or the occurrence of any events requiring bendamustine discontinuation as defined in 
Section 5.8.
Bendamustine may be continued even if rituximab is discontinued due to rituximab-specific 
toxicity. Similarly, rituximab may be continued even if bendamustine is discontinued due to 
bendamustine-specific toxicity. Subjects who are tolerating study drug (idelalisib/placebo) 
should continue study drug even if bendamustine or rituximab are discontinued due to 
bendamustine- or rituximab-related toxicities or due to an inability to continue bendamustine- or 
rituximab therapy.
5.8.
Discontinuation of Study Drug
All study participants may receive idelalisib/placebo indefinitely and may receive rituximab 
through 6 infusions and bendamustine through 12 infusions as noted in Section 5.7. However:

Any subject has the right to discontinue study drug, rituximab, or bendamustine at any time.

Any subject who has objective evidence based on IRC review of definitive CLL progression
will discontinue study drug.


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
Any subject that is unable to tolerate a rechallenge with protocol-described, dose-modified 
study drug (idelalisib/placebo) at Dose Level –1 (100 mg/dose BID) (see Section 5.3.5) 
should be withdrawn from the study drug.

Any subject who becomes pregnant or begins breastfeeding must discontinue study drug.

Any subject who becomes significantly noncompliant with study drug administration, study 
procedures, or study requirements should discontinue study drug.

Any subject for whom the blind is intentionally broken by the subject or the study site should 
discontinue study drug.

The investigator, in consultation with the Gilead Sciences medical expert, may discontinue 
study drug, rituximab, or bendamustine, if it is not in the subject’s best interest to continue.

Following study-wide unblinding, any subject randomized to Arm B should discontinue 
study drug.

Any subject whose benefit-risk profile is not deemed positive by the investigator should 
discontinue study drug.

Any subject who is diagnosed with any grade of SJS, TEN, PJP, or organizing pneumonia, or 
any subject diagnosed with Grade ≥2 pneumonitis should discontinue study drug.
If allowed by local regulations, Gilead Sciences may transition subjects from study drug to 
commercial drug supply when idelalisib becomes commercially available in the country where 
the subject is living.
Subjects who permanently discontinue study drug for a reason other than disease progression 
(as determined by the IRC) shall continue with regular assessments per the schedule of 
procedures until disease progression or another anticancer or experimental therapy is initiated.
5.9.
Discontinuation from Study
Subject study participation may 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, 
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
Physician’s decision to remove the subject from the study;

Pregnancy;

The subject is lost to follow-up; 

Death;

Discontinuation of study by the Sponsor, a Regulatory Agency, or an IRB or EC.
5.10.
Study Treatment Rationale
Selection of the idelalisib treatment regimen (including starting dose level, dose-modifications 
and supportive care, schedule, duration, and conditions of administration) for this study has been 
based primarily on safety, exposure, and activity profiles from previous Phase 1 clinical studies 
involving healthy volunteers, patients with allergic rhinitis, and patients with refractory/relapsed
lymphoid malignancies {Coutre 2011, de Vos 2011, Kahl 2011, Sharman 2011, Webb 2010}. 
The following information was considered in selecting the study drug dosing regimen for this 
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 appear tolerable, the starting 
dose of 150 mg/dose BID appears to appropriately balance safety with efficacy in 
idelalisib-naïve subjects. 

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 a dose-level approximating that to be used in this 
Phase 3 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.

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 a starting 
dose of idelalisib of 150 mg/dose BID appears appropriate to ensure adequate exposure in the 
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
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.

Study drug 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 in Arm A is likely to extend treatment effect. In addition, this design 
permits collection of further single-agent safety information without concomitant 
bendamustine/rituximab administration and thus is likely to enhance understanding of the 
overall safety profile of idelalisib. 
Use of the reference therapies, rituximab and bendamustine, in this study is based on product 
labeling {Cephalon 2012, Genentech Inc 2011}, precedence established with rituximab and 
bendamustine in patients with CLL {Fischer 2011, Iannitto 2011}, and clinical observations 
relating to coadministration of bendamustine/rituximab with idelalisib {de Vos 2011, Sharman 
2011}:

Product labeling for use of rituximab in CLL describes intravenous administration of the 
drug in combination with fludarabine/cyclophosphamide chemotherapy every 4 weeks for a 
total of 6 infusions; the first rituximab dose is administered at dose of 375 mg/m2 (Week 0) 
and the subsequent 5 doses are administered at a dose of 500 mg/m2 (Weeks 4, 8, 12, 16, 
and 20). A similar schedule was adopted by the German CLL Study Group in establishing a 
regimen of bendamustine/rituximab {Fischer 2011}. The doses and schedule of the rituximab 
regimen used in both the control and treatment arms of this study are based on these past 
experiences. 

Product labeling for use of bendamustine in CLL describes intravenous administration of the
drug on Days 1 and 2 every 4 weeks for a total of 12 infusions; a similar schedule was 
adopted by the German CLL Study Group in establishing a regimen of 
bendamustine/rituximab {Fischer 2011}. The data from Phase 1 evaluation documented a an 


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MTD of 70 mg/m2 {Lissitchkov 2006}; this dose level was confirmed to have substantial 
activity based on the Phase 2 experience of the German CLL Study Group {Fischer 2011}
and has been generally adopted as appropriate when bendamustine is coadministered with 
rituximab in patients who had received prior therapy {Cheson 2010}. 

Truncation of bendamustine/rituximab therapy at 6 months is consistent with 
recommendations in product labeling and the existing Phase 2 data {Fischer 2011, Iannitto 
2011} in patients with previously treated CLL.

In a Phase 1, single-arm, dose-ranging study, concomitant administration of idelalisib at dose 
of 150 mg/dose BID together with bendamustine or bendamustine/rituximab has been shown 
to be safe and active {de Vos 2011, Sharman 2011}.

Recommendations for managing rituximab- and bendamustine-related adverse events, and 
delay, dose-modifying, or discontinuing rituximab therapy for specific adverse events are 
consistent with experience described in product labeling {Cephalon 2012, Genentech Inc 
2011}.

Consistent with the current product package insert, subjects who are HBc antibody positive at 
screening shall be monitored for HBV reactivation (manifest as detectable HBV DNA by 
quantitative PCR). Subjects will be tested monthly for the duration of rituximab therapy and 
every 3 months thereafter for 1 year from the end of therapy.


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6.
STUDY PROCEDURES
6.1.
Enrollment and Study Management Procedures
6.1.1.
Subject Recruitment
Study candidates comprise subjects with CLL who are being followed at the specified study sites 
or are referred to the study sites. Subjects will be enrolled from investigational sites in the US
and Europe. The site principal investigator, designated sub-investigators, or other designees will 
discuss the possibility of participation directly with subjects who may be appropriate candidates 
for the study. The study sponsor will post a description of the study on the ClinicalTrials.gov 
website.
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 subject. The IWRS will use this information to assign a subject number 
and maintain a central screening log that tracks screening, screen failures, and randomization.
Any consented subject who is excluded from the study before randomization 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 randomization. 


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Study GS-US-312-0115 shares many screening requirements with Study GS-US-312-0116 and 
GS-US-312-0119. In some instances, a patient may initiate screening for one trial but may prove 
ineligible for that study and may subsequently be judged to be eligible for another of these 
idelalisib studies. To reduce the burden to such a study candidate and to avoid redundancy of 
assessments that do not affect the safety of trial subjects, the following screening assessments 
performed for any of Study GS-US-312-0115, GS-US-312-0116, or GS-US-312-0119 can be 
used in screening for another of these trials or for rescreening for the same study. These tests do 
not need to be repeated if they fall into the screening windows defined below and there has been 
no intervening therapy for CLL between the time of the test and randomization to the study:

CLL peripheral blood or bone marrow evaluations (ie, FISH, DNA mutational analysis, 
flow cytometry, and cytology) used for determining stratification and CLL prognosis –
if obtained within 12 weeks prior to randomization

Baseline CT/MRI scan – if obtained within 6 weeks prior to randomization
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 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 visits designated as a laboratory-only visits (Visits 4, 7, 10, 13, 16, and 19), 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.
At Visit 2 (Randomization and Treatment Start), local hematology results lab values (full CBC) 
should be obtained in addition to the required central lab values in order to prevent missing 
baseline results, should the central lab results become compromised (eg, due to hemolysis, etc.).


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Throughout the study, local lab results may be requested in the event central laboratory results 
are not available for assessment of disease response, progression, safety monitoring, 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 3.5.1.
6.2.1.
Visit 1 and Screening Period (Clinic Visit)
The initial screening visit is designated as Visit 1. At Visit 1, the investigator must inform each 
prospective study participant of the nature of the study, explain the potential risks, and obtain 
written informed consent from the study candidate and/or legal guardian prior to performing any 
study-related screening procedures. Once the informed consent document has been signed, the 
subject may undergo the screening procedures. The presence of radiographically measurable 
lymphadenopathy will be confirmed by the IRC during the screening period.
In order to optimize scheduling convenience for the subject and for the investigational staff, 
screening procedures may be performed over as many days as necessary provided that screening 
is completed within 4 weeks prior to randomization. Of note, the screening period may be 
extended to 6 weeks in subjects for whom there is a delay in the analysis of stratification 
variables (p53 mutation/17p deletion status or IgHV mutation status) or a delay in the acquisition 
of adequate baseline radiographic imaging data.
The tests and evaluations outline in Table 6-1 will be performed at Visit 1 or during the 
screening period prior to randomization.


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Table 6-1.
Procedures and Assessments at Visit 1 (Screening Period)
Assessment or Procedure
Explanation
Informed consent
To be obtained before any screening procedures are initiated
IWRS access
Access IWRS to document that subject is in screening and obtain subject number
Medical history
Including relevant information regarding CLL history, stage of disease
(Rai and Binet staging system) reasons for treatment, prior therapies for CLL, 
documentation of relapsed or refractory CLL, and past history of other medically 
significant medical conditions
CIRS assessment
Recording of 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 assessment of height, weight, lymph nodes, spleen, and liver
Serum virology
Including HBsAg, HBc antibody, HCV antibody, HIV antibody, CMV serology; 
if HCV antibody is positive, subjects must be evaluated for the presence of circulating 
HCV viral RNA
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
Coagulation
aPTT, PT, INR
Urinalysis
Including pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, 
leukocyte esterase
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
12-lead ECG
To be obtained while subject is resting in the supine position
Radiology assessment
CT or MRI imaging of neck, chest, abdomen, and pelvis, to be scheduled within 
6 weeks prior to randomization
Bone marrow biopsy and 
aspirate
To be performed at investigator discretion in subjects for whom assessment of extent 
of CLL involvement and bone marrow cellularity is important in determining eligibility
Abbreviations: -HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
aPTT=activated partial thromboplastin time, AST=aspartate aminotransferase, CIRS=cumulative illness rating scale, 
CLL=chronic lymphocytic leukemia, CMV=cytomegalovirus, CT=computed tomography, DNA=deoxyribonucleic acid, 
ECG=electrocardiogram, FISH= fluorescence in-situ hybridization, GGT=gamma--glutamyltransferase, 
HBc antibody=anti-hepatitis B core antibody, HBsAg=hepatitis B surface antigen, HBV=hepatitis B virus, HCV=hepatitis C 
virus, HIV=human immunodeficiency virus, INR=international normalized ratio, IgHV=immunoglobulin heavy chain variable 
region, IWRS=interactive web response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, 
PT=partial thromboplastin time, RNA=ribonucleic acid, ZAP-70=zeta-associated protein 70


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6.2.2.
Visit 2 (Clinic Visit – Randomization and Treatment Start)
The procedures outlined in Table 6-2 will be performed at Visit 2.
Table 6-2.
Procedures and Assessments at Visit 2 (Day 1)
Assessment or Procedure
Explanation
Pre-Treatment 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 
other procedures are performed and before 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 assessment of weight, lymph nodes, spleen, and liver
Urine β-HCG dipstick
For women of child-bearing potential only; serum -HCG or urine dipstick pregnancy 
test must be negative prior to randomization and initial study treatment
Hematology
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count. An 
additional sample should also be collected and analyzed locally.
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 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
Genotyping and expression 
analysis
Including blood for DNA, RNA and protein isolation for potential future assessment 
of biomarkers (subjects may choose to not provide DNA sample)
Idelalisib pharmacokinetics
Pre-dose collection of plasma sample for idelalisib pharmacokinetics
(with recording of the date and actual clock time of blood collection)
HBV DNA by PCR
Only subjects who are HBc antibody positive and HBV DNA negative at screening, 
per Section 5.4.3.
IWRS access
Access of IWRS to stratify and randomize subject, and to obtain study drug bottle 
number


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Assessment or Procedure
Explanation
Study Treatment Administration
Study drug administration
First dose of study drug (idelalisib/placebo) to be administered to the subject in clinic 
(with recording of the date and actual clock time of the study drug administration)
Pretreatment
Antipyretic and antihistamine to be administered to the subject at the same time as 
study drug (idelalisib/placebo) and ~30 minutes prior to rituximab infusion; an 
intravenous corticosteroid and antiemetics may also be given as premedications per 
local practices
Rituximab infusion
Rituximab, 375 mg/m2, to be administered by intravenous infusion ~30 minutes after 
pretreatment
Bendamustine infusion
Bendamustine intravenous infusion to be started at completion of rituximab; 
bendamustine to be administered over ~60 minutes.
Rituximab infusion 
severity and duration 
assessment
Worst severity of rituximab infusion reaction to be graded and total duration of 
rituximab infusion to be recorded
Post-Treatment Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours +/- 30 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 12-week supply of study drug (idelalisib/placebo) to the subject with 
instructions for self-administration at home
Instruction regarding 
in-clinic study drug dosing
Instruction to the subject that the morning dose of study drug (idelalisib/placebo) 
should not be taken on the day of the next treatment clinic visit.
Abbreviations: -HCG=beta human chorionic gonadotropin, AKT=AKT (a serine/threonine protein kinase), 
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, DNA=deoxyribonucleic acid, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 
GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, mTOR=mammalian target of rapamycin,
PI3K=phosphatidylinositol 3-kinase, RNA=ribonucleic acid
6.2.3.
Visits 3, 6, 9, 12, 15, and 18 (Clinic Visit –Bendamustine Administration) 
The procedures outlined in Table 6-3 will be performed at Visits 3, 6, 9, 12, 15, and 18 
(Day 2 of treatment cycle).
Table 6-3.
Procedures and Assessments at Visits 3, 6, 9, 12, 15, and 18 (+1 Day)
Assessment or Procedure
Explanation
Study Treatment Administration
Study drug 
Morning dose of study drug (idelalisib/placebo)
to be taken orally by the subject at home.
Pretreatment
Antiemetics may be given to minimize bendamustine-related nausea.
Bendamustine infusion
Bendamustine intravenous infusion to be administered over ~60 minutes.


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6.2.4.
Visits 4, 7, 10, 13, 16, and 19 (Laboratory Visits)
The procedures outlined in Table 6-4 will be performed at Visits 4, 7, 10, 13, 16, and 19.
Table 6-4.
Procedures and Assessments at Visits 4, 7, 10, 13, 16, and 19 (2 Days)
Assessment or Procedure
Explanation
Hematologya
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count
Serum chemistrya
Including ALT, AST, ALP, GGT, total bilirubin, LDH
a
More frequent (eg, weekly) hematology/serum chemistry assessments may be appropriate in subjects experiencing Grade 3 
myelosuppression or ALT/AST elevations.
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
GGT=gamma-glutamyltransferase, LDH=lactate dehydrogenase
6.2.5.
Visit 5 (Clinic Visit)
The procedures outlined in Table 6-5 will be performed at Visit 5.
Table 6-5.
Procedures and Assessments at Visit 5 (2 Days)
Assessment or Procedure
Explanation
Pre-Treatment 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 
other procedures are performed and before study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the last clinic visit
Concomitant medications
Recording of concomitant medication use since the last clinic visit
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 assessment of weight, lymph nodes, spleen, and liver
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 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


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Assessment or Procedure
Explanation
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)
HBV DNA by PCR
Only subjects who are HBc antibody positive and HBV DNA negative at screening, 
per Section 5.4.3.
IWRS access
Access of IWRS to document subject visit
Study Treatment Administration
Study drug administration
Morning dose of study drug (idelalisib/placebo) to be administered to the subject in 
clinic (with recording of the date and actual clock time of the study drug 
administration)
Pretreatment
Antipyretic and antihistamine to be administered to the subject at the same time as 
study drug (idelalisib/placebo) and ~30 minutes prior to rituximab infusion; an 
intravenous corticosteroid and antiemetics may also be given as premedications per 
local practices
Rituximab infusion
Rituximab, 500 mg/m2, to be administered by intravenous infusion ~30 minutes after 
pretreatment
Bendamustine infusion
Bendamustine intravenous infusion to be started at completion of rituximab; 
bendamustine to be administered over ~60 minutes.
Rituximab infusion 
severity and duration 
assessment
Worst severity of rituximab infusion reaction to be graded and total duration of 
rituximab infusion to be recorded
Post-Treatment Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours +/- 30 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Instruction regarding 
in-clinic study drug dosing
Instruction to the subject that the morning dose of study drug (idelalisib/placebo) 
should not be taken on the day of the next treatment clinic visit
Abbreviations: AKT=AKT (a serine/threonine protein kinase), 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, Ig=immunoglobulin, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, mTOR=mammalian target of rapamycin, 
PI3K=phosphatidylinositol 3-kinase


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6.2.6.
Visits 8, 14, and 17
(Clinic Visits – Rituximab and Bendamustine Administration)
The procedures outlined in Table 6-6 will be performed at Visits 8, 14, and 17.
Table 6-6.
Procedures and Assessments at Visits 8, 14, and 17 (2 Days)
Assessment or Procedure
Explanation
Pre-Treatment 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 
other procedures are performed and before study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the last clinic visit
Concomitant medications
Recording of concomitant medication use since the last clinic visit
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 assessment of weight, lymph nodes, spleen, and liver
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 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)
HBV DNA by PCR
Only subjects who are HBc antibody positive and HBV DNA negative at screening, 
per Section 5.4.3.
IWRS access
Access of IWRS to document subject visit


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Assessment or Procedure
Explanation
Study Treatment Administration
Study drug administration
Morning dose of study drug (idelalisib/placebo) to be administered to the subject in 
clinic (with recording of the date and actual clock time of the study drug 
administration)
Pretreatment
Antipyretic and antihistamine to be administered to the subject at the same time as 
study drug (idelalisib/placebo) and ~30 minutes prior to rituximab infusion; an 
intravenous corticosteroid and antiemetics may also be given as premedications per 
local practices
Rituximab infusion
Rituximab, 500 mg/m2, to be administered by intravenous infusion ~30 minutes after 
pretreatment
Bendamustine infusion
Bendamustine intravenous infusion to be started at completion of rituximab; 
bendamustine to be administered over ~60 minutes.
Post-Treatment Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours +/- 30 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Instruction regarding 
in-clinic study drug dosing 
Instruction to the subject that the morning dose of study drug (idelalisib/placebo) 
should not be taken on the day of the next treatment clinic visit
Abbreviations: AKT=AKT (a serine/threonine protein kinase), 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, Ig=immunoglobulin, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, mTOR=mammalian target of rapamycin, 
PI3K=phosphatidylinositol 3-kinase


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6.2.7.
Visit 11 (Radiology and Clinic Visit – Rituximab and Bendamustine 
Administration)
The procedures outlined in Table 6-7 will be performed at Visit 11.
Table 6-7.
Procedures and Assessments at Visit 11 (3 Days)
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-Treatment 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 
other procedures are performed and before study-related information is 
communicated to the subject
Adverse events
Recording of adverse events occurring since the last clinic visit
Concomitant medications
Recording of concomitant medication use since the last clinic visit
Study drug return/
accounting
Counting of returned study drug (idelalisib/placebo)
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 assessment of weight, lymph nodes, spleen, and liver
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 CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for CR, 
it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish CR.
Idelalisib pharmacokinetics
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)


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Assessment or Procedure
Explanation
HBV DNA by PCR
Only subjects who are HBc antibody positive and HBV DNA negative at screening, 
per Section 5.4.3.
IWRS access
Access of IWRS to obtain study drug bottle number
Study Treatment Administration
Study drug administration
Morning dose of study drug (idelalisib/placebo) to be administered to the subject in 
clinic (with recording of the date and actual clock time of the study drug 
administration)
Pretreatment
Antipyretic and antihistamine to be administered to the subject at the same time as 
study drug (idelalisib/placebo) and ~30 minutes prior to rituximab infusion; an 
intravenous corticosteroid and antiemetics may also be given as premedications per 
local practices
Rituximab infusion
Rituximab, 500 mg/m2, to be administered by intravenous infusion ~30 minutes after 
pretreatment
Bendamustine infusion
Bendamustine intravenous infusion to be started at completion of rituximab; 
bendamustine to be administered over ~60 minutes.
Post-Treatment Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours +/- 30 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 12-week supply of study drug (idelalisib/placebo) to the subject with 
instructions for self-administration at home
Instruction regarding 
in-clinic study drug dosing
Instruction to the subject that the morning dose of study drug (idelalisib/placebo) 
should not be taken on the day of the next treatment clinic visit
Abbreviations: AKT=AKT (a serine/threonine protein kinase), 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, HRQL=health-related quality of life, 
GGT=gamma-glutamyltransferase, Ig=immunoglobulin, IWRS=interactive web response system, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging, mTOR=mammalian target of rapamycin, PI3K=phosphatidylinositol 3-kinase


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6.2.8.
Visit 20 (Radiology and Clinic Visit)
The procedures outlined in Table 6-8 will be performed at Visit 20.
Table 6-8.
Procedures and Assessments at Visit 20 (3 Days)
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; assessment should be done even if study drug has been interrupted.
Pre-Treatment 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 
other procedures are performed and before study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since the last clinic visit
Concomitant medications
Recording of concomitant medication use since the last clinic visit
Study drug return/
accounting
Counting returned study drug (idelalisib/placebo)
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 assessment of weight, lymph nodes, spleen, and liver
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 CD4+, CD5+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry
Biomarkers
Collection of plasma and serum for evaluation of circulating chemokines and 
cytokines
Serum Igs
Including quantitative levels of IgA, IgE, IgG, and IgM
Bone marrow biopsy and 
aspirate
To be performed post-baseline to confirm response category in subjects with potential 
CR by radiological assessments. If the subject does not otherwise meet criteria for CR, 
it is not necessary to obtain a follow-up bone marrow biopsy/aspirate to establish CR.
Idelalisib pharmacokinetics
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)
HBV DNA by PCR
Only subjects who are HBc antibody positive and HBV DNA negative at screening, 
per Section 5.4.3
IWRS access
Access of IWRS to obtain study drug bottle number


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Assessment or Procedure
Explanation
Study Treatment Administration
Study drug administration
Morning dose of study drug (idelalisib/placebo) to be administered to the subject in 
clinic (with recording of the date and actual clock time of the study drug 
administration)
Post-Treatment Procedures and Assessments
Idelalisib pharmacokinetics
Post-dose collection of plasma sample for idelalisib pharmacokinetics at
1.5 hours +/- 30 mins after study drug administration
(with recording of the date and actual clock time of blood collection)
Study drug dispensing
Dispensing of 12-week supply of study drug (idelalisib/placebo) to the subject with 
instructions for self-administration at home
Abbreviations: AKT=AKT (a serine/threonine protein kinase), 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, HRQL=health-related quality of life, 
GGT=gamma-glutamyltransferase, Ig=immunoglobulin, IWRS=interactive web response system, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging, mTOR=mammalian target of rapamycin, PI3K=phosphatidylinositol 3-kinase


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6.2.9.
Visits 21 and 23 (Clinic Visits)
The procedures outlined in Table 6-9 will be performed at Visits 21 and 23.
Table 6-9.
Procedures and Assessments at Visits 21 and 23 (3 Days)
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 
other procedures are performed and before study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since the last clinic visit
Concomitant medications
Recording of concomitant medication use since the last clinic visit
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 assessment of weight, lymph nodes, spleen, and liver
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 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
HBV DNA by PCR
Only subjects who are HBc antibody positive and HBV DNA negative at screening, 
per Section 5.4.3.
IWRS access
Access of IWRS to document subject visit
Abbreviations: AKT=AKT (a serine/threonine protein kinase), 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, Ig=immunoglobulin, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, mTOR=mammalian target of rapamycin, 
PI3K=phosphatidylinositol 3-kinase


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6.2.10.
Visits 22 and 24 (Radiology and Clinic Visits)
The procedures outlined in Table 6-10 will be performed at Visits 22 and 24.
Table 6-10.
Procedures and Assessments at Visits 22 and 24 (3 Days)
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.
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 
other procedures are performed and before study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since the last clinic visit
Concomitant medications
Recording of concomitant medication use since the last clinic visit
Study drug return/
accounting
Counting returned study drug (idelalisib/placebo)
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 assessment of weight, lymph nodes, spleen, and liver
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 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
HBV DNA by PCR
Only subjects who are HBc antibody positive and HBV DNA negative at screening, 
per Section 5.4.3.
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 bottle number
Study drug dispensing
Dispensing of 12-week supply of study drug (idelalisib/placebo) to the subject with 
instructions for self-administration at home
Abbreviations: AKT=AKT (a serine/threonine protein kinase), 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, HRQL=health-related quality of life, 
GGT=gamma-glutamyltransferase, Ig=immunoglobulin, IWRS=interactive web response system, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging, mTOR=mammalian target of rapamycin, PI3K=phosphatidylinositol 3-kinase


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6.2.11.
Visit 25 and Subsequent Visits (Every 12 Weeks) 
(Radiology and Clinic Visits)
The procedures outlined in Table 6-11 will be performed at Visit 25 and subsequent visits.
Table 6-11.
Procedures and Assessments at Visit 25 and Subsequent Visits 
(Every 12 Weeks [7 Days])
Assessment or Procedure
Explanation
Pre-Visit Tumor Assessment
Radiology assessmentb
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.
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 
other procedures are performed and before study-related information is 
communicated to the subject
Adverse events 
Recording of adverse events occurring since the last clinic visit
Concomitant medications
Recording of concomitant medication use since the last clinic visit
Study drug return/
accounting
Counting returned study drug (idelalisib/placebo)
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 assessment of weight, lymph nodes, spleen, and liver
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 CD4+a, 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


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Assessment or Procedure
Explanation
HBV DNA by PCR
Only subjects who are HBc antibody positive and HBV DNA negative at screening, 
per Section 5.4.3.
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 bottle number
Study drug dispensing
Dispensing of 12-week supply of study drug (idelalisib/placebo) to the subject with 
instructions for self-administration at home
a
CD4+ T-cell count must be performed upon idelalisib discontinuation and continued until count is > 200 cells/mcL, at which 
point PJP prophylaxis may be discontinued
b
As of Amendment 10, Version 11, CT/MRI assessments will no longer be performed at the every 12 week scheduled visits, 
and will only be performed at the time of clinically-suspected disease progression or at study discontinuation.
Abbreviations: AKT=AKT (a serine/threonine protein kinase), ALP=alkaline phosphatase, ALT=alanine 
aminotransferase, AST=aspartate aminotransferase, CMV=cytomegalovirus, CT=computed tomography, EQ-5D=EuroQoL 
Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, HRQL=health-related quality of life, 
GGT=gamma-glutamyltransferase, Ig=immunoglobulin, IWRS=interactive web response system, LDH=lactate dehydrogenase, 
MRI=magnetic resonance imaging, mTOR=mammalian target of rapamycin, PI3K=phosphatidylinositol 3-kinase
6.2.12.
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 6-12. 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 6-12.
Procedures and Assessments at End-of-Study Visit
Assessment or Procedure
Explanationa
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 (idelalisib/placebo)
Performance status
Using Karnofsky performance status criteria (see Appendix 3)
Oxygen saturation
To be assessed by pulse oximetry while subject is breathing room air


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Assessment or Procedure
Explanationa
Physical examination
Including assessment of weight, lymph nodes, spleen, and liver
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
Genotyping and expression 
analysis
Including blood for DNA, RNA and protein isolation for potential future assessment 
of biomarkers (subjects may choose to not provide DNA sample)
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 CD4+b, 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
HBV DNA by PCR
Only subjects who are HBc antibody positive and HBV DNA negative at screening, 
per Section 5.4.3.
Immune monitoring
Lymphocyte subset panel using flow cytometry (immunophenotyping), serum CH50 
level
IWRS
Access IWRS to document that subject has permanently discontinued study therapy
a
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.
b
CD4+ T-cell count must be performed upon idelalisib discontinuation and continued until count is > 200 cells/mcL, at which 
point PJP prophylaxis may be discontinued.
Abbreviations: -HCG=beta human chorionic gonadotropin, AKT=AKT (a serine/threonine protein kinase), 
ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CLL=chronic lymphocytic leukemia, CMV=cytomegalovirus, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, 
FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, 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, 
mTOR=mammalian target of rapamycin, PI3K=phosphatidylinositol 3-kinase, RNA=ribonucleic acid, 
ZAP-70=zeta-associated protein 70
6.2.13.
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.


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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
Subjects will be asked to consent to allow a portion of the blood and tissue samples collected at 
study visits or as part of standard of care during study participation to be stored. The stored 
samples may be used by the Sponsor or its research partners to further investigate the safety and 
mechanism of action of the study drug and to investigate the effects of treatment on the disease. 
At the conclusion of this study, these samples will be retained in storage by the Investigator or 
Gilead Sciences, Inc. for a period up to 10 years.
6.4.
Blood Collection
The maximum amount of blood to be drawn at a visit is ~125 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 ~490 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 ~1.4 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.
Serum and plasma may be retained for subjects who have provided specific informed consent for 
sample banking. As noted in Section 10.1.4 of the protocol, subject confidentiality will be 
maintained, but sufficient information will be retained to permit sample data to be connected 
with the unique subject number assigned to each study participant. These samples will be 
retained consistent with the information provided in Section 10.1.5 of the protocol.
6.5.
Study Procedure Rationale
The planned study assessments and timing have been selected as appropriate for screening of 
subjects, for determination of drug- 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 3.5.


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7.
EFFICACY ASSESSMENTS
7.1.
Tumor Status Assessments
The determination of CLL response and progression will be based on standardized IWCLL 
criteria {Hallek 2008}, as specifically modified for this study to reflect current recommendations 
which consider the mechanism of action of idelalisib and similar drugs {Cheson 2012}. During 
the course of the study, investigators will periodically assess the status of each subject’s CLL. If 
CLL progression is suspected, the IRC will be notified and will review radiographic and 
pertinent clinical data in order to provide expert interpretation (see Section 10.4.3). The findings 
of the IRC will be considered primary for analyses of PFS and other tumor control endpoints.
7.2.
Method of Assessment
In addition to clinical examination, imaging-based evaluation will be used in this study in all 
subjects enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI 
scanning may be used at the investigator’s discretion in subjects for whom this may be a 
preferred alternative to CT scanning; however, if MRI is performed, a non-contrast CT of the 
chest should be performed. Contrast-enhanced scanning is preferred, but iodine-containing or 
gadolinium contrast material may be omitted in subjects for whom use of a contrast agent would 
be medically contraindicated. Chest x-ray, ultrasound, endoscopy, laparoscopy, PET, 
radionuclide scans, or tumor markers will not be considered for response assessment.
For radiographic evaluations, the same method of assessment and the same technique 
(eg, scan type, scanner, subject position, dose of contrast, injection/scan interval) should be used 
to characterize each identified and reported lesion at baseline and during study treatment and 
follow-up. However, if a subject is imaged without contrast at baseline, subsequent assessments 
should be performed with contrast, unless the subject cannot tolerate the contrast.
All relevant clinical and radiographic information required to make each tumor status assessment 
must be made available for source verification and for submission to the IRC (see Section 10.4.3).
CT/MRI performed as standard of care, prior to signing the ICF and within 6 weeks of 
randomization, may be used to fulfill the screening requirement. If this option is used the scans 
must follow the same conditions set above.
7.3.
Timing of Assessments
During screening, clinical and imaging-based tumor assessments should be performed within 
6 weeks prior to randomization. Clinical tumor assessments should be performed at each clinical 
visit. On-study CT/MRI tumor assessments should be performed as indicated in Appendix 7. As 
of Amendment 10, Version 11, CT/MRI assessments will no longer be performed at the every 
12 week scheduled visits, and will only be performed at the time of clinically-suspected disease 
progression or at study discontinuation. An end-of-study CT/MRI tumor assessment should be 
performed unless the subject already has radiographic confirmation of disease progression within 


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4 weeks prior. If a subject permanently discontinues study drug prior to objective documentation 
of CLL progression, investigators should continue further follow-up ~12-week intervals until 
CLL progression is documented by the central IRC.
7.4.
Identification and Follow-up 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 during 
treatment. The cross-sectional dimensions (the largest cross-sectional diameter, 
ie, the LD × the LPD will be recorded (in cm) for each index lesion. The PPDs will be 
calculated. The PPDs and the SPDs for all index lesions will be calculated and recorded. The 
baseline SPDs will be used as references by which objective 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 centimeters 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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 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”.
CCI


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


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7.5.2.
Partial Response
To satisfy criteria for a PR, all of the following criteria must be met:

No evidence of new disease

Change in disease status meeting 2 of the following criteria, with 2 exceptions in which 
only 1 criterion is needed: (1) Only lymphadenopathy is present at baseline; 
(2) Only lymphadenopathy and lymphocytosis are present at baseline. In these 2 cases, only 
lymphadenopathy must improve to the extent specified below:
In a subject with baseline lymphocytosis (ALC4 x 109/L), a decrease in peripheral blood 
ALC by 50% from baseline or a decrease to <4 x 109/L
A decrease by 50% from the baseline in the SPD of the index nodal lesions
In a subject with enlargement of the spleen at baseline, a splenomegaly response as 
defined in Section 7.4.2
In a subject with enlargement of the liver at baseline, a hepamegaly response as defined 
in Section 7.4.2
A decrease by 50% from baseline in the CLL marrow infiltrate or in 
B-lymphoid nodules

No index, splenic, liver, or non-index disease with worsening that meets the criteria for 
definitive PD

Peripheral blood counts meeting 1 of the following criteria:
ANC >1.5 x 109/L or 50% increase over baseline without need for exogenous growth 
factors (eg, G-CSF)
Platelet count 100 x 109/L or 50% increase over baseline without need for exogenous 
growth factors
Hemoglobin 110 g/L (11.0 g/dL) or 50% increase over baseline without red blood cell 
transfusions or need for exogenous growth factors (eg, erythropoietin)
7.5.3.
Stable Disease
To satisfy criteria for SD, the following criteria must be met:

No evidence of new disease

There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD


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7.5.4.
Definitive Progressive Disease
The occurrence of any of the following events indicates definitive PD:

Evidence of any new disease:
A new node that measures >1.5 cm in the LD and >1.0 cm in the LPD
New or recurrent splenomegaly, with a minimum LVD of 14 cm
New or recurrent hepatomegaly, with a minimum LVD of 20 cm
Unequivocal reappearance of an extra-nodal lesion that had resolved (ie, had previously 
been assigned a PPD of 0 cm2)
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 from the nadir by 50% in the SPD of index lesions
Increase from the nadir by 50% in the LD if an individual node or extra-nodal mass that 
now has an LD of >1.5 cm and an LPD of > 1.0 cm
Splenic progression, defined as an increase in splenic enlargement by 50% from nadir 
(with a minimum 2 cm increase and a minimum LVD of 14 cm)
Hepatic progression, defined as an increase in hepatic enlargement by 50% from nadir
(with a minimum 2 cm increase and minimum LVD of 20 cm)
Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or other 
organ abnormalities related to CLL) 
Transformation to a more aggressive histology (eg, Richter syndrome) as established by 
biopsy (with the date of the biopsy being considered the date of CLL progression if the 
subject has no earlier objective documentation of CLL progression).


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
Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to an 
autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an infiltrate of 
clonal CLL cells
The current platelet count is <100 x 109/L and there has been a decrease by >50% from 
the highest on-study platelet count 
The current hemoglobin is <110 g/L (11.0 g/dL) and there has been a decrease by 
>20 g/L (2 g/dL) from the highest on-study hemoglobin
Note: Due to the possibility of bendamustine-induced toxicity, the above criteria for platelet or 
hemoglobin decrease in subjects receiving bendamustine may not be indicative of definitive 
disease progression in the absence of other objective evidence of worsening CLL. If there is 
uncertainty regarding whether there is true progression, the subject should continue study 
treatment and remain under close observation 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 is experiencing persistent definitive CLL progression, then the date of 
progression should be the timepoint at which progression was first objectively documented.
7.5.5.
Non-Evaluable
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE:

There are no images or inadequate or missing images.

Images of the liver and spleen are missing at that time point (with the exception that absence 
of splenic images will not result in an NE designation in a subject known to have undergone 
splenectomy).
Note: A time-point will be considered to have a response of NE if any index lesion is missing. 
PD may be assigned at any time point regardless of the extent of missing index or non-index 
lesions. Missing non-index lesions will not impact the ability to assess for response or disease 
progression.
7.5.6.
No Disease
Subjects have a status of ND if all of the following conditions occur:

No index disease noted at baseline or on-treatment.

No non-index disease noted at baseline or on-treatment.


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
No enlargement of the liver or spleen at baseline or on-treatment

No abnormalities of peripheral blood counts (elevated ALC or abnormally low ANC, 
platelet count, or hemoglobin) and no evidence of CLL in bone marrow (if available) at 
baseline or on treatment
7.6.
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, the occurrence of lymphocytosis will not preclude subjects from meeting the 
criteria for a PR if other criteria for PR are met and will not be considered evidence of CLL 
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.
7.7.
Documentation of Definitive CLL Progression
Of importance, CLL response and progression data will be subjected to IRC review 
(see Section 5.8). If there is uncertainty regarding whether there is definitive progression, the 
subject should continue study drug pending confirmation of progression status by the IRC.


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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; the event does not necessarily have a causal 
relationship with study drug administration or usage. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 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 (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 5.2.1.8)

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 5.4.11 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.

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 medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such events might include:
Allergic bronchospasm requiring intensive treatment in an emergency room or at home
New cancers or blood dyscrasias
Convulsions that do not result in hospitalization
Development of drug dependency or drug abuse


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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 8.7. 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 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 
30 days after last administration of study IMP must be reported to the CRF database as 
instructed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported.
All AEs should be followed up until resolution if possible. If by the last day on study 
(including the off-study medication follow-up period) the AE has not resolved, then the AE will 
be followed up until the investigator and/or Gilead Sciences determine that the subject's 
condition is stable. However, Gilead Sciences may request that certain AEs be followed until 
resolution.
Investigators are not obligated to actively seek SAEs after the 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 
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
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 
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. The end of the adverse-event-reporting period occurs 30 days after the 
discontinuation of study or when any ongoing drug-related adverse events and/or serious adverse 
events have resolved or become stable. A subject withdrawn from the study because of an 
adverse event must be followed until the clinical outcome from the adverse event is determined. 
The investigator should use appropriate judgment in ordering additional tests as necessary to 
monitor the resolution of events ongoing at the completion of study treatment. Gilead Sciences 
may request that certain adverse events be followed longer. Investigators are not obligated to 
actively seek information regarding the occurrence of new serious adverse events beginning after 
the 30-day post-study period. However, if the investigator learns of such a serious adverse event 
and that event is deemed relevant to the use of the study drug, he/she should promptly document 
and report the event. A longer reporting period applies in the case of pregnancy 
(see Section 8.9.1).
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.
Site reporting requirements for adverse events are summarized in Table 8-2, below.


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Table 8-2.
Site Reporting Requirements for Adverse Events
Classification
Reporting Time
Reporting Action
Serious
Within 24 hours
Fax report on designated serious adverse event report form to 
PPD Pharmacovigilancea, and to the site IRB/IEC, as per 
local IRB/IEC requirements; include copies of relevant 
source documentsb (eg, progress notes, autopsy reports, 
laboratory and diagnostic test results, discharge summaries) 
in communication to PPD Pharmacovigilancea
Per eCRF submission procedurec
Record and submit information on appropriate eCRFs
Nonserious
Per eCRF submission procedure
Record and submit information on appropriate eCRFs
a
See contact information in Table 8-3 below.
b
Subject name, address, and other personal identifiers should be obscured but without losing the traceability of a document to
the study subject identifiers.
c
CLL progression or death due to CLL progression should be reported by the investigator as a serious adverse event only if it 
is assessed that the study drugs caused or contributed to the CLL progression (ie, by a means other than lack of effect). 
Unrelated events of CLL progression should be captured on the appropriate eCRF. 
Abbreviations: CLL=chronic lymphocytic leukemia, eCRF=case report form, IRB/IEC= Institutional Review Board/
Independent Ethics Committee
For serious adverse events, in addition to completing the adverse event portion of the eCRF, the 
serious adverse event report form must also be completed. The information in the adverse event 
portion of the eCRF page and the serious adverse event report form(s) must match or be 
reconciled. Where the same data are collected, the forms must be completed in a consistent 
manner. For example, the same adverse event term should be used on both forms. Particularly for 
fatal or life-threatening events, copies of progress notes, autopsy reports, laboratory and 
diagnostic test results, discharge summaries, and other relevant documents should be e-mailed or 
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:
+44 
Gilead Sciences
Medical Monitor
Name:
Title:
Director, Clinical Research
Office Telephone:
Mobile Telephone:
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 in female subjects on study or female 
partners of male subjects on study.
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


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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 PPD Pharmacovigilance or Gilead DSPH using the 
pregnancy report form within 24 hours of becoming aware of the pregnancy. Refer to the 
CRF/eCRF completion guidelines for full instructions on the mechanism of pregnancy reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE, and therefore should be reported as 
such. Furthermore, any SAE occurring as an adverse pregnancy outcome post study must be 
reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to PPD Pharmacovigilance or Gilead DSPH using 
the pregnancy outcome report form. If the end of the pregnancy occurs after the study has been 
completed, the outcome should be reported directly to Gilead DSPH. Gilead DSPH contact 
information is as follows: Email: 
 and Fax:
PPD
PPD


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Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to PPD Pharmacovigilance 
or Gilead DSPH using the pregnancy and pregnancy outcome forms within 24 hours. Monitoring 
of the subject should continue until the conclusion of the pregnancy. If the end of the pregnancy 
occurs after the study has been completed, the outcome should be reported directly to 
Gilead DSPH, fax number
 or email 
8.9.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to PPD Pharmacovigilance or Gilead DSPH within 24 hours of the investigator 
becoming aware of the situation. These reports must consist of situations that involve study IMP, 
but do not apply to concomitant medications. Except for situations that result in AEs, special 
situations involving concomitant medications will not be reported. Any inappropriate use of 
medications prohibited by this protocol should not be reported as “misuse,” but may be more 
appropriately documented as a protocol deviation.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.
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9.
STATISTICAL CONSIDERATIONS
9.1.
Analyis Objectives
As noted in Section 3.1, the primary objective of this clinical trial will be to evaluate the effect of 
the addition of idelalisib to bendamustine/rituximab on PFS.
As described in Section 3.2, the secondary objectives of this clinical trial will focus on 
determining the effect of the addition of idelalisib to bendamustine/rituximab 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
9.2.1.
Primary Endpoint
The primary endpoint of the study is PFS, as defined in Section 3.3.
9.2.2.
Secondary and Tertiary Endpoints
The secondary and tertiary endpoints of the study are defined in Section 3.4, grouped in 
categories relating to tumor control, patient well-being, pharmacodynamic markers of drug 
activity and resistance, exposure, safety, and pharmacoeconomics.
Of these endpoints, 4 endpoints are designated as secondary endpoints for which sequential 
testing will be performed to control Type 1 error rate (see Section 9.3.4.6). These secondary 
endpoints will be ORR, lymph node response rate, OS, and CR rate. Other endpoints will be 
considered tertiary.
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 are randomized regardless of whether subjects 
receive any study drug(s), or receive a different regimen from the regimen they were randomized 
to. Treatment assignment will be designated according to randomization. 
This analysis set will be used in the analyses of subject characteristics, PFS, ORR, OS, and CR 
rate. The analysis of PFS based on the ITT analysis set will be considered the primary analysis of 
the study. 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 (ie, the best overall responses 
of NE and ND) will be included in the denominator in the calculation of response rates. 


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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 desingnated 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 the primary and secondary efficacy 
endpoints: PFS, ORR, lymph node response rate, and CR rate.
9.3.1.3.
Safety Analysis Set
A safety analysis set will include data from subjects who receive 1 dose of study treatment, 
with treatment assignments designated according to the actual treatment received.
This analysis set will be used in the analyses of safety variables as well as study treatment 
administration (for idelalisib, placebo, rituximab, and bendamustine), and post-study therapy.
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. 


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The baseline value used in each analysis will be the last (most recent) pre-treatment value
(or pre-randomization value for non-treated subjects). Subjects with discrepancies between the 
stratification factor values at randomization and the actual values as documented on data review 
will be categorized in the analyses according to the actual values. In the situation that there is 
insufficient information in a stratum (ie, if there are <6 subjects or there is no informative event 
in a stratum), that stratum will be pooled with the smallest adjacent stratum for stratified 
analyses; the smallest stratum is defined as that stratum having the fewest number of subjects or 
the fewest number of events in case the former is a tie and the adjacent stratum is defined as a 
stratum having 2 factors of the 3 at the same level. 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.
Unless otherwise specified, all analyses will be 2-sided at the 0.05 level of significance.
9.3.2.2.
Calculation of Tumor Control and Patient Well-Being Variables
Tumor control assessments will be based on standardized IWCLL criteria {Hallek 2008}, as
specifically modified for this study considering the pharmacology of idelalisib, rituximab, and 
bendamustine. The individual and composite endpoints of response and progression 
 
 will be determined. 
Tumor control will be documented at each assessment by response category (eg, CR, PR, 
SD, definitive PD) 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 relevent objective radiographic or laboratory data. Because of the characteristic 
redistribution lymphocytosis that expected with PI3Kinhibition, lymphocyte count will be 
ignored in the evaluations of progression. Changes in tumor status as provided by the 
investigator and changes in tumor status as adjudicated by the IRC (see Section 10.4.3) will be 
described. The findings of the IRC will be considered primary for analyses of PFS and other 
tumor control endpoints.
The following censoring conventions will be applied:

PFS: Data from surviving, non-progressing subjects will be censored at the earliest of the 
time of initiation of antitumor treatment other than the study treatment or the last time that 
lack of definitive CLL progression was objectively documented. 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.

 
 
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
 
. 

 

 

 
 
.

 
 
9.3.3.
Subject Disposition and Baseline Characteristics
A listing of all ITT analysis set subjects will be generated to describe site, subject number, 
first screening date, first treatment date, subject stratification, randomized study drug assignment 
(idelalisib/placebo), actual study drug assignment, the longest duration of study drug and 
rituximab treatment, and the reason for discontinuing study treatment. Available information on 
subjects who were screened or registered but not randomized or 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 and stratification 
factor for the ITT analysis set. Imbalances in subject characteristics may be compared using the 
Wilcoxon rank-sum test for continuous variables and the Fisher’s exact test for categorical 
variables. 
9.3.4.
Efficacy Analyses
9.3.4.1.
Primary and Supportive Analyses of the Primary Endpoint
For the primary efficacy analysis, the difference in PFS between the treatment arms will be 
assessed in the ITT analysis set using Kaplan-Meier methods and the stratified log-rank test,
adjusted for the stratification factors. Medians, ranges, the proportion of subjects who are 
progression-free at 24 and 48 weeks from randomization (based on Kaplan-Meier estimates), 
hazard ratios and corresponding 95% CIs (as calculated using a Cox proportional hazards 
regression model) will be presented. The significance level of the primary analysis will be 
adjusted as appropriate to account for alpha spending at the planned interim analyses
(see Section 9.5.1).
CCI
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The following exploratory sensitivity analyses will be performed:
The Cox regression approach will be used to explore the influence of the stratification factors,
other baseline characteristics, and treatment on PFS. Beyond the stratification variables, 
additional baseline subject characteristics may be included as covariates, focusing on those with 
expected prognostic significance, particularly if these show imbalance between treatment groups. 
For the Cox regression modeling, a stepwise selection process will be applied to these variables 
to identify the final subset of relevant factors. Each prognostic factor will be preliminarily 
evaluated in the Cox regression model. Only the variables significant at the 0.20 level will be 
considered to build the multivariate model. A forward selection process will be applied to these 
variables to identify the final subset of relevant factors. Once a model has been established, 
treatment will be added to the final subset of factors to study its effect on the model. 
Treatment-by-factor interactions will be explored for the subset of factors included in the final 
model.
9.3.4.2.
Other Time-to-Event Tumor Control and Survival Endpoints
 
 
9.3.4.3.
Categorical Endpoints 
Differences between Arms A and B for ORR, CR and PR rates, l
 
 
 In the analyses of ORR, subjects who do not 
have sufficient baseline or on-study tumor assessment to characterize response will be counted as 
failures. For all analyses, odds ratios and the corresponding 95% CIs will be presented.
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The potential influence of subject baseline characteristics and of treatment on response rates will 
be explored with logistic regression modeling.
9.3.4.4.
Continuous Endpoints
 
 
 
 
 
9.3.4.5.
Health-Related Quality of Life and Performance Status
The FACT-Leu questionnaire data will be scored, processed, and standardized 
(ranging from 0-100) according to the user manual. Missing items in a subscale will be imputed 
consistently 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.
The mean change from baseline in mean scores to each subsequent assessment will be 
summarized. The best change from baseline during the study, defined as the highest value among 
all post-baseline visits minus the baseline value, will also be summarized. Subjects who are 
lost-to-follow-up will be excluded, ie, missing data will not be imputed. In the analyses of 
FACT-Leu data, particular focus will be placed on changes in subject reports relating to CLL 
(focusing specifically on fever, chills, night sweats, lymphadenopathy, and fatigue).
9.3.4.6.
Control of Type I Error Rate in Efficacy Analyses 
In the efficacy analyses, the following procedures will be implemented to preserve the overall 
type I error rate across the primary and secondary endpoints of the study at a 2-sided 
significance level of 0.032.
The primary endpoint analysis will serve as the gatekeeper for the secondary endpoint analyses, 
ie, the primary efficacy hypothesis must be rejected at the 2-sided 0.05 significance level before 
the efficacy hypotheses for the secondary efficacy endpoints can be tested. The secondary 
endpoints will be the following:

ORR

Lymph node response rate 

OS

CR rate
CCI


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If the primary hypothesis is rejected, the 4 secondary endpoints will be sequentially tested at the 
2-sided 0.032 significance level in the order listed above. If a null hypothesis is not rejected, 
formal sequential testing will be stopped and only nominal significance will be cited for the 
remaining secondary endpoints. Analyses and p-values will be reported for all the efficacy 
endpoints, including the primary endpoint, the secondary endpoints, and all of the tertiary 
endpoints.
9.3.5.
Exposure and Safety Analyses
9.3.5.1.
Study Drug Administration and Study Drug Compliance
Descriptive information will be provided by treatment arm regarding the number of doses of 
idelalisib, placebo, rituximab, and bendamustine prescribed, the total number of doses taken, the 
percent of expected doses taken, the number of days (or infusions) of treatment, and the number 
and timing of prescribed dose reductions and interruptions.
Study drug (idelalisib/placebo) 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).
9.3.5.2.
Idelalisib Plasma Concentrations
Bioanalytical analyses will performed independently so that the study team and investigators will 
not have knowledge of data from individual subjects. For Arm A, the 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.
9.3.5.3.
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. To the extent available, information on the sequencing, type, dose, schedule, timing, 
duration of use, and efficacy of prior regimens will be provided. In addition, details regarding 
response and duration of the last prior antineoplastic therapy before randomization will be 
described.
The type and timing of use of concomitant medications will be listed and summarized by type 
and treatment arm. Information regarding the type and use of specific supportive medications 
(eg, pneumocystis prophylaxis, hematopoietic growth factors, corticosteroids) during study 
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9.3.5.4.
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 
(idelalisib, placebo, rituximab, or bendamustine) to 30 days after the last dose of study drug. 
Adverse events will be classified using MedDRA (http://www.meddramsso.com) with 
descriptions by System Organ Class, High-Level Group Term, High-Level Term, 
Preferred Term, and Lower-Level Term. The severity of adverse events will be graded by the 
investigator according to the CTCAE, Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf), 
whenever possible. If a CTCAE criterion does not exist for a specific type of adverse event, the 
grade corresponding to the appropriate adjective will be used by the investigator to describe the 
maximum intensity of the adverse event: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), 
Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the adverse event to the study 
drug will be categorized as related or unrelated.
Treatment-emergent adverse events will be summarized by treatment arm. 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 (idelalisib/placebo) 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)
The severity of rituximab-related infusion reactions and of the total durations of rituximab 
infusions will be compared to determine whether idelalisib pretreatment modifies the magnitude 
of such events or alters the length of the rituximab infusion due to such events; the focus of this 
analysis will be on the first 2 rituximab infusions (ie, those on Day 1 and on Day 29 of therapy). 
Comparisons will be done using the Chi-square test for severity grade and the Wilcoxon 
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Separate listings and summaries will be prepared for long-term follow-up safety data 
(see Section 6.2.13).
9.3.5.5.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed data. 
The focus of laboratory data summarization will be on treatment-emergent laboratory 
abnormalities. A treatment-emergent laboratory abnormality is defined as an abnormality that, 
compared to baseline, worsens by 1 grade in the period from the first dose of study drug 
(idelalisib, placebo, rituximab, or bendamustine) 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.
9.3.5.6.
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).
9.3.6.
Other Analyses
9.3.6.1.
Health Care Resource Utilization
The EQ-D5 questionnaire data will be scored, processed, and standardized according to the user 
manual. As for the FACT-Leu, data will be analyzed using appropriate methods to account for 
incomplete completion of questionnaires. Data collected from the EQ-D5 will not be reconciled 
with adverse event or laboratory data or with FACT-Leu findings.


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Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations.
The basic approach to the health economic analysis will be to combine the resource utilization 
data from the trial with data on unit prices (collected separately) to estimate total costs in 
preparation for a full-cost analysis.
The perspective of this analysis will be that of the third-party payer and the hospital over a 
lifetime horizon in the base case. One possibility is that the addition of idelalisib to 
bendamustine/rituximab will reduce costs directly and, if so, perhaps no further analysis will be 
required. A second possibility is that the addition of idelalisib to bendamustine/rituximab will 
increase costs overall. In this latter case the increase in costs due to adding idelalisib to treatment 
will be compared relative to the health care gains as measured by duration of tumor control, the 
symptom-free survival period, life-years saved (gained), utility gains 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. One-way, 2-way, and probabilistic 
sensitivity analyses will be conducted to assess the robustness of the results.
9.3.6.2.
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. Similarly, 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).
9.4.
Sample Size
9.4.1.
Sample Size Calculation
Based on data from prior studies with bendamustine/rituximab {Fischer 2011, Iannitto 2011}, it 
is reasonable to assume that administration of the combination to subjects with previously treated 
CLL in Arm B of this trial will result in a median PFS of ~15 months. An improvement in 
median PFS from 15 months to 22.5 months due to the addition of idelalisib to 
bendamustine/rituximab in Arm A of the study would correspond to a benefit ratio of 1.5 
(hazard ratio 0.67). This treatment effect seems achievable in view of the fact that the Phase 1-2 
multicenter experience with single-agent idelalisib in heavily pretreated patients has indicated a 
median PFS of >14 months {Coutre 2011}.
It is assumed that PFS times are exponentially distributed in each of the 2 arms. With a hazard 
ratio equal to 1 under the null hypothesis of no difference between the 2 treatment arms and a 
hazard ratio of 0.67 under the alternative hypothesis of superiority of the idelalisib-containing 
combination, 260 events (definitive CLL progressions) is required to achieve a power of 
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assuming a planned accrual period of 18 months (with approximately half of the subjects 
enrolled during the initial 60% of the accrual period, and the remaining half of the subjects 
enrolled during the last 40% of the accrual period), a minimum follow-up period of 24 months,
and an expectation that 15% of subjects will be lost to follow-up (7% during the accrual period 
and 8% during the follow-up period), ~195 subjects per treatment arm (~390 total) are to be 
enrolled in order to achieve the expected number of events by the end of the planned minimum 
24-month follow-up period. This sample size will also provide a substantial safety database for 
the idelalisib/bendamustine/rituximab combination therapy; the safety data set provided by the 
idelalisib-treated subjects (N~195) in this study compares favorably with the safety data set 
derived from the randomized pivotal registration trial for bendamustine (N=153) {Knauf 2009}. 
If the planned subject enrollment does not appear adequate to accrue the expected number of 
events within the proposed follow-up period, the sample size may be adjusted upward.
9.4.2.
Blinded Sample Size Re-estimation
Prior to completion of enrollment, Gilead Sciences may perform a review of blinded data to 
evaluate the overall event rate. If the planned subject accrual does not appear adequate to 
generate the expected number of events within the proposed follow-up period, the sample size 
may be adjusted upward.
9.5.
Timing of Analyses
9.5.1.
Interim Analysis
The DMC will have access to serious adverse events requiring expedited reporting and will be 
provided with accumulating safety data on a regular basis. An interim safety review will be 
conducted by the DMC at ~6 months after the first subject is enrolled. Thereafter, 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 trial is 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 unblinded review of all available efficacy and safety data will be conducted by the DMC 
after ~66% of the expected number of 260 events (definitive CLL progressions
per IRC or deaths) have occurred. These analyses offer the opportunity to assess for evidence of 
substantial clinical benefit or for evidence that establishing clinical benefit is unlikely. For these 
analyses, all available PFS data will be evaluated. The interim analyses will employ the primary 
analysis method that is planned for the final analysis of the PFS endpoint (see Section 9.3.4.1).
Stopping the study for substantial evidence of idelalisib benefit will be considered if the PFS is 
significantly better in Arm A compared to Arm B. The significance level for this interim analysis 
will be 0.001. Based on the assumptions of the study and the timing of the planned analysis, 
boundary-crossing probabilities for the trial are depicted in Table 9-1.


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Table 9-1.
Boundary-Crossing Probabilities at Interim and Final Analyses Based 
on the Assumptions of the Study
Analysis
Expected Events a
n (%)
Boundary-Crossing Probabilities at Each Analysis
Under the Null Hypothesis
Under the Alternative Hypothesis
Interim
172
(66%)
0.001
0.266
Final
260
(100%)
0.049
0.633
a
Definitive CLL progressions or deaths
Alternatively, stopping the study will be considered if the planned interim analyses indicate that 
obtaining a significant improvement in PFS in Arm A relative to Arm B appears futile. For this 
futility analysis, the DMC will be provided with the conditional power at the time of the planned 
interim analysis (ie, when ~66% of the expected number of 260 events have occurred, per IRC). 
The DMC will be requested to consider recommending termination of the study if the 
conditional power is <0.10.
9.5.2.
Final Efficacy Analysis
The final efficacy analysis will be conducted after approximately the 260th event 
(definitive CLL progression or death). It is expected that this number of events will occur after a 
minimum of 24 month follow-up. The timing of the final analysis may be altered appropriately if 
the study is stopped early or if an upward adjustment of the sample size is performed as 
described in Section 9.4.2. Once any outstanding data queries have been resolved, the database 
will be locked the blind will be broken, and the efficacy analysis of the study will be performed.
9.5.3.
Follow-up Analyses
After the final analysis, additional supplemental analyses of efficacy and safety may be 
performed to satisfy regulatory requirements and to perform long-term efficacy, safety, and OS 
follow-up.


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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 US)
and to an IEC for sites enrolling outside of the US). 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 US, 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 are 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 a prerandomization 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 sections for (see Section 5.2.1.7 for idelalisib, Section 5.2.2.7 for 
rituximab, and Section 5.2.3.7 for bendamustine), 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 IRBs/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 US 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
EDC 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 the 
study 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.
Study Steering Committees
A study steering committee (SSC) may be responsible for assisting Gilead Sciences with 
protocol development, review of any study amendments, and coordination of study conduct, 
interpretation of data, and presentation and publication of study results may be instituted during 
the conduct of the study. The SSC will comprise the Gilead Sciences medical monitor for the 
study, the responsible Gilead Sciences biostatistician, the Gilead Sciences study director, and 
several clinicians with expertise in the care of subjects with CLL. Other specialists may be 
invited to participate as members of the SSC at any time if additional expertise is desired. The 
Gilead Sciences study director will serve as the chair of the SSC.
10.4.2.
Data Monitoring Committee
A DMC, operating autonomously from Gilead Sciences, the clinical investigators, and the SSC, 
will be responsible for providing independent recommendations to Gilead Sciences about 
evolving risk-benefit observed in the course of the study and any modifications required during 
the course of the study. The DMC will consist of a biostatistician and 2 physicians experienced 
in treating patients with lymphoid malignancies. The DMC will be chaired by one of these 
individuals. DMC members must not be actively involved in study design, conduct, or subject
accrual and must not have financial, proprietary, professional, or other interests that may affect 
impartial, independent decision-making. Specialists may be invited to participate as non-voting 
members at any time if additional expertise is desired. The DMC will formally interact with the 
external SSC members through the sharing of meeting minutes. Informal interactions between 
the DMC and external SSC members will be limited. The DMC will operate under a charter 
developed as a collaborative document between Gilead Sciences and the DMC.
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:

Examining accumulated safety, efficacy, and other relevant data during the course of the 
study in order to make recommendations concerning continuation, termination, or 
modification of the study

Reviewing the general progress of the study as regards subject accrual, study conduct, and 
protocol violations

Reviewing major study design modifications proposed by Gilead Sciences or by the SSC 
prior to implementation of those modifications 

Providing expert advice to the Gilead Science medical monitor on an ad hoc basis regarding 
matters such as safety concerns or diagnostic evaluations in individual subjects


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Based on the results of its deliberations during the course of the study, the DMC can recommend 
continuation of the study unchanged, study interruption, study termination, modification of the 
trial, or alteration in the DMC monitoring plan.
10.4.3.
Independent Review Committee
An IRC will be established to provide a blinded review of radiographic data and pertinent 
clinical data in order to provide expert interpretation of changes in tumor status. The IRC will 
include 1 independent board-certified radiologist and 1 independent board-certified 
hematologist or oncologist, and will be managed by a CRO selected by Gilead Sciences. The 
review of radiographic and clinical data by the IRC will be performed on an ongoing basis. The 
specifics of the IRC’s processes and reading methods will be described in an independent review 
charter developed by the contracted imaging facility in conjunction with Gilead Sciences. The 
findings of the IRC will be considered primary for analyses of PFS and other tumor control 
endpoints.


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


PPD
PPD
Idelalisib 
Protocol GS-US-312-0115 
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Gilead Sciences, lnc. 
Version 11.0 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 Lakeside Drive 
Foster City, CA 94404 USA 
STUDY ACKNOWLEDGEMENT 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and 
Safety of Idelalisib (GS-1101) in Combination with Bendamustine and Rituximab for Previously 
Treated Chronic Lympbocytic Leukemia 
GS-US-312-0115, Version 11.0, 21 September 2017 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Gilead Sciences Medical Monitor 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator 
Printed Name 
Date 
CONFIDENTIAL 
Page 172 
Signature 
Site Number 
2 I September 2017 


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Appendix 2.
Functional Assessment of Cancer Therapy: Leukemia
FACT-Leu (Version 4) 
Below is a list of statements that other people with yow- illness have said are impo1tant. Please circle 
or mark one nu mber per line to indicate you r response as it applies to the past 7 days. 
PHYSICAL WELL-BEING 
GP I 
I have a lack of energy .............. .. .. .. ... .............. .. .. ..... 
GP2 
I have nausea 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family 
GP4 
I have pain 
GP> 
I am bothered by side effects of treatment 
GP6 
I feel ill . . 
GP7 
I am forced to spend time in bed 
SOCIAL/FAMILY WELL-BEING 
GS! 
I feel close to my friends 
GS2 
I get emotional support from my family 
GS3 
I get support from my friends 
GS4 
My family has accepted my illness 
GS5 
I am satisfied with family communication about my 
illness .. 
GS6 
I feel close to my partner (or the person who is my main 
support) ... 
QI 
Regardless a/ your current level of sexual activity. please 
answer the f ollowing question. If you prefer not to answer it, 
please mark this box D and go ro the next section. 
GS7 
I am satisfied with my sex life 
............................. 
English(Univcrsal) 
Ccpyright 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 November 2007 
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FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
EMOTIONAL WELL-BEING 
GE i 
I feel sad 
GE2 
I am satisfied with how I am coping with my illness .. 
G£3 
I am losing hope in the fight against my illness 
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 
I have accepted my illness 
GF.S 
I am sleeping well 
GF6 
I am enjoying the things I usually do for fun 
GF7 
lam content with the quality ofmy life right now 
English (Universal) 
Copyright 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 Novcmber 2007 
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FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
ADDITIONAL CONCERNS 
BRM3 
I am bothered by fevers (episodes of high body 
tern perature) 
P2 
I have certain parts of my body where I experience pain .. 
BRM2 
I am bothered by the chills .. 
ES3 
I have night sweats ... . . . . . . . . . . . . ' . . . . . . . 
LEUI 
I am bothered by lumps or swelling in certain parts of 
my body (e.g., neck, armpits, or groin) .. 
THI 
I bleed easily .. 
TH2 
I bruise easily 
11112 
I feel weak all over 
Bt.IT6 
I get ti red easily 
Cl 
I am losing weight 
C6 
I have a good appetite. 
An7 
I am able to do my usual activities 
N3 
I worry about getting infections 
L£U5 
I feel uncertain about my future health 
LEU6 
I worry that l might get new symptoms ofmy illness .. 
BRM.9 
I have emotional ups and downs .. 
LEU7 
I feel isolated from others because ofmy illness or 
treatment 
English (Universal) 
Copyright 1987, 1997 
Not 
A little 
Some-
at all 
bit 
what 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
0 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
19 Novcmber2007 
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Appendix 3.
Performance Status Scoring System
Karnofsky Performance Status
General Description
Score
Specific Description
Able to carry on normal activity and 
to work; no special care needed.
100
Normal; no complaints; no evidence of disease.
90
Able to carry on normal activity;
minor signs or symptoms of disease.
80
Normal activity with effort;
some signs or symptoms of disease.
Unable to work; able to live at home 
and care for most personal needs; 
varying amount of assistance 
needed.
70
Cares for self;
unable to carry on normal activity or to do active work.
60
Requires occasional assistance,
but is able to care for most of personal needs.
50
Requires considerable assistance and frequent medical care.
Unable to care for self; requires 
equivalent of institutional or hospital 
care; disease may be progressing 
rapidly.
40
Disabled; requires special care and assistance.
30
Severely disabled;
hospital admission is indicated although death not imminent.
20
Very sick; hospital admission necessary;
active supportive treatment necessary.
10
Moribund; fatal processes progressing rapidly.
0
Dead


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Appendix 4.
EuroQoL-5 Dimensions (EQ-5D)
Sample
ne 
I a e in C te 
ch 
I obili 
a·e 
•al ir,g 
Self-C re 
a ·e op 
ms 
IC self-ca 
g 
or stu 
, or lei ur; act' • • 
a ·e 
s 
y 
Pai O"scomfort 
·e 
ISC 
fon 
ISOO 
a ·e e em 
A 
ion 
ess 
ess 
re el 
or 
sse 


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Sample
o help people sa how good or bad a health state is, 
we a\·e dra, 
a scale rather like a tbennometer) on 
whic the best stare ou can unagine is marked l 00 
and 
e o 
state you can imagine is marked 0. 
\\ e would like you to mdicate on this scale how good 
or bad your own health is oda . in your opinion. 
Please do t is b d aVi ing a line from the box belo\ · 
to wlucbe 'er point on e scale indicates. bow good or 
bad your health state is oda •. 
Your own 
health state 
today 
B~l 
ima~ble 
health ~tale 
I 
0 
\ 
" 
imaginab e 
ea] 
state 


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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.
Serum
Creatinine Units
Gender
Formula
mg/dL
Males
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1
72 subject serum creatinine [mg/dl]
Females
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 0.85
72 subject serum creatinine [mg/dl]
M/dL
Males
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.23
Subject serum creatinine [mg/dl]
Females
eCcr
[mL/min]
=
(140-subject age [years]) subject weight [kilograms] 1.04
Subject serum creatinine [mg/dl]
Abbreviation: eCcr=estimated creatinine clearance


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Appendix 6.
CIRS List of Comorbid Conditions
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.
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
Respiratory 
Asthma
Chronic obstructive pulmonary disease
Cystic fibrosis
Emphysema
Chronic bronchitis
Chronic pleural effusions
Pulmonary fibrosis
Sarcoidosis
Pulmonary embolism
Pulmonary arterial hypertension
Lung cancer
Other chronic respiratory condition:
Other chronic respiratory condition


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Organ System
Diagnosis
Comment
Ophthalmological/
otolaryngological
Loss of vision
Glaucoma
Cataract
Macular degeneration
Diabetic retinopathy
Loss of hearing
Otitis/chronic otitis
Vestibular impairment
Vertigo
Temporomandibular disorder
Sialolithiasis
Chronic sinusitis
Laryngeal/pharyngeal disorders
Other chronic ophthalmological or 
otolaryngological condition:
Upper
Gastrointestinal
Chronic esophagitis
Dysphagia
Achalasia
Gastroduodenal ulceration
Celiac disease
Irritable bowel syndrome
Short bowel syndrome
Malnutrition
Malabsorption
Small bowel obstruction
Hernia
Pseudomyxoma peritonei
Upper gastrointestinal cancer
Other chronic upper gastrointestinal condition:
Other chronic upper gastrointestinal condition:


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Organ System
Diagnosis
Comment
Lower
Gastrointestinal
Diverticulitis
Inflammatory bowel disease
Volvulus
Colon cancer
Other chronic lower gastrointestinal condition:
Other chronic lower gastrointestinal condition:
Hepatic/
Pancreatic
Chronic hepatitis or hepatic cirrhosis
Biliary obstructive disorders
Pancreatitis
Hepatic, biliary, or pancreatic cancer
Other chronic hepatic or pancreatic condition:
Other chronic hepatic or pancreatic condition:
Renal
Chronic kidney disease
Diabetic nephropathy
Pyelonephritis
Renal cancer
Other chronic renal condition:
Other chronic renal condition
Gynecological/
Urological
Recurrent/chronic urinary tract infection
Nephrolithiasis
Bladder dysfunction
Vaginal/vulvar disease
Uterine/ovarian disease
Prostatitis
Bladder, uterine, ovarian, prostate, or other cancer
Prostate hypertrophy
Other chronic gynecological or urological condition:
Other chronic gynecological or urological condition:


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Organ System
Diagnosis
Comment
Dermatologic/
musculoskeletal
Dermatitis
Dermatomyositis
Myopathy
Gout
Psoriasis
Keratosis
Urticaria
Scleroderma
Basal cell carcinoma
Squamous cell carcinoma
Melanoma
Osteomyelitis
Osteoarthritis
Rheumatoid arthritis
Spondyloarthritis
Temporal arteritis/polymyalgia rheumatica
Polychondritis
Fibromyalgia
Osteoporosis
Systemic lupus erythematosus
Dermatomyositis
Sjögren syndrome
Other chronic dermatological or 
musculoskeletal condition:
Other chronic dermatological or 
musculoskeletal condition:


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Organ System
Diagnosis
Comment
Neurological
Cerebrovascular disease
(transient ischemic attack/stroke/hemorrhage)
Dementia
Parkinson disease
Non-Parkinsonian movement disorder 
(eg, ataxia/chorea)
Leukodystrophic disorders
Amyotrophic lateral sclerosis
Multiple sclerosis
Demyelinating disease
Guillain-Barré syndrome
Paralysis (eg, paraplegia/quadriplegia/hemiplegia)
Myelopathy
Cranial nerve disorder
Degenerative disk disease with nerve root 
compression
Migraine headaches
Seizure disorder
Secondary neuropathy 
(eg, diabetic/alcoholic/autoimmune)
Neurofibromatosis/tuberous sclerosis
Benign or malignant central nervous system tumor
Other chronic neurological condition:
Other chronic neurological condition:
Endocrine/
Metabolic
Diabetes
Adrenal disorder
Thyroid disorder
Parathyroid disorder
Pheochromocytoma
Pituitary disorder
Hemochromatosis
Porphyria
Paget's disease
Endocrine or neuroendocrine tumor
Other chronic endocrine or metabolic condition:
Other chronic endocrine or metabolic condition:


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Organ System
Diagnosis
Comment
Psychiatric
Depression
Anxiety
Bipolar disorder
Paranoia
Schizophrenia
Neurosis
Personality disorder
Substance addiction/abuse
Posttraumatic stress disorder
Chronic fatigue syndrome
Other chronic psychiatric condition:
Other chronic psychiatric condition:
Abbreviation: CIRS=Cumulative Illness Rating Scale
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:
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
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25+
End
of
Study
30
day
Long-
term
Week
-4
0
2
4
6
8
10
12
14
16
18
20
22
24
30
36
42
48
Q12
wks
Study Day
Within
-28
days
1
2
15
29
30
43
57
58
71
85
86
99
113
114
127
141
142
155
169
211
253
295
337
With-
in
+30
days
To
+5
yrs
Visit Window
+1
2
2a
+1
1
2a
+1
2
3a
+1
2
2a
+1
2
2a
+1
2
3
3
3
3
3
7
Informed consent
X
Medical history
X
CIRS assessment
X
Serum virology
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
Xd
X
CLL serology
X
X
Coagulation
X
Urinalysis
X
12-lead ECG
X
Genotyping and 
expression 
analysis
X
X
IWRS
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
Adverse events
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
Performance status
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Period
Screen
Treatment
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25+
End
of
Study
30
day
Long-
term
Week
-4
0
2
4
6
8
10
12
14
16
18
20
22
24
30
36
42
48
Q12
wks
Study Day
Within
-28
days
1
2
15
29
30
43
57
58
71
85
86
99
113
114
127
141
142
155
169
211
253
295
337
With-
in
+30
days
To
+5
yrs
Visit Window
+1
2
2a
+1
1
2a
+1
2
3a
+1
2
2a
+1
2
2a
+1
2
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
Physical exam 
(includes nodes, 
liver, spleen)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology/serum 
chemistry
X
Xb
Xc
X
Xc
X
Xc
X
Xc
X
Xc
X
Xc
X
X
X
X
X
X
X
Circulating cells/
biomarkers/
serum Igs/Immune 
monitoring
X
X
X
X
X
X
X
X
X
X
X
X
Xi
CMV viral loadj
Xj
HBV DNA by 
PCRf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Idelalisib/
placebo 
administration in 
clinic
X
X
X
X
X
X
X
Premedication 
X
X
X
X
X
X
X
X
X
X
X
X
Rituximab 
administration
X
X
X
X
X
X
Bendamustine 
administration
X
X
X
X
X
X
X
X
X
X
X
X
PJP prophylaxisk
Xk
Xk
CD4+ T-cell 
countk (related to 
PJP prophylaxis)
Xk


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Period
Screen
Treatment
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25+
End
of
Study
30
day
Long-
term
Week
-4
0
2
4
6
8
10
12
14
16
18
20
22
24
30
36
42
48
Q12
wks
Study Day
Within
-28
days
1
2
15
29
30
43
57
58
71
85
86
99
113
114
127
141
142
155
169
211
253
295
337
With-
in
+30
days
To
+5
yrs
Visit Window
+1
2
2a
+1
1
2a
+1
2
3a
+1
2
2a
+1
2
2a
+1
2
3
3
3
3
3
7
Assess rituximab 
infusion severity 
and duration
X
X
Idelalisib 
pharmacokinetics
X
X
X
X
X
X
X
Idelalisib/
placebo 
dispensing/
accounting
X
X
X
X
X
X
X
Radiology 
assessment 
(CT/MRI)
Xd
Xg
Xg
Xg
Xg
Xg,l
Xa, h
Bone marrow 
biopsy/
aspirate
Xe
Xe
Xe
Xe
Xe
Xe
Post-treatment 
CLL therapy
X
Long-term 
follow-up 
X
a
Windows for the specified clinic visits may be extended to account for delayed recovery from drug-related adverse events (eg, myelotoxicity)
b
Hematology will be assessed locally at Visit 2, in addition to the central lab assessment, so that results will be available if the central lab results are compromised 
c
More frequent (eg, weekly) hematology/serum chemistry assessments may be appropriate in subjects experiencing Grade 3 myelosuppression or ALT/AST elevations  Throughout the 
study, local lab results may be requested in the event central laboratory results are not available for assessment of disease response, progression, safety monitoring, or the evaluation of a 
significant event
d
Radiology assessment (CT/MRI) if performed within <6 weeks of randomization and assessed to be adequate by the IRC and CLL peripheral blood evaluation if performed within 
<12 weeks of randomization and assessed to be adequate by the central lab do not need to be repeated 
e
A bone marrow biopsy/aspirate demonstrating CLL involvement following the last therapy must be available if Grade >2 neutropenia, thrombocytopenia, or anemia is present at 
screening, or 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
f
Only subjects who are HBc antibody positive and HBV DNA negative at screening. Subjects will be tested monthly for the duration of rituximab therapy and every 3 months thereafter 
for 1 year from the last dose of rituximab per Section 5.4.3.


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g
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the study visit; assessment should be done even if study drug has been interrupted
h
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.
i
Circulating cells/serum Igs/Immune monitoring should be performed at the the End of Study visit.
j
CMV viral load should be performed approximately every 4 weeks throughout idelalisib treatment.  If unequivocal clinical or laboratory evidence of CMV infection is present, refer to 
Section 5.4.5 (“Infectious Events”) for required actions.
k
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 
following the last dose of idelalisib as specified in Section 5.4.5 (“Infectious Events”).
l
As of Amendment 10, Version 11, CT/MRI assessments will no longer be performed at the every 12 week scheduled visits, and will only be performed at the time of 
clinically-suspected disease progression or at study discontinuation.
Abbreviations: -HCG=beta human chorionic gonadotropin, CIRS=chronic illness rating scale, CLL=chronic lymphocytic leukemia, CR=complete response, CT=computed tomography,
CMV=cytomegalovirus, ECG=electrocardiogram, 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.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled 
Study Evaluating the Efficacy and Safety of Idelalisib (GS-1101)
in Combination with Bendamustine and Rituximab for 
Previously Treated Chronic Lymphocytic Leukemia
Name of Test Drug:
Idelalisib (GS-1101)
Study Number:
GS-US-312-0115
Protocol Version:
Version 11.0 (Amendment 10)
Protocol Date:
21 September 2017
Analysis Type:
Final
Analysis Plan Version:
2.0
Analysis Plan Date:
06 September 2019
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(rJ GILEAU 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................3
LIST OF ABBREVIATIONS........................................................................................................................................4
1.
INTRODUCTION ................................................................................................................................................6
1.1.
Study Objectives ......................................................................................................................................6
1.2.
Study Design............................................................................................................................................7
1.3.
Sample Size and Power............................................................................................................................9
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................10
2.1.
Interim Analysis.....................................................................................................................................10
2.2.
Final Analysis ........................................................................................................................................10
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................11
3.1.
Analysis Sets..........................................................................................................................................11
3.1.1.
Intent-to-Treat Analysis Set .................................................................................................11
3.2.
Safety Analysis Set ................................................................................................................................11
3.2.1.
Pharmacokinetic/ Pharmacodynamic Analysis Sets.............................................................11
3.3.
Strata and Covariates..............................................................................................................................11
3.4.
Examination of Subject Subsets.............................................................................................................12
3.5.
Multiple Comparisons............................................................................................................................12
3.6.
Missing Data and Outliers......................................................................................................................12
3.7.
Data Handling Conventions and Transformations .................................................................................12
3.7.1.
Data Handling for Efficacy Endpoints .................................................................................13
3.7.2.
Data Handling for Laboratory data.......................................................................................13
3.8.
Visit Windows........................................................................................................................................14
3.8.1.
Analysis Windows................................................................................................................14
3.8.2.
Selection of Data in the Event of Multiple Records in a Window .......................................14
4.
SUBJECT DISPOSITION ..................................................................................................................................15
4.1.
Subject Enrollment.................................................................................................................................15
4.2.
Disposition of Subjects ..........................................................................................................................15
4.3.
Extent of Exposure.................................................................................................................................16
4.3.1.
Duration of Exposure to Study Drug....................................................................................16
4.3.2.
Adherence with Idelalisib/placebo .......................................................................................16
4.4.
Protocol Deviations................................................................................................................................17
5.
BASELINE DATA .............................................................................................................................................18
6.
EFFICACY ANALYSES ...................................................................................................................................19
6.1.
Definition of the Primary Efficacy Endpoint .........................................................................................19
6.2.
Statistical Hypothesis for the Primary Efficacy Endpoint......................................................................19
6.3.
Analysis of the Primary Efficacy Endpoint............................................................................................19
6.4.
Secondary Efficacy Endpoints ...............................................................................................................20
6.4.1.
Definition of Secondary Efficacy Endpoints........................................................................20
6.4.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................20
6.5.
Exploratory Efficacy Endpoints.............................................................................................................21
6.6.
Changes From Protocol-Specified Efficacy Analyses............................................................................21
7.
SAFETY ANALYSES........................................................................................................................................22
7.1.
Adverse Events and Deaths....................................................................................................................22


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7.1.1.
Adverse Event Dictionary ....................................................................................................22
7.1.2.
Adverse Event Severity........................................................................................................22
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................22
7.1.4.
Serious Adverse Events........................................................................................................22
7.1.5.
Treatment-Emergent Adverse Events...................................................................................23
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................23
7.1.7.
Exposure-adjusted TEAE Rate.............................................................................................25
7.1.8.
Treatment-Emergent Adverse Events (TEAEs) of Interest ..................................................25
7.2.
Laboratory Evaluations ..........................................................................................................................27
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................27
7.2.2.
Graded Laboratory Values ...................................................................................................27
7.2.3.
Shift in CTCAE Grade Relative to Baseline ........................................................................28
7.2.4.
Transaminase elevations.......................................................................................................28
7.2.5.
Liver-Related Laboratory Tests............................................................................................29
7.3.
Prior Therapy (Including Radiation) ......................................................................................................29
7.4.
Concomitant Medications ......................................................................................................................29
7.5.
Body Weight and Vital Signs.................................................................................................................30
7.6.
Electrocardiogram Results .....................................................................................................................30
7.7.
Other Safety Measures ...........................................................................................................................30
7.8.
Changes From Protocol-Specified Safety Analyses...............................................................................30
8.
PHARMACOKINETIC ANALYSES ................................................................................................................31
9.
PHARMACODYNAMIC ANALYSES .............................................................................................................32
10.
REFERENCES ...................................................................................................................................................33
11.
SOFTWARE.......................................................................................................................................................34
12.
SAP REVISION..................................................................................................................................................35
13.
APPENDICES ....................................................................................................................................................36
Appendix 1.
Schedule of Assessments........................................................................................................37
Appendix 2.
Gilead List of Medical Search Terms for Rash based on MedDRA Version 22.0 .................41
LIST OF IN-TEXT TABLES
Table 7-1.
Grouped Terms for Adverse Events of Interest......................................................................26


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LIST OF ABBREVIATIONS
AE
adverse event
AEI
adverse event of interest
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ANC
absolute neutrophil count
ATC
Anatomical-Therapeutic-Chemical classification system for drugs 
BID
twice per day
CI
confidence interval
CIRS
Cumulative Illness Rating Scale
CLL
chronic lymphocytic leukemia
CR
complete response
CRi
complete response with incomplete marrow recovery
CSR
clinical study report
CT
computerized tomography
CTCAE
common terminology criteria for adverse events
DMC
data monitoring committee
eCRF
electronic case report form
ECG
electrocardiogram
EOT
end of treatment
EQ-5D
EuroQoL five-dimension utility measure
FACT-Leu
Functional Assessment of Cancer Therapy: Leukemia questionnaire
HLGT
high level group term
HLT
high level term
HR
hazard ratio
HRQL
health-related quality of life
Ig
immunoglobulin (including subtypes A, E, G, and M)
IgHV
immunoglobulin heavy chain variable region
IRC
independent review committee
ITT
intent to treat
IWCLL
International Workshop on CLL
IWRS
interactive web response system
JAK
Janus kinase
LD
longest diameter
LLN
lower limit of normal
LLT
low level term
LNR
lymph node response
LPD
longest perpendicular diameter


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MedDRA
Medical dictionary for regulatory activities
MST
Medical Search Term
MRI
magnetic resonance imaging
ND
no disease
NE
non evaluable
ORR
overall response rate
OS
overall survival
PD
progressive disease
PI3K
phosphatidylinositol 3-kinase
PI3K
phosphatidylinositol 3-kinase p110isoform
PFS
progression-free survival
PR
partial response
PT
preferred term
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SOC
system organ class
SPD
sum of the products of the perpendicular diameters 
StD
standard deviation
SUSAR
suspected, unexpected, serious adverse reaction
SFWB
social/family well-being
SYk
spleen tyrosine kinase
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
WHODRUG
World Health Organization Drug Dictionary


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1.
INTRODUCTION
This document details the final analyses for Study GS-US-312-0115, a Phase 3, randomized, 
double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib (GS-1101) 
in combination with bendamustine and rituximab for previously treated chronic lymphocytic 
leukemia (CLL). Related documents are the study protocol and electronic case report form 
(eCRF).
1.1.
Study Objectives
Primary 
Study Objectives

To evaluate the effect of the addition of idelalisib (formerly 
GS-1101) to bendamustine/rituximab on progression-free survival 
(PFS) in subjects with previously treated CLL
Secondary 
Study Objectives

To evaluate the effect of the addition of idelalisib to 
bendamustine/rituximab on the onset, magnitude, and duration of 
tumor control

To assess the effect of the addition of idelalisib to 
bendamustine/rituximab on measures of subject well-being, 
including overall survival (OS), health-related quality of life 
(HRQL), and performance status

To assess the effects of the addition of idelalisib to 
bendamustine/rituximab on disease associated biomarkers and to 
evaluate potential mechanisms of resistance to idelalisib

To characterize the effect of bendamustine/rituximab on idelalisib
exposure through evaluations of idelalisib plasma concentrations 
over time

To describe the safety profile observed with the addition of 
idelalisib to bendamustine/rituximab

To estimate health resource utilization associated with the addition 
of idelalisib to bendamustine/rituximab


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1.2.
Study Design
Design Configuration 
and 
Subject Population
Study GS-US-312-0115 is a Phase 3, multicenter, 2-arm, randomized, 
double-blind, placebo-controlled, parallel-group clinical trial.
Target Population: Adult subjects with previously treated recurrent 
CLL who have measurable lymphadenopathy; require therapy for 
CLL; have received prior therapy containing a purine analog or 
bendamustine and an anti-CD20 monoclonal antibody; are not 
refractory to bendamustine; have experienced CLL progression 
<36 months since the completion of the last prior therapy; and are 
currently sufficiently fit to receive cytotoxic therapy.
Treatment Groups

Arm A: idelalisib + bendamustine/rituximab (IDL+B/R)

Arm B: placebo + bendamustine/rituximab (PBO+B/R)
Key Eligibility 
Criteria
Please refer to Protocol Section 4.2 for subject inclusion and exclusion 
criteria.
Treatment Duration
Study drug (idelalisib/placebo) 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.
Subjects who are tolerating study drug (idelalisib/placebo) will be 
encouraged to continue study drug even if bendamustine or rituximab 
must be discontinued due to bendamustine- or rituximab-related 
toxicities.
Rituximab will be administered until the earliest of a maximum of 
6 infusions, subject withdrawal from study, definitive progression of 
CLL, intolerable rituximab-related toxicity, pregnancy, substantial 
noncompliance with study procedures, or study discontinuation.
Bendamustine will be administered until the earliest of a maximum of 
12 infusions, subject withdrawal from study, definitive progression of 
CLL, intolerable bendamustine-related toxicity, pregnancy, substantial 
noncompliance with study procedures, or study discontinuation.
Following a decision to unblind the study based on the interim 
analysis results and the data monitoring committee (DMC)’s
recommendation, treatment assignments will be unblinded. Subjects 
randomized to Arm A (idelalisib +bendamustine/rituximab) may 
continue study treatment with idelalisib, whereas subjects randomized 
to Arm B (placebo + bendamustine/rituximab) should discontinue 
placebo tablets and continue with study procedures per protocol.


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Schedule of 
Assessments

The schedule of assessments is located in Appendix 1 of this SAP.
Randomization and 
Stratification

1:1 allocation to Arm A versus Arm B with implementation 
through an interactive web response system (IWRS)

Fixed-block centralized randomization with allocation of subjects 
within the 8 strata as defined by the intersection of 
3 binary stratification factors:
17p deletion and/or p53 mutation in CLL cells:
either vs neither (or indeterminate)
Immunoglobulin heavy chain variable region (IgHV) mutation:
unmutated (or IgHV3-21) vs mutated (or indeterminate)
Disease status: refractory (CLL progression <6 months from 
completion of prior therapy) vs relapsed (CLL progression 
6 months from completion of prior therapy)
Site and/or Stratum 
Enrollment Limits
Approximately 180 centers in North America, South America, 
Australia Pacific, and Europe
Study Duration
The study will continue until approximately the 260th PFS event
occurs. It is expected that the study accrual period is approximately 
18 months and the 260th event will occur after a minimum of 
24 months of follow-up.


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1.3.
Sample Size and Power
Planned Sample Size
The planned sample size is 390 subjects (~195 subjects per 
treatment arm).
Power Statement
Based on data from prior studies, it is reasonable to assume that 
administration of bendamustine/rituximab to subjects with previously 
treated CLL in Arm B of this trial will result in a median PFS of 
~15 months. An improvement in median PFS from 
15 months to 22.5 months due to the addition of idelalisib to
bendamustine/rituximab in Arm A of the study would correspond to a 
benefit ratio of 1.5 (hazard ratio 0.67).
It is assumed that PFS times are exponentially distributed in each of the 
2 arms. With a hazard ratio equal to 1 under the null hypothesis of no 
difference between the 2 treatment arms and a hazard ratio of 0.67 under 
the alternative hypothesis of superiority of the idelalisib-containing
combination, 260 events (definitive CLL progressions or deaths) are 
required to achieve a power of 0.90 based on a stratified log-rank test 
with a 2-sided significance level of 0.05. Further assuming a planned 
accrual period of 18 months (with approximately half of the subjects 
enrolled during the initial 60% of the accrual period, and the 
remaining half of the subjects enrolled during the last 40% of the 
accrual period), a minimum follow-up period of 24 months, and an 
expectation that 15% of subjects will be lost to follow-up 
(7% during the accrual period and 8% during the follow-up period), 
~195 subjects per treatment arm (~390 total) are to be enrolled in 
order to achieve the expected number of events by the end of the 
planned minimum 24-month follow-up period.
It is expected that there will be approximately 135 deaths at the time 
of the final analysis. This would provide >95% power to detect a 
HR of 0.45 for overall survival based on a log-rank test at a 2-sided 
alpha level of 0.032.
Actual Enrollment and 
Impact on Power
The study is fully enrolled as originally planned and there is no 
impact on the power of the planned analyses. 


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analysis
The interim analysis was conducted with the data cut-off date 07 October 2015. IDL+B/R
demonstrated superior efficacy over PBO+B/R in the primary endpoint PFS and all key 
secondary endpoints. Gilead unblinded the study following the DMC’s recommendation.
2.2.
Final Analysis
The final anlaysis will be conducted when all subjects discontinue from the study. A synoptic 
clinical study report (CSR) will be developed and there will be no multiplicity control for the 
primary and secondary efficacy analysis. 


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
3.1.
Analysis Sets
3.1.1.
Intent-to-Treat Analysis Set
The Intent-to-Treat (ITT) Analysis Set includes all subjects who are randomized regardless of 
whether subjects receive any study drug(s), or receive a different regimen from the regimen they 
were randomized to. Treatment assignment will be designated according to randomization.
This analysis set will be used in the analyses of subject characteristics, efficacy endpoints 
including PFS, overall response rate (ORR), OS, lymph node response (LNR) rate, and complete 
response (CR) rate, and health outcome variables.
3.2.
Safety Analysis Set
A Safety Analysis Set will include data from subjects who receive ≥1 dose of study treatment, 
with treatment assignments designated according to the actual treatment received.
This analysis set will be used in the analyses of safety variables as well as study treatment 
administration.
3.2.1.
Pharmacokinetic/ Pharmacodynamic Analysis Sets
The Pharmacokinetic/Pharmacodynamic Analysis Set is not applicaple for the final analysis.
3.3.
Strata and Covariates
Subjects will be stratified to receive study treatment via IWRS based on the following 
stratification factors:

17p deletion and/or p53 mutation in CLL cells: either vs neither (or indeterminate)

IgHV mutation: unmutated (or IgHV3-21) vs mutated (or indeterminate)

Disease status: refractory (CLL progression < 6 months from completion of prior therapy) 
vs relapsed (CLL progression ≥ 6 months from completion of prior therapy)
For subjects with discrepancies between the stratification factor values at randomization 
(ie, according to IWRS) and the actual values as documented in the eCRF, the actual strata 
information will be used in the analyses.
Analyses will be adjusted for the randomization strata. In the situation that there is insufficient 
information in a stratum (ie, if there are < 6 subjects or there is no informative event in a 
stratum), that stratum will be pooled with the smallest adjacent stratum for stratified analyses; 
the smallest stratum is defined as that stratum having the fewest number of subjects or the fewest 
number of events in case the former is a tie and the adjacent stratum is defined as a stratum 
having 2 factors of the 3 at the same level.


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3.4.
Examination of Subject Subsets
Not applicable for the final analysis
3.5.
Multiple Comparisons
Not applicable for the final analysis
3.6.
Missing Data and Outliers
Missing Data
A missing data point for a given study visit may be due to any of the following reasons:

A visit occurred in the window but data were not collected or were unusable

A visit did not occur in the window

A subject permanently discontinued from the study before reaching the window
In general, values for missing data will not be imputed unless methods for handling missing data 
are specified.
Outliers
No data will be excluded from the analyses, including any outliers.
3.7.
Data Handling Conventions and Transformations

By-subject listings will be created for important variables in each eCRF module, and will be 
presented for subjects in the ITT Analysis Set and sorted by subject number, visit, and time 
(if applicable).

Summary tables for continuous variables will contain the following statistics: 
N (number in analysis set), n (number with data), mean, standard deviation (StD), median, 
Q1, Q3, minimum, and maximum.

Summary tables for categorical variables for baseline and safety data will include: N, n, 
and percentage. The tables for efficacy endpoints will include standard error, and 
95% confidence intervals (CIs) on the percentage, where appropriate. Unless otherwise 
indicated, 95% CIs for binary variables will be calculated using the binomial distribution. 
The denominator for the percentages will be the number of subjects in the ITT Analysis Set 
at the same stratum or total as appropriate, unless otherwise specified. Missing data will be 
included as a row in tables where it is appropriate. All percentages will be presented as 
1 decimal point, unless otherwise specified. Percentages equal to 100 will be presented as 
100% and percentages will not be presented for zero frequencies.


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
Tables and figures will be displayed by visit (as appropriate) for each treatment group and 
total (as appropriate).

The actual stratification factor values at randomization from eCRF (not the ones from IWRS) 
will be used in all analyses.

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.

Unscheduled visits will only be included in listings and the best or worst post-baseline 
summary. Unscheduled visits will not be included in the by-visit summary tables, unless 
otherwise specified.

For Kaplan-Meier estimates, the 95% CIs will be calculated using the Greenwood’s formula 
with (complementary) log-log transformation.
3.7.1.
Data Handling for Efficacy Endpoints
If there is a significant degree of non-normality for a continuous endpoint, analyses may be 
performed on log-transformed data or using nonparametric methods, as appropriate.
The baseline for the efficacy endpoints is date of randomization.
3.7.2.
Data Handling for Laboratory data
Laboratory data that are continuous in nature but are less than the lower limit of quantitation or 
above the upper limit of quantitation will be imputed as follows:

A value that is 1 unit less than the limit of quantitation will be used for calculation of 
descriptive statistics if the data is reported in the form of “<x” (x is considered the 
limit of quantitation). For example, if the values are reported as <50 and <5.0, then values of 
49 and 4.9 will be used for calculation of summary statistics, respectively. However, for 
direct bilirubin, a value of “<0.1” will be treated as 0.05 for calculation of summary statistics.

A value that is 1 unit above the limit of quantitation will be used for calculation of 
descriptive statistics if the data is reported in the form of “>x” (x is considered the 
limit of quantitation). For example, if the values are reported as >50 and >5.0, then values of 
51 and 5.1 will be used for calculation of summary statistics, respectively.

The limit of quantitation will be used for calculation of descriptive statistics if the data is 
reported in the form of “≤ x” or “≥ x” (x is considered as the limit of quantitation).
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
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3.8.
Visit Windows
3.8.1.
Analysis Windows
For parameters that will be summarized by visit, the nominal visit as recorded on the eCRF will 
be used. For parameters assessed at the end of treatment (EOT) visit, the assessment results will 
be assigned to the next scheduled visit where the respective data were scheduled to be collected 
for summary. There will be no additional analysis windowing done based on the assessment date. 
Unscheduled visits prior to randomization will be included for the calculation of baseline values. 
Unscheduled scans will be used for determination of the time-to-event and tumor response 
efficacy endpoints.
3.8.2.
Selection of Data in the Event of Multiple Records in a Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value per visit, 
whereas a time-to-event analysis would not require 1 value per analysis window but rather 
1 value for the study. Unless otherwise noted throughout the rest of this document, when a 
single value is needed, the following rule(s) will be used:

If more than 1 assessment occurs during the same nominal visit, select the record closest to 
the nominal day for that visit.

If there are 2 assessments that are equidistant from the nominal day, the data of the 
assessment after the scheduled study day will be used.

The last measurement will be used if multiple measurements are all taken on the same day.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment
The summary of enrollment and randomization were performed in the interim analyses, and will 
not be performed in the final analysis.
4.2.
Disposition of Subjects
Study treatment disposition and study disposition summaries will be provided by 
treatment group.
Study treatment disposition will present the number of subjects who:

were randomized

were randomized but were not treated

were treated with study drug

discontinued study drug with summary of reason for discontinuation
Primary study disposition will present the number of subjects who:

were randomized

were randomized but were not treated

were treated with study drug 

discontinued primary study with summary of reason for discontinuation
Long-term follow-up disposition will present the number of subjects who:

completed/discontinued primary study

entered long-term follow-up

completed long-term follow-up

discontinued the long-term follow-up with summary of reasons for discontinuation
The denominator for the percentages of subjects in each category for the treatment and study 
dispostion will be the number of subjects in the ITT analysis set. The denominator for the 
percentages of subjects in each category for the long-term follow-up disposition dispostion will 
be the number of subjects who entered lonter term follow-up.


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A by-subject listing with reasons for study drug or primary study discontinuation and a separate 
one with long-term follow-up contact will be provided by subject identification (ID) number in 
ascending order to support the above summary table.
4.3.
Extent of Exposure
4.3.1.
Duration of Exposure to Study Drug
Duration of exposure to idelalisib/placebo will be defined as (last idelalisib/placebo dosing 
date-first idelalisib/placebo dosing date + 1) regardless of temporary interruptions in study drug 
administration, and will be expressed in months. Duration of exposure to idelalisib/placebo will 
be summarized for the Safety Analysis Set using descriptive statistics and as the number and 
percentage of subjects exposed for at least 1 day, 2, 4, 6, and 12 months, and every 6 months 
thereafter.
If the last study drug dosing date is missing, the latest date among the study drug end date, 
clinical visit date, laboratory sample collection date, and vital signs assessment date that 
occurred during the on-treatment period will be used. On-treatment period is defined as the time 
between the first dosing date to the study drug end date.
Number and percentage of subjects who had idelalisib/placebo dose interruption, reduction, and 
re-escalation will be summarized. idelalisib/placebo dosing records, drug accountability 
(dispense and return) records, and dose modification records will be listed in details.
Duration of exposure to rituximab will be defined as (last rituximab dose date - first rituximab 
dose date + 1) and will be summarized for the Safety Analysis Set using descriptive statistics.
The same summary will be provided for the duration of exposure to bendamustine. Furthermore, 
the number of rituximab and bendamustine cycles will be summarized using descriptive statistics 
and the number and percentage of subjects who received at least 1, 2 …, 6 cycles will be 
presented.
4.3.2.
Adherence with Idelalisib/placebo
Adherence (%) with idelalisib/placebo will be calculated as:
Adherence (%)  (sum of pills dispensed minus pills returned) divided by (sum over all dosing
period of [total daily pills x dosing duration]), taking into account investigator-prescribed
interruption, reductions, and escalations.
The period matched drug dispense/ return records and drug exposure records are included in the 
calculation. The records with missing return dates are excluded and the duration of treatment at a 
dispense/return period of a study drug is calculated as the minimum of a) the last returned date at 
this period, and b) the next pill dispense date, minus dispense date of the study drug.
Descriptive statistics for adherence along with the number and percentage of subjects belonging
to adherence categories (eg, < 75% or ≥ 75%) will be provided.


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A by-subject listing of study drug administration in clinic will be provided by subject ID number 
in ascending order and visit in chronological order. Continuous dosing recrods of 
idelalisb/placebo will also be provided.
4.4.
Protocol Deviations
Protocol deviations will be categorized before database finalization by Gilead. The important 
(major) protocol deviations will be summarized by type of deviation in the CSR based on the 
ITT Analysis Set. A listing will be provided for all important protocol deviations.


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5.
BASELINE DATA
The analyses of the baseline data including demographics, baseline characteristics, medical 
history, and disease history were performed in the interim analyses, and will not be performed in 
the final analysis.


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6.
EFFICACY ANALYSES
An IRC was established for this study and includes primary board-certified radiologists, a board
certified adjudicating radiologist, and an independent board-certified hematologist or oncologist 
to perform an independent review of response and disease progression for each subject. The 
review comprises of an assessment of radiographic images and prospectively defined clinical 
data acquired during the study according to the Gilead Protocol GS-US-312-0115 Imaging 
Charter. The determination of CLL response and progression will be based on standardized 
criteria promulgated by the International Workshop on CLL {Cheson 2012}, as specifically 
modified for this study to reflect current recommendations which consider the mechanism of 
action of idelalisib and similar drugs {Cheson 2012}. The findings of the IRC will be considered 
primary for analyses of PFS and other tumor control endpoints.
6.1.
Definition of the Primary Efficacy Endpoint
The primary endpoint for this study is PFS, defined as the interval from randomization 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 ({Hallek 2008}, 
{Cheson 2012}) other than lymphocytosis alone.
6.2.
Statistical Hypothesis for the Primary Efficacy Endpoint
H0: Hazard ratio (HR) equals to 1 between Arm A (idelalisib + bendamustine/rituximab) and 
Arm B (Placebo + bendamustine/rituximab)
H1: HR is less than 1 (Arm A is superior to Arm B in terms of PFS)
6.3.
Analysis of the Primary Efficacy Endpoint
For the primary efficacy analysis, the PFS between the 2 treatment arms will be compared based 
on the ITT Analysis Set using a stratified log-rank test, adjusted for the stratification factors used 
for randomization. The analysis strategy for the situation where there is insufficient information 
in a stratum is detailed in Section 3.3. Medians, Q1, Q3, the proportion of subjects who are 
progression-free at 6 months and 12 months from randomization (based on Kaplan-Meier estimates),
HRs, and corresponding 95% CIs (as calculated using a Cox proportional hazards regression 
model) will be presented. The Kaplan-Meier curve will also be plotted.The date of definitive 
CLL progression will be the time point at which progression is identified by relevant objective 
radiographic or clinical data by the IRC. Data will be censored on the date of the last tumor 
assessment (including assessments with a not evaluable [NE] outcome) for subjects who do not 
have disease progression, or who do not die prior to the end of study.
Data will be censored on the date of the last tumor assessment (including assessments of NE) 
prior to the initiation of new anti-tumor therapy for subjects who start new anti-tumor therapy 
prior to documented disease progression.


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Data will be censored on the date of the last tumor assessment (including assessments of NE) 
prior to 2 consecutive missing tumor assessments for subjects who have 2 consecutive 
missing tumor assessments before disease progression or death.
Subjects without adequate baseline tumor response evaluation will be censored on the 
randomization date.
The worst-case sensitivity analysis and Cox regression modeling were performed in the interim 
analyses, and will not be performed in the final analysis.
6.4.
Secondary Efficacy Endpoints
6.4.1.
Definition of Secondary Efficacy Endpoints
Secondary efficacy endpoints include:

ORR defined as the proportion of subjects who achieve a CR, CR with incomplete marrow 
recovery (CRi), or partial response (PR) and maintain their response for at least 12 weeks
(with a 1-week window)

LNR rate defined as the proportion of subjects who achieve a ≥50% decrease from baseline 
in the sum of the products of the perpendicular diameters (SPD) of index lesions per IRC 
assessments. The denominator is the number of subjects in the ITT analysis set sho have both 
baseline and at least one evaluable post-baseline SPD

OS defined as the interval from randomization to death from any cause

CR rate defined as the proportion of subjects who achieve a CR and maintain their response 
for at least 12 weeks (with a 1-week window)
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 ORR and CR rate.
6.4.2.
Analysis Methods for Secondary Efficacy Endpoints
6.4.2.1.
Overall response rate
Responses will be categorized as CR, CRi, PR, stable disease (SD), or PD. For subjects who 
initially responded but did not have an evaluable follow up visit or did not maintain a response 
for at least 12 weeks (with a 1-week window) will be categorized as having a SD. In addition, a 
response category of NE is provided for situations in which there is inadequate information to
otherwise categorize response status. A response category of no disease (ND) is included for 
situations in which there is no evidence of tumor either at baseline or on study.


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ORR is defined as the proportion of subjects who achieve a CR, CRi, or PR during the study and 
maintain the response for at least 12 weeks (with a 1-week window). ORR between the treatment 
arms will be compared using CMH Chi-square tests after adjusting for stratification factors. 
Odds ratios and the corresponding 95% CIs will be presented.
The primary ORR analysis will be evaluated using the IRC assessments based on the 
ITT Analysis Set.
The ORR analyses using investigator assessments were performed in the interim analyses, and 
will not be performed in the final analysis.
6.4.2.2.
Lymph node response rate
Differences in LNR between the 2 treatment arms will be compared using CMH Chi-square tests 
after adjusting for stratification factors. Only subjects that have both baseline and ≥1 evaluable 
post-baseline SPD will be included for this analysis.
6.4.2.3.
Overall Survival
The OS analysis will be performed using the ITT Analysis Set which includes all available 
survival information during the study and long-term follow-up. Data from surviving subjects will 
be censored at the last time that the subject was known to be alive on study or in the long term 
follow up. Differences between treatment arms in OS will be assessed using a stratified log-rank 
test, adjusted for the stratification factors. Medians, Q1, Q3, HRs, and corresponding 95% CIs 
will be presented by treatment arm with Kaplan-Meier plots.
6.4.2.4.
Complete Response Rate
The same analyses as specified for ORR in Section 6.4.2.1 will be performed for the CR rate.
6.5.
Exploratory Efficacy Endpoints 
The analyses for the exploratory efficacy endpoints were performed in the interim analyses, and 
will not be performed in the final analysis.
6.6.
Changes From Protocol-Specified Efficacy Analyses
There are no deviations from the protocol-specified efficacy analyses.


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
The focus of adverse event summarization will be on treatment-emergent AEs (TEAEs). All 
TEAEs and deaths occurring on study will be summarized by treatment arm based on the 
Safety Analysis Set. All AEs will be listed in detail based on the ITT Analysis Set.
7.1.1.
Adverse Event Dictionary
AEs will be coded using the current Medical Dictionary for Regulatory Activities (MedDRA) by 
system organ class (SOC), high level group term (HLGT), high level term (HLT), preferred term 
(PT), and lower level term (LLT).
7.1.2.
Adverse Event Severity
The severity of AEs will be graded by the investigator according to the common terminology 
criteria for adverse events (CTCAE), Version 4.03, whenever possible. If a CTCAE criterion 
does not exist, the grade corresponding to the appropriate adjective will be used by the investigator 
to describe the maximum intensity of the AE. The severity grade will be categorized as:

Grade 1 (mild)

Grade 2 (moderate)

Grade 3 (severe)

Grade 4 (life threatening), or

Grade 5 (fatal)
A missing severity grade will be considered as missing.
7.1.3.
Relationship of Adverse Events to Study Drug
The relationship of an AE to the component of study drug (idelalisib/placebo), rituximab and 
bendamustine should be assessed by the investigator using clinical judgment, describing the 
event as either unrelated or related. Events for which the investigator did not record relationship 
will be considered related to study drug, rituximab and bendamustine. Data listings will show 
relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definitions of SAEs that were specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAE database from the Gilead Pharmacovigilance 
and Epidemiology Department before data finalization.


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7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent
TEAEs are events in a given study period that meet one of the following criteria:

Events with onset dates on or after the start of treatment and up to 30 days after the 
permanent discontinuation of the study treatment.

AEs resulting in treatment discontinuation after the start of treatment.
7.1.5.2.
Incomplete Dates
All AEs with partial onset or stop dates will be identified and the partial dates will be imputed as 
follows:

For AE onset date: If day and month are missing but year is available, then the imputed day 
and month will be 01Jan or the first dosing date if they have the same year, whichever is 
later.  If day is missing but the month and year are available, then the imputed day will be the 
first day of the month or the first dosing date if they have the same month and year,
whichever is later.

For AE stop date: If day and month are missing but year is available, then the imputed day 
and month will be 31Dec or 30 days after the last dose of study treatment if they have the 
same year, whichever is earlier. If day is missing but the month and year are available, then 
the imputed day will be the last day of the month or 30 days after the last dose of study 
treatment if they have the same month and year, whichever is earlier. If AE onset date is later 
than 30 days after the last dose of study treatment, then the imputed day will be the last day 
of the month if day is missing but the month and year are available. 
7.1.6.
Summaries of Adverse Events and Deaths
A brief summary of TEAEs by treatment arms will show the number and percentage of subjects 
who (1) had any TEAE, (2) had any Grade ≥3 TEAE, (3) had any idelalisib/placebo-related 
TEAE, (4) had any rituximab-related TEAE, (5) had any bendamustine-related TEAE, (6) had 
any Grade ≥3 idelalisib/placebo-related TEAE, (7) had any Grade ≥3 rituximab-related TEAE, 
(8) had any Grade ≥3 bendamustine-related TEAE, (9) had any Serious TEAE, (10) had any 
idelalisib/placebo-related Serious TEAE, (11) had any rituximab-related Serious TEAE, (12) had 
any bendamustine-related SAE, (13) had any TEAE leading to idelalisib/placebo reduction,
(14) had any TEAE leading to idelalisib/placebo interruption, (15) had any AE leading to 
idelalisib/placebo discontinuation, (16) had any TEAE leading to death.
A summary (number and percentage of subjects) of TEAEs by SOC, HLT and PT will be 
provided by treatment arms. Summaries of TEAEs by SOC and PT will be provided by treatment 
arms as follows:


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
TEAEs by CTCAE Grade

Grade ≥3 TEAE 

Idelalisib/placebo, rituximab and bendamustine-related TEAEs

TE SAEs

Idelalisib/placebo, rituximab and bendamustine related SAEs

TEAEs leading to idelalisib/placebo interruption

TEAEs leading to idelalisib/placebo reduction

TEAEs leading to idelalisib/placebo discontinuation

TEAEs leading to death
Multiple events will be counted once only per subject in each summary. For data presentation, 
SOC and PT will be sorted by decreasing frequency. For summaries by severity grade, the most 
severe event will be selected. 
In addition to the above summary tables, all TEAEs, TEAEs of Grade 3 or higher, and TE SAEs 
will be summarized by PT only in descending order of total frequency. Data listings will be 
provided for the following:

All AEs, indicating whether the event is treatment emergent

All SAEs

All AEs leading to interruption, reduction and discontinuation of idelalisib/placebo

All AEs leading to death
Relative day from the first dose date will be provided for each AE in the listings. The relative 
day will be calculated as (AE onset date - first dose date + 1).
7.1.6.1.
Summary of Deaths
A summary (number and percentage of subjects) of deaths will be provided by treatment group. 
Summary will include the following categories:

All deaths

On-study deaths

Deaths occurred in long-term follow-up


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Death between the randomization and within 30 days from end of study is considered as on-
study death. A listing of death with date and cause will also be provided.
7.1.7.
Exposure-adjusted TEAE Rate
The exposure-adjusted TEAE rate is defined as the number of subjects with a specific event 
divided by the total exposure-time among the subjects in the treatment group and at risk of an 
initial occurrence of the event. Specifically,
Exposure-Adjusted TEAE Rate =

 =

∑	
Where n is the number of subjects with events, ti is the ith subject exposure time in years and T is 
the total exposure time in years of all subjects. If a subject has multiple events, the ti is the time 
of the first event. For a subject with no event, the ti will be censored at the time of last dosing
date plus 30 days.
The exposure-adjusted TEAE rate will be summarized by treatment arm based on the 
Safety Analysis Set. The rate difference between two arms with 95% CI calculated using normal 
approximation is also provided.
7.1.8.
Treatment-Emergent Adverse Events (TEAEs) of Interest
The treatment-emergent AEs of interest (AEI) include:

Grade ≥ 3 diarrhea/colitis

Grade ≥ 3 rash in Medical Search Term (MST) (Appendix 2)

Any grade pneumonitis

Any grade bowel perforation

Any grade progressive multifocal leukoencephalopathy (PML)

Grade ≥ 3 febrile neutropenia

Grade ≥ 3 infection

Any grade pneumocystis jiroveci pneumonia (PJP)

Any grade cytomegalovirus (CMV) infection

Any grade organising pneumonia (OP)
Table 7-1 below describes grouped terms used for each AEI.


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Table 7-1.
Grouped Terms for Adverse Events of Interest
AEI
Grouped Terms
Diarrhea/Colitis
PT: Diarrhoea or Colitis
Rash
MST defined in Appendix 2
Pneumonitis
PT: Pneumonitis
Febrile neutropenia
PT: Febrile neutropenia
Infection
SOC: Infections and infestations or
PT: Febrile neutropenia
PJP
HLT: Pneumocystis infections
PML
PT: Progressive multifocal leukoencephalopathy
Organising pneumonia
PT: Organising pneumonia
CMV
HLT: Cytomegaloviral infections or
PT: Cytomegalovirus test positive or
Reported terms (i.e., verbatim’s) with the strings “CMV” or “cytomegalo”
Bowel perforation
SMQ for Gastrointestinal perforation
The AEIs will be summarized similarly to TEAE by treatment arms. The following summaries 
will be provided for subjects:

Number of subjects with AEI

Number (%) of Subjects with IDL discontinuation due to AEI

Number (%) of Subjects with IDL interruption caused due to AEI

Number (%) of Subjects who re-challenged after IDL dose interruption 

Number (%) of Subjects who re-challenged successfully after interruption with resumption of 
IDL at the starting dose 

Number (%) of Subjects who re-challenged successfully after interruption with resumption of 
IDL at a reduced dose

Number (%) of Subjects with recurrence of AE of Interest among re-challenged
Time to the first onset of AEIs and time to resolution of the first AEI will be summarized using 
summary statistics. Time to onset of the first event is defined as time from start of study 
treatment to the date of first incident AEI, ie, time in weeks is calculated as (start date of first 
occurrence of AEI
date of first dose of study drug + 1)/7. In the absence of an event, the 
censoring date will be the earliest from the following dates: last dose date + 30 days (if treatment 
discontinued) and death date. Time to resolution of the first AEI is calculated as (AEI stop date -
start date of first occurrence of AEI + 1)/7.


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The exposure-adjusted TEAE rate as well as the 95% confidence interval will be summarized for 
the AEs of interest by treatment group based on the Safety Analysis Set.
In addition, Sumarry of TEAEs of interestleading to idelalisib/placebo discontinuation and listing
of TEAEs of interest will be provided.
7.2.
Laboratory Evaluations
Summaries of laboratory data (including hematology and serum chemistry) will be provided. All 
laboratory data will be listed. Summaries of laboratory data will be based on observed data and 
will be reported using SI units. The focus of laboratory data summarization will be on treatment-
emergent laboratory abnormalities using the Safety Analysis Set.
7.2.1.
Summaries of Numeric Laboratory Results
The summaries of numeric laboratory results were performed in the interim analyses, and will 
not be performed in the final analysis.
7.2.2.
Graded Laboratory Values
Applicable hematological and serum biochemistry laboratory data will be programmatically 
graded according to CTCAE, Version 4.03 severity grade [grade laboratory results as Grade 0, 
mild (Grade 1), moderate (Grade 2), severe (Grade 3), or life threatening (Grade 4)]. Grade 0 
includes all values that do not meet criteria for an abnormality of at least Grade 1. Some
laboratory tests have criteria for both increased and decreased levels; analyses for each direction 
(ie, increased, decreased) will be presented separately. Local labs will be graded based on 
central lab normal ranges with in-house macro. In the event that both central and local lab results 
are collected in the clinical database, the worst toxicity grade will be used for the summary of lab 
toxicities. All central and local labs will be listed.
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
A treatment-emergent laboratory abnormality is defined as an abnormality that, compared to 
baseline, worsens by ≥1 grade in the period from the first dose of study drug to 30 days after the 
last dose of study treatment. If baseline data are missing, then any graded abnormality 
(ie, an abnormality that is Grade ≥1 in severity) will be considered treatment-emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
Summary (number and percentage of subjects) of baseline and worst post-baseline 
treatment-emergent laboratory abnormalities will be provided by treatment arms. Subjects will 
be categorized according to most severe postbaseline abnormality grade.
For all summaries of laboratory abnormalities, the denominator is the number of subjects in the
Safety Analysis Set. A listing of treatment-emergent laboratory abnormalities will be provided.


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7.2.2.3.
Exposure-adjusted Treatment-Emergent Laboratory Abnormalities Rate
The exposure-adjusted treatment-emergent laboratory abnormalities rates were calculated in the 
interim analyses, and will not be performed in the final analysis.
7.2.3.
Shift in CTCAE Grade Relative to Baseline
Shift tables will be presented by showing change in CTCAE severity grade from baseline to the 
worst grade post baseline.
7.2.4.
Transaminase elevations
Analyses of transaminase elevations will be based on laboratory values using the Safety Analysis 
Set. Number and percentage of subjects will be summarized by treatment arms for subjects:

with Grade 3 or 4 ALT/AST elevation 
with Grade 3 or 4 ALT elevation 
with Grade 3 or 4 AST elevation 
with Grade 3 and 4 ALT/AST elevation

with Grade 3 or 4 ALT/AST elevation resolved to both ALT/AST of Grade 1 or less

re-challenged after dose interruption 

with recurrence of Grade 3 or 4 ALT/AST elevation among re-challenged 

with recurrent Grade 3 or 4 ALT/AST elevation resolved to both ALT/AST of Grade 1 or 
less
Cumulative incidence function estimates using the competing risk model will be provided for 
time to onset of the first Grade 3 or 4 treatment-emergent ALT/AST elevations. Grade 3 or 4
ALT/AST elevation is considered as event, death without Grade 3 or 4 ALT/AST elevation is 
considered as competing event and discontinuation of study drug without event will be censored.
Time to onset of the first event is defined as time from start of study treatment to the start date of 
the first Grade 3 or 4 treatment-emergent ALT/AST elevation, ie, time in weeks is calculated as 
(start date of first occurrence date of first dose of study drug + 1)/7. In the absence of an event
or death, the censoring date applied will be the last dose date + 30 days.
For subjects with at least 1 episode of Grade 3 or 4 ALT/AST elevation, time to resolution of the 
first episode of treatment-emergent Grade 3 or 4 ALT/AST elevation to Grade 1 or less will be 
summarized using Kaplan-Meier estimates. In the absence of resolution, the censoring date 
applied will be the earlier one of the last dose date + 30 days and death date.


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7.2.5.
Liver-Related Laboratory Tests
The number and percentage of subjects will be summarized for the following liver-related 
laboratory tests and categories:

AST: (a) 3 to <5 x upper limit of normal (ULN), (b) 5 to <10 x ULN, (c) 10 to <20 x ULN, 
(d) ≥ 20 x ULN

ALT: (a) 3 to <5 x ULN, (b) 5 to <10 x ULN, (c) 10 to <20 x ULN, (d) ≥ 20 x ULN

AST or ALT: (a) 3 to <5 x ULN, (b) 5 to <10 x ULN, (c) 10 to <20 x ULN, (d) ≥20 x ULN

Total bilirubin: (a) > ULN, (b) > 1.5 x ULN, (c) > 2 x ULN 

Alkaline Phosphatase >1.5 x ULN

AST or ALT > 3 x ULN and total bilirubin > 1.5 x ULN

AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
For individual laboratory tests, subjects will be counted once based on the most severe 
post-baseline values.
Among the subjects with elevated AST or ALT (> 3 x ULN), the following 2 approaches will be 
used for counting subjects with total bilirubin elevation/normal alkaline phosphatase 
(≤1.5 x ULN):

Subjects will be counted once when total bilirubin elevation/normal alkaline phosphatase 
occurred at any post-baseline visit.

Subjects will be counted once when total bilirubin elevation/normal alkaline phosphatase 
occurred concurrently at the same post-baseline visit with AST or ALT elevation.
In addition, a listing of subjects meeting each category will be provided.
7.3.
Prior Therapy (Including Radiation)
The analyses for the prior therapies were performed in the interim analyses, and will not be 
performed in the final analysis.
7.4.
Concomitant Medications
Concomitant medications will be coded by means of the current World Health Organization 
Drug (WHODRUG) dictionary into Anatomical-Therapeutic-Chemical classification (ATC) 
codes.


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Concomitant medications are defined as any medications meeting the following criteria:

Starting on or after the first dose of study drug up to 30 days post the last dose

Starting before and continuing after the first dose of study drug up to 30 days post the 
last dose
The incomplete dates handling method used for AE summaries will be used for concomitant 
medication summaries (Section 7.1.5.2).
Summaries of the number and percentage of subjects who used concomitant medications will be 
presented in tabular form by preferred drug name based on the Safety Analysis Set. The 
summary tables will be sorted by descending frequency of preferred terms. Subjects will only be 
counted once for multiple drug use (by preferred drug name).
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.5.
Body Weight and Vital Signs
The analyses for the body weights and vital signs were performed in the interim analyses, and 
will not be performed in the final analysis.
7.6.
Electrocardiogram Results
The summary for the electrocardiogram results was performed in the interim analyses, and will 
not be performed in the final analysis. A by-subject listing for ECG assessment results will be 
provided by subject ID number and visit in chronological order.
7.7.
Other Safety Measures
A data listing will be provided for subjects experiencing pregnancy during the study.
7.8.
Changes From Protocol-Specified Safety Analyses
Not applicable.


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8.
PHARMACOKINETIC ANALYSES
There are no PK samples collected since the interim analysis.


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9.
PHARMACODYNAMIC ANALYSES
Not applicable.


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10.
REFERENCES
Cheson BD, Byrd JC, Rai KR, Kay NE, O'Brien SM, Flinn IW, et al. Novel targeted agents and 
the need to refine clinical end points in chronic lymphocytic leukemia. J Clin 
Oncol 2012;30 (23):2820-2.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. Guidelines 
for the diagnosis and treatment of chronic lymphocytic leukemia: a report from 
the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 
updating the National Cancer Institute-Working Group (NCI-WG) 1996 
guidelines. Blood 2008;111 (12):5446-56.


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


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12.
SAP REVISION
Revision Date
(dd month, yyyy)
Section
Summary of Revision
Reason for Revision
15 August 2019
The analyses that will not repeated in the 
final CSR are deleted.
Update for the final 
Synoptic CSR analysis


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13.
APPENDICES
Appendix 1.
Schedule of Assessments
Appendix 2.
Gilead List of Medical Search Terms for Rash based on MedDRA Version 22.0


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Appendix 1.
Schedule of Assessments
Period
Screen
Treatment
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25+
End
of
Study
30
day
Long-
term
Week
-4
0
2
4
6
8
10
12
14
16
18
20
22
24
30
36
42
48
Q12
wks
Study Day
Within
-28
days
1
2
15
29
30
43
57
58
71
85
86
99
113
114
127
141
142
155
169
211
253
295
337
With-
in
+30
days
To
+5
yrs
Visit Window
+1
2
2a
+1
1
2a
+1
2
3a
+1
2
2a
+1
2
2a
+1
2
3
3
3
3
3
7
Informed consent
X
Medical history
X
CIRS assessment
X
Serum virology
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
Xd
X
CLL serology
X
X
Coagulation
X
Urinalysis
X
12 lead ECG
X
Genotyping and 
expression 
analysis
X
X
IWRS
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
Adverse events
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
Performance status
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Period
Screen
Treatment
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25+
End
of
Study
30
day
Long-
term
Week
-4
0
2
4
6
8
10
12
14
16
18
20
22
24
30
36
42
48
Q12
wks
Study Day
Within
-28
days
1
2
15
29
30
43
57
58
71
85
86
99
113
114
127
141
142
155
169
211
253
295
337
With-
in
+30
days
To
+5
yrs
Visit Window
+1
2
2a
+1
1
2a
+1
2
3a
+1
2
2a
+1
2
2a
+1
2
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
Physical exam 
(includes nodes, 
liver, spleen)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology/serum 
chemistry
X
Xb
Xc
X
Xc
X
Xc
X
Xc
X
Xc
X
Xc
X
X
X
X
X
X
X
Circulating cells/
biomarkers/
serum Igs
X
X
X
X
X
X
X
X
X
X
X
X
X
CMV viral loadj
Xj
HBV DNA by 
PCRf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Idelalisib/
placebo 
administration in 
clinic
X
X
X
X
X
X
X
Premedication 
X
X
X
X
X
X
X
X
X
X
X
X
Rituximab 
administration
X
X
X
X
X
X
Bendamustine 
administration
X
X
X
X
X
X
X
X
X
X
X
X
PJP prophylaxisk
Xk
Xk
CD4+ T cell
Countk (related to
PJP prophylaxis)
Xk
Assess rituximab 
infusion severity 
and duration
X
X


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Period
Screen
Treatment
Follow-up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25+
End
of
Study
30
day
Long-
term
Week
-4
0
2
4
6
8
10
12
14
16
18
20
22
24
30
36
42
48
Q12
wks
Study Day
Within
-28
days
1
2
15
29
30
43
57
58
71
85
86
99
113
114
127
141
142
155
169
211
253
295
337
With-
in
+30
days
To
+5
yrs
Visit Window
+1
2
2a
+1
1
2a
+1
2
3a
+1
2
2a
+1
2
2a
+1
2
3
3
3
3
3
7
Idelalisib 
pharmacokinetics
X
X
X
X
X
X
X
Idelalisib/
placebo 
dispensing/
accounting
X
X
X
X
X
X
X
Radiology 
assessment 
(CT/MRI)
Xd
Xg
Xg
Xg
Xg
Xg
Xa, h
Bone marrow 
biopsy/
aspirate
Xe
Xe
Xe
Xe
Xe
Xe
Post treatment 
CLL therapy
X
Long term follow
up 
X
a.
Windows for the specified clinic visits may be extended to account for delayed recovery from drug related adverse events (eg, myelotoxicity)
b.
Hematology will be assessed locally at Visit 2, in addition to the central lab assessment, so that results will be available if the central lab results are compromised 
c.
More frequent (eg, weekly) hematology/serum chemistry assessments may be appropriate in subjects experiencing Grade 3 myelosuppression or ALT/AST elevations  Throughout the 
study, local lab results may be requested in the event central laboratory results are not available for assessment of disease response, progression, safety monitoring, or the evaluation of a 
significant event
d.
Radiology assessment (CT/MRI) if performed within <6 weeks of randomization and assessed to be adequate by the IRC and CLL peripheral blood evaluation if performed within 
<12 weeks of randomization and assessed to be adequate by the central lab do not need to be repeated 
e.
A bone marrow biopsy/aspirate demonstrating CLL involvement following the last therapy must be available if Grade >2 neutropenia, thrombocytopenia, or anemia is present at 
screening, or 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
f.
Only subjects who are HBc antibody positive and HBV DNA negative at screening. Subjects will be tested monthly for the duration of rituximab therapy and every 3 months thereafter 
for 1 year from the last dose of rituximab
g.
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the study visit; assessment should be done even if study drug has been interrupted
h.
An end of study CT/MRI tumor assessment should be performed unless the subject already has radiographic confirmation of definitive disease progression progression or a CT/MRI 
has been performed within 4 weeks prior to the end of study visit.
i.
Circulating cells/serum Igs/Immune monitoring should be performed at the the End of Study visit.


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j.
CMV viral load should be performed approximately every 4 weeks throughout idelalisib treatment. If unequivocal clinical or laboratory evidence of CMV infection is present, refer to 
Section 5.4.5 (“Infectious Events”) for required actions.
k.
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 
following the last dose of idelalisib as specified in Section 5.4.5 (“Infectious Events”).
l.
As of Amendment 10, Version 11, CT/MRI assessments will no longer be performed at the every 12 week scheduled visits, and will only be performed at the time of clinically
suspected disease progression or at study discontinuation.
Abbreviations: HCG beta human chorionic gonadotropin, CIRS chronic illness rating scale, CLL chronic lymphocytic leukemia, CR complete response, CT computed tomography, 
CMV cytomegalovirus, ECG electrocardiogram, 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.


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Appendix 2. 
Gilead List of Medical Search Terms for Rash based on MedDRA 
Version 22.0 
MedDRA Term 
ame 
MedDRA Code 
MedDRA Level 
Acute generalised exanthematous pustulosis 
10048799 
PT 
Angina bullosa haemorrhagica 
10064223 
PT 
Autoimmune dennatitis 
10075689 
PT 
Blister 
1000519 1 
PT 
Blister rupture 
10073385 
PT 
Butterfly rash 
10067982 
PT 
Cervical bulla 
10050019 
PT 
Dermatitis exfoliative 
10012455 
PT 
Dermatitis exfoliative generalised 
10012456 
PT 
De1111atosis 
10048768 
PT 
Drug eruption 
10013687 
PT 
Drug reaction with eosinophilia and system.ic symptoms 
10073508 
PT 
Eosinophilic pustular folliculitis 
10052834 
PT 
Epide1111olysis 
10053 177 
PT 
Epidermolysis bullosa 
100 14989 
PT 
Eruptive pseudoangiomatosis 
10068095 
PT 
E1ythema multifonne 
100 152 18 
PT 
Erythema nodosum 
10015226 
PT 
Erythrosis 
10056474 
PT 
Exfoliative rash 
10064579 
PT 
Fixed eruption 
10016741 
PT 
Flagellate dermatitis 
10075467 
PT 
Interstitial granulomatous dennatitis 
10067972 
PT 
Lichenoid keratosis 
10064000 
PT 
Macule 
1002542 1 
PT 
Mucocutaneous rash 
1005667 1 
PT 
Mucocutaneous ulceration 
10028084 
PT 
Mucosa vesicle 
10028 103 
PT 
Necrolytic migratory erythema 
1006082 1 
PT 
Neurodennatitis 
10029263 
PT 
Oculomucocutaneous syndrome 
10030081 
PT 
Oral mucosa] blistering 
10030995 
PT 
Oropharyngeal blistering 
10067950 
PT 
Palmar plantar erythrodysaesthesia syndrome 
10033553 
PT 
Palpable purpura 
10056872 
PT 
Papule 
10033733 
PT 
Parnneoplastic rash 
10074687 
PT 
Pemphigoid 
10034277 
PT 
CO FIDE TIAL 
Page 41 
11 September 2019 


Idelalisib (GS- LlOI) 
GS-US-312-0115 
Statistical Analysis Plan 
MedDRA Term Name 
Pemphigus 
Penile blister 
Prurigo 
Rash 
Rash erythematous 
Rash follicular 
Rash generalised 
Rash macular 
Rash maculo papular 
Rash maculovesicular 
Rash morbiJliform 
Rash papular 
Rash papulosquarnous 
Rash pruritic 
Rash pustular 
Rash rubelliform 
Rash scarlatinifonn 
Rash vesicular 
Seborrhoeic dennatitis 
Skin disorder 
Skin plaque 
Skin reaction 
Skin toxicity 
Stevens Johnson syndrome 
Symmetrical dmg related intertriginous and flexw-al 
exanthema 
Toxic epidermal necrolysis 
Toxic erythema of chemotherapy 
Toxic skin eruption 
Umbilical erythema 
Urticaria! vascu!itis 
Vaginal exfoliation 
Vasculitic rash 
Viral rash 
Vu!vovaginal rash 
CO FIDE TIAL 
Version 2.0 
MedDRA Code 
MedDRA Level 
10034280 
PT 
10052898 
PT 
10037083 
PT 
10037844 
PT 
10037855 
PT 
10037857 
PT 
10037858 
PT 
10037867 
PT 
10037868 
PT 
10050004 
PT 
10037870 
PT 
10037876 
PT 
10037879 
PT 
10037884 
PT 
10037888 
PT 
10057984 
PT 
10037890 
PT 
10037898 
PT 
10039793 
PT 
10040831 
PT 
10067723 
PT 
10040914 
PT 
100595 16 
PT 
10042033 
PT 
10078325 
PT 
10044223 
PT 
10074982 
PT 
10057970 
PT 
10055029 
PT 
10048820 
PT 
10064483 
PT 
100471 11 
PT 
10047476 
PT 
1007 1588 
PT 
Page 42 
11 September 2019