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

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The information contained in this document, particularly unpublished data, is the property or 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Knowledge of the critical importance of PI3Kδ in B-cell biology and neoplasia has 
encouraged a search for inhibitors of this enzyme that could provide new options in the 
therapy of lymphoid malignancies, including CLL.
Idelalisib (formerly GS-1101)
1.3.
1.3.1.
Discovery and Efficacy Pharmacology
Gilead Sciences, Inc has developed novel drugs that can suppress tumor growth through 
targeting of PI3Kδ activity. High-throughput screening was the basis for the discovery of 
novel agents that selectively inhibit PI3Kfunction but spare other PI3K isoforms and other 
kinases. Chemical optimization, pharmacological characterization, and toxicological 
evaluation have led to identification of idelalisib (also known as GS-1101), a 415-dalton, 
orally bioavailable, new chemical entity with potential clinical utility in the treatment of 
cancers [Gilead Sciences 2011].
In primary tumor samples and in cell lines derived from patients with CLL, indolent 
non-Hodgkin lymphoma (iNHL), mantle cell lymphoma (MCL), B-cell acute lymphocytic 
leukemia (ALL), or Hodgkin lymphoma (HL), idelalisib induces dose-dependent reductions
in AKT phosphorylation [Herman 2010, Meadows 2010, Lannutti 2011]. In addition, 
idelalisib disrupts the PI3Kactivation and supportive intercellular signaling observed when 
CLL or HL cells are cocultured with stromal cells [Meadows 2010, Hoellenriegel 2011].
These effects have therapeutic consequences. In multiple lymphoid primary tumors and 
malignant cell lines, idelalisib enhances apoptosis and concentration-dependent cell killing 
when applied as a single agent and increases the therapeutic efficacy of other antineoplastic 
agents when given in combination [Hoellenriegel 2011, Meadows 2011]. In preclinical 
systems, coadministration of idelalisib with rituximab has not impaired rituximab-mediated 
activity [Herman 2010].
1.3.2.
Safety Pharmacology
In vitro and in vivo safety pharmacology studies with idelalisib have demonstrated a 
favorable non-clinical safety profile [Gilead Sciences 2011]. These studies indicate that the 
drug may minimally slow bone marrow progenitor proliferation and differentiation and that it 
has expected inhibitory effects on B-cell response to antigen challenge. However, the data 
indicate that idelalisib is unlikely to cause serious off-target effects or adverse effects on 
critical organ systems. idelalisib has no meaningful effect on the human ether-à-go-go-related 
gene (hERG) channel, indicating that idelalisib would not be expected to induce clinical QT 
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The drug has also proved well tolerated in standard in vivo Good Laboratory Practice (GLP) 
studies of pharmacological safety. A functional observation battery in rats revealed no 
adverse effects on behavior or on autonomic, neuromuscular, or sensorimotor function. In a 
cardiopulmonary function study in awake, telemeterized male beagle dogs, single doses of 
idelalisib induced no meaningful abnormalities in pulmonary, cardiovascular, arterial blood 
gas, or electrocardiographic (ECG) (including QT interval) parameters. In an assessment of 
bacterial challenge in rats, idelalisib enhanced, rather than impaired, the phagocytic host 
clearance of staphylococcal bacteria.
1.3.3.
Nonclinical Pharmacology and Metabolism
Consistent with the moderate to high bioavailability seen in nonclinical species, idelalisib 
shows high permeability across human Caco-2 cell monolayers.  At lower concentrations, the 
reverse permeability at low concentration exceeds forward permeability, indicating efflux 
driven by transporters (eg, human P-glycoprotein (MDR1) and breast cancer resistance 
protein [BCRP]); idelalisib is a substrate for the efflux transporters MDR1 and BCRP; 
however, the permeability increases in a concentration-dependent manner, resulting in a 
lower efflux ratio at higher, clinically relevant concentrations of idelalisib. 
Idelalisib exhibits moderately high plasma protein binding in mouse, rat, dog, and human.  In 
dog and human plasma, the protein binding is concentration-independent between 1 and 
20 µM.  Protein binding in human plasma is slightly higher than in mouse, rat, and dog 
plasma, which have comparable free fractions.  In human plasma, idelalisib and GS-563117 
(the major metabolite of idelalisib) have an average free fraction of ~16% and ~12%, 
respectively.
After oral administration of 14C-idelalisib to rats and dogs, radioactivity is widely distributed, 
but relatively excluded from bone, brain, spinal cord, and eye lens in rats and from brain and 
eyes in dogs.  In rats, the radioactivity declines steadily and most tissues have undetectable 
levels by 72 hours post dose.  In bile duct-cannulated rats and dogs, ≥ 69% of radioactivity is 
recovered in bile and urine, indicating high absorption of idelalisib in vivo.
In hepatic tissues from nonclinical species, idelalisib is primarily metabolized by aldehyde 
oxidase, CYP3A, and UGT1A4.  In vitro metabolism in dog and human yields 3 primary 
oxidative metabolites and 5 primary glucuronides.  Of these, the oxidative product 
GS-563117 is the predominant metabolite in vitro and in vivo.  In preclinical species, plasma 
levels of GS-563117 are below those of idelalisib.  In humans, GS-563117 (only circulating 
metabolite and formed via aldehyde oxidase) plasma levels significantly exceed those of 
idelalisib.  After oral administration of 14C-idelalisib to rats and dogs, biliary excretion 
appears to be the major route of elimination of idelalisib and its metabolites as the majority 
of radioactivity is found in feces or bile and little in urine.
Idelalisib is not a substrate for the renal transporters OCT2, OAT1, and OAT3 or the hepatic 
uptake transporters OATP1B1 and OATP1B3.  GS-563117 is not a substrate for OATP1B1 
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Idelalisib is not an inhibitor of CYP1A, CYP2B6, CYP2C9, and CYP2D6, and at 
concentrations above those observed clinically, is an inhibitor of CYP2C8 (IC50 = 13 µM), 
CYP2C19 (IC50 = 76 µM), and CYP3A (IC50 = 44 µM). GS-563117 is not an inhibitor of 
CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and a competitive and time 
dependent inhibitor of CYP3A (IC50 = 3.1 µM), (KI = 0.18 µM, kinact = 0.033 min-1 with 
midazolam as the probe substrate). 
In vitro, idelalisib is not an inhibitor of the transporters BCRP, OCT2, OAT1, and OAT3, 
and is an inhibitor of MDR1 (IC50 = 7.7 µM), OATP1B1 (IC50 = 10.1 µM), OATP1B3 (IC50
= 7.0 µM), and, at concentrations above those observed clinically, of glucuronosyltransferase 
UGT1A1 (IC50 = 42.0 µM).  GS-563117 is not an inhibitor of MDR1, BCRP, OATP1B1, 
OATP1B3, OAT1, OAT3, and OCT2, and at concentrations above those observed clinically, 
an inhibitor of UGT1A1 (IC50 = 16.8 µM).
Any potential clinical implications of these metabolism studies were evaluated in a formal 
drug-drug interaction study (GS-US-313-0130) which evaluated the effect of idelalisib on 
cytochrome P450 3A and the drug transporters P-gp, OATP1B1, and OATP1B3.  
Study GS-US-313-0130 also evaluated the impact of an inducer of metabolizing enzymes 
and transporters (rifampin) on the PK of idelalisib in healthy human subjects. Findings from 
this study are presented in Section 1.3.5.1.
1.3.4.
Toxicology
A comprehensive package of nonclinical studies has been conducted and provides a 
toxicological profile of idelalisib in support of the treatment of adults with advanced cancer. 
The following toxicology studies have been conducted to assess the safety of idelalisib: 
single-dose (in rats and dogs) and repeat-dose oral toxicity studies (up to 26 weeks in rats and 
up to 39 weeks in dogs), in vitro and in vivo genotoxicity studies, and developmental and 
reproductive toxicity studies (fertility and embryo-fetal development in rats).
Once daily administration of idelalisib was associated with B-cell depletion in numerous 
lymphoid organs in rats and dogs, consistent with the known pharmacology of PI3Kδ 
inhibition [So 2012]. All changes were partially or completely reversible following a 4-week 
recovery period. Serum transaminase elevations were noted in the dog in both the 28-day and 
13-week studies at doses ≥7.5 mg/kg/day. Peak elevations occurred approximately 4 weeks 
following initiation of dosing and resolved completely with continued dosing. No evidence 
of chronic hepatic injury was noted in either the 13- or 39-week studies at dose levels up to 
7.5 mg/kg/day (Day 272 AUC0-t 17.1 µg∙hr/mL). In an investigative pharmacology study, a 
further characterization of the pattern of serum transaminase changes associated with 
administration of 15 mg/kg/day of idelalisib to dogs confirmed hepatic adaptation to the 
effect. In this study, mean serum ALT/AST values peaked at approximately Day 24 to 
Day 27 and resolved spontaneously as the dogs continued on idelalisib through the end of the 
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Decreased testes weights were observed in GLP repeat dose studies in rats and dogs. 
Decreased testicular weights were noted in all studies. A male fertility in rats study indicated 
that there was no impact on fertiliy or reproductive potential following daily dosing for 
10 weeks up to 100 mg/kg/day. Spermatogenic assessment of idelalisib-treated animals was 
similar to controls.  Changes in testicular weight in repeat-dose studies is suspected to be 
associated with fluid production and/or tubular contraction and not a degenerative effect.
Pregnant female rats were administered idelalisib in a standard embryo-fetal development 
toxicity study at oral doses of up to 150 mg/kg/day.  Idelalisib was shown to be embryo lethal 
and teratogenic in rats at ≥ 75 mg/kg/day (Gestation Day 17 AUC0-t 251 µg hr/mL). 
Dose-dependent developmental findings included decreased fetal viability, increased early 
and late resorptions, and decreased mean fetal body weights. Dose-dependent external 
malformations included short tails and complete tail loss. Additional external malformations 
were single instances of hydrocephaly and microphthalmia, occurring in separate fetuses 
from different litters.
Idelalisib was negative for mutagenic potential in a bacterial reverse-mutation test and 
negative for inducing chromosomal aberrations in cultured human peripheral blood 
lymphocytes. Idelalisib has shown some evidence of inducing micronuclei in this in vivo test 
system when tested at high dose levels, up to the standard limit of 2000 mg/kg. However, 
based on the mechanism of action of PI3Ks and their role as intracellular signaling proteins 
essential to migratory, proliferative, survival, and differentiation pathways, idelalisib may 
cause a small increase in micronucleated erythrocytes by mechanisms unrelated to the 
inherent genotoxicity of the compound [Tweats 2007]. These data suggest that idelalisib is 
not genotoxic.
Coadministration of cyclophosphamide with idelalisib did not appear to exacerbate the 
myelosuppressive effects of cyclophosphamide. Idelalisib did not impair bacterial clearance 
in a rat S. aureus abscess model.
A phototoxicity study yielded inconclusive results for the assessment of idelalisib due to 
cytotoxicity observed in the assay. However, the predominant oxidative metabolite, 
GS-563117, was determined to be toxic only in the presence of ultraviolet A (UVA) light
1.3.5.
Idelalisib Clinical Studies
1.3.5.1.
Phase 1 Studies in Healthy Subjects and in Patients with Allergic Rhinitis
Various studies in healthy subjectshave evaluatedsafety, pharmacokinetics, food effect, and 
the potential for drug interactions of idelalisib with CYP3A4 inhibitors [Webb 2010, 
Gilead Sciences 2011]. 

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Safety results from these studies indicated that idelalisib was well tolerated when 
administered to healthy subjects at single doses through 400 mg (the highest dose level 
tested) and was also generally well tolerated when administered to healthy subjects over 
7 days at dose levels through 200 mg/dose BID (the highest dose level tested). Dosing with 
200 mg/dose BID for 7 days resulted in a skin rash in 3 out of 6 subjects; histological 
findings were consistent with a delayed-type hypersensitivity maculopapular exanthema. 
Rashes have sometimes occurred in patients with hematological malignancies receiving 
idelalisib, but have not typically proved dose- or treatment-limiting. In placebo-controlled 
single-dose and multiple-dose trials, repeated ECG evaluations performed in tandem with 
pharmacokinetic monitoring showed no evidence of drug-, dose-, or exposure-dependent 
effects on cardiac rhythm or cardiac intervals (eg, QT interval). Pharmacokinetic results 
indicated that idelalisib appeared rapidly in plasma with a median Tmax of 1 to 1.5 hours.  
Cmax and AUC increased in a less-than-dose-proportional manner and mean t1/2 values were 
across the dose range were 6.5 to 9.8 hours.
Idelalisib dosing after a high-fat, high-calorie meal delayed median time of maximum 
concentration (Tmax) from 0.75 hours to 3 hours; mean Cmax was unaffected and mean AUC 
was ~40% higher. These changes in idelalisib exposures are considered modest/clinically 
non-relevant; thus, idelalisib may be given with or without food.
Idelalisib is metabolized in humans primarily by aldehyde oxidase, with some involvement 
of CYP3A4 and UGT1A4. Accordingly, when idelalisib was administered following 4 days 
of daily dosing with ketoconazole (a potent inhibitor of CYP3A4), modest/moderate 
increases in mean idelalisib Cmax and AUC values of ~30% and ~80% higher, respectively, 
which is not considered to be clinically relevant and suggesting that idelalisib is a weak 
CYP3A substrate. GS-563117 is formed from idelalisib primarily via aldehyde oxidase.
The 14C-labeled idelalisib human mass balance results showed that the drug has moderate to 
high oral bioavailability. Idelalisib is eliminated mainly via hepatic metabolism and biliary 
excretion in the feces (~78% of dose); recovery in urine was < 15%. GS-563117, the only 
circulating metabolite observed in human plasma, was also observed in urine and feces. 
Results from the drug interaction/probe Study GS-US-313-0130 indicate that idelalisib does 
not affect the pharmacokinetics of substrates of Pgp, BCRP, OATP1B1 or OATP1B3 
transporters. Idelalisib is not expected to affect the exposures of coadministered agents via 
transporter mediated interactions. 
The exposures (AUC) of probe CYP3A substrate, midazolam, increased ~5-fold upon 
coadministration with idelalisib, driven by competitive and time-dependent CYP3A 
inhibition by GS-563117, the only circulating metabolite of idelalisib. Coadministration of 
the highly potent CYP3A inducer rifampin resulted in a ~75% reduction in idelalisib 
systemic exposures, likely driven by a higher relative contribution of CYP3A to overall 
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Pharmacodynamic results showed that a idelalisib dose of 200 mg inhibited ex vivo basophil 
activation via the PI3K-specific, high-affinity immunoglobulin (Ig)E receptor (anti-FCR1) 
in basophils collected from healthy volunteers. The findings were confirmed when the drug 
was assessed over 7 days in a Phase 1b study in subjects with allergic rhinitis. In this study, 
idelalisib at a dose level of 100 mg/dose BID showed clinical and pharmacodynamic activity 
(attenuating adverse responses to allergenic challenge and decreasing markers of 
inflammation) and was well tolerated.
1.3.5.2.
Phase 1 Studies in Patients with Hematological Malignancies
1.3.5.2.1.
Phase 1 Monotherapy Study in Patients with Hematological Malignancies
A Phase 1 dose-ranging study (Study 101-02) of single-agent idelalisib extended safety and 
pharmacokinetic observations; documented the clinical and pharmacodynamic activity of 
idelalisib in subjects with iNHL, MCL, and CLL; and provided dosing information in support 
of further development [Brown 2011, Coutre 2011, Gilead 2011, Kahl 2011]. In this study, 
idelalisib was administered in cohorts of subjects across a range of dose levels from 
50 mg/dose BID to 350 mg/dose BID. Idelalisib administration was continued as long as 
individual subjects were safely benefitting from therapy. Subjects were evaluated in 4-week 
cycles; response and progression assessments were based on standard criteria [Hallek 2008].
A total of 191 subjects were enrolled to the study at dose levels of 50 mg BID (n=17), 
150 mg QD (n=16), 100 mg BID (n=25), 150 mg BID (n=45), 200 mg BID (n=35), 350 mg 
BID (n=17), and 300 mg QD (n=19). An additional cohort was also enrolled to receive 
idelalisib 150 mg BID in 28 day cycles (21 days on idelalisib/7 days off [n=17]). Subject
characteristics were as follows: males/females n=139 (73%)/52 (27%) with median age of 
64.5 (range 32-91) years.  Diagnoses included: CLL, n=54 (28%); iNHL, n=64 (34%); 
aggressive NHL (MCL and DLBCL), n=49 (26%); AML, n=12 (6%); and MM, n=12 (6%).  
Categorization of disease by response to the last prior therapy included: 
refractory, n=111 (58%); relapsed, n=79 (42%); and unknown, n=1 (1%).  The median 
(range) number of prior therapies was 5 (1-14). Among subjects with iNHL and CLL, the 
majority had received prior rituximab and prior alkylating agent therapy. 
Adverse events were usually mild to moderate and not clearly idelalisib-related.  Among 
Grade ≥3 adverse events, pneumonias and diarrhea were notable.  Pneumonia was observed 
in 23 (12%) subjects, primarily in subjects with CLL.  In most instances, these findings were 
considered bacterial in origin, based either on culture results or on response to conventional 
antibiotics.  Grade ≥3 adverse events of diarrhea were seen in 11 subjects (5.8%).  Other 
Grade ≥3 events included rash in 3 (1.6%) subjects.  The relative contributions of 
disease-related factors, toxicity from prior therapies or ongoing supportive care, and 
idelalisib to these events was not clear.

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

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

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

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

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

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Idelalisib or placebo will be taken orally, BID continuously. Subjects will continue 
whichever study drug (idelalisib/placebo or rituximab) continues to be tolerated, even if the 
other drug has been discontinued due to toxicity.
If permanent discontinuation of study drug, occurs prior to definitive progression of CLL, 
subjects shall remain on study until definitive progression of CLL or withdrawal from the 
study for reasons specified in Section 5.7
Compliant subjects who are tolerating therapy but who develop definitive disease 
progression in the primary clinical trial (Study GS-US-312-0116) can consider enrollment in 
this separate companion extension trial (Study GS-US-312-0117). In the extension trial, 
subjects will take active blinded idelalisib therapy, either at a higher starting dose or at the 
standard starting dose, with allocation based on the original primary study randomization.
The primary objective of Study GS-US-312-0116 will be to evaluate the effect of the 
addition of idelalisib to rituximab on PFS. Secondary and tertiary objectives will focus on 
determining the effect of the addition of idelalisib to rituximab on the onset, magnitude, and 
duration of tumor control; overall survival (OS); health-related quality of life (HRQL); 
changes in subject performance status; disease-associated biomarkers and potential 
mechanisms of resistance; treatment administration; safety; and health resource utilization. In 
Study GS-US-312-0117, the same endpoints will be assessed as in Study GS-US-312-0116; 
the focus of the analysis will be largely descriptive except for the within-subject assessment
of treatment effects among subjects receiving first rituximab alone and then idelalisib alone 
on Arm B of each trial. No formal comparisons of outcomes in Arm A vs Arm B are planned 
within Study GS-US-312-0117.
Design Rationale
2.2.
The randomized, add-on design for the primary trial (Study GS-US-312-0116) is customary 
in the comparative evaluation of new therapies for cancer. While this design provides 
idelalisib efficacy and safety information only in the context of administration of a 
companion antineoplastic agent, it is appropriate because it documents the incremental 
benefit and toxicity of the investigational therapy in the context of a controlled clinical trial 
while ensuring that all participants receive potentially active treatment.
This separate extension trial (Study GS-US-312-0117) enhances subject acceptance of 
randomization in the primary study and provides further information regarding idelalisib
efficacy, resistance, and safety. Among subjects in Arm A, escalation to a higher dose level 
allows evaluation of dose-dependent resistance and a determination if a higher dose can 
reestablish disease control. The safety data obtained in these subjects will add to the overall 
safety database. Among subjects randomized to Arm B in the primary study, evaluation of 
idelalisib at a starting dose of 150 mg/dose BID in the extension study may permit a 
within-subject assessment of the treatment effects with single-agent idelalisib relative to the 
effects previously observed with rituximab alone. Of importance, the extension study 
maintains the partial blinding of the primary study, thus minimizing the bias that might occur 
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who had received placebo on Arm B of the primary study. To ensure confirmation of disease 
progression, tumor size data collected from the primary study will be subjected to 
independent review by an independent review committee (IRC) (see Section 10.4.3); subjects 
will continue with study therapy pending confirmation of progression status by the sponsor 
working in collaboration with the IRC. Subjects must have confirmation that the disease has 
progressed on the primary study before being permitted to receive secondary idelalisib
therapy on the extension study, or in the event the primary study is stopped, subjects who 
have not yet progressed may enroll on the extension study to receive 150 mg BID idelalisib.

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

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

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

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

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

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

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

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

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

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

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

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5) The time from permanent cessation of Study GS-US-312-0116 treatment (rituximab 
and/or idelalisib/placebo) and the initiation of Study GS-US-312-0117 therapy is 
12 weeks. Note: Study procedures performed as part of Study GS-US-312-0116 need 
not be repeated and can be used as screening procedures for Study GS-US-312-0117 if 
performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117.
6) Karnofsky performance score of ≥40.
7) Required baseline laboratory data (within 4 weeks prior to initiation of study treatment) 
as shown in the table below. Note: Confirmation should be considered for out-of-range 
values to determine if the abnormality is real or artifactual. Values should be obtained 
within the screening period and should generally be the most recent measurement 
obtained. Subjects with any degree of neutropenia, thrombocytopenia, or anemia due 
to CLL or prior therapy may enroll.
Table 4-1.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome)
Serum ALT
2.5 x ULN
Serum AST
Renal
eCCra
>30 ml/min
Pregnancy
-HCGb
Negative 
a
As calculated by the Cockcroft-Gault formula (see Appendix 5)
b
For women of child-bearing potential only; serum -HCG must be negative during screening and serum -HCG or 
urine dipstick pregnancy test must be negative at start of study treatment (Visit 2)
Abbreviations: -HCG= beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate 
aminotransferase, eCCr=estimated creatinine clearance, ULN=upper limit of normal
8) For female subjects of childbearing potential, willingness to use a protocol-recommended 
method of contraception (as outlined in section 5.6.4) from the screening visit (Visit 1) 
throughout the study and for 30 days following the last dose of study drug. Note: A 
female subject is considered to be of childbearing potential unless she has had a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically 
documented ovarian failure (with serum estradiol and follicle-stimulating hormone 
[FSH] levels within the institutional postmenopausal range and a negative serum or
urine HCG), or is menopausal (age >55 with amenorrhea for >12 months or 
amenorrhea for > 6 months with serum estradiol and FSH levels within the 
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9) For male subjects of childbearing potential having intercourse with females of 
childbearing potential, willingness to use a protocol-recommended method of 
contraception (as outlined in section 5.6.4) from the start of study drug (Visit 2) 
throughout the study and for 90 days following the last dose of study drug and to refrain 
from sperm donation from the start of study drug (Visit 2) throughout the study and for 
90 days following the last dose of study drug. Note: A male subject is considered able to 
father a child unless he has had a bilateral vasectomy with documented aspermia or a 
bilateral orchiectomy, or has ongoing testicular suppression with a depot luteinizing 
hormone- releasing hormone (LH-RH) agonist (eg, goserelin acetate [Zoladex®]), 
leuprolide acetate  [Lupron®]), or triptorelin pamoate [Trelstar®]).
10) In the judgment of the investigator, participation in the protocol offers an acceptable 
benefit-to-risk ratio when considering current CLL disease status, medical condition, and 
the potential benefits and risks of alternative treatments for CLL. 
11) Willingness and ability to comply with scheduled visits, drug administration plan, 
imaging studies, laboratory tests, other study procedures, and study restrictions. 
Note: Psychological, social, familial, or geographical factors that might preclude 
adequate study participation should be considered.
12) Evidence of a personally signed informed consent indicating that the subject is aware of 
the neoplastic nature of the disease and has been informed of the procedures to be 
followed, the experimental nature of the therapy, alternatives, potential benefits, possible 
side effects, potential risks and discomforts, and other pertinent aspects of study 
participation.
4.2.2.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study:
1) Known histological transformation from CLL to an aggressive lymphoma 
(ie, Richter transformation). Note: Biopsy documentation of the absence or presence of 
transformation is not required.
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of the start 
of study treatment (Visit 2). Note: Subjects with localized fungal infections of skin or 
nails are eligible. Subjects may be receiving prophylactic antiviral or antibacterial 
therapies at the discretion of the investigator; anti-pneumocystis prophylaxis is 
encouraged. For subjects who are at substantial risk of an infection (eg, influenza) that 
may be prevented by immunization, consideration should be given to providing the 
vaccine prior to initiation of protocol therapy.
3) Pregnancy or breastfeeding. 
4) Intentional breaking of the blind in Study GS-US-312-0116 by the investigator or the 
study subject.

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

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

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

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

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

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

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

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

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

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

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

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

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

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anticipated. However, among subjects with evidence of Grade 3 serum ALT/AST 
abnormalities, evaluation for HBV reactivation (manifest as positivity for serum HBsAg)
should be considered as a precautionary measure. In a subject with active HBV, anti-HBV 
antiviral agents should be initiated. At the discretion of the investigators, study drug may be 
continued if HBV infection can be adequately controlled, particularly if the subject is 
experiencing clinical benefit from study therapy and there are few other options for treating 
the subject’s CLL.
5.4.4.
Hematological and Immunological Events
In the Phase 1 experience with idelalisib in CLL, patients with Grade3 neutropenia, anemia, 
and and/or thrombocytopenia were enrolled to clinical trials. Decreased levels of neutrophil 
counts, hemoglobin, or platelet counts during therapy were largely due to minor fluctuations 
in these parameters among patients with pre-existing hematological abnormalities due to 
disease or prior therapy. Thus, idelalisib did not appear to induce overt myelosuppression. 
Obvious patterns of drug-mediated reductions in circulating CD4+ lymphocyte counts or 
suppression of serum IgG levels were also not observed.
Given that patients with CLL commonly have Grade 3 hematological abnormalities due to 
underlying disease or prior therapy and that idelalisib is not associated with substantial 
myelotoxicity or off-target immunosuppression, alterations in study drug dose level for such 
events should only focus on subjects with protracted or symptomatic neutropenia or 
thrombocytopenia, unresponsive to G-CSF supportive care. No modification of idelalisib for 
changes in circulating CD4+ counts or Ig levels is planned.
5.4.5.
Infectious Events
Patients with CLL receiving idelalisib have developed serious bacterial, fungal, and viral 
infections during therapy [Gilead Sciences 2011]. Similarly, serious bacterial, fungal, and 
new or reactivated viral infections have also occurred during and for ~1 year following 
rituximab-based therapy [Gea-Banacloche 2010]. New or reactivated viral infections in 
patients receiving rituximab have included cytomegalovirus, herpes simplex virus, 
parvovirus B19, varicella zoster virus, West Nile virus, HBV (see Section 5.4.3) and HCV. 
Because patients with lymphoid malignancies (particularly those with CLL) are susceptible 
to infection due to the underlying disease, neutropenia, and the effects of prior therapy, the 
specific causal role of idelalisib or rituximab in any of these types of events is unclear.
Patients with previously treated CLL have developed Pneumocystis (carinii) jiroveci
pneumonia while receiving idelalisib. While idelalisib has not specifically been implicated in 
such cases, patients with lymphoid malignancies (particularly those with CLL) may be 
susceptible to pneumocystis infections due to the underlying disease and the effects of prior 
therapy. Pre-existing risk factors of specific concern may include previous pneumocystis 
pneumonia, underlying disease (eg, CLL), prior therapy (eg, alemtuzumab, progenitor cell 
transplantation), or immunocompromised status (low CD4+ lymphocyte counts, HIV
infection) [Green 2007].

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In a subject with a history of recurrent infections, prophylaxis with intravenous Ig should be 
considered [Raanani 2009]. Unless there is a contra-indication in a specific study subject, 
consideration should be given to initiation of antibiotic prophylaxis against pneumocystis 
infection (eg, with trimethoprim-sulfamethoxazole, dapsone, aerosolized pentamidine, or 
atovaquone) beginning prior to study drug administration. Such support may also offer the 
benefit of reducing the risk for other bacterial infections [Green 2007]. Local practices or 
guidelines regarding infection prophylaxis may be followed.
For subjects who develop an infection, appropriate medical therapy (with antibiotics, 
antifungals, or antiviral) or other interventions should be instituted. Whenever appropriate, 
subjects should continue with study drug during treatment for the infection.
5.4.6.
Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) due to polyomavirus JC has been 
observed in patients who have received rituximab therapy [Carson 2009] for hematologic 
malignancies. The specific causal role of rituximab is unknown because many of these 
patients had other risk factors (eg, low CD4+ counts) and the majority had received 
rituximab in combination with chemotherapy or as part of a hematopoietic stem cell 
transplant. Most cases of PML were diagnosed within 12 months of the last infusion of 
rituximab.
The diagnosis of PML should be considered in any subject presenting with new-onset or 
worsening neurologic manifestations, especially weakness or paralysis, vision loss, impaired 
speech, or cognitive deterioration. Evaluation of PML should include consultation with a 
neurologist, brain MRI, and lumbar puncture. In subjects diagnosed with PML, study drug 
should also be permanently discontinued.
5.4.7.
Pulmonary Events
Documented bacterial, fungal, viral, and pneumocystis pneumonias have been observed in 
patients receiving idelalisib, primarily in patients with CLL. Some patients receiving 
idelalisib alone or in combination have developed evidence of pneumonitis without 
documented lung infection. The specific role of idelalisib in these events is unclear; 
nonclinical evaluations of pulmonary function and pathology do not indicate a direct toxic 
effect of idelalisib on the lungs [Gilead Sciences 2011] and disease-related factors or toxicity 
from prior or concomitant therapies may have contributed to these clinical events. 
Rituximab-related noninfectious pneumonitis has been described [Subramanian 2010] with 
an incidence of ~4.3% [Salmasi 2010]. In patients developing rituximab-associated 
pneumonitis, the mean time from the first rituximab infusion to the onset of respiratory 
symptoms was 3 months, with a peak incidence after administration of a mean cumulative 
dosage of 1600 mg/m2 [Lioté 2010].

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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11.
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lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL cells 
into the circulation. Cancer. 2010 May 1;116(9):2201-7.

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

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

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

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

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Page 155
10 September 2013
FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
ADDITIONAL CONCERNS 
Not 
A little 
Some-
Quite 
Very 
at all 
bit 
what 
a bit 
much 
BRM3 
I am bothered by fevers (episodes of high body 
temperature) 
0 
2 
3 
4 
P2 
I have certain parts of my body where I experience pain.... 
0 
BRM2 
I am bothered by the chills .. 
ESJ 
I have night sweats .... 
LEU! 
I am bothered by lumps or swelling in certain parts of 
my body (e.g., neck, armpits, or groin) ..................... . 
THI 
I bleed easily . 
Tlll 
l bruise easily .... 
Hll2 
I feel weak all over . ................ ..... . 
BMT6 
r get tired easily ..... . 
C2 
Tam losing weight ..... . 
co 
I have a good appetite 
An7 
I am able to do my usual activities .................. . 
NJ 
I worry about getting infections .................. . 
LEUS 
I feel uncertain about my future health 
LEU6 
l worry that 1 might get new symptoms of my illness 
BRM9 
I have emotional ups and downs ... 
LEu? 
I feel isolated from others because of my illness or 
treatment ............................................................... ............ . 
Enghsh (Universal) 
Cop)Tight 1987, 1997 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
2 
3 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
19No\'embcr2007 
Page 3 of3 

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Page 156
10 September 2013
Appendix 3.
Performance Status Scoring System
Karnofsky Performance Status
General Description
Score
Specific Description
Able to carry on normal 
activity and to work; no 
special care needed.
100
Normal; no complaints; no evidence of disease.
90
Able to carry on normal activity; minor signs or symptoms of 
disease.
80
Normal activity with effort; some signs or symptoms of 
disease.
Unable to work; able to live 
at home and care for most 
personal needs; varying 
amount of assistance needed.
70
Cares for self; unable to carry on normal activity or to do 
active work.
60
Requires occasional assistance, but is able to care for most of 
personal needs.
50
Requires considerable assistance and frequent medical care.
Unable to care for self; 
requires equivalent of 
institutional or hospital care; 
disease may be progressing 
rapidly.
40
Disabled; requires special care and assistance.
30
Severely disabled; hospital admission is indicated although 
death not imminent.
20
Very sick; hospital admission necessary; active supportive 
treatment necessary.
10
Moribund; fatal processes progressing rapidly.
0
Dead

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

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

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

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

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

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

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