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 GS-1101 (CAL-101) as Therapy for Patients 
with Previously Treated Chronic Lymphocytic Leukemia 
A Companion Trial to Study GS-US-312-0116: A Phase 3, 
Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Efficacy and Safety of GS-1101 (CAL-101) 
in Combination with Rituximab as Therapy for Patients 
with Previously Treated Chronic Lymphocytic Leukemia 
Sponsor: 
Gilead Sciences, Inc. 
199 East Blaine Street 
Seattle, WA 98102 
USA 
IND Number: 
101254 
EudraCT Number: 
2011-006293-72 
Indication: 
Chronic Lymphocytic Leukemia  
Protocol ID: 
GS-US-312-0117 
Gilead Sciences Study 
Director: 
Name: 
 
Office Telephone: 
 
Office Fax: 
 
Mobile Telephone: 
 
E-mail: 
 
Gilead Sciences Medical 
Monitor: 
Name: 
 
Office Telephone: 
 
Office Fax: 
 
Mobile Telephone: 
 
E-mail: 
 
Protocol Version/Date: 
Original 
23 January 2012 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an 
investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable institutional review board or independent ethics committee. This information is 
only to be used by you in connection with authorized clinical studies of the investigational 
drug described in the protocol. You must not disclose any of the information to others 
without written authorization from Gilead Sciences, Inc., except to the extent necessary to 
obtain informed consent from those persons to whom the drug may be administered. 
PPD
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GS-1101 
Protocol GS-US-312-0117 
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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 .......................................................................................................................................21 
1.1. 
Chronic Lymphocytic Leukemia.....................................................................................................21 
1.2. 
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies ............................................................22 
1.3. 
GS-1101..........................................................................................................................................22 
1.3.1. 
Discovery and Efficacy Pharmacology .........................................................................22 
1.3.2. 
Safety Pharmacology ....................................................................................................23 
1.3.3. 
Nonclinical Pharmacology and Metabolism .................................................................23 
1.3.4. 
Toxicology ....................................................................................................................24 
1.3.5. 
GS-1101 Clinical Studies..............................................................................................25 
1.4. 
Summary and Justification for the Current Study...........................................................................29 
2. 
STUDY DESIGN ........................................................................................................................................32 
2.1. 
Design Overview and Study Schema..............................................................................................32 
2.2. 
Design Rationale.............................................................................................................................33 
3. 
OBJECTIVES AND ENDPOINTS .............................................................................................................35 
3.1. 
Endpoints ........................................................................................................................................35 
3.1.1. 
Tumor Control...............................................................................................................35 
3.1.2. 
Patient Well-Being........................................................................................................36 
3.1.3. 
Pharmacodynamic Markers of Drug Activity and Resistance.......................................37 
3.1.4. 
Exposure........................................................................................................................37 
3.1.5. 
Safety ............................................................................................................................37 
3.1.6. 
Pharmacoeconomics......................................................................................................37 
3.2. 
Endpoint Selection Rationale..........................................................................................................37 
3.2.1. 
Tumor Control Endpoints..............................................................................................37 
3.2.2. 
Measures of Patient Well-Being....................................................................................40 
3.2.3. 
Pharmacodynamic Markers of Drug Activity and Resistance.......................................41 
3.2.4. 
Assessments of Exposure..............................................................................................42 
3.2.5. 
Evaluations of Safety ....................................................................................................43 
3.2.6. 
Pharmacoeconomic Measures.......................................................................................44 
4. 
SUBJECT POPULATION...........................................................................................................................45 
4.1. 
Number of Subjects.........................................................................................................................45 
4.2. 
Subject Selection Criteria................................................................................................................45 
4.2.1. 
Inclusion Criteria...........................................................................................................45 
4.2.2. 
Exclusion Criteria..........................................................................................................47 
4.3. 
Enrollment Criteria Rationale .........................................................................................................47 
5. 
TREATMENT OF SUBJECTS ...................................................................................................................49 
5.1. 
Enrollment.......................................................................................................................................49 
5.1.1. 
Interactive Web Response System ................................................................................49 
5.1.2. 
Treatment Assignment ..................................................................................................49 
5.1.3. 
Blinding.........................................................................................................................49 
5.2. 
Investigational Study Drug (GS-1101/Placebo)..............................................................................50 
5.2.1. 
Description....................................................................................................................50 

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5.2.2. 
Source............................................................................................................................50 
5.2.3. 
Packaging and Labeling ................................................................................................50 
5.2.4. 
Storage and Handling....................................................................................................51 
5.2.5. 
Dispensing.....................................................................................................................51 
5.2.6. 
Return............................................................................................................................51 
5.2.7. 
Accountability...............................................................................................................52 
5.2.8. 
Overdose Precautions....................................................................................................52 
5.2.9. 
Inadvertent Exposure and Spill Precautions..................................................................52 
5.3. 
Study Drug Administration.............................................................................................................53 
5.3.1. 
Premedication................................................................................................................53 
5.3.2. 
Administration Instructions...........................................................................................53 
5.3.3. 
Dosing Schedule............................................................................................................53 
5.3.4. 
Dose Levels...................................................................................................................53 
5.3.5. 
Dose Schedule Interruptions and Vomited Doses.........................................................53 
5.3.6. 
Safety Monitoring and Study Drug Interruption/Dose Modification ............................54 
5.4. 
Recommendations for Evaluation, Intervention, and Drug Discontinuation for Specific 
Adverse Events or Conditions.........................................................................................................56 
5.4.1. 
Dermatological Events..................................................................................................56 
5.4.2. 
Gastrointestinal Events..................................................................................................56 
5.4.3. 
Hepatic Events ..............................................................................................................57 
5.4.4. 
Hematological and Immunological Events ...................................................................58 
5.4.5. 
Infectious Events...........................................................................................................58 
5.4.6. 
Progressive Multifocal Leukoencephalopathy ..............................................................59 
5.4.7. 
Pulmonary Events .........................................................................................................59 
5.4.8. 
Tumor Lysis Syndrome.................................................................................................60 
5.4.9. 
Pregnancy, Lactation, and Reproduction ......................................................................60 
5.5. 
Emergency Unblinding ...................................................................................................................60 
5.6. 
Concomitant and Supportive Therapy.............................................................................................61 
5.6.1. 
Anticancer or Experimental Therapies Other than Investigational 
Treatments.....................................................................................................................61 
5.6.2. 
Antibiotics.....................................................................................................................61 
5.6.3. 
Antiemetics and Antidiarrheals.....................................................................................62 
5.6.4. 
Contraception................................................................................................................62 
5.6.5. 
Corticosteroids ..............................................................................................................63 
5.6.6. 
Granulocyte Colony-Stimulating Factors and Erythropoietin.......................................63 
5.6.7. 
Drugs that Inhibit CYP3A4-Dependent Metabolism ....................................................64 
5.6.8. 
Immunization ................................................................................................................64 
5.6.9. 
Surgery..........................................................................................................................64 
5.6.10. 
Diet................................................................................................................................64 
5.7. 
Duration of Study Therapy..............................................................................................................64 
5.8. 
Discontinuation of Study Treatment ...............................................................................................64 
5.9. 
Study Treatment Rationale..............................................................................................................65 
6. 
STUDY PROCEDURES .............................................................................................................................69 
6.1. 
Enrollment and Study Management Procedures .............................................................................69 
6.1.1. 
Subject Recruitment......................................................................................................69 
6.1.2. 
Subject Compensation for Participation........................................................................69 
6.1.3. 
Screening.......................................................................................................................69 
6.2. 
Explanation of Study Visits ............................................................................................................70 
6.2.1. 
Visit 1 and Screening Period (Clinic Visit)...................................................................70 
6.2.2. 
Visit 2 (Day 1) (Clinic Visit).........................................................................................72 
6.2.3. 
Visit 3 (Day 15) (Clinic Visit).......................................................................................73 
6.2.4. 
Visit 4 (Day 29) (Clinic Visit).......................................................................................74 
6.2.5. 
Visit 5 (Day 43) (Clinic Visit).......................................................................................75 
6.2.6. 
Visit 6 (Day 57) (Clinic and Radiology Visit) ..............................................................76 

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6.2.7. 
Visit 7 (Day 71) (Laboratory Visit)...............................................................................77 
6.2.8. 
Visit 8 (Day 85) (Clinic Visit).......................................................................................78 
6.2.9. 
Visit 9 (Day 113) (Clinic and Radiology Visit) ............................................................79 
6.2.10. 
Visit 10 (Day 141) (Clinic Visit)...................................................................................80 
6.2.11. 
Visit 11 (Day 169) (Clinic and Radiology Visit) ..........................................................81 
6.2.12. 
Visit 12 (Day 211) (Clinic Visit)...................................................................................82 
6.2.13. 
Visit 13 (Day 253) (Clinic and Radiology Visit) ..........................................................83 
6.2.14. 
Visit 14 (Day 295) (Clinic Visit)...................................................................................84 
6.2.15. 
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks) 
(Clinic and Radiology Visits)........................................................................................85 
6.2.16. 
End-of-Treatment Visit (Clinic Visit) ...........................................................................86 
6.2.17. 
Immediate Post-Treatment Safety Follow-up ...............................................................87 
6.2.18. 
Long-Term Follow-Up..................................................................................................87 
6.3. 
Blood Collection .............................................................................................................................87 
6.4. 
Study Procedure Rationale..............................................................................................................88 
7. 
EFFICACY ASSESSMENTS .....................................................................................................................90 
7.1. 
Tumor Status Assessments..............................................................................................................90 
7.2. 
Method of Assessment....................................................................................................................90 
7.3. 
Timing of Assessments ...................................................................................................................90 
7.4. 
Identification and Measurement of Tumor Lesions and Organomegaly.........................................90 
7.4.1. 
Index Lesions ................................................................................................................90 
7.4.2. 
Spleen and Liver ...........................................................................................................91 
7.4.3. 
Non-Index Lesions........................................................................................................92 
7.5. 
Definitions of Tumor Response and Progression............................................................................92 
7.5.1. 
Complete Response.......................................................................................................93 
7.5.2. 
Partial Response............................................................................................................93 
7.5.3. 
Stable Disease ...............................................................................................................94 
7.5.4. 
Definitive Progressive Disease......................................................................................94 
7.5.5. 
Non-Evaluable...............................................................................................................96 
7.5.6. 
No Disease ....................................................................................................................96 
7.5.7. 
Lymphocytosis During Therapy....................................................................................96 
7.5.8. 
Documentation of Definitive CLL Progression ............................................................96 
8. 
SAFETY ASSESSMENTS..........................................................................................................................98 
8.1. 
Adverse Event Definitions..............................................................................................................98 
8.1.1. 
Adverse Event...............................................................................................................98 
8.1.2. 
Serious Adverse Event ..................................................................................................99 
8.1.3. 
Unexpected Adverse Event .........................................................................................100 
8.2. 
Eliciting Adverse Event Information ............................................................................................100 
8.3. 
Recording Adverse Events............................................................................................................100 
8.4. 
Grading of the Severity of an Adverse Event................................................................................100 
8.5. 
Describing Adverse Event Relationship to Study Drug and Study Procedures ............................101 
8.6. 
Adverse Event Reporting Period...................................................................................................102 
8.7. 
Adverse Event Reporting Requirements.......................................................................................102 
8.7.1. 
Site Reporting Requirements ......................................................................................102 
8.7.2. 
Gilead Sciences Reporting Requirements ...................................................................104 
8.7.3. 
Reporting of Adverse Events Relating to the Primary Endpoint and 
Other Anticipated Medical Events in the Study Population........................................104 
8.8. 
Study Drug Overdose....................................................................................................................105 
8.9. 
Pregnancy Requirements...............................................................................................................105 
9. 
STATISTICAL CONSIDERATIONS.......................................................................................................107 
9.1. 
Analysis Conventions ...................................................................................................................107 
9.1.1. 
Analysis Sets...............................................................................................................107 

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9.1.2. 
Data Handling Conventions ........................................................................................108 
9.2. 
Analysis Plan ................................................................................................................................110 
9.2.1. 
Subject Disposition and Baseline Characteristics .......................................................110 
9.2.2. 
Efficacy Analyses........................................................................................................110 
9.2.3. 
Exposure and Safety Analyses ....................................................................................111 
9.2.4. 
Other Analyses............................................................................................................114 
9.3. 
Sample Size...................................................................................................................................115 
9.4. 
Timing of Analyses.......................................................................................................................116 
9.4.1. 
Interim Analysis..........................................................................................................116 
9.4.2. 
Final Analysis .............................................................................................................116 
10. RESPONSIBILITIES ................................................................................................................................117 
10.1. 
Investigator Responsibilities .........................................................................................................117 
10.1.1. 
Compliance with Ethical and Regulatory Guidelines..................................................117 
10.1.2. 
Institutional Review Board/Independent Ethics Committee .......................................117 
10.1.3. 
Informed Consent........................................................................................................118 
10.1.4. 
Confidentiality ............................................................................................................118 
10.1.5. 
Study Files and Retention of Records and Biological Samples ..................................118 
10.1.6. 
Case Report Forms......................................................................................................120 
10.1.7. 
Drug Accountability....................................................................................................120 
10.1.8. 
Inspections ..................................................................................................................121 
10.1.9. 
Protocol Compliance...................................................................................................121 
10.2. 
Sponsor Responsibilities...............................................................................................................121 
10.2.1. 
Protocol Modifications................................................................................................121 
10.2.2. 
Communications with Regulatory Authorities............................................................121 
10.2.3. 
Data Management .......................................................................................................121 
10.2.4. 
Study Reporting and Publication.................................................................................122 
10.3. 
Joint Investigator/Sponsor Responsibilities ..................................................................................123 
10.3.1. 
Access to Information for Monitoring.........................................................................123 
10.3.2. 
Access to Information for Auditing or Inspections .....................................................123 
10.3.3. 
Public Notification of Study Conduct .........................................................................123 
10.3.4. 
Study Discontinuation.................................................................................................123 
10.4. 
Study Committees.........................................................................................................................123 
10.4.1. 
Study Steering Committee ..........................................................................................123 
10.4.2. 
Data Monitoring Committee .......................................................................................124 
10.4.3. 
Independent Review Committee .................................................................................125 
11. REFERENCES ..........................................................................................................................................126 
12. APPENDICES ...........................................................................................................................................138 
 
Appendix 1. 
Investigator Signature Page.........................................................................................139 
Appendix 2. 
Functional Assessment of Cancer Therapy: Leukemia 
(FACT-Leu) ................................................................................................................140 
Appendix 3. 
Performance Status Scoring System............................................................................143 
Appendix 4. 
EuroQoL-5 Dimensions (EQ-5D) ...............................................................................144 
Appendix 5. 
Cockcroft-Gault Method for Estimating Creatinine Clearance...................................146 
Appendix 6. 
Cumulative Illness Rating Scale (CIRS).....................................................................147 
Appendix 7. 
Schedule of Study Procedures.....................................................................................152 

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LIST OF IN-TEXT TABLES 
Table 4-1. 
Required Screening Laboratory Values ........................................................................46 
Table 5-1. 
Study Drug Dose Levels ...............................................................................................53 
Table 5-2. 
Recommendations for Study Drug Dose Modifications Based on 
Type and Severity of Adverse Events or Laboratory 
Abnormalities................................................................................................................55 
Table 5-3. 
Protocol-Recommended Contraceptive Methods..........................................................63 
Table 6-1. 
Procedures and Assessments at Visit 1 (During Screening 
Period)...........................................................................................................................71 
Table 6-2. 
Procedures and Assessments at Visit 2 (Day 1) ............................................................72 
Table 6-3. 
Procedures and Assessments at Visit 3 (Day 15) ..........................................................73 
Table 6-4. 
Procedures and Assessments at Visit 4 (Day 29) ..........................................................74 
Table 6-5. 
Procedures and Assessments at Visit 5 (Day 43) ..........................................................75 
Table 6-6. 
Procedures and Assessments at Visit 6 (Day 57) ..........................................................76 
Table 6-7. 
Procedures and Assessments at Visit 7 (Day 71) ..........................................................77 
Table 6-8. 
Procedures and Assessments at Visit 8 (Day 85) ..........................................................78 
Table 6-9. 
Procedures and Assessments at Visit 9 (Day 113) ........................................................79 
Table 6-10. 
Procedures and Assessments at Visit 10 (Day 141) ......................................................80 
Table 6-11. 
Procedures and Assessments at Visit 11 (Day 169) ......................................................81 
Table 6-12. 
Procedures and Assessments at Visit 12 (Day 211) ......................................................82 
Table 6-13. 
Procedures and Assessments at Visit 13 (Day 253) ......................................................83 
Table 6-14. 
Procedures and Assessments at Visit 14 (Day 295) ......................................................84 
Table 6-15. 
Procedures and Assessments at Visit 15 and Subsequent Visits 
(Day 337 and Every 12 Weeks) ....................................................................................85 
Table 6-16. 
Procedures and Assessments at End-of-Treatment Visit...............................................86 
Table 6-17. 
Blood Drawing Requirements Through Visit 15 (Week 48).........................................88 
Table 8-1. 
Grading of Adverse Event Severity.............................................................................101 
Table 8-2. 
Site Reporting Requirements for Adverse Events.......................................................103 
Table 8-3. 
Contact Information for Reporting Serious Adverse Events.......................................104 
LIST OF IN-TEXT FIGURES 
Figure 2-1. 
Study Design.................................................................................................................32 

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PROTOCOL SYNOPSIS 
Gilead Sciences, Inc 
199 East Blaine Street 
Seattle, WA 98102, USA 
Study Title:  
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and 
Safety of Two Different Dose Levels of Single-Agent GS-1101 (CAL-101) 
as Therapy for Patients with Previously Treated Chronic Lymphocytic 
Leukemia 
A Companion Study to Study GS-US-312-0116: A Phase 3, Randomized, 
Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety 
of GS-1101 (CAL-101) in Combination with Rituximab as Therapy for 
Patients with Previously Treated Chronic Lymphocytic Leukemia 
Study Centers 
Planned: 
Approximately 70 centers in the United States and in Europe 
IND Number: 
101254 
EudraCT 
Number: 
2011-006293-72 
Objectives: 
• To determine the effect of GS-1101 on the onset, magnitude, and 
duration of tumor control  
• To compare tumor control in subjects receiving rituximab alone in Study 
GS-US-312-0116 to that observed in the same subjects when receiving 
the standard dose of GS-1101 alone in Study GS-US-312-0117 
• To assess the effect of GS-1101 on measures of subject well-being, 
including overall survival (OS), health-related quality of life (HRQL), 
and performance status 
• To assess the effects of GS-1101 on disease-associated biomarkers and 
to evaluate potential mechanisms of resistance to GS-1101 
• To characterize exposure to GS-1101 as determined by treatment 
administration and evaluation of GS-1101 plasma concentrations over 
time 
• To describe the safety profile observed with GS-1101  
• To estimate health resource utilization associated with administration of 
GS-1101  

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Study Design: 
This study is being conducted as part of an overall clinical program 
evaluating the efficacy and safety of GS-1101 in the therapy of patients with 
previously treated chronic lymphocytic leukemia (CLL).  
Within this program, the primary clinical trial (Study GS-US-312-0116) is a 
Phase 3, multicenter, 2-arm, randomized, double-blind, placebo-controlled, 
parallel-group study. 
This clinical trial (Study GS-US-312-0117) is a separate, multicenter, 2-arm, 
double-blind, parallel-group extension study that is a companion trial to 
Study GS-US-312-0116; in this trial, compliant subjects from GS-US-312-
0116 who are tolerating primary study therapy but experience definitive 
CLL progression are eligible to receive active blinded GS-1101 therapy at 
the standard dose or a higher dose, with allocation based on the original 
primary study randomization. 
Study Schema: 
Randomized
Double-Blind
Initial Therapy
GS-1101, 150 mg BID
Until PD
Placebo BID 
Until PD
Disease 
progression
Double-Blind
Continuing  Therapy
Double-Blind
Extension
Therapy
GS-1101, 150 mg BID
R, 375 mg/m2 Wk 0
R 500 mg/m2 Wk 2,4,6,8,12,16,20
Stratification and 
Randomization
GS-1101, 150 mg BID
Until PD
GS-1101, 300 mg BID
Until PD
Placebo
R, 375 mg/m2 Wk 0
R 500 mg/m2 Wk 2,4,6,8,12,16,20
Screening
Primary Study
Study GS-US-312-0116
Extension Study
Study GS-US-312-0117
Arm A
N=80
Arm B
N=80
 
 
 
Treatment Groups 
• Arm A: GS-1101 + rituximab (Study GS-US-312-0116) 
⇒high-dose GS-1101 (300 mg BID) (Study GS-US-312-0117) 
• Arm B: Placebo + rituximab (Study GS-US-312-0116) 
⇒standard-dose GS-1101 (150 mg BID) (Study GS-US-312-0117) 
Treatment Assignment 
• Assignment to Arm A or Arm B with allocation based on the original 
primary study randomization 
• Implementation through an interactive web response system (IWRS) 
Stratification 
Not applicable for Study GS-US-312-0117 

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Number of 
Subjects 
Planned: 
Total of up to ~160 subjects (up to ~80 subjects per treatment arm) 
Target 
Population 
Subjects in the primary Phase 3 study (Study GS-US-312-0116) who are 
compliant, are tolerating primary study therapy, and have definitive 
progression of CLL while receiving primary study drug therapy 
(GS-1101/placebo). 
Diagnosis and 
Main 
Eligibility 
Criteria: 
Inclusion Criteria 
Subjects must meet all of the following conditions to be eligible for 
enrollment into the study: 
1) Participation in Study GS-US-312-0116. 
2) Occurrence of confirmed, definitive CLL progression while receiving 
study drug therapy (GS-1101/placebo) in Study GS-US-312-0116. Note: 
Definitive disease progression is CLL progression based on standard 
criteria and occurring for any reason (ie, increasing 
lymphadenopathy, organomegaly, or bone marrow involvement; 
decreasing platelet count, hemoglobin, or neutrophil count; or 
worsening of disease-related symptoms) other than lymphocytosis. 
Subjects must have confirmation by the sponsor working in 
collaboration with an independent review committee (IRC) that the 
disease has progressed on the primary clinical trial 
(Study GS-US-312-0116) before receiving secondary GS-1101 therapy 
on this extension trial (Study GS-US-312-0117). 
3) Presence of measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures ≥2.0 cm in the longest dimension [LD] 
and ≥1.0 cm in the longest perpendicular dimension [LPD] as assessed 
by computed tomography [CT] or magnetic resonance imaging [MRI]).  
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab 
and/or GS-1101/placebo) and no intervening or continuing therapy 
(including radiotherapy, chemotherapy, immunotherapy, systemic 
corticosteroids, or investigational therapy) for the treatment of CLL. 
5) The time from permanent cessation of Study GS-US-312-0116 treatment 
(rituximab and/or GS-1101/placebo) and the initiation of Study GS-US-
312-0117 therapy is ≤12 weeks. Note: Study procedures performed as 
part of Study GS-US-312-0116 need not be repeated and can be used 
as screening procedures for Study GS-US-312-0117 if performed 
within 4 weeks prior to initiation of study drug therapy on Study GS-
US-312-0117. 
6) Karnofsky performance score of ≥40. 

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7) Required baseline laboratory data (within 4 weeks prior to initiation of 
study treatment) as shown in the table below. Note: Confirmation 
should be considered for out-of-range values to determine if the 
abnormality is real or artifactual. Values should be obtained within 
the screening period and should generally be the most recent 
measurement obtained. Subjects with any degree of neutropenia, 
thrombocytopenia, or anemia due to CLL or prior therapy may enroll. 
Required Screening Laboratory Values 
Organ System 
Parameter 
Required Value 
Serum total bilirubin 
≤1.5 x ULN (unless elevated due to Gilbert’s syndrome) 
Serum ALT 
Hepatic 
Serum AST 
≤2.5 x ULN 
Renal 
eCCr
a 
>30 ml/min 
Pregnancy 
β-HCGb 
Negative  
a As calculated by the Cockcroft-Gault formula 
b For women of child-bearing potential only; serum β-HCG must be negative during screening and serum β-HCG 
or urine dipstick pregnancy test must be negative at randomization (Visit 2) 
Abbreviations: β-HCG=beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate 
aminotransferase, eCCr=estimated creatinine clearance, ULN=upper limit of normal 
 
8) For female subjects of childbearing potential, willingness to abstain 
from heterosexual intercourse or use a protocol-recommended method of 
contraception from the screening visit (Visit 1) throughout the study 
treatment period and for 30 days following the last dose of study drug. 
Note: A female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy; has medically documented ovarian failure (with serum 
estradiol and follicle-stimulating hormone [FSH] levels within the 
institutional postmenopausal range and a negative serum or urine 
βHCG), or is menopausal (age ≥55 years with amenorrhea for ≥6 
months).  
9) For male subjects of childbearing potential having intercourse with 
females of childbearing potential, willingness to abstain from 
heterosexual intercourse or use a protocol-recommended method of 
contraception from the start of study therapy (Visit 2) throughout the 
study treatment period and for 90 days following the last dose of study 
drug and to refrain from sperm donation from the start of study 
treatment (Visit 2) throughout the study treatment period and for 90 days 
following the last dose of study drug. Note: A male subject is 
considered able to father a child unless he has had a bilateral 
vasectomy with documented aspermia or a bilateral orchiectomy, or 
has ongoing testicular suppression with a depot luteinizing hormone- 
releasing hormone (LH-RH) agonist (eg, goserelin acetate 
[Zoladex®]), leuprolide acetate [Lupron®]), or triptorelin pamoate 
[Trelstar®]). 

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

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Study 
Procedures/ 
Frequency: 
Subjects participating in the extension study will be assigned to 1 of the 
2 treatment arms, with allocation based on the original randomization in 
the primary study. In the extension study, blinded GS-1101 high-dose or 
standard-dose therapy will be taken orally, twice per day (BID), 
continuously.  
Clinic/laboratory visits will occur every 2 weeks for the first 12 weeks, 
every 4 weeks between Weeks 12 and 24, and every 6 weeks between 
Weeks 24 and 48. Subjects continuing on study treatment past Week 48 
will have clinic visits every 12 weeks. Subjects will be assessed for safety 
at each visit. Subjects will be assessed for CLL disease status by physical 
and laboratory examinations at each visit and by CT or MRI at Weeks 8, 
16, 24, 36, and 48 and every 12 weeks thereafter through Week 96. For 
follow-up visits after Week 96, CT or MRI is only required at the End-of-
Treatment visit. 
Test Therapy, 
Dose, and  
Mode of 
Administration: 
• Arm A: GS-1101, 300 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be provided 
as 2 tablets of active GS-1101 for oral administration 
• Arm B: GS-1101, 150 mg/dose BID starting on Day 1 and 
administered continuously thereafter; the study drug will be provided 
as 1 tablet of active GS-1101 and 1 tablet of placebo for oral 
administration 
Reference 
Therapy, Dose, 
and Mode of 
Administration: 
Not applicable 
Duration of 
Treatment: 
Study drug will be taken continuously until the earliest of subject 
withdrawal from study, definitive progression of CLL, intolerable study 
drug-related toxicity, pregnancy, substantial noncompliance with study 
procedures, or study discontinuation. 

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Criteria for 
Evaluation: 
Tumor Control  
• Progression-free survival (PFS) – defined as the interval from the 
start of study therapy to the earlier of the first documentation of 
definitive disease progression or death from any cause; definitive 
disease progression is CLL progression based on standard criteria and 
occurring for any reason (ie, increasing lymphadenopathy, 
organomegaly or bone marrow involvement; decreasing platelet 
count, hemoglobin, or neutrophil count; or worsening of 
disease-related symptoms) other than lymphocytosis alone 
• Overall response rate (ORR) – defined as the proportion of subjects 
who achieve a complete response (CR) or partial response (PR)  
• Time to response (TTR) – defined as the interval from start of study 
therapy to the first documentation of CR or PR 
• Duration of response (DOR) – defined as the interval from the first 
documentation of CR or PR to the earlier of the first documentation 
of definitive disease progression or death from any cause 
• Time to treatment failure (TTF) – defined as the interval from start of 
study therapy to the earliest of the first documentation of definitive 
disease progression, the permanent cessation of study drug due to an 
adverse event, or death from any cause 
• Percent change in lymph node area – defined as the percent change 
from baseline in the sum of the products of the greatest perpendicular 
diameters (SPD) of index lymph nodes 
• Lymph node response rate – defined as the proportion of subjects 
who achieve a ≥50% decrease from baseline in the SPD of index 
lymph nodes 
• Splenomegaly response rate – defined as the proportion of subjects 
with baseline splenomegaly who achieve an on-study normalization 
or a decrease by ≥50% from baseline in the pretreatment enlargement 
of the splenic longest vertical dimension (LVD) (by imaging) or in 
the pretreatment enlargement of the splenic LVD below the left costal 
margin (by palpation) 
• Hepatomegaly response rate – defined as the proportion of subjects 
with baseline hepatomegaly who achieve an on-study normalization 
or a decrease by ≥50% from baseline in the pretreatment enlargement 
of the hepatic LVD (by imaging) or in the pretreatment enlargement 
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• Platelet response rate – defined as the proportion of subjects with 
baseline thrombocytopenia (platelet count <100 x 109/L) who achieve 
an on-study platelet count ≥100 x 109/L or demonstrate a ≥50% 
increase in platelet count from baseline 
• Hemoglobin response rate – defined as the proportion of subjects with 
baseline anemia (hemoglobin <110 g/L [11.0 g/dL]) who achieve an 
on-study hemoglobin ≥110 g/L (11.0 g/dL) or demonstrate a ≥50% 
increase in hemoglobin from baseline 
• Neutrophil response rate – defined as the proportion of subjects with 
baseline neutropenia (absolute neutrophil count [ANC] <1 x 109/L) 
who achieve an ANC ≥1 x 109/L or demonstrate a ≥50% increase in 
ANC from baseline 
Patient Well-Being 
• Overall survival (OS) – defined as the interval from start of study 
therapy to death from any cause 
• Change in HRQL domain and symptom scores based on  the 
Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu) – 
defined as the change from baseline and the time to definitive 
increments or decrements of 10%, 20%, and 40% from baseline; time 
to definitive increment (better than baseline by the specified amount) 
is the interval from start of study therapy to the first timepoint when 
the HRQL measure is consistently better than at baseline (including 
that timepoint as well as all the subsequent timepoints) in a subject 
whose last HRQL score is better than at baseline; and time to 
definitive HRQL decrement (worse than baseline by the specified 
amount) is the interval from start of study therapy to the earliest of 
death or the first timepoint when the HRQL measure is consistently 
worse than at baseline (including that timepoint as well as all the 
subsequent timepoints) in a subject whose last performance status 
score is worse than at baseline 
• Changes in Karnofsky performance status – defined as the change 
from baseline in the performance status and the time to definitive 
performance status improvement or worsening; time to definitive 
performance status improvement (better than baseline) is the interval 
from start of study therapy to the first timepoint when the 
performance status is consistently better than at baseline (including 
that timepoint as well as all the subsequent timepoints) in a subject 
whose last performance status score is better than at baseline; and 
time to definitive performance status worsening (worse than baseline) 
is the interval from study therapy until the earliest of death or the first 
timepoint when the performance status is consistently worse than at 
baseline (including that timepoint as well as all the subsequent 

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timepoints) in a subject whose last performance status score is worse 
than at baseline 
Pharmacodynamic Markers of Drug Activity and Resistance 
• Changes from baseline in PI3K/AKT/mTOR pathway activation as a 
measure of PI3Kδ pathway activity  
• Changes from baseline in the plasma concentrations of disease-
associated chemokines and cytokines 
Exposure 
• Study drug administration as assessed by prescribing records and 
compliance as assessed by quantification of used and unused drug 
• Trough (pre-dose) and peak (1.5-hour samples) of GS-1101 plasma 
concentrations as assessed by a validated bioanalytical method 
Safety 
• Overall safety profile of each study treatment regimen characterized 
by the type, frequency, severity, timing of onset, duration, and 
relationship to study therapy of any adverse events or abnormalities 
of laboratory tests; serious adverse events; or adverse events leading 
to discontinuation of  study treatment  
Pharmacoeconomics 
• Change in health status – defined as the change from baseline in 
overall health and single-item dimension scores as assessed using the 
EuroQoL Five-Dimension (EQ-5D) utility measure  
• Health resource measures, including resource utilization, total costs, 
and measures of cost per unit of benefit (eg, cost per additional 
progression-free month, cost per quality-adjusted life-year) 
Statistical 
Methods: 
Analysis Methods  
Appropriate data analysis sets will be defined. The full-analysis set will 
include data from all subjects who receive ≥1 dose of any study therapy 
on this study; in this data set, study drug assignment (high-dose or 
standard-dose GS-1101) will be designated according to the planned 
allocation to this study. A safety analysis set will comprise data from 
subjects in the full-analysis set with treatment assignments designated 
according to the actual study drug (high-dose or standard-dose GS-1101) 
received. Other data sets (responding, evaluable, and 
pharmacodynamic/pharmacokinetic data sets) will be defined and will 
include data from subjects who have the necessary baseline and on-study 
measurements to provide interpretable results for specific parameters of 
interest.  

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Subject characteristics and study results will be described and 
summarized by treatment arm and assessment for the relevant analysis 
sets. Descriptive summaries will be prepared to show sample size, mean, 
standard deviation, 95% confidence intervals (CIs) on the mean, median, 
minimum, and maximum for continuous variables and counts, 
percentages, and 95% CIs on the percentage for categorical variables. 
For endpoints relating to tumor control, patient well-being, and 
biomarkers, analyses will be done based on the full-analysis, responding, 
evaluable, or pharmacodynamic data sets, as appropriate. Time-to-event 
analyses will be performed with reference to the date of first treatment on 
this study (Study GS-US-312-0117). Similarly, evaluations of on-therapy 
changes will reference the baseline values obtained prior to treatment in 
this study. Analyses will focus on evaluation of outcomes within each 
treatment arm and will be largely descriptive in nature; formal 
comparisons of outcomes in Arm A vs Arm B are not planned. Time-to-
event endpoints will be summarized using Kaplan-Meier methods; 
medians, ranges, and the corresponding 95% CI will be presented. 
Continuous and categorical variables will also be summarized as 
appropriate. Changes from baseline in categorical variables and changes 
from baseline in continuous endpoints will be analyzed using appropriate 
methods. 
Efficacy outcomes among subjects receiving rituximab alone in 
Study GS-US-312-0116 will be evaluated relative to those same 
outcomes among the same subjects receiving standard-dose GS-1101 
alone in Study GS-US-312-0117. More specifically, time-to-event 
endpoints will be compared using the paired Prentice-Wilcoxon test; 
continuous endpoints will be compared using the paired t-test; and 
categorical or non-normal data will be compared using the Wilcoxon 
signed-rank test. 
Based on the safety analysis set, information regarding study treatment 
administration, study drug compliance, safety variables, and post-study 
therapies will be described and summarized. Using data from the 
pharmacokinetic analysis set, GS-1101 plasma concentrations will also 
be described and summarized. 

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Sample Size Calculation 
The sample size for this extension study is not based upon a formal 
statistical hypothesis. The upper bound of the sample size in this study is 
determined by the sample size of the preceding primary clinical trial 
(Study GS-US-312-0116) in which ~160 subjects (~80 per arm) are 
expected to be enrolled. Assuming a ~10% dropout rate during 
Study GS-US-312-0116 and a further ~10% dropout rate in the transition 
from the primary study to the extension study, ~130 subjects are expected 
to be enrolled into Study GS-US-312-0117. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice 
(GCP), including archiving of essential documents. 

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS 
β-HCG 
Beta human chorionic gonadotropin 
ABCG2 
adenosine triphosphate-binding cassette sub-family G member 2 (see also BCRP) 
AKT 
AKT (a serine/threonine protein kinase) 
ALC 
absolute lymphocyte count 
ALL 
acute lymphocytic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
ATC 
Anatomical-Therapeutic-Chemical classification system for drugs  
BCRP 
breast cancer resistance protein (see also ABCG2) 
BID 
twice per day 
BTK 
Bruton tyrosine kinase 
CAL-101 
Former name for GS-1101 
CCL 
chemokine (C-C motif) ligand 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIRS 
Cumulative Illness Rating Scale 
CLL 
chronic lymphocytic leukemia 
cGMP 
current Good Manufacturing Practice 
Cmax 
maximum concentration 
CMV 
cytomegalovirus 
CR 
complete response 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
trough concentration 
CXCL 
chemokine (C-X-C motif) ligand 
CYP 
cytochrome P450 enzyme 
DLCO 
diffusing capacity of the lung for carbon monoxide 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSPH 
Gilead Sciences Department of Safety and Public Health 
ECG 
electrocardiogram 
eCCr 
estimated creatinine clearance 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EQ-5D 
EuroQoL Five-Dimension utility measure 

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED) 
FACT-Leu 
Functional Assessment of Cancer Therapy: Leukemia questionnaire 
FCεRI 
high-affinity IgE receptor 
FDA 
United States Food and Drug Administration 
FDAMA 
Food and Drug Modernization Act 
FDG 
fluorodeoxyglucose (18F) 
FISH 
fluorescence in-situ hybridization, 
FSH 
follicle-stimulating hormone 
G-CSF 
granulocyte colony-stimulating factor 
GGT 
gamma-glutamyltransferase 
GLP 
Good Laboratory Practice 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HBc antibody 
anti-hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
hERG 
human ether-à-go-go-related gene 
HL 
Hodgkin lymphoma 
HIV 
human immunodeficiency virus 
HRQL 
health-related quality of life 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
Ig 
immunoglobulin (including subtypes A, E, G, and M) 
IgHV 
immunoglobulin heavy chain variable region 
IND 
Investigational New Drug (application) 
iNHL 
indolent non-Hodgkin lymphoma 
INR 
international normalized ratio 
IRB 
institutional review board 
IRC 
independent review committee 
ITT 
intention to treat 
IUD 
intrauterine device 
IWCLL 
International Workshop on CLL 
IWRS 
interactive web response system 
JAK 
Janus kinase 
K2-EDTA 
potassium-ethylenediaminetetraacetic acid 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
LH-RH 
luteinizing hormone-releasing hormone 
LLN 
lower limit of normal 
LPD 
longest perpendicular diameter 
LVD 
longest vertical dimension 
MTD 
maximum tolerated dose 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONTINUED) 
mTOR 
mammalian target of rapamycin 
ND 
no disease 
NHL 
non-Hodgkin lymphoma 
NOAEL 
no-observed-adverse effect level 
NOEL 
no-observed-effect level 
OCT 
organic cation transporter 
ORR 
overall response rate 
OS 
overall survival 
pAKT 
phosphorylated AKT 
PD 
progressive disease 
PET 
positron-emission tomography 
PI3K 
phosphatidylinositol 3-kinase 
PI3Kδ 
phosphatidylinositol 3-kinase p110δ isoform 
PFS 
progression-free survival 
PML 
progressive multifocal leukoencephalopathy 
PPD 
product of the perpendicular diameters 
PRO 
patient-reported outcome 
PR 
partial response 
PT 
prothrombin time 
PVA 
polyvinyl alcohol 
PVC/PCTFE 
polyvinyl chloride/polychlorotrifluoroethylene 
QD 
once per day 
QT (interval) 
measure of time between start of Q wave and end of T wave in electrical cycle of heart 
RNA 
ribonucleic acid 
SADR 
serious adverse drug reaction 
SD 
stable disease 
SPD 
sum of the products of the perpendicular diameters of measured lymph nodes 
SSC 
study steering committee 
SUSAR 
suspected, unexpected, serious adverse reaction 
SYK 
spleen tyrosine kinase 
t1/2 
half-life 
Tmax 
time of maximum concentration 
TTF 
time to treatment failure 
TTR 
time to response 
UGT 
uridine 5'-diphospho-glucuronosyltransferase 
ULN 
upper limit of normal 
WHODRUG 
World Health Organization Drug Dictionary 
ZAP=70 
zeta-associated protein 70 
 

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1. 
INTRODUCTION 
1.1. 
Chronic Lymphocytic Leukemia 
Chronic lymphocytic leukemia (CLL) is a neoplasia resulting from the progressive 
accumulation of functionally incompetent monoclonal B lymphocytes in blood, bone 
marrow, lymph nodes, spleen, and liver [Dighiero 2008]. CLL constitutes the most 
commonly occurring leukemia in Europe and the United States [Sant 2010, SEER 2011]. 
While some patients never require treatment, many will need therapy for disfiguring or 
obstructing lymphadenopathy, debilitating constitutional B symptoms (fevers, night sweats, 
fatigue, weight loss) [Redaelli 2004], or recurrent cytopenias and infections [Perkins 2002, 
Keating 2002a]. CLL is largely a disease of the elderly; at diagnosis, 70% of patients are 
≥65 years of age and the median age is 72 years [SEER 2011]. 
In younger and relatively healthy patients with CLL, chemoimmunotherapy regimens that 
include the anti-CD20 monoclonal antibody, rituximab, are commonly employed to control 
disease manifestations [Gribben 2011]. Such combination therapies are effective in providing 
durable remissions [Byrd 2005, Hallek 2010, Robak 2010, Fischer 2011, and Iannitto 2011]. 
However, while rituximab is usually well tolerated [Gentile 2010], the chemotherapeutic 
agents (typically fludarabine, cyclophosphamide, or bendamustine) in such regimens are 
acutely cytotoxic, induce permanent bone marrow compromise, and can cause secondary 
malignancies [Kyasa 2004, Tam 2008, Carney 2010]. Furthermore, in elderly patients or in 
those with comorbid conditions, such regimens are associated with less efficacy and greater 
toxicity [Tam 2008, Eichhorst 2009b, Goede 2011]. 
Increasing attention has been paid to the problem of treating patients with CLL who have 
comorbidities. Because of the relatively late age of diagnosis, a large proportion (~90%) of 
patients with CLL have co-morbidities and a substantial proportion (~45%) have major 
chronic conditions such as coronary artery disease, diabetes, or chronic obstructive 
pulmonary disease [Thurmes 2008]. At the time the disease is first identified, ~25% of 
patients with CLL do not meet conventional criteria for participation in clinical studies 
containing cytotoxic agents [Thurmes 2008]. By the time treatment is necessary or during 
treatment for CLL, patients continue to advance in age and have new or worsening chronic 
conditions; as a result, the proportion of patients with comorbidities increases during the 
course of the illness. Such patients have been substantially underrepresented in clinical trials 
due to concerns regarding the ability of such patients to tolerate intensive 
chemoimmunotherapy [Thurmes 2008, Eichhorst 2009a]. Instruments such as the 
Cumulative Illness Rating Scale (CIRS) [Linn 1968] are now being applied in order to 
categorize patient populations as fit or relatively unfit and to evaluate regimens tailored to 
these groups of patients [Eichhorst 2009a, Hallek 2010, Giudice 2011]. 
Health constraints in older or compromised patients have prompted noncytotoxic approaches 
to therapy. Alternative immunotherapeutics, such as the monoclonal antibodies, 
alemtuzumab [Keating 2002b] or ofatumumab [Wierda 2010], have been developed. 
However the therapeutic utility of these drugs is modest; median progression-free survival 
(PFS) values in patients with recurrent CLL have been 4.7 months and 5.8 months, 
respectively. Moreover, these treatments can have clinical liabilities. Alemtuzumab causes 
extreme immunosuppression that leads to frequent opportunistic infection. Administration of 

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the large amounts of protein recommended in ofatumumab product labeling results in 
frequent infusion reactions and cumbersome infusion schedules. 
In view of these issues, repeated use of rituximab monotherapy or rituximab-corticosteroid 
combinations have been advocated in treatment guidelines for older or frail patients with 
recurrent CLL [Eichhorst 2010, Zelenetz 2011]. While single-agent rituximab use can offer 
palliative benefit with good tolerability in some patients with previously treated CLL, tumor 
control is not lasting, especially in patients with bulky adenopathy [Gentile 2010]. Addition 
of high-dose corticosteroids to rituximab can extend median PFS up to 12 months, but this 
combination is commonly associated with severe hyperglycemia and frequent 
life-threatening or fatal infections [Bowen 2007, Dungarwalla 2008]. New, noncytotoxic, 
well-tolerated, and convenient therapies that can successfully be combined with rituximab or 
given as single-agent therapy are needed in order to enhance and prolong tumor control in 
patients with comorbid conditions. 
1.2. 
Phosphatidylinositol 3-Kinase in Lymphoid Malignancies 
Phosphatidylinositol 3-kinases (PI3Ks) are enzymes that regulate several cellular functions 
including motility, proliferation, and survival [Okkenhaug 2003a]. PI3K activation recruits 
and activates numerous intracellular signaling enzymes. The most important of these is the 
serine/threonine kinase, AKT, which mediates a positive pleiotropic effect on cell survival, 
proliferation, growth, and metabolism [Engelman 2006] acting by signaling through 
mammalian target of rapamycin (mTOR) [Hay 2005, Osaki 2004]. 
PI3K signaling is mediated by 4 catalytic isoforms of the p110 subunit of the enzyme – α, β, 
γ, and δ. While potentially important in multiple cell types, PI3K p110δ (PI3Kδ) shows an 
expression pattern that is particularly prominent in cells of hematopoietic origin 
[Vanhaesebroeck 2005]. Mice deficient in PI3Kδ have no gross abnormalities, are fertile, 
fecund, and live a normal life span without an increased susceptibility to infections 
[Okkenhaug 2003b]. However, the B-lymphocyte population in these animals shows a 
decrease in maturation, diminished receptor-induced proliferation, and increased 
susceptibility to apoptotic cell death. Conversely, mice with aberrantly elevated PI3K 
signaling develop lymphadenopathy and have an increased incidence of lymphoma 
[Donahue 2004]. In CLL, sustained activation of the PI3K/AKT/mTOR pathway has been 
shown to promote malignant B-cell survival through mechanisms that are dependent on the 
PI3Kδ isoform [Cuni 2004, Herman 2010, Lannutti 2011]. 
Knowledge of the critical importance of PI3Kδ in B-cell biology and neoplasia has 
encouraged a search for inhibitors of this enzyme that could provide new options in the 
therapy of lymphoid malignancies, including CLL. 
1.3. 
GS-1101 
1.3.1. 
Discovery and Efficacy Pharmacology 
Gilead Sciences, Inc has developed novel drugs that can suppress tumor growth through 
targeting of PI3Kδ activity. High-throughput screening was the basis for the discovery of 
novel agents that selectively inhibit PI3Kδ function but spare other PI3K isoforms and other 
kinases. Chemical optimization, pharmacological characterization, and toxicological 
evaluation have led to identification of GS-1101 (also known as CAL-101), a 415-dalton, 

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orally bioavailable, new chemical entity with potential clinical utility in the treatment of 
cancers [Gilead Sciences 2011]. 
In primary tumor samples and in cell lines derived from patients with CLL, indolent 
non-Hodgkin lymphoma (iNHL), mantle cell lymphoma (MCL), B-cell acute lymphocytic 
leukemia (ALL), or Hodgkin lymphoma (HL), GS-1101 induces dose-dependent reductions 
in AKT phosphorylation [Herman 2010, Meadows 2010, Lannutti 2011]. In addition, 
GS-1101 disrupts the PI3Kδ activation and supportive intercellular signaling observed when 
CLL or HL cells are cocultured with stromal cells [Meadows 2010, Hoellenriegel 2011]. 
These effects have therapeutic consequences. In multiple lymphoid primary tumors and 
malignant cell lines, GS-1101 enhances apoptosis and concentration-dependent cell killing 
when applied as a single agent and increases the therapeutic efficacy of other antineoplastic 
agents when given in combination [Hoellenriegel 2011, Meadows 2011]. In preclinical 
systems, coadministration of GS-1101 with rituximab has not impaired rituximab-mediated 
activity [Herman 2010]. 
1.3.2. 
Safety Pharmacology 
In vitro and in vivo safety pharmacology studies with GS-1101 have demonstrated a 
favorable non-clinical safety profile [Gilead Sciences 2011]. These studies indicate that the 
drug may minimally slow bone marrow progenitor proliferation and differentiation and that it 
has expected inhibitory effects on B-cell response to antigen challenge. However, the data 
indicate that GS-1101 is unlikely to cause serious off-target effects or adverse effects on 
critical organ systems. GS-1101 has no meaningful effect on the human ether-à-go-go-related 
gene (hERG) channel, indicating that GS-1101 would not be expected to induce clinical QT 
prolongation. 
The drug has also proved well tolerated in standard in vivo Good Laboratory Practice (GLP) 
studies of pharmacological safety. A functional observation battery in rats revealed no 
adverse effects on behavior or on autonomic, neuromuscular, or sensorimotor function. In a 
cardiopulmonary function study in awake, telemeterized male beagle dogs, single doses of 
GS-1101 induced no meaningful abnormalities in pulmonary, cardiovascular, arterial blood 
gas, or electrocardiographic (ECG) (including QT interval) parameters. In an assessment of 
bacterial challenge in rats, GS-1101 enhanced, rather than impaired, the phagocytic host 
clearance of staphylococcal bacteria. 
1.3.3. 
Nonclinical Pharmacology and Metabolism 
In rats and dogs, plasma-concentration time profiles of GS-1101 are available following 
single oral and intravenous administration as well as following repeated oral administration 
as part of toxicology studies [Gilead Sciences 2011]. The metabolism of GS-1101 has been 
studied in vitro and in vivo; the major metabolite has been identified and characterized in 
rats, dogs, and humans. No human-specific metabolites have been identified. 
Drug disposition data document GS-1101 oral bioavailability in test species, characterize 
similar plasma protein binding across species, and demonstrate that GS-1101 metabolism is 
dependent upon both hepatic oxidation catalyzed in part by cytochrome P450 (CYP) 3A4 and 
on glucuronidation mediated by uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A4. 
Nonclinical findings show that biliary excretion and hepatic metabolism to renal excretion 

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products are important in GS-1101 elimination. Nonclinical drug-drug interaction data show 
that GS-1101 is unlikely to alter CYP-dependent metabolism of other drugs but could alter 
absorption or disposition of agents that are substrates for P-glycoprotein, the organic cation 
transporter-2 (OCT2), or the adenosine triphosphate-binding cassette sub-family G 
member 2 (ABCG2) transporter (also known as the breast cancer resistance protein [BCRP]). 
1.3.4. 
Toxicology 
In support of clinical development in patients with lymphoid cancers, GS-1101 has 
undergone toxicological evaluation in conformance with the International Conference on 
Harmonisation (ICH) S9 guidance on nonclinical evaluation for anticancer pharmaceuticals 
[FDA 2010]. 
1.3.4.1. 
General Toxicology 
Completed GLP toxicology studies have included 28-day evaluations in both rats and dogs 
and a study evaluating the hematological effects of co-administration of GS-1101 and 
cyclophosphamide [Gilead Sciences 2011]. These studies have shown GS-1101 to be 
tolerated at exposure levels greater than those expected to provide therapeutic activity and 
have identified signals to be monitored in the clinic. Reversible lymphoid depletion in rats 
and dogs was consistent with GS-1101-mediated inhibition of PI3Kδ. In rats, partially 
reversible inflammation of the tongue was noted in GS-1101-treated animals; this may have 
represented an exaggeration of background effects related to gavage-mediated irritation. Mild 
congestion or hemorrhage in the large intestine has been seen in dogs receiving high doses of 
GS-1101. Rats also showed cardiac and hepatic chronic inflammatory infiltrates, although 
attribution to GS-1101 was uncertain because background infiltrates of a similar nature were 
observed in control recovery animals. In dogs, evidence of hepatocellular injury and chronic 
inflammation was accompanied by elevations of serum transaminase values (serum alanine 
aminotransferase [ALT] and serum aspartate aminotransferase [AST]). These hepatic effects 
appeared dose-related, reversible, and monitorable using standard serum chemistry 
laboratory parameters. In both rats and dogs, persistent minimal to mild degeneration of the 
seminiferous tubules and decreased spermatozoa were present in male animals receiving 
GS-1101. When co-administered with cyclophosphamide in rats, GS-1101 did not worsen 
cyclophosphamide-mediated changes in hematological parameters. 
Data from 13-week GLP toxicology studies in rats and dogs are available. These data 
confirm the 28-day toxicology findings. GS-1101 was well tolerated with no notable clinical 
observation or changes in body weight at exposure levels approximating or exceeding those 
observed in subjects at the planned clinical starting dose of 150 mg/dose administered twice 
per day (BID). In both species, dose-dependent lymphoid depletion was observed that was 
consistent with PI3Kδ inhibition by GS-1101. In dogs, expected transient low-level 
elevations of serum ALT in 2 animals receiving the highest GS-1101 dose were observed at 
Day 29 of the study; of note, animals showed spontaneous recovery during continued 
GS-1101 dosing, with no elevations at Day 60 or Day 90. Microscopic review of dog tissues 
indicated no evidence of persistent or residual liver pathology at the conclusion of the study. 
Consistent with previous studies, findings of persistent hypospermatogenesis and decreased 
testicular weight were observed in both species. 

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In an investigative study, a further characterization of the pattern of serum transaminase 
changes associated with administration of high-dose of GS-1101 to dogs confirmed hepatic 
adaptation to the effect. In this study, mean serum ALT/AST values peaked at approximately 
Day 24 to Day 27 and resolved spontaneously as the dogs continued on GS-1101 through the 
end of the study on Day 44. 
1.3.4.2. 
Genotoxicity 
GS-1101 was not genotoxic in a standard battery of assays [Gilead Sciences 2011]. In the 
Ames assay, GS-1101 did not cause mutagenic effects. In human peripheral blood 
lymphocytes, the compound induced no chromosomal aberrations. In a rat micronucleus 
study, GS-1101 did not show evidence of clastogenicity. 
1.3.4.3. 
Reproductive Toxicology 
Data from a non-GLP embryo-fetal developmental toxicity study in rats suggested no 
evidence of maternal toxicity at GS-1101 doses of 25, 50, 75, and 100 mg/kg/day. No 
GS-1101-related findings were observed based on external examination of the fetus at any 
dose level although lower fetal body weights were evident at 100 mg/kg/day and were 
considered related to treatment with GS-1101. Thus, the no-observed-effect level (NOEL) for 
maternal toxicity was 100 mg/kg/day and the NOEL for fetal developmental toxicity was 
75 mg/kg/day. Definitive GLP reproductive toxicology studies in rats and rabbits are 
planned. 
As noted in Section 1.3.4.1, 28-day and 13-week general toxicology studies in rats and dogs 
indicated dose-dependent reductions in testicular weights, with persistent minimal to mild 
degeneration of the seminiferous tubules and decreased spermatozoa in rats and 
hypospermatogenesis in dogs. The no-observed-adverse effect level (NOAEL) was 
50 mg/kg/day for rats and 5 mg/kg/day for dogs. The impact of these testicular changes on 
fertility, if any, has not been assessed. 
1.3.5. 
GS-1101 Clinical Studies 
1.3.5.1. 
Phase 1 Studies in Healthy Subjects and in Patients with Allergic Rhinitis 
Three studies in healthy subjects (Studies 101-01, 101-04, and 101-05) have provided 
information regarding drug safety, pharmacokinetics, food effects, and the potential for drug 
interactions with CYP3A4 inhibitors [Webb 2010, Gilead Sciences 2011]. One of these trials 
also included a preliminary evaluation of absorption, metabolism and excretion in healthy 
volunteers; in this trial, unlabeled GS-1101 was co-administered with a trace amount of 
[14C]GS-1101 given either orally or intravenously and biological samples were assessed by 
accelerator mass spectrometry. 
Safety results from these studies indicated that GS-1101 was well tolerated when 
administered to healthy subjects at single doses through 400 mg (the highest dose level 
tested) and was also generally well tolerated when administered to healthy subjects over 
7 days at dose levels through 200 mg/dose BID (the highest dose level tested). Dosing with 
200 mg/dose BID for 7 days resulted in a skin rash in 3 out of 6 subjects; histological 
findings were consistent with a delayed-type hypersensitivity maculopapular exanthema. 
Rashes have sometimes occurred in patients with hematological malignancies receiving 
GS-1101, but have not typically proved dose- or treatment-limiting. In placebo-controlled 

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single-dose and multiple-dose trials, repeated ECG evaluations performed in tandem with 
pharmacokinetic monitoring showed no evidence of drug-, dose-, or exposure-dependent 
effects on cardiac rhythm or cardiac intervals (eg, QT interval). 
Pharmacokinetic results indicated that increases in plasma GS-1101 maximum concentration 
(Cmax) and area under the concentration-time curve (AUC) values were dose-proportional 
with increasing single-dose administration but less-than-dose-proportional with increasing 
multiple-dose administration. There was only modest accumulation with BID dosing over 
7 days. Consistent with mean half-life (t1/2) values in the range of 6 to 10 hours, steady state 
was achieved within 7 days of repeated dosing. Mean plasma GS-1101 trough concentrations 
(Ctrough) exceeded target values known to be associated with pharmacological activity based 
on nonclinical testing. 
Ingestion of a high-fat, high-calorie meal just prior to administration of GS-1101 moderately 
delayed absorption, increasing the drug’s median time of maximum concentration (Tmax) 
from 0.75 hours to 3 hours without altering mean Cmax. The aggregate effect was an increase 
of 1.4-fold in mean AUC. While the data indicate a food effect, the changes in GS-1101 
pharmacokinetics were modest; thus, GS-1101 may be given with or without food. 
When GS-1101 was administered following 4 days of daily dosing with ketoconazole 
(a potent inhibitor of CYP3A4), increases in mean GS-1101 Cmax and AUC values were 
1.3- and 1.8-fold, respectively. The data indicate that some alterations in GS-1101 
pharmacokinetics occur but that GS-1101 is not a sensitive substrate for CYP3A4. Thus, 
co-administration of CYP3A4 inhibitors and GS-1101 is not contraindicated and does not 
require special monitoring. 
The 14C-labeled GS-1101 results showed that the drug has an oral bioavailability of 56%. 
Hepatic metabolism and biliary excretion appeared to be particularly important in GS-1101 
elimination. Consistent with the metabolism data from animal studies, an oxidation product 
was observed in human plasma and a hydrolyzed product was observed in urine and feces. 
[14C]-GS-1101-derived materials were primarily excreted in feces (>65% of total dose) with 
lesser elimination via urine (<15% of total dose). 
Pharmacodynamic results showed that a GS-1101 dose of 200 mg inhibited ex vivo basophil 
activation via the PI3Kδ-specific, high-affinity immunoglobulin (Ig)E receptor (anti-FCεR1) 
in basophils collected from healthy volunteers. The findings were confirmed when the drug 
was assessed over 7 days in a Phase 1b study in subjects with allergic rhinitis. In this study, 
GS-1101 at a dose level of 100 mg/dose BID showed clinical and pharmacodynamic activity 
(attenuating adverse responses to allergenic challenge and decreasing markers of 
inflammation) and was well tolerated. 
1.3.5.2. 
Phase 1 Studies in Patients with Hematological Malignancies 
1.3.5.2.1. 
Phase 1 Monotherapy Study in Patients with Hematological Malignancies 
A Phase 1 dose-ranging study (Study 101-02) of single-agent GS-1101 extended safety and 
pharmacokinetic observations; documented the clinical and pharmacodynamic activity of 
GS-1101 in subjects with iNHL, MCL, and CLL; and provided dosing information in support 
of further development [Brown 2011, Coutre 2011, Gilead 2011, Kahl 2011]. In this study, 
GS-1101 was administered in cohorts of subjects across a range of dose levels from 

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50 mg/dose BID to 350 mg/dose BID. GS-1101 administration was continued as long as 
individual subjects were safely benefitting from therapy. Subjects were evaluated in 4-week 
cycles; response and progression assessments were based on standard criteria [Hallek 2008]. 
Altogether, 192 subjects were enrolled to the study, including 55 subjects with CLL. As 
expected given the demographics of these diseases, subjects were predominantly male and 
were often elderly, ranging in age to 82 years for the subjects with CLL. The majority (82%) 
of the subjects with CLL had bulky tumors (≥1 lymph node ≥5 cm in diameter) and 31% had 
the adverse prognostic factor of a 17p chromosomal deletion (which commonly confers a 
p53 mutation in the tumors of these subjects). Subjects were heavily pretreated with 
chemoimmunotherapy; the median number of prior therapies by disease was 5 among 
subjects with CLL, but ranged up to 15 prior treatments. Among those with CLL, prior 
rituximab, alkylator, and fludarabine use were nearly universal and 33% had received prior 
alemtuzumab. Considering only rituximab use after initial therapy, 35% had received single-
agent rituximab at least once (some patients up to 3 times) and a total of 51/54 (94%) had 
received rituximab given alone or in combination with other agents. In the estimation of the 
investigators, a substantial proportion (72%) of these subjects had disease that was refractory 
to the last prior therapy. In these subjects, therapy was administered for a median of 9 cycles, 
ranging up to 24 cycles (ie, 96 weeks). 
In this single-agent experience, GS-1101 was generally well tolerated at dose levels through 
350 mg BID (the highest dose tested). No maximum tolerated dose (MTD) was apparent 
within the tested dose range. Furthermore, subjects typically found the drug tolerable over 
periods extending to >2 years; there was no profile suggestive of bothersome chronic events 
such as headache, nausea, diarrhea, or fatigue. No subject had tumor lysis syndrome. No 
overt pattern of myelosuppression was associated with GS-1101 treatment. The data also did 
not suggest drug-related reductions in circulating CD4+ cells or serum Igs. 
Among Grade 3-4 nonhematological adverse events, pneumonia/pneumonitis was observed 
most frequently, occurring in 24% of subjects with CLL. In most instances, these cases were 
considered bacterial in origin, based either on culture results or on response to conventional 
antibiotics. Subjects with CLL have occasionally been diagnosed with Pneumocystis (carinii) 
jiroveci pneumonia; the specific causal role of GS-1101 has been difficult to elucidate 
because infection was sometimes present before starting GS-1101 or the subjects had other 
pre-existing risk factors. Such subjects were not receiving pneumocystis prophylaxis. The 
rate of pneumonia over time (0.045 events/subject/month) with GS-1101 was not worse than 
the expected rate (0.06 events/patient/month) reported historically in comparable patients 
with recurrent CLL [Perkins 2002]. 
Monitorable, reversible elevations of hepatic transaminases were observed in some subjects; 
~5% of subjects with previously treated CLL had Grade 3-4 increases in serum ALT or AST. 
The onset of changes was time-dependent; among those with serum ALT/AST abnormalities, 
onset typically occurred 2 to 8 weeks after GS-1101 initiation. In subjects with Grade 1-2 
events, serum ALT/AST elevations resolved despite continued GS-1101 dosing. In subjects 
with Grade 3-4 events, GS-1101 was temporarily interrupted. Upon resolution of serum 
ALT/AST abnormalities, resumption of GS-1101 at a reduced dose did not result in 
recurrence of serum transaminase increases in the majority (>70%) of subjects who were 
rechallenged. This pattern suggests an adaptation to the effect similar to that observed in 

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dogs receiving GS-1101. Such an adaptive response is commonly observed with other drugs 
that induce transaminase elevations [Tujios 2011]. 
GS-1101 proved highly active in subjects with CLL, iNHL, and MCL. Among subjects with 
CLL, GS-1101 reduced lymphadenopathy in all 51 (100%) of those with ≥1 post-treatment 
tumor assessment. In subjects with CLL tumors having a known 17p chromosomal deletion, 
substantial antitumor activity was observed, although PFS appeared shorter in these subjects 
relative to other trial participants without such a deletion or in whom the 17p chromosomal 
deletion status was unknown. 
The pattern of changes in CLL was particular notable. Rapid and substantial reductions in 
lymph node size were observed in subjects with CLL with >80% of subjects showing a 
lymph node response (≥50% reductions in index nodal lesions). Among subjects who entered 
the trial with baseline thrombocytopenia or anemia, GS-1101 induced sustained increases in 
mean platelet counts and hemoglobin levels. In study participants who entered the study with 
enlarged spleens due to CLL, >70% showed a resolution in splenomegaly. The median PFS 
was 14 months, with some subjects having tumor controlling for durations exceeding 2 years. 
Antitumor activity and tumor control were longest in subjects starting GS-1101 at doses of 
≥150 mg/dose BID. 
A characteristic finding in the single-agent experience was that the majority of subjects had 
an initial increase in peripheral absolute lymphocyte count (ALC) from baseline. The 
increase was maximal during the first 2 cycles and generally decreased thereafter but could 
be persistent in some subjects or could be seen repeatedly in subjects who had interruption 
and resumption of drug therapy (eg, due to intercurrent illness). The characteristics of this 
lymphocytosis indicated a mobilization of CLL cells from tissues rather than a proliferative 
event or a disease flair. The effect was evident within 4 hours of initiating treatment, was 
asymptomatic, and was associated with quiescence of CLL cells as indicated by reductions in 
AKT phosphorylation and decreases in circulating levels of disease-associated chemokines, 
CCL3 and CCL4, and the stroma-derived chemokine, CXCL13. The lymphocyte 
mobilization phenomenon is consistent with in vitro data showing that GS-1101 depresses 
chemokine-mediated signaling between CLL cells and stromal cells [Hoellenriegel 2011]. 
These preclinical data support the concept that drug-mediated PI3Kδ inhibition releases CLL 
cells from sanctuary sites in lymph nodes and bone marrow. This action is not unique to 
GS-1101 alone. Drugs that inhibit spleen tyrosine kinase (SYK) [Friedberg 2010], Bruton 
tyrosine kinase (BTK) [Burger 2010a], or mTOR [Zent 2010] cause a CLL cell redistribution 
from tissue sites to the peripheral blood. Because of the occurrence of this type of pattern, 
investigators working with GS-1101 or inhibitors of these other pathways now rely upon 
measures of disease control other than peripheral blood lymphocyte count in determining 
whether a patient’s disease has progressed. 
An analysis of steady-state GS-1101 plasma concentrations (Day 28 Cmax, AUC0-6h, or Ctrough) 
relative to dose in subjects with both NHL and CLL showed increases in these parameters 
through the dose level of 150 mg/dose BID. At higher doses, flattening of the mean dose-
plasma exposure curve was observed, resulting in smaller incremental increases in exposure. 
Considering all safety, efficacy, and pharmacokinetic findings together, the data supported 
150 mg/dose BID as an appropriate GS-1101 monotherapy starting dose for future studies in 
patients with CLL and other lymphoid malignancies. 

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1.3.5.2.2. 
Phase 1 Combination Study in Patients with Hematological Malignancies 
A separate Phase 1 trial (Study 101-07) has evaluated the safety and preliminary activity of 
GS-1101 given in combination with rituximab to subjects with recurrent iNHL or CLL 
[Brown 2011, Leonard 2011]. 
In this study, rituximab was administered at a standard dose of 375 mg/m2 per infusion 
weekly for 8 weeks in all subjects. GS-1101 was started simultaneously with the rituximab, 
first at a dose level of 100 mg/dose BID (n=13) and then at a dose level of 150 mg/dose BID 
(n=12) and was administered continuously to both subjects with CLL (n=13) and subjects 
with iNHL (n=12) for as long as individual subjects were safely benefiting from therapy. 
Subjects were evaluated in 4-week cycles; response and progression assessments were based 
on standard criteria [Hallek 2008]. 
Among the subjects with CLL, the median age was 63 and ranged to 85 years. Bulky tumors 
(≥1 lymph node ≥5 cm in diameter) were present in 63% of the subjects. The median number 
of prior therapies by disease was 2 and ranged up to 8 prior treatments. All had received prior 
rituximab and the majority had received prior fludarabine or alkylating agents. 
Approximately one-third of subjects had CLL that was refractory to the last prior therapy. At 
the time of data cut-off, therapy had been administered for a median of 5 cycles, ranging up 
to 12 cycles (ie, 48 weeks). 
No GS-1101-related dose-limiting toxicities were observed within the tested subject cohorts. 
Grade 3-4 adverse events largely comprised background events resulting from pre-existing 
disease- or treatment-related conditions or from intercurrent illness. Among subjects with 
CLL, 2 (15%) developed pneumonia. For subjects receiving GS-1101 together with 
rituximab, Grade 3-4 elevations in ALT/AST were not observed in those with CLL, although 
3 subjects (25%) of those with iNHL had such events. 
The GS-1101 plus rituximab combination showed a high level of antitumor activity in both 
subjects with CLL and those with iNHL. Altogether 92% of subjects with CLL receiving the 
combination of GS-1101 and rituximab had reductions in nodal size and 77% showed a 
lymph node response (≥50% reduction in index nodal lesions). Although concomitant 
administration of rituximab did not eliminate the redistribution lymphocytosis that is 
associated with GS-1101, it blunted the magnitude of the change. As a result, the overall 
response rate (ORR) was also 77% among subjects participating in this study. At the time of 
last data analysis, PFS through 48 weeks was 70% and a median PFS had not yet been 
observed. 
Collectively, the emerging data from this study support further evaluation of GS-1101 
together with rituximab in subjects with CLL and indicate that co-administration of GS-1101 
with rituximab is tolerable when using GS-1101 at full dose, ie, at a starting dose level of 
150 mg/dose BID. 
1.4. 
Summary and Justification for the Current Study 
Gilead Sciences is conducting this Phase 3 study program to evaluate the efficacy and safety 
of GS-1101 in patients with previously treated, recurrent CLL. Collectively the data derived 
from the primary clinical trial (Study GS-US-312-0116) and from this extension trial 
(Study GS-US-312-0117) address the activity of GS-1101 together with rituximab, the 

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activity of GS-1101 when given alone, and the potential for dose-dependent restoration of 
drug activity in subjects who have disease that appears to be drug resistant. 
The design and conduct of this clinical trial program is supported by knowledge of the 
demographics of patients with CLL, the natural history and current therapies for the disease, 
and the nonclinical and clinical information regarding GS-1101. The collective data support 
the following conclusions: 
• CLL is a serious, disabling, and potentially life-threatening disorder of older patients that 
requires sequential treatment with agents that provide alternative mechanisms of tumor 
control. Existing cytotoxic agents have serious acute and chronic toxicities, making them 
less suitable for frail or unfit patients. Single-agent rituximab can offer disease palliation 
with good tolerability in some patients with relapsed CLL but tumor control is not 
lasting, especially in patients with bulky adenopathy. Development of a non-cytotoxic 
combination therapy of GS-1101 with rituximab or a monotherapy regimen of GS-1101 
that can address disease pathogenesis with a new mechanism of action and might offer 
complementary nodal and peripheral blood activity would address an unmet medical 
need, particularly when applied in patients with substantial comorbidities or 
myelosuppression from prior chemotherapies. 
• PI3Kδ over-expression plays an important role in CLL biology. Further evaluation of 
GS-1101 as a potential treatment for CLL has sound scientific rationale founded on 
knowledge of the actions of the drug to selectively abrogate PI3Kδ activity and to inhibit 
malignant cell growth and stromal cell signaling in nonclinical models of CLL. These 
data are supported by clinical documentation of GS-1101 inhibition of PI3Kδ signaling in 
patients with CLL. 
• The potential for clinical efficacy of GS-1101 monotherapy or of GS-1101 plus rituximab 
in patients with relapsed or refractory CLL is supported by the observed antitumor 
activity of GS-1101 – given alone or in combination with rituximab – in patients with 
heavily pretreated CLL and iNHL. 
• The safety of advancing development of the GS-1101 monotherapy and of a regimen of 
GS-1101 plus rituximab in this Phase 3 clinical trial program is well supported by safety 
pharmacology and toxicology studies and by Phase 1 single-agent and combination safety 
data obtained in healthy volunteers and in subjects with lymphoid cancers.  
• Dose-safety, dose-exposure, and dose-activity relationships identified in Phase 1 studies 
have established a firm basis for the dosing regimen and dose modification provisions in 
this study. 
• Observations relating to patterns of CLL response among subjects receiving GS-1101 
alone or in combination with rituximab in Phase 1 trials provide the foundation for 
efficacy monitoring in this trial. Of particular note is that GS-1101 mobilizes CLL cells 
from tissues into the peripheral blood. This characteristic pharmacological action is 
prominent early in therapy but can persist over time and should not be confused with 
disease progression in patients who have persistent control of other CLL-related signs 
and symptoms. For this reason, in this Phase 3 study program, subjects will be continued 
on therapy until the occurrence of definitive disease progression, ie, disease progression 

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that is manifest by worsening CLL-related signs or symptoms other than lymphocytosis 
alone.  
• Thorough nonclinical and clinical characterization of the type, severity, manifestations, 
and expected timing of adverse events establish the safety monitoring plan in this trial 
program. 
• The scientific correlative work performed in prior preclinical and clinical studies 
provides strong scientific underpinnings for the companion laboratory studies to be 
performed as a component of this clinical trial program. 
• Given the seriousness of previously treated CLL in patients with substantial comorbidity, 
and the aggregate potential benefits considered in the context of potential risks, further 
development of GS-1101 in this Phase 3 clinical trial program is justified. 
The rationale for specific design features is provided in relevant sections of the protocol, 
including Section 3.2 (Endpoint Selection Rationale), Section 2.2 (Design Rationale), 
Section 4.3 (Enrollment Criteria Rationale), Section 5.9 (Study Treatment Rationale), and 
Section 6.4 (Study Procedure Rationale). 

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2. 
STUDY DESIGN 
2.1. 
Design Overview and Study Schema 
This study is being conducted as part of an overall clinical program that is evaluating the 
efficacy and safety of GS-1101 in the therapy of patients with previously treated CLL (see 
Figure 2-1). Within this program, the primary clinical trial (Study GS-US-312-0116) is a 
Phase 3, multicenter, 2-arm, randomized, double-blind, placebo-controlled, parallel-group 
study. This clinical trial (Study GS-US-312-0117) is a separate, multicenter, 2-arm, double-
blind, parallel-group extension study that is a companion study to the primary study. 
Figure 2-1. 
Study Design 
Randomized
Double-Blind
Initial Therapy
GS-1101, 150 mg BID
Until PD
Placebo BID 
Until PD
Disease 
progression
Double-Blind
Continuing  Therapy
Double-Blind
Extension
Therapy
GS-1101, 150 mg BID
R, 375 mg/m2 Wk 0
R 500 mg/m2 Wk 2,4,6,8,12,16,20
Stratification and 
Randomization
GS-1101, 150 mg BID
Until PD
GS-1101, 300 mg BID
Until PD
Placebo
R, 375 mg/m2 Wk 0
R 500 mg/m2 Wk 2,4,6,8,12,16,20
Screening
Primary Study
Study GS-US-312-0116
Extension Study
Study GS-US-312-0117
Arm A
N=80
Arm B
N=80
 
Candidates for the primary study will be adults with previously treated recurrent CLL who 
have measurable lymphadenopathy, require therapy for CLL, have experienced CLL 
progression <24 months since the completion of the last prior therapy, and are currently not 
sufficiently fit to receive cytotoxic therapy because of chemotherapy-induced bone marrow 
damage or comorbidities. 
Primary study subjects will be stratified based on 17p deletion and/or a p53 mutation status 
(either vs neither), immunoglobulin heavy chain variable region (IgHV) mutation status 
(unmutated vs mutated), and any prior therapy with an anti-CD20 therapeutic monoclonal 
antibody (yes vs no) and randomized in a 1:1 ratio to receive 1 of the 2 treatment arms.  
In the primary study, subjects will be administered rituximab intravenously in the clinic 
starting at a dose of 375 mg/m2 on Day 1 (Week 0) and will continue with a dose of 
500 mg/m2 on Day 15 (Week 2), Day 29 (Week 4), Day 43 (Week 6), Day 57 (Week 8), 
Day 85 (Week 12), Day 113 (Week 16), Day 141 (Week 20) (for a total of 8 infusions). 
Rituximab will be administered until the earliest of subject withdrawal from study, definitive 
progression of CLL, intolerable rituximab-related toxicity, pregnancy, substantial 
noncompliance with study procedures, study discontinuation, or a maximum of 8 infusions. 
GS-1101 or placebo will be taken orally, twice per day continuously while on study 
treatment. GS-1101 or placebo treatment will persist until the earliest of subject withdrawal 
from study, definitive progression of CLL, intolerable study drug-related toxicity, pregnancy, 
substantial noncompliance with study procedures, or study discontinuation. Subjects will be 

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encouraged to continue with protocol-specified therapy for each of the therapeutic agents 
(GS-1101/placebo or rituximab) that continues to be tolerated, even if the other agent needs 
to be discontinued due to drug-specific toxicity. 
Compliant subjects who are tolerating therapy but who develop definitive disease 
progression in the primary clinical trial (Study GS-US-312-0116) can consider enrollment in 
this separate companion extension trial (Study GS-US-312-0117). In the extension trial, 
subjects will take active blinded GS-1101 therapy, either at a higher starting dose or at the 
standard starting dose, with allocation based on the original primary study randomization. 
The primary objective of Study GS-US-312-0116 will be to evaluate the effect of the 
addition of GS-1101 to rituximab on PFS. Secondary objectives will focus on determining 
the effect of the addition of GS-1101 to rituximab on the onset, magnitude, and duration of 
tumor control; overall survival (OS); health-related quality of life (HRQL); changes in 
subject performance status; disease-associated biomarkers and potential mechanisms of 
resistance; treatment administration; safety; and health resource utilization. In Study GS-US-
312-0117, the same endpoints will be assessed as in Study GS-US-312-0116; the focus of the 
analysis will be largely descriptive except for the within-subject assessment of treatment 
effects among subjects receiving first rituximab alone and then GS-1101 alone on Arm B of 
each trial. No formal comparisons of outcomes in Arm A vs Arm B are planned within 
Study GS-US-312-0117. 
2.2. 
Design Rationale 
The randomized, add-on design for the primary trial (Study GS-US-312-0116) is customary 
in the comparative evaluation of new therapies for cancer. While this design provides 
GS-1101 efficacy and safety information only in the context of administration of a 
companion antineoplastic agent, it is appropriate because it documents the incremental 
benefit and toxicity of the investigational therapy in the context of a controlled clinical trial 
while ensuring that all participants receive potentially active treatment. 
This separate extension trial (Study GS-US-312-0117) enhances subject acceptance of 
randomization in the primary study and provides further information regarding GS-1101 
efficacy, resistance, and safety. Among subjects in Arm A, escalation to a higher dose level 
allows evaluation of dose-dependent resistance and a determination if a higher dose can 
reestablish disease control. The safety data obtained in these subjects will add to the overall 
safety database. Among subjects randomized to Arm B in the primary study, evaluation of 
GS-1101 at a starting dose of 150 mg/dose BID in the extension study may permit a within-
subject assessment of the treatment effects with single-agent GS-1101 relative to the effects 
previously observed with rituximab alone. Of importance, the extension study maintains the 
partial blinding of the primary study, thus minimizing the bias that might occur if the overall 
design entailed only a 1-way crossover to open-label GS-1101 among subjects who had 
received placebo on Arm B of the primary study. To ensure confirmation of disease 
progression, tumor size data collected from the primary study will be subjected to  
independent review by an independent review committee (IRC) (see Section 10.4.3); subjects 
will continue with study therapy pending confirmation of progression status by the sponsor 
working in collaboration with the IRC. Subjects must have confirmation that the disease has 

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progressed on the primary study before being permitted to receive secondary GS-1101 
therapy on the extension study. 

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3. 
OBJECTIVES AND ENDPOINTS 
• To determine the effect of GS-1101 on the onset, magnitude, and duration of tumor 
control 
• To compare tumor control in subjects receiving rituximab alone in Study GS-US-312-
0116 to that observed in the same subjects when receiving the standard dose of GS-1101 
alone in Study GS-US-312-0117 
• To assess the effect of GS-1101 on measures of subject well-being, including overall 
survival (OS), health-related quality of life (HRQL), and performance status 
• To assess the effects of GS-1101 on disease-associated biomarkers and to evaluate 
potential mechanisms of resistance to GS-1101 
• To characterize exposure to GS-1101 as determined by treatment administration and 
evaluation of GS-1101 plasma concentrations over time 
• To describe the safety profile observed with GS-1101  
• To estimate health resource utilization associated with administration of GS-1101 
3.1. 
Endpoints 
3.1.1. 
Tumor Control 
• Progression-free survival (PFS) – defined as the interval from the start of study therapy to 
the earlier of the first documentation of definitive disease progression or death from any 
cause; definitive disease progression is CLL progression based on standard criteria and 
occurring for any reason (ie, increasing lymphadenopathy, organomegaly or bone marrow 
involvement; decreasing platelet count, hemoglobin, or neutrophil count; or worsening of 
disease-related symptoms) other than lymphocytosis alone 
• Overall response rate (ORR) – defined as the proportion of subjects who achieve a 
complete response (CR) or partial response (PR)  
• Time to response (TTR) – defined as the interval from start of study therapy to the first 
documentation of CR or PR 
• Duration of response (DOR) – defined as the interval from the first documentation of CR 
or PR to the earlier of the first documentation of definitive disease progression or death 
from any cause 
• Time to treatment failure (TTF) – defined as the interval from start of study therapy to the 
earliest of the first documentation of definitive disease progression, the permanent 
cessation of study drug due to an adverse event, or death from any cause 
• Percent change in lymph node area – defined as the percent change from baseline in the 
sum of the products of the greatest perpendicular diameters (SPD) of index lymph nodes 
• Lymph node response rate – defined as the proportion of subjects who achieve a ≥50% 
decrease from baseline in the SPD of index lymph nodes 

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• Splenomegaly response rate – defined as the proportion of subjects with baseline 
splenomegaly who achieve an on-study normalization or a decrease by ≥50% from 
baseline in the pretreatment enlargement of the splenic longest vertical dimension (LVD) 
(by imaging) or in the pretreatment enlargement of the splenic LVD below the left costal 
margin (by palpation) 
• Hepatomegaly response rate – defined as the proportion of subjects with baseline 
hepatomegaly who achieve an on-study normalization or a decrease by ≥50% from 
baseline in the pretreatment enlargement of the hepatic LVD (by imaging) or in the 
pretreatment enlargement of the hepatic LVD at the right midclavicular line (by 
percussion) 
• Platelet response rate – defined as the proportion of subjects with baseline 
thrombocytopenia (platelet count <100 x 109/L) who achieve an on-study platelet count 
≥100 x 109/L or demonstrate a ≥50% increase in platelet count from baseline 
• Hemoglobin response rate – defined as the proportion of subjects with baseline anemia 
(hemoglobin <110 g/L [11.0 g/dL]) who achieve an on-study hemoglobin ≥110 g/L (11.0 
g/dL) or demonstrate a ≥50% increase in hemoglobin from baseline 
• Neutrophil response rate – defined as the proportion of subjects with baseline neutropenia 
(absolute neutrophil count [ANC] <1 x 109/L) who achieve an ANC ≥1 x 109/L or 
demonstrate a ≥50% increase in ANC from baseline 
3.1.2. 
Patient Well-Being 
• Overall survival (OS) – defined as the interval from start of study therapy to death from 
any cause 
• Change in HRQL domain and symptom scores based on  the Functional Assessment of 
Cancer Therapy: Leukemia (FACT-Leu) (see Appendix 2) – defined as the change from 
baseline and the time to definitive increments or decrements of 10%, 20%, and 40% from 
baseline; time to definitive increment (better than baseline by the specified amount) is the 
interval from start of study therapy to the first timepoint when the HRQL measure is 
consistently better than at baseline (including that timepoint as well as all the subsequent 
timepoints) in a subject whose last HRQL score is better than at baseline; and time to 
definitive HRQL decrement (worse than baseline by the specified amount) is the interval 
from start of study therapy to the earliest of death or the first timepoint when the HRQL 
measure is consistently worse than at baseline (including that timepoint as well as all the 
subsequent timepoints) in a subject whose last performance status score is worse than at 
baseline 
• Changes in Karnofsky performance status – defined as the change from baseline in the 
performance status (see Appendix 3) and the time to definitive performance status 
improvement or worsening; time to definitive performance status improvement (better 
than baseline) is the interval from start of study therapy to the first timepoint when the 
performance status is consistently better than at baseline (including that timepoint as well 
as all the subsequent timepoints) in a subject whose last performance status score is better 
than at baseline; and time to definitive performance status worsening (worse than 

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baseline) is the interval from study therapy until the earliest of death or the first timepoint 
when the performance status is consistently worse than at baseline (including that 
timepoint as well as all the subsequent timepoints) in a subject whose last performance 
status score is worse than at baseline 
3.1.3. 
Pharmacodynamic Markers of Drug Activity and Resistance 
• Changes from baseline in PI3K/AKT/mTOR pathway activation as a measure of PI3Kδ 
pathway activity 
• Changes from baseline in the plasma concentrations of disease-associated chemokines 
and cytokines 
3.1.4. 
Exposure 
• Study drug administration as assessed by prescribing records and compliance as assessed 
by quantification of used and unused drug 
• Trough (pre-dose) and peak (1.5-hour samples) of GS-1101 plasma concentrations as 
assessed by a validated bioanalytical method 
3.1.5. 
Safety 
• Overall safety profile of each study treatment regimen characterized by the type, 
frequency, severity, timing of onset, duration, and relationship to study therapy of any 
adverse events or abnormalities of laboratory tests; serious adverse events; or adverse 
events leading to discontinuation of study treatment 
3.1.6. 
Pharmacoeconomics 
• Change in health status – defined as the change from baseline in overall health and 
single-item dimension scores as assessed using the EuroQoL Five-Dimension (EQ-5D) 
utility measure (Appendix 4) 
• Health resource measures, including resource utilization, total costs, and measures of cost 
per unit of benefit (eg, cost per additional progression-free month, cost per quality-
adjusted life-year) 
3.2. 
Endpoint Selection Rationale 
The proposed endpoints have been chosen based on relevance to the pathophysiology and 
clinical manifestations of CLL, the known pharmacology of GS-1101, and the goals of the 
study in documenting GS-1101 benefit-to-risk ratio. These types of endpoints have been 
employed in prior studies in CLL and can be evaluated with acceptable reliability and 
accuracy. 
3.2.1. 
Tumor Control Endpoints 
Assessments of the magnitude and duration of changes in tumor size are routinely employed 
in registration-directed oncology clinical studies to determine therapeutic effect. Unlike OS, 
these endpoints directly assess the ability of the drug to control the malignancy. Such 
assessments are also integral to treatment decisions; because subjects are being treated until 

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disease progression, repeated tumor assessment must be performed in order to define the 
proper duration of treatment for each study participant. Standard response and progression 
criteria have been established by the International Workshop on CLL (IWCLL) 
[Hallek 2008]; the assessments of treatment effects in this study will be based on these 
criteria, taking into account the specific pharmacology of GS-1101. 
In CLL, disease-related nodal enlargement is a major cause of patient discomfort and can 
cause organ dysfunction [Dighiero 2008]. Extensive lymphadenopathy constitutes a reason to 
treat CLL and controlling the size of pathologically enlarged lymph nodes is an important 
therapeutic goal for improving patient well-being and relieving obstructive symptoms 
[Hallek 2008]. Given that the natural history of recurrent CLL is inexorable nodal growth, 
enhancing tumor shrinkage and prolonging tumor control provides strong evidence of 
pharmacological activity.  
Endpoints of overall tumor control as evaluated in this trial are customarily assessed and 
reported in studies of new therapies in patients with cancer. PFS offers a well established 
outcome measure that directly measures treatment effect, conveys important longitudinal 
information regarding tumor control, can be characterized in all subjects using intention-to-
treat (ITT) principles, and is readily analyzed using statistical methods such as Kaplan-Meier 
techniques. ORR provides an integrated assessment of the magnitude and extent of changes 
in lymphadenopathy, organomegaly, bone marrow infiltration, and bone marrow function 
that conveniently categorizes and describes treatment effects. TTR and DOR are important in 
characterizing the rapidity of achieving tumor shrinkage and the duration of tumor control. 
TTF offers a further characterization of subject outcome that incorporates the added 
dimension of drug tolerability; the degree of correspondence between PFS and TTF provides 
an assessment of how commonly adverse effects are compromising the ability to maintain 
therapy. 
Beyond providing descriptions on overall response assessment using ORR, this protocol will 
also seek to characterize the individual components of response that are important in 
assessment of CLL [Hallek 2008]. Thus, changes in lymph node area and in the proportion of 
subjects having a lymph node response will be analyzed. In addition, among subjects who 
enter the study with splenomegaly, the proportion achieving substantial (≥50%) reductions in 
spleen size will be assessed. Similarly, the proportions of subjects who experience 
improvements in platelets, hemoglobin, and neutrophil counts will be characterized in order 
to provide specific insight into the degree to which therapy alters these individual parameters.  
Because GS-1101 mobilizes CLL cells from tissues into the peripheral blood as part of its 
pharmacological effect, there is a risk of falsely declaring a subject to have experienced 
disease progression if lymphocyte count is considered as the sole basis for potential CLL 
worsening. To account for this potential problem, changes in lymphocyte count will not be 
considered in determining whether a subject has progressive disease, ie, subjects will only be 
declared to have progressive CLL if they meet any of the IWCLL criteria for progressive 
disease other than lymphocytosis alone. Thus, subjects with worsening lymphadenopathy, 
organomegaly, bone marrow involvement, progressive cytopenias, appearance of new 
disease, recurrence of B symptoms, or transformation to an aggressive lymphoid malignancy 
histology (eg, Richter syndrome) will be considered to have progressed. Subjects with 
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Given that lymphocytosis has no prognostic significance in patients with relapsed/refractory 
disease [Silverman 2002, Tsimberidou 2007] and is not generally considered a reason to treat 
in patients with CLL [Hallek 2008, Eichhorst 2010, Zelenetz 2011], this approach does not 
jeopardize subject safety or subsequent therapy. Furthermore, it will allow complete 
collection of all response and progression data (both considering lymphocytosis and ignoring 
lymphocytosis) with the intent of providing complete information for regulatory authority 
review. 
The current IWCLL guidelines indicate that physical examination is generally sufficient to 
evaluate nodal response and progression in patients with CLL [Hallek 2008] but that 
radiographic assessments may be appropriate in clinical trials. Computed tomography (CT) is 
considered the preferred imaging method unless patients have contraindications that require 
use of magnetic resonance imaging (MRI). Given the low fluorodeoxyglucose (FDG) avidity 
of CLL, positron- emission tomography (PET) does not have a role in evaluation of this 
disease. The incremental benefits of using radiographic imaging are limited in patients 
undergoing long-term follow-up following first-line therapy [Blum 2007, Eichhorst 2011]. 
However, in the patients with advanced CLL and bulky adenopathy such as those who will 
be enrolled to this trial, it is known that CT scans commonly detect bulky intra-abdominal 
lymphadenopathy and splenomegaly that would be missed by palpation alone and that the 
presence of large-volume, intra-abdominal disease of the nodes and spleen is associated with 
a poor prognosis [Norin 2010]. Thus, while use of CT confers greater radiation exposure, 
subjects have the chance to benefit from radiographic imaging because it will offer more 
accurate information regarding their response to protocol therapy and the appropriate 
duration of protocol treatment. Having this information is particularly important in this trial 
because PI3Kδ inhibition precludes use of lymphocyte counts as evidence for disease 
progression. In addition, the risk is offset by the fact that the trial subjects will primarily be 
patients who have already received more potent mutagens (eg, purine analogs, alkylating 
agents), and all of whom have advanced cancer and limited treatment options at study entry. 
Based on published data [Keating 2002, Wierda 2010], median OS for patients with 
comparably advanced CLL is <18 months, so the long-term secondary malignancy risk from 
CT-related radiation exposure is very low. Finally, in the context of a registration-directed 
pivotal trial of a new drug with a new mechanism of action, radiographic imaging is critically 
important to provide reassurance regarding subject safety and trial validity. In this regard, CT 
evaluations of the lung can be used retrospectively to assess for radiographic evidence of 
drug-induced lung changes [White 2010, Maroto 2011]. Furthermore, CT measurements 
have greater accuracy and reproducibility than palpation, are subject to independent expert 
review, and can be audited against electronic case report form (eCRF) information. 
The timing of radiographic tumor assessments has been carefully considered. To avoid 
duplication, the CT scan documenting CLL progression in Study GS-US-312-0116 will serve 
as the baseline CT scan for Study GS-US-312-0117. Among patients receiving GS-1101 in 
Phase 1b/2 studies who experienced a nodal response (≥50% regression in tumor area), such 
responses were observed with the first 16 week of therapy [Coutre 2011, Leonard 2011]; the 
planned timing of tumor assessments (at Weeks 8, 16, 24, 36, 48 and then every 12 weeks on 
thereafter through 96 weeks) in this study fits with this known timing of changes in lymph 
node size during GS-1101 therapy. Scans at 8-week intervals during the first 24 weeks allow 
initial documentation of response (at Week 8 or 16) and follow-up confirmation of response 

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8 weeks later (at Week 16 or 24) consistent with current response criteria [Hallek 2008]. 
During this period, early documentation of disease progression allows subjects who are not 
benefiting from study therapy to move rapidly to alternative treatments. After 24 weeks on 
study, the reduction in the frequency of CT scans (to 12-week intervals through 96 weeks) 
reduces the overall protocol burden for subjects while still allowing characterization of the 
expected median PFS in this trial. Permitting investigators to omit scans after 96 weeks (ie, 
after ~2 years) further limits the burden on subjects after this period. As outlined in 
Section 7.3, iodine-containing or gadolinium contrast material may be omitted in subjects for 
whom use of a contrast agent would be medically contraindicated. 
3.2.2. 
Measures of Patient Well-Being 
3.2.2.1. 
Overall Survival 
While OS provides an ultimate measure of patient well-being, it has not routinely been used 
as the primary endpoint in CLL clinical trials. Unlike PFS, it does not specifically measure 
drug-mediated tumor control, and thus provides only an indirect assessment of treatment 
effect. Depending upon the treatment setting, long OS times in patients with CLL can 
preclude use of this endpoint as an efficient method for understanding drug benefits. In both 
the front-line and recurrent disease settings, post-study treatments can influence OS in 
unpredictable ways, potentially confounding differences between treatment groups. 
However, given the life-threatening nature of systemic malignancy, documentation of OS is 
customary in oncology therapeutic clinical trials, including those evaluating subjects with 
recurrent CLL [Keating 2002, Wierda 2010]. Evaluation of OS in this study continues the 
survival assessment from the primary study (Study GS-US-312-0116). The study program as 
a whole (considering both the primary randomized trial and secondary extension study) 
offers the potential to better understand OS and causes of death in a frail population of 
patients with both CLL and comorbidities. 
3.2.2.2. 
Health-Related Quality of Life 
Direct patient reporting of outcomes using standardized methods has become an increasingly 
important component of therapeutic assessment. Evaluation of patient-reported outcomes 
(PROs) is particularly relevant in patients who cannot be cured of disease [Fairclough 2002]. 
PRO questionnaires have been previously used in CLL to understand how patients differ 
from the general population in terms of health concerns [Holzner 2004, Eichhorst 2007, 
Shanafelt 2007, Else 2008], to understand differences in perceptions of well-being in younger 
vs older patients [Levin 2007, Else 2008], to determine how treatment affects HRQL 
[Catovksy 2007, Eichhorst 2007, Efficace 2008], and to assess the pharmacoeconomic cost 
of improvements in HRQL [Stephens 2005]. 
Patients with CLL have overtly impaired well-being relative to comparable controls 
[Holzner 2004, Eichhorst 2007, Shanafelt 2007, Else 2008]. Fatigue is cited as a common 
complaint, being present in the substantial majority of patients. Impairment of HRQL prior to 
any treatment is apparent in those with B symptoms or in patients with anemia, supporting 
the concept of initiating treatment when patients experience symptomatic disease. Factors 
associated with lower overall HRQL have included older age, greater fatigue, severity of 
co-morbid health conditions, advanced stage, and ongoing treatment for CLL [Shanafelt 
2007]. Younger patients appear to have worse emotional and social well-being but older 

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patients experience worse physical HRQL [Levin 2007]. In comparative evaluation of 
chemotherapy-containing regimens, differences in HRQL between therapies (eg, fludarabine 
vs fludarabine-cyclophosphamide vs chlorambucil) reflected differences in toxicity while 
improved HRQL was associated with greater efficacy [Catovksy 2007, Eichhorst 2007]. 
In this study, it is postulated that GS-1101-mediated tumor control will be correlated with 
greater positive changes in HRQL and that assessments of the drug’s safety profile will be 
supported by HRQL evaluations. The FACT-Leu (Appendix 2) has been selected to evaluate 
such outcomes for the study. The FACT-Leu comprises a general HRQL measure for patients 
receiving cancer treatment that yields a total score and subscales for physical, functional, 
social/family and emotional well-being [Cella 1993] and a diagnosis-specific measure for 
patients with leukemia [Webster 2002]. The FACT-Leu was developed to assess symptoms 
(eg, fevers, chills, night sweats, nodal swelling, fatigue) specifically relevant to patients with 
leukemia. FACT instruments have documented psychometric properties [Cella 1993, 
Webster 2002, Brucker 2005, Cella 2005, Victorson 2008]. 
The FACT-Leu instrument is available in appropriate languages for this study. FACT-Leu 
data will be obtained at baseline and during each investigational clinic visit during treatment. 
Having FACT-Leu data concurrent with tumor response information will allow an evaluation 
of the potential relationship between tumor response and symptomatic changes as reported by 
patients. To avoid biasing HRQL results, the FACT-Leu will be administered at each visit 
before other procedures are performed and before any study information is conveyed to the 
subject. 
3.2.2.3. 
Changes in Performance Status 
Performance status evaluation provides an integrated assessment of patient well-being 
before, during, and after treatment and, ideally, may indicate how drug efficacy and toxicity 
affect patient functioning. In patients with CLL performance status can be predictive of PFS 
or OS [Sorensen 1997, Hallek 1996, Youngson 1995]. 
In this study, it is hypothesized that GS-1101-mediated tumor control will be correlated with 
changes in performance status and that assessments of the drug’s safety profile might be 
supported by performance status evaluations. The well-established, reliable, and validated 
Karnofsky performance score [Karnofsky 1949, Yates 1980, Schag 1984] (see Appendix 3) 
will be employed in the trial for characterization of the subject population and repeated 
assessment of performance status. 
3.2.3. 
Pharmacodynamic Markers of Drug Activity and Resistance 
In CLL, disease-related perturbations in inflammatory status can be clinically overt; patients 
often develop bothersome B symptoms (fevers, night sweats, and weight loss) that are 
characteristic of excessive systemic inflammation [Redaelli 2004]. Consistent with such 
disease manifestations, the PI3Kδ/AKT/mTOR pathway is constitutively overactive in 
circulating CLL cells [Coutre 2011]. In addition, chemokines and cytokines that are markers 
of aberrant B-cell trafficking or perturbations in inflammation are overexpressed by CLL 
tissues or by stromal cells and circulate in plasma [Burger 2010b, Coutre 2011]. In Phase 1 
studies of GS-1101 it has been confirmed that GS-1101 largely normalizes AKT 

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phosphorylation and induces dose-dependent reductions in plasma concentrations of 
circulating chemokines and cytokines in patients with CLL [Coutre 2011]. 
In this study, it is hypothesized that incremental changes in these biomarkers provide direct 
evidence of mechanism-specific GS-1101 effects on PI3Kδ activity or indirectly document 
drug effects on overall tumor cell volume. In either case, improvements in these 
pharmacodynamic measures provide corroborative evidence in support of GS-1101 
pharmacological activity; conversely, worsening of these biomarkers may indicate 
acquisition of resistance to GS-1101. In addition, it is possible that disease-or 
inflammation-related biomarkers may provide corollary information relating to the adverse 
effects of GS-1101 on the liver; such data might allow better prediction of which subjects 
might be most susceptible to ALT/AST elevations during GS-1101 treatment. Finally, it can 
also be postulated that genetic, protein, or metabolic changes in CLL cells could provide 
signatures that would correlate with drug sensitivity and resistance. 
Based on these considerations, this study will evaluate PI3K/AKT/mTOR pathway activation 
status in CLL cells. For this purpose, blood will be evaluated by flow cytometry using a 
clinically validated assay [Hoellenriegel 2011]. CLL cells will be identified using anti-CD5 
and anti-CD19 antibodies. AKT activation will be determined by quantifying 
phosphorylation at the Ser473 and Thr308 AKT sites using specific anti-pAKT Thr308 and 
anti-pAKT Ser473 antibodies. Additional assessments of PI3K/AKT/mTOR pathway 
signaling (eg, evaluating phosphorylation state for other downstream enzymes) may also be 
explored. 
Plasma will be collected for assessment of circulating concentrations of relevant chemokines 
and cytokines with a particular focus on CCL2, CCL3, CCL4, CXCL12, CXCL13, CCL17, 
CCL19, CCL21, CCL22, sCD40 ligand, tumor necrosis factor-α, and C-reactive protein. In 
addition serum markers of iron metabolism (eg, hepcidin, iron, ferritin, transferrin) that might 
provide markers linking disease-related inflammation with perturbations of liver iron and 
sensitivity to liver injury will be evaluated [Nemeth 2003, Ferrucci 2010]. Clinically 
validated assays (eg, enzyme-linked immunosorbent assays [ELISAs]) will be used to 
measure circulating concentrations of chemokines and cytokines at baseline and during the 
course of GS-1101 therapy. 
CLL cell deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein will be 
collected at baseline and at the conclusion of a subject’s treatment on study. DNA and RNA 
samples will be analyzed using gene array technologies to evaluate for changes in DNA 
mutations or in RNA expression patterns that might be associated with intrinsic or acquired 
resistance to study treatments. Similarly, protein will be evaluated for state-specific changes 
in protein phosphorylation to evaluate for differences in pathway activation at baseline or 
during therapy that might be associated with differences in response or in acquisition of 
resistance to therapy. 
3.2.4. 
Assessments of Exposure 
3.2.4.1. 
Study Drug Administration and Compliance 
Evaluation of study drug administration and compliance provides context for assessments of 
safety, pharmacokinetics, and pharmacological activity. Evaluations of treatment 
administration and modifications from planned therapy document the influence of 

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treatment-emergent adverse events on prescribing practice. Compliance assessment offers a 
general indication of patients’ acceptance of therapy, integrating factors of tolerability, 
palatability, and convenience. 
In this study, information regarding planned treatment and modification from planned 
treatment (eg, dose reductions and interruptions) will be kept. The compliance of the subject 
will be verified by accounting for used and unused drug. 
3.2.4.2. 
Pharmacokinetics 
Given the intent of this protocol to assess longer-term dosing, collection of plasma for 
GS-1101 concentrations is important for evaluating the steady-state maintenance of exposure 
over time. These data may allow correlations of exposure with measures of efficacy, toxicity, 
and resistance, will be important part of exploring exploration of 2 different GS-1101 dose 
levels. Because the GS-1101 pharmacokinetic profile has been well characterized in Phase 1 
studies, limited plasma sampling will be performed in this study. Samples will be collected 
pre-dose and 1.5 hours post-dose relative to the morning administration of GS-1101. This 
approach will provide information regarding plasma Ctrough values and will describe drug 
absorption as characterized by plasma concentrations at the approximate Tmax after the 
morning dose. The 1.5-hour timepoint has been assessed in prior Phase 1 studies, allowing 
across-study correlations of exposure. Based on discussions with investigators, collecting 
more than 2 samples in the morning is not considered reasonable given the need to minimize 
time requirements for study participants and to avoid substantial inconvenience for clinic 
staff. 
Evaluation of GS-1101 plasma concentrations will be performed using liquid 
chromatography with tandem mass spectrometry. The method has been fully validated in the 
context of prior Phase 1 studies. Plasma samples will be retained for potential later analyses 
of GS-1101 metabolites. 
3.2.5. 
Evaluations of Safety 
In defining the therapeutic relevance of a drug in a particular clinical setting, it is imperative 
that its safety profile be fully characterized. As is conventional in all clinical studies, proper 
description of each adverse event or laboratory abnormality requires an understanding of the 
type, incidence, timing, severity, and relatedness to study drug. While information on all 
reported adverse events will be collected, listed, and summarized, particular focus will be 
placed on monitoring and reporting adverse events and laboratory abnormalities that were 
encountered in the prior toxicology studies and clinical experience with GS-1101. Safety 
parameters of specific interest in reporting study results will include those relating to 
infection, pulmonary events (eg, pneumonia/pneumonitis), liver injury, rash, and bone 
marrow dysfunction. Additional scrutiny will be applied to Grade 3-4 adverse events, to 
adverse events causing interruption or discontinuation of GS-1101, and to serious adverse 
events. 
In addition, the protocol will evaluate for potential adverse GS-1101 effects on laboratory 
parameters of immune function; the absolute number of CD4+ and CD8+, CD16/CD56+, 
CD19+, and CD20+ cells will be assessed by flow cytometry. Serum concentrations of IgA, 
IgE, IgG, and IgM will be obtained. 

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For consistency of interpretation, adverse events will be coded using the standard Medical 
Dictionary for Regulatory Activities (MedDRA) [http://www.meddramsso.com]), and the 
severity adverse events and laboratory abnormalities will be graded using the well-defined 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). 
Standard definitions for seriousness will be applied (see Section 8.1.2). 
3.2.6. 
Pharmacoeconomic Measures 
It is increasingly important to understand the potential cost implications of introducing a new 
medication into patient care for CLL [Main 2010, Hornberger 2011]. In order to analyze the 
pharmacoeconomic consequences of GS-1101 administration, data will be collected 
regarding the health status of subjects and regarding health care resource utilization. 
Heath status information will be obtained with the EQ-5D, which is a self-administered, 
generic, indirect utility measure [EuroQoL Group 1990] (Appendix 4). The EQ-5D consists 
of a visual analogue scale on which subjects are asked to rate their current overall health 
status and 5 single-item dimensions which ask subjects to rate their health in terms of 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression. For each of the 
5 items, patients must choose between 3 levels of difficulty in accomplishing tasks in that 
dimension. The visual analog scale is then used in combination with the dimension scores to 
generate a health utility score that can be incorporated into analyses of cost effectiveness. 
The EQ-5D has been successfully used in the evaluation of patients with B-cell and other 
cancers [Doorduijn 2005, Witzens-Harig 2009, Yang 2010]. 
The EQ-5D instrument is available in appropriate languages for this study. EQ-5D data will 
be obtained at baseline and during each investigational clinic visit during treatment. The 
EQ-5D will be administered immediately after administration of the FACT-Leu instrument, 
before other procedures are performed and before any study information is conveyed to the 
subject. The EQ-5D instrument takes only 5 minutes to complete. 
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations. 
The basic approach will be to combine the resource utilization data from the trial with data 
on unit prices (collected separately) to estimate total costs. The costs will be described 
relative to the health care findings as measured by duration of tumor control, the symptom-
free survival period, and/or utility outcomes or some other appropriate measure of clinical 
benefits. 

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4. 
SUBJECT POPULATION 
4.1. 
Number of Subjects 
The planned sample size is ~160 subjects but will be bounded by the number of subjects 
enrolled to the primary clinical trial (Study GS-US-312-0116). 
4.2. 
Subject Selection Criteria 
The following eligibility criteria are designed to select subjects for whom study participation 
is considered appropriate. All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether this protocol is suitable for a particular subject. 
Eligibility criteria may not be waived by the investigator and conformance to the eligibility 
criteria is subject to review in the case of a Good Clinical Practice (GCP) or a regulatory 
authority audit. Any questions regarding a subject’s eligibility should be discussed with the 
study sponsor medical monitor prior to enrollment. 
4.2.1. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in 
this study: 
1) Participation in Study GS-US-312-0116. 
2) Occurrence of confirmed, definitive CLL progression while receiving study drug therapy 
(GS-1101/placebo) in Study GS-US-312-0116. Note: Definitive disease progression is 
CLL progression based on standard criteria and occurring for any reason (ie, 
increasing lymphadenopathy, organomegaly, or bone marrow involvement; decreasing 
platelet count, hemoglobin, or neutrophil count; or worsening of disease-related 
symptoms) other than lymphocytosis. Subjects must have confirmation by the sponsor 
working in collaboration with an independent review committee (IRC) that the disease 
has progressed on the clinical trial (Study GS-US-312-0116) before receiving 
secondary GS-1101 therapy on this extension trial (Study GS-US-312-0117). 
3) Presence of radiographically measurable lymphadenopathy (defined as the presence of 
≥1 nodal lesion that measures ≥2.0 cm in the longest dimension [LD] and ≥1.0 cm in the 
longest perpendicular dimension [LPD] as assessed by CT or MRI).  
4) Permanent cessation of Study GS-US-312-0116 treatment (rituximab and 
GS-1101/placebo) and no intervening or continuing therapy (including radiotherapy, 
chemotherapy, immunotherapy, systemic corticosteroids, or investigational therapy) for 
the treatment of CLL.  
5) The time from permanent cessation of Study GS-US-312-0116 treatment (rituximab 
and/or GS-1101/placebo) and the initiation of Study GS-US-312-0117 therapy is 
≤12 weeks. Note: Study procedures performed as part of Study GS-US-312-0116 need 
not be repeated and can be used as screening procedures for Study GS-US-312-0117 if 
performed within 4 weeks prior to initiation of study drug therapy on Study GS-US-
312-0117. 
6) Karnofsky performance score of ≥40. 

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7) Required baseline laboratory data (within 4 weeks prior to initiation of study treatment) 
as shown in the table below. Note: Confirmation should be considered for out-of-range 
values to determine if the abnormality is real or artifactual. Values should be obtained 
within the screening period and should generally be the most recent measurement 
obtained. Subjects with any degree of neutropenia, thrombocytopenia, or anemia due 
to CLL or prior therapy may enroll. 
Table 4-1. 
Required Screening Laboratory Values 
Organ System 
Parameter 
Required Value 
Serum total bilirubin 
≤1.5 x ULN (unless elevated due to Gilbert’s syndrome) 
Serum ALT 
Hepatic 
Serum AST 
≤2.5 x ULN 
Renal 
eCCr
a 
>30 ml/min 
Pregnancy 
β-HCGb 
Negative  
a 
As calculated by the Cockcroft-Gault formula (see Appendix 5) 
b 
For women of child-bearing potential only; serum β-HCG must be negative during screening and serum β-HCG or 
urine dipstick pregnancy test must be negative at start of study treatment (Visit 2) 
Abbreviations: β-HCG= beta human chorionic gonadotropin, ALT=alanine aminotransferase, AST=aspartate 
aminotransferase, eCCr=estimated creatinine clearance, ULN=upper limit of normal 
8) For female subjects of childbearing potential, willingness to abstain from heterosexual 
intercourse or use a protocol-recommended method of contraception from the screening 
visit (Visit 1) throughout the study treatment period and for 30 days following the last 
dose of study drug. Note: A female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; 
has medically documented ovarian failure (with serum estradiol and follicle-
stimulating hormone [FSH] levels within the institutional postmenopausal range and a 
negative serum or urine βHCG), or is menopausal (age ≥55 years with amenorrhea for 
≥6 months).  
9) For male subjects of childbearing potential having intercourse with females of 
childbearing potential, willingness to abstain from heterosexual intercourse or use a 
protocol-recommended method of contraception from the start of study therapy (Visit 2) 
throughout the study treatment period and for 90 days following the last dose of study 
drug and to refrain from sperm donation from the start of study treatment (Visit 2) 
throughout the study treatment period and for 90 days following the last dose of study 
drug. Note: A male subject is considered able to father a child unless he has had a 
bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or has 
ongoing testicular suppression with a depot luteinizing hormone- releasing hormone 
(LH-RH) agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate  [Lupron®]), or 
triptorelin pamoate [Trelstar®]). 
10) In the judgment of the investigator, participation in the protocol offers an acceptable 
benefit-to-risk ratio when considering current CLL disease status, medical condition, and 
the potential benefits and risks of alternative treatments for CLL.  
11) Willingness and ability to comply with scheduled visits, drug administration plan, 
imaging studies, laboratory tests, other study procedures, and study restrictions. Note: 
Psychological, social, familial, or geographical factors that might preclude adequate 
study participation should be considered. 

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12) Evidence of a personally signed informed consent indicating that the subject is aware of 
the neoplastic nature of the disease and has been informed of the procedures to be 
followed, the experimental nature of the therapy, alternatives, potential benefits, possible 
side effects, potential risks and discomforts, and other pertinent aspects of study 
participation. 
4.2.2. 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study: 
1) Known histological transformation from CLL to an aggressive lymphoma (ie, Richter 
transformation).  
2) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of the start 
of study treatment (Visit 2). Note: Subjects with localized fungal infections of skin or 
nails are eligible. Subjects may be receiving prophylactic antiviral or antibacterial 
therapies at the discretion of the investigator; anti-pneumocystis prophylaxis is 
encouraged.  
3) Pregnancy or breastfeeding.  
4) Intentional breaking of the blind in Study GS-US-312-0116 by the investigator or the 
study subject. 
5) Concurrent participation in another therapeutic clinical trial. 
6) Prior or ongoing clinically significant illness, medical condition, surgical history, 
physical finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the 
investigator’s opinion, could adversely affect the safety of the subject or impair the 
assessment of study results. 
4.3. 
Enrollment Criteria Rationale 
The eligibility criteria are designed to limit enrollment to subjects who participated in the 
primary clinical trial (Study GS-US-312-0116), are compliant, have been generally able to 
tolerate study therapy and study procedures, and have experienced definitive CLL 
progression while receiving study treatment (rituximab and/or GS-1101/placebo) in the 
primary study. 
The requirement of measurable lymphadenopathy ensures that subjects have disease that can 
adequately be assessed for evidence of drug activity. Prior therapy provisions are intended to 
ensure that subjects are transitioning directly from Study GS-US-312-0116 to Study GS-US-
312-0117 without receiving intervening treatments. The stipulation of ≤12-week interval 
from Study GS-US-312-0116 treatment until Study GS-US-312-0117 treatment precludes 
excessively protracted intervals between participation in the 2 studies but also permits 
sufficient time for clinicians and subjects to determine whether participation is appropriate.  
To ensure that subjects are not so acutely ill from life-threatening comorbidities that they 
require hospitalization and stabilization, subjects with Karnofsky performance scores <40 (ie, 
those who are bed-bound or hospitalized) will not be enrolled. Baseline laboratory 
evaluations are designed to limit participation to subjects who have not developed serious 
organ compromise that would pose a safety risk or confound the interpretation of adverse 

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effects. Pregnancy testing and restrictions on eligibility relating to reproduction, pregnancy, 
and nursing are important because GS-1101 is a new chemical entity and it is unknown if it 
may have adverse effects on conception, on fetal development, or on the health of a breast-
feeding child. To minimize missing data and premature discontinuations, subjects should 
have sufficient psychological and social resources to comply with study procedures and 
restrictions. Consistent with GCP guidelines, subjects must provide informed consent before 
initiation of any study procedures. 

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5. 
TREATMENT OF SUBJECTS 
5.1. 
Enrollment 
5.1.1. 
Interactive Web Response System 
An interactive web response system (IWRS) will be employed to manage the conduct of the 
trial. The IWRS will be used to maintain a central log documenting enrollment, to manage 
dose modifications, to assess current inventories of study drug, to initiate any necessary 
resupply of study drug, and to document discontinuation of study treatment. 
5.1.2. 
Treatment Assignment 
After a subject has completed the necessary documentation of definitive CLL progression in 
the primary clinical trial (GS-US-312-0116) and has been confirmed to be eligible, the 
subject can be entered into this trial (Study GS-US-312-0117). In order to obtain a treatment 
arm allocation for a subject, a site representative will access the IWRS and supply the system 
with the required information. 
Subjects will be assigned to either of the following treatment assignments with allocation 
based on the original primary study randomization: 
• Arm A: GS-1101 + rituximab (Study GS-US-312-0116) 
⇒high-dose GS-1101 (300 mg BID) (Study GS-US-312-0117) 
• Arm B: Placebo + rituximab (Study GS-US-312-0116) 
⇒standard-dose GS-1101 (150 mg BID) (Study GS-US-312-0117) 
The IWRS will assign blister card numbers and instructions for dispensing of blinded study 
drug (high-dose or standard-dose GS-1101). It is anticipated that subjects will usually begin 
study drug immediately at Visit 2 of the study.  
5.1.3. 
Blinding 
The identity of the treatments will be concealed by central blinding of study drug 
assignments. Blinding will be accomplished through use of a placebo that is well-matched to 
the active drug in appearance, packaging, labeling, and schedule of administration 
(see Section 5.2.1). During the study, subjects, caregivers, investigational site personnel, 
Gilead Sciences study team members, and all other study personnel will remain blinded to 
the identity of the treatment assignments; these assignments will be available only to the 
IWRS, the data monitoring committee (DMC) for the study, an independent bioanalytical 
group that is not part of the study team, and drug safety personnel who are not part of the 
study team. Unblinding during the study will only occur in the case of subject emergencies 
(see Section 5.5) or as requested by the DMC. Where required by local regulation, expedited 
reporting of serious adverse events to specific regulatory authorities will include information 
regarding the study drug treatment assignment (high-dose or standard-dose GS-1101); this 
will be done in such a way that subjects, investigational site personnel, institutional review 
board/independent ethics committees (IRB/IEC), and study team members remain blinded as 
to the treatment assignment for the subject described in the adverse event report. 

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The final unblinded analysis of the study will only be performed when the database is 
completed and locked. While bioanalytical assays to determine GS-1101 concentrations may 
be performed prior to unblinding, pharmacokinetic data that would allow identification of 
treatment assignments for individual subjects will not be available to the study team until 
after the blind is broken and the primary analysis has occurred. Except for emergency 
unblinding, individual subjects, caregivers, and site personnel will not be informed of the 
treatment assignments until the implications of revealing such data for the overall GS-1101 
study program have been determined by the clinical project leader for the GS-1101 
development program. 
5.2. 
Investigational Study Drug (GS-1101/Placebo) 
5.2.1. 
Description 
Subjects allocated to Arm A of the study will be provided with 2 tablets of active GS-1101 
for oral administration at each dose. Each tablet contains 150 mg or 100 mg of active 
GS-1101. The 150-mg tablets will be used for initial therapy; the 100-mg tablets are provided 
for use by those subjects who require a dose reduction (see Table 5-1).  
Subjects allocated to Arm B of the study will be provided with 1 tablet of active GS-1101 
and 1 tablet of placebo for oral administration at each dose. Each active tablet contains 
150 mg or 100 mg of active GS-1101. The 150-mg tablets (and matching placebo) will be 
used for initial therapy; the 100-mg tablets (and matching placebo) are provided for use by 
those subjects who require a dose reduction.  
The 150-mg tablets are pink, film-coated, and include the following inactive excipients: 
microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch 
glycolate, magnesium stearate, red iron oxide, polyethylene glycol, talc, polyvinyl alcohol 
(PVA), and titanium dioxide. The 100-mg tablets are orange, film-coated, and include the 
following inactive excipients: microcrystalline cellulose, hydroxypropyl cellulose, 
croscarmellose sodium, sodium starch glycolate, magnesium stearate, yellow iron oxide, 
polyethylene glycol, talc, PVA, and titanium dioxide. 
The placebo tablets match the active GS-1101 formulations in appearance. The placebo 
tablets matching the 150-mg tablets are pink, film-coated, and include the following inactive 
ingredients: silicified microcrystalline cellulose, sodium starch glycolate, magnesium 
stearate, red iron oxide, polyethylene glycol, talc, PVA, and titanium dioxide. The placebo 
tablets matching the 100-mg tablets are orange, film-coated, and include the following 
inactive ingredients: silicified microcrystalline cellulose, sodium starch glycolate, 
magnesium stearate, yellow iron oxide, polyethylene glycol, talc, PVA and titanium dioxide. 
Details regarding the shape and size of each tablet dosage form will be provided in the 
pharmacy manual for the study. 
5.2.2. 
Source 
Both active GS-1101 and placebo will be supplied free of charge by Gilead Sciences.  
5.2.3. 
Packaging and Labeling 
Study drug (GS-1101 or GS-1101/placebo) will be provided in blister cards. The blister cards 
are made of polyvinyl chloride/polychlorotrifluoroethylene (PVC/PCTFE) film and have 

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aluminum foil lidding materials. Each blister card contains 120 tablets (4-week supply plus a 
modest overage) of one of the relevant dose strengths. The 100-mg or 150-mg and matching 
placebo tablets will be combined in order to obtain the daily doses to be used in this study. 
Thus, in Arm A, the 300-mg GS-1101 dose will be obtained by administering two 150-mg 
tablets and the 200-mg GS-1101 dose will be obtained by administering two 100-mg tablets. 
In Arm B, the 150-mg GS-1101 dose will be obtained by administering one 150-mg tablet 
and one placebo tablet and the 100-mg GS-1101 dose will be obtained by administering one 
100-mg tablet and one placebo tablet.  
Each blister card will have a unique number. Labeling for blister cards dispensed to subjects 
in Arm A will appear identical to blister cards dispensed to subjects in Arm B. All labels for 
study drugs to be distributed to centers in the United States, the EU, and other countries will 
meet all applicable requirements of the United States Food and Drug Administration 
(FDA), the EU Annex 13 of Current Good Manufacturing Practice (cGMP) (Manufacture of 
Investigational Medicinal Products, July 2003), and/or other local regulations as applicable. 
5.2.4. 
Storage and Handling 
Blister cards containing tablets of study drug (GS-1101 or GS-1101/placebo) should be 
stored at controlled room temperature (ie, ~25°C, with a range of 15 to 30°C). While the 
stability of study drug tablets stored at controlled room temperature has been confirmed, brief 
excursions to temperatures as low as 5°C or as high as 40°C (eg, during shipping) will not 
adversely affect the drug. Freezing should be avoided. Updated stability data will be 
provided to the sites, as appropriate. 
5.2.5. 
Dispensing 
The clinic staff (eg, pharmacist or other qualified person) will be responsible for dispensing 
study drug according to the IWRS directions. It is planned that drug will be dispensed at 
4-week intervals through the first 24 weeks of treatment and at 12-week intervals thereafter. 
Sufficient study drug will be provided for each study period at the beginning of the period. 
Multiple blister cards may be dispensed at a single visit. Tablets should be kept in the 
original blister cards provided until they are self-administered by the subject. 
At the time of starting study treatment, the IWRS will provide the clinic staff with the blister 
card numbers designating the blister cards to be dispensed. The clinic staff (eg, pharmacist or 
other qualified person) will write the subject number on each blister card that is dispensed. 
Immediately before dispensing, the clinic staff will write the blister card number for each 
dispensed blister card in the study drug administration record corresponding to the subject 
number. 
5.2.6. 
Return 
The study drug should be retrieved from each subject at the end of each dispensing interval. 
The quantity of study drug and the date returned by the subject should be recorded in the 
study drug accountability records. All study drug returned by the subject should be retained 
for review by the study site monitor prior to return to Gilead Sciences or destruction. 

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5.2.7. 
Accountability 
The disposition of all study drug should be documented from the time of receipt at the site 
through subject dispensing and return. 
Study personnel must ensure that all study drug is kept in a secure locked area with access 
limited to authorized personnel. The study drug must not be used outside the context of this 
protocol. Under no circumstances should the investigator or site personnel supply study drug 
to other investigators or clinics, or allow the study drug to be used other than as directed by 
this protocol. 
The investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by Gilead Sciences or its designee, including, but not 
limited to, the date received, lot number, amount received, and the disposition of all study 
drug. Upon receipt of a drug shipment, the shipment must be logged into the IWRS. Study 
drug accountability records must also be maintained that include the subject number to whom 
the study drug was dispensed and the date, quantity and lot number of the study drug 
dispensed. 
Depending upon the decision of Gilead Sciences, remaining unused study drug supply will be 
returned to Gilead Sciences or its designee after the study is completed or will be discarded 
or destroyed at the clinical site. If the study drug is discarded or destroyed at the clinical site, 
standard institutional policy should be followed. Records documenting the date of study drug 
shipping or destruction, relevant lot numbers, and amount shipped or destroyed should be 
maintained. 
5.2.8. 
Overdose Precautions 
In Phase 1 studies, an MTD for GS-1101 was not reached when the drug was administered 
continuously at dose levels through 350 mg/dose BID (700 mg per day) [Coutre 2011, Kahl 
2011]. However, in this protocol, an overdose is defined as administration of more than the 
prescribed daily dose (ie, >600 mg in a single day). In a subject who experiences an overdose 
consideration should be given as to whether GS-1101 administration should be temporarily 
interrupted. If the overdose ingestion is recent and substantial, and if there are no medical 
contraindications, use of gastric lavage or induction of emesis may be considered. 
Observation for any symptomatic side effects should be instituted, and biochemical and 
hematological parameters should be followed closely (consistent with the protocol or more 
frequently, as needed). Appropriate supportive management to mitigate adverse effects 
should be initiated. 
The Gilead Sciences medical monitor should be contacted if a study drug overdose occurs. 
Cases of study drug overdose will result in specific reporting requirements (see Section 8.8). 
5.2.9. 
Inadvertent Exposure and Spill Precautions 
Based on available data from nonclinical studies, GS-1101 does not appear to be acutely 
toxic, genotoxic, or irritative at levels that are likely to result from inadvertent exposure to 
the contents of broken tablets. However, personnel handling the drug should use reasonable 
precautions to avoid eye contact, skin contact, inhalation, or ingestion of the study drug 
product. For further information regarding inadvertent exposure and spill precautions, please 
consult the GS-1101 investigator brochure. 

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5.3. 
Study Drug Administration 
5.3.1. 
Premedication 
No specific premedications or supporting medications are required in conjunction with study 
drug administration, although institution of antibiotic prophylaxis for Pneumocystis (carinii) 
jiroveci should be considered in all subjects (see Section 5.6.2). 
5.3.2. 
Administration Instructions 
The prescribed dose of study drug (GS-1101/placebo) should be taken orally. At each dose 
administration, the tablet number corresponding to the appropriate dose of study drug is to be 
swallowed whole with 100 to 200 mL (~ 4 to 8 ounces) of water. In case of breakage of the 
tablets in the oral cavity, additional water should be taken as a rinse.  
Study drug may be taken with or without food. There are no known dietary restrictions 
related to study drug use. 
5.3.3. 
Dosing Schedule 
Study drug should be taken on a BID schedule at approximately the same times each day. 
Ideally, doses should be taken at ~12-hour intervals (eg, at ~7 AM and at ~7 PM). While it is 
realized that variations in dosing schedule may occur in the outpatient setting, the prescribed 
regimen should be followed as closely as possible, especially in the clinic. 
At specified clinic visits, the study drug will be administered in the clinic with dosing 
appropriately timed relative to blood sampling for GS-1101 pharmacokinetics. As detailed in 
Section 6.2, clinic staff should record GS-1101 administration information, including the 
exact clock time of each dose, for doses of study drug administered in the clinic or hospital. 
Thereafter, subjects will be given an adequate supply of tablets to take at home. 
5.3.4. 
Dose Levels 
Study drug dose levels for Arm A and Arm B are described in Table 5-1. The lower dose 
level (Dose Level -1) is provided in case a subject requires a study drug dose modification. 
Table 5-1. 
Study Drug Dose Levels 
Treatment Arm 
Starting Dose 
Dose Level -1 
Arm A 
300 mg/dose BID 
200 mg/dose BID 
Arm B 
150 mg/dose BID 
100 mg/dose BID 
Abbreviation: BID=twice per day 
5.3.5. 
Dose Schedule Interruptions and Vomited Doses 
Subjects who have a delay in administration of a dose of the study drug of <6 hours should 
take the planned dose as soon as possible after the intended time of administration. For 
subjects who have a delay in administration of study drug of ≥6 hours, the dose should not be 
taken. Study drug administration may continue but the missed dose should not be made up 
and the planned timing of subsequent study drug dosing should not be altered. 
Vomited doses may be retaken, but only if the tablet is visible in the vomitus. 

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5.3.6. 
Safety Monitoring and Study Drug Interruption/Dose Modification 
Subjects must be monitored closely for adverse events or laboratory abnormalities during the 
course of the study. Reference should be made to the CTCAE, Version 4.03 for grading the 
severity of adverse events and laboratory abnormalities. 
Based on Phase 1 clinical experience adverse events potentially attributable to GS-1101 in 
patients with CLL have included infrequent hepatic events (manifest primarily as 
asymptomatic and isolated elevations in serum ALT/AST), and instances of pneumonitis, 
gastrointestinal inflammation, or rash. Myelosuppression has not been an overt toxicity of 
GS-1101 in previous experience but provisions for intervention in subjects experiencing very 
protracted treatment-emergent neutropenia or thrombocytopenia are provided as a precaution. 
It is possible that GS-1101 is responsible for other adverse events for which a causal 
relationship has not yet been established. 
If a subject experiences an adverse event that is suspected to be related to study drug and 
requires a dose modification during the course of study therapy, then study drug 
administration should be held, as necessary, until the adverse event resolves or stabilizes to 
an acceptable degree (generally to Grade ≤1). Thereafter, study drug may be reinstituted, but 
the dose should be reduced to Dose Level -1 (see Table 5-1). If the adverse event occurs 
again, one further attempt at reinitiation of therapy at Dose Level -1 may be attempted if the 
investigator feels that a second rechallenge is medically appropriate. If the subject cannot 
tolerate GS-1101 at Dose Level -1 after 2 rechallenges, then the subject should be 
discontinued from study drug therapy. 
After the study drug dose is reduced, the dose need not be re-escalated, even if there is 
minimal or no toxicity with the reduced dose. However, if the subject tolerates the lower 
dose level of study drug for ≥4 weeks then the dose level may be increased to the starting 
dose level (see Table 5-1) at the discretion of the investigator. Such re-escalation may be 
particularly warranted if further evaluation reveals that the adverse event that led to the dose 
reduction was not study-drug-related. The starting dose level should not intentionally be 
exceeded in this study. 
Whenever possible, any dose adjustment of study drug should be discussed between the 
investigator and the Gilead Sciences medical monitor prior to implementation. To implement 
either a dose reduction or a dose reescalation, the investigator/study staff member will call 
the IWRS, enter the subject number, and inform the IWRS of the need for dose titration. The 
IWRS will provide details regarding the blister card to be dispensed to the subject. The 
appropriate clinic staff should instruct the subject/caregiver about the change in dose. 
Recommendations for dose modification based on the type and severity of adverse events or 
laboratory abnormalities are provided in Table 5-2 below. 

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Table 5-2. 
Recommendations for Study Drug Dose Modifications Based on 
Type and Severity of Adverse Events or Laboratory Abnormalities 
Hepatic Study-Drug-Related Event (Elevation in ALT, AST, or Bilirubin) 
CTCAE Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ALT/AST 
>ULN-3 x ULN 
>3-5 x ULN 
>5-20 ULN 
>20 x ULN 
Bilirubin 
>ULN-1.5 x ULN 
>1.5-3 x ULN 
>3-10 x ULN 
>10 x ULN 
GS-1101 Dosing 
Recommendation 
Maintain dose level 
Maintain dose level. 
Monitor ALT, AST, 
ALP, and bilirubin at 
least 1x per week until 
all abnormalities  
are ≤Grade 1 
Withhold study drug and confirm abnormalities 
within 3 days. Monitor ALT, AST, ALP, and 
bilirubin at least 1x per week until all 
abnormalities are Grade ≤1. May resume drug at 
next lower dose level. 
Cutaneous Study-Drug-Related Event  
CTCAE Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
GS-1101 Dosing 
Recommendation 
Withhold study drug until toxicity is Grade 0.  
Resume study drug at current dose level. If 
rechallenge at same dose level results in 
recurrent rash, may resume study drug at next 
lower dose level. 
Withhold study drug until toxicity is Grade 0. 
May resume study drug at next lower dose level.
Hematological Study-Drug-Related Event 
CTCAE Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neutropenia 
(ANC x 109/µL) 
ANC <LLN-1.5 
ANC <1.5-1.0 
ANC <1.0-0.5 
ANC <0.5 
Thrombocytopenia 
(platelets x 109/µL) 
Platelets <LLN-75 
Platelets <75-50 
Platelets<50-25 
Platelets<25 
GS-1101 Dosing 
Recommendation  
Maintain dose level 
Maintain dose level 
Maintain dose level 
For neutropenia 
of Grade 4 for 
≥14 days, consider 
G-CSF support or may 
withhold study drug 
until Grade ≤3. May 
resume study drug at 
next lower dose.  
For Grade 4 
thrombocytopenia with 
bruising or bleeding, 
withhold study drug 
until Grade ≤3. May 
resume study drug at 
next lower dose level. 
Other Study-Drug-Related Event 
CTCAE Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
GS-1101 Dosing 
Recommendation 
Maintain dose level 
Maintain dose level 
Withhold study drug until toxicity is Grade ≤1. 
May resume study drug at next lower dose level 
unless subject has developed a condition 
requiring discontinuation of therapy (see 
Section 5.8). 
Abbreviations:   ALP=alkaline phosphatase, ALT=alanine aminotransferase, ANC=absolute neutrophil count, 
AST=aspartate aminotransferase, CTCAE=Common Terminology Criteria for Adverse Events, G-CSF=granulocyte-colony-
stimulating factor, LLN= lower limit of normal, ULN=upper limit of normal 

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5.4. 
Recommendations for Evaluation, Intervention, and Drug 
Discontinuation for Specific Adverse Events or Conditions 
5.4.1. 
Dermatological Events 
GS-1101 administration has occasionally been associated with the occurrence of a 
maculopapular rash affecting the trunk and extremities [Gilead Sciences 2011]. Based on 
skin biopsy data in several subjects, the findings have been consistent with a delayed-type 
hypersensitivity reaction. Rechallenge with GS-1101 has resulted in recurrence of rash in 
some but not all subjects. 
In subjects who develop a rash while on study drug, causes related to concomitant 
medications, environmental exposures, or infection should be considered and eliminated. 
Depending upon the severity of the initial dermatological event, rechallenge with study drug 
therapy at the same or a lower dose level (see Table 5-2) should be considered if continued 
drug administration offers the potential for clinical benefit. 
5.4.2. 
Gastrointestinal Events 
Inflammation of the tongue has been noted in rats undergoing repeated gavage administration 
of GS-1101; this inflammation may have represented a drug-related exacerbation of 
gavage-mediated irritation. Mild congestion or hemorrhage in the large intestine has been 
seen in dogs receiving high doses of GS-1101. In patients, isolated cases of gastrointestinal 
inflammation (eg, stomatitis, colitis, cecitis) have been noted. Cholangitis manifest as 
hyperbilirubinemia out of proportion to serum transaminase elevations has been observed. 
While disease-related factors, neutropenia, toxicity from prior therapies, effects of ongoing 
supportive care, or pre-existing cholelithiasis may have initiated such events, it is possible 
that GS-1101 played a contributory role due to its immunomodulatory effects 
[Gilead Sciences 2011]. 
For study subjects who develop severe abdominal pain, particularly if early during therapy, 
the possibility of a bowel obstruction or perforation should be considered. Appropriate 
clinical and radiographic examination should be performed and supportive care and surgical 
intervention should be considered. Upon recovery, study therapy may be continued if 
appropriate for the clinical situation. 
For subjects who develop persistent diarrhea, causes related to concomitant medications or 
gastrointestinal infection should be considered and eliminated. Depending upon the clinical 
circumstances, endoscopy and biopsy may be warranted. In such subjects, rechallenge with 
GS-1101 at a lower dose level has resulted in recurrence of symptoms in some but not all 
subjects and has not been associated with other severe adverse events. One patient who 
developed evidence of inflammatory bowel disease during GS-1101 therapy has been treated 
with sulfasalazine (Azulfidine®) and antidiarrheals (eg, loperamide) while continuing on 
GS-1101. 
Thus, depending upon the type and severity of the initial gastrointestinal event, rechallenge 
with study drug at a reduced dose level and with and appropriate support care may be 
warranted if continued drug administration offers the potential for clinical benefit. 

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5.4.3. 
Hepatic Events 
Dogs receiving GS-1101 for 28 days were observed to have dose-related hepatic 
inflammation and cellular necrosis, primarily affecting sinusoids in the centrilobular to 
midzonal regions of the liver [Gilead Sciences 2011]. The changes were associated with 
elevations in serum ALT/AST concentrations. In dogs, serum transaminase elevations 
typically reversed despite continued administration of GS-1101. In some patients with 
lymphoid malignancies, reversible serum ALT/AST elevations have been observed 
[Coutre 2011, Kahl 2011]. In these patients, onset has typically occurred within 2 to 8 weeks 
of starting GS-1101 therapy. Patients with NHL have been affected more commonly than 
those with CLL, suggesting that disease-related factors may alter the sensitivity to 
GS-1101-mediated hepatic effects. While conclusive evidence for a dose-response 
relationship does not exist, higher doses or exposures of GS-1101 may be associated with a 
greater risk of adverse hepatic events. 
Among patients with Grade 1-2 ALT/AST abnormalities, continued dosing has been 
possible; transaminase values commonly resolve despite continued GS-1101 treatment. For 
those with Grade 3-4 ALT/AST elevations, drug interruption has resulted in resolution over 
2 to 6 weeks. Successful rechallenge at lower dose levels of GS-1101 has been achieved in 
the majority of patients. Thus, in subjects with uncomplicated hepatic events, the instructions 
in Table 5-2 should be followed in an attempt to maximize the potential that subjects who 
appear to be benefiting can continue with study drug treatment. 
In selected subjects who experience more complicated hepatic adverse events, further 
work-up may be warranted, as requested by the Gilead Sciences medical monitor. Such an 
evaluation may be particularly warranted in subjects who first experience a serum ALT/AST 
elevation ≥12 weeks from the start of study drug therapy, who have an elevation in serum 
bilirubin concentration or coagulation parameters, or who have other characteristics that 
suggest an atypical change in transaminase values. Further workup may include: obtaining a 
history of recent symptoms/illnesses and of relevant past history (eg, history of hepatitis or of 
hepatitis A or hepatitis B vaccination); obtaining information regarding concomitant drug use 
(prescription and nonprescription medications, dietary supplements, alcohol, illicit drugs, 
special diets); questioning the subject regarding potential exposure to environmental toxins; 
ruling out viral hepatitis A, B, C, D (if hepatitis B is positive), and E, Epstein-Barr virus, 
cytomegalovirus, autoimmune hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis, 
hypoxic/ischemic hepatopathy, and biliary tract disease; obtaining additional tests to evaluate 
liver function (eg, prothrombin time [PT], activated partial thromboplastin time [aPTT], 
international normalized ratio [INR], albumin); and considering gastroenterology or 
hepatology consultation [FDA 2009]. 
Of note, HBV reactivation can occur in patients treated with rituximab with a median time to 
diagnosis of hepatitis among patients with hematologic malignancies of 4 months after the 
initiation of rituximab but such events can occur months after completion of rituximab 
therapy. The risk is very low among patients with negative anti-HBc serology [Matsue 2010]. 
Because subjects with serum anti-HBc antibodies are excluded from the primary study 
(Study GS-US-312-0116), this complication is not anticipated. However, among subjects 
with evidence of Grade ≥3 serum ALT/AST abnormalities, evaluation for HBV reactivation 
(manifest as positivity for serum HBsAg) should be performed as a precautionary measure. 

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In a subject with active HBV, anti-HBV antiviral agents should be initiated. At the discretion 
of the investigators, study drug may be continued if HBV infection can be adequately 
controlled, particularly if the subject is experiencing clinical benefit from study therapy and 
there are few other options for treating the subject’s CLL. 
5.4.4. 
Hematological and Immunological Events 
In the Phase 1 experience with GS-1101 in CLL, patients with Grade≥3 neutropenia, anemia, 
and and/or thrombocytopenia were enrolled to clinical trials. Decreased levels of neutrophil 
counts, hemoglobin, or platelet counts during therapy were largely due to minor fluctuations 
in these parameters among patients with pre-existing hematological abnormalities due to 
disease or prior therapy. Thus, GS-1101 did not appear to induce overt myelosuppression. 
Obvious patterns of drug-mediated reductions in circulating CD4+ lymphocyte counts or 
suppression of serum IgG levels were also not observed. 
Given that patients with CLL commonly have Grade ≥3 hematological abnormalities due to 
underlying disease or prior therapy and that GS-1101 is not associated with substantial 
myelotoxicity or off-target immunosuppression, alterations in study drug dose level for such 
events should only focus on subjects with protracted or symptomatic neutropenia or 
thrombocytopenia, unresponsive to G-CSF supportive care. No modification of GS-1101 for 
changes in circulating CD4+ counts or Ig levels is planned. 
5.4.5. 
Infectious Events 
Patients with CLL receiving GS-1101 have developed serious bacterial, fungal, and viral 
infections during therapy [Gilead Sciences 2011]. Similarly, serious bacterial, fungal, and 
new or reactivated viral infections have also occurred during and for ~1 year following 
rituximab-based therapy [Gea-Banacloche 2010]. New or reactivated viral infections in 
patients receiving rituximab have included cytomegalovirus, herpes simplex virus, 
parvovirus B19, varicella zoster virus, West Nile virus, HBV (see Section 5.4.3) and HCV. 
Because patients with lymphoid malignancies (particularly those with CLL) are susceptible 
to infection due to the underlying disease, neutropenia, and the effects of prior therapy, the 
specific causal role of GS-1101 or rituximab in any of these types of events is unclear. 
Patients with previously treated CLL have developed Pneumocystis (carinii) jiroveci 
pneumonia while receiving GS-1101. While GS-1101 has not specifically been implicated in 
such cases, patients with lymphoid malignancies (particularly those with CLL) may be 
susceptible to pneumocystis infections due to the underlying disease and the effects of prior 
therapy. Pre-existing risk factors of specific concern may include previous pneumocystis 
pneumonia, underlying disease (eg, CLL), prior therapy (eg, alemtuzumab, progenitor cell 
transplantation), or immunocompromised status (low CD4+ lymphocyte counts, HIV 
infection) [Green 2007]. 
Unless there is a contra-indication in a specific study subject, consideration should be given 
to initiation of antibiotic prophylaxis against pneumocystis infection (eg, with trimethoprim-
sulfamethoxazole, dapsone, aerosolized pentamidine, or atovaquone) beginning prior to study 
drug administration. Such support may also offer the benefit of reducing the risk for other 
bacterial infections [Green 2007]. Local practices or guidelines may be followed. 

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For subjects who develop an infection, appropriate medical therapy (with antibiotics, 
antifungals, or antiviral) or other interventions should be instituted. Whenever appropriate, 
subjects should continue with study drug during treatment for the infection. 
5.4.6. 
Progressive Multifocal Leukoencephalopathy 
Progressive multifocal leukoencephalopathy (PML) due to polyomavirus JC has been 
observed in patients who have received rituximab therapy [Carson 2009] for hematologic 
malignancies. The specific causal role of rituximab is unknown because many of these 
patients had other risk factors (eg, low CD4+ counts) and the majority had received 
rituximab in combination with chemotherapy or as part of a hematopoietic stem cell 
transplant. Most cases of PML were diagnosed within 12 months of the last infusion of 
rituximab. 
The diagnosis of PML should be considered in any subject presenting with new-onset 
neurologic manifestations. Evaluation of PML may include consultation with a neurologist, 
brain MRI, and lumbar puncture. In subjects diagnosed with PML, study drug should also be 
permanently discontinued. 
5.4.7. 
Pulmonary Events 
Documented bacterial, fungal, viral, and pneumocystis pneumonias have been observed in 
patients receiving GS-1101, primarily in patients with CLL. Some patients receiving 
GS-1101 alone or in combination have developed evidence of pneumonitis without 
documented lung infection. The specific role of GS-1101 in these events is unclear; 
nonclinical evaluations of pulmonary function and pathology do not indicate a direct toxic 
effect of GS-1101 on the lungs [Gilead Sciences 2011] and disease-related factors or toxicity 
from prior or concomitant therapies may have contributed to these clinical events. 
Rituximab-related noninfectious pneumonitis has been described [Subramanian 2010] with 
an incidence of ~4.3% [Salmasi 2010]. In patients developing rituximab-associated 
pneumonitis, the mean time from the first rituximab infusion to the onset of respiratory 
symptoms was 3 months, with a peak incidence after administration of a mean cumulative 
dosage of 1600 mg/m2 [Lioté 2010]. 
Given the potential for infectious or drug-related adverse events, clinicians should be 
particularly observant for evidence of respiratory events in subjects participating in this trial. 
Subjects should be evaluated who describe pulmonary symptoms (eg, dyspnea on exertion, 
cough, shortness of breath); manifest a decline from baseline of ≥5% in oxygen saturation, or 
demonstrate evidence of pulmonary inflammation (eg, focal or diffuse interstitial pattern or 
ground-glass opacities on chest CT). Potential bacterial, fungal, or viral etiologies should be 
assessed. Pneumocystis (carinii) jiroveci should be considered, especially if the subject is not 
receiving pneumocystis prophylaxis. Depending upon the changes observed and the response 
to antibiotic intervention, recommended diagnostic work-up may include blood and sputum 
cultures; polymerase chain reaction or antigen testing for pneumocystis and respiratory 
viruses (eg, CMV, influenza virus, respiratory syncytial virus, parainfluenza virus, 
rhinovirus); chest X-ray, CT or other imaging methods; pulmonary function testing and 
diffusing capacity of the lung for carbon monoxide (DLCO); bronchoscopic lavage and/or 
biopsy; or open-lung biopsy. Noninfectious etiologies such as pulmonary edema or 
thromboembolism should also be considered. 

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As appropriate for the clinical situation and culture results, subjects should be treated 
empirically or given specific antibiotics, antifungals, or antiviral agents for a cultured 
organism. Supportive care, including oxygen or mechanical ventilation, should be provided 
as necessary.  
For subjects with a symptomatic pneumonitis in the absence of infection (eg, onset of cough 
without fever and lack of response to anti-infective measures), study drug should be 
interrupted and therapy with corticosteroids should be instituted [Lioté 2010]. Resumption of 
study drug at Dose Level -1 should only be considered if the subject is experiencing evidence 
of substantial clinical benefit from therapy and other options for treating the subject’s CLL 
are very limited; reoccurrence of drug-related pneumonitis upon rechallenge should result in 
permanent discontinuation of study treatment. 
5.4.8. 
Tumor Lysis Syndrome 
Patients with tumor lysis syndrome may experience hyperkalemia, hypocalcemia, 
hyperuricemia, hyperphosphatemia, cardiac dysrhythmias, and acute renal failure. 
Tumor lysis syndrome has not been observed with GS-1101 monotherapy. However, if tumor 
lysis were to occur in a subject participating in this study, the subject should receive rapid 
reversal of hyperkalemia, intravenous hydration, antihyperuricemic agents, and appropriate 
cardiac and renal support, including dialysis as indicated. Upon recovery to baseline 
functioning, such subjects should continue study therapy to maintain tumor control. 
5.4.9. 
Pregnancy, Lactation, and Reproduction 
GS-1101 was not overtly teratogenic when administered to pregnant female rats in a 
dose-range-finding study [Gilead Sciences 2011]. However, definitive reproductive 
toxicology studies in animals have not yet been performed and the specific effects of 
GS-1101 on human embryogenesis or fetal development are unknown. Whether GS-1101 is 
excreted in human breast milk is unknown. General toxicology studies in rats and dogs 
indicated dose-dependent reductions in testicular weights, with persistent minimal to mild 
degeneration of the seminiferous tubules and decreased spermatozoa in rats and 
hypospermatogenesis in dogs. The implications of these testicular changes for animal or 
human fertility are unknown. 
Given the preliminary nature of data regarding the risks to a fetus or infant as a result of 
exposure to GS-1101, women of reproductive potential entering this study must have a 
negative serum pregnancy test at baseline and must not be breastfeeding. Males and females 
of childbearing potential should abstain from sexual intercourse or use an effective form of 
contraception (see Section 5.6.4). If a female study participant becomes pregnant or decides 
to breastfeed during the course of the study, all study therapy must be discontinued. Study 
candidates will be informed of the testicular findings through the informed consent process. 
5.5. 
Emergency Unblinding 
Every attempt should be made to preserve the integrity of study drug dose assignment 
blinding. Unblinding in individual subjects who experience adverse events is rarely required 
to provide effective intervention and support. For subjects having adverse events or 
laboratory abnormalities that require drug cessation or medical intervention, the 
investigational staff should strive to provide necessary support to the subject without 

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breaking the blind. In the exceptional circumstance that knowledge of the study drug dose 
assignment appears essential for providing appropriate medical management, the investigator 
should contact the Gilead Sciences medical monitor to discuss the rationale for breaking the 
blind and the adverse consequences of the unblinding for the subject’s continued 
participation in the study. If the investigator still believes that unblinding is warranted, the 
investigator will be able to access the allocation system in order to obtain the treatment 
assignment for that subject. No randomization lists or other unblinding information will be 
provided to the site. After breaking the blind, the investigational site staff should record 
details regarding the reasons for breaking the blind and any adverse events leading to the 
breaking of the blind in the source documents and in the appropriate eCRF. 
If the site breaks the blind, the appropriateness of continued study drug therapy should be 
discussed with the Gilead Sciences medical monitor. Subjects who intentionally subvert the 
blind (eg, through chemical analysis of the drug) should be discontinued from study drug 
therapy.  
5.6. 
Concomitant and Supportive Therapy 
To the extent possible, administration of any prescription or over-the-counter drug products 
other than study medication should be minimized during the study period. Subjects should be 
discouraged from use of street drugs, herbal remedies, self-prescribed drugs, tobacco 
products, or excessive alcohol at any time during the clinical study. 
If considered necessary for the subject’s well-being, drugs for concomitant medical 
conditions or for symptom management may be given at the discretion of the investigator. 
The decision to authorize the use of any drug other than study drug should take into account 
subject safety, the medical need, the potential for drug interactions, the possibility for 
masking symptoms of a more significant underlying event, and whether use of the drug will 
compromise the outcome or integrity of the study 
Subjects should be instructed about the importance of the need to inform the clinic staff of 
the use of any drugs or remedies (whether prescribed, over-the-counter, or illicit) before and 
during the course of the study. Any concomitant drugs taken by a subject during the course 
of the study and the reason for use should be recorded on the eCRFs. 
Information regarding use or restrictions on specific concomitant medications, dietary 
measures, or other interventions is provided below. 
5.6.1. 
Anticancer or Experimental Therapies Other than Investigational 
Treatments 
No other anticancer therapies (including chemotherapy, radiation, antibody therapy, 
immunotherapy, or other experimental therapies) of any kind are permitted while the subject 
is receiving study treatment. Subjects are not allowed to participate concurrently in any other 
therapeutic clinical study. 
5.6.2. 
Antibiotics 
Except in a subject who has a contra-indication, investigators should consider initiation of 
antibiotic prophylaxis against pneumocystis infection (eg, with trimethoprim-
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drug administration. Such support may also offer the benefit of reducing the risk for other 
bacterial infections [Green 2007]. Investigator discretion and local practices or guidelines 
may be followed. 
For subjects who develop an infection, appropriate medical therapy (with antibiotics, 
antifungals, or antiviral) or other interventions should be instituted. Whenever appropriate, 
subjects may continue with study drug during treatment for the infection. 
5.6.3. 
Antiemetics and Antidiarrheals 
Drug-related nausea and/or vomiting have not been commonly observed with GS-1101 in 
prior studies. However, subjects who experience nausea or vomiting while on study therapy 
may receive antiemetics based on the judgment of the treating physician and local 
institutional practices. At the occurrence of persistent nausea or vomiting of severity 
Grade ≥1, it is suggested that the subject receive an oral or transdermal serotonin antagonist 
(eg, dolasetron, granisetron, ondansetron, tropisetron, palonosetron). The neurokinin receptor 
antagonist, aprepitant, may be considered but is a mild inhibitor of CYP3A4 and so may 
modestly increase GS-1101 plasma exposures. Other classes of antiemetic medications that 
may be employed include dopamine antagonists or benzodiazepines. If possible, systemic 
corticosteroids should be avoided (see Section 5.6.5). 
As needed, subjects may be prescribed loperamide (Imodium® or others) or diphenoxylate 
and atropine (Lomotil®) to control diarrheal symptoms. 
5.6.4. 
Contraception 
In the context of this protocol, a female subject is considered to be of childbearing potential 
unless she has had a hysterectomy, a bilateral tubal ligation, or a bilateral oophorectomy; has 
medically documented ovarian failure (with serum estradiol and FSH levels within the 
institutional postmenopausal range and a negative serum or urine βHCG); or is menopausal 
(age ≥55 years with amenorrhea for ≥6 months). 
Sexually active females of childbearing potential must accept continuous heterosexual 
abstinence as a lifestyle choice or agree to use a protocol-recommended method of 
contraception during heterosexual intercourse throughout the study treatment period and for 
30 days following discontinuation of the study drug. The investigator should counsel subjects 
on the most effective methods for avoiding pregnancy during the trial. Protocol-
recommended contraceptive methods are described in Table 5-3. 

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Table 5-3. 
Protocol-Recommended Contraceptive Methods 
Combination Methods 
Individual Methods 
Hormonal Methods 
(One method to be used 
with a barrier method) 
Barrier Methods 
(Both of these methods to be used OR one of these 
methods to be used with a hormonal method) 
IUD 
Estrogen and progesterone 
Diaphragm with spermicide 
Copper T 380A IUD 
Oral contraceptives 
Male condom (with spermicide) 
LNg 20 IUD 
Transdermal patch 
 
Tubal sterilization 
Vaginal ring 
 
Hysterectomy 
Progesterone 
 
 
Injection 
 
 
Implant 
 
Abbreviation: IUD=intrauterine device 
In the context of this protocol, a male subject is considered able to father a child unless he 
has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or is 
receiving ongoing testicular suppression with a depot luteinizing hormone-releasing hormone 
(LH-RH) agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or 
triptorelin pamoate [Trelstar®]). 
Sexually active male subjects who can father a child must accept continuous heterosexual 
abstinence as a lifestyle choice; limit intercourse to female partners who are surgically sterile, 
post-menopausal, or using effective contraception (as noted in Table 5-3); or agree to use a 
protocol-recommended method of contraception during heterosexual intercourse throughout 
the study treatment period and for 90 days following discontinuation of the study drug (as 
noted in Table 5-3).  
The Gilead Sciences medical monitor should be consulted regarding any questions relating to 
childbearing status or contraception. 
5.6.5. 
Corticosteroids 
Subjects may receive topical, inhaled, or enteric corticosteroids while on study. The use of 
systemic corticosteroids is discouraged because their potential antineoplastic activity in 
patients with CLL may confound interpretation of antitumor effects mediated by study drug 
therapy. However, subjects who develop severe or life-threatening conditions that may be 
alleviated by systemic corticosteroid therapy are permitted to receive such drugs and are not 
required to discontinue study participation. 
5.6.6. 
Granulocyte Colony-Stimulating Factors and Erythropoietin 
Granulocyte-macrophage colony-stimulating factor (GM-CSF) should not be administered 
given the potential for GM-CSF-related inflammatory symptoms. 
G-CSF (filgrastim, PEG-filgrastim, lenograstim) may be administered in response to Grade 4 
neutropenia or neutropenic complications; use should be particularly considered if providing 
hematopoietic support might help to maintain study drug treatment (see Table 5-2). 
While erythropoietic agents (eg, erythropoietin or darbepoetin) may be administered for 
Grade ≥3 anemia, their use in this study is discouraged given the potential to confound 
assessments of improvements in bone marrow function related to study treatment. 

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Reference may be made to the American Society of Clinical Oncology guidelines 
[Rizzo 2008, Smith 2006]. 
5.6.7. 
Drugs that Inhibit CYP3A4-Dependent Metabolism 
GS-1101 is metabolized in part by CYP3A4. However, a clinical drug-drug interaction study 
indicated that administration of a potent CYP3A4 inhibitor together with GS-1101 induced 
only a modest increase in GS-1101 plasma exposure (see Section 1.3.5.1). Thus, 
co-administration of CYP3A4 inhibitors and GS-1101 is not contraindicated and does not 
require special monitoring. 
5.6.8. 
Immunization 
Because of its actions to inhibit PI3Kδ-dependent B-cell function, high doses of GS-1101 can 
impair primary or secondary responses to immunization in animals [Gilead Sciences 2011]. 
The specific clinical relevance of these findings with GS-1101 is unknown. However, for 
subjects who are at substantial risk of an infection (eg, influenza) that might be prevented by 
immunization, consideration should be given to providing the vaccine prior to initiation of 
study therapy. 
Of note, the safety of immunization with live viral vaccines following GS-1101 therapy has 
not been studied and vaccination with live virus vaccines during study treatment is not 
recommended. 
5.6.9. 
Surgery 
There are no known effects of GS-1101 on coagulation or wound healing. Pending receipt of 
additional information, study drug may be continued in the peri-procedural period in subjects 
who require surgery or invasive procedures. 
5.6.10. 
Diet 
There are no specific dietary restrictions in the study. Study drug may be taken with or 
without food. 
5.7. 
Duration of Study Therapy 
Subjects may continue receiving study drug until the earliest of the inability to tolerate a 
second rechallenge with protocol-described, dose-modified GS-1101 Dose Level –1 (see 
Section 5.3.6) or the occurrence of any events requiring treatment discontinuation as defined 
in Section 5.8. 
5.8. 
Discontinuation of Study Treatment 
All study participants may receive study drug indefinitely; however: 
• Any subject has the right to withdraw from the study at any time. 
• Any subject who has objective evidence of definitive CLL progression while receiving 
study treatment should be withdrawn from the study treatment. 
• Any subject whose medical condition substantially changes after entering the study 
should be carefully evaluated by the investigator in consultation with the Gilead Sciences 

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medical monitor. Such subjects should be withdrawn from study treatment if continuing 
would place them at risk. 
• Any subject who becomes pregnant or begins breastfeeding should be removed from 
study treatment. 
• Any subject who becomes significantly noncompliant with study drug administration, 
study procedures, or study requirements should be withdrawn from study treatment in 
circumstances that increase risk or substantially compromise the interpretation of study 
results. 
• Any subject for whom the blind is intentionally broken by the subject or the study site 
should discontinue study treatment. 
• The investigator, in consultation with the Gilead Sciences medical monitor, may 
withdraw any subject from the study treatment, if, in the investigator’s opinion, it is not 
in the subject’s best interest to continue.  
• Gilead Sciences, relevant regulatory agencies, or IRB/IECs may request discontinuation 
of the study at any time. 
• If allowed by local regulations, Gilead Sciences may transition subjects from study 
treatment to commercial drug supply when GS-1101 becomes commercially available in 
the country where the subject is living. 
The date the subject is withdrawn from study treatment or from the study (including 
long-term follow-up) and the reason for discontinuation will be recorded with the IWRS and 
also should be described on the appropriate eCRF. 
When a subject is withdrawn from study treatment or is permanently removed from study 
treatment (regardless of the reason), all of the evaluations required at the end-of-treatment 
visit should be performed and any additional evaluations should be completed that may be 
necessary to ensure that the subject is free of untoward effects. The subject should be 
encouraged to seek appropriate follow-up for any continuing health problems. 
Subjects who discontinue study treatment may still continue on study follow-up. Thus, all 
subjects receiving ≥1 dose of study drug will be followed during the immediate 
post-treatment and during the long-term follow-up periods unless the subject withdraws 
consent for such follow-up to be conducted. 
5.9. 
Study Treatment Rationale 
Subjects will be assigned to treatment (Arm A or Arm B) in this study based on their 
randomization in the primary study. The 1:1 randomization in the primary trial (GS-US-312-
0116) ensures that sufficient Arm B subjects will cross over from rituximab alone to single-
agent GS-1101 at the 150-mg/dose BID starting dose level in this extension trial (GS-US-
312-0117) to allow an adequate evaluation of efficacy and safety in this trial. The 
randomization and allocation processes will be established and performed through an IWRS; 
the intent is to maximize the integrity and security of the subject disposition and to ensure 
appropriate access and convenience-of-use by the investigational sites. 

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Double blinding is included to provide protection against biased interpretations of efficacy 
and safety data by subjects, caregivers, investigators, Gilead Sciences personnel, or others 
involved in study conduct.  
Selection of the GS-1101 treatment regimen (including starting dose level, dose-
modifications and supportive care, schedule, duration, and conditions of administration) for 
this study program has been based primarily on safety, exposure, and activity profiles from 
previous Phase 1 clinical studies involving healthy volunteers, patients with allergic rhinitis, 
and patients with refractory/relapsed lymphoid malignancies [Webb 2010, Coutre 2011, 
Kahl 2011]. The following information was considered in selecting the study drug dosing 
regimen for the primary study and this companion extension study: 
• GS-1101 was symptomatically well tolerated in patients with lymphoid malignancies 
receiving dose levels of 50 mg/dose BID through 350 mg/dose BID (the highest dose 
level tested). No specific MTD was apparent over the dose range tested. However, 
monitorable, reversible transaminase elevations were observed in some patients and may 
have been more frequent at higher dose levels (~10% rate among patients with CLL 
receiving starting doses of ≥150 mg/dose). Thus, while doses through 350 mg/dose BID 
are tolerable, the starting dose of 150 mg/dose BID appears to appropriately balance 
safety with efficacy in GS-1101-naïve subjects. The starting dose of 300 mg/dose BID in 
this study also appears appropriate for evaluation; it is lower than the dose level of 
350 mg/dose BID that has been tolerable in prior studies and is likely to be suitable in 
subjects who have already been tolerating GS-1101 therapy at ≥100 mg/dose BID.  
• Upon disease progression, permitting escalation from 150 mg/dose BID to 
300 mg/dose BID among subjects allocated to Arm A offers a systematic evaluation of 
higher doses in subjects who are tolerating GS-1101 treatment and might benefit from 
increased PI3Kδ inhibition. The pharmacological basis for considering such an 
intervention is based on the concept that some individuals might have 
lower-than-expected plasma exposures or dose-dependent resistance to the compound at 
150 mg/dose BID and might benefit from a higher dose. The intent is to determine if the 
higher dose can reestablish disease control or whether absolute resistance to PI3Kδ 
inhibition has been acquired. The safety data obtained in these subjects would add to the 
overall safety database. 
• In an allergic rhinitis study, GS-1101 induced statistically significant improvements in 
clinical and pharmacodynamic endpoints when administered at 100 mg/dose BID over 
7 days. These data support the pharmacological relevance of GS-1101-mediated PI3Kδ 
inhibition when administered at the dose-levels to be used in this study. 
• A positive correlation was noted between GS-1101 dose and measures of tumor control 
and chemokine normalization in patients with B-cell malignancies. The majority of 
patients appear to have tumor responses and protracted PFS when receiving starting doses 
of ≥100 mg/dose BID. Thus, treatment with a GS-1101 at a starting dose of 150 mg/dose 
BID appears to offer most patients the potential to benefit from therapy and the dose level 
of 300 mg/dose BID may provide additional benefit in patients with disease resistance as 
systematically evaluated in this trial.  

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• Based on evaluations of GS-1101 steady-state plasma Cmax, AUC, and Ctrough values over 
a range of doses, administration of starting doses of GS-1101 of ≥150 mg/dose BID 
appears appropriate to ensure adequate exposure in the majority of patients.  
• In Phase 1 studies, the mean plasma t1/2 of GS-1101 was ~6.5 to 9.8 hours across all dose 
levels and there was no substantive plasma accumulation over 7 or 28 days. The 
collective data support a study drug administration schedule of BID administration to 
maintain GS-1101 plasma Ctrough values without inducing excessively high plasma Cmax 
values.  
• The changes in exposure observed when administering GS-1101 after a high-fat, 
high-calorie meal are modest (~40% increase in mean AUC with no change in mean 
Cmax). Thus, GS-1101 can be administered with or without food.  
• Clinical evidence suggests that potent inhibitors of CYP3A4 may induce a modest 
increase in GS-1101 plasma concentrations in humans. However, given the fact that 
GS-1101 is well tolerated and appears to be a relatively weak substrate for CYP3A4, 
administration of drugs that inhibit CYP3A4 together with GS-1101 does not appear to 
be contraindicated and special precautionary measures do not appear necessary.  
• The GS-1101 dose modification provisions described in the protocol are designed to 
balance a primary concern for subject safety with the potential for observing 
pharmacological and antitumor activity in circumstances under which a subject 
experiencing an adverse event may still be able to continue on therapy at a lower 
GS-1101 dose level. The enhanced monitoring to be performed and the actions to be 
taken in response to toxicity are based on experience with interruption, dose-
modification, rechallenge, and re-escalation already piloted in GS-1101 Phase 1 trials. In 
addition, GS-1101 antitumor activity has been observed in the Phase 1 studies across all 
dose levels tested, including doses in the range of the modified dose levels planned for 
this protocol. Thus, use of the lower dose level to accommodate individual subject 
tolerability in this protocol is justified because subjects receiving such a GS-1101 dose 
level still have the potential for benefit. 
• In both the primary and extension studies, study treatment will be continued for each 
subject until the occurrence of disease progression. Such a strategy is considered 
appropriate under the assumption that persistent interference with PI3Kδ signaling is 
likely to extend treatment effect. In addition, this design permits collection of further 
single-agent safety information and thus is likely to enhance understanding of the overall 
safety profile of GS-1101.  
• Appropriate disincentives for unblinding of study drug are included in the trial (see 
Section 5.5). Investigational personnel will not have access to information at the site that 
would permit unblinding and must obtain the individual subject treatment assignment 
code only through the treatment allocation system. Clinic staff will be made aware that 
such unblinding may preclude a subject from continuing with study drug administration. 
Unblinding will also involve discussion between the investigator and the Gilead Sciences 
medical monitor; this provision is not intended to prevent an investigator from 
proceeding with unblinding, but to ensure that appropriate consultation is obtained, that 

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the investigator is aware of the consequences of the unblinding for the subject’s 
continued participation in the study, and that appropriate permission is granted to the 
treatment allocation system to release the treatment assignment only for that subject. 

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

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6.2. 
Explanation of Study Visits 
The specific study procedures to be conducted for each subject enrolled in the study are 
presented in tabular form in Appendix 7 and are described in the sections that follow. 
Additional information on the study procedures is provided in the study manual. 
For visits at which HRQL and healthy utility data are obtained, it is important that the subject 
be administered the FACT-Leu and the EQ-5D before any other procedures are performed 
and before any study-related information is communicated to the subject; this is necessary to 
avoid biasing the PRO responses provided by the subject. Once the subject has completed the 
FACT-Leu and the EQ-5D assessments, the remaining procedures may be performed. 
At visits involving GS-1101 administration and pharmacokinetic sampling in the clinic, care 
should be taken to perform procedures with the appropriate timing relative to GS-1101 
administration. The actual sample collection times of pharmacokinetic blood specimens 
should be recorded. If a heparinized venous catheter is placed for sample collection in order 
to avoid repeated needle sticks, at least 2 mL of blood should be removed and discarded prior 
to each sample collection in order to avoid heparin contamination of the sample. 
At the visit designated as a laboratory-only visit (Visit 7), subjects will have laboratory 
assessments that may be performed at the investigational site or at an accredited local 
laboratory or clinic that is convenient for the subject/caregiver. If blood is collected at a local 
laboratory, samples are not to be analyzed at the local laboratory. For these visits, subjects 
and/or caregivers will be provided with central laboratory kits that will contain materials 
necessary for the collection and shipment of the laboratory samples by the local laboratory 
clinic to the central laboratory. 
In addition to clinical assessments of tumor status, CT or MRI imaging of the neck, chest, 
abdomen, and pelvis will be performed as a component of tumor assessments during the 
study based on the rationale provided in Section 3.2.1; the same method of assessment (CT 
or MRI) and the same technique should be used to characterize each identified and reported 
lesion at baseline and while on study. 
6.2.1. 
Visit 1 and Screening Period (Clinic Visit) 
The initial screening visit is designated as Visit 1. At Visit 1, the investigator must inform 
each prospective study participant of the nature of the study, explain the potential risks, and 
obtain written informed consent from the study candidate and/or legal guardian prior to 
performing any study-related screening procedures. Once the informed consent document has 
been signed, the subject may undergo the screening procedures. 
In order to optimize scheduling convenience for the subject and for the investigational staff, 
study procedures performed as part of Study GS-US-312-0116 need not be repeated and can 
be used as screening procedures for Study GS-US-312-0117 if performed within 4 weeks 
prior to initiation of study drug therapy on Study GS-US-312-0117. In addition, screening 
procedures may be performed over as many days as necessary provided that screening is 
completed within 4 weeks prior to initiation of study drug therapy on Study GS-US-312-
0117.  
The tests and evaluations outline in Table 6-1 will be performed at Visit 1 or during the 
screening period prior to initiation of study treatment. 

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Table 6-1. 
Procedures and Assessments at Visit 1 (During Screening Period) 
Assessment  
or Procedure 
Explanationa 
Informed consent 
To be obtained before any screening procedures are initiated 
IWRS access 
Access IWRS to document that subject is in screening and provide  the subject number from 
Study GS-US-312-0116 
CIRS assessment 
Recording of current comorbid conditions using the CIRS scoring instrument (see Appendix 6) 
Concomitant 
medications 
Recording of ongoing concomitant medication use 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including height, weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly 
Serum β-HCG 
Women of childbearing potential only 
CLL peripheral blood 
evaluation 
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 12 trisomy; DNA 
mutational analysis for p53, IgHV (including IgHV3-21), and other genes of interest in CLL (eg, 
Notch); flow cytometry for CD5, CD10, CD11c, CD19, CD20, CD23, CD38, CD45, kappa and 
lambda light chains, and ZAP-70; cytology for karyotyping; bone marrow aspirate may be used if 
peripheral blood lymphocyte count is too low 
CLL serology 
Serum β2 microglobulin 
 
 
 
 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Radiology assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis, to be scheduled prior to initiation of study 
treatment at Visit 2; the same method of assessment (CT, MRI) and the same technique should be 
used to characterize each identified and reported lesion at baseline and while on study 
Bone marrow biopsy 
and aspirate 
To be performed at investigator discretion to determine extent of CLL involvement and bone 
marrow cellularity. 
a 
Study procedures performed as part of Study GS-US-312-0116 need not be repeated and can be used as screening 
procedures for Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug therapy on 
Study GS-US-312-0117. 
Abbreviations: β-HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, CIRS=cumulative illness rating scale, CLL=chronic lymphocytic leukemia, CT=computed 
tomography, DNA=deoxyribonucleic acid, FISH= fluorescence in-situ hybridization, GGT=gamma--glutamyltransferase, 
Ig=immunoglobulin, IgHV=immunoglobulin heavy chain variable region, IWRS=interactive web response system, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, RNA=ribonucleic acid, ZAP-70=zeta-associated 
protein 70 
PPD

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6.2.2. 
Visit 2 (Day 1) (Clinic Visit) 
Subjects will be assessed to determine if they still meet eligibility criteria and can initiate 
study treatment. The procedures outlined in Table 6-2 will be performed at Visit 2 (Day 1). 
Table 6-2. 
Procedures and Assessments at Visit 2 (Day 1) 
Assessment or 
Procedure 
Explanation 
Pre-Dose Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the 
subject 
Adverse events 
Recording of adverse events occurring since the initiation of the screening period 
Concomitant 
medications 
Recording of concomitant medication use since the initiation of the screening period 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
β-HCG 
For women of child-bearing potential only; serum β-HCG or urine dipstick pregnancy test must 
be negative prior to initial study treatment 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
GS-1101 
pharmacokinetics 
Pre-dose collection of plasma sample for GS-1101 pharmacokinetics (with recording of the date 
and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug blister card number 
Study Therapy Administration 
Study drug 
administration 
First dose of study drug to be administered to the subject (with recording of the date and actual 
clock time of the study drug administration) 
Post-Therapy Procedures and Assessments 
GS-1101 
pharmacokinetics 
Post-dose collection of plasma sample for GS-1101 pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
study drug dosing at 
next full clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 3. 
Abbreviations: β-HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer 
Therapy-Leukemia, HRQL=health-related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web 
response system, LDH=lactate dehydrogenase, RNA=ribonucleic acid 

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6.2.3. 
Visit 3 (Day 15) (Clinic Visit) 
The procedures outlined in Table 6-3 will be performed at Visit 3 (Day 15 [±2 days]).  
Table 6-3. 
Procedures and Assessments at Visit 3 (Day 15) 
Assessment or 
Procedure 
Explanation 
Pre-Dose Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed 
and before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the 
subject 
Adverse events 
Recording of adverse events occurring since the initiation of the screening period 
Concomitant 
medications 
Recording of concomitant medication use since the initiation of the screening period 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
GS-1101 
pharmacokinetics 
Recording of the date and actual clock time of the last prior subject self-administration of study 
drug (should be the prior evening dose)Pre-dose collection of plasma sample for GS-1101 
pharmacokinetics (with recording of the date and actual clock time of the date and actual clock 
time of blood collection) 
IWRS access 
Access of IWRS to document subject visit 
Study Therapy Administration 
Study drug 
administration 
Study drug to be administered to the subject (with recording of the date and actual clock time of 
the study drug administration) 
Post-Therapy Procedures and Assessments 
GS-1101 
pharmacokinetics 
Post-dose collection of plasma sample for GS-1101 pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Instruction regarding 
study drug dosing at 
next full clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 4. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-Leukemia, HRQL=health-
related quality of life, GGT=gamma-glutamyltransferase, IWRS=interactive web response system, LDH=lactate 
dehydrogenase 

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6.2.4. 
Visit 4 (Day 29) (Clinic Visit) 
The procedures outlined in Table 6-4 will be performed at Visit 4 (Day 29 [±2 days]). 
Table 6-4. 
Procedures and Assessments at Visit 4 (Day 29) 
Assessment or 
Procedure 
Explanation 
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 3 
Concomitant 
medications 
Recording of concomitant medication used since Visit 3 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
GS-1101 
pharmacokinetics 
Pre-dose collection of plasma sample for GS-1101 pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug blister card number 
Study Therapy Administration and Dispensing 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
GS-1101 
pharmacokinetics 
Post-dose collection of plasma sample for GS-1101 pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
dosing at next full 
clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 5. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-
Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging 

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

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6.2.6. 
Visit 6 (Day 57) (Clinic and Radiology Visit) 
The procedures outlined in Table 6-6 will be performed at Visit 6 (Day 57 [±2 days]).  
Table 6-6. 
Procedures and Assessments at Visit 6 (Day 57) 
Assessment or 
Procedure 
Explanation 
Pre-Visit Tumor Assessment 
Radiology assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the same 
method of assessment (CT or MRI) should be used as was used at baseline and the assessment 
should be done even if study drug has been interrupted.  
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 5 
Concomitant 
medications 
Recording of concomitant medication used since Visit 5 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD5+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Bone marrow biopsy 
and aspirate 
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR. 
GS-1101 
pharmacokinetics 
Pre-dose collection of plasma sample for GS-1101 pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug bottle number 
Study Therapy Administration 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
GS-1101 
pharmacokinetics 
Post-dose collection of plasma sample for GS-1101 pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
dosing at next full 
clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 8. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment 
of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging 

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6.2.7. 
Visit 7 (Day 71) (Laboratory Visit) 
The procedures outlined in Table 6-7 will be performed at Visit 7 (Day 71 [±2 days]). 
Table 6-7. 
Procedures and Assessments at Visit 7 (Day 71) 
Assessment or 
Procedure 
Explanation 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including ALT, AST, ALP, GGT, total bilirubin, LDH 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
GGT=gamma-glutamyltransferase, LDH=lactate dehydrogenase 

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6.2.8. 
Visit 8 (Day 85) (Clinic Visit) 
The procedures outlined in Table 6-8 will be performed at Visit 8 (Day 85 [±2 days]). 
Table 6-8. 
Procedures and Assessments at Visit 8 (Day 85) 
Assessment or 
Procedure 
Explanation 
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 6 
Concomitant 
medications 
Recording of concomitant medication used since Visit 6 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
GS-1101 
pharmacokinetics 
Pre-dose collection of plasma sample for GS-1101 pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug blister card number 
Study Therapy Administration and Dispensing 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
GS-1101 
pharmacokinetics 
Post-dose collection of plasma sample for GS-1101 pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
dosing at next full 
clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 9. 
Scheduling of Visit 9 
radiology assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 9; the same 
method of assessment (CT, MRI) should be used as was used at baseline. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-
Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging 

GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 79 
23 January 2012 
6.2.9. 
Visit 9 (Day 113) (Clinic and Radiology Visit) 
The procedures outlined in Table 6-9 will be performed at Visit 9 (Day 113 [±3 days]). 
Table 6-9. 
Procedures and Assessments at Visit 9 (Day 113) 
Assessment or 
Procedure 
Explanation 
Pre-Visit Tumor Assessment 
Radiology assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the same 
method of assessment (CT or MRI) should be used as was used at baseline and the assessment 
should be done even if study drug has been interrupted.  
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 8 
Concomitant 
medications 
Recording of concomitant medication used since Visit 8 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD5+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Bone marrow biopsy 
and aspirate 
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR. 
GS-1101 
pharmacokinetics 
Pre-dose collection of plasma sample for GS-1101 pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug blister card number 
Study Therapy Administration 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
GS-1101 
pharmacokinetics 
Post-dose collection of plasma sample for GS-1101 pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
dosing at next full 
clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 10. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment 
of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging 

GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 80 
23 January 2012 
6.2.10. 
Visit 10 (Day 141) (Clinic Visit) 
The procedures outlined in Table 6-10 will be performed at Visit 10 (Day 141 [±3 days])  
Table 6-10. 
Procedures and Assessments at Visit 10 (Day 141) 
Assessment or 
Procedure 
Explanation 
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 9 
Concomitant 
medications 
Recording of concomitant medication used since Visit 9 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
GS-1101 
pharmacokinetics 
Pre-dose collection of plasma sample for GS-1101 pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug  blister card number 
Study Therapy Administration 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
GS-1101 
pharmacokinetics 
Post-dose collection of plasma sample for GS-1101 pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 4-week supply of study drug to the subject with instructions for self-administration 
at home   
Instruction regarding 
dosing at next full 
clinic visit 
Instruction to the subject that the morning dose of study drug should not be taken on the day of 
Visit 11. 
Scheduling of 
Visit 11 radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 11; the same 
method of assessment (CT, MRI) should be used as was used at baseline. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-
Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging 

GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 81 
23 January 2012 
6.2.11. 
Visit 11 (Day 169) (Clinic and Radiology Visit) 
The procedures outlined in Table 6-11 will be performed at Visit 11 (Day 169 [±3 days]).  
Table 6-11. 
Procedures and Assessments at Visit 11 (Day 169) 
Assessment or 
Procedure 
Explanation 
Pre-Visit Tumor Assessment 
Radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the same 
method of assessment (CT or MRI) should be used as was used at baseline and the assessment 
should be done even if study drug has been interrupted.  
Pre-Therapy Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 10 
Concomitant 
medications 
Recording of concomitant medication used since Visit 10 
Study drug 
return/accounting 
Counting returned study drug. Recording of the date and actual clock time of the last prior subject 
self-administration of study drug (should be the prior evening dose) 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Bone marrow biopsy 
and aspirate 
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR. 
GS-1101 
pharmacokinetics 
Pre-dose collection of plasma sample for GS-1101 pharmacokinetics (with recording of the date 
and actual clock time of the date and actual clock time of blood collection) 
IWRS access 
Access of IWRS to obtain study drug blister card numbers 
Study Therapy Administration 
Study drug 
administration 
Dose of study drug to be administered to the subject (with recording of the date and actual clock 
time of the study drug administration) 
Post-Therapy Procedures and Assessments 
GS-1101 
pharmacokinetics 
Post-dose collection of plasma sample for GS-1101 pharmacokinetics at 1.5 hours after study drug 
administration (with recording of the date and actual clock time of blood collection) 
Study drug 
dispensing 
Dispensing of 12-week supply of study drug to the subject with instructions for self-administration 
at home   
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment 
of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging 

GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 82 
23 January 2012 
6.2.12. 
Visit 12 (Day 211) (Clinic Visit) 
The procedures outlined in Table 6-12 will be performed at Visit 12 (Day 211 [±3 days])  
Table 6-12. 
Procedures and Assessments at Visit 12 (Day 211) 
Assessment or 
Procedure 
Explanation 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 11 
Concomitant 
medications 
Recording of concomitant medication used since Visit 11 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
IWRS access 
Access of IWRS to document subject visit 
Study drug 
administration 
Subject to continue with study drug as prescribed. 
Scheduling of 
Visit 13 radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 13; the same 
method of assessment (CT, MRI) should be used as was used at baseline. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-
Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging 

GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 83 
23 January 2012 
6.2.13. 
Visit 13 (Day 253) (Clinic and Radiology Visit) 
The procedures outlined in Table 6-13 will be performed at Visit 13 (Day 253 [±3 days]).  
Table 6-13. 
Procedures and Assessments at Visit 13 (Day 253) 
Assessment or 
Procedure 
Explanation 
Pre-Visit Tumor Assessment 
Radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the same 
method of assessment (CT or MRI) should be used as was used at baseline and the assessment 
should be done even if study drug has been interrupted.  
During-Visit Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 10 
Concomitant 
medications 
Recording of concomitant medication used since Visit 10 
Study drug 
return/accounting 
Counting returned study drug.  
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Bone marrow biopsy 
and aspirate 
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR. 
IWRS access 
Access of IWRS to obtain study drug blister card numbers 
Study drug 
administration 
Subject to continue with study drug as prescribed. 
Study drug 
dispensing 
Dispensing of 12-week supply of study drug to the subject with instructions for self-administration 
at home   
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment 
of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging 

GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 84 
23 January 2012 
6.2.14. 
Visit 14 (Day 295) (Clinic Visit) 
The procedures outlined in Table 6-14 will be performed at Visit 14 (Day 295 [±3 days])  
Table 6-14. 
Procedures and Assessments at Visit 14 (Day 295) 
Assessment or 
Procedure 
Explanation 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are 
performed and before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any 
other procedures are performed and before any study-related information is 
communicated to the subject 
Adverse events  
Recording of adverse events occurring since Visit 10 
Concomitant 
medications 
Recording of concomitant medication used since Visit 10 
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical 
examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or 
splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, 
total protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, 
cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of 
absolute number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow 
cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
IWRS access 
Access of IWRS to document subject visit 
Study drug 
administration 
Subject to continue with study drug as prescribed. 
Scheduling of 
Visit 15 radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for Visit 15; the 
same method of assessment (CT, MRI) should be used as was used at baseline. 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment of Cancer Therapy-
Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, LDH=lactate 
dehydrogenase, MRI=magnetic resonance imaging 

GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 85 
23 January 2012 
6.2.15. 
Visit 15 and Subsequent Visits (Day 337 and Every 12 Weeks) (Clinic and 
Radiology Visits) 
The procedures outlined in Table 6-15 will be performed at Visit 15 (Day 337 [±3 days]) and 
every 12 weeks thereafter [±7 Days]). 
Table 6-15. 
Procedures and Assessments at Visit 15 and Subsequent Visits 
(Day 337 and Every 12 Weeks) 
Assessment or 
Procedure 
Explanation 
Pre-Visit Tumor Assessment 
Radiology 
assessmenta 
CT or MRI imaging of neck, chest, abdomen, and pelvis within 1 week prior to the visit; the same 
method of assessment (CT or MRI) should be used as was used at baseline and the assessment 
should be done even if study drug has been interrupted.  
During-Visit Procedures and Assessments 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed and 
before any study-related information is communicated to the subject 
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed and before any study-related information is communicated to the subject 
Adverse events  
Recording of adverse events occurring since prior visit 
Concomitant 
medications 
Recording of concomitant medication used since prior visit 
Study drug 
return/accounting 
Counting returned study drug.  
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total 
protein, albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
Bone marrow biopsy 
and aspirate 
To be performed post-baseline to confirm response category in subjects with potential CR by 
radiological assessments. If the subject does not otherwise meet criteria for CR, it is not necessary 
to obtain a follow-up bone marrow biopsy/aspirate to establish CR. 
IWRS access 
Access of IWRS to obtain study drug blister card numbers 
Study drug 
administration 
Subject to continue with study drug as prescribed. 
-Study drug 
dispensing 
Dispensing of 12-week supply of study drug to the subject with instructions for self-administration 
at home   
Scheduling of next 
visit radiology 
assessment 
CT or MRI imaging of neck, chest, abdomen, and pelvis to be scheduled for next clinic visit (every 
12 weeks); the same method of assessment (CT, MRI) should be used as was used at baseline. 
a 
For follow-up visits after Week 96, CT or MRI is only required at the end-of-treatment visit (see Table 6-16). 
Abbreviations: ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CR=complete response, CT=computed tomography, EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assessment 
of Cancer Therapy-Leukemia, GGT=gamma-glutamyltransferase, HRQL=health-related quality of life, Ig=immunoglobulin, 
LDH=lactate dehydrogenase, MRI=magnetic resonance imaging 

GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 86 
23 January 2012 
6.2.16. 
End-of-Treatment Visit (Clinic Visit) 
At the time of discontinuation from the study, the subject should have the procedures and 
assessments performed as documented in Table 6-16. An end-of-study CT/MRI tumor 
assessment should be performed unless the subject already has radiographic confirmation of 
definitive disease progression ≤4 weeks prior to study drug discontinuation.  
Table 6-16. 
Procedures and Assessments at End-of-Treatment Visit 
Assessment or 
Procedure 
Explanation 
Radiology 
assessmenta 
CT or MRI imaging of neck, chest, abdomen, and pelvis; the same method of assessment (CT or 
MRI) should be used as was used at baseline 
FACT-Leu 
HRQL instrument (Appendix 2) to be administered before any other procedures are performed  
EQ-5D 
Health utility instrument (Appendix 4) to be administered after FACT-Leu but before any other 
procedures are performed 
Adverse events  
Recording of adverse events occurring since prior visit; if a clinically significant adverse event or 
abnormal result is observed that is not resolved by the end-of treatment visit, repeat evaluations 
should be performed to document resolution or stabilization of the abnormality 
Concomitant 
medications 
Recording of concomitant medication used since prior visit 
Study drug 
return/accounting 
Counting returned study drug.  
Performance status 
Using Karnofsky performance status criteria (see Appendix 3) 
Oxygen saturation 
To be assessed by pulse oximetry while subject is breathing room air 
Physical 
examination 
Including weight, evidence of palpable lymphadenopathy, hepatomegaly, and/or splenomegaly 
Serum β-HCG 
Women of childbearing potential only 
CLL peripheral 
blood evaluation 
Including FISH for chromosome 11q deletion, 13q deletion, 17p deletion and 12 trisomy; DNA 
mutational analysis for p53, IgHV (including IgHV3-21), and other genes of interest in CLL (eg, 
Notch); flow cytometry for CD5, CD10, CD11c, CD19, CD20, CD23, CD38, CD45, kappa and 
lambda light chains, and ZAP-70; cytology for karyotyping; bone marrow aspirate may be used if 
peripheral blood lymphocyte count is too low 
CLL serology 
Serum β2 microglobulin 
 
 
 
Hematology 
Including hematocrit, hemoglobin, erythrocyte count; absolute counts of leukocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, platelet count 
Serum chemistry 
Including sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphorus, total protein, 
albumin, ALT, AST, ALP, GGT, total bilirubin, LDH, uric acid, cholesterol, triglycerides 
Circulating cells  
Including cells for analysis of PI3K/AKT/mTOR pathway activation and quantitation of absolute 
number of CD4+, CD8+, CD16/CD56+, CD19+, and CD+20 cells by flow cytometry 
Biomarkers 
Collection of plasma and serum for evaluation of circulating chemokines and cytokines 
Serum Igs 
Including quantitative levels of IgA, IgE, IgG, and IgM 
IWRS 
Access IWRS to document that subject has permanently discontinued study therapy and to indicate 
whether subject agrees to continue to undergo long-term follow-up 
a 
An end-of-treatment CT/MRI tumor assessment should be performed unless the subject already has radiographic 
confirmation of definitive disease progression ≤4 weeks prior to study drug discontinuation. 
Abbreviations: β-HCG=beta human chorionic gonadotropin, ALP=alkaline phosphatase, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase, CLL=chronic lymphocytic leukemia, CT=computed tomography, FISH= fluorescence in-
situ hybridization, GGT=gamma-glutamyltransferase, IgHV=immunoglobulin heavy-chain variable-region, 
IWRS=interactive web response system, LDH=lactate dehydrogenase, MRI=magnetic resonance imaging, 
RNA=ribonucleic acid, ZAP-70=zeta-associated protein 70 
PPD

GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 87 
23 January 2012 
6.2.17. 
Immediate Post-Treatment Safety Follow-up 
After the last dose of study treatment subjects should be followed for any drug-related 
adverse events and/or ongoing serious adverse events until those events have resolved or 
become stable, whichever occurs later. Follow-up may be obtained in person or by telephone 
contact. 
6.2.18. 
Long-Term Follow-Up 
Long-term, post-treatment follow-up will be requested of all subjects who withdraw from 
study therapy for any reason. 
The long-term post-treatment follow-up will be conducted (as measured from the last dose of 
study drug) at ~6-month intervals during Year 1 and Year 2, and at ~12-month intervals 
during Years 3, 4, and 5. Data on post-study therapies for CLL, on the occurrence of new 
non-CLL-related health problems (eg, myelodysplasia, Richter’s transformation, chronic 
hepatic abnormalities, etc), and on survival will be collected from all subjects who receive 
≥1 dose of study drug. 
Long-term follow-up information will be gathered during a routine clinic visit or other 
contact with the subject, or via telephone. These data will be collected in the source 
documents (eg, subject medical record) and transcribed into a specific electronic eCRF. Any 
unsuccessful efforts to contact the subject (eg, dates of unanswered phone calls, return of 
certified letter sent to subject’s home, etc) will be documented. 
6.3. 
Blood Collection 
Computations of blood drawing requirements for this study are shown in Table 6-17. The 
maximum amount of blood to be drawn at a visit is 105 mL and the total amount of blood to 
be drawn over the initial 52-week study period (including the 4-week screening period and 
through Week 48 of the study including a possible end-of-therapy visit) is ~551 mL. For a 
40-kg person (the smallest participant expected to enroll in the study), this equates to 
maximum blood volume per body weight per visit of ~2.8 mL/kg and a total blood volume 
per body weight per average 6-week period of ~1.6 mL/kg. These quantities of blood are 
within accepted limits of 3.0 mL/kg of body weight for a single blood draw and 7.0 mL/kg of 
body weight for a 6-week period [National Institutes of Health 2003]. 

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Table 6-17. 
Blood Drawin2 Requirements Throu2h Visit 15 (Week 48) 
Final 
Original 
Sample 
Tube 
Blood Pel' 
Tubes (n) 
Blood Volume (mL) 
Test 
Tube 
Maximum 
Total in 
Maximum 
Type 
Type 
(mL) 
Pel' Visit 
Study• 
Pet· Visit 
CLL peripheral blood 
Plasma 
Sodimn 
50 
I 
2 
50 
evaluation 
heparin 
Genotyping 
DNA 
Cells 
K2-EDTA 
12 
1 
2 
12 
and 
RNA 
Pax gene 
expression 
Protein 
Cells 
KrEDTA 
8 
1 
2 
8 
analysis 
Coagulation 
Plasma 
Citrate 
4 
1 
1 
4 
Hematology 
Plasma. 
K2-EDTA 
3 
1 
16 
3 
Serum chemistly 
(including 13-HCG and 
Semm 
Clot 
5 
1 
16 
5 
CLL serology) 
Circulating cells for 
PI3K/ AKT /mTOR 
pathway activation 
Cells 
KrEDTA 
4 
1 
13 
4 
and 
immunophenotyping 
Biomarkers 
Plasma 
KrEDTA 
5 
1 
13 
5 
Sermn 
Clot 
5 
1 
13 
5 
Senun Igs 
Sermn 
Clot 
5 
1 
13 
5 
GS-1101 
Plasma 
KrEDTA 
2 
2 
8 
4 
pharmacokinetics 
Total 
105 
0 
0 
0 
a 
Computed for uuttal 52-week penod (constdermg 4 weeks for screenmg and 48 weeks on study) 
Abbreviations: 
human chorionic gonadotropin, AKT =AKT (a serine/threonine protein kinase), 
CLL=chronic lymphocytic leukemia, DNA =deoxyribonucleic acid, Ig=inununoglobulin, KrEDTA=potassituu-
ethylenediaminetetraacetic acid, mTOR=manunalian target of rapamycin, PI3K=phosphatidylinositol3-kinase, 
RNA=ribonucleic acid 
Total in 
Study• 
100 
24 
16 
4 
48 
80 
52 
65 
65 
65 
32 
551 
Specific details regarding blood sample collection and processing requirements will be 
provided separately in the study manual. 
6.4. 
Study Procedure Rationale 
The planned study assessments and timing have been selected as appropriate for screening of 
subjects, for detennination of GS-1 1 0 1-related or disease-related toxicities, for dose 
modification during the study, for characterization of dmg exposure and desired 
phmmacological effects, and for evaluation of dm g activity. The scheduling of testing is 
designed to collect a complete safety and phatmacology data set while maintaining subject 
tolerance of study procedures. The planned schedule of tumor assessments is consistent with 
expected rate of changes and appropriately balances precise measurement of tumor control 
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with the expense and subject inconvenience associated with clinical and radiological 
procedures. For discussion of the rationale for endpoint selection, see Section 3.2. 

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7. 
EFFICACY ASSESSMENTS 
7.1. 
Tumor Status Assessments 
The determination of CLL response and progression will be based on standardized IWCLL 
criteria [Hallek 2008], as specifically modified for this study considering the pharmacology 
of GS-1101 and the methods to be used in evaluation. Treatment decisions by the 
investigator in this study will be based on these assessments. Radiographic and clinical tumor 
assessments will be subject to independent confirmation by the IRC (see Section 10.4.3).  
7.2. 
Method of Assessment 
In addition to clinical examination, imaging-based evaluation will be used in this study in all 
subjects enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI 
scanning may be used at the investigator’s discretion in subjects for whom this may be a 
preferred alternative to CT scanning. Contrast-enhanced scanning is preferred, but iodine-
containing or gadolinium contrast material may be omitted in subjects for whom use of a 
contrast agent would be medically contraindicated. Chest x-ray, ultrasound, endoscopy, 
laparoscopy, PET, radionuclide scans, or tumor markers will not be considered for response 
assessment. 
For radiographic evaluations, the same method of assessment and the same technique (eg, 
scan type, scanner, subject position, dose of contrast, injection/scan interval) should be used 
to characterize each identified and reported lesion at baseline and during study treatment and 
follow-up. CT or MRI of the neck, chest, abdomen, and pelvis should be performed with cuts 
of ≤1.0 cm (ideally ≤0.5 cm) in slice thickness contiguously. 
7.3. 
Timing of Assessments 
All baseline clinical and CT/MRI tumor assessments should be performed within 4 weeks 
prior to the start of treatment. In order to optimize scheduling convenience for the subject and 
for the investigational staff, clinical and CT/MRI tumor assessments performed as part of 
Study GS-US-312-0116 need not be repeated and can be used as baseline tumor assessments 
for Study GS-US-312-0117 if performed within 4 weeks prior to initiation of study drug 
therapy on Study GS-US-312-0117. Clinical tumor assessments should be performed at each 
clinical visit. On-study CT/MRI tumor assessments should be performed at ~8- to 12-week 
intervals as dictated by the study protocol. For follow-up visits after Week 96, CT or MRI is 
only required at the end-of-treatment visit. An end-of-treatment CT/MRI tumor assessment 
should be performed unless the subject already has radiographic confirmation of disease 
progression ≤4 weeks prior to study drug discontinuation.  
7.4. 
Identification and Measurement of Tumor Lesions and 
Organomegaly 
7.4.1. 
Index Lesions 
At baseline, up to 6 lymph nodes should be selected as index lesions that will be used to 
quantitate the status of the disease during study treatment. Ideally, the index lesions should 
be located in disparate regions of the body. Only peripheral nodes need be selected as index 

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lesions. However, it is optimal if mediastinal and retroperitoneal areas of disease are assessed 
whenever these sites are involved. 
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable 
at baseline. A nodal lesion is considered abnormal and measurable if it has 2 perpendicular 
diameters that can be accurately measured in cross section and each of the perpendicular 
diameters measures ≥1.0 cm. Abnormal, measurable nodal lesions will be subcategorized as 
either large or small. Large nodal lesions have a longest diameter (LD) that is >1.5 cm and a 
longest perpendicular diameter (LPD) that is ≥1.0 cm. Small nodal lesions have an LD that is 
>1.0 cm and ≤1.5 cm and an LDP that is >1.0 cm. Index lesions measuring >1.5 cm in the 
LD, regardless of the measurement of the LPD, will be prioritized during baseline index 
lesion selection. 
Index lesions will be measured and recorded at baseline and at the stipulated intervals during 
treatment. The cross-sectional dimensions (the largest cross-sectional diameter, ie, the LD × 
LPD) will be recorded (in cm) for each index lesion. The product of the perpendicular 
diameters (PPD) (in cm2) will be calculated. The PPDs and the sum of the products (SPDs) 
(in cm2) for all index lesions will be calculated and recorded. The baseline and nadir PPDs 
for individual lesions and the baseline and nadir SPDs will be used as references by which 
tumor response and progression will be characterized during treatment.  
At follow-up time points, the PPDs for individual lesions and the SPD of all nodal index 
lesions will be considered. Because nodal index lesions that have one or both diameters 
>0 cm and <1.0 cm cannot be reliably measured, a default value of 1.0 cm will be assigned 
for each diameter that meets these criteria and the resulting PPD will be used in SPD 
calculations. Based on this convention, a CR may be achieved even if an SPD value is 
>0 cm2. 
New or enlarging nodal lesions that are still ≤1.0 cm by ≤1.0 cm will not be considered to 
represent recurrent or progressive disease. A new node that measures >1.5 cm in any 
diameter or a new node that measures >1.0 cm to ≤1.5 cm in the LD and measures >1.0 cm in 
the LPD will be considered progressive disease. 
In cases in which a large lymph node mass has split into multiple components, only those 
elements that are >1.0 cm in at least 1 diameter will be considered abnormal and used in 
calculating the SPD. Progression of the lesion can only be based on the SPD of abnormal 
sub-components. Lesion sub-components that are considered normal but measurable will 
have the true PPDs calculated, with the result used only for calculating an accurate nadir. 
Similarly, lesion sub-components that are visible but neither abnormal nor measurable will 
have the default PPD of 1.0 cm2 (1.0 cm × 1.0 cm), stored only for the purposes of 
calculating the nadir SPD value. 
7.4.2. 
Spleen and Liver 
Both the spleen and liver will be assessed by CT/MRI scan and by physical examination.  
By imaging, the spleen will be considered enlarged if it is >10 cm in LVD [Bezerra 2005], 
with the LVD being obtained by multiplying the number of sections on which the spleen is 
visualized by the thickness of the sections (eg, if the spleen is seen in 14 contiguous cross-
sectional images with 0.5-cm thickness, the LVD is recorded as 7 cm).  

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Physical examination of the spleen should comprise assessment of its vertical dimension 
below the left costal margin by palpation. By physical examination, the spleen will be 
considered enlarged if it is palpable below the left costal margin. If the spleen is not palpable 
below the left costal margin, it should be assigned a value of 0 cm for physical examination 
assessment.  
By imaging, the liver will be considered enlarged if it is >18 cm in LVD [Erturk 2006], with 
the LVD being obtained by multiplying the number of sections on which the liver is 
visualized by the thickness of the sections (eg, if the liver is seen in 34 contiguous cross-
sectional images with 0.5-cm thickness, the LVD is recorded as 17 cm).  
Physical examination of the liver should comprise assessment of its LVD at the right 
midclavicular line by percussion. The liver will be considered enlarged if it is >15 cm in 
LVD as assessed by percussion [Walker 1990]. 
The spleen and liver should be measured clinically and radiographically at baseline and at the 
stipulated intervals during treatment. The baseline and nadir values will be used as references 
by which tumor response and progression will be characterized during treatment. For 
subjects with splenomegaly at baseline or at the splenic LVD nadir, respective response and 
progression evaluations of the spleen will consider only changes relative to the enlargement 
of the spleen at baseline or nadir, not changes relative to the total splenic LVD. For subjects 
with hepatomegaly at baseline or at the liver LVD nadir, respective response and progression 
evaluations of the liver will consider only changes relative to the enlargement of the liver at 
baseline or nadir, not changes relative to the total hepatic LVD. 
7.4.3. 
Non-Index Lesions 
Any other measurable and abnormal nodal lesions not selected for quantitation as index 
lesions may be considered non-index lesions. In addition, non-measurable evidence of CLL 
such as nodal lesions with both diameters <1.0 cm, extra-nodal lesions, bone lesions, 
leptomeningeal disease, ascites, pleural or pericardial effusions, lymphangitis of the skin or 
lung, abdominal masses that are not confirmed and followed by imaging techniques, cystic 
lesions, previously irradiated lesions, lesions with artifacts, and disease documented by 
indirect evidence only (eg, by laboratory tests such as LDH) may be considered as non-index 
disease. 
The presence or absence of non-index disease should be recorded at baseline and at the 
stipulated intervals during treatment. If present at baseline, up to 6 non-index lesions should 
be recorded. The non-index disease at baseline will be used as a general reference to further 
characterize regression or progression of CLL during assessments of the objective tumor 
response during treatment. Measurements are not required and these lesions should be 
followed as “present” or “absent”. 
7.5. 
Definitions of Tumor Response and Progression  
Responses will be categorized as CR, PR, stable disease (SD), progressive disease (PD). In 
addition, a response category of not evaluable (NE) is provided for situations in which there 
is inadequate information to otherwise categorize response status. While enrollment is 
limited to subjects who have measurable disease, a response category of no disease (ND) is 

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included solely to account for the unexpected situation in which a subject is found to have no 
evidence of tumor either at baseline or on treatment. 
The date of response, date of progression, and best overall response will be determined. The 
best nodal, splenic, hepatic, and peripheral blood counts response will be characterized. The 
best overall response is the best response recorded from the start of treatment until disease 
progression (taking as a reference for disease progression the smallest measurements 
recorded at baseline or post-baseline). All relevant clinical and radiographic information 
required to make each tumor status assessment must be made available for source 
verification and for submission to the IRC (see Section 10.4.3). Where imaging data are 
available, these data will supersede physical examination data in determining tumor status. 
7.5.1. 
Complete Response 
To satisfy criteria for a CR, all of the following criteria must be met and must persist for 
≥8 weeks (minimum of 49 days to allow for CT/MRI scheduling): 
• No evidence of new disease 
• ALC in peripheral blood of <4 x 109/L 
• Regression of all index nodal masses to normal size (ie, ≤1.5 cm in the LD for nodes that 
were considered large at baseline and ≤1.0 cm in the LPD for nodes that were considered 
small at baseline) (see Section 7.4.1 for definitions of large and small nodes)   
• Normal spleen and liver size 
• Regression to normal of all nodal non-index disease and disappearance of all detectable 
non-nodal, non-index disease 
• Morphologically negative bone marrow defined as <30% of nucleated cells being 
lymphoid cells and no lymphoid nodules in a bone marrow sample that is normocellular 
for age 
• No known disease-related constitutional symptoms 
• Peripheral blood counts meeting all of the following criteria: 
o ANC ≥1.5 x 109/L without need for exogenous growth factors (eg, G-CSF) 
o Platelet count ≥100 x 109/L without need for exogenous growth factors 
o Hemoglobin ≥110 g/L (11.0 g/dL) without red blood cell transfusions or need for 
exogenous growth factors (eg, erythropoietin) 
Note: Subjects who fulfill all the criteria for a CR (including bone marrow criteria) but 
who have a persistent anemia, thrombocytopenia, or neutropenia or a hypocellular bone 
marrow that is related to prior or ongoing drug toxicity (and not to CLL) will be 
considered as a CR with incomplete marrow recovery (CRi).  
7.5.2. 
Partial Response 
To satisfy criteria for a PR, all of the following criteria must be met and must persist for 
≥8 weeks (minimum of 49 days to allow for CT/MRI scheduling): 

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• No evidence of new disease 
• A change in disease status meeting ≥2 of the following criteria:  
o Decrease in peripheral blood ALC by ≥50% from baseline 
o A decrease by ≥50% from the baseline in the SPD of the index nodal lesions 
o In a subject with enlargement of the spleen at baseline: normal spleen size or a 
decrease by ≥50% from baseline (minimum 2-cm decrease or reduction in LVD to 
normal) in the pretreatment enlargement of the splenic LVD 
o In a subject with enlargement of the liver at baseline: normal liver size or a decrease 
by ≥50% from baseline (minimum 2-cm decrease or reduction in LVD to normal) in 
the pretreatment enlargement of the liver LVD 
o A decrease by ≥50% from baseline in the CLL marrow infiltrate or in B-lymphoid 
nodules 
• No index, splenic, liver, or non-index disease with worsening that meets the criteria for 
definitive PD 
• Peripheral blood counts meeting ≥1 of the following criteria: 
o ANC ≥1.5 x 109/L or ≥50% increase over baseline without need for exogenous 
growth factors (eg, G-CSF) 
o Platelet count ≥100 x 109/L or ≥50% increase over baseline without need for 
exogenous growth factors 
o Hemoglobin ≥110 g/L (11.0 g/dL) or ≥50% increase over baseline without red blood 
cell transfusions or need for exogenous growth factors (eg, erythropoietin) 
7.5.3. 
Stable Disease 
To satisfy criteria for stable disease (SD), the following criteria must be met: 
• No evidence of new disease 
• There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD 
7.5.4. 
Definitive Progressive Disease 
The occurrence of any of the following events indicates definitive PD:  
• Evidence of any new disease: 
o A new node that measures >1.5 cm in any diameter 
o A new node that measures >1.0 cm to ≤1.5 cm in the LD and >1.0 cm in the LPD 
o New splenomegaly or recurrent splenomegaly (in a subject for whom spleen size had 
normalized) with a splenic LVD that now measures >2 cm larger than the cut-off 
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o New hepatomegaly or recurrent hepatomegaly (in a subject for whom liver size had 
normalized) with an hepatic LVD that now measures >2 cm larger than the cut-off 
value for the normal hepatic LVD 
o New non-index disease (eg, effusions, ascites, or other organ abnormalities related to 
CLL) 
Note: Isolated new effusions, ascites, or other organ abnormalities are not 
sufficient evidence alone of PD unless histologically confirmed. Thus, a declaration 
of PD should not be made if this is the only manifestation of apparently new 
disease. 
• Evidence of worsening of lymph nodes, spleen or liver, or non-index disease:  
o Increase by ≥50% from the nadir in the SPD of index lesions 
o Evidence of worsening of individual index lymph nodes or nodal masses:  
 Increase from the nadir by ≥50% in the PPD for any individual node if the node 
now has a LD of >1.5 cm and there is an absolute change from the nadir of 
≥0.5 cm in the LD or LPD and to ≥2.0 cm. 
 Increase from the nadir by ≥50% in the LD for any individual node if the node 
now has a LD of >1.5 cm and there is an absolute change from the nadir of 
≥0.5 cm in the LD 
 Increase from the nadir by ≥50% in the LPD for any individual node if the node 
now has a LPD of >1.5 cm and there is an absolute change from the nadir of 
≥0.5 cm in the LPD  
 If a lesion had been classified as a small lymph node, there is an additional 
requirement that the lesion has an LD of >1.0 cm and an LPD of >1.0 cm 
o In a subject with enlargement of the spleen at splenic nadir, there is an increase by 
≥50% from the nadir value (minimum 2-cm increase) in the nadir enlargement of the 
LVD and the splenic LVD now measures >2 cm larger than the cut-off value for the 
normal splenic LVD 
o In a subject with enlargement of the liver at hepatic nadir, there is an increase by 
≥50% from the nadir value (minimum 2-cm increase) in the nadir enlargement of the 
LVD with an hepatic LVD that now measures >2 cm larger than the cut-off value for 
the normal hepatic LVD 
o Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or other 
organ abnormalities related to CLL)  
o Transformation to a more aggressive histology (eg, Richter syndrome) as established 
by lymph node biopsy 
• Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to 
an autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an 
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o The current platelet count is <100 x 109/L and there has been a decrease by >50% 
from the highest on-study platelet count  
o The current hemoglobin is <110 g/L (11.0 g/dL) and there has been a decrease by 
>20 g/L (2 g/dL) from the highest on-study hemoglobin  
7.5.5. 
Non-Evaluable 
Subjects have a status of NE if any of the following conditions occur:  
• No data or the data are inadequate or missing such that a response determination cannot 
be made 
7.5.6. 
No Disease 
Subjects have a status of ND if all of the following conditions occur:  
• No index disease noted at baseline or on-treatment  
• No non-index disease noted at baseline or on-treatment. 
• No enlargement of the liver or spleen at baseline or on-treatment 
• No abnormalities of peripheral blood counts (elevated ALC or abnormally low ANC, 
platelet count, or hemoglobin) and no evidence of CLL in bone marrow (if available) at 
baseline or on treatment 
7.5.7. 
Lymphocytosis During Therapy 
GS-1101 can mobilize CLL cells from tissues into the peripheral blood. This characteristic 
pharmacological action can be prominent early in therapy but can persist over time and 
should not be confused with disease progression in subjects who have persistent control of 
other CLL-related signs and symptoms. In the absence of other objective evidence of 
disease progression, lymphocytosis alone will not be considered evidence of disease 
progression. Subjects with lymphocytosis should be continued on study therapy until the 
occurrence of definitive disease progression (ie, disease progression that is manifest by 
worsening CLL-related signs other than lymphocytosis alone), or the occurrence of another 
reason to discontinue study therapy as described in Section 5.8. In particular, worsening of 
constitutional symptoms in the absence of objective evidence of worsening CLL will not be 
considered definitive disease progression. In such subjects, both CLL-related and 
non-CLL-related causes for the constitutional symptoms should be considered. If disease 
progression is suspected, CT/MRI and peripheral blood counts should be obtained and bone 
marrow biopsy should be considered in order to provide objective evidence of CLL status. 
7.5.8. 
Documentation of Definitive CLL Progression 
Of importance, tumor size data collected from the primary study will be subjected to IRC 
review (see Section 10.4.3). Subjects must have confirmation by the sponsor working in 
collaboration with the IRC that the disease has progressed on the primary clinical trial 
(Study GS-US-312-0116) before being permitted to receive secondary GS-1101 therapy on 
this extension trial ( GS-US-312-0117). If there is uncertainty regarding whether there is 
definitive progression, the subject should continue study treatment and remain under close 
observation (eg, evaluated at 4-week intervals) pending confirmation of progression status. 
CT/MRI should be attempted in order to document definitive disease progression. If obtained 

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within the specified screening period for the extension study, this scan can serve as the 
baseline scan for the extension study. 

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8. 
SAFETY ASSESSMENTS 
8.1. 
Adverse Event Definitions 
8.1.1. 
Adverse Event 
An adverse event (adverse event) is any untoward medical occurrence in a clinical 
investigation subject administered a medicinal product; the event does not necessarily have a 
causal relationship with study drug administration or usage. An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. 
In this study, any of the following events will be considered an adverse event: 
• Any complication that occurs as a result of a protocol-mandated procedure (eg, 
venipuncture, biopsy) in the screening, on-treatment, or post-treatment periods. 
• Any pre-existing condition that increases in severity or changes in nature during or as a 
consequence of study drug administration. Worsening manifestations of the underlying 
cancer (eg, increase in pain, tumor flare reaction, tumor lysis syndrome) may be 
considered adverse events in this study. 
• Any injury or accident occurring during the screening, on-treatment, or post-treatment 
periods. If a medical condition is known to have caused the injury or accident (eg, a fall 
secondary to dizziness), the medical condition (dizziness) and the accident (fall) should 
be reported as 2 separate adverse events.  
• Any abnormality in physiological testing or a physical examination finding that requires 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test). 
• Any laboratory (eg, clinical chemistry, hematology, urinalysis) or investigational  
abnormality (eg, ECG, X-ray) independent of the underlying medical condition that 
requires clinical intervention, results in further investigation (beyond ordering a repeat 
[confirmatory] test), or leads to investigational medicinal product interruption or 
discontinuation unless it is associated with an already reported clinical event. If the 
laboratory abnormality is part of a syndrome, the syndrome or diagnosis (eg, anemia) not 
the laboratory result (eg, decreased hemoglobin) should be recorded.  
• A complication related to pregnancy or termination of a pregnancy (see Section 8.9 for 
additional information). 
None of the following events is considered an adverse event: 
• Lymphocytosis 
• Laboratory abnormalities not requiring clinical intervention or further investigation. Such 
abnormalities will be captured as part of overall laboratory monitoring. 
• A diagnostic, medical or surgical procedure (eg, surgery, endoscopy, tooth extraction, 
transfusion). However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an adverse event. For example, an acute 

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appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event and the resulting appendectomy should be recorded in the source 
documents.  
• A pre-existing disease or condition or laboratory abnormality present or detected before 
the initial screening visit and that does not worsen. 
• An intervention not associated with an untoward medical occurrence (eg, hospitalization 
for elective surgery or for social and/or convenience reasons). 
8.1.2. 
Serious Adverse Event 
A serious adverse event is defined is an untoward medical occurrence that results in any of 
the following outcomes: 
• Death (ie, all deaths occurring between signing of the consent form to within 30 days 
after last study drug administration), including deaths due to disease progression. Deaths 
that occur as a result of an adverse event that started during the study period should be 
reported. The reported adverse event should be the event that caused the death. Death is 
the outcome of this serious adverse event. 
• Life-threatening situation (ie, with an immediate risk of death from the event as it 
occurred but not including an event that, had it occurred in a more serious form, might 
have caused death). 
• In-patient hospitalization or prolongation of existing hospitalization. Of note, an 
untoward medical occurrence that occurs during hospitalization is an adverse event but a 
complication that prolongs hospitalization is a serious adverse event. In-patient 
hospitalization comprises formal admission to a hospital for medical reasons, for any 
length of time, whether or not hospitalization extends overnight. However, hospital 
admissions for administration of the study drug, procedures required by the study 
protocol, or tumor-related diagnostic procedures are not considered serious.  
• Persistent or significant disability/incapacity. 
• Congenital anomaly/birth defect in the offspring of a subject who received the 
investigational medicinal product. 
• Other medically significant event. Such events may not be immediately life-threatening 
or result in death or hospitalization, but based upon appropriate medical and scientific 
judgment, may jeopardize the subject or may require medical or surgical intervention to 
prevent one of the outcomes listed above. Examples of such events might include: 
o Allergic bronchospasm requiring intensive treatment in an emergency room or at 
home 
o New cancers or blood dyscrasias 
o Convulsions that do not result in hospitalization 
o Development of drug dependency or drug abuse 

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8.1.3. 
Unexpected Adverse Event 
An unexpected adverse event is defined as an event that has a nature or severity, or 
specificity that is not consistent with the applicable investigator brochure or that is 
symptomatically and pathophysiologically related to a known toxicity but differs because of 
greater severity or specificity. For example, under this definition, hepatic necrosis would be 
unexpected (by virtue of greater severity) if the investigator brochure only referred to 
elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure 
only listed cerebral vascular accidents. “Unexpected,” as used in this definition, refers to an 
adverse drug experience that has not been previously observed and reported rather than an 
experience that has not been anticipated based on the pharmacological properties of the study 
drug.  
8.2. 
Eliciting Adverse Event Information 
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study subject. In addition, each study subject will be 
questioned about adverse events at each scheduled clinic visit or during each telephone 
contact with the subject following initiation of study treatment. The type of question asked 
should be open-ended, eg, "Have you had any new health problems?” or a similar type of 
query.  
8.3. 
Recording Adverse Events 
All adverse events will be assessed by the investigator or qualified designee and recorded in 
the eCRFs. The investigator should attempt to establish a diagnosis of the event on the basis 
of signs, symptoms and/or other clinical information. In such cases, the diagnosis should be 
documented as the adverse event and/or serious adverse event and not described as the 
individual signs or symptoms. The following information should be recorded: 
• Description of the adverse event using concise medical terminology 
• Description as to whether or not the adverse event is serious (see Section 8.1.2) 
• The start date (date of adverse event onset) 
• The stop date (date of adverse event resolution) 
• The severity of the adverse event (see Section 8.4) 
• A description of the potential relatedness of the adverse event to study drug or a study 
procedure (see Section 8.5)  
• The action taken due to the adverse event 
• The outcome of the adverse event 
8.4. 
Grading of the Severity of an Adverse Event 
The severity of adverse events will be graded using the CTCAE, Version 4.03 (provided in 
study manual and available at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-

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14_QuickReference_8.5x11.pdf). For each episode, the highest severity grade attained should 
be reported.  
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 
(fatal) to describe the maximum intensity of the adverse event. For purposes of consistency 
with the CTCAE, these intensity grades are defined in Table 8-1. 
Table 8-1. 
Grading of Adverse Event Severity 
Grade 
Adjective 
Description 
Grade 1 
Mild 
Sign or symptom is present, but it is easily tolerated, is not expected to have a 
clinically significant effect on the subject’s overall health and well-being, does not 
interfere with the subject’s usual function, and is not likely to require medical 
attention. 
Grade 2 
Moderate 
Sign or symptom causes interference with usual activity or affect clinical status, 
and may require medical intervention. 
Grade 3 
Severe 
Sign or symptom is incapacitating or significantly affects clinical status and likely 
requires medical intervention and/or close follow-up. 
Grade 4 
Life-threatening Sign or symptom results in a potential threat to life. 
Grade 5 
Fatal 
Sign or symptom results in death. 
 
The distinction between the seriousness and the severity of an adverse event should be noted. 
Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. 
For example, a headache may be severe in intensity, but would not be classified as serious 
unless it met one of the criteria for serious events listed in Section 8.1.2 above. 
8.5. 
Describing Adverse Event Relationship to Study Drug and Study 
Procedures 
The relationship of an adverse event to study drug should be assessed using clinical 
judgment, describing the event as either unrelated (no) or related (yes) consistent with the 
following definitions: 
• No: Evidence exists that the adverse event had an etiology other than the study drug. For 
serious adverse events, an alternative causality must be provided (eg, pre-existing 
condition, underlying disease, intercurrent illness, or concomitant medication). 
• Yes:  A temporal relationship exists between the adverse event onset and administration 
of the investigational medicinal product that cannot be readily explained by the subject’s 
clinical state or concomitant therapies. Furthermore, the adverse event appears with some 
degree of certainty to be related to the study drug based on the known therapeutic and 
pharmacologic actions or adverse event profile of the investigational medicinal product. 
In case of cessation or reduction of the dose, the adverse event abates or resolves. In case 
of interruption and rechallenge, the event reappears upon rechallenge. 
Of note, even in circumstances when the study drug is given intermittently or is interrupted 
temporarily before the onset of the adverse event, consideration should be given as to 
whether the study drug may have contributed to the event.  

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As noted in Section 5.5, unblinding should be avoided unless absolutely necessary for a 
subject’s well-being; breaking the blind should not be performed merely to obtain enhanced 
certainty regarding the relationship of an adverse event to study drug.  
The relationship to protocol-mandated study procedures (eg, procedures such as venipuncture 
or biopsy) should be assessed using the following considerations: 
• No: Evidence exists that the adverse event has an etiology other than the study procedure. 
• Yes: The adverse event occurred as a result of a protocol-mandated procedure.  
8.6. 
Adverse Event Reporting Period 
The start of the adverse event reporting for a study subject will coincide with signing of the 
informed consent for Study GS-US-312-0117. Any new adverse events occurring thereafter 
should not be reported within Study GS-US-312-0116, but instead should be reported within 
Study GS-US-312-0117. The end of the adverse-event-reporting period for Study GS-US-
312-0117 occurs 30 days after the completion of study treatment or when any ongoing drug-
related adverse events and/or serious adverse events have resolved or become stable. A 
subject withdrawn from the study because of an adverse event must be followed until the 
clinical outcome from the adverse event is determined. The investigator should use 
appropriate judgment in ordering additional tests as necessary to monitor the resolution of 
events ongoing at the completion of study treatment. Gilead Sciences may request that 
certain adverse events be followed longer. A longer reporting period applies in the case of 
pregnancy (see Section 8.9).  
8.7. 
Adverse Event Reporting Requirements 
8.7.1. 
Site Reporting Requirements 
Classification of an event as serious or nonserious (see Section 8.1.2) determines the 
reporting procedures to be followed by the site.  
Site reporting requirements for adverse events are summarized in Table 8-2, below. 

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

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Table 8-3. 
Contact Information for Reporting Serious Adverse Events 
Function 
Contact Information 
PPD Pharmacovigilance 
(US) 
Facsimile: 
  
PPD Pharmacovigilance 
(International) 
Facsimile: 
 
 
Name: 
 
 
Title: 
Associate Director, Clinical Research 
Office Telephone: 
 
Mobile Telephone: 
 
Facsimile: 
 
Gilead Sciences Medical 
Monitor 
E-mail: 
 
 
8.7.2. 
Gilead Sciences Reporting Requirements 
Gilead Sciences is required to expedite reports to regulatory authorities worldwide relating to 
serious adverse events including events related to study procedures; serious adverse drug 
reactions (SADRs); or suspected, unexpected, serious adverse reactions (SUSARs) consistent 
with relevant legislation or regulations, including the applicable US FDA Code of Federal 
Regulations (CFR), the European Commission Clinical Trials Directive (2001/20/EC, and 
revisions), and other country-specific legislation or regulations.  
Each serious adverse event report received from the investigator through PPD 
Pharmacovigilance will be evaluated by Gilead Sciences Drug Safety and Public Health 
(DSPH). Gilead Sciences DSPH will assess the seriousness of the event (see Section 8.1.2), 
the expectedness of the event (see Section 8.1.3), and the relationship to participation in the 
study (see Section 8.5). For regulatory reporting purposes, expectedness will be determined 
by Gilead Sciences using reference safety information specified in the investigator brochure 
and the event will be classified as related if either the investigator or Gilead Sciences 
determines that the event may be related to the study drug (see Section 8.5). 
Gilead Sciences or its designee will also provide all investigators and the DMC with a safety 
letter e-mail, fax, or overnight mail notifying them of a SUSAR. Investigators will be 
requested to provide written notification of the SUSAR to the IRB/IEC as soon as is 
practical, consistent with local regulatory requirements and local institutional policy. 
8.7.3. 
Reporting of Adverse Events Relating to the Primary Endpoint and 
Other Anticipated Medical Events in the Study Population 
To maintain the integrity of the study, serious adverse events that are associated with the 
following disease-related effects, and that are assessed as unrelated to study treatment, will 
not be reported in an expedited fashion by Gilead Sciences: 
• Progression of CLL 
• Death related to progression of CLL 
These events will be exempt from global expedited reporting requirements for the duration of 
the study because they define the primary efficacy endpoint for this study. They will be 
reported, as appropriate, in the final clinical study report and in any relevant aggregate safety 
reports.  
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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The safety information from this study will also be reviewed by an independent DMC on an 
ongoing basis. The DMC can have access to partially blinded or unblinded data in order to 
determine if it is safe to continue the study according to the protocol. 
8.8. 
Study Drug Overdose 
An overdose is ingestion or administration of an amount of study drug that exceeds the dose 
mandated by the protocol (see Sections 5.2.8), any misuse or abuse of study drug, or any 
misuse or abuse of any other product taken as a concomitant medication. An overdose is 
considered to have occurred if this definition is met, whether or not the administration is 
accidental or intentional, is suspected or confirmed, and whether or not the overdose is 
associated with an adverse experience. 
An overdose must be reported using the Gilead Sciences DSPH Clinical Overdose form. The 
completed DSPH Clinical Overdose form must be forwarded within 24 hours to DSPH or if 
applicable, to the CRO. Any questions or concerns should be discussed with the 
Gilead Sciences medical monitor. 
Along with information regarding the circumstances of the overdose, any clinical sequelae in 
association with the overdose should be reported as an adverse event or serious adverse event 
according to the reporting requirements for those events (see Section 8.6). Overdose will be 
considered a serious adverse event only if any of the seriousness criteria are met (see 
Section 8.1.2). Details of signs or symptoms, clinical management and outcome should be 
reported, if available. 
8.9. 
Pregnancy Requirements 
Each female subject should be instructed to discontinue further study therapy and inform the 
investigator immediately if she becomes pregnant at any time between the initiation of study 
drug until 30 days after the last ingestion of study drug. 
The investigator must report any pregnancy to PPD Pharmacovigilance within 24 hours of 
the time the investigator becomes aware of the pregnancy.  
The investigator should counsel the subject regarding the possible effects of prior 
investigational medicinal product exposure on the fetus and the need to inform the study site 
of the outcome of the pregnancy. 
All pregnancies of study subjects and female partners of male subjects that occur during the 
study should be reported using the Pregnancy Report eCRF. Monitoring of the pregnancy in 
both female study subjects and female partner of male study subjects should continue until 
the conclusion of the pregnancy. The outcome of the pregnancy should be reported on the 
Pregnancy Outcome Report eCRF within 5 days of the conclusion of the pregnancy. If the 
end of the pregnancy occurs after the study has been completed, the outcome should be 
reported directly to Gilead Sciences DSPH (facsimile: 
 e-mail: 
  
Neither the pregnancy itself nor an induced elective abortion to terminate the pregnancy 
without medical reasons is considered an adverse event; such occurrences should be reported 
on the appropriate pregnancy report forms. However, if the outcome of the pregnancy meets 
the criteria for classification as a serious adverse event (ie, spontaneous abortion, induced 
PPD
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abortion due to complications, stillbirth, neonatal death, or congenital anomaly [including 
that in an aborted fetus]), the investigator should follow the procedures for reporting serious 
adverse events, ie, report the event to PPD Pharmacovigilance by telephone and follow up by 
submission of the appropriate adverse event eCRFs (see Section 8.7.1). 
Additional information about pregnancy outcomes that are classified as serious adverse 
events includes:  
• Any spontaneous abortion, including miscarriage and missed abortion will be reported as 
an serious adverse event. 
• A induced therapeutic abortion to terminate any pregnancy due to complications or other 
medical reasons will be recorded as an serious adverse event. The underlying medical 
reason for this procedure should be recorded as the adverse event term. 
• All neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as serious adverse events. In addition, any infant death after 1 month that the 
investigator assesses as possibly related to the in utero exposure to the study drug should 
also be reported. 
• In the case of a live birth, the “normality” of the newborn can be assessed at time of birth 
(ie, there is no required minimum follow-up of a presumably normal infant before the 
Pregnancy Outcome Report eCRF can be completed). 
• The “normality” of an aborted fetus can be assessed by gross visual inspection unless 
there are pre-abortion laboratory findings suggestive of a congenital anomaly, in which 
case pathologic examination should be requested.  

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Analysis Conventions 
9.1.1. 
Analysis Sets 
9.1.1.1. 
Full Analysis Set 
The full-analysis set includes all subjects who receive ≥1 dose of any study treatment 
(high-dose GS-1101 or standard-dose GS-1101). In the full-analysis set, study drug 
assignment will be designated according to initial allocation in this study, regardless of 
whether subjects receive a different study therapy from that to which they were allocated.  
This analysis set will be used in the analyses of subject characteristics, PFS, ORR, TTF, and 
OS. Subjects in the full-analysis set who do not have sufficient baseline or on-study tumor 
status information to be adequately assessed for ORR will be counted as failures in the 
analysis of ORR.  
9.1.1.2. 
Responding Analysis Set 
The responding analysis set includes subjects in the full-analysis set who have measurable 
nodal disease, who can be evaluated for tumor response with both baseline and on-study 
tumor evaluations, and who achieve a CR or PR. The subjects will be grouped for analyses 
with treatment assignments designated according to the actual study drug received.  
This analysis set will be used in the analyses of TTR and DOR. 
9.1.1.3. 
Evaluable Analysis Sets 
The evaluable analysis sets include subjects in the full-analysis set who have the necessary 
baseline and on-study measurements to provide interpretable results for specific parameters 
of interest.  
These analysis sets will be used in the analyses of percent changes in lymph node area, 
lymph node response rate, splenomegaly response rate, hepatomegaly response rate, platelet 
response rate, hemoglobin response rate, neutrophil response rate, changes in HRQL, and 
changes in performance status.  
9.1.1.4. 
Safety Analysis Set 
A safety analysis set will include subjects in the full-analysis set grouped for analyses with 
treatment assignments designated according to the actual study drug received.  
This analysis set will be used in the analyses of safety variables as well as study treatment 
administration, post-study therapy, and health economic variables. 
9.1.1.5. 
Pharmacodynamic/Pharmacokinetic Analysis Sets 
The pharmacodynamic/pharmacokinetic analysis sets include subjects in the safety analysis 
set who have the necessary baseline and on-study measurements to provide interpretable 
results for specific parameters of interest.  
These analysis sets will be used in the analyses of AKT phosphorylation, 
chemokines/cytokines, and GS-1101 plasma concentrations. 

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9.1.2. 
Data Handling Conventions 
9.1.2.1. 
General Methods  
By-subject listings will be created for important variables from each eCRF module. 
Summary tables for continuous variables will contain the following statistics: N (number in 
population), n (number with data), mean, standard deviation, 95% confidence intervals (CIs) 
on the mean, median, minimum, and maximum. Summary tables for categorical variables 
will include: N, n, percentage, and 95% CIs on the percentage. Unless otherwise indicated, 
95% CIs for binary variables will be calculated using the binomial distribution (exact 
method) and will be 2-sided. Data will be described and summarized by relevant treatment 
arm, analysis set, and timepoint. As appropriate, changes from baseline to each subsequent 
timepoint will be described and summarized by treatment arm. Similarly, as appropriate, the 
best change from baseline during the study will also be described and summarized by 
treatment arm. Graphical techniques (eg, waterfall plots, Kaplan-Meier curves, line plots) 
may be used when such methods are appropriate and informative.  
Time-to-event analyses will be performed with reference to the date of first treatment on this 
clinical trial (Study GS-US-312-0117). Similarly, evaluations of on-therapy changes will 
reference the baseline values obtained prior to treatment in this study. The baseline value 
used in each analysis will be the last (most recent) pre-treatment value. Data from all sites 
will be pooled for all analyses. Analyses will be based upon the observed data unless 
methods for handling missing data are specified. If there is a significant degree of non-
normality, analyses may be performed on log-transformed data or nonparametric tests may 
be applied, as appropriate.  
Analyses will generally focus on evaluation of outcomes within each treatment arm; formal 
analyses comparing outcomes in Arm A to those in Arm B are not planned. Unless otherwise 
specified, all analyses will be 2-sided at the 0.05 level of significance.  
9.1.2.2. 
Calculation of Tumor Control and Patient Well-Being Variables 
Tumor control assessments will be based on standardized IWCLL criteria [Hallek 2008], as 
specifically modified for this study considering the pharmacology of GS-1101. The 
individual and composite endpoints of response and progression (considering changes in 
lymph node area, liver and spleen size, bone marrow, platelet counts, hemoglobin, neutrophil 
counts, and peripheral blood lymphocyte counts) will be determined. Tumor control will be 
documented at each assessment by response category (eg, CR, PR, SD, definitive PD, NE, 
ND) as defined for each response parameter, SPD value, percentage change in SPD values 
from baseline or nadir, date that response is first documented, date that response is 
confirmed, and date of definitive CLL progression.  
The date of definitive CLL progression will be the timepoint at which progression is first 
identified by CT/MRI, physical examination, or by worsening platelet count or hemoglobin. 
However, where imaging data are available, these data will supersede physical examination 
data in determining tumor status. For purposes of analysis, subjects who have only physical 
examination evidence of definitive disease progression that is not confirmed by CT/MRI will 
be considered to have progressed at the time of the physical examination finding. Because of 
the characteristic redistribution lymphocytosis that expected with PI3Kδ inhibition, 

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lymphocyte count will be ignored in the evaluation of progression. Calculations of 
progression considering lymphocyte count will be described but not analyzed.  
Changes in tumor status as provided by the investigator and changes in tumor status as 
adjudicated by the IRC (see Section 10.4.3) will be described and compared. The findings of 
the IRC will be considered primary for analyses of all tumor control endpoints. 
For time-to-event endpoints other than OS, only events occurring ≤30 days following the 
permanent discontinuation of study treatment will be considered as events; for subjects with 
events occurring >30 days following the permanent discontinuation of study treatment, the 
data will be censored. The following censoring conventions will be applied: 
• PFS: Data from surviving, non-progressing subjects will be censored at the earliest of the 
time of initiation of antitumor treatment other than the study treatment or the last time 
that lack of definitive CLL progression was objectively documented while on study 
treatment. 
• DOR: Data from surviving, non-progressing subjects will be censored at the earliest of 
the time of initiation of antitumor treatment other than the study treatment or the last time 
that lack of definitive CLL progression was objectively documented while on study 
treatment. 
• TTF: Data from surviving subjects who do not have treatment failure will be censored at 
the earliest of the time of initiation of antitumor treatment other than the study treatment 
or the last on-therapy time that lack of treatment failure was objectively documented. 
• OS: Data from surviving subjects will be censored at the last time that the subject was 
known to be alive.  
• Time to definitive increment in HRQL: Data from subjects who do not have definitive 
HRQL increment by the specified amount (10%, 20%, or 40%) will be censored at the 
earliest of the time of initiation of antitumor treatment other than the study treatment or 
the last HRQL assessment while on study treatment. 
• Time to definitive decrement in HRQL: Data from surviving subjects who do not have 
definitive HRQL decrement by the specified amount (10%, 20% or 40%) will be 
censored at the earliest of the time of initiation of antitumor treatment other than the 
study treatment or the last HRQL assessment while on study treatment. 
• Time to definitive performance status improvement: Data from subjects who do not have 
definitive performance status improvement will be censored at the earliest of the time of 
initiation of antitumor treatment other than the study treatment or the last performance 
status assessment while on study treatment.  
• Time to definitive performance status worsening: Data from surviving subjects who do 
not have definitive performance status worsening will be censored at the earliest of the 
time of initiation of antitumor treatment other than the study treatment or the last 
performance status assessment while on study treatment. 

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9.2. 
Analysis Plan 
9.2.1. 
Subject Disposition and Baseline Characteristics 
A listing of all full-analysis subjects will be generated to describe site, subject number, first 
screening date, first treatment date, allocated study drug assignment, actual study drug 
assignment, the longest duration of study drug treatment, and the reason for discontinuing 
study treatment. Available information on subjects who were screened or registered but not 
treated will be listed separately. A table will be created summarizing these categories in 
terms of number and percent for the full-analysis set. 
Subject baseline characteristics will be listed and summarized by treatment arm for the full-
analysis and responding analysis sets. As appropriate for the specific variable, subject 
baseline characteristics acquired in Study GS-US-312-0116 will be referenced in Study GS-
US-312-0117. Subject characteristics between Arm A and Arm B may be compared using the 
Wilcoxon rank-sum test for continuous variables and the Fisher’s exact test for categorical 
variables. Similarly, within each arm, subject characteristics between GS-US-312-0116 and 
GS-US-312-0117 may also be compared. 
9.2.2. 
Efficacy Analyses 
9.2.2.1. 
Time-to-Event Tumor Control and Survival Endpoints 
PFS, TTR, DOR, TTF, and OS will be described in the appropriate analysis set using 
Kaplan-Meier methods by treatment group. Medians, ranges, and corresponding 95% CIs  
will be presented.  
The Cox regression approach will be used to explore the influence of the primary study 
stratification factors and other baseline characteristics on PFS and OS. The stratification 
variables from the primary study and additional baseline subject characteristics may be 
included as covariates, focusing on those with expected prognostic significance. For the Cox 
regression modeling, a stepwise selection process will be applied to these variables to 
identify the final subset of relevant factors. Each prognostic factor will be preliminarily 
evaluated in the Cox regression model. Only the variables significant at the 0.20 level will be 
considered to build the multivariate model. A forward selection process will be applied to 
these variables to identify the final subset of relevant factors. .  
9.2.2.2. 
Categorical Endpoints  
ORR, CR and PR rates, nodal response rate, splenomegaly response rate, hepatomegaly 
response rate, platelet response rate, hemoglobin response rate, and neutrophil response rate 
will be described. In the analyses of ORR, subjects who do not have sufficient baseline or on-
study tumor assessment to characterize response will be counted as failures. For all analyses, 
the corresponding 95% CIs will be presented. 
The potential influence of subject baseline characteristics on response rates will be explored 
with multiple logistic regression modeling. 
9.2.2.3. 
Continuous Endpoints 
Changes in lymph node area and changes in performance status, PI3K/AKT/mTOR pathway 
activation, and plasma chemokines/cytokines will be assessed by treatment group. Both 

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changes from baseline to each subsequent timepoint and best overall on-study changes will 
be analyzed using appropriate methods (eg, analysis of covariance [ANCOVA] or paired 
t-tests). Means and standard errors will be presented. 
9.2.2.4. 
Health-Related Quality of Life and Performance Status 
The FACT-Leu questionnaire data will be scored, processed, and standardized (ranging from 
0-100) according to the user manual. Missing items in a subscale will be imputed consistent 
with the user manual instructions. Data collected from the FACT-Leu instrument will not be 
reconciled with adverse event or laboratory data or with EQ-D5 findings. 
Because a significant portion of the study subjects will have CLL disease progression during 
the course of the study and no HRQL or performance status data will be collected after 
disease progression, the duration of data collection for these variables will vary among the 
study subjects. Hence, at each HRQL or performance status assessment timepoint, changes 
from baseline in HRQL parameters or in performance status in the 2 treatment groups will be 
described by treatment group. considering both: 1) all subjects in the evaluable analysis sets 
for HRQL or performance status with the worst score assigned to those subjects who have 
progressed at the time of the analysis, and 2) all subjects in the evaluable analysis sets for 
HRQL or performance status who have not progressed at the time of the analysis. Subjects 
who are lost-to-follow-up without disease progression will be excluded, ie, missing data will 
not be imputed. In addition, Kaplan-Meier methods will be used for each of the FACT-Leu 
subscale scores, assessing time to changes in each variable by increments or decrements of 
10%, 20%, and 40% from baseline. Similarly Kaplan-Meier methods will be used assessing 
time to definitive performance status improvement or worsening from baseline. For these 
analyses, medians, ranges, and corresponding 95% CIs for each treatment group will be 
presented. In the analyses of FACT-Leu data, particular focus will be placed on changes in 
subject reports relating to CLL (focusing specifically on fever, chills, night sweats, 
lymphadenopathy, and fatigue).  
9.2.3. 
Exposure and Safety Analyses 
9.2.3.1. 
Treatment Administration and Study Drug Compliance 
Descriptive information will be provided by treatment arm regarding the number of doses of 
study therapy prescribed, the total number of doses taken, the percent of expected doses 
taken, the number of days of treatment, and the number and timing of prescribed dose 
reductions and interruptions. 
Study drug compliance will be described by treatment arm in terms of the proportion of study 
drug actually taken based on returned pill count relative to the amount that was dispensed 
(taking into account physician-prescribed reductions and interruptions). 
9.2.3.2. 
GS-1101 Plasma Concentrations 
Bioanalytical analyses will performed independently so that the study team and investigators 
will not have knowledge of data from individual subjects. GS-1101 plasma concentrations 
immediately pre-dose and at 1.5 hours after administration of the dose of study drug at each 
relevant clinic visit will be summarized by treatment and visit using descriptive statistics. 

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9.2.3.3. 
Prior, Concomitant, and Post-Treatment Medication Use 
Prior, concomitant, and post-treatment medications will be coded by means of the World 
Health Organization Drug Dictionary (WHODRUG) dictionary into 
Anatomical-Therapeutic-Chemical classification (ATC) codes. 
Descriptions of prior medication use will be focused on drugs and regimens used as 
treatments for CLL. Information regarding CLL therapy that was administered prior to 
Study GS-US-312-0116 will be referenced in reporting the results of Study GS-US-312-
0117. In addition, relevant treatment administration information collected during 
Study GS-US-312-0116 will be referenced in reporting the results of this study. As 
appropriate and if available, information on the sequencing, type, dose, schedule, timing, 
duration of use, and efficacy of prior regimens will be provided, focusing particularly on 
findings observed in Study GS-US-312-0116. 
The type and timing of use of concomitant medications will be listed and summarized by 
type and treatment arm. Information regarding the type and use of specific supportive 
medications (eg, pneumocystis prophylaxis, hematopoietic growth factors, corticosteroids) 
during study treatment will be described. 
The number, type, and timing of post-study-treatment regimens for CLL will be summarized 
by treatment arm, characterizing the disposition of all subjects who were eligible for 
post-study treatment and also those who were not eligible for post-study treatment (eg, 
subjects who are never treated at all, die while on study treatment, are still on study, are lost 
to follow-up, etc). 
9.2.3.4. 
Adverse Events 
All adverse events will be listed. The focus of adverse event summarization will be on 
treatment-emergent adverse events. A treatment-emergent adverse event is defined as an 
adverse event that occurs or worsens in the period from the first dose of study treatment to 
30 days after the last dose of study treatment. Adverse events that occur before the first dose 
of study treatment or >30 days after the subject has been discontinued from study treatment 
will be included in data listings. 
Adverse events will be classified using MedDRA (http://www.meddramsso.com) with 
descriptions by System Organ Class, High-Level Group Term, High-Level Term, Preferred 
Term, and Lower-Level Term. The severity of adverse events will be graded by the 
investigator according to the CTCAE, Version 4.03 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf), 
whenever possible. If a CTCAE criterion does not exist for a specific type of adverse event, 
the grade corresponding to the appropriate adjective will be used by the investigator to 
describe the maximum intensity of the adverse event: Grade 1 (mild), Grade 2 (moderate), 
Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the 
adverse event to the study drug will be categorized as related or unrelated. 
Treatment-emergent adverse events will be summarized by treatment arm and by visit. 
Summary tables will be presented to show the number of subjects reporting treatment-
emergent adverse events by severity grade and corresponding percentages. A subject who 
reports multiple treatment-emergent adverse events within the same Preferred Term (or 

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System Organ Class) is counted only once for that Preferred Term (or System Organ Class) 
using the worst severity grade. Adverse event descriptions will be presented in alphabetical 
order of System Organ Class, then by decreasing frequency in the “overall” column for a 
given Preferred Term. 
Separate listings and summaries will be prepared for the following types of treatment-
emergent adverse events: 
• Study-drug-related adverse events 
• Adverse events that are Grade ≥3 in severity 
• Adverse events leading to study drug interruption and/or dose modification 
• Adverse events leading to study drug discontinuation 
• Serious adverse events (with categorization of the primary reason that the adverse event 
is considered serious, eg, death, hospitalization, etc) 
Separate listings and summaries will be prepared for long-term follow-up safety data (see 
Section 6.2.18). 
9.2.3.5. 
Laboratory Evaluations 
All laboratory data will be listed. Summaries of laboratory data will be based on observed 
data and will be reported using conventional units. The focus of laboratory data 
summarization will be on treatment-emergent laboratory abnormalities. A treatment-
emergent laboratory abnormality is defined as an abnormality that, compared to baseline, 
worsens by ≥1 grade in the period from the first dose of study treatment to 30 days after the 
last dose of study treatment. If baseline data are missing, then any graded abnormality (ie, an 
abnormality that is Grade ≥1 in severity) will be considered treatment emergent. Laboratory 
abnormalities that occur before the first dose of study treatment or >30 days after the subject 
has been discontinued from study treatment will be included in data listings. 
Hematological, serum biochemistry, and urine data will be programmatically graded 
according to CTCAE severity grade, when applicable. For parameters for which a CTCAE 
scale does not exist, reference ranges from the central laboratory will be used to determine 
programmatically if a laboratory parameter is below, within, or above the normal range for 
the subject’s age, sex, etc. 
Hematological and serum biochemistry and their changes from baseline will be summarized 
by treatment arm and by visit. Summary tables will be presented for each relevant assay to 
show the number of subjects by CTCAE severity grade with corresponding percentages. For 
parameters for which a CTCAE scale does not exist, the frequency of subjects with values 
below, within, and above the normal ranges will be summarized. Subjects will be 
characterized only once for a given assay, based on their worst severity grade observed 
during a period of interest (eg, during the study or from baseline to a particular visit). 
Shift tables for hematology and serum biochemistry will also be presented by showing 
change in CTCAE severity grade from baseline to each visit. For parameters for which a 
CTCAE scale does not exist, shift tables will be presented showing change in results from 
baseline (normal, low and high [or abnormal]) to each visit (normal, low and high [or 

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abnormal]). Tables will be prepared to show frequencies adjusted for baseline values; for this 
frequency, subjects with the same or worse toxicity grade at baseline are not considered. 
Separate listings and summaries will be prepared for laboratory abnormalities that are 
Grade ≥3 in severity. 
9.2.3.6. 
Oxygen Saturation Values 
All oxygen saturation data will be listed. Summaries of oxygen saturation data will be based 
on observed data and will be reported as % saturation. Data and changes from baseline will 
be summarized by treatment arm and by visit. Summary tables will be presented for values 
below 92% and for declines from baseline of ≥5% to show the number of subjects with 
corresponding percentages. Subjects will be characterized only once for each of these 
categorizations, based on their lowest value observed during a period of interest (eg, during 
the study or from baseline to a particular visit). 
9.2.4. 
Other Analyses 
9.2.4.1. 
Between-Study Comparisons 
It is expected that  patients with a progressive malignancy like CLL will normally fare better 
with an earlier therapy than with a later therapy. However, if the converse situation proves 
true – eg, if an investigational treatment (GS-1101) administered later shows similar or 
greater benefit than a standard treatment (rituximab) administered earlier – strong evidence 
of investigational drug effect is demonstrated. Evaluating data derived from the same study 
subjects during their sequential participation in 2 clinical trials offers unique analytical 
challenges. However, in this integrated Phase 3 study program, it is likely that comparing 
baseline characteristics and outcomes among Arm B subjects participating in Study GS-US-
312-0116 and Study GS-US-312-0117 will be informative. Such an evaluation characterizes 
how the subjects and the CLL disease process change with time and treatment. In addition, 
such an analysis provides relevant supporting information documenting the benefits of 
single-agent GS-1101 relative to single-agent rituximab in the same subjects. 
Accordingly, the subject baseline characteristics at the start of Study GS-US-312-0116 
relative to those at the start of Study GS-US-312-0117 will be evaluated. Subject baseline 
characteristics between the studies may be compared using the Wilcoxon rank-sum test for 
continuous variables and the Fisher’s exact test for categorical variables.  
Time-to-event efficacy variables (eg, PFS, TTR, DOR, TTF, time to performance status, or 
HRQL changes) will be evaluated using the paired Prentice-Wilcoxon test, comparing results 
in Study GS-US-312-0116 to those in Study GS-US-312-0117 among subjects who 
participate in Arm B of both studies. Within each study period, medians, ranges, hazard 
ratios and corresponding 95% CIs will be presented using Kaplan Meier methods. As 
appropriate, Cox regression techniques may be used to explore the influence of baseline 
characteristics on treatment differences when comparing these outcomes between the studies. 
For categorical variables (eg, ORR, lymph node response rate, splenomegaly response rate, 
hepatomegaly response rate), the Wilcoxon signed-rank test will be employed to compare 
outcomes between Study GS-US-312-0116 and Study GS-US-312-0117 for Arm B subjects. 
For all analyses, odds ratios and the corresponding 95% CIs will be presented. Differences 
between studies for Arm B subjects relating to continuous variables (eg, percentage changes 

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in lymph node area; changes in performance status, PI3K/AKT/mTOR pathway activation 
and plasma chemokines/cytokines) will be analyzed using appropriate methods (eg, analysis 
of covariance [ANCOVA] or paired t-tests). Means and standard errors will be presented. As 
appropriate, the potential influence of subject baseline characteristics on treatment effects 
may be explored with multiple logistic regression techniques. 
9.2.4.2. 
Health Care Resource Utilization 
The EQ-D5 questionnaire data will be scored, processed, and standardized according to the 
user manual. As for the FACT-Leu, data will be analyzed using appropriate methods to 
account for incomplete completion of questionnaires. Data collected from the EQ-D5 will not 
be reconciled with adverse event or laboratory data or with FACT-Leu findings. 
Health care resource utilization data collection will be based on information provided in the 
eCRFs and will be focused on the most relevant direct medical resource utilization such as 
physician visits, laboratory tests, medications (including dose and route), medical procedures, 
interventions (eg, transfusions), and hospitalizations. 
The basic approach to the health economic analysis will be to combine the resource 
utilization data from the trial with data on unit prices (collected separately) to estimate total 
costs.  
The perspective of this analysis will be that of the third-party payer(s) and the hospital over a 
lifetime horizon in the base case. The costs will be described relative to the health care 
findings as measured by duration of tumor control, the symptom-free survival period, life-
years, utility outcomes, or other measure of appropriate clinical benefits. In order to facilitate 
the calculation of utilities for use in the cost effectiveness analyses, the health status of 
subjects will be evaluated using PFS, Karnofsky performance status, FACT-Leu, and EQ-5D. 
9.2.4.3. 
Data Explorations  
Changes in biomarkers during acquisition of resistance will be evaluated descriptively. Data 
explorations may be performed to evaluate potential associations between subject 
characteristics and outcome measures. Explorations may be performed to assess the potential 
associations between different outcomes measures (eg, relationships between HRQL changes 
and clinical/radiographic endpoints of tumor control). 
9.3. 
Sample Size 
The sample size for this extension study is not based upon a formal statistical hypothesis. The 
upper bound of the sample size in this study is determined by the sample size of the 
preceding primary study (Study GS-US-312-0116) in which ~160 subjects (~80 per arm) are 
expected to be enrolled. It is estimated that this extension study (Study GS-US-312-0117) 
will have a total GS-1101-treated N~130 (assuming a ~10% dropout rate during 
Study GS-US-312-0116 and a further ~10% dropout rate in the transition from the primary 
study to the extension study). 

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9.4. 
Timing of Analyses 
9.4.1. 
Interim Analysis 
The DMC will have access to serious adverse events requiring expedited reporting and will 
be provided with accumulating safety data on a regular basis. Interim safety reviews will be 
conducted by the DMC in conjunction with safety reviews of the primary clinical trial 
(Study GS-US-312-0116). Thus, interim safety reviews will be performed by the DMC at 
intervals of ~6 months; the specific frequency of these reviews will depend upon the rate at 
which the trials are enrolled, the nature of any emerging safety signals, and monitoring 
recommendations from the DMC. At each review, all available safety data will be 
summarized and evaluated.  
An interim efficacy analysis of this clinical trial (Study GS-US-312-0117) is planned that 
take place at the time of the final analysis of the primary study (Study GS-US-312-0116). 
The intent is to provide the data from this extension study in support of regulatory review of 
data from the primary study. The blind will be broken to the study team at Gilead Sciences 
for analysis purposes. However, the study will be continued to obtain further follow-up 
efficacy and safety information; individual subjects, caregivers, and site personnel will not be 
informed of the treatment assignments until the implications of revealing such data for the 
overall GS-1101 study program have been determined. 
9.4.2. 
Final Analysis 
An additional, final analysis of efficacy and safety may be performed to satisfy regulatory 
requirements and to perform long-term efficacy, safety and OS follow-up. The timing of this 
analysis is expected to occur within 36 months of accrual of the final subject to 
Study GS-US-312-0117. 

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

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report should include the dates of initiation and completion of the trial, a description of any 
changes in study procedures or amendments to the protocol, any deviations from the 
protocol, the number and type of subjects evaluated, the number of subjects who 
discontinued (and the reasons for discontinuation), the number of subjects who completed the 
trial, and the results of the trial, including a description of any adverse events. 
Gilead Sciences will assist the investigator in the preparation of this report, as needed. 
10.1.3. 
Informed Consent 
After adequately, explaining the aims, methods, objectives, and potential hazards of the study 
and before undertaking any study-related procedures, the investigator is responsible for 
obtaining written informed consent from each individual participating in this study. The 
investigator must utilize an IRB/IEC-approved consent form for documenting written 
informed consent. Each informed consent will be appropriately signed and dated by the 
subject or the subject’s legally authorized representative and the person obtaining consent. 
The approved informed consent must not be changed without prior approval by 
Gilead Sciences and the IRB/IEC. 
10.1.4. 
Confidentiality 
The investigator must assure that each subject’s anonymity will be strictly maintained and 
that each subject’s identity is protected from unauthorized parties. Only subject initials, date 
of birth, and an identification code (but no subject names) should be recorded on any form or 
biological sample submitted to the Gilead Sciences or designees (eg, laboratories), or to the 
IRB/IEC. However, sufficient information must be retained at the site to permit sample data 
and data in the database to be connected with the unique subject number assigned to each 
study participant. 
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the GS-1101 investigator brochure, this protocol, eCRFs, the investigational new 
drug, and any other study information, remain the sole and exclusive property of 
Gilead Sciences during the conduct of the study and thereafter. This information is not to be 
disclosed to any third party (except employees or agents directly involved in the conduct of 
the study or as required by law) without prior written consent from Gilead Sciences. The 
investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain. 
10.1.5. 
Study Files and Retention of Records and Biological Samples 
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into at least the following 2 categories: (1) investigator’s 
study file, and (2) subject clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
the IRB/IEC and governmental approval with correspondence, informed consent, drug 
records, staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 

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The required source data referenced in the monitoring plan for the study, and should include 
sequential notes containing at least the following information for each subject: 
• Subject identification (name, date of birth, gender) 
• Documentation that subject meets eligibility criteria, eg, history, physical examination, 
and confirmation of diagnosis (to support inclusion and exclusion criteria) 
• Participation in trial (including trial number) 
• Trial discussed and date of informed consent 
• Dates of all visits 
• Documentation that protocol-specific procedures were performed 
• Results of efficacy parameters, as required by the protocol 
• Start and end date (including dose regimen) of trial medication (including relevant drug 
dispensing and return information) 
• Record of all adverse events and other safety parameters (including start and end date, 
causality and intensity) 
• Concomitant medication (including start and end date and dose if relevant dose changes 
occur) 
• Date of trial completion and reason for discontinuation, if applicable 
All clinical study documents must be retained by the investigator until at least 2 years after 
the last approval of a marketing application in an ICH region (ie, the United States, Europe, 
or Japan) and until there are no pending or contemplated marketing applications in an ICH 
region; or, if no application is filed or if the application is not approved for such indication, 
until 2 years after the investigation is discontinued and regulatory authorities have been 
notified. Investigators may be required to retain documents longer if required by applicable 
regulatory requirements, by local regulations, or by an agreement with Gilead Sciences. The 
investigator must notify Gilead Sciences before destroying any clinical study records. The 
investigator will promptly notify Gilead Sciences in the event of accidental loss or 
destruction of any study records.  
Should the investigator wish to assign the study records to another party or move them to 
another location, Gilead Sciences must be notified in advance. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all 
of the documents, special arrangements must be made between the investigator and 
Gilead Sciences to store these in sealed containers outside of the site so that they can be 
returned sealed to the investigator in case of a regulatory audit. When source documents are 
required for the continued care of the subject, appropriate copies should be made for storage 
outside of the site. 
Biological samples retained by the investigator will be stored and maintained by the 
investigator until notification is received from Gilead Sciences that the retained samples and 
records no longer need to be retained. The investigator must obtain written permission from 

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Gilead Sciences before disposing of any retained samples. The investigator should promptly 
notify Gilead Sciences in the event of accidental loss or destruction of any study samples. 
With the permission of Gilead Sciences, the retained samples may be transferred to an 
acceptable designee, such as another investigator, another institution, a contract storage site, 
or to Gilead Sciences. 
10.1.6. 
Case Report Forms 
An eCRF is required and must be completed for each enrolled subject, with all required study 
data accurately recorded such that the information matches the data contained in medical 
records (eg, physicians’ notes, nurses’ notes, clinic charts, or other study-specific source 
documents). As required by the protocol, eCRFs should also be completed for those subjects 
who fail to complete the study (even during the screening period). If a subject withdraws 
from the study, the reason must be noted on the eCRF. If a subject is withdrawn from the 
study because of a treatment-limiting adverse event, thorough efforts should be made to 
clearly document the outcome.  
The eCRFs for this study will exist within a Web-based electronic data capture (EDC) 
system. After the investigator or the investigator’s designees (eg, research coordinators) have 
been appropriately trained, they will be given access to the EDC system and will enter the 
data required by the protocol into the EDC system. Any change of data will be made via the 
EDC system, with all changes tracked by the system to provide an audit trail. 
The eCRF must be completed and signed by the principal investigator or subinvestigator (as 
appropriate) within a reasonable time period after data collection. This signature serves to 
attest that the information contained in the eCRF is true. 
10.1.7. 
Drug Accountability  
As described in the relevant section (see Section 5.2.7), the investigator is responsible for 
ensuring adequate accountability of all used and unused investigational medicinal product, 
placebos, and comparators. This responsibility includes acknowledgment of receipt of each 
shipment of study product (quantity and condition), subject dispensing records, and returned 
or destroyed study product. Dispensing records will document quantities received from 
Gilead Sciences and quantities dispensed to subjects, including lot number, date dispensed, 
subject identifier number, subject initials, and the initials of the person dispensing the 
medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for 
investigational medicinal product disposal/destruction in order to ensure that it complies with 
Gilead Sciences requirements. Drug may be returned or destroyed on an ongoing basis during 
the study if appropriate. At the end of the study, following final drug inventory reconciliation 
by the monitor, the study site will dispose of and/or destroy all unused investigational 
medicinal product supplies, including empty containers, according to these procedures. If the 
site cannot meet Gilead Sciences’ requirements for disposal, arrangements will be made 
between the site and Gilead Sciences or its representative for destruction or return of unused 
investigational medicinal product supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by 
the study monitor over the course of the study. 

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10.1.8. 
Inspections 
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from Gilead Sciences or its representatives, to 
IRB/IECs, and to regulatory authority or health authority inspectors. It is important that the 
investigator and relevant institutional personnel are available during monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process. 
10.1.9. 
Protocol Compliance 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
10.2. 
Sponsor Responsibilities 
10.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, will 
be made only by Gilead Sciences. All protocol modifications must be submitted to the 
IRB/IEC in accordance with local requirements. Except as noted in Section 10.1.2, IRB/IEC 
approval must be obtained before changes can be implemented. 
10.2.2. 
Communications with Regulatory Authorities 
Gilead Sciences, working either directly or through designees, will assume responsibility for 
regulatory interactions with relevant regulatory authorities. Gilead Sciences will maintain an 
IND for GS-1101 in support of the study in the United States and will maintain similar 
regulatory applications with other regulatory authorities, as required for conduct of the study. 
In fulfilling this responsibility, Gilead Sciences (or a designee) will collect, assemble, and 
communicate all required regulatory documents (eg, Form FDA 1572, investigator financial 
disclosure forms, protocol and protocol amendments, investigator brochures, informed 
consent documents, annual reports) as required by regulation. Gilead Sciences (or a designee) 
will also assume responsibility for adverse event reporting to regulatory authorities as 
described in Section 8.7.2. 
10.2.3. 
Data Management 
Electronic data capture will be used to enter study data eCRFs and to transfer the data into a 
study-specific electronic database. During the data collection process, automated quality 
assurance programs will be used to identify missing data, selected protocol violations, out-of-
range data, and other data inconsistencies. Requests for data clarification or correction will 
be forwarded to the investigative site for resolution. As appropriate, eCRFs, listings, tables, 
and SAS datasets will be provided to the investigational sites for review. 
Quality assurance and quality control systems will be implemented and maintained according 
to written standard operating procedures to ensure that the data are generated, recorded, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements. Data 
collection and storage systems will provide audit trail, security mechanisms, and electronic 
signature capabilities that meet the requirements of FDA Title 21 of CFR Part 11 regarding 
electronic records and electronic signatures.  

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Data security will be controlled through appropriate and specific restriction of access only to 
data and systems required by individual users to accomplish their roles in the data 
management process. Individual login and password protections will be employed at study 
sites and at Gilead Sciences or its designee. The database will exist on physically secured 
servers. Data backups will be done regularly and will be stored in separate facilities. Printed 
documents relating to the study will be secured when not under review.  
10.2.4. 
Study Reporting and Publication 
Gilead Sciences may make information obtained during this study available in order to 
further the scientific or business needs of the company or as required by law or regulation. In 
this regard, Gilead Sciences may provide study information to private or public organizations 
(eg, business partners, collaborators, consultants, CROs, investors, other physicians who are 
conducting similar studies, funding organizations, regulatory authorities, or other government 
authorities).  
Gilead Sciences will prepare a clinical study report for submission to relevant regulatory 
agencies. Gilead Sciences will ensure that the report meets the standards set out in the ICH 
Guideline for Structure and Content of Clinical Study Reports (ICH E3). An abbreviated 
report may be prepared in certain cases, as appropriate. 
Gilead Sciences intends that the data from this study will be presented and published. The 
Gilead Sciences study director will work in collaboration with the principal investigators in 
preparing presentations and writing manuscripts for publication.  
Investigators should not present or publish the data from the individual sites of this study 
without agreement among the principal investigators and Gilead Sciences. However, after 
conclusion of the study and without prior written approval from Gilead Sciences, 
investigators in this study may communicate, orally present, or publish in scientific journals 
or other scholarly media the results of the trial if either of the following conditions is met: 
• The results of the study in their entirety have been publicly disclosed in an abstract, 
manuscript, or presentation form by Gilead Sciences or with the consent of 
Gilead Sciences; or 
• The primary clinical trial (Study GS-US-312-0116) and this companion extension trial 
(Study GS-US-312-0117) have been closed at all study sites for ≥2 years. 
No such communication, presentation, or publication will include Gilead Sciences’ 
confidential information (see Section 10.1.4). 
The investigator will submit to Gilead Sciences any proposed publication or presentation 
along with the respective scientific journal or presentation forum at least 30 days before 
submission of the publication or presentation. The investigator will comply with 
Gilead Sciences’ request to delete references to its confidential information (other than the 
study results) in any paper or presentation. If deemed necessary by Gilead Sciences, the 
investigator also agrees to withhold publication or presentation for an additional 60 days in 
order to obtain patent protection. 

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10.3. 
Joint Investigator/Sponsor Responsibilities 
10.3.1. 
Access to Information for Monitoring 
In accordance with ICH Good Clinical Practice (ICH GCP) guidelines, the study monitor 
must have direct access to the investigator’s source documentation in order to verify the data 
recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy 
of the data being entered on them. The monitor should have access to any subject records 
needed to verify the entries on the eCRFs. The investigator agrees to cooperate with the 
monitor to ensure that any problems detected in the course of these monitoring visits are 
resolved. 
10.3.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of Gilead Sciences may conduct inspections or 
audits of the clinical study. If the investigator is notified of an inspection by a regulatory 
authority the investigator agrees to notify the Gilead Sciences medical monitor immediately. 
The investigator agrees to provide to representatives of a regulatory agency or 
Gilead Sciences access to records, facilities, and personnel for the effective conduct of any 
inspection or audit. 
10.3.3. 
Public Notification of Study Conduct 
Consistent with Section 113 of the Food and Drug Modernization Act of 1997 (FDAMA) and 
with requirements of the International Committee of Medical Journal Editors (ICMJE) as a 
condition of consideration for publication of study results, Gilead Sciences will be 
responsible for ensuring that this protocol is listed at the ClinicalTrials.gov website (or 
equivalent) and that information at the website relating to study design and conduct is 
appropriately updated during the course of the study. In order to facilitate this process, 
investigators will need to supply Gilead Sciences with appropriate contact information for 
study site personnel. 
10.3.4. 
Study Discontinuation 
Both the sponsor and the investigator reserve the right to terminate the study at any time. 
Should this be necessary, both parties will arrange discontinuation procedures and notify the 
appropriate regulatory authorities and IRB/IECs. In terminating the study, Gilead Sciences 
and the investigator will assure that adequate consideration is given to the protection of the 
subjects’ interests.  
10.4. 
Study Committees 
10.4.1. 
Study Steering Committee 
A study steering committee (SSC) will be responsible for assisting Gilead Sciences with 
protocol development, review of any study amendments, coordination of study conduct, 
interpretation of data, and presentation and publication of study results. The SSC comprises 
the Gilead Sciences medical monitor for the study, the Gilead Sciences study director, and 
several clinicians with expertise in the care of subjects with CLL. Other specialists may be 

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invited to participate as members of the SSC at any time if additional expertise is desired. 
Academic SSC members may be involved in accruing subjects to the study. The 
Gilead Sciences study director serves as the chair of the SSC. It is expected that the members 
of the SSC will be the same as those for the SSC of the primary clinical trial 
(Study GS-US-312-0116).  
10.4.2. 
Data Monitoring Committee 
A DMC, operating autonomously from Gilead Sciences, the clinical investigators, and the 
SSC, will be responsible for providing independent recommendations to Gilead Sciences 
about evolving risk-benefit observed in the course of the study and any modifications 
required during the course of the study. The DMC will consist of a biostatistician and 
≥2 physicians experienced in treating patients with lymphoid malignancies. The DMC will 
be chaired by one of these individuals. DMC members must not be actively involved in study 
design, conduct, or subject accrual and must not have financial, proprietary, professional, or 
other interests that may affect impartial, independent decision-making. Specialists may be 
invited to participate as non-voting members at any time if additional expertise is desired. 
The DMC will formally interact with the external SSC members through the sharing of 
meeting minutes. Informal interactions between the DMC and external SSC members will be 
limited. The DMC will operate under a charter developed as a collaborative document 
between Gilead Sciences and the DMC. It is expected that the members of the DMC will be 
the same as those for the primary study (Study GS-US-312-0116).  
The primary responsibility of the DMC is to protect the safety and welfare of subjects 
participating in this clinical trial and to ensure the integrity of the clinical trial. In general, the 
DMC will be responsible for: 
• Reviewing the general progress of the study as regards subject accrual, study conduct, 
and protocol violations 
• Examining accumulated safety, efficacy, and other relevant data at prespecified points 
during the course of the study  
• Reviewing major study design modifications prior to implementation of those 
modifications 
• Making recommendations concerning continuation, modification, interruption, or 
termination of each study 
• Advising the company on changes to informed consent documents 
• Proposing updates to the DMC monitoring plan, changes in the DMC membership, 
actions to be taken relating to conflict of interest or confidentiality breaches, the need for 
additional expertise during DMC deliberations, revisions to the DMC charter, or 
alterations in the support provided to the DMC 
• Providing expert advice to the Gilead Science medical monitor on an ad hoc basis 
regarding matters such as safety concerns or diagnostic evaluations in individual subjects 
 

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Based on the results of its deliberations during the course of the study, the DMC can 
recommend appropriate actions (eg, continuation of the study unchanged, continuation of the 
study with modifications in design or monitoring plan, interruption of study accrual, study 
termination). 
10.4.3. 
Independent Review Committee 
An IRC will be established to provide a blinded review of radiographic data and pertinent 
clinical data in order to provide expert interpretation of changes in tumor status. The IRC will 
include ≥1 independent board-certified radiologist and ≥1 independent board-certified 
hematologist or oncologist, and will be managed by a CRO selected by Gilead Sciences. The 
review of radiographic and clinical data by the IRC will be performed on an ongoing basis. 
The specifics of the IRC’s processes and reading methods will be described in an 
independent review charter developed by the contracted imaging facility in conjunction with 
Gilead Sciences. The same organization that is providing IRC services for 
Study GS-US-312-0116 will provide IRC services for this study.  

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

PPD
PPD
GS-1 101 
Protocol GS-US-312-01 I 7 
Final 
Gilead Sciences, Inc. 
Original 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
199 EAST BLAINE STREET 
SEATTLE, WA 98102 
STUDY ACKNOWLEDGEMENT 
A Phase 3, Double-Blind Extension Study Evaluating the Efficacy and Safety of 
Two Different Dose Levels of Single-Agent GS-1101 (CAL-101) as Therapy 
for Patients with Previously Treated Chronic Lymphocytic Leukemia 
GS-US-312-0117 Original Protocol, 23 January 2012 
This protocol has been approved by Gilead Sciences, Inc. The followi 
this am::>_r_ov.;..a;;,;l.;... ------------. 
Gilead Sciences Study Director 
2..0 I 2._ 
Date 
INVESTIGATOR STATEMENT 
J have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. 1 will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to 
all information provided by Gilead Sciences, Inc. I will discuss this material with them to 
ensure that they are fully informed about the drugs and the study. 
Principal Investigator 
Printed Name 
Date 
CONFIDENTIAL 
Page 139 
Signature 
Site Number 
23 January 2012 

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Appendix 2. 
Functional Assessment of Cancer Therapy: Leukemia 
(FACT-Leu) 
 
FACT-Leu (Version 4) 
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 davs. 
PHYSICA 
ot 
at all 
PI 
I have a lack of energy ............................................ 
0 
GP2 
I have nausea ...................................................................... 
0 
Because of my physical condition, I have trouble 
meeting the needs of my famiJy .... ........................... 
0 
GP,1 
I have pain ................................................................ 
0 
GPS 
I am bothered by side effects of treatment.. ....................... 
0 
01'6 
I feel ill ' ......... ' ........................................................... '' ....... 
0 
GP7 
I am forced to spend time in bed ......................................... 
0 
OCIAL/F AMlL Y WELLwBEI G 
ot 
at all 
GS I 
I feel close to my friends .................................................... 
0 
GSl 
I get emotional suppo.tt from my family ............................ 
0 
GS3 
[get upport from my friends........ .................................. .. 
0 
My family has accepted my illness............................. .. 
0 
GS5 
I am satisfied with family communication about. my 
il ness...... ................................................................. 
0 
I feel close to my partner (or the person who is my majn 
support) ............................................................................... 
0 
Ql 
Regardle . ofvour current level of exual aclivily. plea e 
Si 
an 
er the following que lion. Ifyou prefa 1101 to an wer il, 
please mark thi box 0 and go to rhe next ection. 
I am ati fied with my sex life . . ........ ..... . . ... .. .. .. .. .. .............. 
0 
Efll!lisb(Univ« I) 
c.,nsJ•• 1 gg7, 1997 
A Jittle 
Some-
bat 
what 
2 
2 
2 
2 
2 
2 
2 
A little 
Some-
bit 
what 
2 
2 
2 
2 
2 
2 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
Very 
1nuch 
4 
4 
4 
4 
4 
4 
4 
Very 
nmch 
4 
4 
4 
4 
4 
4 
4 
P•I'J' I of3 

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FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
ot 
at all 
GEl 
I feel sad ............................................................................... 
0 
GE2 
I am satisfied with how I am coping with my illness .......... 
0 
Gill 
I am losing hope in the fight against my illness ................... 
0 
Gil-l 
I feel I ervous ............................... ..... .................. .................. 
0 
I worry about dying . ........................................................... 
0 
I worry that my condition will get worse ............................ 
0 
F NCTIONAL WELL-BEING 
ot 
at aU 
OF ! 
I am abl.e to work (include work at home) .......................... 
0 
0F2 
My work (include work at home) .is fulfilling ..................... 
0 
GFl 
I am able to enjoy life ........................................................... 
0 
GFII 
I have accepted my illness .. ............. .................. .. ... .. " ........ 
0 
I am sleeping well ... 
, ... ... ... ............ ....... ............ ..... ... ............. 
0 
GF6 
I am enjoying the things I usuaJly do for fun ...................... 
0 
01'7 
I am content with the quality of my life right now ............... 
0 
A little 
Some-
bit 
what 
2 
2 
2 
2 
2 
2 
A little 
Some-
bit 
what 
2 
2 
2 
2 
2 
2 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
Quite 
a bit 
3 
3 
.., 
.) 
3 
3 
3 
3 
Very 
much 
4 
4 
4 
4 
4 
4 
Very 
much 
4 
4 
4 
4 
4 
4 
4 
19 November 2007 
Page 2 of3 

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FACT-Leu (Version 4) 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
BR..\11 
I.EUI 
llH 
THl 
Htl2 
BMT6 
C6 
An7 
LF.tJS 
!.EU6 
I.EU 
ADDITIONA CONCERNS 
ot 
A little 
Some-
at all 
bit 
what 
I am bothered by fevers ( epi ode of high body 
temperature) ........................................................................ 
0 
I have certain parts of my body where I experience pain.... 
0 
I am bothered by the chills ...... .......................... .................. 
0 
I have night sweats ........................ ...................................... 
0 
I am bothered by lumps or swelling in certain parts of 
my body (e.g. neck armpits or groin) ................ .............. 
0 
I bleed easily ....................................................................... 
0 
I bruise easily .................................. .................................... 
0 
I feel weak all over.......................... ..................................... 
0 
I get tired easily __ ................................................................ 
0 
I an1losing weight ................................................................ 
0 
I have a good appetite .. ...................................................... . 
0 
I am able to do my usual activities ...................................... 
0 
I worry about getting infections . .. ...................................... 
0 
I feel uncertain about my future health ............................... 
0 
I worry that I might get new symptoms of my illness......... 
0 
I have ernotiona] ups and downs......................................... 
0 
I feel isolated from others because of my illness or 
treatment . . 
. . . . . .. . . . . . 
. . . . . . .. .. .. . .. 
0 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Quite 
a bit 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Vety 
much 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
19 November 2007 
Page 3 of3 

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

GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 144 
23 January 2012 
Appendix 4. 
EuroQoL-5 Dimensions (EQ-5D) 
EuroQoL-5 Dimensions (EQ-5D) 
 
Sample 
By placing a checkmark in one-box in each group below, please indicate which 
best de.scribe. your own health state. today. 
lolobility 
I ha•:e no prol*ms in walking about 
I ha .. ·e some problems in walking about 
I am con:ined to bed 
Self-Care 
I have no problems with 
I have so.-ne prob'.ems. washing or dressi'lg myself 
I am unable to wash or dress myself 
Usual Activities 
work, study, housework, famity, or leisure activities) 
I ha ... e no problems with performing my usual activities 
I have some problems with performing my usual acti\Jlties 
I am unable to petform my usual activities 
Pain/Discomfort 
I have no pain ot discomfort 
I have moderate pai-l or discomfort 
I ha'le extreme pai\ or discomfort 
Anxiety/De1>ression 
I am no1 anxious ot deFNessed 
I am moderately anxious ot dep1essed 
I am extremely anxious or depressed 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 
D 

GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 145 
23 January 2012 
 
 
Sample 
To help people say how good or bad a health state i;, 
we h.aw drawn a scale (rather like a thennometer) on 
which the best state you can imagine is marked 100 
and the worst state you cau imagine is marked 0. 
We would like you to indicate on Ibis scale how good 
or bad your own healrh is today, in your opinion. 
Please do this by drawing a line from the box below 
to whichever point on the scale indicates how good or 
bad yonr health stare is today. 
Your own 
health state 
today 
100 
t 
f. f 
l r 
f I 
t• o t 
I 
0 
"'"""' 

GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 146 
23 January 2012 
Appendix 5. 
Cockcroft-Gault Method for Estimating Creatinine Clearance  
Formulas for calculating the estimated creatinine clearance (eCcr) are provided in the table 
below. The formula appropriate to the units in which serum creatinine was measured and the 
subject’s gender should be used. 
Cockcroft-Gault Formulas for Calculating Estimated Creatinine Clearance 
Serum  
Creatinine Units Gender 
Formula 
 
 
 
 
 
(140-subject age [years]) × subject weight [kilograms] × 1
Males 
eCcr 
[mL/min] 
= 
72 × subject serum creatinine [mg/dl] 
 
 
 
 
 
 
 
 
(140-subject age [years]) × subject weight [kilograms] × 
0.85 
mg/dL 
Females 
eCcr 
[mL/min] 
= 
72 × subject serum creatinine [mg/dl] 
 
 
 
 
 
 
 
 
 
 
(140-subject age [years]) × subject weight [kilograms] × 
1.23 
Males 
eCcr 
[mL/min] 
= 
Subject serum creatinine [mg/dl] 
 
 
 
 
 
 
 
 
(140-subject age [years]) × subject weight [kilograms] × 
1.04 
µM/dL 
Females 
eCcr 
[mL/min] 
= 
Subject serum creatinine [mg/dl] 
 
 
 
 
 
 
Abbreviation: eCcr=estimated creatinine clearance 

GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 147 
23 January 2012 
Appendix 6. 
Cumulative Illness Rating Scale (CIRS) 
The CIRS used in this protocol is designed to provide an assessment of recurrent or ongoing 
chronic comorbid conditions, classified by 14 organ systems. Using the drop-down lists of 
organ-specific diagnoses, please select any conditions present in the study subject. If the 
subject has a recurrent or ongoing chronic conditions that are not described in the list for a 
given organ system, please indicate the name of the conditions under “other chronic 
condition” for that organ system. Please take into account that CLL-induced discomfort, 
symptoms, or disability should not be considered. If additional explanation would be helpful, 
text comments may be inserted.  
CIRS List of Comorbid Conditions 
Organ System 
Diagnosis 
Comment 
Chronic heart failure 
 
Angina pectoris 
 
Medically relevant arrhythmia 
 
Valve dysfunction 
 
Congenital heart disease 
 
Cardiomyopathy 
 
Myocarditis 
 
Chronic pericarditis 
 
Endocarditis 
 
Other chronic cardiac condition: 
 
Cardiac 
Other chronic cardiac condition: 
 
Hypertension 
 
Thrombosis 
 
Peripheral diabetic microvascular disease 
 
Peripheral artery disease 
 
Aortic aneurysm 
 
Aortitis 
 
Raynaud disease 
 
Vasculitis 
 
Other chronic vascular condition: 
 
Vascular 
Other chronic vascular condition 
 
Sickle cell anemia 
 
Hemoglobinopathy 
 
Polycythemia 
 
Thrombocythemia 
 
Hemophilia 
 
Paroxysmal nocturnal hemoglobinuria 
 
Thrombotic thrombocytopenic purpura 
 
Dysfibrinogenemia 
 
HIV 
 
Other chronic hematological or immunological 
condition: 
 
Hematological/ 
immunological 
Other chronic hematological or immunological condition 
 

GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 148 
23 January 2012 
Organ System 
Diagnosis 
Comment 
Asthma 
 
Chronic obstructive pulmonary disease 
 
Cystic fibrosis 
 
Emphysema 
 
Chronic bronchitis 
 
Chronic pleural effusions 
 
Pulmonary fibrosis 
 
Sarcoidosis 
 
Pulmonary embolism 
 
Pulmonary arterial hypertension 
 
Lung cancer 
 
Other chronic respiratory condition: 
 
Respiratory  
Other chronic respiratory condition 
 
Loss of vision  
 
Glaucoma 
 
Cataract 
 
Macular degeneration 
 
Diabetic retinopathy 
 
Loss of hearing 
 
Otitis/chronic otitis 
 
Vestibular impairment 
 
Vertigo 
 
Temporomandibular disorder 
 
Sialolithiasis  
 
Chronic sinusitis 
 
Laryngeal/pharyngeal disorders 
 
Ophthalmological/ 
otolaryngological 
Other chronic ophthalmological or otolaryngological 
condition: 
 
Chronic esophagitis 
 
Dysphagia 
 
Achalasia 
 
Gastroduodenal ulceration 
 
Celiac disease 
 
Irritable bowel syndrome 
 
Short bowel syndrome 
 
Malnutrition 
 
Malabsorption 
 
Small bowel obstruction 
 
Hernia 
 
Pseudomyxoma peritonei 
 
Upper gastrointestinal cancer 
 
Other chronic upper gastrointestinal condition: 
 
Upper  
gastrointestinal 
Other chronic upper gastrointestinal condition: 
 
Diverticulitis 
 
Inflammatory Hernia bowel disease 
 
Volvulus 
 
Colon cancer 
 
Other chronic lower gastrointestinal condition: 
 
Lower 
gastrointestinal 
Other chronic lower gastrointestinal condition: 
 
Chronic hepatitis or hepatic cirrhosis 
 
Biliary obstructive disorders 
 
Pancreatitis 
 
Hepatic, biliary, or pancreatic cancer 
 
Other chronic hepatic or pancreatic condition: 
 
Hepatic/ 
pancreatic 
Other chronic hepatic or pancreatic condition: 
 

GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 149 
23 January 2012 
Organ System 
Diagnosis 
Comment 
Chronic kidney disease 
 
Diabetic nephropathy 
 
Pyelonephritis 
 
Renal cancer 
 
Other chronic renal condition: 
 
Renal  
Other chronic renal condition 
 
Recurrent/chronic urinary tract infection 
 
Nephrolithiasis 
 
Bladder dysfunction 
 
Vaginal/vulvar disease 
 
Uterine/ovarian disease 
 
Prostatitis 
 
Bladder, uterine, ovarian, prostate, or other cancer 
 
Prostate hypertrophy 
 
Other chronic gynecological or urological condition: 
 
Gynecological/ 
urological 
Other chronic gynecological or urological condition: 
 
Dermatitis 
 
Dermatomyositis 
 
Myopathy 
 
Gout 
 
Psoriasis 
 
Keratosis 
 
Urticaria 
 
Scleroderma 
 
Basal cell carcinoma 
 
Squamous cell carcinoma 
 
Melanoma 
 
Osteomyelitis 
 
Osteoarthritis 
 
Rheumatoid arthritis 
 
Spondyloarthritis 
 
Temporal arteritis/polymyalgia rheumatica 
 
Polychondritis 
 
Fibromyalgia 
 
Osteoporosis 
 
Systemic lupus erythematosus 
 
Dermatomyositis 
 
Sjögren syndrome 
 
Other chronic dermatological or musculoskeletal 
condition: 
 
Dermatologic/ 
musculoskeletal 
Other chronic dermatological or musculoskeletal 
condition: 
 

GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 150 
23 January 2012 
Organ System 
Diagnosis 
Comment 
Cerebrovascular disease (transient ischemic 
attack/stroke/hemorrhage) 
 
Dementia 
 
Parkinson disease 
 
Non-Parkinsonian movement disorder (eg, ataxia/chorea)
 
Leukodystrophic disorders 
 
Amyotrophic lateral sclerosis 
 
Multiple sclerosis 
 
Demyelinating disease 
 
Guillain-Barré syndrome 
 
Paralysis (eg, paraplegia/quadriplegia/hemiplegia) 
 
Myelopathy 
 
Cranial nerve disorder 
 
Degenerative disk disease with nerve root compression 
 
Migraine headaches 
 
Seizure disorder 
 
Secondary neuropathy (eg, 
diabetic/alcoholic/autoimmune) 
 
Neurofibromatosis/tuberous sclerosis 
 
Benign or malignant central nervous system tumor 
 
Other chronic neurological condition: 
 
Neurological 
Other chronic neurological condition: 
 
Diabetes 
 
Adrenal disorder 
 
Thyroid disorder 
 
Parathyroid disorder 
 
Pheochromocytoma 
 
Pituitary disorder 
 
Hemochromatosis 
 
Porphyria 
 
Paget's disease 
 
Endocrine or neuroendocrine tumor 
 
Other chronic endocrine or metabolic condition: 
 
Endocrine/ 
metabolic 
Other chronic endocrine or metabolic condition: 
 
Depression 
 
Anxiety 
 
Bipolar disorder 
 
Paranoia 
 
Schizophrenia 
 
Neurosis 
 
Personality disorder 
 
Substance addiction/abuse 
 
Posttraumatic stress disorder 
 
Chronic fatigue syndrome 
 
Other chronic psychiatric condition: 
 
Psychiatric 
Other chronic psychiatric condition: 
 
Abbreviation:  CIRS=Cumulative Illness Rating Scale 

GS-1101 
Protocol GS-US-312-0117 
Final 
Gilead Sciences, Inc. 
Original 
 
CONFIDENTIAL 
Page 151 
23 January 2012 
For each condition selected from the CIRS List of Comorbid Conditions, please rate the 
severity of that condition. For the severity rating, please use the scoring guidelines shown in 
the table below, considering the magnitude of symptoms, how manageable the condition is, 
and the extent of intervention required: 
CIRS Rating Scale 
Score 
Severity 
Findings 
1 
Mild 
Mild discomfort, symptoms or disability 
Easy to control 
Requiring either no therapy/medication or only as needed 
2 
Moderate 
Moderate  discomfort, symptoms or disability 
Manageable 
Requiring daily treatment or first-line therapy 
3 
Severe 
Severe discomfort, symptoms or disability 
Hard to control 
Requiring second-line therapy or multiple medications 
4 
Extremely 
severe 
Life threatening, permanently disabling disability, causing organ 
failure 
Poorly manageable 
Requiring urgent intervention or resistant to therapy 
Abbreviation:  CIRS=Cumulative Illness Rating Scale 
 

PPD
GS-1101 
Protocol GS-US-312-0117 
Gilead Sciences, Inc. 
A 
d' 7 
IX . 
S h d I 
c e u eo f S d P 
tu ly roce 
Pel'iod 
Screen 
Visit 
1 
2 
3 
Week 
-4 
0 
2 
Within 
Study Day 
-28 
1 
15 
Davs 
Visit Window 
±2 
Informed consent 
X 
CIR.S assessment 
X 
(women of childbearing potential) 
X 
X 
CLL peripheral blood evaluation 
X 
CLL serology 
X 
IWRS 
X 
X 
X 
I 
HRQL/healthy utility - FACT-Leu/EQ-50 
X 
X 
Adverse events 
X 
X 
Concomitant medications 
X 
X 
X 
Performance status 
X 
X 
X 
Physical exam (includes nodes, liver, spleen) 
X 
X 
Oxygen saturation (by pulse oximetry) 
X 
X 
X 
Hematology 
X 
X 
X 
Serum chemistry 
X 
X 
X 
Circulating cells 
X 
X 
Biomarkers 
X 
X 
Serumlgs 
X 
X 
Study drug administration in clinic 
X 
X 
GS-1101 pharmacokinetics 
X 
X 
Study drug dispensing/accounting 
X 
Radiology assessment (CTIMRJ) 
X 
Bone marrow biopsy/aspirate 
X 
Post-treatment CLL therapy 
Long-term follow-up 
d ures 
4 
5 
6 
7 
4 
6 
8 
10 
29 
43 
57 
71 
±2 
±2 
±2 
±2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x" 
a 
For follow-up Vlstts after Week 96, CT or MRI ts only requtred at the end-of-treatment VlStt. 
Treatment 
8 
9 
10 
11 
12 
13 
14 
12 
16 
20 
24 
30 
36 
42 
85 
113 
141 
169 
211 
253 
295 
±2 
±3 
±3 
±3 
±3 
±3 
±3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x" 
x" 
x" 
15 
16+ 
48 
Q12 
End of 
337 Weeks treatment 
±3 
±7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x" 
x• 
x" 
x" 
x" 
Final 
Original 
Follow-up 
Post-
Long-
therapy term 
Within 
To 
+30 
+5 
days 
years 
l 
I 
X 
X 
X 
X 
b 
At baseline, to be performed at investigator discretion to determine extent of CLL involvement and bone marrow cellularity. Post-baseline, to be performed to confirm response category in 
subjects with potential CR by physical examination and radiological assesstnents. 
Abbre"iations: 13-HCG=beta human chorionic gonadotropin, CIR.S=chronic illness rating scale, CLL=chronic lymphocytic leukemia, CR=complete response, CT=computed tomography, 
EQ-5D=EuroQoL Five-Dimension, FACT-Leu=Functional Assesstnent of Cancer Therapy- Leukemia, HRQL= health-related quality of life, lg=intmunoglobulin, IWRS=interactive web response 
system, MRI= magnetic resonance intaging. 
CONFIDENTIAL 
Page 152 
23 Januaty 2011