Clinical trial NCT01799889
Conditions: Chronic Lymphocytic Leukemia Mantle Cell Lymphoma Diffuse Large B-cell Lymphoma Non-FL Indolent Non-Hodgkin's Lymphoma Follicular Lymphoma
Keywords: SYK inhibitor
Sponsor: Gilead Sciences
Start date: 2013-03-14; Completion date: 2020-01-30
Enrollment: 326 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to evaluate efficacy of entospletinib in participants with relapsed or refractory hematologic malignancies. Participants with the following relapsed or refractory hematologic malignancies will be enrolled into the study: relapsed or refractory chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or non-FL indolent non-Hodgkin lymphomas (iNHL; including lymphoplasmacytoid lymphoma/ Waldenström macroglobulinemia \[LPL/WM\], small lymphocytic lymphoma \[SLL\], or marginal zone lymphoma \[MZL\]).

Detailed description:

Arms: arm 1: Participants with CLL, receive original formulation (mono-mesylate \[MM\]) of entospletinib 800 mg (4 × 200 mg tablets) (before amendment 8) or new formulation of entospletinib (spray dried dispersion \[SDD\]) 400 mg (2 × 200 mg tablets) (after amendment 8) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity. arm 2: Participants with FL, receive original formulation of entospletinib 800 mg (4 × 200 mg tablets) (before amendment 8) or new formulation of entospletinib 400 mg (2 × 200 mg tablets) (after amendment 8) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity. arm 3: Participants with DLBCL, receive original formulation of entospletinib 800 mg (4 × 200 mg tablets) (before amendment 8) or new formulation of entospletinib 400 mg (2 × 200 mg tablets) (after amendment 8) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity. arm 4: Participants with MCL, receive original formulation of entospletinib 800 mg (4 × 200 mg tablets) (before amendment 8) or new formulation of entospletinib 400 mg (2 × 200 mg tablets) (after amendment 8) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity. arm 5: Participants with non-FL iNHL (ie, participants with LPL/WM, SLL, or MZL), receive original formulation of entospletinib 800 mg (4 × 200 mg tablets) (before amendment 8) or new formulation of entospletinib 400 mg (2 × 200 mg tablets) (after amendment 8) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity. arm 6: Participants with CLL, who are prior B-cell receptor (BCR) inhibitor naive, receive new formulation of entospletinib 100 mg (1 × 100 mg tablet) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity. arm 7: Participants with CLL, who are prior BCR inhibitor naive, receive new formulation of entospletinib 200 mg (1 × 200 mg tablet) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity. arm 8: Participants with CLL, who are prior BCR inhibitor naive, receive new formulation of entospletinib 400 mg (2 × 200 mg tablets) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity. arm 9: Participants with CLL and simple progression (non-Richters), who are exposed to Bruton tyrosine kinase (BTK) inhibitor, receive new formulation of entospletinib 400 mg (2 × 200 mg tablets) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity. arm 10: Participants with CLL and simple progression (non-Richters), who are exposed to phosphatidylinositol 3-kinase (PI3K) inhibitor, receive new formulation of entospletinib 400 mg (2 × 200 mg tablets) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity. arm 11: Participants with CLL, who transform to Richters or Richters-like syndrome and are exposed to BTK inhibitor, receive new formulation of entospletinib 400 mg (2 × 200 mg tablets) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity. arm 12: Participants with CLL, who transform to Richters or Richters-like syndrome and are exposed to PI3K inhibitor, receive new formulation of entospletinib 400 mg (2 × 200 mg tablets) orally twice daily. Treatment with entospletinib will continue until disease progression or unacceptable toxicity.
Interventions: intervention 1: Entospletinib MM intervention 2: Entospletinib SDD
Intervention descriptions: intervention 1: Entospletinib MM tablet administered orally intervention 2: Entospletinib SDD tablet administered orally

Protocol documents:
Prot_000.pdf: 
Study Title: 
Sponsor: 
IND No.: 
Clinical Trials.gov 
Identifier: 
EudraCT No. 
Indication: 
Protocol ID: 
Gilead Sciences Medical 
Monitor: 
Protocol Version/Date: 
(rJ GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 2, Open-Label Study Evaluating the Efficacy, Safety, 
Tolerability, and Phaimacodynamics of GS-9973 in Subjects with 
Relapsed or Refracto1y Hematologic Malignancies 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
116416 
NCT0l 799889 
2013-001845-15 
Chronic Lymphocytic Leukemia and non-Hodgkin Lymphomas 
GS-US-339-0102 
Name: 
Telephone: 
E-mail: 
Original: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
Amendment 4: 
Amendment 5: 
Amendment 6: 
Amendment 7: 
Amendment 8: 
IPIPD 
IPIPD 
PPU 
19 November 2012 
11 Januaiy 2013 
04 June 2013 
04 November 2013 
20 December 2013 
06 June 2014 
03 August 2015 
13 November 2015 
31 Mai·ch 2017 
CONFIDENTIALITY STATEMENT 
The info1mation contained in this document, paiiiculai·ly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The infonnation is only to be used by you in 
connection with authorized clinical studies of the investigational dmg described in the protocol. 
You will not disclose any of the info1mation to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessaiy to obtain infonned consent from those 
persons to whom the dmg may be administered. 


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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....................................................................17
1.
INTRODUCTION ..............................................................................................................................................21
1.1.
Background ............................................................................................................................................21
1.2.
Chronic Lymphocytic Leukemia............................................................................................................21
1.3.
Non-Hodgkin Lymphoma ......................................................................................................................22
1.4.
Spleen Tyrosine Kinase..........................................................................................................................24
1.4.1.
Spleen Tyrosine Kinase in Hematologic Malignancies........................................................24
1.4.2.
Clinical Experience in Hematologic Malignancies treated with SYK 
Inhibitors ..............................................................................................................................25
1.4.3.
Mechanism of action of SYK Target Inhibition...................................................................26
1.5.
GS-9973 .................................................................................................................................................27
1.5.1.
Nonclinical Pharmacology ...................................................................................................27
1.5.2.
Nonclinical Drug Metabolism and Pharmacokinetics ..........................................................29
1.5.3.
Nonclinical Toxicology........................................................................................................30
1.5.4.
Clinical Trials of GS-9973 ...................................................................................................31
1.5.5.
GS-9973 Target Drug Concentrations..................................................................................33
1.5.6.
Use of Concomitant Medications with GS-9973..................................................................34
1.6.
Rationale for the Current Study and Design...........................................................................................35
1.6.1.
Rationale for the Dose Selection..........................................................................................35
1.6.2.
Rationale for Dose Exploration in GS-9973 Sensitive Malignancies...................................36
1.7.
Rationale for Amendment 5 ...................................................................................................................36
1.7.1.
Initial Clinical Experience with GS-9973 in Subjects with CLL .........................................36
1.7.2.
Rationale for addition of three CLL cohorts ........................................................................38
2.
OBJECTIVES AND ENDPOINTS ....................................................................................................................40
2.1.
Objectives...............................................................................................................................................40
2.2.
Endpoints ...............................................................................................................................................40
3.
STUDY DESIGN................................................................................................................................................42
3.1.
Overview................................................................................................................................................42
3.1.1.
CLL, FL, DLBCL, MCL......................................................................................................43
3.1.2.
CLL Dose Ranging Cohort...................................................................................................43
3.1.3.
LPL, SLL, MZL ...................................................................................................................44
3.2.
Treatment Regimen................................................................................................................................45
4.
SUBJECT POPULATION..................................................................................................................................46
4.1.
Number of Subjects and Subject Selection ............................................................................................46
4.2.
Eligibility Criteria ..................................................................................................................................46
4.2.1.
Inclusion Criteria..................................................................................................................46
4.2.2.
Exclusion Criteria.................................................................................................................49
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................51
5.1.
Enrollment..............................................................................................................................................51
5.2.
Description and Handling of GS-9973 and GS-9973 SDD....................................................................51


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5.2.1.
Formulation..........................................................................................................................51
5.2.2.
Source...................................................................................................................................51
5.2.3.
Packaging and Labeling .......................................................................................................52
5.2.4.
Storage and Handling...........................................................................................................52
5.2.5.
Study Drug Accountability...................................................................................................52
5.3.
Treatment Plan .......................................................................................................................................52
5.3.1.
Premedication.......................................................................................................................52
5.3.2.
Administration Instructions..................................................................................................53
5.3.3.
Dosing Schedule...................................................................................................................53
5.3.4.
Dose Schedule Interruptions and Vomited Doses ................................................................53
5.3.5.
Transition of GS-9973 MM formulation to GS-9973 SDD formulation..............................53
5.3.6.
Management of Dose Limiting Toxicities............................................................................54
5.3.7.
Management of Low Grade Chronic Toxicities...................................................................58
5.3.8.
Specific Considerations for Managing Hyperbilirubinemia.................................................58
5.3.9.
Duration of Therapy.............................................................................................................58
5.4.
Study Drug Disposal ..............................................................................................................................58
5.5.
Concomitant and Supportive Therapy....................................................................................................58
5.5.1.
Excluded Medication............................................................................................................59
5.5.2.
Anticancer or Experimental Therapies Other than Investigational 
Treatments............................................................................................................................60
5.5.3.
Antibiotics............................................................................................................................60
5.5.4.
Antiemetics and Antidiarrheals............................................................................................60
5.5.5.
Contraception .......................................................................................................................61
5.5.6.
Corticosteroids .....................................................................................................................61
5.5.7.
Colony-Stimulating Factors and Erythropoietin...................................................................61
5.5.8.
Immunization .......................................................................................................................61
5.5.9.
Surgery .................................................................................................................................61
5.5.10.
Diet.......................................................................................................................................62
5.6.
Discontinuation of Study Drug ..............................................................................................................62
6.
STUDY PROCEDURES ....................................................................................................................................63
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................63
6.2.
Pretreatment Assessments......................................................................................................................63
6.2.1.
Screening Visits....................................................................................................................63
6.3.
Cycle-Based Assessments......................................................................................................................64
6.3.1.
Day 1 of each 28-Day Cycle (± 2 days after Cycle 1)..........................................................65
6.3.2.
Safety Monitoring Visits (± 2 days): Days 8, 15 and 22 of Cycle 1 and 
Day 15 of Cycle 2 ................................................................................................................66
6.4.
Unscheduled Safety Visits .....................................................................................................................68
6.5.
Assessment of Tumor Response.............................................................................................................68
6.5.1.
Clinical Evaluation after 72 weeks (18 months)...................................................................69
6.6.
At Disease Progression ..........................................................................................................................69
6.7.
End of Study...........................................................................................................................................71
6.8.
Immediate Post-Treatment Safety Follow-up ........................................................................................72
6.9.
Description of Study Procedures............................................................................................................72
6.9.1.
Medical History....................................................................................................................72
6.9.2.
Physical Examination...........................................................................................................72
6.9.3.
Karnofsky Performance Status.............................................................................................73
6.9.4.
Vital Signs............................................................................................................................73
6.9.5.
Electrocardiogram................................................................................................................73
6.9.6.
Adverse Events.....................................................................................................................74
6.9.7.
Prior/Concomitant Medications............................................................................................74
6.9.8.
Laboratory Safety Tests........................................................................................................74
6.10.
Blood Collection ....................................................................................................................................75


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6.11. 
6.12. 
6.13. 
6.14. 
6.15. 
6.16. 
6.19. 
6.20. 
6.21. 
6.22. 
Pregnancy Testing for Females of Childbearing Potential.. ................................................................... 7 6 
Ttunor Iinaging (CT or MRI) ................................................................................................................. 76 
Phannacodynamic Assessments ............................................................................................................. 77 
6 .13 .1. 
Senun Cytokines and Che1nokines ....................................................................................... 77 
6.13.2. 
Circulating Tumor Cells (CTC) - RNA Analysis ................................................................ 77 
SLL/CLL/MCL Molecular Characterization .......................................................................................... 77 
6.14.1. 
FlowCytoinetiy .................................................................................................................... 78 
6.14.2. 
Cytogenetics ......................................................................................................................... 78 
6.14.3. 
Molecular Pathology ............................................................................................................ 78 
Samples for Molecular/Phannacogenomic Testing ................................................................................ 79 
Archival Tumor Tissue .......................................................................................................................... 79 
Bio og1ca Sa1np e Storage ..................................................................................................................... 80 
Efficacy Assessments: Non-Hodgkin Lymphoma ................................................................................. 81 
6.20.1. 
Ttunor Status Assessments ................................................................................................... 81 
6.20.2. 
Method of Assess1nent ......................................................................................................... 81 
6.20.3. 
Timing of Assessments ........................................................................................................ 82 
6.20.4. 
Identification of Index and Non-Index Tumor Lesions ........................................................ 82 
6.20.5. 
Follow-up of Index and Non-Index Tumor Lesions ............................................................. 83 
6.20.6. 
Date of Time Point Response and Progression .................................................................... 85 
6.20. 7. 
Definitions of Tumor Response and Progression ................................................................. 85 
Efficacy Assessments: Chronic Lymphocytic Leukemia ....................................................................... 90 
6.21.1. 
Ttunor Status Assessments ................................................................................................... 90 
6.21.2. 
Method of Assess1nent ......................................................................................................... 90 
6.21.3. 
Timing of Assessments ........................................................................................................ 90 
6.21.4. 
Identification and Follow-up of Tumor Lesions and Organomegaly ................................... 91 
6.21.5. 
Definitions of Tumor Response and Progression ................................................................. 93 
6. 21. 6. 
Ly1nphocytosis Dw'ing Therapy ........................................................................................... 97 
Documentation of Definitive CLL Progression ..................................................................................... 97 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................................................... 98 
7.1. 
Adverse Events ....................................................................................................................................... 98 
7.2. 
Serious Adverse Events .......................................................................................................................... 99 
7.3. 
Describing Adverse Event Relationship to Study Dmg and Study Procedw-es .................................... 100 
7.4. 
Adverse Thug Reactions ....................................................................................................................... 101 
7.5. 
Unexpected Adverse Event .................................................................................................................. 101 
7.6. 
Grading of the Severity of an Adverse Event.. ..................................................................................... 101 
7.7. 
Special Situation Repo1t s ..................................................................................................................... 102 
7.8. 
Investigator Requirements and Instiuctions for Repo1t ing Adverse Events and Serious 
Adverse Events to Gilead ..................................................................................................................... 102 
7 .8.1. 
Special Situation Repo1ting Instiuctions ............................................................................ 105 
7.8.2. 
Gilead Sciences Repo1t ing Requirements for Adverse Events ........................................... 105 
7.8.3. 
Post-Study Repo1ting Requirements .................................................................................. 105 
7.9. 
Clinical Laborato1y Abnonnalities and Other Abnonnal Assessments as Adverse Events or 
Serious Adverse Events ........................................................................................................................ 106 
7.10. 
Toxicity Management .......................................................................................................................... 106 
7 .11. 
Conti·aception Requirements ................................................................................................................ 106 
7.11.1. 
Definitions .......................................................................................................................... 106 
7.11.2. 
Conti·aception Requirements for Female Subjects ............................................................. 107 
7 .11.3. 
Conti·aception Requirements for Male Subjects ................................................................. 108 
7 .11.4. 
Unacceptable Birth Conti·ol Methods ................................................................................. 108 
7.12. 
Procedw-es to be followed in the Event of Pregnancy .......................................................................... 108 
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8.
STATISTICAL CONSIDERATIONS..............................................................................................................110
8.1.
Objectives.............................................................................................................................................110
8.2.
Endpoints .............................................................................................................................................110
8.2.1.
Primary Endpoint ...............................................................................................................110
8.2.2.
Secondary Endpoints..........................................................................................................110
8.2.3.
Exploratory Endpoints........................................................................................................111
8.3.
Analysis Sets........................................................................................................................................111
8.3.1.
Full Analysis Set ................................................................................................................111
8.3.2.
Pharmacokinetic/Pharmacodynamic Analysis Sets............................................................111
8.4.
Data Handling Conventions .................................................................................................................111
8.4.1.
General Methods ................................................................................................................111
8.4.2.
Calculation of Tumor Control Variables............................................................................112
8.5.
Analysis Plan........................................................................................................................................112
8.5.1.
Subject Disposition and Baseline Characteristics...............................................................112
8.5.2.
Efficacy Analyses...............................................................................................................112
8.5.3.
Exposure and Safety Analyses ...........................................................................................114
8.5.4.
Exploratory Analyses .........................................................................................................116
8.6.
Continuous Data Review of PFS Endpoint Rate at 16 weeks (CLL after BCR Targeted 
Therapy, MCL and DLBCL) or 24 weeks (CLL and FL)....................................................................117
8.7.
Power and Sample Size Calculation.....................................................................................................118
8.8.
Multiplicity...........................................................................................................................................120
8.9.
Timing of Analysis...............................................................................................................................120
8.10.
Final Analysis ......................................................................................................................................120
9.
RESPONSIBILITIES........................................................................................................................................121
9.1.
Investigator Responsibilities ................................................................................................................121
9.1.1.
Good Clinical Practice........................................................................................................121
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval.............................................................................................................................121
9.1.3.
Informed Consent...............................................................................................................122
9.1.4.
Confidentiality....................................................................................................................122
9.1.5.
Study Files and Retention of Records ................................................................................122
9.1.6.
Case Report Forms.............................................................................................................124
9.1.7.
Drug Accountability...........................................................................................................124
9.1.8.
Inspections..........................................................................................................................124
9.1.9.
Protocol Compliance..........................................................................................................125
9.2.
Sponsor Responsibilities ......................................................................................................................125
9.2.1.
Protocol Modifications.......................................................................................................125
9.2.2.
Study Reporting and Publication........................................................................................125
9.3.
Joint Investigator/Sponsor Responsibilities .........................................................................................125
9.3.1.
Access to Information for Monitoring................................................................................125
9.3.2.
Access to Information for Auditing or Inspections ............................................................126
9.3.3.
Study Discontinuation........................................................................................................126
9.4.
Independent Review Committee ..........................................................................................................126
10.
REFERENCES .................................................................................................................................................127
11.
APPENDICES ..................................................................................................................................................135
Appendix 1.
Investigator Signature Page..................................................................................................136
Appendix 2.
Study Procedures Table........................................................................................................137


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LIST OF IN-TEXT TABLES
Table 1-1.
GS-339-0102:  Treatment-Emergent Non-hematologic Adverse Events Occurring in 
≥ 10% of Subjects, N=109*....................................................................................................37
Table 4-1.
Required Screening Laboratory Values..................................................................................48
Table 5-1.
Transition of GS-9973 MM formulation to GS-9973 SDD formulation................................54
Table 5-2.
GS-9973 MM Dose Levels.....................................................................................................55
Table 5-3.
GS-9973 SDD Dose Levels....................................................................................................55
Table 5-4.
Dose Modification Guidelines................................................................................................56
Table 5-5.
Examples of Contraindicated Medications in this Study that require prior Gilead 
Medical Monitor discussion and approval..............................................................................59
Table 6-1.
Blood Samples Collected During the Course of the Study.....................................................74
Table 6-2.
Blood Drawing Requirements ................................................................................................75
Table 7-1.
Site Reporting Requirements for Adverse Events ................................................................104
Table 7-2.
Contact Information for Reporting Serious Adverse Events ................................................104
Table 8-1.
Estimated Posterior Mean and 95% Credible Interval of Response Rate with 
Sample Size = 40..................................................................................................................119
Table 8-2.
Estimated Posterior Mean and 95% Credible Interval of Response Rate with 
Sample Size = 20..................................................................................................................119
Table 8-3.
Probability and Sample Size of Claiming a Futility by the End of Study Using 
Futility Criteria Pr(θ<0.2|data) > 0.9 ....................................................................................120
LIST OF IN-TEXT FIGURES
Figure 1-1.
Positive and Negative Regulators of Antigen-dependent BCR Signaling..............................25
Figure 1-2.
GS-9973 Kinome Scan...........................................................................................................28
Figure 1-3.
GS-9973 AUCtau at Steady State ............................................................................................32
Figure 1-4.
GS-9973 Cmax at Steady State.................................................................................................33
Figure 1-5.
Inhibition of Basophil Activation...........................................................................................33
Figure 1-6.
Inhibition of pSYK.................................................................................................................34
Figure 1-7.
GS-339-0102: Investigator Assessed Nodal Responses in CLL (n=41).................................38
Figure 3-1.
Study Schema.........................................................................................................................42
Figure 3-2.
Futility Boundary with Prior Distribution Beta (0.5, 1.5).......................................................44
Figure 5-1.
GS-9973 AUCtau following GS-9973 MM and GS-9973 SDD formulations.........................54


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc. 
333 Lakeside Drive
Foster City, CA 94404
Study Title:
A Phase 2, Open-Label Study Evaluating the Efficacy, Safety, 
Tolerability, and Pharmacodynamics of GS-9973 in Subjects with 
Relapsed or Refractory Hematologic Malignancies
IND Number:
116416
Study Centers 
Planned:
Multiple centers in North America
Objectives:
The primary objective of this study is:

To evaluate the efficacy of GS-9973 in subjects with relapsed or 
refractory hematologic malignancies
The secondary objectives of this study are:

To evaluate the safety and tolerability of GS-9973 in subjects with 
relapsed or refractory hematologic malignancies 

To evaluate GS-9973 exposures  in subjects with relapsed or 
refractory hematologic malignancies
Study Design:
Phase 2, open-label study evaluating the efficacy, safety and tolerability 
of GS-9973 administered twice daily (BID) over multiple 28-day cycles 
in subjects with relapsed or refractory hematologic malignancies.  
Historically the study planned to investigate 5 cohorts of Entospletinib in  
subjects with an chronic lymphocytic leukemia (CLL), mantle cell 
lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), follicular 
lymphoma (FL), and a fifth cohort consisting of the non-FL indolent 
non-Hodgkin lymphomas (iNHL), ie, subjects with 
Lymphoplasmacytoid Lymphoma/ Waldenström macroglobulinemia 
(LPL/WM), Small Lymphocytic Lymphoma (SLL), or Marginal Zone 
Lymphoma (MZL), with a mono-methanesulfonate salt at 800 mg bid of 
the original mono-mesylate (MM) formulation. After completion of 
enrollment of the original CLL cohort the study was amended to include 
the addition of 3 CLL cohorts (1 dose finding prior BCR naïve), 2 prior 
BCR exposure [1 prior BTK inhibitor, and 1 prior PI3K inhibitor]); all 
3 additional cohorts receive a new formulation of GS-9973 designated 
spray dried dispersion [GS-9973 SDD]. The SDD formulation had 
greater bioavilability and lesser drug-drug interactions (no H2 and 
reduce PPI). As of protocol amendment 8, subjects receiving GS-9973 
MM formulation will be transitioned to the GS-9973 SDD formulation 
(Section 5.3.5).


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The 2 CLL cohorts with prior B-Cell receptor (BCR) exposure enroll 
based on the most recent progression followed BCR-exposure. The BCR 
naïve patients cohort designated as  CLL dose ranging cohort  are 
randomly assigned to  one of 3 doses evaluating 100 mg, 200 mg and 
400 mg (200 mg x 2) BID dosing of GS-9973 SDD.
Cohort 
Dose (BID)* 
formulation
CLL
800mg 
Amendment 8: 400mg
MM
Amendment 8: SDD
MCL
800mg
Amendment 8: 400mg
MM
Amendment 8: SDD
DLBCL
800mg
Amendment 8: 400mg
MM
Amendment 8: SDD
FL
800 mg
Amendment 8: 400mg
MM
Amendment 8: SDD
Other iNHL
800mg
Amendment 8: 400mg
MM
Amendment 8: SDD
CLL prior BCR inhibitor 
naïve 
400mg
200mg
100mg
SDD
SDD
SDD
CLL
Prior BTK inhibitor
400mg
SDD
CLL
Prior PI3K inhibitor
400mg
SDD
*Note 800mg of  MM is PK/PD equivalent of 400 mg SDD
For subjects with MCL, DLBCL, FL, CLL (except for the CLL dose 
ranging cohort), a Bayesian, continuous data review, which will be 
conducted independently, will be used to update the estimates of 
progression-free survival (PFS) rates at 16 weeks (CLL after BCR 
targeted therapy, MCL and DLBCL) or 24 weeks (CLL and FL), 
assessing the efficacy once each subject’s primary endpoint becomes 
available for a cohort. Because it consists of 3 different histologies, 
accrual to the ‘non-FL iNHL’ cohort will continue to a maximum of
45 subjects without interim review. The continuous data review for 
MCL, DLBCL, FL and CLL cohorts (except for the CLL dose ranging 
cohort) will be conducted independently.  Futility assessment will begin 
when the first eligible 10 subjects’ primary endpoints become available.
Given the initial activity seen in the CLL cohort, which was treated with 
the original formulation, and improved PK of the new formulation, 
exploration of lower doses will be pursued in the 3 CLL cohorts
{Sharman 2015}.  Subjects who are treated at lower doses of GS-9973 


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SDD may have their dose escalated up to 400 mg (200 mg x 2) BID, if 
after 8 weeks there is less stable disease or at the time of disease 
progression, if the investigator feels it is in the subject’s best interest.
Up to 40 subjects will be studied in each cohort of MCL, DLBCL, FL 
and CLL, up to 45 subjects will be enrolled in the non-FL iNHL cohort; 
up to 60 subjects will be enrolled in each cohort of CLL dose ranging, 
CLL prior BTK inhibitor exposure and CLL prior PI3K inhibitor 
exposure).
In the BCR targeted therapies cohorts, subjects who have progressed will 
be enrolled to either simple progression (Non-Richter’s) or 
transformation (Richter’s) to Richter’s or Richter’s-like disease. A
biopsy is not required but encouraged if there is a clinical concern of 
possible transformation. In each BCR targeted therapies sub-cohort
a) progression (Non- Richter’s) or b) transformation (Richter’s), a 
separate futility assessment will occur after the first 10 subjects are 
accrued in each sub-cohort.  Thereafter, continuous data review may be 
conducted when a new primary endpoint becomes available.

If the futility criterion is not met, subsequent subjects will be enrolled 
until a total number of 20 (Richter’s) or 40 (Non-Richter’s) subjects 
per cohort.  The CLL subjects who were previously treated with BCR 
inhibitors will be recruited for a cohort dosed at 400 mg twice daily 
(BID) of GS-9973 SDD.

The sponsor may consider terminating enrollment to that cohort, 
taking into account efficacy, drug exposure data, and subtype 
(for DLBCL) unless there are subjects who remain on treatment and 
have not yet reached 16 weeks (CLL who have failed prior BCR 
therapy, MCL and DLBCL) or 24 weeks (CLL and FL).  In this case, 
enrollment will be suspended until the next on-going subject primary 
endpoint becomes available and another data review is conducted. If, 
after review of all available subjects, the futility boundary has still 
been crossed and low  drug exposure or subtype (DLBCL) does not 
explain the lack of activity, enrollment to that malignancy will be 
terminated
Number of 
Subjects Planned:
185 to 385
Target 
Population:
Subjects with relapsed or refractory hematologic malignancies
Duration of 
Treatment:
Until progression of disease, unacceptable toxicity, or withdrawal of 
consent
Safety Review:
Safety data will be reviewed continuously during the course of the study.


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Main Diagnosis 
and Eligibility 
Criteria:
(see Protocol for 
Details)
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible 
for participation in this study:
1) Male or female 18 years of age
a) Diagnosis of B-cell iNHL, DLBCL, MCL (mantle cell, nodal, 
diffuse or blastoid), or CLL, as documented by medical records 
and with histology based on criteria established by the World 
Health Organization. If the subject has DLBCL, subtyping is 
required.  Submission of 15 unstained slides is required for 
subtyping if the subtype is not already known.  Subjects for whom 
tissue is not available but the subtype is already known may be 
included if pathology report including the subtype is provided.
b) If the subject has iNHL, the lymph node histology report 
confirms 1 of the following subtypes:
i)
FL Grade 1, 2, or 3a
ii) SLL (ie, SLL/CLL histology with an absolute lymphocyte 
count of < 5 x 109/L at diagnosis and on Screening laboratory 
assessment performed within 35 days prior to the start of 
study drug administration)
iii) LPL/WM
iv) MZL (splenic, nodal, or extranodal)
2) For institutions that have Phase 3 or Phase 4 protocols studying 
idelalisib (Zydelig): subjects with malignancies being studied in 
these protocols must be a screen failure in the respective idelalisib 
protocol
3) Prior treatment for lymphoid malignancy and requiring treatment for 
progressive disease. Criteria for progressive disease is established
Cheson criteria for NHL and by  IWCLL criteria for CLL, and for 
LPL/WM patients per Update on Recommendations for Assessing 
Response from the Third International Workshop onWaldenström’s 
Macroglobulinemia
4) (see Section 4 for details)
a) Subjects with denovo DLBCL for whom there is no curative 
option with conventional treatment
b) If the subject has MCL, iNHL, or BCR based therapy naïve CLL, 
the prior treatment must be comprised of at least 1 of the following:
i)
regimen containing a therapeutic antibody administered for 
≥2 doses of antibody treatment
ii) regimen containing 1 cytotoxic agent administered for 
2 cycles of cytotoxic treatment


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iii) regimen containing yttrium90-ibritumomab tiuxetan or 
iodine131-tositumomab
iv) experimental therapy as part of a clinical trial protocol
c) The previously BCR treated patients will be limited to subjects 
with CLL (other BCR targeted therapies may be accepted after 
approval of the medical monitor) only in the context of this 
cohort are Richter’s transformation eligible.
i)
CLL subjects whom have had more than 1 BCR targeted 
therapy will be enrolled into the cohort of the most recent 
treatment ibrutinib or idelalisib received prior to progression.
5) Presence of radiographically measurable progressive disease as
defined  using Cheson criteria for NHL, and iNHL and by IWCLL 
criteria for CLL;  lymphadenopathy or extranodal lymphoid 
malignancy (defined as the presence of ≥1 lesion that measures 
2.0 cm in the longest diameter [LD] and 1.0 cm in the longest 
perpendicular diameter [LPD] as assessed by CT or MRI) ; 
a) Subjects with LPL/WM who do not have radiographically 
measurable progressive disease must have a monoclonal serum 
IgM > 2x ULN, as verified by serum protein electrophoresis 
(SPEP) and with lymphoplasmacytic marrow involvement are 
eligible.  LPL/WM enrollment is limited to those sites which 
have cryoglobulin analysis capabilities
6) All acute toxic effects of any prior antitumor therapy resolved to 
Grade 1 before the start of study drug (with the exception of 
alopecia [Grade 1 or 2 permitted], neurotoxicity [Grade 1 or 
2 permitted], or bone marrow parameters [Grade 1, 2, or 3 permitted)
7) Karnofsky performance status of 60
8) Life expectancy of at least 3 months
9) Required screening laboratory data (within 5 weeks prior to 
administration of study drug) 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 used for 
screening must be obtained within the screening period and should 
be the most recent measurement obtained. Subjects with any degree 
of neutropenia, thrombocytopenia, or anemia with documentation 
that it is due to malignancy may enroll.


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Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hematopoietic
ANC
0.5 x 109/L
Platelets
50 x 109/L
Hemoglobin
80 g/L (8.0 g/dL)
Hepatic
Serum total 
bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome 
or hemolysis)
Serum ALT
2.5 x ULN
Serum AST
Renal
Serum 
creatinine
OR
Estimated 
creatinine 
clearance
< 1.5 x ULN
OR
> 60 ml/min as calculated by the Cockroft-Gault method
Coagulation
INRa
< 1.7
Pregnancy
-HCGb
Negative
Infection
HIV
Negative HIV antibody
HBV
Negative HBsAg and negative HBc antibody
HCV
Negative viral RNA (if HCV antibody is positive)
a
For subjects on anticoagulative therapy the required value is < 3.0
b
For women of childbearing potential only; serum -HCG must be negative during screening 
and serum -HCG or urine dipstick pregnancy test must be negative at start of study therapy
10) For female subjects of childbearing potential, willingness to abstain 
from heterosexual intercourse or use a protocol-recommended 
method of contraception from the screening visit throughout the 
study treatment period and for 30 days following the last dose of 
GS-9973. See Section 7.11 for information regarding 
recommendations for contraception
11) 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 drug throughout the study 
treatment period and for 90 days following the last dose of 
GS-9973or GS-9973 SDD and to refrain from sperm donation from 
the start of study drug throughout the study treatment period and for 
90 days following the last dose of GS-9973 or GS-9973 SDD . See 
Section 7.11 for information regarding recommendations for 
contraception
12) Willingness to comply with scheduled visits, drug administration 
plan, imaging studies, laboratory tests, other study procedures, and 
study restrictions


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13) Have the ability to understand and sign a written informed consent 
form, which must be obtained prior to initiation of any study specific 
procedures
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not eligible 
for study participation:
1) Known histological transformation from iNHL or CLL to an 
aggressive form of NHL (ie, Richter transformation) except if the 
CLL patient is enrolling in the BCR previously treated cohort 
(see inclusion 3C).  Subjects who have a history of iNHL or CLL 
with a subsequent confirmed high grade histology will be considered 
transformed for purpose of this study and excluded if they are not 
part of the CLL BCR previously treated cohort. Note: Biopsy 
documentation of the absence or presence of transformation is not 
required
2) Known active central nervous system or leptomeningeal lymphoma. 
Note: Central nervous system imaging is only required in subjects with 
suspected lymphomatous involvement based on symptoms or signs
3) Presence of known intermediate- or high-grade myelodysplastic 
syndrome (ie, subjects are excluded who have 5 bone marrow 
blasts; karotypic abnormalities other than normal, Y deletion, 
5q deletion, or 20q deletion; or 2 lineages of cytopenias) 
{Greenberg 1997}.
4) Because they are likely to interfere with GS-9973 absorption, current 
therapy with agents that reduce gastric acidity, including but not 
limited to proton pump inhibitors
5) History of any prior lymphoid malignancy other than registrational 
histology except for CLL subjects with prior BCR therapy
a) Subjects with diagnoses other than CLL who were previously 
treated with a BCR inhibitor are excluded from this study.  
6) History of non-lymphoid malignancy except for the following: 
adequately treated local basal cell or squamous cell carcinoma of the 
skin, cervical carcinoma in situ, superficial bladder cancer, 
asymptomatic prostate cancer without known metastatic disease and 
with no requirement for therapy or requiring only hormonal therapy 
and with normal prostate-specific antigen for 1 year prior to start of 
study therapy, other adequately treated Stage 1 or 2 cancer currently 
in complete remission, or any other cancer that has been in complete 
remission for ≥ 5 years


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7) Evidence of ongoing systemic bacterial, fungal, or viral infection at 
the time of start of study drug. Note: Subjects with localized fungal 
infections of skin or nails are eligible.
8) Ongoing, drug-induced liver injury, chronic active Hepatitis C Virus 
(HCV), HIV, chronic active Hepatitis B Virus (HBV), alcoholic liver 
disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, 
ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis 
of the liver, or portal hypertension
9) Ongoing (within the past 6 weeks) hepatic encephalopathy
10) Ongoing drug-induced pneumonitis
11) Ongoing inflammatory bowel disease
12) Ongoing alcohol or drug addiction as determined by investigator 
13) Pregnancy or breastfeeding
14) History of prior allogeneic bone marrow progenitor cell or solid 
organ transplantation
15) Ongoing immunosuppressive therapy, including systemic 
corticosteroids for treatment of lymphoid malignancy. Concurrent 
use of methotrexate for rheumatologic conditions is permitted.  
Note: Subjects may use topical, enteric, or inhaled corticosteroids 
as therapy for comorbid conditions and systemic steroids for 
autoimmune anemia and/or thrombocytopenia. Ongoing use of 
low-dose systemic corticosteroids (5 mg/day of methylprednisolone
or equivalent) for rheumatologic conditions is permitted. During 
study participation, subjects may receive systemic or other 
corticosteroids needed for treatment-emergent comorbid conditions. 
See next entry for exception related to steroids
16) Concurrent participation in an investigational drug trial with 
therapeutic intent defined as prior study therapy within 21 days prior 
to study drug.  Exception: the cohorts with relapsed CLL following  
BCR pathway inhibitors whom in the opinion of the investigators 
cannot have a 21 day washout period  >5 half lives washout period 
will be allowed, along with  up to 20 mg of prednisone at the start of 
the trial, for control of disease related symptoms, with planned taper 
over 2 weeks
17) Any other prior or ongoing condition that, in the opinion of the 
investigator, could adversely affect the safety of the subject or impair 
the assessment of study results
Cytokine and 
Chemokines:
To assess the biological effects of GS-9973, cytokine and chemokine 
levels will be measured in all assessable subjects.


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Resistance 
Mechanisms: 
Test Product, Dose, 
and Mode of 
Administration: 
Criteria for 
Evaluation: 
CONFIDENTIAL 
Final 
Amendment8 
To assess changes in the molecular signature of malignant cells 
following treatment with GS-9973 or GS-9973 SDD to explore 
mechanisms of resistance to GS-9973 or GS-9973 SDD, blood for 
circulating tumor cells will be obtained from SLL, CLL, and MCL 
subjects. 
Oral administrntion ofup to 800 mg GS-9973 BID, taken fasting in the 
NHL and iNHL subsets. 
Oral administrntion of 100 mg, 200 mg or 400 mg (200 mg x 2) GS-9973 
SDD BID, taken fasting in the CLL dose ranging coho1i of subjects not 
previously treated with BTK inhibitors or PBK inhibitors. 
Oral administration of 400 mg (200 mg x 2) GS-9973 SDD BID, taken 
fasting in the CLL coho1is of subjects refracto1y to or intolerant of BTK 
inhibitors or PBK inhibitors 
Primary Endpoint 
• 
Progression free survival (PFS) rate at 16 weeks (CLL after BCR 
targeted therapy, MCL and DLBCL) or 24 weeks (CLL and iNHL). 
PFS is defined as the interval from the first dose of GS-9973 or 
GS-9973 SDD to the earlier of the first documentation of definitive 
disease progression or death from any cause. 
Secondary Endpoints 
• 
Safety: all abnonnal laborato1y data, and AEs. Safety will be 
assessed by grading of laborato1y values and AEs according to the 
NCI Common Tenninology Criteria for Adverse Events (CTCAE) 
version 4.03 
• 
Tumor response: objective response rate (ORR), duration of response 
(DOR), and time to response (TTR). 
Exploratory Endpoints 
I 
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Statistical Methods:
Analysis Methods
A Bayesian, continuous data review approach using Beta-Binomial 
model will be used to update the estimates of progression-free survival 
(PFS) rates at 16 weeks (CLL after BCR targeted therapy, MCL and 
DLBCL) or 24 weeks (CLL and FL), assessing the efficacy once each 
subject’s primary endpoint becomes available for a malignancy. The 
response is defined as subject not experiencing progression or death by 
week 16 (CLL after BCR targeted therapy, MCL and DLBCL) and 
24 (CLL and FL).  In this Beta-Binomial model, a binomial likelihood 
for the data and a conjugate Beta (0.5, 1.5) prior distribution for response 
rate θ are assumed. Statistical inference and decision-making will be 
based on the posterior distribution of response rate θ, which is a Beta 
distribution with parameters x+0.5 and n-x+1.5, where x is the observed 
number of subjects who achieve the response and n is the total number of 
subjects who have a response result for a given malignancy.
For the primary analysis of the primary efficacy endpoint, PFS will be 
described using Kaplan-Meier methods in the full analysis set. Medians, 
ranges, the proportion of subjects who are progression-free at 
Week 16 (CLL after BCR targeted therapy, MCL and DLBCL) and 
24 (CLL and iNHL) will be presented. Data for subjects with iNHL will 
be presented by histologic subtype (ie, FL, SLL, LPL, and MZL). Data in 
the CLL prior BTK inhibitor exposed and prior PI3K inhibitor exposed 
cohort will be represented separately. Data in the CLL dose ranging 
cohort will be presented by dose level. The findings of the Independent 
Review Committee (IRC) will be considered primary for analyses of 
PFS. The full analysis set includes all subjects who receive 1 dose of 
GS-9973/GS-9973 SDD.
Sample Size Calculation
With the decision rule employed, and assuming that enrollment will be 
terminated once the futility criterion is met, a sample size of 40 subjects 
in a cohort gives this design a high probability (~84%) of claiming 
futility when the true response rate is low (0.1). When the true response 
rate is high (0.5), this design has a low probability (0.15%) of claiming 
futility.
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
C 
degrees Celsius
F
degrees Fahrenheit
ADR
adverse drug reaction
AE
adverse event
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
AM
Morning
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the concentration versus time curve
AUCtau
area under the plasma concentration versus time curve over the dosing interval (tau)
BAT
Basophil Activation Test
BCR
B-cell receptor
BCRP
breast cancer resistance protein (ABCG2 gene product)
BID
bis in die (twice a day)
BLNK
B-cell linker protein
BTK
bruton tyrosine kinase
BUN
blood urea nitrogen
Cmax
maximum observed concentration of drug
CFR
(United States) Code of Federal Regulations
CI
confidence interval
CLL
chronic lymphocytic leukemia
cm/s
centimeter per second
CR
complete response
CRO
contract research organization
CT
computed tomography
CTA
clinical trial application
CTC
circulating tumor cells
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DLBCL
diffuse large B-cell lymphoma
DICOM
Digital Imaging and Communication in Medicine
dL
Deciliter
DNA
deoxyribonucleic acid
DOR
duration of response
DSPH
Drug Safety and Public Health
EC
ethics committee


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EC50
50% effective inhibitory concentration
ECG
Electrocardiogram
eCRF
electronic case report form(s)
EDC
electronic data capture
EOS
end of study
EU
European
FDA
(United States) Food and Drug Administration
FL
follicular lymphoma
FLIPI
follicular lymphoma international prognostic index
FNA
Fine needle aspirate
FSH
follicle stimulating hormone
g
Gram
GCP
Good Clinical Practice (Guidelines)
G-CSF
granulocyte  colony-stimulating factor
GM-CSF
granulocyte-macrophage colony-stimulating factor
GSI
Gilead Sciences, Inc.
h, hr
Hour
HBc
hepatitis B core
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
-HCG
beta human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HL
Hodgkin lymphoma
IB
investigator’s brochure
IC
immune-complex
IC50
concentration necessary to achieve 50% inhibition of target
ICF
informed consent form
ICH
International Conference on Harmonisation
ID
Identification
IEC
independent ethics committee
IFE
immunofixation electrophoresis
IND
Investigational New Drug (Application)
iNHL
indolent non-Hodgkin lymphoma
IRB
institutional review board
IRC
independent review committee
ITAM
immunoreceptor tyrosine-based activation motifs
IWCLL
International Workshop on Chronic Lymphocytic Leukemia
IxRS
Interactive Voice/Web Response System
K2-EDTA
potassium-ethylenediaminetetraacetic acid


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kg
Kilogram
L
Liter
LD
longest diameter
LDH
lactate dehydrogenase
LPD
longest perpendicular diameter 
LPL
lymphoplasmacytoid lymphoma
LVD
longest vertical dimension
MAPK
mitogen-activated protein kinase
MCL
mantle cell lymphoma
mg
Milligram
mL
Milliliter
mm
Millimeter
MMRM
mixed model for repeated measures
MR
minor response
MRI
magnetic resonance imaging
mTOR
mammalian target of rapamycin
MZL
marginal zone lymphoma
NCI
National Cancer Institute
ND
no disease
NE
not evaluable
ng
Nanogram
NHL
non-Hodgkin lymphoma
nM
Nanomolar
NOAEL
no observable adverse effect level
OATP1B1/3
organic anion transporting polypeptide 1B1/3 (SLCO1B1/3 gene products)
OS
overall survival
ORR
objective response rate
PBMC
peripheral blood mononuclear cells
PD
progressive disease
PET
positron-emission tomography
PFS
progression-free survival
P-gp
multidrug resistance protein 1 (P-glycoprotein, MDR1, ABCB1 gene product)
PI
principal investigator
PI3K
phosphatidylinositol 3-kinase
PK
pharmacokinetic(s)
PM
evening
PPD
product of the perpendicular diameters
PR
partial response
pSYK
phospho-spleen tyrosine kinase
QD
once-daily


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REB
research ethics board
RNA
ribonucleic acid
SD
stable disease
SDD
spray-dried dispersion tablets
STD
standard deviation
SADR
serious adverse drug reaction
SAE
serious adverse event
SLL
small lymphocytic lymphoma
SOP
standard operating procedure
SPD
sum of the products
SPEP
serum protein electrophoresis
SUSAR
Suspected Unexpected Serious Adverse Reaction
SYK
spleen tyrosine kinase
Tmax
time (observed time point) of Cmax
t½
an estimate of the terminal elimination half-life of the drug, calculated by dividing the 
natural log of 2 by the terminal elimination rate constant (λz)
TNF
tumour necrosis factor
TNF-α
tumour necrosis factor-α
TTF
time to treatment failure
TTR
time to response
UGT1A1
uridine 5’-diphospho-glucuronosyltransferase 1 family, polypeptide A1
ULN
upper limit of the normal range
US
United States
VGPR
very good partial response
WHO
World Health Organization
WM
Waldenström macroglobulinemia
αIgM
anti-IgM
β
population mean slope
z
terminal elimination rate constant, estimated by linear regression of the terminal 
elimination phase of the concentration of drug versus time curve


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1.
INTRODUCTION
1.1.
Background
B-cell lymphoid malignancies comprise the most common hematologic malignancies 
{Surveillance Epidemiology and End Results (SEER) Program 2011}. These cancers arise in 
organs such as blood, bone marrow, spleen, and liver from the accumulation of monoclonal 
B lymphocytes in lymph nodes. Among the variants of these cancers are non-Hodgkin 
lymphomas (NHL) – including diffuse large B-cell lymphoma (DLBCL), indolent non-Hodgkin 
lymphoma (iNHL), and mantle cell lymphoma (MCL) - and chronic lymphocytic leukemia 
(CLL). These disorders are characterized by lymphadenopathy that is frequently disturbing for 
patients and can sometimes induce life-threatening organ dysfunction; patients may also have 
constitutional symptoms (fevers, night sweats, and/or weight loss) and fatigue {Diehl 2004, 
Dighiero 2008, Salles 2007, Williams 2010}.
The goal of therapy for these diseases is to induce tumor regression and delay tumor progression 
in order to control disease-related complications and potentially extend life. Patients who require 
treatment are commonly given chemotherapeutic and/or immunotherapeutic agents {Eichhorst 
2010, Friedberg 2011, Gribben 2011, Jost 2007, Wierda 2010, Zelenetz 2011}. Among patients
with iNHL, CLL, and MCL, front-line combination therapies can be effective in providing 
durable remissions {Hallek 2010, Lenz 2005, Recher 2011, Santoro 1987, Schulz 2007}. In 
DLBCL such front-line regimens can be curative in the majority of patients {Kuruvilla 2009, 
Recher 2011, Santoro 1987}. However, most treated patients with iNHL, CLL, and MCL will 
eventually experience disease relapse. Some patients with DLBCL or NHL will experience 
recurrent disease even with initial induction therapy and later salvage therapy. For any of these 
cancers, further sequential therapies are given in an attempt to control disease manifestations. 
However, progressive resistance to treatment develops despite the use of agents with differing 
mechanisms of action. Patients with relapsed progressive disease have a poor prognosis; median 
survival for these groups of patients is generally 2 years {Di Bella 2010, Friedberg 2011, Goy 
2005, Hess 2009, Keating 2002a, Moskowitz 2009, Wierda 2010}. Agents with novel 
mechanisms of action are needed to offer additional treatment options for patients with lymphoid 
malignancies who are experiencing progressive lymphadenopathy or symptoms due to disease 
progression. 
1.2.
Chronic Lymphocytic Leukemia
CLL is a neoplasm 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, Surveillance Epidemiology and End Results (SEER) Program 2011}.  While some 
patients never require treatment, many will need therapy for disfiguring or obstructing 
lymphadenopathy, debilitating constitutional B symptoms (fevers, night sweats, fatigue, weight 
loss) {Sant 2010}, or recurrent cytopenias and infections {Keating 2002b, Perkins 2002}.  CLL 
is largely a disease of the elderly; at diagnosis, 70% of patients are 65 years of age and the 
median age is 72 years {Surveillance Epidemiology and End Results (SEER) Program 2011}.  


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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}.  However, in elderly patients or in those with comorbid 
conditions, such regimens are associated with less efficacy and greater toxicity {Eichhorst 2009, Tam 
2008, Thurmes 2008}.  
These health constraints in older or compromised patients have prompted noncytotoxic 
approaches to therapy.  Alternative immunotherapeutics have been developed, such as 
monoclonal antibodies: alemtuzumab (targeting CD52 on mature lymphocytes) {Keating 
2002a}or ofatumumab (inhibiting CD20 necessary for early stage B-cell activation) {Wierda 
2010}.  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, Zelenetz 2011}, or ofatumumab (inhibiting CD20 necessary for early stage B-cell 
activation) {Wierda 2010}.  Addition of high-dose methylprednisone to rituximab can extend 
median PFS to 12 months, but this combination is commonly associated with severe 
hyperglycemia and frequent life-threatening or fatal infections {Bowen 2007, 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}. New noncytotoxic, well-tolerated, and convenient therapies 
are needed in order to enhance and prolong tumor control in patients with comorbid conditions. 
Richter’s syndrome (RS) is characterized by the development of high-grade non-Hodgkin’s 
lymphoma (NHL) in a patient with chronic lymphocytic leukemia (CLL) or small lymphocytic
lymphoma, associated with typically unfavorable clinical response to standard therapies.
1.3.
Non-Hodgkin Lymphoma
NHL comprises a diverse group of malignancies arising in lymphoid tissue.  The neoplasms 
represent a progressive clonal expansion of B cells, T cells, or natural killer cells arising from the 
accumulation of genetic lesions that affect proto-oncogenes or tumor suppressor genes, resulting 
in cell immortalization {Friedberg 2008b}.  A B-cell origin is documented in 80% to 85% of 
cases.  Chromosomal translocations that reduce lymphocyte apoptosis are typical.  In the 
United States, NHL is the sixth most common cancer; it is estimated that during the year 2010, 
~66,000 new patients were diagnosed and ~20,000 patients died of NHL {Jemal 2010}.  In 
Europe, it is anticipated that ~74,000 new cases occurred, leading to ~31,000 deaths {Ferlay 
2010}.  As mortality due to other causes has declined, the incidence of lymphoma has increased; 
almost exclusively a disease of adulthood, diagnosis most commonly occurs in patients between 
50 and 70 years of age {Friedberg 2008b}
Of the B-cell NHLs, 4 subtypes (follicular lymphoma [FL], small lymphocytic lymphoma [SLL], 
lymphoplasmacytoid lymphoma [LPL] [also known as Waldenström macroglobulinemia], and 
marginal zone lymphoma [MZL]) have differing pathological features {Campo 2011}, but are 
generally included among those characterized as indolent in nature because they have common 
clinical presentations, show a slowly progressive natural history, and generally require similar 
treatments {Pileri 2004}.  Patients with iNHL typically present with painless and gradually 
progressive peripheral adenopathy {Friedberg 2008b, Salles 2007}.  Some patients may 
experience primary extra-nodal involvement or B symptoms (ie, temperature > 38°C, night 
sweats, or weight loss > 10% from baseline within 6 months).  As the disease advances, fatigue 


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is often noted.  Bone marrow involvement is common and may result in cytopenias.  Patients 
with iNHL commonly have splenomegaly and hepatomegaly.  Elevated serum levels of lactate 
dehydrogenase (LDH) reflect general tumor burden.  Abnormal transaminase values may 
indicate hepatic involvement or chronic lymphoma-related inflammation.
Computed tomography (CT) or magnetic resonance imaging (MRI) scans of the neck, chest, 
abdomen, and pelvis, as well as bone marrow aspirate and biopsy, are employed to stage iNHL 
{Zelenetz 2010}.  Positron-emission tomography (PET) is sometimes used to identify occult 
sites of disease in patients who appear to have localized iNHL based on CT and bone marrow 
biopsy {Seam 2007}.  The Ann Arbor staging system categorizes patients by whether they have 
a single site of involvement (Stage 1), ≥ 2 sites of disease on the same side of the diaphragm 
(Stage 2), sites of disease on both side of the diaphragm (Stage 3), or disseminated disease 
(Stage 4) {Lister 1989}.  For FL, the Follicular Lymphoma International Prognostic Index 
(FLIPI) has been developed to define outcomes {Solal-Celigny 2004}.  The FLIPI characterizes 
patients in terms of 5 adverse prognostic factors; age > 60 years, Ann Arbor stage III-IV, 
hemoglobin < 12 g/dL, number of nodal areas > 4, and serum LDH above normal.  Patients are 
scored as low risk (≤1 factor), intermediate risk (2 factors), or high risk (≥ 3 factors).  While a 
protracted course is common in iNHL, life expectancy varies by the types of factors represented 
in the FLIPI score; median survival is ~4 to > 10 years from diagnosis depending upon such 
prognostic characteristics {Solal-Celigny 2004}.  Patients are at risk of transformation of iNHL to 
aggressive DLBCL at a rate of 2% to 3% per year {Bastion 1997, Montoto 2007}; such 
transformation is usually associated with a poor clinical outcome.
Radiation therapy to involved sites is the most common treatment for the infrequent patients with 
localized iNHL (Stage 1 or non-bulky Stage 2 disease) {Tsang 2005, Wilder 2001}.  Systemic 
therapy is considered for the majority of patients with iNHL, in whom extensive lymphoma 
(Stage 2 bulky, Stage 3, or Stage 4 disease) is present {Zelenetz 2010}.  Watchful waiting is 
possible but patients are generally treated if they have lymphoma-related symptoms or end-organ 
dysfunction, bulky disease, cytopenias, persistent disease progression, or a strong preference for 
immediate therapy.  Because iNHL requiring systemic therapy is essentially incurable and 
patients may be older and have comorbidities, the goal of therapy is primarily to alleviate 
lymphoma-related symptoms and prolong the progression-free interval.  
For older or infirm patients, single-agent rituximab or alkylating agents such as 
cyclophosphamide or chlorambucil may be administered {Zelenetz 2010}.  Most patients receive 
chemoimmunotherapy in which rituximab is given together with cyclophosphamide, 
doxorubicin, vincristine, and prednisone (R-CHOP) {Buske 2009, Hiddemann 2005} or 
cyclophosphamide, vincristine, prednisone (R-CVP) {Marcus 2005, Marcus 2008}.  Alternative 
regimens include rituximab with the alkylating agent, bendamustine, or fludarabine- or 
mitoxantrone-based therapy that may include an alkylating agent {Herold 2007, Zinzani 2004}.  
Meta-analysis data from randomized trials indicate that the addition of rituximab to 
chemotherapy not only improves tumor control, but also extends overall survival (OS) in 
previously untreated patients {Schulz 2007}.  Based on controlled trials, rituximab has formal 
regulatory approval for use as a component of front-line chemoimmunotherapy of iNHL.  In 
addition, maintenance or consolidation therapy with rituximab or yttrium90-ibritumomab tiuxetan 
has been shown to prolong PFS {Morschhauser 2008, van Oers 2006, Vidal 2009}.


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Despite the chemosensitivity of iNHL to front-line therapy, existing systemic therapies for iNHL 
are not typically curative.  Some patients will be refractory to initial therapy and most patients 
will ultimately relapse.  Several treatments have received regulatory approval in the 
United States and/or Europe for treatment of refractory or relapsed disease, including rituximab, 
yttrium90-ibritumomab tiuxetan, iodine131-tositumomab, and bendamustine.  The principal 
support for use in these settings has comprised non-randomized single-arm trials that have 
focused on documenting treatment-related tumor responses in populations of patients with 
disease that has become resistant to either alkylating agents or rituximab immunotherapy 
{Friedberg 2008a, Kaminski 2005, Maloney 1997, Vose 2000, Witzig 2002}. 
Yttrium90-ibritumomab tiuxetan and iodine131-tositumomab use has been limited because of 
medical and practical restrictions on the use of these agents; these drugs are contraindicated in 
patients with substantial pre-existing myelotoxicity or bone marrow lymphoma involvement. The 
use of these agents is constrained by the complexity of dosimetry calculations and drug 
preparation, the need for administration by specifically trained clinicians at specially equipped 
sites, protracted Grade 3-4 hematological toxicity that commonly results in infectious 
complications and impedes subsequent therapy, and long-term risks of hypothyroidism.  
Other clinical approaches that have been reported include alkylating agent monotherapy, 
alkylating-agent-based combination therapy (CVP, CHOP), or administration of purine 
analogues (fludarabine, cladribine) {Zelenetz 2010}.  Similarly, patients have also been treated 
with bortezomib or lenalidomide {Di Bella 2010, Goy 2009, Witzig 2002}. 
Due to the acquisition of drug resistance, progressively less activity is observed, particularly 
when administering previously used therapies; the disease course is characterized by a 
continuous decrease in the quality and the duration of tumor response with each subsequent 
treatment {Salles 2007}.  Patients face the burden of cumulative myelosuppressive toxicity, a 
problem that has been documented with fludarabine {Janikova 2009} and commonly limits 
continued therapy with cytotoxic agents such as bendamustine {Friedberg 2008a, Kahl 2010}.  In 
addition, there is a well-documented risk of myelodysplasia and/or acute myelogenous leukemia 
associated with use of alkylating agents, doxorubicin, fludarabine, iodine131-tositumomab, and 
Y90-ibritumomab tiuxetan {Friedberg 2006}.  Consequently, new therapies with novel 
mechanisms of action are needed to offer additional treatment options for patients with iNHL.  
The need is especially acute in those patients whose disease has become refractory to existing 
chemoimmunotherapeutic approaches, particularly in those with lymphoma that is refractory to 
both rituximab and alkylating agents. 
1.4.
Spleen Tyrosine Kinase
1.4.1.
Spleen Tyrosine Kinase in Hematologic Malignancies
Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily 
expressed in cells of hematopoietic lineage. It is an important mediator of immunoreceptor 
signaling in macrophages, neutrophils, mast cells, and B cells. SYK contains 2 adjacent SH2 
domains that bind to immunoreceptor tyrosine-based activation motifs (ITAMs) to 
autophosphorylate and activate the enzyme. This allows SYK to phosphorylate its specific 
substrates including other enzymes and adaptor proteins, orchestrating a complex series of 
cellular responses such as cell proliferation, differentiation, survival, and phagocytosis. 


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Recent studies have suggested a role for the dysregulation of the tyrosine kinase SYK in B-cell 
malignancies.  SYK is expressed in B-cells and is essentially involved in multiple signal 
transduction pathways downstream of the B-cell receptor (BCR).  In this process, SYK
trans-autophosphorylates, and activates effector molecules such as PLC, PI3K, and 
mitogen-activated protein kinase (MAPK) and their associated signaling pathways, to induce a 
variety of responses including: proliferation, survival, differentiation, anergy, and apoptosis 
(Figure 1-1).  In B-cells, GS-9973 effectively blocks BCR-mediated activation and proliferation 
(data on file). Additionally, the BCR can deliver antigen-independent signals that have also been 
postulated to require SYK activity.  Both antigen-dependent and independent signals have been 
implicated in the pathogenesis of several common B-cell malignancies, including CLL, DLBCL, 
FL, MCL, MZL, and B-lineage acute lymphoblastic leukemia (B-ALL) {Efremov 2011}.  As a 
result, inhibitors of SYK activity are an attractive therapeutic option for hematopoietic B-cell 
lymphomas and other NHL varieties where SYK inhibition would prevent B-cell 
receptor-mediated signaling and therefore the uncontrolled growth of lymphoma cells.
Figure 1-1.
Positive and Negative Regulators of Antigen-dependent BCR 
Signaling
Source: {Efremov 2011}
1.4.2.
Clinical Experience in Hematologic Malignancies treated with SYK 
Inhibitors
Positive results have been reported from a Phase 2 clinical trial with the putative SYK inhibitor 
fostamatinib showing objective anti-tumor responses in CLL and DLBCL patients {Friedberg 
2010}. These responses occurred despite off target toxicities that limited drug exposure.  
GS-9973 is a highly selective inhibitor of SYK and hence has the potential for an improved 
efficacy and tolerability profile in patients with hematologic malignancies (see Section 1.6).
SHP1 
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1.4.3.
Mechanism of action of SYK Target Inhibition
1.4.3.1.
Circulating Tumor Cells (CTC)
Determining levels of target inhibition is a key element in the evaluation of new agents. In vitro 
experiments demonstrated that treatment of malignant B-cell lines with GS-9973 inhibited the 
phosphorylation of key BCR signaling related nodes including pSYK, pBTK, pAKT, pS6, 
pMEK, pERK, and pNF-kB among others. GS-9973 inhibited basophil activation and SYK 
phosphorylation in peripheral blood from healthy subjects receiving the study drug
(see Section 1.5.5).  We have detected pSYK expression in circulating lymphocytes from 
patients with CLL that could be inhibited by in vitro exposure to GS-9973.  Circulating 
malignant cells were also identified from 2 of 5 patients with MCL but evaluation of pSYK 
expression in these cells has not yet been carried out.
1.4.3.2.
Systemic Cytokines and Chemokines
In hematologic malignancies, disease-related perturbations in inflammatory status can be 
clinically overt and patients often develop bothersome B symptoms (fevers, night sweats, and 
weight loss) that are characteristic of excessive systemic inflammation. In addition, chemokines 
and cytokines that are markers of aberrant B-cell trafficking or perturbations in inflammation are 
over-expressed by malignant and stromal cells and circulate in plasma. In vitro cell culture 
experiments demonstrated that SYK inhibition by GS-9973 or GS-9973 SDD reduced the levels 
of the secreted chemokines and cytokines (CCL3, CCL4, and others) by DLBCL, MCL, and 
B-ALL cell lines.  To evaluate the downstream effects of SYK inhibition by GS-9973 in 
Study GS-US-339-0102 we will assess the baseline and on treatment systemic levels of disease 
related cytokines and chemokines. These will include at a minimum, but will not be limited to:
CCL3, CCL4, CXCL12, CXCL13, tumor necrosis factor-α, and C-reactive protein. 
1.4.3.3.
Hypothesis-driven assessments
The hypothesis-driven molecular mechanisms of resistance to GS-9973 to be tested in this study 
are based on established molecular drivers behind each of the specific hematologic malignancies 
investigated and their known interactions with SYK signaling pathways (see Figure 1-1). These 
hypotheses fall into the following categories: 
1.4.3.3.1.
p110α gene amplification and/or other PI3K pathway related alterations
Circulating tumor cells from subjects with SLL, CLL, or MCL will be assessed at a minimum for 
pSYK, pBtk, pPLCγ1/2, pErk, pP38, pAkt, pS6, pNFκB, and PTEN and PI3K mutations and 
amplifications to evaluate changes in protein expression and in signaling pathway activation that 
may have developed in resistant tumors. To increase our understanding of GS-9973 activity and 
tumor resistance, other key signaling nodes may also be evaluated for alterations that are related 
to malignant B-cell proliferation, migration, and survival.  


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1.4.3.3.2.
Mutations/alterations in pathways related to apoptosis evasion (eg bcl-2, TP53, 
ATM) in the presence of high c-myc expression/signaling
Once tumor cells are forced to re-enter the circulation through the inhibition of BCR and 
chemokine signaling by GS-9973, they cannot receive trophic and anti-apoptotic stimuli from the 
solid tissue microenvironment (including BAFF) to sustain their survival in the presence of high 
c-myc expression. Thus, it is possible that the presence of tumor cell clones with additional 
mutations/alterations (eg, ATM, TP53, bcl-2, etc.) that suppress apoptosis in the presence of high 
c-myc signaling may lead to clonal escape and repopulation of the lymph nodes. 
We will assess circulating tumor cells for mutations/alterations of ATM, TP53, bcl-2 and other 
proteins that are directly related to apoptosis regulation.
1.4.3.3.3.
ZAP-70 over-expression
Hypermutation of IgVH genes is a prognostic marker for outcome in CLL:  patients with 
unmutated IgVH genes have shorter survival rates and more rapid disease progression than 
patients with mutated IgVH genes.  A small subset of genes was found differentially expressed in 
VH-mutated versus unmutated cases. ZAP-70 was found to be the most discriminating gene 
between the 2 subsets of CLL, with higher expression of ZAP-70 present in unmutated IgVH 
B-CLL cells. 
Importantly, defects in BCR signaling in SYK-deficient B cells can be reconstituted by the 
expression of ZAP-70. This raises the important question whether SYK inhibition alone will be 
sufficient to suppress BCR signaling in ZAP-70 over-expressing cells. To address this question 
in this study we will assess ZAP-70 protein levels and P38 phosphorylation status in circulating 
tumor cells.
1.4.3.4.
Genomics Assessments
In addition to the specific biomarker assessments outlined above, a genomics approach will also 
be used to generate new leads for better understanding of resistance to BCR targeted agents in 
B-cell malignancies. These new leads may increase our understanding of the mechanisms of 
resistance and pathophysiology of B-cell malignancies for informing the design of future rational 
drug combinations.
1.5.
GS-9973
1.5.1.
Nonclinical Pharmacology
GS-9973 is an adenosine triphosphate (ATP) competitive inhibitor of SYK with an IC50 of 
8.5 ± 3.6 nM.  GS-9973 binds in the ATP pocket of the SYK active site and disrupts the kinase 
activity of the enzyme.  Kinase selectivity profiling showed a > 14-fold selectivity of GS-9973 
for SYK versus 359 nonmutant kinases. Furthermore, there was < 50% binding of GS-9973 at 
1 M to any of a panel of 67 ion channels, transporters, and receptors. Therefore, GS-9973 
demonstrated at least 14-fold selectivity against a total of 426 biological targets tested
(See Figure 1-2).


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Figure 1-2.
GS-9973 Kinome Scan
The cellular activity of GS-9973 was evaluated in 2 anti-IgM (IgM)-stimulated 
CD86 expression assays in human peripheral and mouse splenic B-cells. GS-9973 potently 
inhibited IgM-stimulated CD86 expression with a mean EC50 of 125.0 78.2 nM and 
94.5 19.6 nM in human peripheral and murine splenic B-cells, respectively. Additionally, 
GS-9973 was evaluated in vitro in an FcRI-triggered IgE-stimulated hexosaminidase 
release assay in mouse bone marrow derived mast cell (BMMC) cultures. GS-9973 inhibited the 
FcRI-stimulated hexosaminidase release into the media with a mean EC50 of 159.3 14.8 n. 
GS-9973 was evaluated in vitro in an immune-complex (IC)-stimulated TNFrelease assay in 
primary human monocytes. GS-9973 inhibited the IC-stimulated TNFrelease with a mean 
EC50 of 147.0 15.6 n. These data support the concept that SYK inhibition blocks with similar 
potency, B-cell, IgE, and Fcreceptor signaling in vitro.
The potency of GS-9973 was evaluated in human whole blood by an IgE-stimulated 
CD63 expression assay in human basophils. GS-9973 inhibited the IgE-stimulated 
CD63 expression on CD123+/HLADR- human basophils with a mean EC50 SD of 
0.387 0.220 M. Additionally, GS-9973 inhibited the pervanadate-induced 
autophosphorylation of SYK at phospho-SYK(Y525) in whole blood with a mean EC50 SD of 
830 560 nM. These data support the concept that SYK inhibition can block SYK activity in 
whole blood as determined by functional inhibition of CD63 expression and direct target 
inhibition of SYK autophosphorylation.
GS-9973 was evaluated in a battery of safety pharmacology studies. The IC50 for the inhibitory 
effect of GS-9973 on human ether-à-go-go-related gene (hERG) potassium current in vitro was 
estimated to be greater than 1 μM. Because GS-9973 is 97.3% protein bound in human plasma 
and the total plasma concentrations of GS-9973 are in the 1 to 3 micromolar range, with a 
corresponding range of free GS-9973 of 27 to 81 nM, it is unlikely that a clinically relevant 
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effect on QT interval would occur. No GS-9973-related effects were noted on neurological or 
respiratory function in rats at doses up to 1000 mg/kg, the highest dose tested. In dogs, GS-9973 
caused small increases in heart rates (during the night cycle) at doses ≥ 15 mg/kg but had no 
effects on electrocardiograms (ECGs) or blood pressure at up to 150 mg/kg, the highest dose 
evaluated.
GS-9973 is a potent and selective SYK inhibitor and disrupts the kinase activity of the enzyme.  
No significant off target or adverse pharmacological effects of clinical relevance were noted in 
preclinical evaluations.
Further information on the nonclinical pharmacology of GS-9973 is available in the 
Investigator’s Brochure.
1.5.2.
Nonclinical Drug Metabolism and Pharmacokinetics
Despite high plasma protein binding, GS-9973 had a moderate volume of distribution, close to 
that of total body water. The systemic clearance was low in rats, moderate in dogs, and moderate 
to high in monkeys.
Single-day dose escalation of GS-9973 administered orally to rats, dogs, and monkeys showed a 
less than dose proportional increase in GS-9973 systemic exposure in all species over the dose 
ranges tested.
Consistent with the moderate to high bioavailability seen in nonclinical species, GS-9973 
showed high forward permeability across Caco-2 monolayers and low potential for efflux.
GS-9973 showed good metabolic stability with human hepatic material in vitro.  In humans, 
clearance through metabolism is therefore expected to be low.  The primary routes of 
metabolism of GS-9973 involved oxidative opening of the morpholine ring as well as further 
oxidation or conjugation.  In humans, CYP2C9, CYP3A, and CYP1A2 were shown to oxidize 
GS-9973.
Metabolism followed by biliary excretion is likely to be the major route of elimination of 
GS-9973 and its metabolites, as < 5% of the radiolabeled dose administered orally to rats was 
recovered in urine.
GS-9973 will be unlikely to cause clinical drug interactions through inhibition of CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A. GS-9973 is an inhibitor of 
UGT1A1 and may transiently inhibit UGT1A1 activity in vivo at the expected clinical 
concentrations.  The effect may be mitigated by the high plasma protein binding of GS-9973 
(> 97%).
GS-9973 is an inhibitor of the uptake transporters OATP1B1 and OATP1B3 as well as the efflux 
transporters P-gp and BCRP with an IC50 value of approximately 2 µM for each of these 
transporters.  GS-9973 may affect the activity of these transporters in vivo at the expected 
clinical concentrations and could transiently affect the disposition of other drugs.  The high 
plasma protein binding of GS-9973 (> 97%) may mitigate some of the potential drug-drug 
interactions at clinically relevant doses.


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GS-9973 is not expected to be a clinically relevant inducer of cytochrome P450 enzymes 
CYP1A2 or CYP3A4 and other drug metabolizing enzymes or transporters through activation of 
either the aryl hydrocarbon receptor (AhR) or pregnane-X-receptor (PXR).
Further information on the nonclinical drug metabolism and pharmacokinetics of GS-9973 is 
available in the Investigator’s Brochure.
1.5.3.
Nonclinical Toxicology
GS-9973 was well tolerated in single-dose studies at doses of 1000 mg/kg in dogs and 
cynomolgus monkeys. GS-9973 was well tolerated in rats for 14 days up to 1000 mg/kg/day and 
for 4 weeks at 50 mg/kg/day. In dogs, GS-9973 was well tolerated for 7 days at 50 mg/kg/day 
and at 10 mg/kg/day for 4 weeks. GS-9973 was well-tolerated in cynomolgus monkeys for 
14 days or 13 weeks at 100 mg/kg/day, the highest dose tested. The highest feasible dose in 
cynomolgus monkeys was 100 mg/kg/day, as no increase in exposure was achieved by higher 
doses.
The target organ(s) of toxicity identified in rats was the duodenum, and in rabbits and dogs were 
predominantly the gastrointestinal tract and lymphoid organs. No target organs were identified in 
the cynomolgus monkey. Additional organs potentially affected in individual dogs at higher 
doses included gallbladder, pancreas (rabbits and dogs), urinary bladder, and epididymis. The 
gastrointestinal tract toxicity presented as enteropathy in the duodenum in rats, and hemorrhage 
and/or inflammation in rabbits and dogs. Gastrointestinal tract toxicity in rats, rabbits, and dogs 
was associated with decreased food consumption and/or decreased body weight or body weight 
gain. However, decreased food consumption and body weight changes also occurred in rabbits 
and dogs at doses below those which caused histological evidence of gastrointestinal toxicity.
Assessments in the clinical program will include monitoring for signs and symptoms of 
gastrointestinal distress and changes in clinical pathology parameters (changes in red cell mass, 
neutrophils, lymphocytes, liver enzymes, and total and indirect bilirubin) that could occur after 
GS-9973 administration. Because evidence of lymphoid tissue depletion was noted in rabbits and 
dogs at high doses, clinical assessments will also include monitoring for signs and symptoms of 
infection.
Increases in total and/or indirect bilirubin in rats, rabbits, and dogs at ≥30 mg/kg/day may have 
been due to the inhibition of the enzyme UGT1A1. GS-9973 inhibits this uridine glucuronyl 
transferase enzyme with an IC50 of 2 µM. This enzyme is involved in glucuronidation of 
bilirubin, and inhibitors of UGT1A1 have the potential to produce increased levels of total and 
indirect (unconjugated) bilirubin in the circulation {Zhang 2005}. As no histological evidence of 
hepatobiliary toxicity was noted concurrently with bilirubin increases in GS-9973-treated rats or 
dogs, and GS-9973 levels above the IC50 for UGT1A1 were achieved in serum, this seems a 
plausible mechanism for the noted increases in bilirubin.


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Hemorrhage and/or sinus erythrocytosis in lymph nodes with decreases in red cell mass in 
individual animals was noted in rabbits and dogs, but not rats or cynomolgus monkeys. Although 
the mechanism for these changes is not clear, SYK deficiency in rodents and rodents with 
SYK-deficient bone marrow have been associated with hemorrhage, the latter in the presence of 
normal bleeding times and therefore suggesting normal platelet function {Turner 2000}. No 
evidence of altered coagulation parameters were noted at any dose level in the GS-9973 
nonclinical studies and no biologically relevant effects were noted in an in vitro study of platelet 
aggregation. Other inhibitors of SYK have been found to have no effect on platelet function at 
efficacious dose levels in patients with rheumatoid arthritis as determined by ex vivo assays, and 
similarly, SYK inhibition has not been found to affect bleeding time in rodents {Braselmann 
2006}. Evidence of hemorrhage and/or decreases in red cell mass will be monitored during
clinical studies.
Adverse effects on lymphoid tissues including spleen, lymph nodes, and/or the thymus were 
noted in rabbits and dogs, but not in rats or cynomolgus monkeys, despite higher exposures 
achieved in both the rat and monkey. Recently published data demonstrated that species-specific 
lymphoid changes can occur in dogs but not rats, cynomolgus monkeys, or humans treated with 
small molecule kinase inhibitors that inhibit pathways that overlap with SYK signaling 
pathways; rabbits were not evaluated {Morris 2010}. Lymphoid toxicity occurs in dogs treated 
with p38α MAPK inhibitors, but not in rats or cynomolgus monkeys despite higher exposure 
levels achieved in these species. There has not been evidence of significant immunotoxicity in 
numerous clinical trials with p38α MAPK inhibitors. The relevance of the findings in rabbits and 
dogs to humans is unknown.
GS-9973 was negative in the bacterial mutation, in vitro chromosomal aberration, and rat 
micronucleus assays. GS-9973 can be considered non-genotoxic.  Dose-range finding 
embryo-fetal developmental toxicity studies have been completed in the rat and rabbit. Maternal 
toxicity was demonstrated by dose-dependent decreases in the body weight gains of the dams. 
Dose-dependent developmental findings included increased incidence of early and late fetal 
resorptions at 500 mg/kg/day (rat only) and reduced fetal weights (500 and ≥15 mg/kg/day; 
rat and rabbit, respectively) which correlated with the maternal toxicity.
Further information on the nonclinical toxicology of GS-9973 is available in the 
Investigator’s Brochure.
1.5.4.
Clinical Trials of GS-9973
GS-9973 has been studied in single and multiple ascending dose studies in 304 healthy subjects,
7 subjects with rheumatoid arthritis who were on stable doses of methotrexate, 80 subjects with 
CLL and 95 subjects with NHL.  Of these subjects, 460 received GS-9973 and 26 received 
placebo.  In pharmacokinetics studies at steady state in healthy subjects, GS-9973 was well 
tolerated when given in a fasted state for 7 days at doses of 25, 75, 200, 600, 900, and 1200 mg 
BID (GS-US245-0101) and when given in a fed state for 6 days at doses of 100 and 900 mg BID 
(GS-US-245-0106), for 4 days at doses of 200 and 600 mg BID (GS-US-339-0101), and at 
1200 mg BID for 5 days (GS-US-339-0109) see Figure 1-3 and Figure 1-4. Exposure, as 
measured by AUC and maximum concentration Cmax, did not increase appreciably at doses of 
600 mg and above under fasted condition.


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To provide a margin for inter-patient variability, a dose of 900 mg BID was chosen for the study 
of subjects with rheumatoid arthritis receiving stable doses of methotrexate in Study 
GS-US-245-0101.  A dose of 900 mg GS-9973 BID was given in a fasted state for 26 days in 
7 subjects.  The median AUCtau in these subjects was similar to that of the healthy subjects.  In 
general, this dose was well tolerated.   One subject developed reversible, Grade 2 alkaline 
phosphatase and transaminase elevations starting 7 days after her last dose of GS-9973, 
concurrent with new onset of a bronchopneumonia.  One other subject reported not feeling well 
and experienced hot flashes, fever, shivers, rash, headache, dizziness, and fainting 1 day after her 
last dose of GS-9973 with reversible Grade 1 alkaline phosphatase and Grade 3 transaminase 
elevations which peaked 1 week later.  While these events are potentially confounded by 
concurrent illnesses, hepatic enzymes will be closely monitored during this study.
Consistent with the known inhibition of UGT1A1 by GS-9973, 8 of the 178 healthy subjects 
developed asymptomatic indirect bilirubin elevations (6 Grade 1, 1 Grade 2 and 1 Grade 3) that 
resolved following discontinuation of the drug.  Three of the 7 subjects with rheumatoid arthritis 
who received GS-9973 for 26 days developed asymptomatic indirect bilirubin elevations 
(2 Grade 1, 1 Grade 3) which improved despite continued dosing.
Figure 1-3.
GS-9973 AUCtau at Steady State
fasted
fed
fasted
fed
fasted
fed
fasted
fed
no MTX
w MTX
0
20000
40000
60000
200 mg
  BID
600 mg
 BID
900 mg
  BID
1200 mg
 BID
median (Q1,Q3)
900 mg
  BID
GS-9973 AUC (h*ng/ml)
0 
0 
0 
1-------i 
1-------i 
1-------i 
1-------i 
1-------i 


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Protocol GS-US-339-0102
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Gilead Sciences, Inc.
Amendment 8
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Figure 1-4.
GS-9973 Cmax at Steady State
1.5.5.
GS-9973 Target Drug Concentrations
In healthy subjects, SYK inhibition, as measured by the ability to inhibit CD63 basophil 
activation and pSYK activation was evaluated in peripheral blood mononuclear cells (PBMCs) at 
multiple doses and schedules of GS-9973.  Plasma GS-9973 exposures were correlated with the 
degree of SYK inhibition.  GS-9973 inhibited SYK as measured by ex-vivo basophil activation 
(see Figure 1-5) and pSYK (see Figure 1-6) assays with EC70s of 923 and 275 ng/mL,
respectively.
Figure 1-5.
Inhibition of Basophil Activation
fasted
fed
fasted
fed
fasted
fed
fasted
fed
no MTX
w MTX
0
2000
4000
6000
8000
200 mg
  BID
600 mg
 BID
900 mg
  BID
1200 mg
 BID
median (Q1,Q3)
900 mg
  BID
GS-9973 Cmax (ng/ml)
0 
0 
0 t 
t -1- :f 
(/) ci, 125 
= C: 
.c = 
g- lJ: 100 
gi 
co (/) 
75 
"C > 
2-g 
-~ 
50 
-
nl 
.:i_ E 
'-
25 
1-----1 
1-----1 
:-
• . .. ' . 
0 
0 
0 
fft+I 
0 
0 
0 
0 
1-----1 
1-----1 
1-----1 
10000 


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Final
Gilead Sciences, Inc.
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Figure 1-6.
Inhibition of pSYK
1.5.6.
Use of Concomitant Medications with GS-9973
In vivo and in vitro data indicates that GS-9973 is a substrate of CYP2C9 and CYP3A. 
Co-administration of CYP2C9 or CYP3A inducers may decrease GS-9973 exposure. As such, 
co-administration of strong CYP3A and CYP2C9 inducers and moderate CYP2C9 inducers are 
prohibited in this study. Caution should be exercised when co-administering drugs that are 
moderate or strong inhibitors of CYP2C9 (eg fluconazole, voriconazole or amiodarone) as they 
may increase GS-9973 exposure. Administration of strong CYP3A and CYP2C9 inducers or 
moderate CYP2C9 inducers should be avoided for 2 weeks prior to study drug administration. 
Studies in healthy volunteers have demonstrated a significant reduction in GS-9973 exposure 
when proton pump inhibitors are co-administered. Therefore, proton pump inhibitors are 
prohibited in combination with GS-9973. Use of a proton pump inhibitor should be avoided for 
1 week prior to study drug administration. Examples of medicines that are prohibited in this 
study are provided in Section 5.5.1 Table 5-5.
In vitro data indicates that GS-9973 has the potential to inhibit several transporters and the 
metabolizing enzyme UGT1A1, which may affect the plasma concentrations of substrates of 
these transporters and/or enzyme. Caution should be exercised when co-administering 
medications that are transported by OATP1B1, OATP1B3, MATE1, P-gp and BCRP or 
metabolized by UGT1A1; dose adjustment or switching to an alternative medication may be 
necessary if clinically indicated.
In a study in healthy volunteers, GS-9973 400 mg twice daily (SDD formulation) increased 
rosuvastatin exposure by approximately 3.8-fold, which may theoretically increase the risk of 
rhabdomyolysis. In reviewing the safety of subjects whom have received a statin with GS-9973 
there have been no reports of rhabdomyolysis nor a different adverse events profile, but in the 
interest of caution, restrictions apply to the use of HMG-CoA reductase inhibitors with GS-9973 
in this study. These restrictions are included in Section 5.5.1.
a, 125 
.E 
1100 
ca 
..ll: al 
;; 
75 
C.-o 
4> 
50 
0 
ca 
§ 25 
0 z 
EC50 
EC70 
EC90 
MEAN (ng/mL) 
uM 
110 
0.22 
275 
0.54 
1171 
2.31 
o---------------
1 
10 
100 
1000 
10000 
[GS-9973) ng/ml 


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1.6.
Rationale for the Current Study and Design
The purpose of this study is to obtain data on the efficacy, safety, tolerability, and 
pharmacodynamics of GS-9973 in subjects with hematologic malignancies. The initial 
malignancies to be studied are CLL, iNHL, MCL, and DLBCL. A new spray dried dispersion 
(SDD) formulation is being introduced in the study known as GS-9973 SDD which has favorable 
PK and reduced DDI with proton pump inhibitors. Due to the improved bioavailability of the 
new formulation a dose ranging cohort will be introduced into the study in order to evaluate 
doses between 100 to 400 mg BID. As significant clinical activity was noted in the initial CLL 
cohort treated with GS-9973, the decision was made to increase the number of CLL subjects 
treated with GS-9973 SDD through the addition of 2 CLL cohorts consisting of patients who 
were previously treated with ibrutinib or idelalisib and whom had disease progression at a dose 
that will approximate the target coverage seen with GS-9973. A Bayesian approach will be used 
to establish boundary rules that identify progression-free survival (PFS) rates at 16 weeks 
(CLL after BCR targeted therapy, MCL and DLBCL) or 24 weeks (CLL and iNHL) that are not 
sufficiently promising to warrant further development (ie, < 20%). For each malignancy, if, after 
at least 10 subjects are evaluated for response, the observed PFS rate for a given malignancy 
crosses the futility boundary, further accrual to that malignancy may be terminated taking into 
account efficacy, drug exposure, and subtype (for DLBCL).  Since the non-FL iNHL cohort of 
45 subjects consists of 3 histologies (LPL, SLL, and MZL), a Bayesian interim analysis will not 
be applied to this cohort.
1.6.1.
Rationale for the Dose Selection
As noted above, in fed and fasted healthy subjects, GS-9973 has been well tolerated for 
4 to 7 days at up to 1200 mg BID. In these subjects, drug exposure, as measured by AUC at 
steady state, plateaued at doses ≥600 mg BID.  Target coverage, as measured by basophil 
activation and pSYK inhibition was consistently achieved at this dose level (See Figure 1-5 and 
Figure 1-6). Further, 7 subjects with rheumatoid arthritis receiving stable doses of methotrexate 
tolerated GS 9973 at a dose of 900 mg BID for 26 days.  To account for variability in exposure, 
the dose of GS-9973 to be evaluated initially in subjects with CLL, iNHL, MCL, and DLBCL is 
800 mg BID under fasted conditions. As of protocol amendment 8, subjects receiving GS-9973 
MM formulation will be transitioned to the GS-9973 SDD formulation (Section 5.3.5).
A PK study of the new bis-MSA spray-dried formulation evaluating dose-exposure demonstrated 
improved PK parameters and improved target coverage at trough.  Given data from 
GS-US-339-0111, “Open-Label, Adaptive Study of Novel GS-9973 Tablet Formulations to 
Evaluate the Effect of Acid Reducing Agents and Food on GS-9973 Pharmacokinetics, and 
Relative Bioavailability of the Novel GS-9973 Tablet Formulations” the magnitude of GS-9973 
exposure upon coadministration with omeprazole was less than reduction observed in Study 
GS-US-245 0106 of the original formulation. Even though the new formulation did not 
completely annul the DDI effect of a coadministered PPI agent, the interaction of GS-9973 new 
Formulation with an H2 receptor antagonist (H2RA) is not considered clinically meaningful


GS-9973
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1.6.2.
Rationale for Dose Exploration in GS-9973 Sensitive Malignancies
The GS-9973 dose of 800 mg BID was chosen to provide maximum drug exposure for subjects 
with malignant disease. As noted above, this dose and schedule resulted in consistent target 
coverage in normal subjects. However, it is possible that this dose and schedule results in drug 
exposure that exceeds what is required for maximum target coverage. If GS-9973 demonstrates 
promising anti-cancer activity in a cohort, exploration of lower doses may be required before 
further studies are pursued. If these 2 conditions are met, additional cohorts of 40 subjects with 
that malignancy may be studied to evaluate the safety profile, pharmacodynamic parameters and 
anti-tumor activity at lower GS-9973 doses. GS-9973 doses of 200 or 400 mg given once daily
or BID will be studied in the additional cohort(s) and will be selected based upon the emerging 
pharmacodynamic, pharmacokinetic and anti-tumor data from the subjects already studied. 
Subjects who are treated at lower doses of GS-9973 should have their dose escalated up to 
800 mg BID at the time of disease progression if the investigator feels it is in the subject’s best 
interest. As of protocol amendment 8, subjects receiving GS-9973 MM formulation will be 
transitioned to the GS-9973 SDD formulation (Section 5.3.5).
Transaminase Elevations Following Treatment with GS-9973
ALT and AST elevations have occurred in 13 of 109 subjects evaluated on this study; all 
subjects received GS-9973 800 mg BID.  The ALT elevations were generally higher than the 
AST elevations, consistent with a hepatic origin.  The distribution of highest ALT elevations 
were 1 Grade 1, 0 Grade 2, 6 Grade 3 and 5 Grade 4.  GS-9973 dosing was continued for 
Grade 1 and 2 elevations and these subjects did not develop Grade 3 or 4 transaminase 
elevations. Dosing was interrupted for Grades 3 and 4 elevations. In the 4 subjects for 
whom GS-9973 was interrupted, in each case the ALT and AST values were lower at the 
next determination and returned to Grade 1 or less after 7, 12 and 21 days (Grade 3’s) and after 
27 days (Grade 4).  Two subjects were subsequently re-started on GS-9973 at 600 mg BID 
without recurrence of the ALT elevation.  Based upon this experience, we have provided specific 
guidance in the protocol for the management of Grade 3 and 4 transaminase elevations.
1.7.
Rationale for Amendment 5
1.7.1.
Initial Clinical Experience with GS-9973 in Subjects with CLL
The CLL cohort for this study has completed accrual.  The initial results were presented at the 
2013 American Society of Hematology Annual Meeting {Sharman 2013}. The results were later 
updated in the GS-9973 Investigator’s Brochure Fourth Edition dated 14-March-2014. GS-9973 
was generally well tolerated; adverse events regardless of cause that occurred in more than 10% 
of subjects are listed in Table 1-1.  Transient grade 3 or 4 transaminase elevations, which 
declined upon holding GS-9973, occurred in 11 of 109 (10.1%) of subjects.  Four subjects were 
re-challenged and remain on study without recurrence of the transaminase elevation, 1 withdrew 
consent 1 developed a Grade 2 rash and went off study and the remaining 3 were waiting for 
resolution prior to re-challenge.


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Table 1-1.
GS-339-0102:  Treatment-Emergent Non-hematologic Adverse Events 
Occurring in ≥ 10% of Subjects, N=109*
Grade 1
Grade 2
Grade 3
Grade 4
All Grades
Any event
106 (97.2%)
Fatigue
20 (18.3%)
22 (20.2%)
9 (8.3%)
51 (46.8%)
Nausea
26 (23.9%)
10 (9.2%)
3 (2.8%)
40 (36.7%)
Diarrhoea
33 (30.3%)
5 (4.6%)
1 (0.9%)
39 (35.8%)
Decreased appetite
16 (14.7%)
9 (8.3%)
25 (22.9%)
Headache
21 (19.3%)
3 (2.8%)
1 (0.9%)
25 (22.9%)
Constipation
14 (12.8%)
8 (7.3%)
2 (1.8%)
24 (22%)
Dizziness
21 (19.3%)
1 (0.9%)
22 (20.2%)
Pyrexia
13 (11.9%)
7 (6.4%)
2 (1.8%)
22 (20.2%)
Cough
11 (10.1%)
5 (4.6%)
1 (0.9%)
17 (15.6%)
Oedema peripheral
12 (11%)
5 (4.6%)
17 (15.6%)
Insomnia
10 (9.2%)
5 (4.6%)
15 (13.8%)
Dyspepsia
6 (5.5%)
8 (7.3%)
14 (12.8%)
Vomiting
10 (9.2%)
2 (1.8%)
1 (0.9%)
14 (12.8%)
Dyspnoea
3 (2.8%)
4 (3.7%)
6 (5.5%)
13 (11.9%)
ALT increased
1 (0.9%)
6 (5.5%)
5 (4.6%)
12 (11%)
AST increased
1 (0.9%)
1 (0.9%)
7 (6.4%)
2 (1.8%)
11 (10.1%)
*
Information in table is based on IB Edition 4
GS-9973 demonstrated promising results in subjects with CLL, producing a 68% nodal partial 
response (Figure 1-7).


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Gilead Sciences, Inc.
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Figure 1-7.
GS-339-0102: Investigator Assessed Nodal Responses in CLL (n=41)
1.7.2.
Rationale for addition of three CLL cohorts
1.7.2.1.
CLL Subjects Whom are Intolerant, Develop Progressive Disease, or 
Transformation While Receiving Ibrutinib or Idelalisib
Ibrutinib is an inhibitor of Bruton’s Tyrosine Kinase (BTK), a kinase that is closely associated 
with B-cell receptor signaling, that has reported an overall response rate of 71% and 2-year 
progression free survival of 75% in subjects with CLL {Byrd 2013}. Idelalisib is an inhibitor of 
PI3K-delta, a kinase that is also closely associated with B-cell receptor signaling.  Idelalisib, 
when combined with rituximab, increased PFS and OS compared to rituximab alone in subjects 
previously treated CLL.  This study was terminated at the first interim analysis due to the 
overwhelming activity of the combination arm and the results have recently been presented at the 
2013 American Society of Hematology Annual Meeting {Furman 2013}.  It is desirable to obtain 
preliminary data on the activity of GS-9973 in CLL subjects who have been previously treated 
with ibrutinib or idelalisib or other BCR targeted therapies whose disease has progressed.  These 
subjects will be studied in 2 separate cohorts.
1.7.2.2.
Study GS-US-339-0111 of GS-9973 New Formulation
GS-9973 Formulation
Among subjects treated with GS-9973 formulation 1 (N = 28), one subject (3.6%) reported an SAE
of cholecystitis following treatment with GS-9973 plus famotidine. AEs resulting in study drug 
discontinuation were reported for 7 subjects (25.0%). Overall, 25 subjects (89.3%) reported an AE.
The most common AEs were the following: headache (11 subjects, 39.3%); back pain and nausea
(8 subjects each, 28.6%); diarrhea (6 subjects, 21.4%); alanine aminotransferase (ALT) increased,
aspartate aminotransferase (AST) increased, constipation, and rash (4 subjects each, 14.3%); and
0 
0.... 
V) 
C 
(l) 
OJ 
C 
!1l 
.c u 
0 ..., 
(/1 
(l) 
en 
100 
90 
80 
70 
60 
50 
40 
30 
20 
10 
0 
-10 
-20 
-30 
-40 
-50 
-60 
-70 
-80 
-90 
-100 
-
Very high risk (w 17p deletion and/or TP53 mutatiOn) 
iz:::z:::.I High risk (w NOTCH1 and/or SF3B1 mutation and/or 11q deletion) 
C=:::J Low risk (none of the above deletion or mutation) 
C=:::J Undetermined 


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Gilead Sciences, Inc.
Amendment 8
CONFIDENTIAL
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abdominal distension, abdominal pain, dizziness, pruritus, and vomiting (3 subjects each,
10.7%). Grade 3 AEs were reported for 2 subjects (7.1%) and included the following terms:
cholecystitis, hyperbilirubinemia, idiosyncratic drug reaction, and pyrexia; no Grade 4 AEs were 
reported.
GS-9973 Formulation SDD
Among subjects treated with GS-9973 formulation 2 (N = 28), no subjects reported an SAE.  
AEs resulting in study drug discontinuation were reported for 3 subjects (10.7%). Overall, 
19 subjects (67.9%) reported an AE. The most common AEs included the following: headache 
(11 subjects, 39.3%); back pain and nausea (6 subjects each, 21.4%); ALT increased, rash, and 
pruritus (4 subjects each, 14.3%); and AST increased and constipation (3 subjects each, 10.7%). 
No Grade 3 or 4 AEs were reported.
Laboratory Abnormalities seen in Study GS-US-339-0111
Study drug dosing was suspended and the study was terminated before Part B was initiated,
because the protocol defined stopping rule of 3 or more subjects having a Grade 3 treatment
emergent drug-related AE or laboratory abnormality was met. Seven of 28 subjects (25.0%)
administered GS-9973, and 4 of 28 subjects (14.3%) administered GS-9973 SDD had 
Grade 3 laboratory abnormalities during Part A of the study. The most frequently reported 
Grade 3 laboratory abnormalities for subjects administered GS-9973 were blood in urine 
associated with menstrual flow (3 of 28 subjects, 10.7%), ALT increased (2 of 28 subjects, 
7.1%), and bilirubin increased (2 of 28 subjects, 7.1%). For subjects administered GS-9973 
SDD, the most frequently reported Grade 3 laboratory abnormalities were LDL cholesterol 
increased (2 of 28 subjects, 7.1%) and blood in urine associated with menstrual flow 
(2 of 28 subjects, 7.1%).


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2.
OBJECTIVES AND ENDPOINTS
2.1.
Objectives
The primary objective of this study is:

To evaluate the efficacy of GS-9973 in subjects with relapsed or refractory hematologic 
malignancies
The secondary objectives of this study are:

To evaluate the safety and tolerability of GS-9973 in subjects with relapsed or refractory 
hematologic malignancies

To evaluate GS-9973 exposures in subjects with relapsed or refractory hematologic 
malignancies
2.2.
Endpoints
Primary Endpoints

PFS rate at 16 weeks (CLL after BCR targeted therapy, MCL and DLBCL) or 24 weeks 
(CLL and iNHL) as established for each malignancy.  PFS is defined as the interval from the 
first dose of GS-9973 to the earlier of the first documentation of definitive disease 
progression or death from any cause.  The findings of the IRC will be considered primary for 
analyses of PFS rate.  
Secondary Endpoints:

Safety: abnormal laboratory data, adverse events (AEs) and treatment-emergent AEs. Safety 
will be assessed by grading of laboratory values and AEs according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Efficacy:

Objective response rate (ORR). ORR will be determined from the subjects’ best response 
during GS-9973 therapy and will include complete response (CR) or partial response (PR)
[or very good partial response (VGPR) or minor response (MR) for subjects with LPL/WM].

Duration of response (DOR). DOR will be defined as time from the first response (CR or PR 
[or VGPR or MR for subjects with LPL/WM]) is achieved until the earlier of the first 
documentation of definitive disease progression or death from any cause.  

Time to response (TTR). TTR will be defined as time from the first dose of GS-9973 to the 
first time the response (CR or PR [or VGPR or MR for subjects with LPL/WM]) is achieved.
The findings of the IRC will be considered primary for analyses of secondary efficacy endpoints.


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Exploratory Endpoints: 
I 
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Amendment8 
31 March 2017 


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3.
STUDY DESIGN
3.1.
Overview
This protocol describes a Phase 2, open-label study evaluating the efficacy, safety, tolerability, 
pharmacokinetics and pharmacodynamics of GS-9973/GS-9973 SDD in subjects with relapsed 
or refractory hematologic malignancies.  Eight separate cohorts consisting of subjects with CLL,
iNHL, MCL, or DLBCL will be studied concurrently. Subjects with iNHL will be studied in 
2 cohorts: 1 consisting of only subjects with FL and the other consisting of subjects with 
LPL/WM, SLL, and MZL. Two additional cohorts have been added to the study under 
amendment 4, consisting of subjects with CLL who have previously been treated with ibrutinib 
or idelalisib and now have progressive disease (CLL prior BTK inhibitor exposure and CLL 
prior PI3K inhibitor exposure, respectively). A dose ranging cohort consists of 100 mg, 200 mg 
and 400 mg (200 mg x 2) new formulation of GS-9973 SDD are added under amendment 5.
(See Figure 3-1). As of protocol amendment 8, subjects receiving GS-9973 MM formulation will 
be transitioned to the GS-9973 SDD formulation (Section 5.3.5).
Figure 3-1.
Study Schema
GS-9973 
Original Formulation 
800 mg BID 
Sample size: 
10-40/cohort 
GS-9973 SDD 
New 
Formulation 
400 mg BID 
Sample Size: 
20-60/cohort 
GS-9973 SDD 
(Randomized) 
New Formulation 
Original Protocol 
LPL, SLL, MZL 
Continue accrual to a 
maximum of 40 total subjects 
-------------------------------
DLBCL 
Consider 
stopping accrual 
in that malignancy 
Continue accrual 
to a maximum of 
40 subjects 
Consider 
stopping accrual 
in that malignancy 
Continue accrual 
to a maximum of 
20 (Richter's) or 
40 (non-Richter's) 
subjects 
--------------------------------
100, 200 or 400 mg BID i---.... 
Sample Size: 60-100 
CLLDose 
Ranging 
Continue until accrual of at least 
20 subjects at each dose level 


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3.1.1.
CLL, FL, DLBCL, MCL
A Bayesian, continuous data review approach will be used to update the estimates of PFS rates at 
16 weeks (CLL after BCR targeted therapy, MCL and DLBCL) or 24 weeks (CLL and iNHL) as
each subject’s primary endpoint becomes available for a malignancy.  The criterion used for the 
futility boundary is defined as highly likely (>90%) that the PFS rates at 16 weeks (CLL after 
BCR targeted therapy, MCL and DLBCL) or 24 weeks (CLL and iNHL) are less than 0.2 given 
the available subjects’ efficacy data.
Futility assessment begins when the first 10 subjects’ primary endpoints become available. 
Thereafter, continuous data review will be conducted when a new primary endpoint becomes
available.

If the futility criterion is not met, subsequent subjects will be enrolled until a total of 
pre-defined number of subjects are recruited for a cohort.

If the futility criterion is met, the sponsor will consider terminating enrollment to that 
malignancy, taking into account efficacy, drug exposure and subtype (for DLBCL), unless 
there are subjects who remain on treatment and have not yet reached 16 weeks (CLL after 
BCR targeted therapy, MCL and DLBCL) or 24 weeks (CLL and FL). In this case, 
enrollment will be suspended until the next on-going subjects’ primary endpoint becomes
available, and another data review is conducted. If, after review of all available subjects, the 
futility boundary has still been crossed and the lack of drug exposure or for DLBCL, subtype 
does not explain the lack of activity, enrollment to that malignancy will be terminated.  
The futility boundary is provided in Figure 3-2 with details in Section 8.6.  The boundary is 
represented in terms of the total number of subjects and the number of progression-free subjects 
at Week 16 (CLL after BCR targeted therapy, MCL and DLBCL) or Week 24 (CLL and FL).  
Subjects who withdraw or are lost to follow-up before Week 16 (CLL after BCR targeted 
therapy, MCL and DLBCL) or week 24 (CLL and FL) will be considered as not achieving PFS
for the analysis.
At each data review, if the observed ratio of the number of PFS at Week 16 (CLL after BCR 
targeted therapy, MCL and DLBCL) or Week 24 (CLL and FL) over the total number of subjects
is at or below the futility boundary, then the futility criterion has been met.
The data review for the CLL prior BTK inhibitor exposure and CLL prior PI3K inhibitor 
exposure cohorts will be conducted independently for Richter’s and non-Richter’s.
3.1.2.
CLL Dose Ranging Cohort
For the CLL dose ranging cohort, subjects enrolled will be randomized 1:1:1 to receive 100 mg, 
200 mg or 400 mg (200 mg x 2) of GS-9973 SDD BID. Therefore 20 subjects are treated at each 
of the three dose levels.


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Because the CLL dose raging cohort consists of 3 different dose levels each with approximately 
20 subjects, the continuation data review of futility will not be conducted for this cohort. 
3.1.3.
LPL, SLL, MZL
Because the ‘other non-FL iNHL’ cohort consists of 3 different histologies, accrual will continue 
to a maximum of 45 subjects without a Bayesian analysis.
Figure 3-2.
Futility Boundary with Prior Distribution Beta (0.5, 1.5)
Futility Boundary with Prior Distribution Beta(0.5 1.5) 
0 
C"') 
P(PFS rate <0.21data)>0.9 
XIY: X-# of su 
ing progression- free subjects; Y-# of subjects. 
VJ 
t5 
I!) 
(I) 
N 
E 
::J 
VJ 
(I) 
(I) 
0 
'-
N 
-
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0 
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I!) 
..-
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c.. 
C) 
0 
C: ·s: 
..-
·s: 
'-
::J 
VJ 
0 
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:it: 
0 
32s 
_,34 
)21 
314 
Futility 
0110 
5 
10 
15 
20 
25 
30 
35 
40 
# of subjects 
Sample size: minimal =10, maximal=40 


GS-9973
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3.2.
Treatment Regimen
Initially subjects with iNHL and NHL will receive treatment with 800 mg GS-9973 BID
(under fasted conditions (as defined in Section 5.5.10). As of protocol amendment 8, subjects 
receiving GS-9973 MM formulation will be transitioned to the GS-9973 SDD formulation 
(Section 5.3.5). 
GS-9973 SDD doses of 100, 200 or 400 mg given BID will be studied in the additional cohorts.
A specific dosing regimen will be selected based upon the emerging pharmacodynamic, 
pharmacokinetic and anti-tumor data from the CLL dose ranging subjects and all cohorts will be 
transition to the dose level of GS-9973 SDD.
Initially subjects in the CLL prior BTK inhibitor exposure or CLL prior PI3K inhibitor exposure
cohorts will receive GS-9973 SDD 400 mg twice daily (BID). Subjects in the CLL dose ranging 
cohorts will receive the GS-9973 SDD at the dose level assigned in the randomization. 
For study purposes, a cycle is considered to be 28 days. In the absence of toxicity requiring a 
drug holiday (as defined in Section 8.10), dosing will be continuous without interruption. 
Subjects will have evaluations for safety and provide blood for drug levels and 
pharmacodynamic monitoring prior to starting treatment and then 1.5 hours thereafter per the 
following schedule: at initial dose, weekly during Cycle 1, every 2 weeks during Cycle 2, and 
then once each cycle thereafter. Additional PK samples will be collected at 4 hours after dosing 
on Cycle 1 Day 1 and Cycle 1 Day 8.  Subjects will undergo a radiographic assessment to 
determine their tumor response to treatment every 8 weeks during the first 24 weeks and then 
every 12 weeks thereafter for all diagnoses, except LPL/WM who did not have measurable 
disease at the time of the study and who are not suspected to have measurable disease at the time 
of progression. For those LPL/WM patients, the reassessments will consist of bone marrow 
evaluation, serum monoclonal IgM, done by same technique as used in screening, and 
cryoglobulin.  A bone marrow must be done at PD if that is the only source of the PD and at CR 
to confirm the CR to determine their tumor response to treatment every 8 weeks during the first 
24 weeks and then every 12 weeks thereafter.
Treatment with GS-9973 or GS-9973 SDD may continue in the absence of disease progression or
unacceptable toxicity.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Subjects with one of the designated malignancies who meet the eligibility criteria will be studied.  
Up to 60 subjects for the CLL dose ranging cohort and CLL BCR targeted therapy cohorts 
(CLL prior BTK inhibitor exposure and CLL prior PI3K inhibitor exposure, respectively), up to 
40 subjects for each of the other cohorts and up to 8 cohorts (385 subjects in total) will be 
studied. 
Subjects with a documented diagnosis of histologically or cytologically confirmed CLL and 
selected types of B-cell NHL, with progressive disease are eligible for the study:

CLL as established by the International Workshop on CLL (IWCLL) {Hallek 2008}.  
Subjects with atypical immunophenotype must lack t(11;14) translocation or cyclin D1 
over-expression.

B-cell NHL of the following subtypes as defined by the World Health Organization (WHO)
Lymphoma Classification:
MCL
DLBCL
iNHL
4.2.
Eligibility Criteria
4.2.1.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study:
1) Male or female 18 years of age
a) Diagnosis of B-cell iNHL, DLBCL, MCL (mantle cell, nodal, diffuse or blastoid), or 
CLL as documented by medical records and with histology based on criteria established 
by the World Health Organization. If the subject has DLBCL, subtyping is required.  
Submission of 15 unstained slides is required for subtyping if the subtype is not already 
known.  Subjects for whom tissue is not available but the subtype is already known may 
be included if pathology report including the subtype is provided.
b) If the subject has iNHL, the lymph node histology report confirms 1 of the following 
subtypes:
i)
FL Grade 1, 2, or 3a


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ii) SLL (ie, SLL/CLL histology with an absolute lymphocyte count of < 5 x 109/L at 
diagnosis and on Screening laboratory assessment performed within 35 days prior to 
the start of study drug administration)
iii) LPL/WM
iv) MZL (splenic, nodal, or extranodal)
2) For institutions that have Phase 3 or Phase 4 protocols studying idelalisib (Zydelig): 
subjects with malignancies being studied in these protocols must be a screen failure in the 
respective idelalisib protocol
3) Prior treatment for lymphoid malignancy and requiring treatment for progressive disease. 
Criteria for progressive disease is established Cheson criteria for NHL and by IWCLL 
criteria for CLL
a) LPL/WM patients do not need to have progressive disease but need to meet criteria of 
needing treatment per Update on Recommendations for Assessing Response from the 
Third International Workshop onWaldenström’s Macroglobulinemia
4) (see Section 4 for details)
a) Subjects with denovo DLBCL for whom there is no curative option with conventional 
treatment
b) If the subject has MCL, iNHL, or BCR based therapy naïve CLL, the prior treatment 
must be comprised of at least 1 of the following:
i)
regimen containing a therapeutic antibody administered for ≥2 doses of antibody 
treatment
ii) regimen containing 1 cytotoxic agent administered for 2 cycles of cytotoxic 
treatment
iii) regimen containing yttrium90-ibritumomab tiuxetan or iodine131-tositumomab
iv) experimental therapy as part of clinical trial protocol
c) The previously BCR treated patients will be limited to subjects with CLL (other BCR 
targeted therapies may be accepted after approval of the medical monitor) only in the 
context of this cohort are Richter’s transformation eligible.  
i)
CLL subjects whom have had more than 1 BCR targeted therapy will be enrolled into 
the cohort of the most recent treatment ibrutinib or idelalisib received prior to 
progression.


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5) Presence of radiographically measurable progressive disease as defined using Cheson 
criteria for NHL, and iNHL and by IWCLL criteria for CLL;  lymphadenopathy or 
extranodal lymphoid malignancy (defined as the presence of ≥1 lesion that measures 
2.0 cm in the longest diameter [LD] and 1.0 cm in the longest perpendicular diameter 
[LPD] as assessed by CT or MRI) ; 
a) Subjects with LPL/WM who do not have radiographically measurable progressive 
disease must have a monoclonal serum IgM > 2x ULN as verified by serum protein 
electrophoresis (SPEP) and with lymphoplasmacytic marrow involvement are eligible.  
LPL/WM enrollment is limited to those sites which have cryoglobulin analysis capabilities
6) All acute toxic effects of any prior antitumor therapy resolved to Grade 1 before the start of 
study drug (with the exception of alopecia [Grade 1 or 2 permitted], neurotoxicity 
[Grade 1 or 2 permitted], or bone marrow parameters [Grade 1, 2, or 3 permitted)
7) Karnofsky performance status of 60
8) Life expectancy of at least 3 months
9) Required screening laboratory data (within 5 weeks prior to administration of study drug) as 
shown in Table 4-1. Note: Confirmation should be considered for out-of-range values to 
determine if the abnormality is real or artifactual. Values used for screening must be 
obtained within the screening period and should be the most recent measurement obtained. 
Subjects with any degree of neutropenia, thrombocytopenia, or anemia with 
documentation that it is due to malignancy may enroll.
Table 4-1.
Required Screening Laboratory Values
Organ System
Parameter
Required Value
Hematopoietic
ANC
0.5 x 109/L
Platelets
50 x 109/L
Hemoglobin
80 g/L (8.0 g/dL)
Hepatic
Serum total bilirubin
1.5 x ULN (unless elevated due to Gilbert’s syndrome or hemolysis)
Serum ALT
2.5 x ULN
Serum AST
Renal
Serum creatinine
OR
Estimated creatinine 
clearance
< 1.5 x ULN
OR
> 60 ml/min as calculated by the Cockroft-Gault method
Coagulation
INRa
< 1.7
Pregnancy
-HCGb
Negative 
Infection
HIV
Negative HIV antibody
HBV
Negative HBsAg and negative HBc antibody
HCV
Negative viral RNA (if HCV antibody is positive)
a
For subjects on anticoagulative therapy the required value is < 3.0
b
For women of childbearing potential only; serum -HCG must be negative during screening and serum -HCG or urine 
dipstick pregnancy test must be negative at start of study therapy


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10) For female subjects of childbearing potential, willingness to abstain from heterosexual 
intercourse or use a protocol-recommended method of contraception from the screening visit 
throughout the study treatment period and for 30 days following the last dose of GS-9973. 
See Section 7.11 for information regarding recommendations for contraception
11) 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 drug throughout the 
study treatment period and for 90 days following the last dose of GS-9973 or GS-9973 SDD 
and to refrain from sperm donation from the start of study drug throughout the study 
treatment period and for 90 days following the last dose of GS-9973 or GS-9973 SDD.
See Section 7.11 for information regarding recommendations for contraception
12) Willingness to comply with scheduled visits, drug administration plan, imaging studies, 
laboratory tests, other study procedures, and study restrictions
13) Have the ability to understand and sign a written informed consent form, which must be 
obtained prior to initiation of any study specific procedures
4.2.2.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not eligible for study participation:
1) Known histological transformation from iNHL or CLL to an aggressive form of NHL 
(ie, Richter transformation) if the CLL patient has not had ibrutinib or idelalisib as their 
immediately prior therapy.  CLL patients who were treated with a BCR inhibitor as the most 
recent therapy and who experience a transformation of their tumor, will not be excluded.
Subjects who have a history of iNHL or CLL with a subsequent confirmation high grade 
histology will be considered transformed for purpose of this study. Note: Biopsy 
documentation of the absence or presence of transformation is not required
2) Known active central nervous system or leptomeningeal lymphoma. Note: Central nervous 
system imaging is only required in subjects with suspected lymphomatous involvement 
based on symptoms or signs
3) Presence of known intermediate- or high-grade myelodysplastic syndrome (ie, subjects are 
excluded who have 5 bone marrow blasts; karotypic abnormalities other than normal, 
Y deletion, 5q deletion, or 20q deletion; or 2 lineages of cytopenias) {Greenberg 1997}
4) Because they are likely to interfere with GS-9973 absorption, current therapy with agents that 
reduce gastric acidity, including but not limited to proton pump inhibitors
5) History of any prior  lymphoid malignancy other than registrational histology except for CLL 
subjects with prior BCR therapy
a) Subjects with diagnoses other than CLL who were previously treated with a BCR 
inhibitor are excluded from this study.  


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6) History of non-lymphoid malignancy except for the following: adequately treated local basal 
cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder 
cancer, asymptomatic prostate cancer without known metastatic disease and with no 
requirement for therapy or requiring only hormonal therapy and with normal 
prostate-specific antigen for 1 year prior to start of study therapy, other adequately treated 
Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in 
complete remission for ≥5 years
7) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of start of study 
drug. Note: Subjects with localized fungal infections of skin or nails are eligible. 
8) Ongoing, drug-induced liver injury, chronic active Hepatitis C Virus (HCV), chronic active 
Hepatitis B Virus (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary 
biliary cirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis of the 
liver, or portal hypertension
9) Ongoing (within the past 6 weeks) hepatic encephalopathy
10) Ongoing drug-induced pneumonitis
11) Ongoing inflammatory bowel disease
12) Ongoing alcohol or drug addiction as determined by investigator
13) Pregnancy or breastfeeding
14) History of prior allogeneic bone marrow progenitor cell or solid organ transplantation
15) Ongoing immunosuppressive therapy, including systemic corticosteroids for treatment of 
lymphoid malignancy. Concurrent use of methotrexate for rheumatologic conditions is 
permitted.  Note: Subjects may use topical, enteric, or inhaled corticosteroids as therapy for 
comorbid conditions and systemic steroids for autoimmune anemia and/or thrombocytopenia. 
Ongoing use of low-dose systemic corticosteroids (5 mg/day of methylprednisolone or 
equivalent) for rheumatologic conditions is permitted. During study participation, subjects 
may receive systemic or other corticosteroids needed for treatment-emergent comorbid 
conditions.  See next entry for exception related to steroids.
16) Concurrent participation in an investigational drug trial with therapeutic intent defined as 
prior study therapy within 21 days prior to study drug.  Exception: the cohorts with relapsed 
CLL following  BCR pathway inhibitors  whom in the opinion of the investigators  cannot 
have a 21 day washout period  >5 half lives washout period will be allowed, along with  up 
to 20 mg of prednisone at the start of the trial, for control of disease related symptoms, with 
planned taper over 2 weeks
17) Any other prior or ongoing condition that, in the opinion of the investigator, could adversely 
affect the safety of the subject or impair the assessment of study results


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Enrollment
It is the responsibility of the Investigator to ensure that the subjects are eligible for the study 
prior to enrollment. Once eligibility is confirmed subjects will be assigned a unique subject 
number.  In this  open-label study all subjects will receive up to 800 mg GS-9973 BID or one of 
3 doses (100 mg, 200 mg or 400 mg) of GS-9973 SDD BID under fasted conditions (as defined 
in Section 5.5.10). As of protocol amendment 8, subjects receiving GS-9973 MM formulation 
will be transitioned to the GS-9973 SDD formulation (Section 5.3.5). All baseline tests and 
procedures must be completed prior to the administration of the first dose of study drug on 
Day 1. Once a subject number is assigned to a subject, it will not be reassigned to another 
subject.
5.2.
Description and Handling of GS-9973 and GS-9973 SDD
5.2.1.
Formulation
GS-9973 tablet is available as 200 mg strength tablets. The tablets contain commonly used 
excipients including lactose monohydrate, microcrystalline cellulose, crospovidone, povidone, 
sodium lauryl sulfate, silicon dioxide, magnesium stearate, polyethylene glycol, polyvinyl 
alcohol, talc, titanium dioxide, and FD&C blue #2 aluminum lake. The 200 mg GS-9973 tablets 
are capsule-shaped, plain-faced, film-coated blue tablets.
GS-9973 SDD (ENTO) tablets, 100 mg and 200 mg strength, are available as blue, capsule-
shaped film-coated tablets that are plain-faced. In addition to the active ingredient, ENTO tablets 
contain the following inactive ingredients: methanesulfonic acid, hydroxypropyl methylcellulose 
(hypromellose), mannitol, microcrystalline cellulose, crospovidone, poloxamer 188, silicon 
dioxide, magnesium stearate, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and 
FD&C blue #2 aluminum lake.
GS-9973 SDD (ENTO) tablets, 200 mg strength, are also available as beige, capsule-shaped 
film-coated tablets debossed with “GSI” on one side and “9973” on the other side. In addition to 
the active ingredient, ENTO tablets contain the following inactive ingredients: methanesulfonic 
acid, hydroxypropyl methylcellulose (hypromellose), mannitol, microcrystalline cellulose, 
crospovidone, poloxamer 188, silicon dioxide, magnesium stearate, polyethylene glycol, 
polyvinyl alcohol, talc, titanium dioxide, ferrosoferric oxide/black iron oxide, iron oxide red, and 
iron oxide yellow.
5.2.2.
Source
GS-9973 and GS-9973 SDD will be supplied free of charge by Gilead Sciences.  Any questions 
or concerns regarding study drug supply should be referred to the Gilead Sciences clinical 
project manager.


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5.2.3.
Packaging and Labeling
Sixty (60) GS-9973/GS-9973 SDD tablets are packaged in white, high-density polyethylene 
bottles with silica gel desiccant, and polyester packing material. Each bottle is capped with a 
child-resistant polypropylene screw cap fitted with an induction-sealed, aluminum-faced liner.
All study drug labels will meet all applicable requirements of the protocol and the regulatory 
authorities.  
5.2.4.
Storage and Handling
GS-9973 tablets should be stored at a controlled room temperature of 25 C (77 F); excursions 
are permitted from 15 C to 30 C (59 F to 86 F).
GS-9973 SDD tablets should be stored at a controlled room temperature of 25 C (77 F); 
excursions are permitted from 15 C to 30 C (59 F to 86 F).
Measures that minimize drug contact with the body should always be considered during 
handling, preparation, and disposal procedures. Any unused study drug should be disposed of in 
accordance with local requirements.
5.2.5.
Study Drug Accountability
The investigator or designee (eg, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug bottles during the study. This includes acknowledgement of 
receipt of each shipment of study drug (quantity and condition) and tracking of bottles 
assigned/utilized for subject dosing. All unused study drug bottles must be returned to the site by 
the subjects.
Investigational Drug Accountability records will be provided to each study site to:

Record the date of receipt and quantity of study drug.

Record the date of dispensation, subject identifier, and study drug bottle number(s)
dispensed.

Record the date of return and quantity of used and unused study drug bottle(s).
Dispensing records will include the initials of the person dispensing the study drug or supplies.
5.3.
Treatment Plan
5.3.1.
Premedication
No specific premedications or supporting medications are required in conjunction with 
GS-9973/GS-9973 SDD administration, although institution of antibiotic prophylaxis for 
Pneumocystis (carinii) jiroveci may be considered in all subjects (see Section 5.5.3).


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5.3.2.
Administration Instructions
GS-9973/GS-9973 SDD should be taken under fasted conditions (as defined in Section 5.5.10). 
Subjects should be instructed not to bite or chew the tablets. In case of breakage of the tablets in 
the oral cavity, additional water should be taken as a rinse.
5.3.3.
Dosing Schedule
GS-9973/GS-9973 SDD should be taken at approximately the same times each day. Ideally, doses 
should be taken at approximately 12-hour intervals, while in a fasted state. While it is realized 
that variations in the dosing schedule may occur, the prescribed regimen should be followed as 
closely as possible. Compliance with the protocol dosing schedule will be documented in the 
subject’s chart and the electronic data capture (EDC) at each scheduled visit.  Counseling 
regarding subject compliance may be required.
5.3.4.
Dose Schedule Interruptions and Vomited Doses
Subjects who have a delay in administration of a dose of GS-9973 or GS-9973 SDD 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 GS-9973 or GS-9973 SDD of 6 hours, the dose 
should not be taken. GS-9973 or GS-9973 SDD administration may continue but the missed dose 
should not be made up and the planned timing of subsequent GS-9973 or GS-9973 SDD dosing 
should not be altered.
Vomited doses should be retaken, but only if the tablets are visible in the vomitus.
5.3.5.
Transition of GS-9973 MM formulation to GS-9973 SDD formulation
As of protocol amendment 8, subjects receiving GS-9973 MM formulation will be transitioned to 
the GS-9973 SDD formulation. A comparison of the GS-9973 steady-state AUCtau in healthy 
subjects following GS-9973 MM formulation and GS-9973 SDD formulation is provided in 
Figure 5-1 (data from studies GS-US-245-0101, GS-US-245-1222, GS-US-339-0111, GS-US-
339-1627 and GS-US-339-1914), and the new dose levels for GS-9973 SDD formulation are 
provided in Table 5-1. The GS-9973 SDD dose levels in Table 5-1 are expected to provide 
similar GS-9973 systemic exposure as the indicated dose of GS-9973 MM formulation
(Figure 5-1).


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Figure 5-1. 
GS-9973 AUCtau following GS-9973 MM and GS-9973 SDD 
formulations 
50,000 
:J' 
.§ 
.s::. 
40,000 
Cl 
,S J 30,000 
20,000 
0) 
10,000 
0 
0 
0 
o--.---P""-----..------..------
0 
GS-9973 MM formulation 
GS-9973 SOD formulation 
Median (Q1, Q3) 
Table 5-1. 
Transition of GS-9973 MM formulation to GS-9973 SDD formulation 
Current dose level 
New dose level 
GS-9973 MM Dose 
Current enrollment at this dose 
GS-9973 SDD Dose 
(mg BID fasting) 
level (N) as ofMarch2017 
(mg BID fasting) 
800 
11 
400 
600 
2 
400 
400 
1 
200 
200 
0 
200 
a 
All cohorts that received GS-9973 MM fonuulation are closed to further enrolhuent. 
5.3.6. 
Management of Dose Limiting Toxicities 
Adverse events and laborato1y abno1malities will be graded using the CTCAE, Version 4.03. 
Dose modification of GS-9973/GS-9973 SDD should be perfonned for the following dose 
limiting AEs: 
• 
Grade 4 hematological toxicities persisting for ~ 14 days 
• 
Grade 
3 toxicities of other types 
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Of note, the occurrence of asymptomatic lymphocytosis will not be considered a toxicity 
requiring dose modification.  Dose reduction will not be required for untreated vomiting, 
diarrhea, or constipation; interruption of dosing until these symptoms are adequately treated is 
permitted.
Table 5-2.
GS-9973 MM Dose Levels
Dose Level
GS-9973 MM Dose
(mg BID fasting)
0
800
-1
600
-2
400
-3
200
Table 5-3.
GS-9973 SDD Dose Levels
Dose Level
GS-9973 SDD Dose
(mg BID fasting)
CLL Prior BTK inhibitor Exposure, CLL Prior PI3K 
inhibitor Exposure or CLL Dose Ranging randomized to 
400mg BID or Dose level 0
400
CLL Dose Ranging randomized to 200mg BID or Dose 
level -1
200
CLL Dose Ranging randomized to 100mg BID or Dose 
level -2
100
If a subject experiences an AE or laboratory abnormality that is suspected to be related to 
GS-9973/GS-9973 SDD, and requires a dose reduction, GS-9973/GS-9973 SDD administration 
should be interrupted, as necessary, until the AE or laboratory abnormality resolves or stabilizes 
to an acceptable degree (generally to Grade 1 or the pretreatment severity grade, whichever is 
higher). More frequent monitoring (eg, once per week) may be warranted until adverse events or 
laboratory abnormalities are clearly improving. When treatment is reinstituted, the dose of 
GS-9973/GS-9973 SDD should be reduced by 1 dose level (see Table 5-2 and Table 5-3).
Successive adjustments to progressively lower dose levels can be made. If the subject cannot 
tolerate GS-9973/GS-9973 SDD at the lowest dose level then the subject should discontinue 
GS-9973/GS-9973 SDD therapy. 
After a 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 a reduced dose of GS-9973/GS-9973 
SDD for ≥4 weeks then the GS-9973/GS-9973 SDD dose may be increased to the next higher 
dose level, at the discretion of the investigator. Such re-escalation should strongly be considered 
if further evaluation reveals that the AE that led to the dose reduction was not GS-9973/GS-9973 


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SDD-related. Successive adjustments to progressively higher dose levels can be made at 4-week 
intervals up to the highest dose level. Dose escalations above the highest dose level are not 
allowed. Any study drug dose re-escalation must be discussed between the investigator and the 
Gilead Sciences Medical Monitor or designee prior to implementation. 
Whenever the study drug dose is de-escalated or re-escalated, the appropriate clinic staff should 
dispense the study drug for the new dose level and instruct the subject/caregiver about the 
change in dose level.
Note:  Dose modifications and clinical management for subjects who enter the study with 
pre-existing Grade 3 or 4 abnormalities due to their underlying malignancy will be discussed 
with the study Medical Monitor or designee prior to the initiation of treatment.
5.3.6.1.
Guidelines for Dose Modifications
Recommendations for dose modifications based on the type and severity of adverse events or 
laboratory abnormalities are provided in Table 5-4.  The dose adjustment recommendations are 
based on the CTCAE grade of specific toxicities. However, exceptions are expected for subjects 
who initiate study treatment with low blood counts. Clinical judgment should apply, and in cases 
of uncertainty, the study medical monitor should be contacted.
The dose modification instructions focus on the types of events most commonly attributed to 
GS-9973/GS-9973 SDD or other drugs that target B-cell receptor signaling pathways.  The 
recommendations provided in Table 5-4 comprise only guidelines; variations from these 
recommendations may be warranted based on an investigator’s individual judgment in 
considering potential risks, benefits, and therapeutic alternatives available to each subject.
Table 5-4.
Dose Modification Guidelines
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Neutropenia
Maintain current dose level and schedule.
Consider G CSF support 
and continue dosing at 
same or lower dose level 
at investigator discretion.
Thrombocytopenia
Maintain current dose level and schedule.
Withhold for bruising or 
bleeding until Grade ≤ 3. 
May resume dosing  at 
initial or lower dose level 
at investigator discretion
Dermatological
Maintain current dose level and schedule.
Withhold dosing until 
≤Grade 1.  Resume 
dosing at current dose 
level.
If re-challenge at current 
dose level results in 
recurrence, may resume 
dosing at same or lower 
dose level at investigator 
discretion.
Withhold dosing until 
Grade 1.
May resume at lower 
dose level or discontinue 
dosing at investigator 
discretion.
I 


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Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Gastrointestinal 
Inflammation-
Diarrhea
Provide anti-diarrheal
(e.g., loperamide) 
and maintain current 
dose level and 
schedule
Provide anti-diarrheal 
(e.g., loperamide). 
Withhold dosing until 
Grade 1. Resume 
dosing at current dose 
level.
If re-challenge results 
in recurrence, may 
resume at initial or 
lower dose level at 
investigator 
discretion.
Consider addition of 
anti-inflammatory 
(e.g., sulfasalazine, 
budesonide).
Provide anti-diarrheal 
(e.g., loperamide). 
Withhold dosing until 
Grade 1. Resume at 
lower dose level.
Consider addition of 
anti-inflammatory 
(e.g., sulfasalazine, 
budesonide).
Provide anti-diarrheal 
(e.g., loperamide). 
Withhold dosing until 
Grade 1. May resume at 
lower dose level or 
discontinue dosing at 
investigator discretion.
Consider addition of 
anti-inflammatory 
(e.g., sulfasalazine, 
budesonide).
Hepatic
(elevations in ALT, 
AST, or bilirubin)   
(ALT/AST3xULN)
(Direct Bilirubin
1.5xULN)
(ALT/AST>3-5xULN)
(Direct Bilirubin
>1.5-3xULN)
(ALT/AST>5-20xULN)
(Direct Bilirubin
>3-10xULN)
(ALT/AST>20xULN)
(Direct Bilirubin
>10xULN)
Maintain current 
dose level and 
schedule.
Maintain current dose 
level and schedule. 
Monitor ALT, AST, 
ALP, and direct
bilirubin at least 
1x per week.
Withhold dosing. 
Monitor ALT, AST, 
ALP, and direct bilirubin 
at least 1x per week until 
all abnormalities are 
Grade 1.
If direct bilirubin was 
Grade <3, resume dosing 
at same dose level. If 
direct bilirubin was 
Grade 3, resume at 
lower dose level.
Withhold dosing. 
Monitor ALT, AST, 
ALP, and direct bilirubin 
at least 1x per week until 
all abnormalities are 
Grade 1.
If direct bilirubin was 
Grade <4, resume dosing 
at lower dose level. If 
direct bilirubin was 
Grade 4, discontinue 
dosing.
Pneumonitis 
(dyspnea, cough, 
hypoxia and/or 
diffuse interstitial 
pattern or ground-
glass opacities on 
chest CT and no 
obvious infectious 
cause)
Maintain current 
dose level and 
schedule. Consider 
Pneumocystis 
therapy
Withhold dosing until 
Grade 1.
Consider systemic 
corticosteroids and 
Pneumocystis 
treatment.
May resume at initial 
or lower dose level at 
investigator 
discretion.
Withhold dosing until Grade 1.
Consider systemic corticosteroids and consider 
Pneumocystis treatment.
May resume at lower dose level or discontinue dosing 
at investigator discretion.
Other Study Drug 
Related, 
Non-hematological 
Adverse Events
Maintain current dose level and schedule
Withhold dosing until Grade 1.
May resume dosing at initial or lower dose level or 
discontinue dosing at investigator discretion.


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5.3.7.
Management of Low Grade Chronic Toxicities
Since subjects will be receiving the study drugs daily, low grade chronic side effects, such as 
nausea, fatigue and diarrhea, while not meeting the above definition for dose limiting toxicities,
may not be tolerable when experienced for long periods of time.  Following discussion with the 
Gilead Sciences Medical Monitor, dose reduction may be permitted if low grade chronic side 
effects cannot be managed effectively with supportive care.
5.3.8.
Specific Considerations for Managing Hyperbilirubinemia
5.3.8.1.
Unconjugated (Indirect) Bilirubin Elevations
GS-9973 is an inhibitor of UGT1A1 and reversible increases in unconjugated (indirect) bilirubin 
values occurred in healthy subjects receiving GS-9973/GS-9973 SDD.  In the absence of 
symptoms or other hepatic laboratory abnormalities, GS-9973/GS-9973 SDD dose modification 
is not required for elevated indirect bilirubin levels.
5.3.9.
Duration of Therapy
Subjects may continue receiving GS-9973/GS-9973 SDD until the occurrence of any events 
requiring treatment discontinuation as defined in Section 5.6.
5.4.
Study Drug Disposal
At the start of the study, the study monitor will evaluate each study center’s study drug disposal 
procedures and provide appropriate instruction for return or destruction of unused study drug 
supplies. If the site has a process instruction (eg, Standard Operating Procedures [SOPs]) for 
on-site drug destruction which is reviewed by the study monitor, then the site should destroy 
used (empty bottles) and unused study drug supplies performed in accordance with the site’s 
(hospital/pharmacy) procedure. The destruction process should include records noting the 
identification and quantity of each unit destroyed the method of destruction, and person who 
disposed of the drug. A copy of the site’s SOP/process document will be obtained for central 
files at the pre-study or otherwise applicable monitoring visit. Upon study completion, a copy of 
the relevant Investigational Drug Accountability records must be filed at the site and provided 
for the sponsor files. If the site does not have acceptable procedures in place for drug destruction, 
arrangements will be made between the site and Gilead Sciences (or Gilead Sciences’ 
representative) for return of unused study drug supplies.
5.5.
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, or excessive alcohol 
at any time during the clinical 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 electronic Case Report Forms (eCRFs).


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All concomitant medications and over the counter medications must be approved by the 
Gilead Sciences Medical Monitor or designee prior to study enrollment.
Should subjects have a need to initiate treatment with any excluded concomitant medication, the
Gilead Sciences Medical Monitor or designee must be consulted prior to initiation of the new 
medication. In instances where an excluded medication is initiated prior to discussion with the 
Gilead Sciences Medical Monitor or designee, the Investigator must notify Gilead Sciences as 
soon as he/she is aware of the use of the medication.
5.5.1.
Excluded Medication
During the course of the clinical trial, study subjects are anticipated to continue the use of 
prescribed medications identified during the screening procedures, consistent with study 
inclusion and exclusion criteria.
The following therapies are not permitted at any point during the trial beginning with the first 
dose of study drug.

Any non-study anti-cancer chemotherapy or non-study immunotherapy (approved or 
investigational)

Co-administration of strong CYP3A and CYP2C9 inducers or moderate CYP2C9 inducers
are prohibited in this study. Administration of these medications should be avoided for 
2 weeks prior to study drug administration. Examples of these medicines are provided in 
Table 5-5.

Caution should be exercised when co-administering drugs that are moderate or strong
inhibitors of CYP2C9 (eg fluconazole, voriconazole or amiodarone) as they may increase 
GS-9973 exposure. These agents are not prohibited.

Proton pump inhibitors are prohibited in combination with GS-9973. Use of a proton pump 
inhibitor should be avoided for 1 week prior to study drug administration.
Table 5-5.
Examples of Contraindicated Medications in this Study that require 
prior Gilead Medical Monitor discussion and approval 
Strong
Moderate
CYP3A Inducer
carbamazepine, phenytoin, rifampin, St. 
John’s Wort, enzalutamide, rifabutin, 
phenobarbital, mitotane, avasimibe
Not prohibited
CYP2C9 Inducer
carbamazepine, rifampin, ritonavir, 
enzalutamide
Proton Pump 
Inhibitors
omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole, dexlansoprazole


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
Caution should be exercised when co-administering medications that are transported by 
OATP1B1, OATP1B3, MATE1, P-gp and BCRP or metabolized by UGT1A1; dose 
adjustment or switching to an alternative medication may be necessary if clinically indicated.

The following restrictions apply to the use of HMG-CoA reductase inhibitors with GS-9973:
5.5.2.
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 
investigational drug trial with therapeutic intent.
5.5.3.
Antibiotics
Except in a subject who has a contraindication, investigators should consider initiation of 
antibiotic prophylaxis against pneumocystis infection (eg, with trimethoprim-sulfamethoxazole, 
dapsone, aerosolized pentamidine, or atovaquone) beginning prior to GS-9973 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 should 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 GS-9973/GS-9973 SDD during treatment for the infection.
5.5.4.
Antiemetics and Antidiarrheals
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.  If possible, 
systemic corticosteroids should be avoided (see Section 5.5.6).
As needed, subjects may be prescribed supportive medications to control diarrheal symptoms.
Concomitant Medication
Restriction
Atorvastatin
Maximum dose 20 mg QD
Rosuvastatin
Maximum dose 10 mg QD
Pravastatin
Maximum dose 40 mg QD
Simvastatin
Maximum dose 20 mg QD
Lovastatin
Maximum dose 20 mg QD
Fluvastatin
Maximum dose 20 mg BID or 40 mg QD
Pitavastatin
Maximum dose 1 mg QD


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5.5.5.
Contraception
Please see Section 7.11 for contraception guidelines. 
The Gilead Sciences Medical Monitor or designee should be consulted regarding any questions 
relating to childbearing status or contraception.
5.5.6.
Corticosteroids
Subjects may not receive systemic corticosteroids as part of their cancer treatment while in this 
study.  Subjects may receive topical, inhaled, or enteric corticosteroids for non-malignant 
conditions while on study. The use of systemic corticosteroids is discouraged because their 
potential antineoplastic activity in subjects with a hematologic malignancy may confound 
interpretation of antitumor effects mediated by GS-9973/GS-9973 SDD treatment. 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.
5.5.7.
Colony-Stimulating Factors and Erythropoietin
Colony stimulating factors, preferably G-CSF preparations, may be administered in response to 
Grade 4 neutropenia or neutropenic complications; use should be considered particularly if 
providing hematopoietic support might help to maintain study drug treatment.
Erythropoietic agents may be administered for Grade 3 anemia.
Reference may be made to the American Society of Clinical Oncology guidelines {Rizzo 2008, 
Smith 2006}.
5.5.8.
Immunization
Because of their actions to inhibit SYK-dependent B-cell function, GS-9973 could, in theory, 
impair primary or secondary responses to immunization although the clinical relevance is 
unknown. However, for subjects who are at substantial risk of an infection (eg, influenza, herpes 
zoster) 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-9973/GS-9973 SDD
therapy has not been studied and vaccination with live virus vaccines during study treatment is 
not recommended.
5.5.9.
Surgery
The effects of GS-9973 on coagulation or wound healing in humans are not known. Pending 
receipt of additional information, GS-9973 should be discontinued in the peri-procedural period 
in subjects who require surgery or invasive procedures.  Cases in which this is not in the best 
interest of the subject should be discussed with the Gilead Sciences Medical Monitor or designee.  


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Given the half-life of GS-9973 (~10 hours), drug levels should be minimal 48 hours after the last 
dose of GS-9973/GS-9973 SDD, although the biological effects on SYK and possibly other 
targets may persist longer than this.
5.5.10.
Diet
GS-9973/GS-9973 SDD must be taken under fasted conditions.  Fasting is defined as no food or 
liquids other than water for 2 hours pre- and 1 hour post- dose.  
5.6.
Discontinuation of Study Drug
Study participants may receive GS-9973/GS-9973 SDD indefinitely, with the following 
exceptions:

Any subject has the right to withdraw from the study at any time.

Any subject who has objective evidence of definitive cancer progression despite optimal 
therapy should be withdrawn from the study treatment (see Section 6.6).

Any subject who cannot tolerate GS-9973/GS-9973 SDD at the lowest dose level
(see Table 5-2 and Table 5-3) should be withdrawn from study drug.

Any subject whose medical condition substantially changes after entering the study should be 
carefully evaluated by the investigator in consultation with the Gilead Sciences Medical 
Monitor or designee. Such subjects should be withdrawn from study drug if continuing 
would place them at risk.

Any subject who becomes pregnant or begins breastfeeding should be withdrawn from study 
drug.

Any subject who becomes significantly noncompliant with study drug administration, study 
procedures, or study requirements should be withdrawn from study drug in circumstances 
that increase risk or substantially compromise the interpretation of study results.

The investigator, in consultation with the Gilead Sciences Medical Monitor or designee, may 
withdraw any subject from the study drug, 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 drug to 
commercial drug supply when GS-9973/GS-9973 SDD becomes commercially available in 
the country where the subject is living.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and in the following text.
Any deviation from protocol procedures should be noted in the source documents and the 
Sponsor should be notified.
The study center will not be released to initiate dosing until:

The Research Ethics Board (REB)/Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) has reviewed and approved the study and the informed consent document;

All requested regulatory documents are submitted to and approved by Gilead Sciences;

A Master Services Agreement and/or Study Agreement is executed;

The study initiation meeting is conducted by the Gilead Sciences clinical monitor 
(or designee).
The initiation meeting will include a review of the protocol, the Investigator’s Brochure, and 
Investigator responsibilities.
Documentation of the personally signed and dated informed consent of each subject, using the 
study-specific informed consent form (ICF), is required before initiating the Screening process. 
Generic Screening consent forms should not be used in lieu of the study-specific ICF.
6.1.
Subject Enrollment and Treatment Assignment
It is the responsibility of the Investigator to ensure that subjects are eligible to participate in the 
study prior to enrollment and throughout the study. Once consent is obtained, all screening tests 
and procedures are assessed, and study eligibility is confirmed, subjects will be enrolled to 
receive GS-9973 as described in Section 5.1 of the protocol.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visits
Subjects will be screened within 35 days before enrollment (Cycle 1, Day 1) to determine 
eligibility for participation in the study.
The following procedures will be performed and documented at screening:

Obtain written informed consent

Medical history

Review prior/concomitant medication


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
Complete physical examination including height and weight

Vital signs including blood pressure, respiratory rate, pulse, oxygen saturation by pulse 
oximetry, temperature

12-lead ECG

Karnofsky performance status (see Section 6.9.3)

Obtain blood samples for:
Chemistry (see Section 6.9.8)
Hematology (see Section 6.9.8)
Coagulation (see Section 6.9.8)
HBV, HCV, and HIV virology
Serum pregnancy test (for females of childbearing potential)

Urinalysis

CT or MRI of neck, chest, abdomen, and pelvis (scans taken as part of standard medical 
practice up to 35 days prior to Day 1 of Cycle 1 visit are acceptable).  Subjects with 
LPL/WM who previously failed screening for this study, due to an absence of 
lymphadenopathy on CT or MRI scans, do not need to be re-scanned if the scans were 
performed within 16 weeks of first study drug administration to meet eligibility criteria.

If the subject has DLBCL, subtyping is required.  Submission of 15 unstained slides is 
required for subtyping if the subtype is not already known.

Subjects with LPL/WM only; evaluation of serum monoclonal IgM by both SPEP and IFE 
(immunofixation electrophoresis).  LPL/WM enrollment limited to those sites which have 
cryoglobulin analysis capabilities.

Record any AEs occurring after signing of the consent form

Complete subject/visit information in IxRS
6.3.
Cycle-Based Assessments
Although dosing with study drug will be given twice daily without scheduled breaks, for the 
purpose of describing protocol-required assessments, a cycle will be considered to be 28 days.


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6.3.1.
Day 1 of each 28-Day Cycle (± 2 days after Cycle 1)
Subjects who have met all eligibility criteria will come to the clinic on Day 1 to perform study 
required procedures prior to dosing at Cycle 1 Day 1.
The following procedures will be conducted on Day 1:

Modified physical examination capturing changes from prior exams and weight will be 
performed 

Vital signs including blood pressure, respiratory rate, pulse, oxygen saturation by pulse 
oximetry, temperature

Karnofsky performance status (see Section 6.9.3)

Concomitant Medication Review 

Obtain blood samples for: 
Chemistry (see Section 6.9.8)
Hematology (see Section 6.9.8)
Coagulation (see Section 6.9.8)
GS-9973 plasma concentration pre-dose (Cycles 2-6 only); GS-9973 SDD plasma 
concentration pre-dose and at 1.5 hours post-dose (± 10 minutes) for CLL dose ranging, 
CLL prior BTK inhibitor exposure, or CLL prior PI3K inhibitor exposure cohorts only
ONLY For subjects with SLL, CLL or MCL 
Cytokines and chemokines (see Section 6.13.1) on Cycle 2, Day 1 and Cycle 12 Day 1 
ONLY
CTC RNA Pre-dose Cycle 12, Day 1 ONLY

Urinalysis

Record the approximate number of hours between the last 2 doses of GS-9973/GS-9973 SDD
and the time the blood samples for plasma concentration were obtained

Urine pregnancy test (for females of childbearing potential)

Collect used/unused study drug and assess study drug compliance (Cycle 2 onwards)

Dispense study drug

Record any AEs


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Final 
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• 
Archive tumor tissue specimen as applicable. Effo1is to acquire tissue sample should begin 
on Day 1 of Cycle 1. 
Day 1 of Cycle 1 ONLY: 
• 
Administration of study diug at site under fasted conditions (defined in Section 5.5.10) as per 
Section 5.3.2. 
• 
Obtain blood samples for GS-9973/GS-9973 SDD plasma concentration pre-dose, 1.5 hours 
post-dose (± 10 minutes) and at 4 hours post-dose (± 10 minutes) 
• 
For subjects with SLL, CLL or MCL: Obtain pre-dose blood samples for Chemokines and 
Cytokines, CTC RNA, and CTC Molecular Characterization 
• 
Record any AEs prior to discharge 
• 
Genoinic testing for CLL dose ranging, CLL prior BTK inhibitor exposure, or CLL prior 
PBK inhibitor exposure coho1i s only: PBMC samples will be isolated from blood samples, 
so1ied by cell surface marker ( CD 3) and stored separately ( see Section 6 .15). 
• 
Buccal Swab for CLL dose ranging, CLL prior BTK inhibitor exposure, or CLL prior PBK 
inhibitor exposure cohorts only (gennline DNA) 
I 
• 
Obtain blood samples for BAT Assay pre-dose, 1. 5 hours post-dose and at 4 hours post-dose 
for CLL dose ranging, CLL prior BTK inhibitor exposure, or CLL prior PBK inhibitor 
exposure coho1i s only 
Day 1 of Cycle 2 ONLY: 
• 
Obtain blood samples for GS-9973/GS-9973 SDD plasma concentration 12 hours post- last 
dose ( ± 4 hours). If necessaiy the dose may be held until this blood sample has been &·awn. 
• 
For subjects with SLL, CLL or MCL: Obtain blood samples for Chemokines and Cytokines 
6.3.2. 
Safety Monitoring Visits(± 2 days): Days 8, 15 and 22 of Cycle 1 and Day 15 
of Cycle 2 
The following procedures will be conducted on the designated days during Cycles 1 and 2. 
Please see Study Procedures Table in Appendix 2. 
• 
Modified physical examination capturing changes from prior exams and weight will be 
perfonned 
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
Vital signs including blood pressure, respiratory rate, pulse, oxygen saturation by pulse 
oximetry, temperature

Karnofsky performance status (see Section 6.9.3)

Concomitant Medication Review

Obtain blood samples for:
Chemistry (see Section 6.9.8)
Hematology (see Section 6.9.8)
Coagulation (see Section 6.9.8)
GS-9973 SDD plasma concentration pre-dose, 1.5 hours post-dose (± 10 minutes) and at 
4 hours post-dose (± 10 minutes) for CLL dose ranging, CLL prior BTK inhibitor 
exposure, or CLL prior PI3K inhibitor exposure cohorts only on Cycle 1, Day 8
BAT Assay pre-dose and at 4 hours post-dose for CLL dose ranging, CLL prior BTK 
inhibitor exposure, or CLL prior PI3K inhibitor exposure cohorts only on Cycle 1, Day 8
for BAT Assay pre-dose for CLL dose ranging, CLL prior BTK inhibitor exposure, or 
CLL prior PI3K inhibitor exposure cohorts only on Cycle 1, Day 15
GS-9973 SDD plasma concentration pre-dose and at 1.5 hours post-dose (± 10 minutes)
for CLL dose ranging, CLL prior BTK inhibitor exposure, or CLL prior PI3K inhibitor 
exposure cohorts only on Cycle 1, Day 15, Cycle 1, Day 22 and Cycle 2, Day 15
ONLY for subjects with SLL, CLL or MCL 
Cytokines and chemokines on Cycle 1, Day 8
CTC Molecular Characterization on Cycle 2, Day 15
Genomic testing for CLL dose ranging, CLL prior BTK inhibitor exposure, or CLL prior 
PI3K inhibitor exposure cohorts only on Cycle 2, Day 15

Record the approximate number of hours between the last 2 doses of GS-9973 SDD and the 
time the blood samples for plasma concentration were obtained

Urine pregnancy test (for females of childbearing potential) only on Day 15 of 
Cycles 1 and 2

12-lead ECG

Record any AEs


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6.4.
Unscheduled Safety Visits
Unscheduled safety visits will be conducted as needed during the study.  Some or all of the 
following procedures can be obtained as clinically indicated:

Modified physical examination capturing changes from prior exams and weight will be 
performed

Vital signs including blood pressure, respiratory rate, pulse, oxygen saturation by pulse 
oximetry, temperature

Karnofsky performance status (see Section 6.9.3)

Concomitant Medication Review

Obtain blood samples for:
Chemistry (see Section 6.9.8)
Hematology (see Section 6.9.8)
Coagulation (see Section 6.9.8)

12-lead ECG

Record any AEs
6.5.
Assessment of Tumor Response
The procedures to assess tumor response will be conducted every 8 weeks during the 
first 24 weeks on study and then every 12 weeks up to 72 weeks, regardless of cycle number and 
regardless of any dose interruptions (ie, Weeks 8, 16, 24, 36, 48, 60, 72, etc).  Tumor 
assessments must be done any time during the specified week (+/-3 days around the week). 
Therefore there is a 13-day window to conduct tumor assessments that begins 3 days prior to the 
start of the last week of the corresponding 28-day cycle and ends 3 days after the last day of that
same corresponding cycle.  The description of the assessments to be conducted are detailed in 
Section 6.12 and outlined in the Study Procedures Table in Appendix 2.
A bone marrow biopsy and aspirate will be collected for all subjects who achieve a CR for 
confirmatory purpose. For LPL/WM without adenopathy and CLL subjects a bone marrow 
biopsy/aspirate will be collected to confirm a PD if based only upon declines in the platelet count 
and/or hemoglobin for CLL subjects or rise in Serum monoclonal IgM in LPL/WM. For all 
LPL/WM patients who achieve CR or PD and are not evaluable by radiological criteria require 
confirmation by bone marrow evaluation. If the subject does not otherwise meet criteria for CR 
or if the nature of PD does not require bone marrow confirmations, it is not necessary to obtain a 
bone marrow biopsy/aspirate (See Sections 6.20 and 6.21).  


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ONLY for subjects with LPL/WM, an evaluation of serum monoclonal IgM by both SPEP and 
IFE will be conducted including cryoglobulin testing (LPL/WM enrollment limited to those sites 
which have cryoglobulin analysis capabilities).  Serum monoclonal IgM as assessed by SPEP 
will only be considered if baseline total serum IgM quantitation by nephelometry is not 
available. 
This procedure should be conducted on the Day 1 visit occurring during the week window 
allotted for tumor response assessments.  LPL/WM subjects who do not have lymphadenopathy 
on their screening CT/MRI evaluations are not required to have repeated scans for tumor 
assessment unless clinically indicated, but all subjects in this subset will require BM evaluations 
for suspected PD or CR assessments.
Subjects who stop study drug for reasons other than progression of disease (eg, experience 
unacceptable toxicity) should be continued on the study and followed every 6 months or 
according to institutional standard of care (if more frequent) until progression is documented or 
another anti-tumor regimen is initiated. An end of study visit need only to be conducted per 
Section 6.7 if the subject comes off of study and is no longer to be followed.
6.5.1.
Clinical Evaluation after 72 weeks (18 months)
After 72 weeks on study, the subject will be followed for disease status at a minimum of every 
6 months or according to institutional standard of care (if more frequent).  At each study visit the 
subject’s disease status will be assessed and information will be collected to determine response 
to treatment. If no change in disease status is identified and the subject is dispensed additional 
GS-9973/GS-9973 SDD, the most recent prior response documented for the study will be 
recorded.
All subjects with CLL should have the following laboratory test results recorded at each visit: 
ALC, PLT, Hgb, ANC. All subjects with WM should have the following laboratory test results 
recorded at each evaluation visit: IgM, serum M protein.
All subjects will have a CT scan at least once every 6 months and at time of clinical change in 
response (PR or CR after SD, or CR after PR) or progression. In addition, for initial CR a bone 
marrow evaluation is required.
6.6.
At Disease Progression
All subjects will be followed until initiation of next treatment.  If the subject was not receiving 
study drug at the time tumor progression was documented, or was at a dose level below the 
maximum and could potentially tolerate a higher dose, after discussion with the Gilead Sciences 
Medical Monitor, the subject may continue on study and study drug may be re-started or 
escalated using the algorithm defined in Section 5.3.5 if the investigator feels it is in the subject’s 
best interests to do so.


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If the investigator feels the subject is having progressive disease, tumor imaging as described in 
Section 6.12 should be c~mied out unless the most recent imaging had documented progressive 
disease. The images and any other material needed to document progression are to be transfe1Ted 
to the IRC as soon as possible. While waiting for confinnation of progressive disease from the 
IRC, the subject should continue to receive study drng unless his/her medical condition wan ants 
immediate ti·eatment with different therapy. When progression is confomed, the following 
procedures should be can ied out while the subject is still receiving study diug. 
• 
Complete physical examination including weight 
• 
Vital signs including blood pressure, respirato1y rate, pulse, oxygen saturation by pulse 
oximetiy, temperature 
• 
Kamofsky perfo1mance status (see Section 6.9.3) 
• 
Concomitant Medication Review 
• 
Obtain blood samples for: 
-
Chemistry (see Section 6.9.8) 
-
Hematology (see Section 6.9.8) 
-
Coagulation (see Section 6.9.8) 
-
GS-9973/GS-9973 SDD plasma concenti·ation ( excluding subjects off study di11g at time 
of progression) 
For subjects with SLL, CLL or MCL 
-
CTC Molecular characterization (see Section 6.14) 
-
Cytokines and chemokines (see Section 6.13.1) 
-
CTC RNA pre-dose (see Section 6.13.2) 
• 
Record the approximate number of hours between the last 2 doses of study diug and the time 
the blood samples for plasma concenti·ation were obtained ( excluding subjects off study di11g 
at time of progression) 
• 
Urine pregnancy test (females of childbearing potential) 
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
For CLL subjects a bone marrow biopsy/aspirate will be collected to confirm a PD.  If the 
nature of PD does not require bone marrow confirmations, it is not necessary to obtain a bone 
marrow biopsy/aspirate (See Section 6.20).

Collect used/unused study drug and assess study drug compliance by pill counts 
(excluding subjects off study drug at time of progression)

Record any AEs

Complete subject/visit information in IxRS
6.7.
End of Study
The following procedures will be conducted when a subject goes off study and prior to initiating 
a new anti-tumor regimen.  If a subject stops study drug for a reason other than progressive 
disease, they will be followed as per the scheduled imaging in Section 6.5 with additional CBC 
(hematology) at time of assessments. If the subject chooses not to continue participation on the 
study once study drug has been stopped or it is not consistent with good medical practice then 
the end of study procedures listed below are to be conducted within 30 days of the last dose of 
study drug or prior to initiating a new anti-tumor regimen. Please see Study Procedures Table in 
Appendix 2.
The end of study visit and disease progression visit Section 6.6 can occur simultaneously; 
however, if the end of study visit was not performed at the same time as disease progression, 
perform the following:

Complete physical examination including weight

Vital signs including blood pressure, respiratory rate, pulse, oxygen saturation by pulse 
oximetry, temperature

Karnofsky performance status (see Section 6.9.3)

Concomitant Medication Review

Obtain blood samples for:
Chemistry (see Section 6.9.8)
Hematology (see Section 6.9.8)
Coagulation (see Section 6.9.8)
GS-9973/GS-9973 SDD plasma concentration


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For subjects with SLL, CLL or MCL 
CTC Molecular characterization (see Section 6.14)
Cytokines and chemokines(see Section 6.13.1)
CTC RNA pre-dose (see Section 6.13.2)

Record the approximate number of hours between the last 2 doses of GS-9973/GS-9973 SDD
and the time the blood samples for plasma concentration were obtained

Urine pregnancy test (females of childbearing potential)

Collect used/unused study drug and assess study drug compliance by pill counts 

Tumor response assessment (according to Section 6.5), if not conducted within the last 
4 weeks

Record any AEs

Complete subject/visit information in IxRS
6.8.
Immediate Post-Treatment Safety Follow-up
After the last dose of study drug, subjects should be followed for any drug-related AEs and/or 
ongoing serious adverse events (SAEs) until those events have resolved or become stable, 
whichever occurs later. The site will contact the study subject regardless of AE/SAE status or 
initiation of new anti-tumor regimen 30 (7) days following completion of the subject’s last 
dose of study drug to assess for AEs.  Subjects will specifically be asked about the development 
of any adverse events since stopping the study.  Contact the subject by phone (or in person, if 
necessary) to assess the subject’s condition and record any adverse events reported during the 
follow-up contact.  Document the phone call or visit.
6.9.
Description of Study Procedures
6.9.1.
Medical History
A complete medical history will be obtained by the Investigator or designee. Medical history will 
include information on the subject’s prior anti-tumor therapies, significant past medical events 
(including prior hospitalizations or surgeries), and any concurrent medical illness. 
6.9.2.
Physical Examination
The Investigator or qualified designee will perform a physical examination at screening and time 
points outlined in the Study Procedures Table (Appendix 2). Screening abnormal findings will be 
reported on the medical history page of the eCRF. Any changes from the Screening (baseline) 
physical examination which represent a clinically significant deterioration will be documented 
on the AE page of the eCRF.


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Height measurement (in centimeters) will be obtained at Screening. Weight measurements 
(in kilograms) will be obtained at Screening and time points outlined in the Study Procedures 
Table (Appendix 2).
6.9.3.
Karnofsky Performance Status
Karnofsky Performance Status will be assessed using the following scale:
Karnofsky 
Performance Status
Description
100
Normal.  No complaints
90
Able to carry on normal activity.  Minor signs or symptoms of disease.
80
Normal activity with effort.  Some signs or symptoms of disease.
70
Able to care for self.  Unable to carry on normal activity or to do active work.
60
Requires occasional assistance, but is able to care for most needs.
50
Requires considerable assistance and frequent medical care.
40
Disabled.  Requires special care and assistance.
30
Severely disabled.  Hospitalization is indicated although death not imminent.
20
Hospitalization necessary, very sick, active supportive treatment necessary
10
Moribund.  Fatal processes progressing rapidly.
0
Dead
Source: {Schag 1984}
6.9.4.
Vital Signs
Vital signs, including oxygen saturation by pulse oximetry, blood pressure, respiratory rate, 
pulse, and temperature will be measured at the time points listed in the Study Procedures Table 
in Appendix 2. All measurements will be recorded on the appropriate eCRF page with 
appropriate source documentation. Any abnormal measurements may be repeated and reported as 
AEs, if appropriate.  All measures of blood pressure will be performed using standard 
sphygmomanometry.  Vital signs should be taken after the subject has been sitting for at least 
5 minutes.
6.9.5.
Electrocardiogram
Twelve (12)-lead ECGs reporting ventricular rate, PR, QRS, QT, and QTc intervals will be 
obtained at screening, safety monitoring visits and, if clinically indicated, during the course of 
the study.
The Investigator or qualified designee will review all ECGs. The ECG tracings will be 
maintained in the source documentation of each subject and the appropriate data reported on the 
eCRF.


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6.9.6.
Adverse Events 
Subjects will be assessed for AEs per guidelines in the CTCAE (version 4.03) during each 
outpatient visit as outlined in the Study Procedures Table (Appendix 2). Any AEs reported 
throughout the study will be recorded in the eCRF with appropriate source documentation.  The 
site will contact the study subject by phone (or in person, if necessary) 30 (7) days following 
completion of the subject’s last dose of study drug to assess for AEs.
6.9.7.
Prior/Concomitant Medications
At screening all medication taken up to 30 days prior to the screening visit will be recorded on 
the eCRF.  At each study visit, the site will capture any and all medications taken by the subject 
since the last visit or during the visit (as applicable). Concomitant medications include 
prescription, non-prescription medications, vitamins, and minerals.
6.9.8.
Laboratory Safety Tests 
Blood will be collected for laboratory safety tests according to the Study Procedures Table in 
Appendix 2. The date and time of blood collection will be recorded in the subject’s source 
documentation. The tests will be analyzed using standard procedures. White blood cell 
differentials will be reported as absolute counts. All laboratory tests must be reviewed by the 
Investigator or qualified designee.
The following analytes will be tested (see Table 6-1):
Table 6-1.
Blood Samples Collected During the Course of the Study
Serum Chemistry
Hematology
Other
Sodium
Potassium
Chloride
Glucose
BUN
Creatinine
ALT
AST
Alkaline phosphatase
Total bilirubin
Direct bilirubin
Total protein
Albumin
Calcium
Magnesium
Phosphate
Total CPK
White Blood Cell (WBC) Count
Hemoglobin
Hematocrit
Reticulocyte counts
Platelet Count
Differential
Pharmacodynamic 
measurements
GS-9973 plasma 
concentration
Pharmacogenomics 
assessment
Coagulation
PT/INR
aPTT
Pregnancy Testing
Virology
Serum Qualitative -HCG (females of 
childbearing potential)a
Urineb Pregnancy (females of 
childbearing potential)
Hep B
Hep C
HIV
a
Serum pregnancy will be conducted at Screening. 
b
Urine pregnancy will be conducted pre-dose on Days 1 and 15 of Cycles 1 & 2, Disease Progression and at EOS


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6.10.
Blood Collection
Computations of blood drawing requirements for this study are shown in Table 6-2. The 
maximum amount of blood to be drawn at a visit is 86.3 mL and the maximum amount of blood 
to be drawn over the initial 52-week study period (including the 5-week screening period and 
through Week 47 of the study) is ~419.1 mL. For a 45-kg person (the smallest participant 
expected to enroll in the study) this equates to maximum blood volume per body weight per visit 
of ~2.03 mL/kg and a total blood volume per body weight per average 6-week period of 
~1.07 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. {U.S. Department of 
Health and Human Services 2010}
Table 6-2.
Blood Drawing Requirements
Test
Sample 
Type
Blood 
Per 
Tube 
(mL)
Tubes (n)
Blood Volume (mL)
Maximum 
Per Visit
Maximum 
in Studya
Maximum 
Per Visit
Maximum 
in Studya
Serum virology
Hep B surface 
antigen, Hep C 
antibody
Serum
2.5
1
1
2.5
2.5
HIV1/HIV2 
antibody
Serum
3.5
1
1
3.5
3.5
Coagulation
Plasma
1.8
1
17
1.8
30.6
Hematology
Whole 
Blood
2
1
17
2
34
Serum chemistry (including -HCG)
Serum
2.5
1
17
2.5
42.5
CTC*
SLL/ CLL / MCL
Molecular 
Characterization
Flow Cytometry
Whole 
Blood
8
1
3
8
15
Cytogenetics
Whole 
Blood
8
1
3
8
15
Molecular 
Pathology
Whole 
Blood
8
1
3
8
15
RNA
Whole 
Blood
2.5
2
13
5
65
CLL 
Basophil 
Activation 
Assay
Whole 
Blood
2
3
6
6
12
PBMC for 
genomics
Whole 
Blood
10
3
9
30
90
Chemokines / Cytokines
Serum
5
2
18
10
90
GS-9973 Drug Levels
Plasma
4
1
1
4
4
Total
91.3
419.1
a
Computed for the initial 52-week period (considering 5 weeks for screening and 47 weeks on study with the maximum 
number of samples for a specific test) 
*
The CTC samples will be collected only for SLL, CLL, and MCL subjects
CTC=Circulating Tumor Cells, -HCG=beta human chorionic gonadotropin, RNA=ribonucleic acid, PBMC=peripheral blood 
mononuclear cells


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Specific details regarding blood sample collection and processing requirements will be provided 
separately in the laborato1y manual. The above volumes are approximate and may change 
depending on the need to fmther assess clinical status of a sub· ect as detennined b the 
Investi ator. 
6.11. 
Pregnancy Testing for Females of Childbearing Potential 
All female subjects of childbearing potential will have a sernm pregnancy test at Screening and 
urine pregnancy test on Days 1 and 15 of each cycle, Disease Progression and at the End of 
Study visit. The results must be confomed as negative prior to pennitting continued pa1t icipation 
on the study. 
6.12. 
Tumor Imaging (CT or MRI) 
CT or MRI scans will be obtained to document sites of disease, identify target lesions as 
described in Section 6.20.4 and 6.21.4 and to assess response and disease progression. CT scan 
is the prefened method for radiographic tumor assessment. MRI scanning may be used at the 
investigator's discretion in subjects for whom this may be a prefe1Ted alternative to CT scanning; 
however, if MRI is perfo1med, a non-contrast CT of the chest should also be perfonned. 
Contrast-enhanced scanning is prefen ed, but iodine-containing or gadolinium contrast material 
may be omitted in subjects for whom use of a contrast agent would be medically contraindicated. 
Imaging of the neck, chest, abdomen and pelvis by CT scan (with contrast) or MRI will be 
perfo1med as pait of the Screening Procedures ( or within 5 weeks before Dosing Day 1 if the 
scan was perfo1med as pait of standard medical practice). Imaging will then occur eve1y 
8 weeks from Cycle 1 Day 1 date during the first 24 weeks of the study and then eve1y 12 weeks 
thereafter until week 72 regai·dless of any dose inte1n1ptions. After week 72 scans will occur at 
least eve1y 6 months(± 4 weeks). At all timepoints after Screening, imaging of the chest, 
abdomen, and pelvis will be required. Imaging of the neck is required at each follow-up time 
point if the neck scan was positive at baseline or if palpable neck lymphadenopathy appeai·s 
during the course of the study. 
The imaging procedure and specification ( eg, the same contrast agent, slice thickness, etc.) used 
to define measurable target and non-target lesions must be used throughout the study for each 
subject. Any subject with symptoms suggestive of disease progression should be evaluated for 
tumor response at the time the symptoms occur. Tumor burden will be chai·acterized at baseline 
and subsequent response assessments will be caITied out according to Section 3. Scans need to be 
of high quality and digitalized in the Digital Imaging and Communication in Medicine (DI COM) 
fo1mat to be collected and to allow for reading by the IRC (see Section 9.4). 
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6.13.
Pharmacodynamic Assessments 
To evaluate the biological effects of GS-9973, samples for pharmacodynamic assessments of 
drug activity, such as CD63 modulation on basophils, will be obtained on CLL subjects only 
prior to starting treatment, 1.5 hours and 4 hours after the first dose, predose and 4 hours on 
Day 8 of Cycle 1 and predose on Day 15 of Cycle 1. The collection of some or all of these 
samples may not be feasible at the site due to shipment logistics depending on their 
geographic location. In addition, sampling timepoints may be eliminated based upon 
emerging data.   
Because this is a rapidly evolving area of investigation, it is not possible to precisely specify 
which tests will eventually be done on the specimens provided.  The testing outlined below is 
based upon the current state of knowledge and may be modified to drop tests no longer 
indicated or to add new tests based upon the knowledge base at the time.
6.13.1.
Serum Cytokines and Chemokines
Samples will be analyzed for disease related systemic cytokines and chemokines, which will 
include at a minimum, but will not be limited to, CCL3, CCL4, CXCL12, CXCL13, and tumor 
necrosis factor-α.
6.13.2.
Circulating Tumor Cells (CTC) – RNA Analysis
For SLL, CLL, and MCL subjects only, RNA sample assessments will include at a minimum,
but will not be limited to, expression of c-myc, PTEN, p53, ZAP-70, beta-2 microglobulin levels
and bcl-2. 
6.14.
SLL/CLL/MCL Molecular Characterization
Peripheral blood will be collected from SLL, CLL, and MCL subjects on Day 1 of Cycle 1,
Day 15 of Cycle 2, and at disease progression to assess molecular markers for disease 
progression, response to treatment, and overall prognosis. The baseline status as well as any 
changes in these molecular markers will be correlated with response to GS-9973.
For consenting subjects in the CLL dose ranging, CLL prior BTK inhibitor exposure, or CLL 
prior PI3K inhibitor exposure cohorts only, cells will also be extracted from lymph node 
aspirates at Cycle 1 Day 1 and time of progression for DNA and RNA analysis.
Because this is a rapidly evolving area of investigation, it is not possible to precisely specify 
which tests will eventually be done on the specimens provided.  The testing outlined below is 
based upon the current state of knowledge and may be modified to drop tests no longer 
indicated or to add new tests based upon the knowledge base at the time.


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6.14.1.
Flow Cytometry
6.14.1.1.
SLL and CLL

Differential cell count

Lymphoid panel – CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11c, CD19, CD 20, CD38, 
CD45, CD56, CD57, Kappa, Lambda

ZAP-70 panel: CD3, CD5, CD19, ZAP-70, CD45
6.14.1.2.
MCL

Differential cell count

Lymphoid panel – CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11c, CD19, CD 20, CD38, 
CD45, CD56, CD57, Kappa, Lambda
6.14.2.
Cytogenetics 
6.14.2.1.
SLL and CLL

CTG-banding followed by FISH - specific probes: 11q22,3 (ATM)/17p13 (TP53); 
CEP12/13q14 (D13S319)/13q34; CEP6/6q23 (c-MYB); t(11;14)(CCND1/IGH); c-MYC 
Break-apart
6.14.2.2.
MCL

CTG-banding followed by FISH - specific probes: t(11;14)(CCND1/IGH); c-MYC 
Break-apart
6.14.3.
Molecular Pathology 
6.14.3.1.
SLL and CLL

Molecular Diagnostic tests: 
IGHV mutation analysis with specific IGHV family and mutation frequency; 
beta-2 microglobulin levels
NOTCH1 mutation analysis; 
TP53 mutation analysis; 
MatBA CLL/SLL Array CGH - microarray-based comparative genomic hybridization to 
simultaneously detect the gain and loss of multiple loci in specimen DNA, includes Loss 
of 8p, loss of 11q (ATM), loss of 13q (MIR15A/16-1), loss of 13q (RB1), loss of 17p 
(TP53), gain of 2p, gain of 3q, gain of 8q, gain of 12.


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6.14.3.2. 
MCL 
• 
Molecular Diagnostic tests: 
-
B-cell clonality (IGH) 
-
NOTCH! mutation analysis 
-
TP53 mutation analysis 
-
MatBAMCL 
6.15. 
Samples for Molecular/Pharmacogenomic Testing 
Final 
Amendment 8 
A separate blood specimen will be collected on Cycle 1 Day 1, Cycle 2 Day 15, and time of 
disease progression to isolate PBMC for CLL. The PBMC samples will be s01ted for B cell 
emichment and stored separately. Matched buccal swab samples will be collected at C cle 1 
Da 1 for DNA extrnction and anal sis to serve as ennline control. 
6.16. 
Archival Tumor Tissue 
Fifteen (15) recently prepared (not more than 2 weeks prior to submission) unstained slides from 
archival tumor tissue will be requested for all subjects who have tissue available. 
Innnunohistochemical staining and/or mass spectrnphotometric analysis of proteins harvested 
from these tumor samples will be conducted to assess known disease prognostic markers, as well 
as expression of SYK and other proteins, including kinases and various growth factors within the 
tumor, and other measmes related to the underlying malignancy. Genetic basis for disease may 
also be explored in these samples. 
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If the subject has DLBCL, subtyping is required. Submission of 15 unstained slides is required 
for subtyping. Given the possibility that not all DLBCL subjects will respond to therapy, we will 
investigate tumor characteristics that may be associated with clinical responses, such as CD79b 
mutations. Protein markers such B cell receptor signaling phosphoprotiens, gene expression and 
DNA will be evaluated from tumor tissue to info1m mechanisms of diug activity. 
6.17. 
Optional Future Biomarker Research 
-
6.19. 
Biological Sample Storage 
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6.20.
Efficacy Assessments: Non-Hodgkin Lymphoma 
6.20.1.
Tumor Status Assessments
The determination of NHL response and progression will be based on standardized criteria 
{Cheson 2007, Rourke 2010} as specifically modified for this study to reflect the biology of the 
diseases under study and the pharmacology of study drugs and the methods to be used in 
evaluation. During the course of the study, investigators will periodically assess the status of 
each subject’s NHL. If progression is suspected, the IRC will be notified and will review 
radiographic and pertinent clinical data in order to provide expert interpretation.  Treatment 
decisions by the investigator will be based on these assessments. Radiographic tumor 
assessments will be subject to independent confirmation by the IRC (see Section 9.4). The 
findings of the IRC will be considered primary for analyses of PFS and other tumor control 
endpoints.
6.20.2.
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. PET scanning can be performed as 
appropriate. As appropriate, study drug dosing delays, bone marrow aspirate/biopsy information 
(eg, for confirmation of CR) and biopsy information (eg, for documentation of disease 
transformation to an aggressive histology) will also be considered. For LPL/WM, quantitative 
monoclonal IgM protein as assessed by SPEP and IFE will be considered.  Clinical palpation, 
chest x-ray, ultrasound, endoscopy, laparoscopy, 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. Furthermore, the use of IV contrast should be consistent across timepoints.  In the 
event that the screening/baseline CT scan of the neck, chest, abdomen and pelvis is performed 
without IV contrast, the follow-up time points should also be performed without IV contrast. 
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.  At Screening CT or MRI of neck, chest,
abdomen, and pelvis is required.  At all timepoints after Screening imaging of the chest, 
abdomen, and pelvis will be required.  Imaging of the neck is required at each follow-up time 
point if the neck scan was positive at baseline or if palpable neck lymphadenopathy appears 
during the course of the study.
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 9.4).


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For subjects with WM, serum monoclonal IgM as assessed by SPEP will only be considered if 
baseline total serum IgM quantitation by nephelometry is not available.  The same laboratory 
method for IgM assessment within a given subject should be used throughout the study.
6.20.3.
Timing of Assessments
During screening, clinical and imaging-based tumor assessments should be performed within 
5 weeks prior to the start of study drug. Clinical tumor assessments should be performed at each 
clinic visit. On-study CT/MRI tumor assessments should be performed at ~8- to 12-week 
intervals. An End of Study CT/MRI tumor assessment should be performed unless the subject 
already has radiographic confirmation of disease progression 4 weeks prior to study 
discontinuation. If a subject permanently discontinues study drug prior to objective 
documentation of NHL progression, investigators should continue further follow-up at ~8 or 
~12-week intervals until NHL progression is documented.
6.20.4.
Identification of Index and Non-Index Tumor Lesions 
At baseline, tumor lesions will be categorized as index lesions or non-index lesions as described 
below. 
Up to 6 lesions (eg, lymph nodes, liver or spleen nodules, and/or other circumscribed extra-nodal 
masses in any combination across these categories) 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 and include mediastinal and retroperitoneal 
areas of disease whenever these sites are involved. 
Index lesions will be measured and recorded at baseline and at the stipulated intervals during 
treatment. The cross-sectional dimensions (the largest cross-sectional diameter, ie, the longest 
diameter [LD] × the longest perpendicular diameter [LPD]) will be recorded (in cm) for each 
index lesion. The product of the perpendicular diameters (PPD) will be calculated. The PPDs and 
the sum of the products (SPDs) for all index lesions will be calculated and recorded. The 
baseline SPDs will be used as references by which objective tumor response will be 
characterized during treatment. The nadir LDs of individual lesions and the nadir SPDs will be 
used as references by which objective tumor progression will be characterized during treatment. 
All PPD and SPD measurements will be reported in centimeters squared.
6.20.4.1.
Index Lesions
6.20.4.1.1.
Nodal Index Lesions
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable at 
baseline. A lymph node lesion is considered abnormal if it has a single diameter that is 1.0 cm 
and is considered measurable if it has 2 perpendicular diameters that can be accurately measured 
in cross section with the LD being 1.0 cm and the LPD also being 1.0 cm. 


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Abnormal, measurable nodal lesions will be subcategorized as either large or small:

Large nodal lesions have a LD that is > 1.5 cm and a LPD that is 1.0 cm. 

Small nodal lesions have an LD that is > 1.0 cm and 1.5 cm and an LPD 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.
6.20.4.1.2.
Extra-nodal Index Lesions
An extra-nodal mass may be selected as an index lesion if it is both abnormal and measurable at 
baseline. An extra-nodal mass of any size is considered abnormal. It is considered measurable if 
it has 2 perpendicular diameters that can be accurately measured in cross section with the LD 
being 1.0 cm and the LPD also being 1.0 cm.
6.20.4.2.
Non-Index Lesions
Any other measurable and abnormal nodal or extra-nodal lesions not selected for quantitation as 
index lesions may be considered non-index lesions. In addition, non-measurable evidence of 
lymphoma such as nodal lesions or extra-nodal lesions with both diameters < 1.0 cm, 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, or lesions with artifacts may be considered as non-index disease. 
The presence or absence of non-index disease should be recorded at baseline and at the stipulated 
intervals during treatment. If present at baseline, up to 6 non-index lesions should be recorded. 
The non-index disease at baseline will be used as a general reference to further characterize 
regression or progression of lymphoma during assessments of the objective tumor response 
during treatment. Measurements are not required and these lesions should be followed as 
“present”, “unequivocally progressed” or “absent”.
6.20.5.
Follow-up of Index and Non-Index Tumor Lesions
6.20.5.1.
Nodal Lesions
At follow-up time points, the LDs for individual nodal 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.


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In cases in which a large lymph node mass has split into multiple components, all 
subcomponents regardless of size will be used in calculating the SPD. Progression will be based 
on the SPD of all sub-components. Lesion sub-components will have PPDs calculated.  
Similarly, lesion sub-components that are visible but neither abnormal nor measurable will have 
the default PPD of 1.0 cm2 (1.0 cm 1.0 cm) used in calculating the SPD.
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer 
be separated by this boundary, the newly merged lesion will be measured bi-dimensionally.
6.20.5.2.
Extra-nodal Lesions
At follow-up time points, the LD of each single extra-nodal lesion and the SPD of all extra-nodal 
index lesions will be considered. Because extra-nodal index lesions that have one or both 
diameters 1.0 cm and > 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. If an extra-nodal lesion is no longer clearly visible, it will be considered resolved
and its PPD will be defined as 0 cm2. 
If an extra-nodal lesion that had resolved (ie, had a PPD of 0 cm2) subsequently reappears 
unequivocally, the subject will be considered to have progressive disease. A new unequivocal 
extra-nodal lesion of any size that appears at a site that was not previously involved with 
lymphoma and is discernable to the radiologist by CT/MRI scan will be considered progressive 
disease. 
6.20.5.3.
Definition of Diffuse Disease in the Liver and Spleen
The radiologist will make a qualitative assessment of change in the size of the liver and spleen, 
and will not perform quantitative measurements of these organs. 
Liver and spleen size should be reported as normal, enlarged not due to lymphoma, enlarged due 
to lymphoma (nodules must be present for this to be reported), unequivocal increase not due to 
lymphoma, or unequivocal progression (nodules must be present for this to be reported). 
6.20.5.4.
Bone Marrow
Bone marrow assessments will be based on morphologic evaluation of bone marrow biopsies. 
Immunohistochemistry may be used to assess response if the sample is indeterminate by 
morphology.  
In a subject who has a baseline bone marrow biopsy showing bone marrow NHL or does not 
have a baseline bone marrow examination, declaration of an on-study CR requires bone marrow 
biopsy documentation of the absence of bone marrow NHL. In a subject who has a baseline bone 
marrow biopsy showing no evidence of NHL, declaration of an on-study CR does not require 
bone marrow examination as long as other criteria for CR are met. 


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6.20.5.5.
Biopsy
Biopsy is not required in the determination of subject eligibility. However, subjects with 
evidence of transformed aggressive lymphoma on biopsy are ineligible for study participation. 
During study participation, a subject who has a biopsy indicating transformation to an aggressive 
lymphoma will be considered to have PD even in the absence of other evidence of PD. If the 
subject has no earlier objective documentation of PD, the date of the biopsy will be considered 
the date of NHL progression. 
6.20.5.6.
Serum Monoclonal IgM Protein (LPL/WM Only)
Assessment of circulating monoclonal IgM by quantitative SPEP and IFE should be performed 
for subjects with LPL/WM. 
6.20.6.
Date of Time Point Response and Progression
For subjects who have imaging examinations on various dates that are nevertheless assigned to 
the same time point, the following rules apply for the calculation of the endpoint date:

The response date will be the last date associated with that particular imaging time point.

The progression date will be the first date associated with that particular imaging time point.
6.20.7.
Definitions of Tumor Response and Progression
6.20.7.1.
Best Overall Response
Responses will be categorized as CR, PR, SD, or PD. In addition, a response category of not 
evaluable (NE) is provided for situations in which there is inadequate information to otherwise 
categorize response status. A response category of no disease (ND) is included for situations in 
which there is no evidence of tumor either at baseline or on treatment. 
The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until progressive disease/recurrence (taking as reference for 
PD the smallest measurements recorded since treatment started). Subjects with NE or ND will be 
counted as failures in the analyses of tumor response.

A radiological best overall response of CR, PR, SD, PD, NE and ND is allowed.

Neither a PR nor an SD designation may follow a CR. Once a CR is observed, the subject 
will continue to be considered to have CR status until the criteria for PD are met.

An SD designation may not follow a PR designation. In cases where a subject has an 
apparent worsening of lesions following a PR, the subject will continue to be considered to 
have PR status until the criteria for PD are met.


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
Subjects will be defined NE if there is no adequate on-treatment radiological response 
assessment. NOTE: These subjects will be counted as failures in the primary analysis of 
tumor response data.

For subjects with LPL/WM, a minor response and very good partial response is allowed 
based on a reduction of monoclonal IgM concentrations.
6.20.7.2.
Complete Response
To satisfy criteria for a CR, all of the following criteria must be met:

No evidence of new disease

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 LD for nodes that were considered 
small at baseline) (see Section 6.20.4.1.1 for definitions of large and small nodes)

Regression to normal of all nodal non-index disease and disappearance of all detectable  
extra-nodal index and non-index disease

Normal spleen and liver size by imaging studies, no hepatic or splenic lymphoma nodules, 
and no new organ enlargement

Morphologically negative bone marrow based on an adequate unilateral core biopsy 
(> 20 mm unilateral core); if the sample is indeterminate by morphology, it should be 
negative by immunohistochemistry

If PET performed (eg, for DLBCL), no evidence of residual disease

If the subject has WM, disappearance of serum monoclonal protein by IFE and normal serum 
IgM level
6.20.7.3.
Very Good Partial Response (LPL/WM) only
To satisfy criteria for VGPR, both of the following criteria must be met: 

A >90% decrease from baseline in monoclonal IgM concentration by SPEP or total serum 
IgM quantitation by nephelometry

Other criteria for CR are met (see Section 6.20.7.2)
6.20.7.4.
Partial Response
To satisfy criteria for a PR, all of the following criteria must be met except for subjects with WM 
as noted below:

No evidence of new disease

A 50% decrease from baseline in the SPD of the index nodal and extra-nodal lesions 
(eg, splenic or hepatic nodules)


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
No increase in the size of non-index nodes  or non-measurable disease

No increase in the size of the liver or spleen and no new organ enlargement

Persistence of bone marrow involvement in a subject who meets other criteria for CR based 
on the disappearance all nodal and extra-nodal masses

If PET performed (eg, for DLBCL): 
Typically FDG-avid lymphoma: if no pretreatment MRI
scan or if the PET scan was positive before therapy, the on-treatment PET is positive in 
1 previously involved site
Variably FDG-avid lymphoma/FDG-avidity unknown: if no pretreatment PET scan or if 
the pretreatment PET scan was negative for lymphoma, CT criteria should be used in 
assessing the tumor during treatment. If the PET scan was positive before therapy, the 
on-treatment PET is positive in 1 previously involved site.

For subjects with LPL/WM:
A 50% decrease from baseline in monoclonal IgM concentration by SPEP or total 
serum IgM quantitation by nephelometry
Any decrease from baseline in the SPD of the index nodal and extral-nodal lesions 
(eg, splenic or hepatic nodules)
6.20.7.5.
Minor Response (LPL/WM only)
To satisfy criteria for MR, the following criteria must be met: 
A ≥25% but <50% decrease from baseline in monoclonal IgM concentration by SPEP or total 
serum IgM quantitation by nephelometry

No increase from baseline in the SPD of the index nodal and extra-nodal lesions (eg, splenic 
or hepatic nodules) 

No increase in the size of non-index nodes or non-measurable disease

No increase in the size of the liver or spleen and no new organ enlargements
6.20.7.6.
Stable Disease
To satisfy criteria for SD, all of the following criteria must be met:

No evidence of new disease

Neither sufficient tumor shrinkage from baseline to qualify for PR nor sufficient evidence of 
tumor growth from nadir to qualify for PD


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
If the subject has LPL/WM, neither a sufficient decrease from baseline in either monoclonal 
IgM concentration or total serum IgM quantitation by nephelometry to qualify for MR or PR 
nor a sufficient increase from nadir in either monoclonal IgM concentration by SPEP or total 
serum quantitation by nephelometry to qualify for PD
6.20.7.7.
Progressive Disease
The occurrence of any of the following events indicates PD:

Evidence of any new disease that was not present as baseline:
A new node that measures > 1.5 cm in any diameter
A new node that measures > 1.0 cm to ≤  1.5 cm in the LD and > 1.0 cm in the LPD
Unequivocal reappearance of an extra-nodal lesion that had resolved (ie, had previously 
been assigned a PPD of 0 cm2)
A new unequivocal extra-nodal lesion of any size
New non-index disease (eg, effusions, ascites, or other organ abnormalities) of any size 
unequivocally attributable to lymphoma (usually requires PET, biopsy, cytology, or other 
non-radiologic confirmation to confirm disease attributable to lymphoma). Note: Isolated 
new effusions, ascites, or bone lesions are not sufficient evidence alone of PD unless 
histologically confirmed. In subjects with no prior history of pulmonary lymphoma, new 
lung nodules identified by CT are usually benign. Thus, a declaration of PD should not be 
made if this is the only manifestation of an apparently new lesion.

Evidence of worsening of nodal or extra-nodal index lesions:
Increase from the nadir by 50% in the SPD of index lesions
Increase from the nadir by 50% in the LD if an individual node or extra-nodal mass that 
now has an LD > 1.5 cm and an LPD of > 1.0 cm.  

Unequivocal increase in the size of non-index lesions or non-measurable disease (eg, pleural 
effusions or bone lesions)

An unequivocal increase in the size of the liver, spleen, or other organ 

If PET performed (eg, DLBCL):
The appearance of any new lesion compatible with lymphoma with confirmation by other 
radiographic or histological modalities. 
The reappearance of any activity in a pre-existent lesion that meets size criteria for a new 
lesion on CT


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
Pseudo-progression characterized by a paradoxical rise in serum IgM followed by a delayed 
response has been recognized early in the course of treatment of subjects with WM/LPL 
treated with chemotherapy and immunotherapy. The time to responses following 
pseudo-progression may be delayed for >4 months in some cases.  Expert opinion 
specifically cautions against premature disease response assessment in LPL/Waldenström’s 
therefore unless there is compelling clinical and objective data of progression all subjects 
should have at least 4 months of treatment before an assessment of PD is made.  When 
assessing for progression a bone marrow biopsy and/or CT scan should be used in 
conjunction with serum IgM levels to assess disease burden.  Criteria  for progression  based 
on serum IgM include, a 25% increase from the nadir in either monoclonal IgM 
concentration by SPEP or total serum IgM quantitation by nephelometry (with confirmation 
by a repeat measurement) at least 6 weeks apart.  

An absolute increase of at least 0.5 gram/dL is required to define progression with 
confirmation at least 6 weeks apart.
Note: If there is uncertainty regarding whether there is true progression, the subject may 
continue study treatment and remain under close observation (eg, evaluated at 4-week 
intervals). If subsequent evaluations suggest that the subject is experiencing progression, then 
the date of progression should be the timepoint at which progression was first identified. A 
single PD determination followed by a determination that indicates either no change or 
improvement in disease prior to the single PD observation will not be considered PD.
6.20.7.8.
Non-Evaluable
In a subject who does not have evidence of PD, no images or inadequate or missing images
indicates a response status of NE.  In a subject with LPL/WM, missing on-study monoclonal 
IgM concentration by SPEP or total serum IgM quantitation by nephelometry will result in 
response status of NE.  If the baseline IgM value is missing, IgM will not be considered for the 
on-study disease assessments.
6.20.7.9.
No Disease
In a subject who does not have evidence of PD, the occurrence of the following condition 
indicates a response status of ND:

No index disease noted at baseline or on-treatment. 

No non-index disease noted at baseline or on-treatment.

Enlargement of the liver or spleen is absent both at baseline and on-treatment

In a subject with LPL/WM, the additional requirement that serum monoclonal IgM protein as 
assessed by SPEP is absent at both baseline and on-study.


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6.21.
Efficacy Assessments: Chronic Lymphocytic Leukemia
6.21.1.
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-9973 and the methods to be used in evaluation. During the course of this study, investigators 
will periodically assess the status of each subject’s CLL.  If CLL progression is suspected, the 
IRC will be notified and radiographic and pertinent clinical data provided in order to provide 
expert interpretation (see Section 9.4).  The findings of the IRC will be considered primary for 
analyses of PFS and other tumor control endpoints.  
6.21.2.
Method of Assessment
In addition to clinical examination, imaging-based evaluation will be used in this study in all 
subjects enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI 
scanning may be used at the investigator’s discretion in subjects for whom this may be a 
preferred alternative to CT scanning; however, if MRI is performed, a non-contrast CT of the 
chest should be performed. Contrast-enhanced scanning is preferred, but iodine-containing or 
gadolinium contrast material may be omitted in subjects for whom use of a contrast agent would 
be medically contraindicated. Chest x-ray, ultrasound, endoscopy, laparoscopy, radionuclide 
scans, or tumor markers will not be considered for response assessment.
At Screening CT or MRI of neck, chest, abdomen, and pelvis is required.  At all timepoints after 
Screening imaging of the chest, abdomen, and pelvis will be required.  Imaging of the neck is 
required at each follow-up time point if the neck scan was positive at baseline or if palpable neck 
lymphadenopathy appears during the course of the study.
For radiographic evaluations, the same method of assessment and the same technique 
(eg, scan type, scanner, subject position, dose of contrast, injection/scan interval) should be used 
to characterize each identified and reported lesion at baseline and during study treatment and 
follow-up. However, if a subject is imaged without contrast at baseline, subsequent assessments 
should be performed with contrast, unless the subject cannot tolerate the contrast.  All relevant 
clinical and radiographic information required to make each tumor status assessment must be 
made available for source verification and for submission to the IRC (see Section 9.4).
6.21.3.
Timing of Assessments
During screening, clinical and imaging-based tumor assessments should be performed within 
5 weeks prior to the start of study drug. Clinical tumor assessments should be performed at each 
clinic visit. On-study CT/MRI tumor assessments should be performed at ~8- to 12-week 
intervals. An End of Study CT/MRI tumor assessment should be performed unless the subject 
already has radiographic confirmation of disease progression 4 weeks prior to study drug 
discontinuation.  If a subject permanently discontinues study drug prior to objective 
documentation of CLL progression, investigators should continue further follow-up at ~8 or 
~12-week intervals until CLL progression is documented.


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6.21.4.
Identification and Follow-up of Tumor Lesions and Organomegaly
6.21.4.1.
Index Lesions
At baseline, up to 6 lymph nodes should be selected as index lesions that will be used to 
quantitate the status of the disease during study treatment. Ideally, the index lesions should be 
located in disparate regions of the body. Only peripheral nodes need be selected as index lesions. 
However, it is optimal if mediastinal and retroperitoneal areas of disease are assessed whenever 
these sites are involved.
Index lesions will be measured and recorded at baseline and at the stipulated intervals during 
treatment. The cross-sectional dimensions (the largest cross-sectional diameter, ie, the LD × the 
LPD will be recorded (in cm) for each index lesion. The product of the perpendicular diameters 
(PPD) for each index lesion and the SPD for all index lesions will calculated and recorded.  The 
baseline SPD will be used as references by which objective tumor response will be characterized 
during treatment. The nadir dimensions of individual lesions and the nadir SPD will be used as 
references by which CLL progression will be characterized. All LD and LPD diameters will be 
reported in centimeters and all PPD and SPD measurements will be reported in centimeters 
squared.
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable at 
baseline. A lymph node lesion is considered abnormal if it has a single diameter that is 1.5 cm 
and is considered measurable if it has 2 perpendicular diameters that can be accurately measured 
in cross section with the LD being 1.0 cm and the LPD also being 1.0 cm. 
At follow-up time points, the LDs for individual lesions and the SPD of all nodal index lesions 
will be considered. Because nodal index lesions that have one or both diameters > 0 cm and 
1.0 cm cannot be reliably measured, a default value of 1.0 cm will be assigned for each 
diameter that meets these criteria and the resulting PPD will be used in SPD calculations. Based 
on this convention, a CR may be achieved even if an SPD value is > 0 cm2, (ie, if all lymph 
nodes measure < 1.0 cm2).
A new node that measures > 1.5 cm in the LD and >1.0 cm in the LPD will be considered 
progressive disease.
In cases in which a large lymph node mass has split into multiple components, all 
subcomponents regardless of size will be used in calculating the SPD. Progression of the lesion 
will be based on the SPD of sub-components. Lesion sub-components will have the true PPDs 
calculated. Similarly, lesion sub-components that are visible but neither abnormal nor 
measurable will have the default PPD of 1.0 cm2 (1.0 cm 1.0 cm) used in calculating the SPD.
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer 
be separated by this boundary, the newly merged lesion will be measured bi-dimensionally.


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6.21.4.2.
Spleen and Liver
Both the spleen and liver should be assessed by CT/MRI scan at baseline and at the stipulated 
intervals during treatment. The baseline and nadir values for the longest vertical dimension 
(LVD) of each organ will be used as reference to further characterize the objective tumor 
response of the measurable dimensions of CLL during treatment. All spleen and liver LVD 
measurements should be recorded in centimeters.
6.21.4.2.1.
Spleen
By imaging, the spleen will be considered enlarged if it is >12 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). 
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 (ie, the portion of the LVD that is >12 cm by imaging) at baseline or nadir, not 
changes relative to the total splenic LVD. 
A 50% decrease (minimum 2 cm decrease) from baseline in the enlargement of the spleen in its 
LVD or decrease to 12 cm by imaging is required for declaration of a splenomegaly response.
Conversely, an increase in splenic enlargement by 50% from nadir (minimum increase of 
2 cm) is required for declaration of splenic progression.
6.21.4.2.2.
Liver
By imaging, the liver will be considered enlarged if it is >18 cm in LVD {Erturk 2006}. 
A 50% decrease (minimum 2 cm decrease) from baseline in the enlargement of the liver in its 
LVD or decrease to 18 cm by imaging is required for declaration of a hepatomegaly response. 
Conversely, an increase in liver enlargement by 50% from nadir (minimum increase of 2 cm) is 
required for declaration of hepatic progression.
6.21.4.3.
Non-Index Lesions
Any other measurable and abnormal nodal lesions not selected for quantitation as index lesions 
may be considered non-index lesions. In addition, non-measurable evidence of CLL such as 
nodal lesions with both diameters < 1.0 cm, extra-nodal lesions, bone lesions, leptomeningeal 
disease, ascites, pleural or pericardial effusions, lymphangitis of the skin or lung, abdominal 
masses that are not confirmed and followed by imaging techniques, cystic lesions, previously 
irradiated lesions, lesions with artifacts may be considered as non-index disease.
The presence or absence of non-index disease should be recorded at baseline and at the stipulated 
intervals during treatment. If present at baseline, up to 6 non-index lesions should be recorded. 
The non-index disease at baseline will be used as a general reference to further characterize 
regression or progression of CLL during assessments of the objective tumor response during 
treatment. Measurements are not required and these lesions should be followed as “present”, 
unequivocally progressed or “absent”.


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6.21.4.4.
Biopsy
Biopsy is not required in the determination of subject eligibility. However, subjects with 
evidence of Richter’s transformation to an aggressive lymphoma on biopsy are ineligible for 
study participation. 
During study participation, a subject who has a biopsy indicating Richter’s transformation to an 
aggressive lymphoma will be considered to have PD even in the absence of other evidence of 
PD. If the subject has no earlier objective documentation of PD, the date of the biopsy will be 
considered the date of CLL progression.
6.21.5.
Definitions of Tumor Response and Progression 
Responses will be categorized as CR, PR, SD, or PD. In addition, a response category of not 
evaluable (NE) is provided for situations in which there is inadequate information to otherwise
categorize response status. A response category of no disease (ND) is included for situations in 
which there is no evidence of tumor either at baseline or on treatment.
The best overall response will be determined. The best overall response is the best response 
recorded from the start of treatment until progressive disease/recurrence (taking as reference for 
PD the smallest measurements recorded since treatment started). Subjects with NE or ND will be 
included in the denominator in the analyses of tumor response rates
6.21.5.1.
Complete Response
To satisfy criteria for a CR, all of the following criteria must be met:

No evidence of new disease

Absolute Lymphocyte Count (ALC) in peripheral blood of < 4 x 109/L

Regression of all index nodal masses to normal size (1.5 cm in the LD)  

Normal spleen and liver size

Regression to normal of all nodal non-index disease and disappearance of all detectable 
non-nodal, non-index disease

Morphologically negative bone marrow defined as < 30% of nucleated cells being lymphoid 
cells and no lymphoid nodules in a bone marrow sample that is normocellular for age

Peripheral blood counts meeting all of the following criteria:
ANC > 1.5 x 109/L without need for exogenous growth factors (eg, G-CSF)
Platelet count 100 x 109/L without need for exogenous growth factors


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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). 
6.21.5.2.
Partial Response
To satisfy criteria for a PR, all of the following criteria must be met:

No evidence of new disease

Change in disease status meeting 2 of the following criteria, with 2 exceptions in which 
only 1 criterion is needed: (1) Only lymphadenopathy is present at baseline; (2) Only 
lymphadenopathy and lymphocytosis are present at baseline. In these 2 cases, only 
lymphadenopathy must improve to the extent specified below): 
In a subject with baseline lymphocytosis (ALC 4 x 109/L), a decrease in peripheral 
blood ALC by 50% from baseline or a decrease to < 4 x 109/L
A decrease by 50% from the baseline in the SPD of the index nodal lesions
In a subject with enlargement of the spleen at baseline, a splenomegaly response as 
defined in Section 6.21.4.2.1
In a subject with enlargement of the liver at baseline, a hepatomegaly response as defined 
in Section 6.21.4.2.2
A decrease by 50% from baseline in the CLL marrow infiltrate or in B-lymphoid 
nodules

No index, splenic, liver, or non-index disease with worsening that meets the criteria for 
definitive PD

Peripheral blood counts meeting 1 of the following criteria:
ANC > 1.5 x 109/L or 50% increase over baseline without need for exogenous growth 
factors (eg, G-CSF)
Platelet count 100 x 109/L or 50% increase over baseline without need for exogenous 
growth factors
Hemoglobin 110 g/L (11.0 g/dL) or 50% increase over baseline without red blood 
cell transfusions or need for exogenous growth factors (eg, erythropoietin)


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6.21.5.3.
Stable Disease
To satisfy criteria for SD, the following criteria must be met:

No evidence of new disease

There is neither sufficient evidence of tumor shrinkage to qualify for PR nor sufficient 
evidence of tumor growth to qualify for definitive PD  
6.21.5.4.
Definitive Progressive Disease
The occurrence of any of the following events indicates definitive PD: 

Evidence of any new disease:
A new node that measures > 1.5 cm in the LD and >1.0 cm in the LPD
New or recurrent splenomegaly, with a minimum LVD of 14 cm
New or recurrent hepatomegaly, with a minimum LVD of 20 cm
Unequivocal reappearance of an extra-nodal lesion that had resolved
A new unequivocal extra-nodal lesion of any size
New non-index disease unequivocally attributable to CLL (eg, soft tissue, effusions, 
ascites, or other organ abnormalities related to CLL)
Note: Isolated new effusions, ascites, or other organ abnormalities are not sufficient evidence 
alone of PD unless histologically confirmed. Thus, a declaration of PD should not be made if 
this is the only manifestation of apparently new disease.

Evidence of worsening of index lesions, spleen or liver, or non-index disease: 
Increase from the nadir by 50% in the SPD of index lesions
Increase from the nadir by 50% in the LD if an individual node or extra-nodal mass that 
now has an LD of >1.5 cm and an LPD of > 1.0 cm
Splenic progression, defined as an increase in splenic enlargement by 50% from nadir 
(with a minimum 2 cm increase and a minimum LVD of 12 cm)
Hepatic progression, defined as an increase in hepatic enlargement by 50% from nadir 
(with a minimum 2 cm increase and minimum LVD of 18 cm)


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Unequivocal increase in the size of non-index disease (eg, effusions, ascites, or other 
organ abnormalities related to CLL) 
Transformation to a more aggressive histology (eg, Richter syndrome) as established by 
biopsy (with the date of the biopsy being considered the date of CLL progression if the 
subject has no earlier objective documentation of CLL progression).

Decrease in platelet count or hemoglobin that is attributable to CLL, is not attributable to an 
autoimmune phenomenon, and is confirmed by bone marrow biopsy showing an infiltrate of 
clonal CLL cells
The current platelet count is < 100 x 109/L and there is a decrease by > 50% from the 
highest on-study platelet count 
The current hemoglobin is < 110 g/L (11.0 g/dL) and there is a decrease by > 20 g/L 
(2 g/dL) from the highest on-study hemoglobin 
Note: If there is uncertainty regarding whether there is true progression, the subject should 
continue study treatment and remain under close observation (eg, evaluated at 4-week 
intervals) pending confirmation of progression status by the IRC. In particular, worsening of 
constitutional symptoms in the absence of objective evidence of worsening CLL will not be 
considered definitive disease progression. In such subjects, both CLL-related and 
non-CLL-related causes for the constitutional symptoms should be considered. Worsening of 
disease during temporary interruption of study treatment (eg, for intercurrent illness) is not 
necessarily indicative of resistance to study treatment. In these instances, CT/MRI or other 
relevant evaluations should be considered in order to document whether definitive disease 
progression has occurred. If subsequent evaluations suggest that the subject has experienced 
persistent definitive CLL progression, then the date of progression should be the timepoint at 
which progression was first objectively documented.
6.21.5.5.
Non-Evaluable
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE: 

There are no images or inadequate or missing images.

Images of the liver and spleen are missing at that time point (with the exception that absence 
of splenic images will not result in an NE designation in a subject known to have undergone
splenectomy).
Note: A time-point will be considered to have a response of NE if any index lesion is missing. 
PD may be assigned at any time point regardless of the extent of missing index or non-index 
lesions. Missing non-index lesions will not impact the ability to assess for response or disease 
progression.


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6.21.5.6.
No Disease
Subjects have a status of ND if all of the following conditions occur: 

Index disease absent at both baseline and on-treatment. 

Non-index disease absent at both baseline and on-treatment.

Enlargement of the liver and spleen absent at both baseline and on-treatment

Abnormalities of peripheral blood counts (elevated ALC and abnormally low ANC, platelet 
count, and hemoglobin) and evidence of CLL in bone marrow (if available) absent at both 
baseline and on treatment
6.21.6.
Lymphocytosis During Therapy
GS-9973 will probably mobilize CLL cells from tissues into the peripheral blood. This 
characteristic pharmacological action can be prominent early in therapy but can persist over time 
and should not be confused with disease progression in subjects who have persistent control of 
other CLL-related signs and symptoms. In the absence of other objective evidence of disease 
progression, the occurrence of lymphocytosis will not preclude subjects from meeting the 
criteria for a PR if other criteria for PR are met and will not be considered evidence of CLL 
progression if occurring in isolation. Subjects with lymphocytosis should be continued on study 
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 {Cheson 2012}.
6.22.
Documentation of Definitive CLL Progression
Of importance, CLL response and progression data will be subjected to IRC review 
(see Section 9.4). If there is uncertainty regarding whether there is definitive progression, the 
subject should continue study drug(s) pending confirmation of progression status by the IRC.


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
AEs also include the following:

All AEs that occur from the signing of the informed consent onwards and throughout the 
duration of the study, including the 30-day follow-up off-study period.

Pre- or post-treatment complications that occur as a result of a protocol-mandated procedure 
(eg, venipuncture or biopsy) during or after screening (before the administration of study 
investigational medicinal product)

Any pre-existing condition that increases in severity, or changes in nature during or as a 
consequence of the study investigational medicinal product phase of this trial, will also be 
considered an AE

Complications and termination of pregnancy
An AE does not include the following:

Medical or surgical procedures (eg, surgery, endoscopy, tooth extraction, transfusion) 
performed; the condition that led to the procedure may be an AE if applicable

Pre-existing diseases or conditions or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.7)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed. It is considered to be pre-existing and should be 
documented on the medical history eCRF

Uncomplicated pregnancy

An induced elective abortion to terminate a pregnancy without medical reason


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7.2.
Serious Adverse Events
A serious adverse event (SAE) or serious adverse drug reaction (SADR) is defined as follows:
Any adverse drug experience occurring at any dose that results in any of the following outcomes:

Death

Life-threatening situation (subject is at immediate risk of death)

In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity

Congenital anomaly/birth defect in the offspring of a subject who received investigational 
medicinal product

Other: medically significant events that 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 are as follows:

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias or convulsions that do not result in hospitalization

Development of drug dependency or drug abuse
Clarification regarding Serious Adverse Events

Death is an outcome of an AE, and not an AE in itself.

An SAE may occur even if the subject was not on investigational medicinal product at the 
time of occurrence of the event. Dosing may have been given as treatment cycles or 
interrupted temporarily before the onset of the SAE.

“Life-threatening” means that the subject was at immediate risk of death from the event as it 
occurred. This does not include an event that might have led to death if it had occurred with 
greater severity.

Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE.


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
“In-patient hospitalization” means the subject is formally admitted to a hospital for medical 
reasons, for any length of time. This may or may not be overnight. It does not include 
presentation and care within an emergency department.

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 AE and/or SAE and not the individual signs/symptoms.
Disease Progression and Death Related to Disease Progression:
Given the endpoints of the study, in order to maintain the integrity of the study, the following 
events that are assessed as unrelated to study drugs will not be considered SAEs:

Progression of malignancy being studied

Death due to  malignancy being studied
Disease progression and death from disease progression should be reported as SAEs by the 
investigator only if it is assessed that the study drugs caused or contributed to the disease 
progression (ie, by a means other than lack of effect). Unrelated disease progression should be 
captured on the eCRF.
These events will be reported, as appropriate, in the final clinical study report and in any relevant 
aggregate safety reports.
7.3.
Describing Adverse Event Relationship to Study Drug and Study Procedures
The relationship of an AE or SAE to investigational medicinal product 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 AE has an etiology other than the investigational medicinal 
product. For SAEs, an alternative causality must be provided (eg, pre-existing condition, 
underlying disease, intercurrent illness, or concomitant medication).

Yes: A temporal relationship exists between the AE onset and administration of the 
investigational medicinal product that cannot be readily explained by the subject’s clinical 
state or concomitant therapies. Furthermore, the AE appears with some degree of certainty to 
be related, based on the known therapeutic and pharmacologic actions or AE profile of the 
investigational medicinal product. In case of cessation or reduction of the dose the AE may 
abate or resolve and it may reappear upon rechallenge.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting.


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The relationship of an AE or SAE to study procedures (eg, invasive procedures such as 
venipuncture or biopsy) 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 AE has an etiology other than the study procedure.

Yes: A temporal relationship exists between the AE onset and a protocol-mandated 
procedure that cannot be readily explained by the subject’s clinical state or concomitant 
therapies. Furthermore, the AE appears with some degree of certainty to be related to the 
study procedure based on the known potential complications of that procedure.
7.4.
Adverse Drug Reactions
An adverse drug reaction (ADR) is defined as an AE that is considered causally related to an 
investigational medicinal product. A serious ADR (SADR) is an ADR which meets the 
seriousness criteria.
7.5.
Unexpected Adverse Event
An unexpected AE is defined as an event that has a nature or severity, or specificity that is not 
consistent with the applicable Investigator’s 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’s 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’s 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.
7.6.
Grading of the Severity of an Adverse Event
The severity grading of AEs will be assessed as Grade 1, 2, 3, 4 or 5 using the CTCAE 
(version 4.03).
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
The distinction between the seriousness and the severity of an AE should be noted. Severe is a 
measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For example, a 
headache may be severe in intensity, but would not be classified as serious unless it met one of 
the criteria for serious events listed above.


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7.7.
Special Situation Reports
Special situation reports include pregnancy reports, reports of medication error, abuse, misuse, or 
overdose, and reports of adverse reactions associated with product complaints. 
A pregnancy report is used to report pregnancies following maternal or paternal exposure to the 
product. 
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question).
In cases of a discrepancy in drug accountability, overdose will be established only when it is 
clear that the subject has taken the excess dose(s) or the investigator has reason to suspect that 
the subject has taken the additional dose(s). 
Product complaint is defined as any written or verbal report arising from potential deviations in 
the manufacture, packaging or distribution of the product.
Instructions for reporting Special Situation Reports are described in Section 7.8.1
7.8.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed from screening 
onwards.
All AEs, regardless of cause or relationship, that occur from initiation of study medication until 
4 weeks after last administration of study IMP must be reported to the CRF/eCRF database as 
instructed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported. 


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All AEs should be followed up until resolution if possible. If by the last day on study 
(including the off-study medication follow-up period) the AE has not resolved, then the AE will 
be followed up until the investigator and/or Gilead Sciences determine that the subject's 
condition is stable. However, Gilead Sciences may request that certain AEs be followed until 
resolution.
Investigators are not obligated to actively seek SAEs after the period. However, if the 
investigator learns of any SAEs that occur after study participation has concluded and the event 
is deemed relevant to the use of IMP, he/she should promptly document and report the event to 
Gilead DSPH.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 

At the time of study start, SAEs will be reported using a paper serious adverse event 
reporting form. During the study conduct, sites may transition to an electronic SAE (eSAE) 
system. Gilead will notify sites in writing and provide training and account information prior 
to implementing an eSAE system.
Serious Adverse Event Paper Reporting Process

All SAEs will be recorded on the serious adverse event report form and submitted by faxing 
the report form within 24 hours of the investigator’s knowledge of the event to the attention 
of Gilead DSPH or to the designated CRO.
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours as described above.

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline. 

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.


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• If for any reason it is not possible to record the SAE infonnation electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event repo1ting 
fo1m and subinit within 24 hours as described above. 
• 
As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repo1ted via a paper fonn because the eCRF database has been locked, no 
fuither action is necessa1y. 
• 
For fatal or life-threatening events, copies of hospital case repo1ts, autopsy repo1ts, and other 
documents are also to be subinitted by e-mail or fax when requested and applicable. 
Transinission of such documents should occur without personal subject identification, 
maintaining the ti·aceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensure the timely completion of accurate safety 
repo1ts. 
Any medications necessaiy for u-eatment of the SAE must be recorded onto the concomitant 
medication section of the subject's CRF/eCRF and the event description section of the SAE 
fo1m. 
Site repo1ting requirements for AEs ai·e sUllllnai·ized in Table 7-1. 
Table 7-1. 
Site Reporting Requirements for Adverse Events 
Classification 
Reporting Time 
Reporting Action 
Record and submit all SAE infonnation on appropriate eCRFs 
and from there transmit the SAE information to Gilead 
Within 24 hours 
Sciences DSPH. Print out the SAE repo1t in order to submit to 
Serious 
the site IRB/IEC, as per local IRB/IEC requirements. Detailed 
instrnctions can be found in the eCRF completion guidelines. 
Per eCRF submission 
Record and submit infonnation on appropriate eCRFs 
procedure 
Nonserious 
Per eCRF submission 
Record and submit infonnation on appropriate eCRFs 
procedure 
Conta.ct details for PPD Phaimacovigilance ai·e provided in Table 7-2: 
Table 7-2. 
Contact Information for Reporting Serious Adverse Events 
PPD Phannacovigilance: 
Repo1t an SAE to PPD Phaimacovigilance if eSAE repo1ting is unavailable. Also repo1t Special 
Situations and Pregnancies to PPD Phaimacovigilance per below (Section 7.8.1). 
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7.8.1.
Special Situation Reporting Instructions
Instructions for Reporting Pregnancies:

The Investigator should report all pregnancies to PPD Pharmacovigilance using the 
Pregnancy Report form within 24 hours of becoming aware of the pregnancy as outlined in 
Section 7.12.
Instructions for Reporting Other Special Situations:

All other Special Situation reports must be reported on the Special Situation Report Form and 
forwarded to PPD Pharmacovigilance within 24 hours.

All clinical sequelae in relation to Special Situation reports will be reported as AEs or SAEs 
at the same time using the AE and/or the SAE eCRF. Details of the symptoms and signs, 
clinical management and outcome will be reported, when available.
7.8.2.
Gilead Sciences Reporting Requirements for Adverse Events
Depending on relevant legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead Sciences may be required to expedite 
reports to regulatory authorities for the following types of AEs: SAEs including events related to 
study procedures; SADRs; and suspected, unexpected, serious adverse reactions (SUSARs). In 
accordance with the EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee 
will notify worldwide regulatory agencies and the relevant IEC in concerned Member States of 
applicable SUSARs as outlined in current regulations.
Each SAE report received from the investigator will be evaluated by Gilead Sciences DSPH who 
will assess the seriousness of the event (see Section 7.2), the relationship to participation in the 
study (Section 7.3), and the expectedness of the event (see Section 7.5). For regulatory reporting 
purposes, expectedness will be determined by Gilead Sciences DSPH using reference safety 
information specified in the Investigator’s Brochure.
Gilead Sciences or its designee will also provide all investigators and the DMC (if applicable) 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.
7.8.3.
Post-Study Reporting Requirements
All AEs and SAEs including deaths, regardless of cause or relationship, must be reported for 
subjects on study through the last study visit and the 30-day follow-up phone call (or in person, if 
necessary).
Any SAEs and deaths that occur after the End of Study visit but within 30 days of the last dose 
of investigational medicinal product, regardless of causality, should also be reported.


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Investigators are not obligated to actively seek SAEs after the 30 day time period. However, if 
the investigator learns of any SAEs that occur after study participation and the event is deemed 
relevant to the use of investigational medicinal products, he/she should promptly document and 
report the event to Gilead Sciences DSPH.
7.9.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (eg, clinical chemistry, hematology, and urinalysis) that require medical or surgical 
intervention or lead to investigational medicinal product interruption or discontinuation must be 
recorded as an AE, as well as an SAE, if applicable. In addition, laboratory or other abnormal 
assessments (eg, electrocardiogram, X-rays, vital signs) that are associated with signs and/or 
symptoms must be recorded as an AE or SAE if they meet the definition of an AE or SAE as 
described in Sections 7.1 and 7.3, respectively. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (ie, anemia) not the laboratory result (ie, decreased 
hemoglobin).
Severity should be recorded and graded according to the CTCAE (version 4.03).
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
7.10.
Toxicity Management
Treatment-emergent toxicities will be noted by the Investigator and brought to the attention of 
the Gilead Sciences Medical Monitor or designee. Whether or not considered treatment-related, 
all subjects experiencing AEs must be monitored periodically until symptoms subside, any 
abnormal laboratory values have resolved or returned to baseline levels or they are considered 
irreversible, or until there is a satisfactory explanation for the changes observed.
Grade 3 or 4 clinically significant laboratory abnormalities should be confirmed by repeat testing 
as soon as practical to do so, and preferably within 3 calendar days after receipt of the original 
test results.
Any questions regarding toxicity management should be directed to the Gilead Sciences Medical 
Monitor or designee.
7.11.
Contraception Requirements 
7.11.1.
Definitions
7.11.1.1.
Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.  


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Women are considered to be in a postmenopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative cause.  In 
addition, women of any age with amenorrhea of > 12 months may also be considered 
postmenopausal if their follicle stimulating hormone (FSH) level is in the postmenopausal range 
and they are not using hormonal contraception or hormonal replacement therapy.
Permanent sterilization includes hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy in a female subject of any age.
7.11.1.2.
Definition of Male Fertility
For the purposes of this study, a male born subject is considered  fertile after the initiation of 
puberty unless permanently sterile by bilateral orchidectomy or medical documentation.
7.11.2.
Contraception Requirements for Female Subjects
7.11.2.1.
Study Drug Effects on Pregnancy and Hormonal Contraception
GS-9973 is contraindicated in pregnancy as the risks of treatment with GS-9973 during 
pregnancy have not been evaluated. GS-9973 has insufficient data to exclude the possibility of a 
clinically relevant interaction with hormonal contraception that results in reduced contraception 
efficacy.  Therefore, contraceptive steroids are not recommended as a contraceptive method 
either solely or as a part of a contraceptive regimen. Please refer to the latest version of the 
investigator’s brochure for additional information.
7.11.2.2.
Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures.  They must also not rely on hormone-containing contraceptives as a 
form of birth control during the study.  They must have a negative serum pregnancy test at 
Screening.  Female subjects must agree to one of the following from Screening until 30 days 
following the end of relevant systemic exposure.

Complete abstinence from intercourse of reproductive potential.  Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of <1% per year
Tubal sterilization
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)


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Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the end of relevant systemic exposure.
7.11.3.
Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid.  Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment and until 90 days after the 
end of relevant systemic exposure.  Additional contraception recommendations should also be 
considered if the female partner is not pregnant.
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
after the end of relevant systemic exposure.
7.11.4.
Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides
only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.
The Gilead Sciences Medical Monitor or designee should be consulted regarding any questions 
relating to childbearing status or contraception.
7.12.
Procedures to be followed in the Event of Pregnancy
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 last receiving 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 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 is completed, the outcome should be reported directly to 
Gilead Sciences DSPH (facsimile: 
 e-mail: PPD
PPD


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Neither the pregnancy itself nor an induced elective abortion to terminate the pregnancy without 
medical reasons is considered an AE; such occurrences should be reported on the appropriate 
pregnancy report forms. However, if the outcome of the pregnancy meets the criteria for 
classification as an SAE (ie, spontaneous abortion, induced abortion due to complications, 
stillbirth, neonatal death, or congenital anomaly [including that in an aborted fetus]), the 
investigator should follow the procedures for reporting SAEs, ie, report the event by submission 
of the appropriate AE and/or SAE eCRFs (see Section 7.8.1). 
Pregnancy outcomes that are classified as SAEs include:

Any spontaneous abortion, including miscarriage and missed abortion.

An induced therapeutic abortion to terminate any pregnancy due to complications or other 
medical reasons. The underlying medical reason for this procedure should be recorded as the 
AE term.

All neonatal deaths that occur within 1 month of birth, regardless of causality. 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 as a SAE.
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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8.
STATISTICAL CONSIDERATIONS
8.1.
Objectives
The primary objective of this study is:

To evaluate the efficacy of GS-9973 in subjects with relapsed or refractory hematologic 
malignancies
The secondary objectives of this study are:

To evaluate the safety and tolerability of GS-9973 in subjects with relapsed or refractory 
hematologic malignancies

To evaluate GS-9973 plasma exposure in subjects with relapsed or refractory hematologic 
malignancies 
8.2.
Endpoints
8.2.1.
Primary Endpoint
PFS rate at 16 weeks (CLL after BCR targeted therapy, MCL and DLBCL) or 24 weeks 
(CLL and iNHL).  PFS is defined as the interval from the first dose of GS-9973 to the earlier of 
the first documentation of definitive disease progression or death from any cause. The findings 
of the IRC will be considered primary for analyses of PFS rate.
PFS rate of the CLL prior BTK inhibitor exposure and CLL prior PI3K inhibitor exposure
cohorts will be estimated separately. 
PFS rate of the CLL dose ranging cohort will be estimated by dose levels.
8.2.2.
Secondary Endpoints
Safety: abnormal laboratory data and AEs.  Safety will be assessed by grading of laboratory 
values and AEs according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03
Efficacy:

Objective response rate (ORR). ORR will be determined from the subjects’ best response 
during GS-9973 therapy and will include complete response (CR) or partial response (PR)
(or VGPR or MR for subjects with LPL/WM).

Duration of response (DOR). DOR will be defined as time from the first response (CR or PR 
[or VGPR or MR for subjects with LPL/WM]) is achieved until the earlier of the 
first documentation of definitive disease progression or death from any cause.  


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
Time to response (TTR). TTR will be defined as time from the first dose of GS-9973 to the 
first time the response (CR or PR [or VGPR or MR for subjects with LPL/WM]) is achieved.
The findings of the IRC will be considered primary for analyses of secondary efficacy endpoints.
8.2.3.
Exploratory Endpoints 
8.3.
Analysis Sets
8.3.1.
Full Analysis Set
The full analysis set includes all subjects who receive 1 dose of GS-9973. This analysis set will 
be used in the analyses of subject characteristics, study drug treatment administration, safety, and 
efficacy endpoints including PFS, and ORR. The analyses of TTR and DOR will be based on the 
subjects in full analysis set who achieve a CR or PR (or VGPR or MR for subjects with 
LPL/WM).
8.3.2.
Pharmacokinetic/Pharmacodynamic Analysis Sets
The Pharmacokinetic/Pharmacodynamic 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 GS-9973 drug 
levels and changes in CD63 expression in peripheral blood basophils. Analysis for GS-9973 
SDD and original formulation will be done separately.
8.4.
Data Handling Conventions
8.4.1.
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 for all subjects and by cohort, analysis set, and 
timepoint. As appropriate, changes from baseline to each subsequent timepoint will be described 
and summarized. Similarly, as appropriate, the best change from baseline during the study will 
also be described and summarized. Graphical techniques (eg, waterfall plots, Kaplan-Meier 
curves, line plots) may be used when such methods are appropriate and informative. 
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. 
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8.4.2.
Calculation of Tumor Control Variables
Tumor control assessments will be based on standardized response and progression criteria for 
NHL {Cheson 2007} and CLL {Hallek 2008}, as specifically modified for this study considering 
the pharmacology of GS-9973 {Cheson 2012}. 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) 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 disease progression. 
Changes in tumor status as provided by the investigator and changes in tumor status as 
adjudicated by the IRC (see Section 9.4) 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 of PFS and DOR, the following censoring conventions will be 
applied:

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 progression was objectively documented.  

Data from subjects who have disease progression or die after 2 consecutive missing tumor 
assessments will be censored at the last time prior to the missing assessments that lack of 
definitive disease progression is objectively documented.
8.5.
Analysis Plan
8.5.1.
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, malignancy, duration of study drug treatment, and the reason 
for discontinuing study treatment. Available information on subjects who were screened or 
registered but not treated may 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 for the full-analysis set.
8.5.2.
Efficacy Analyses
8.5.2.1.
Primary Efficacy Endpoint
For the primary analysis of the primary efficacy endpoint, PFS will be described using 
Kaplan-Meier methods in the full analysis set. Medians, ranges, the proportion of subjects who 
are progression-free at Week 16 (CLL after BCR targeted therapy, MCL and DLBCL) and 
24 (CLL and iNHL) (based on Kaplan-Meier estimates) will be presented. The findings of the 
IRC will be considered primary for analyses of PFS rate.


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As a sensitivity analysis, the aforementioned analysis will be done excluding subjects without 
adequate drug exposure.
8.5.2.2.
Time-to-Event Tumor Control Endpoints
TTR and DOR will be described in the subjects in full analysis set who achieve a CR or PR
(or VGPR or MR for LPL/WM) using Kaplan-Meier methods. 
8.5.2.3.
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 full analysis set. 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.
As a sensitivity analysis, the aforementioned analysis will be done excluding subjects without 
adequate drug exposure.
8.5.2.4.
Continuous Endpoints
Changes in lymph node area, CD63 expression, and plasma chemokines/cytokines will be 
assessed using mixed model for repeated measures (MMRM) with baseline values as covariates 
and timepoints as factor; in these analyses, means of changes from baseline at each subsequent 
timepoint will be estimated and plotted over time. 
8.5.2.5.
Sensitivity Analyses for Efficacy in CLL subjects
Novel targeted agents can cause a rapid reduction in lymph node size and spleen mass 
concomitant with an increase in lymphocytosis from baseline {Cheson 2012}. A sensitivity 
analysis is planned by considering PR with lymphocytosis as response. 
To satisfy criteria for PR with lymphocytosis, the following criteria must be met:

No evidence of new disease. 

A decrease by 50% from the baseline in the SPD of the index nodal lesions.

Peripheral blood counts meeting 1 of the following criteria:
ANC > 1.5 x 109/L or 50% increase over baseline without need for exogenous growth 
factors (eg, G-CSF)
Platelet count 100 x 109/L or 50% increase over baseline without need for exogenous 
growth factors
Hemoglobin 110 g/L (11.0 g/dL) or 50% increase over baseline without red blood 
cell transfusions or need for exogenous growth factors (eg, erythropoietin)


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
There is neither sufficient evidence to qualify for CR/PR nor sufficient evidence to qualify 
for definitive PD
Sensitivity analyses will be carried out for ORR, DOR and TTR:

Objective response rate (ORR). ORR will be determined from the subjects’ best response 
during GS-9973 therapy and will include CR or PR or PR with lymphocytosis.

Duration of response (DOR). DOR will be defined as time from the first response (CR or PR 
or PR with lymphocytosis) is achieved until the earlier of the first documentation of 
definitive disease progression or death from any cause.  

Time to response (TTR). TTR will be defined as time from the first dose of GS-9973 to the 
first time the response (CR or PR or PR with lymphocytosis) is achieved.
8.5.3.
Exposure and Safety Analyses
8.5.3.1.
Treatment Administration and Study Drug Compliance
Descriptive information will be provided by cohort 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.
GS-9973 compliance will be described for all subjects and by cohort 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).
8.5.3.2.
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) into Anatomical-Therapeutic-Chemical 
classification (ATC) codes.
Descriptions of prior medication use will be focused on drugs and regimens used as treatments 
for cancer. As appropriate and, if available, information on the sequencing, type, dose, schedule, 
timing, duration of use, and efficacy of prior regimens will be provided.
The type and timing of use of concomitant medications will be listed and summarized. 
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 lymphoid cancer will be 
summarized, characterizing the disposition of all subjects who are eligible for post-study 
treatment and those who are not eligible for post-study treatment (eg, subjects who are never 
treated at all, die while on study treatment, are still on study, are lost to follow-up, etc).


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8.5.3.3.
Adverse Events
All AEs will be listed. The focus of AE summarization will be on treatment-emergent AEs. A 
treatment-emergent AE is defined as an AE 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 is discontinued from 
study treatment will be included in data listings.
Adverse events will be classified using the Medical Dictionary for Regulatory Activities 
(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 AEs will be graded by the investigator according to the CTCAE, Version 4.03 
whenever possible. If a CTCAE criterion does not exist for a specific type of AE, the grade
corresponding to the appropriate adjective will be used by the investigator to describe the 
maximum intensity of the AE: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 
(life threatening), or Grade 5 (fatal). The relationship of the AE to the study drug will be 
categorized as related or unrelated.
Treatment-emergent AEs will be summarized. Summary tables will be presented to show the 
number of subjects reporting treatment-emergent AEs by severity grade and corresponding 
percentages. A subject who reports multiple treatment-emergent AEs within the same Preferred 
Term (or System Organ Class) is counted only once for that Preferred Term (or System Organ 
Class) using the worst severity grade. Adverse event descriptions will be presented 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 
AEs:

Study-drug-related AEs

AEs that are Grade 3 in severity

AEs leading to study drug interruption and/or dose modification

AEs leading to study drug discontinuation

SAEs (with categorization of the primary reason that the AE is considered serious, eg, death, 
hospitalization, etc)
8.5.3.4.
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 


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be considered treatment emergent. Laborato1y abnonnalities that occm before the first dose of 
study treatment or > 30 days after the subject is discontinued from study treatment will be 
included in data listings. 
Hematological, sennn biochemistiy, and coagulation data will be programmatically graded 
according to a Gilead modified CTCAE severity grade, when applicable. For parameters for 
which a CTCAE scale does not exist, reference ranges from the centi·al laborato1y will be used to 
detennine programmatically if a laborato1y parameter is below, within, or above the nonnal 
range for the subject's age, sex, etc. 
Hematological, sernm biochemistiy, and coagulation results and their changes from baseline will 
be summarized. Summaiy tables will be presented for each relevant assay to show the number of 
subjects by CTCAE severity grade with coITesponding percentages. For parameters for which a 
CTCAE scale does not exist, the frequency of subjects with values below, within, and above the 
n01mal ranges will be summarized. Subjects will be characterized only once for a given assay, 
based on their worst severity grade observed dming a period of interest ( eg, dming the study or 
from baseline to a paiiiculai· visit). 
Shift tables for hematology, sennn biochemistiy, and coagulation will also be presented by 
showing change in CTCAE severity grade from baseline to each visit. For pai·ameters for which 
a CTCAE scale does not exist, shift tables will be presented showing change in results from 
baseline (no1mal, low and high [or abnonnal]) to each visit (nonnal, low and high 
[ or abno1mal]). Tables will be prepai·ed to show frequencies adjusted for baseline values; for this 
frequency, subjects with the same or worse toxicity grade at baseline ai·e not considered. 
Separate listings and summai·ies will be prepai·ed for laborato1y abno1malities that are Grade ~3 
in severity. 
8.5.4. 
Exploratory Analyses 
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8.6. 
Continuous Data Review of PFS Endpoint Rate at 16 weeks (CLL after BCR 
Targeted Therapy, MCL and DLBCL) or 24 weeks (CLL and FL) 
For subjects with MCL, DLBCL, CLL ( except for the CLL dose ranging coho1i), and FL, a 
Bayesian, continuous data review approach using a Beta-Binomial model ( {Thall 1994}) will be 
used to update the estimates of the PFS rates at 16 weeks (CLL after BCR targeted therapy, MCL 
and DLBCL) or 24 weeks (CLL and FL) and, therefore, assess efficacy once each subject's 
prima1y endpoint becomes available for a malignancy. The Bayesian analysis method will be 
applied separately to each of the MCL, DLBCL, FL coho1is and the CLL cohorts ( except for the 
CLL dose ranging coho1i). 
In this model, response is defined as a subject not experiencing progression or death by 
Week 16 (CLL after BCR targeted therapy, MCL and DLBCL) or week 24 (CLL and FL). Only 
subjects with known progression/death status at Week 16 (CLL after BCR targeted therapy, 
MCL and DLBCL) or week 24 (CLL and FL) are included in the analysis. Subjects who 
withdraw or are lost to follow-up before Week 16 (CLL after BCR targeted therapy, MCL and 
DLBCL) or week 24 (CLL and FL) will be considered as a non-responder for the analysis. In this 
Beta-Binomial model, a binomial likelihood for the data and a conjugate Beta (0.5, 1.5) prior 
distribution for response rate 0 are assumed. Statistical inference and decision-making will be 
based on the posterior distribution of response rate 0, which is a Beta distribution with 
parameters x+O. 5 and n-x+ I. 5, where x is the observed number of subjects who achieve the 
response and n is the total number of subjects who have a response result for a given malignancy. 
More details about the Bayesian design and analysis model will be provided in the statistical 
analysis plan (SAP). 
The Bayesian model will be fit to the data sequentially as subjects' response status becomes 
available; decisions based on the estimate of response rate will be made accordingly. The 
posterior distribution of the response rate 0 in each malignancy will be provided on an ongoing 
basis and at the end of the trial. Let Pr(0<0.2ldata) denote the probability that the response 
rate 0 is less than 0.2 given the cunent data. The decision rules and actions to be taken based on 
the updated posterior distribution of response rate 0 given the cunent data are as follows: 
• If Pr(0<0.2ldata) > 0.9 in a coho1i , the sponsor will consider tenninating enrollment to that 
coho1i, taking into account efficacy, dmg exposme, and subtype (for DLBCL), unless there 
are subjects who remain on treatment and have not yet reached 16 weeks (CLL after BCR 
targeted therapy, MCL and DLBCL) or 24 weeks (CLL and FL). In that case, enrollment will 
be suspended until the next on-going subjects' prima1y endpoint become available and 
another data review is conducted. If, after review of all available subjects, the futility 
boundaiy has still been crossed and the lack of diu g exposme or DLBCL subtype does not 
explain the lack of activity, enrollment to that coho1i may be tenninated. 
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
Otherwise, continue recruiting subjects until a total of 40 subjects are enrolled for a cohort
(CLL, FL, CLL subjects after BCR targeted therapy without experiencing Richter’s 
transformation, MCL and DLBCL), or a total of 20 subjects are enrolled for CLL subjects 
after BCR targeted therapy experiencing Richter’s transformation. 
This monitoring will continue until a maximum of 40 or 20 subjects with a given cohort is 
reached.
To simplify decision-making, a plot of the a futility boundary(Pr(θ<0.2|data) > 0.9) in terms of 
the total number of subjects and the number of progression-free subjects at Week 16 (CLL after 
BCR targeted therapy, MCL and DLBCL) or Week 24 (CLL and iNHL) based on the above 
decision rule will be in Figure 3-2.
The data review for the two cohorts of BCR targeted therapy (CLL prior BTK inhibitor exposure
and CLL prior PI3K inhibitor exposure) will be conducted independently for Richter’s and non-
Richter’s.
The continuation data review of futility will not be conducted for the CLL dose ranging cohort. 
8.7.
Power and Sample Size Calculation
This study comprises of multiple cohorts. The planned sample size for CLL, FL, DLBCL, MCL 
is from 10 up to 40 each cohort; for the cohort of LPL, SLL and MZL is 45; for the CLL BCR 
targeted therapy cohort (CLL prior BTK inhibitor exposure and CLL prior PI3K inhibitor
exposure, respectively) is from 20 up to 60 (up to 20 for subjects experiencing Richter’s 
transformation and up to 40 for those without experiencing Richter’s transformation); for the 
CLL dose ranging cohort is 60 (20 at each dose level). The total sample size is from 185 up to 
385.
Given a Beta(0.5, 1.5) prior and a sample size of 40 subjects per cohort Table 8-1 shows the 
posterior mean and 95% credible interval for response rate after observing response rate ranging 
from 0.1 to 0.65.
Given the same prior and a sample size of 20 subjects for the CLL subjects experiencing 
Richter’s transformation after BCR targeted therapy, Table 8-2 shows the posterior mean and 
95% credible interval for response rate after observing response rate ranging from 0.1 to 0.65.


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Table 8-1.
Estimated Posterior Mean and 95% Credible Interval of Response 
Rate with Sample Size = 40
Observed Response Rate
Posterior Mean
95% Credible Interval
0.10
0.107
(0.034, 0.215)
0.20
0.202
(0.097, 0.335)
0.30
0.297
(0.171, 0.442)
0.40
0.393
(0.253, 0.543)
0.50
0.488
(0.340, 0.637)
0.60
0.583
(0.433, 0.726)
0.65
0.631
(0.482, 0.769)
Table 8-2.
Estimated Posterior Mean and 95% Credible Interval of Response
Rate with Sample Size = 20
Observed Response Rate
Posterior Mean
95% Credible Interval
0.10
0.114
(0.020, 0.272)
0.20
0.205
(0.068, 0.392)
0.30
0.295
(0.129, 0.497)
0.40
0.386
(0.199, 0.593)
0.50
0.477
(0.277, 0.681)
0.60
0.568
(0.362, 0.763)
0.65
0.614
(0.407, 0.801)
With the decision rule employed in this study and assuming enrollment is terminated once the 
futility criterion is met, for a given true response rate within a malignancy, Table 8-3 shows the 
probability of claiming futility and the sample size needed to claim futility for this design, which 
is based on 10,000 simulations. When the true response rate is low (0.1), this design has a high 
probability (~84%) of claiming futility and when the true response rate is high (0.5), this design 
has a low probability (0.15%) of claiming futility.


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Table 8-3.
Probability and Sample Size of Claiming a Futility by the End of 
Study Using Futility Criteria Pr(θ<0.2|data) > 0.9
True response rate
Probability of claiming 
futility
Sample size to claim
futility or *
25th
Median
75th
0.10
0.8408
10
14
28
0.20
0.3162
21
40
40
0.30
0.0685
40
40
40
0.40
0.0125
40
40
40
0.50
0.0015
40
40
40
0.60
0.0003
40
40
40
0.65
0.0001
40
40
40
*
When futility cannot be claimed, the sample size is converted to the maximum size of 40.
8.8.
Multiplicity
Since this is an exploratory study with a learning objective, no multiplicity adjustment will be 
applied.
8.9.
Timing of Analysis
The analysis for the primary efficacy endpoint will be initiated after data for at least 10 subjects 
are available for a given cohort. Due to the Bayesian adaptive nature of this study, analyses will 
be performed on an ongoing basis. To facilitate timely decision-making, analysis will be 
conducted immediately to sequentially update knowledge regarding drug efficacy among the 
5 investigated hematologic malignancies whenever new data for the primary efficacy endpoint 
are mature for analysis.
8.10.
Final Analysis
Final study reporting is expected to occur after the earliest of all subjects have completed study 
or 48 weeks after accrual of the final subject. 


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union Clinical 
Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.  The investigator 
will ensure that the basic principles of “Good Clinical Practice,” as outlined in 21 CFR 312, 
subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, 
part 56, 1998, are adhered to.
Since this is a “covered” clinical trial, the investigator will ensure that 21 CFR, Part 54, 1998, is 
adhered to; 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 subinvestigators 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. The investigator and subinvestigator agree to notify Gilead Sciences of any 
change reportable interests during the study and for one year following completion of the study. 
Study completion is defined as the date that the last subject has completed the protocol defined 
activities.
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.”
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Approval
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/IEC. 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 made to the protocol after receipt of IRB/IEC approval must also be 
submitted to the IRB/IEC for approval before implementation.


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9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must utilize an IRB- or 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.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, and an 
identification code (ie, not names) should be recorded on any form or biological sample 
submitted to the Sponsor, IRB/IEC, or laboratory. NOTE The investigator must keep a screening 
log showing codes, names, and addresses for all subjects screened and for all subjects enrolled in 
the trial.
The investigator agrees that all information received from Gilead Sciences, including but not 
limited to the Investigator Brochure, this protocol, CRFs, 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.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data are listed in the Source Data verification Plan, 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, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);


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• 
paiiicipation in trial (including ti·ial number); 
• 
ti·ial discussed and date of info1med consent; 
• 
dates of all visits; 
• 
documentation that protocol specific procedures were perfo1med; 
• 
results of efficacy parameters, as required by the protocol; 
Final 
Amendment8 
• 
staii and end date (including dose regimen) of ti·ial medication (preferably drng dispensing 
and return should be documented as well); 
• 
record of all adverse events and other safety parameters (staii and end date, and preferably 
including causality and intensity); 
• 
concomitant medication (including staii and end date, dose if relevant; dose changes should 
be motivated); 
• 
date of ti·ial completion and reason for early discontinuation, if applicable. 
All clinical study documents must be retained by the investigator until at least 2 yeai·s after the 
last approval of a mai·keting application in an ICH region (ie, United States, Europe, or Japan) 
and until there are no pending or contemplated mai·keting 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 regulato1y authorities have been notified. Investigators may be 
required to retain documents longer if required by applicable regulato1y requirements, by local 
regulations, or by an agreement with Gilead Sciences. The investigator must notify Gilead 
Sciences before desti·oying any clinical study records. 
Should the investigator wish to assign the study records to another paiiy or move them to another 
location, Gilead Sciences must be notified in advance. 
If the investigator cannot guai·antee this ai·chiving requirement at the study site for any or all of 
the documents, special atTangements 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 regulato1y audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site. 
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9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the Sponsor to perform central monitoring of 
safety data. Subsequent to data entry, a study monitor will perform source data verification 
within the EDC system. Original entries as well as any changes to data fields will be stored in the 
audit trail of the system. Prior to database lock (or any interim time points as described in the 
clinical data management plan), the Investigator will use his/her log in credentials to confirm that 
the forms have been reviewed, and that the entries accurately reflect the information in the 
source documents. The eCRF captures the data required per the protocol schedule of events and 
procedures. System-generated or manual queries will be issued to the investigative site staff as 
data discrepancies are identified by the monitor or internal Gilead staff, who routinely review the 
data for completeness, correctness, and consistency. The site coordinator is responsible for 
responding to the queries in a timely manner, within the system, either by confirming the data as 
correct or updating the original entry, and providing the reason for the update (eg, data entry 
error). At the conclusion of the trial, Gilead will provide the site with a read-only archive copy 
of the data entered by that site. This archive must be stored in accordance with the records 
retention requirements outlined in Section 9.1.5.
9.1.7.
Drug Accountability 
Gilead recommends that used and unused IMP supplies be returned to the shipping facility from 
which it came for eventual destruction. The study monitor will provide instructions for return. If 
return is not possible, the study monitor will evaluate each study center’s IMP disposal 
procedures and provide appropriate instruction for destruction of unused IMP supplies. If the site 
has an appropriate SOP for drug destruction as determined by Gilead QA, the site may destroy 
used (empty or partially empty) and unused IMP supplies in accordance with that site’s approved 
SOP. A copy of the site’s approved SOP will be obtained for central files. 
If IMP is destroyed on site, the Investigator must maintain accurate records for all IMP 
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from Gilead Sciences or its representatives, to IRBs [or] 
IECs, or to regulatory authority or health authority inspectors.


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9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead Sciences. All protocol modifications must be submitted to the IRB [or] IEC
in accordance with local requirements. Approval must be obtained before changes can be 
implemented.
9.2.2.
Study Reporting and Publication
A clinical study report will be prepared and provided to the regulatory agency(ies). 
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). Note that an abbreviated report may 
be prepared in certain cases.
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 only after the following conditions have been met:

the results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead Sciences in an abstract, manuscript, or presentation form; or

the study has been completed at all study sites for at least 2 years.
No such communication, presentation, or publication will include Gilead Sciences’ confidential 
information.
The investigator will submit 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 and agrees 
to withhold publication or presentation for an additional 60 days in order to obtain patent 
protection if deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Access to Information for Monitoring
In accordance with 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 CRFs for consistency.


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The monitor is responsible for routine review of the CRFs 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 CRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved.
9.3.2.
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.
9.3.3.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead Sciences and the 
investigator will assure that adequate consideration is given to the protection of the subjects’ 
interests.
9.4.
Independent Review Committee
An IRC will be established to provide a 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 central imaging vendor in conjunction with Gilead Sciences. 


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10.
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Lymphocytic Leukemia. Available at: 
http://seer.cancer.gov/statfacts/html/clyl.html. Accessed 12 May 2011.
Tam CS, Otero-Palacios J, Abruzzo LV, Jorgensen JL, Ferrajoli A, Wierda WG, et al. Chronic 
lymphocytic leukaemia CD20 expression is dependent on the genetic subtype: a 
study of quantitative flow cytometry and fluorescent in-situ hybridization in 510 
patients. Br J Haematol 2008;141 (1):36-40.
Thall PF, Simon R. A Bayesian approach to establishing sample size and monitoring criteria for 
phase II clinical trials. Control Clin Trials 1994;15 (6):463-81.
Thurmes P, Call T, Slager S, Zent C, Jenkins G, Schwager S, et al. Comorbid conditions and 
survival in unselected, newly diagnosed patients with chronic lymphocytic 
leukemia. Leuk Lymphoma 2008;49 (1):49-56.
Tsang RW, Gospodarowicz MK. Radiation therapy for localized low-grade non-Hodgkin's 
lymphomas. Hematol Oncol 2005;23 (1):10-7.
Turner M, Schweighoffer E, Colucci F, Di Santo JP, Tybulewicz VL. Tyrosine kinase SYK: 
essential functions for immunoreceptor signalling. Immunology today 2000;21 
(3):148-54.
U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse 
Events (CTCAE). Version 4.0 (Published: May 28, 2009). v4.03 (Published: June 
14, 2010)  NIH Publication No. 09-5410.  2010.
van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD, et al. Rituximab 
maintenance improves clinical outcome of relapsed/resistant follicular non-
Hodgkin lymphoma in patients both with and without rituximab during induction: 
results of a prospective randomized phase 3 intergroup trial. Blood 2006;108 
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Vidal L, Gafter-Gvili A, Leibovici L, Dreyling M, Ghielmini M, Hsu Schmitz SF, et al. 
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Final
Gilead Sciences, Inc.
Amendment 8
CONFIDENTIAL
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Vose JM, Wahl RL, Saleh M, Rohatiner AZ, Knox SJ, Radford JA, et al. Multicenter phase II 
study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade 
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Gilead Sciences, Inc.
Amendment 8
CONFIDENTIAL
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31 March 2017
11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table


GS-9973 
Protocol GS-US-339-0102 
Final 
Gilead Sciences, Inc. 
Amendment 8 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 2, Open-Label Study Evaluating the Efficacy, Safety, Tolerability, and 
Pharmacodynamics of GS-9973 in Subjects with Relapsed or Refractory Hematologic 
Malignancies 
GS-US-339-0102 Protocol Amendment 8: 31 March 2017 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PPD 
PD 
Medical Monitor 
~1gnamre 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully infonned about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 136 
31 March2017 


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Gilead Sciences, Inc.
Amendment 8
CONFIDENTIAL
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Appendix 2.
Study Procedures Table
Study Phase
Screening
Cycle 1
(28 days)
Subsequent 
Cycles
(28 days)
Safety 
Monitoring 
Visits
Tumor Response 
Assessments
Disease Progression 
or EOSc
30-Day 
Follow Up
Cycle Day
Screening
1
1
Variesa
Q8 or 12 wks or 
6 monthsb
N/A
Window
-35
±2 days
±2 days
N/A
Study Assessments
Informed Consent
X
Medical History
X
Physical Examd
X
X
X
X
X
Vital Signse
X
X
X
X
X
12-lead ECG
X
X
Karnofsky Performance Status
X
X
X
X
X
Prior/Concomitant Meds
X
X
X
X
X
AEsf
X
X
X
X
X
X
CT or MRI
Xg
Xh
Xi
Bone Marrow Biopsy and Aspirate
Xj
Xj
DLBCL Subtypingk
X
Collect Archival Tumor Tissue (if available)
Xl
Complete Subject/Visit info in IxRS
X
X
X
X
Sample Collection
Chemistry
X
X
Xx
X
X
Beta-2-microglobulin
X
X
X
Hematology 
X
X
Xx
X
X
Coagulation
X
X
Xx
X
X
Urinalysis
X
X
X
HBV, HCV and HIV Virology
X


GS-9973
Protocol GS-US-339-0102
Final
Gilead Sciences, Inc.
Amendment 8
CONFIDENTIAL
Page 138
31 March 2017
Study Phase
Screening
Cycle 1
(28 days)
Subsequent 
Cycles
(28 days)
Safety 
Monitoring 
Visits
Tumor Response 
Assessments
Disease Progression 
or EOSc
30-Day 
Follow Up
Cycle Day
Screening
1
1
Variesa
Q8 or 12 wks or 
6 monthsb
N/A
Window
-35
±2 days
±2 days
N/A
Pregnancy Testn
X
X
X
X
X
GS-9973 Plasma Concentrationo, p, v
X
X
X
X
Buccal Swabu
X
Serum monoclonal IgM SPEP/IFE and cryoglobulin 
testingq
X
X
Study Drug Dosing 
GS-9973 up to 800 mg BID Fasting or 100, 200 or 
400 mg GS-9973 SDD BID Fasting
X-----------------------------------------------------------------------------------X
Dispense Study Drug
X
X
Study Drug Compliancer
X
X
X
Collect Used/Unused Study Drugw
X
X
For CLL, SLL and MCL subjects only
Cytokines and Chemokines
Xm
Xm
Xm
X
CTC Molecular Characterization
X
Xs
X
CTC RNAw
Xw
Xw
Xw
CLL ONLY:  Pharmacodynamic Measurements 
(BAT Assay)
Xt
CLL ONLY: Pharmacogenomic Testing
X
Xs
X
a
Days 8, 15, and 22 of Cycle 1 and Day 15 of Cycle 2
b
Tumor assessments will be performed every 8 weeks during the first 24 weeks of the study and then every 12 weeks thereafter regardless of cycle number and regardless of 
dose interruptions.  Tumor assessments may be performed at other timepoints during the treatment phase as clinically indicated (to assess tumor progression).  After week 72 
scans will occur at least every 6 months (± 4 weeks).  The same evaluation procedures must be used throughout the study for each subject.  Scans should be of high quality
and digitalized in the DICOM format to allow for reading at a centralized facility.
CCI


GS-9973
Protocol GS-US-339-0102
Final
Gilead Sciences, Inc.
Amendment 8
CONFIDENTIAL
Page 139
31 March 2017
c
If a subject stops study drug for a reason other than progressive disease and consistent with good medical practice, they will be followed as per the scheduled imaging in 
Section 6.5 with additional CBC (hematology) at time of assessments.
d
Complete physical examination will be performed at Screening and at Disease Progression or EOS. A modified physical examination capturing changes from prior exams will 
be performed at other visits. Weight should be measured (in kilograms) at each physical examination. Height will be measured (in centimeters) at Screening only.
e
Vital signs (including blood pressure, respiratory rate, pulse, oxygen saturation by pulse oximetry and temperature) should be taken after the subject has been sitting for at 
least 5 minutes.
f
Adverse events will be assessed once ICF is signed, pre- and post-dose during applicable clinic visits, and 30 (±7) days following completion of the subject’s last dose of 
study drug.  Subjects should be contacted by phone (or in person, if necessary) 30 days (± 7 days) after the subject’s last dose of study drug to assess AEs.  Subjects should 
specifically be asked about the development of any adverse events since stopping the study.
g
CT or MRI scans of neck, chest, abdomen, and pelvis taken as part of standard medical practice up to 35days prior to Day 1 of Cycle 1 visit are acceptable for use at the 
Screening.  Subjects with LPL/WM who previously failed screening for this study, due to an absence of lymphadenopathy on CT or MRI scans, do not need to be re-scanned 
if the scans were performed within 16 weeks of first study drug administration to meet eligibility criteria.
h
At all timepoints after Screening imaging of the chest, abdomen, and pelvis will be required.  Imaging of the neck is required at each follow-up time point if the neck scan was 
positive at baseline or if palpable neck lymphadenopathy appears during the course of the study.
i
Tumor evaluations should be conducted at the End of Study Visit if not conducted in the previous 4 weeks. If a subject permanently discontinues study drug prior to objective 
documentation of progression, investigators should continue further follow-up at the ~8 or ~12-week intervals until progression is documented.
j
A bone marrow biopsy and aspirate will be collected for all subjects who achieve a CR for confirmatory purpose.  For CLL subjects a bone marrow biopsy/aspirate will be 
collected to confirm a PD.  If the subject does not otherwise meet criteria for CR or if the nature of PD does not require bone marrow confirmations, it is not necessary to 
obtain a bone marrow biopsy/aspirate (See Sections 6.18 and 6.20).
k
If the subject has DLBCL, subtyping is required.  Submission of 15 unstained slides is required for subtyping if the subtype is not already known.  Subjects for whom tissue is 
not available but the subtype is already known may be included if approved by the Medical Monitor following discussion with the investigator.
l
Fifteen recently prepared unstained slides from archival tumor tissues will be collected. Efforts to acquire tissue sample should begin on Day 1 of Cycle 1.
m
Collect on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1 and Cycle 12, Day 1 only
n
For females of childbearing potential, a serum pregnancy test will be performed at Screening and urine pregnancy tests will be performed on Days 1 of each Cycle and Day 15 
of Cycles 1 & 2 and at EOS.
o
Record the approximate number of hours between the last 2 doses of GS-9973 and the time the blood samples for plasma concentration were obtained
p
GS-9973: PK samples will be collected on Day 1 of Cycle 1 pre-dose, 1.5 hours post-dose and 4 hours post-dose; on Day 1 of Cycles 2-6 pre-dose (12 hours post last dose).
GS-9973 SDD: PK samples will be collected on Day 1 of Cycle 1 pre-dose, 1.5 hours post-dose and 4 hours post-dose; on Day 8 of Cycle 1 pre-dose, 1.5 hours post-dose and 
4 hours post-dose; on Days 15 and 22 of Cycle 1 pre-dose and 1.5 hours post-dose; and on Day 1 of subsequent cycles pre-dose and 1.5 hours post-dose.
q
Subjects with LPL/WM only.  This procedure should be conducted on the Day 1 visit occurring during the week window allotted for tumor response assessments.
r
Includes date/time of last dose of GS-9973 (excluding Day 1 of Cycle 1)
s
Collect on Cycle 2, Day 15 only
t
On Day 1 of Cycle 1, samples will be collected pre-dose, 1.5 hours post-dose (± 10 minutes) and 4 hours post-dose ((± 10 minutes); on cycle 1 day 8 (predose and 4 hours 
post dose) and cycle 1 day 15 (predose)
u
For CLL dose ranging, CLL prior BTK inhibitor exposure, or CLL prior PI3K inhibitor exposure cohorts only
v
Excluding subjects off study drug at time of progression
w
Samples will be collected pre-dose on Cycle 1 Day 1, Cycle 12 Day 1 and at Disease Progression or EOS only
x
May be collected up to 2 days prior to the Day 1 visit

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 2, Open-Label Study Evaluating the Efficacy, 
Safety, Tolerability, and Pharmacodynamics of GS-9973 in 
Subjects with Relapsed or Refractory Hematologic 
Malignancies
Name of Test Drug:
Entospletinib (ENTO)
Study Number:
GS-US-339-0102
Protocol Version (Date):
Amendment 8 (31 March 2017)
Analysis Type:
Final CSR 
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
16 September 2019
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(rJ GILEAU 
-


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF TABLES.........................................................................................................................................................3
LIST OF FIGURES.......................................................................................................................................................3
LIST OF ABBREVIATIONS........................................................................................................................................5
1.
INTRODUCTION ................................................................................................................................................7
1.1.
Study Objectives ......................................................................................................................................7
1.2.
Study Design............................................................................................................................................7
1.2.1.
Design Configuration .............................................................................................................7
1.2.2.
CLL (non-dose-ranging cohorts), MCL, DLBCL, and FL cohorts ........................................9
1.2.3.
CLL Dose Ranging Cohort...................................................................................................10
1.2.4.
Other iNHL (LPL/WM, SLL, and MZL) Cohort .................................................................10
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................11
2.1.
Final Analysis ........................................................................................................................................11
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................12
3.1.
Analysis Sets..........................................................................................................................................12
3.1.1.
All Enrolled Analysis Set.....................................................................................................12
3.1.2.
Full Analysis Set ..................................................................................................................12
3.1.3.
Safety Analysis Set...............................................................................................................12
3.1.4.
Pharmacokinetic Analysis Sets.............................................................................................12
3.2.
Subject Grouping ...................................................................................................................................12
3.3.
Strata and Covariates..............................................................................................................................13
3.4.
Examination of Subject Subsets.............................................................................................................13
3.5.
Multiple Comparisons............................................................................................................................13
3.6.
Missing Data and Outliers......................................................................................................................13
3.6.1.
Missing Data ........................................................................................................................13
3.6.2.
Outliers.................................................................................................................................14
3.7.
Data Handling Conventions and Transformations .................................................................................14
3.8.
Analysis Visit Windows.........................................................................................................................15
3.8.1.
Definition of Study Day .......................................................................................................15
3.8.2.
Analysis Windows................................................................................................................15
4.
SUBJECT DISPOSITION ..................................................................................................................................16
4.1.
Subject Enrollment and Disposition.......................................................................................................16
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................16
4.2.1.
Duration of Exposure to Study Drug....................................................................................16
4.2.2.
Adherence to Study Drug.....................................................................................................17
4.3.
Protocol Deviations................................................................................................................................17
5.
BASELINE CHARACTERISTICS....................................................................................................................18
5.1.
Demographics ........................................................................................................................................18
5.2.
Other Baseline Characteristics ...............................................................................................................18
5.3.
Medical History......................................................................................................................................18
5.4.
Prior Anticancer Therapy.......................................................................................................................19
6.
EFFICACY ANALYSES ...................................................................................................................................20
6.1.
Primary Efficacy Endpoint.....................................................................................................................20
6.1.1.
Definition of the Primary Efficacy Endpoint .......................................................................20
6.1.2.
Analysis of the Primary Efficacy Endpoint..........................................................................20


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6.2.
Secondary Efficacy Endpoint.................................................................................................................21
6.2.1.
Definition of Secondary Efficacy Endpoints........................................................................21
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................22
6.3.
Changes from Protocol-Specified Efficacy Analyses ............................................................................22
7.
SAFETY ANALYSES........................................................................................................................................23
7.1.
Adverse Events and Deaths....................................................................................................................23
7.1.1.
Adverse Event Dictionary ....................................................................................................23
7.1.2.
Adverse Event Severity........................................................................................................23
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................23
7.1.4.
Serious Adverse Events........................................................................................................23
7.1.5.
Treatment-Emergent Adverse Events...................................................................................23
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................24
7.2.
Laboratory Evaluations ..........................................................................................................................26
7.2.1.
Graded Laboratory Values ...................................................................................................26
7.2.2.
Shift in Relative to the Baseline...........................................................................................27
7.3.
Body Weight and Vital Signs.................................................................................................................27
7.4.
Prior and Concomitant Medications.......................................................................................................27
7.4.1.
Prior Medications .................................................................................................................27
7.4.2.
Concomitant Medications.....................................................................................................28
7.5.
Electrocardiogram (ECG) Results..........................................................................................................28
7.6.
Post Treatment Anti-Cancer Therapies ..................................................................................................29
7.7.
Changes from Protocol-Specified Safety Analyses................................................................................29
8.
PHARMACOKINETIC (PK) ANALYSES........................................................................................................30
8.1.
Statistical Analysis Methods ..................................................................................................................30
8.1.1.
Plasma Concentration...........................................................................................................30
9.
PHARMACODYNAMIC (PD) ANALSES .......................................................................................................31
10.
REFERENCES ...................................................................................................................................................32
11.
SOFTWARE.......................................................................................................................................................33
12.
SAP REVISION..................................................................................................................................................34
13.
APPENDICES ....................................................................................................................................................35
Appendix 1.
Schedule of Assessments........................................................................................................35
Appendix 2.
PFS Definition and Derivation Diagram ................................................................................39
LIST OF TABLES
Table 1-1.
Dose Levels and Formulations .................................................................................................8
Table 3-1.
Subject Grouping for Cohorts of CLL (except for the CLL Dose Ranging and the 
CLL after BCR Targeted Therapy Cohorts) and other Disease Indications ...........................13
Table 3-2.
Subject Grouping for the CLL Dose Ranging Cohort ............................................................13
Table 3-3.
Subject Groupings for the CLL after BCR Targeted Therapy Cohorts ..................................13
Table 12-1.
Event/Censoring Scheme of Analysis for PFS .......................................................................40
LIST OF FIGURES
Figure 1-1.
Study Schema...........................................................................................................................8


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Figure 1-2.
Futility Boundary with Prior Distribution Beta (0.5, 1.5).......................................................10


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LIST OF ABBREVIATIONS
AE
adverse event
ATC
Anatomical-Therapeutic-Chemical (drug coding system)
BCR
B-cell receptor
BID
twice a day
BLQ
below the limit of quantitation
BMI
body mass index
BOR
best overall response
CI
confidence interval
CLL
chronic lymphocytic leukemia
CR
complete response
eCRF
electronic case report form
CRF
case report form
CSR
clinical study report
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
DLBCL
diffuse large B-cell lymphoma
DOR
duration of response
ECG
electrocardiogram
ENTO
Entospletinib
FL
follicular lymphoma
HLGT
high-level group term
HLT
high-level term
iNHL
indolent non-Hodgkin lymphoma
IRC
independent review committee
LOQ
lower limit of quantification
LLT
low level term
LPL
lymphoplasmacytoid lymphoma
MedDRA
Medical Dictionary for Regulatory Activities
MCL
mantle cell lymphoma
MM
mono-mesylate
MRI
magnetic resonance imaging
MZL
marginal zone lymphoma
ND
no disease
NE
not evaluable
NHL
non-Hodgkin lymphoma
ORR
objective response rate
PD
progressive disease
PFS
progression-free survival


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PK
pharmacokinetic
PPI
proton pump inhibitors
PR
partial response
PT
preferred term
QTc
QT interval corrected
QTc-B
QT interval corrected for heart rate using Bazett’s formula
QTc-F
QT interval corrected for heart rate using Fridericia’s formula
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SDD
spray dried dispersion
SE
standard error
SLL
small lymphocytic lymphoma
StD
standard deviation
SOC
system organ class
SPD
sum of the product of the diameters (of nodal or tumor masses)
SPEP
serum protein electrophoresis
TEAE
treatment-emergent adverse event
TLF
tables, figures, and listings
TTR
time to response
WHO
World Health Organization
WM
Waldenström macroglobulinemia


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1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-339-0102.  This SAP is based on the study protocol Amendment 8 dated 
31 March 2017 and the electronic case report form (eCRF). The SAP will be finalized before 
database finalization. Any changes made after the finalization of the SAP will be documented in 
the CSR. 
Based on the Sponsor’s strategic plan for entospletinib development, the CSR will be in synoptic 
version. 
1.1.
Study Objectives
The primary objective of this study is as follows:

To evaluate the efficacy of entospletinib (ENTO; GS-9973) in subjects with relapsed or 
refractory hematologic malignancies
The secondary objectives of this study are as follows:

To evaluate the safety and tolerability of ENTO in subjects with relapsed or refractory 
hematologic malignancies

To evaluate ENTO exposures in subjects with relapsed or refractory hematologic 
malignancies
1.2.
Study Design
1.2.1.
Design Configuration
This is a Phase 2, open-label study evaluating the efficacy, safety, and tolerability of ENTO
administered twice daily (BID) over multiple 28-day cycles in subjects with relapsed or 
refractory hematologic malignancies. Historically the study planned to investigate 5 cohorts of 
ENTO in subjects with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), 
diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and a fifth cohort consisting 
of the non-FL indolent non-Hodgkin lymphomas (iNHL), ie, subjects with lymphoplasmacytoid 
lymphoma/Waldenström macroglobulinemia (LPL/WM), small lymphocytic lymphoma (SLL), 
or marginal zone lymphoma (MZL), with a mono-methanesulfonate salt at 800 mg bid of the 
original mono-mesylate (MM) formulation (Figure 1-1). After completion of enrollment of the 
original CLL cohort, the study was amended to include the addition of 3 CLL cohorts (1 dose 
finding prior B-Cell receptor (BCR) naïve cohort and 2 prior BCR exposure cohorts
[ie, 1 prior BTK inhibitor and 1 prior PI3K inhibitor cohort]). All 3 additional cohorts receive a 
new formulation of ENTO designated spray dried dispersion (SDD). The SDD formulation had 
greater bioavailability and lesser drug-drug interactions (no H2 and reduce proton pump 
inhibitors (PPI)). As of protocol amendment 8, subjects receiving ENTO MM formulation are
transitioned to the ENTO SDD formulation. 


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Figure 1-1.
Study Schema
The 2 CLL cohorts with prior BCR exposure enroll based on the most recent progression 
followed BCR-exposure. The BCR naïve patient cohort designated as CLL dose ranging cohort 
are randomly assigned to one of 3 doses evaluating 100 mg, 200 mg, and 400 mg
(200 mg x 2) BID dosing of ENTO SDD (Table 1-1).
Table 1-1.
Dose Levels and Formulations
Cohort
Dose (BID)*
Formulation
CLL
800mg 
Amendment 8: 400mg
MM
Amendment 8: SDD
MCL
800mg
Amendment 8: 400mg
MM
Amendment 8: SDD
DLBCL
800mg
Amendment 8: 400mg
MM
Amendment 8: SDD
FL
800 mg
Amendment 8: 400mg
MM
Amendment 8: SDD
Other iNHL (LPL/WM, SLL, and MZL)
800mg
Amendment 8: 400mg
MM
Amendment 8: SDD
CLL prior BCR inhibitor naïve
400mg
200mg
100mg
SDD
SDD
SDD
CLL Prior BTK inhibitor
400mg
SDD
CLL Prior PI3K inhibitor
400mg
SDD
*Note 800mg of MM is PK/PD equivalent of 400 mg SDD
Original Protocol 
LPL, SLL, MZL 
Continue accrual to a 
maximum of 40 total subjects 
GS-9973 
Original Formulation 
800 mg BIO 
-------------------------------
Sample size: 
10-40/cohort 
GS-9973SOO 
New 
Formulation 
400 mg BIO 
Sample Size: 
20-60/cohort 
GS-9973SOO 
OLBCL 
Consider 
stopping accrual 
in that malignancy 
Continue accrual 
to a maximum of 
40 subjects 
Consider 
stopping accrual 
in that malignancy 
Continue accrual 
to a maximum of 
20 (Richter's) or 
40 (non-Richter's) 
subjects 
(Randomized) 
New Formulation ~-------------------------------
100, 200 or 400 mg BIO --• 
Sample Size: 60 
• 
CLLOose 
Ranging 
Continue until accrual of 
20 subjects at each dose level 


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1.2.2.
CLL (non-dose-ranging cohorts), MCL, DLBCL, and FL cohorts
A Bayesian, continuous data review approach is used to update the estimates of progression-free 
survival (PFS) rates at 16 weeks (CLL after BCR targeted therapy, MCL, and DLBCL) or 
24 weeks (CLL and FL) for a malignancy.  The data reviews for the CLL prior BTK inhibitor 
exposure and CLL prior PI3K inhibitor exposure cohorts are conducted independently for 
Richter’s and non-Richter’s. The criterion used for the futility boundary is defined as highly 
likely (>90%) that the PFS rates at 16 weeks (CLL after BCR targeted therapy, MCL, and 
DLBCL) or 24 weeks (CLL and FL) are less than 0.2 given the available subjects’ efficacy data.
Futility assessment begins when the first 10 subjects’ primary endpoints become available. 
Thereafter, continuous data reviews are conducted when a new primary endpoint becomes 
available.

If the futility criterion is not met, subsequent subjects will be enrolled until a total of 
pre-defined number of subjects are recruited for a cohort.

If the futility criterion is met, the sponsor will consider terminating enrollment to that 
malignancy, taking into account efficacy, drug exposure and subtype (for DLBCL), unless 
there are subjects who remain on treatment and have not yet reached 16 weeks (CLL after 
BCR targeted therapy, MCL, and DLBCL) or 24 weeks (CLL and FL). In this case, 
enrollment will be suspended until the next on-going subjects’ primary endpoints become 
available, and another data review is conducted. If, after review of all available subjects, the 
futility boundary has still been crossed and the lack of drug exposure or for DLBCL, subtype 
does not explain the lack of activity, enrollment to that malignancy will be terminated.  
The futility boundary is provided in Figure 1-2 with details in Section 2.1.  The boundary is 
represented in terms of the total number of subjects and the number of progression-free subjects 
at Week 16 (CLL after BCR targeted therapy, MCL, and DLBCL) or Week 24 (CLL and FL).  
Subjects who withdraw or are lost to follow-up before Week 16 (CLL after BCR targeted 
therapy, MCL, and DLBCL) or week 24 (CLL and FL) will be considered as not achieving PFS 
for the analysis.
At each data review, if the observed ratio of the number of PFS at Week 16 (CLL after BCR 
targeted therapy, MCL and DLBCL) or Week 24 (CLL and FL) over the total number of subjects 
is at or below the futility boundary, the futility criterion has been met.


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Figure 1-2.
Futility Boundary with Prior Distribution Beta (0.5, 1.5)
1.2.3.
CLL Dose Ranging Cohort
For the CLL dose ranging cohort, subjects are randomized in the ratio of 1:1:1 to receive 
100 mg, 200 mg or 400 mg (200 mg x 2) of ENTO SDD BID. 20 subjects are planned to be 
treated at each of the three dose levels. Because the CLL dose raging cohort consists of 
3 different dose levels each with approximately 20 subjects, the continuation data review of 
futility will not be conducted for this cohort.
1.2.4.
Other iNHL (LPL/WM, SLL, and MZL) Cohort
Because the ‘Other iNHL’ cohort consists of 3 different histologies, the accrual continues to a 
maximum of 45 subjects without a Bayesian analysis.
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Futility Boundary with Prior Distribution Beta(0.5, 1.5) 
P(PFS rate <0.21data)>0.9 
XJY: X -# of surviving progression- free subjects; Y-# of subjects. 
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35 
40 


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Final Analysis
After all subjects have completed the study, outstanding data queries have been resolved or 
adjudicated as unresolvable, and the data have been cleaned and finalized, the final analysis of 
the data will be performed. Due to the Sponsor’s strategic plan, the final CSR will be in synoptic 
version. 


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3.
GENERAL CONSIDERATIONS FOR DATAANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (StD) or standard error (SE), median, first 
quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the All Enrolled Analysis Set and sorted 
by subject ID number, visit date, and time (if applicable). Data collected on log forms, such as 
AEs, will be presented in chronological order within the subject. The treatment group to which 
subjects are initially assigned will be used in the listings. Age, sex at birth, race, and ethnicity 
will be included in the listings, as space permits.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing.
3.1.1.
All Enrolled Analysis Set
All Enrolled Analysis Set includes all subjects who received a study subject identification 
number in the study after screening. The All Enrolled Analysis Set will be used for subject 
enrollment summaries. 
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all enrolled subjects who took at least one dose of study 
drug (ie, ENTO) with treatment group designated according to the planned treatment. This is the 
primary analysis set for efficacy analyses.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least one dose of study drug 
(ie, ENTO) with treatment group designated according to the actual treatment. This is the 
primary analysis set for safety analyses. 
3.1.4.
Pharmacokinetic Analysis Sets
The Pharmacokinetic (PK) Analysis Set will include all enrolled subjects who took at least 
one dose of study drug (ie, ENTO) and have at least one nonmissing postdose concentration 
value reported by the PK laboratory. This is the primary analysis set for all PK analyses. 
3.2.
Subject Grouping
For summary tables, unless otherwise specified, subjects will be grouped by disease indications,
prior treatment status, and dose levels as follows in Table 3-1, Table 3-2, and Table 3-3.


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Table 3-1.
Subject Grouping for Cohorts of CLL (except for the CLL Dose 
Ranging and the CLL after BCR Targeted Therapy Cohorts) and 
other Disease Indications 
CLL
N = xx
FL
N = xx
DLBCL
N = xx
MCL
N=xx
Other iNHL
N = xx
Total
N=xx
xx
xx
xx
xx
xx
xx
Table 3-2.
Subject Grouping for the CLL Dose Ranging Cohort
100mg BID
N = xx
200mg BID
N = xx
400mg BID
N = xx
Total
N=xx
xx
xx
xx
xx
Table 3-3.
Subject Groupings for the CLL after BCR Targeted Therapy Cohorts 
Non-Richters
(Prior BTK 
Exposure)
N = xx
Non-Richters
(Prior PI3K 
Exposure)
N = xx
Richters
(Prior BTK 
Exposure)
N = xx
Richters
(Prior PI3K 
Exposure)
N = xx
Total
N = xx
xx
xx
xx
Xx
xx
3.3.
Strata and Covariates
No planned analyses using strata and/or covariates.
3.4.
Examination of Subject Subsets
No planned subset analyses.
3.5.
Multiple Comparisons
Not applicable.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
The handling of missing or incomplete date for AE onset is described in Section 7.1.5.2, and for
prior medication and concomitant medications in Section 7.4.
I 
I 


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3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.7.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:

If only month and year of birth is collected, then “15” will be imputed as the day of birth

If only year of birth is collected, then “01 July” will be imputed as the day and month of birth

If year of birth is missing, then date of birth will not be imputed
In general, age (in years) collected at Study Day 1 (the first dosing date of study drug) will be 
used for analyses and presented in listings. If age at Study Day 1 is not available for a subject,
age derived based on date of birth and the Day 1 visit date will be used instead. If an enrolled 
subject was not dosed with study drug, the enrollment date will be used instead of the Day 1 visit 
date. For screen failures, the date the first informed consent was signed will be used for the age 
derivation. Age required for longitudinal and temporal calculations and analyses (eg, estimates of 
creatinine clearance, age at date of AE) will be based on age derived from date of birth and the 
date of the measurement or event, unless otherwise specified.
Non-PK laboratory data that are continuous in nature but are less than the lower limit of 
quantitation (LOQ) or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “x” (where x is considered the LOQ). For example, if the 
values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or 
< 0.1, etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be 
used to calculate summary statistics.

A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “> x” (where x is considered the LOQ). Values with decimal 
points will follow the same logic as above.

The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of 
“≤ x” or “≥ x” (where x is considered the LOQ).
Concentration values that are below the limit of quantitation (BLQ) will be presented as “BLQ” 
in the concentration data listing. Values that are BLQ will be treated as 0 at predose time points, 
and one half the value of the LOQ at postdose time points for summary purposes. Concentration 
values that are BLQ will be imputed as one-half LOQ before log transformation. 


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3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the first dosing date of study drug and derived as follows:

For post-treatment study days: Assessment Date First Dosing Date + 1

For days prior to the first dose: Assessment Date First Dosing Date
Therefore, Study Day 1 is the day of first dose of study drug administration. 
Baseline is defined as the last non-missing record on or prior to the date/time of the first dose of 
study drug, unless otherwise specified.
3.8.2.
Analysis Windows
The nominal visit and related date as recorded on the CRF will be used when data are 
summarized by visit and no analysis window will be derived. Any data relating to unscheduled 
visits will not be assigned to a particular visit or time point. In listings, both visit names and 
dates will be presented. 


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by the grouping specified in Section 3.2 based 
on All Enrolled Analysis Set. The summary will present the number and percentage of subjects 
enrolled. For each column, the denominator for the percentage calculation will be the total 
number of subjects analyzed for that column.
A summary of subject disposition will be provided based on All Enrolled Analysis Set. This 
summary will present the number and percentage of subjects in the following categories:

Treated and Non-treated

ENTO discontinuations and reasons

Study discontinuations and reason
The denominator of the percentage calculation will be the total number of subjects in All 
Enrolled Analysis Set corresponding to that column. 
The by-subject listings will be provided by subject identification (ID) number in ascending order 
to support the above summary tables.
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug will be examined by assessing the total duration of exposure to 
study drug and the level of adherence to the study drug specified in the protocol. The summaries 
will be based on Safety Analysis Set.
4.2.1.
Duration of Exposure to Study Drug
Total duration of exposure to study drugs will be defined as last dosing date minus first dosing 
date plus 1, regardless of any temporary interruptions in study drug administration, and will be 
expressed in months using up to 1 decimal place (eg, 4.5 months). If the last study drug dosing
date is missing, the following rules will be followed:

If the study drug is permanently withdrawn, the latest date among the study drug end date, 
clinical visit date, laboratory sample collection date, and vital signs assessment date that 
occurred during the on-treatment period will be used. 

If the study drug completion status is unknown, the earlier of the date of death or database 
lock date for analysis will be used. 


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The total duration of exposure to study drug will be summarized using descriptive statistics and 
using the number and percentage of subjects exposed for at least 1 day, 1, 2, 3, 4, 6, 9, 
12 months, and every 6 months thereafter.
The number and percentage of subjects who have dose modification or dose interruption will
also be summarized.
4.2.2.
Adherence to Study Drug
By-subject listings of ENTO administration, accountability (dispenses and returns), and dose 
interruption/modification will be provided by subject ID number (in ascending order) and visit 
(in chronological order).
4.3.
Protocol Deviations
Subjects who do not meet the eligibility criteria for study entry but are enrolled in the study will 
be summarized regardless of whether they are exempted by the sponsor or not. The summary 
will present the number and percentage of subjects who do not meet at least 1 eligibility criterion 
and the number of subjects who do not meet specific criteria based on the All Enrolled Analysis 
Set. A by-subject listing will be provided for those subjects who do not meet at least 1 eligibility 
(inclusion or exclusion) criterion. The listing will present the eligibility criterion (or criteria if 
more than 1 deviation) that subjects do not meet and related comments, if collected.
Protocol deviations occurring after subjects enter the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation reason (eg, nonadherence to study drug, violation of select inclusion/exclusion criteria) 
will be summarized for the All Enrolled Analysis Set. A by-subject listing will be provided for 
those subjects with important protocol deviation.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics
Subject demographic variables (ie, age, sex, race, and ethnicity) and baseline characteristics 
(body weight [in kg], height [in cm], body mass index [BMI; in kg/m2]) will be summarized 
using descriptive statistics for continuous variables and using number and percentage of subjects 
for categorical variables. The summary of demographic data will be provided for the FAS.
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include Karnofsky performance status and creatinine clearance 
(mL/min). These baseline characteristics will be summarized using descriptive statistics for 
continuous variables and using number and percentage of subjects for categorical variables. The 
summary of these baseline characteristics will be provided for the FAS. No formal statistical 
testing is planned.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Medical History
Medical history will be collected at screening for the disease-specific and general conditions 
(ie, conditions not specific to the disease being studied).
Disease-specific medical history will be summarized by the number and percentage of subjects 
with each prepopulated condition. The summary will be provided for the FAS. No formal 
statistical testing is planned. Time since diagnosis (years) will be calculated by (date of the first 
dosing date of study drug date of diagnosis)/365.25. Time since diagnosis will be summarized 
using summary statistics for a continuous variable. Disease stage at diagnosis and at screening 
will be summarized using summary statistics for a categorical variable. No formal statistical 
testing is planned. A by-subject listing of disease-specific medical history will be provided by 
subject ID number in ascending order.
In deriving the time since diagnosis, all partial dates of diagnosis and last regimen will be 
identified, and the partial dates will be imputed as follows:

If day and month are missing but year is available, then the imputed day and month will be 
01 Jan.

If day is missing but the month and year are available, then the imputed day will be the first 
day of the month.

Partial date will not be imputed if the year is missing.


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General medical history data will not be coded but will be listed only. A by-subject listing of 
general medical history will be provided by subject ID number in ascending order.
5.4.
Prior Anticancer Therapy
Number of prior regimens and time since the completion of the last regimen will be summarized 
using descriptive statistics based on the FAS. A partial completion date will be imputed using the 
algorithm defined in Section 5.3.
For the cohorts of CLL after BCR Targeted Therapy, prior BCR therapy, time since treatment 
failure, treatment failure reason, and best clinical response will be summarized. 
A by-subject listing of prior anticancer therapy will be provided by subject ID number in 
ascending order.


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6.
EFFICACY ANALYSES
6.1.
Primary Efficacy Endpoint
6.1.1.
Definition of the Primary Efficacy Endpoint
The primary efficacy endpoint of this study is PFS rate at 16 weeks (CLL after BCR targeted 
therapy, MCL, and DLBCL) or 24 weeks (CLL and iNHL). PFS is defined as the interval from 
the first dose of ENTO to the earlier of the first documentation of definitive disease progression 
or death from any cause. 
The determination of NHL response and progression (defined in the Protocol Section 6.20) is 
based on standardized criteria {Cheson 2007, Rourke 2010} as specifically modified for this 
study to reflect the biology of the diseases under study and the pharmacology of ENTO and the 
methods to be used in evaluation. The determination of CLL response and progression
(defined in the Protocol Section 6.21) is based on standardized IWCLL criteria {Hallek 2008} as 
specifically modified for this study considering the pharmacology of ENTO and the methods to 
be used in evaluation. 
In accordance with the Gilead Protocol 339-0102 Imaging Charter, if there is uncertainty 
regarding whether there is true progression, the subject may continue study treatment and remain 
under close observation (eg, evaluated at 4-week intervals). If subsequent evaluations suggest 
that the subject is experiencing progression, then the date of progression should be the time point 
at which progression was first identified. A single PD determination followed by a determination 
that indicated either no change or improvement in disease prior to the single PD observation will 
not be considered as PD. 
Subjects without progression or death will be censored at the last adequate post-baseline tumor 
assessment time. If subjects receive other anti-cancer therapy or have ≥ 2 consecutive missing 
post-baseline tumor assessments immediately before documented progression or death, they will 
be censored at the last adequate post-baseline tumor assessment time before starting anti-cancer 
therapy or before ≥ 2 consecutive missing tumor assessments whichever is earlier. If subjects 
don’t have adequate baseline tumor assessment or adequate post-baseline tumor assessment, they 
will be censored on the date of Study Day 1 unless subjects die before or on the 2nd scheduled 
post-baseline tumor assessment without receiving other anti-cancer therapy. Please see
Appendix 2 for details on PFS event and censoring time derivation.
The findings of the IRC will be considered primary for analyses of PFS rate. The findings of 
investigator assessment will be provided in the listing.
6.1.2.
Analysis of the Primary Efficacy Endpoint
The primary analysis of PFS will be performed using the Kaplan-Meier (KM) method based on 
IRC response assessments for the FAS. Medians, Q1, Q3 of the PFS distributions, and the 
proportion of subjects who are progression-free at Week 16 (for CLL after BCR targeted 
therapy, MCL, and DLBCL) and Week 24 (for CLL and iNHL) from the first dosing date will be 


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provided along with corresponding 95% confidence intervals (CIs). The loglog transformation 
will be used to compute the CIs. 
PFS rate of the CLL prior BTK inhibitor exposure and CLL prior PI3K inhibitor exposure 
cohorts will be estimated separately. PFS rate of the CLL dose ranging cohort will be estimated 
by dose levels. 
6.2.
Secondary Efficacy Endpoint
6.2.1.
Definition of Secondary Efficacy Endpoints
Same as the primary efficacy endpoint analysis, the response assessments by IRC will be used
for the secondary efficacy endpoints’ analyses based on the FAS. The response assessments after 
other anti-cancer therapy (if they are available) won’t be included for secondary efficacy 
endpoints analyses. 

Objective response rate (ORR).
Best overall response (BOR) of complete response (CR), partial response (PR), stable disease 
(SD), progressive disease (PD), not evaluable (NE), no disease (ND), and not applicable (NA) is 
allowed. For subjects with LPL/WM, a very good partial response (VGPR) or minor response 
(MR) is also allowed. Again, a single PD determination followed by a determination that 
indicated either no change or improvement in disease prior to the single PD observation will not 
be considered as PD.
ORR is defined as the proportion of subjects with BOR during ENTO therapy of CR or PR 
(or VGPR or MR for subjects with LPL/WM). Subjects who do not have sufficient baseline 
tumor assessment, whose on-study tumor status information is not adequate for response status 
assessment or who received new anti-cancer therapy prior to achieving CR or PR (or VGPR or 
MR for subjects with LPL/WM), will be considered as non-responders.

Duration of response (DOR). 
DOR is defined as the interval from the first time when the objective response (CR or PR [or 
VGPR or MR for subjects with LPL/WM]) is achieved to the earlier of the first documentation of 
definitive disease progression or death from any cause. 

Time to response (TTR). 
TTR is defined as the interval from the first dose of ENTO to the first time when the response 
(CR or PR [or VGPR or MR for subjects with LPL/WM]) is achieved.  


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6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
6.2.2.1.
Objective Response Rate
ORR and 95% CIs will be summarized. The number and proportion of subjects whose best 
overall response were evaluated as CR, PR, VGPR, MR, SD, PD, NE, ND, and NA will also be 
tabulated.
Both IRC and investigator’s response assessments will be presented in by-subject listings.
6.2.2.2.
Duration of Response 
DOR analysis will be conducted in the responding subjects of FAS set. Responding subjects are 
those who achieve a CR or PR (or VGPR/MR for LPL/WM subjects). The censoring rule is same 
as PFS analyses (see Appendix 2).
DOR will be summarized using the KM method. The KM estimates of the DOR survival 
function will be presented. The median of DOR will be provided along with the corresponding
95% CIs. Additionally, the Q1 and Q3 will also be provided. The log-log transformation will be 
used to compute the CIs.
6.2.2.3.
Time to Response
TTR analysis will be conducted in the responding subjects in FAS. Responding subjects are 
those who achieve a CR or PR (or VGPR/MR for LPL/WM subjects). TTR will be summarized 
using descriptive statistics.
6.3.
Changes from Protocol-Specified Efficacy Analyses
The study final CSR is determined in synoptic version. The sensitivity analyses will not be 
performed. 


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7.
SAFETY ANALYSES
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of 
MedDRA. System organ class (SOC), high-level group term (HLGT), high-level term (HLT), 
preferred term (PT), and lower-level term (LLT) will be provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, 4, or 5 according to CTCAE 
Version 4.03{U.S. Department of Health and Human Services 2010}. The severity grade of 
events for which the investigator did not record severity will be categorized as “missing” for 
tabular summaries and data listings. The missing category will be listed last in summary 
presentation.
Severity of adverse events will be determined by the investigator as mild, moderate, or severe. 
The severity of events for which the investigator did not record severity will be categorized as 
“missing” for tabular summaries and data listings. The missing category will be listed last in 
summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the investigator’s 
choice, not that of the medical monitor. Events for which the investigator did not record 
relationship to study drug will be considered related to study drug for summary purposes. 
However, by-subject data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definitions of SAEs that were specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAE database from the Gilead Pharmacovigilance 
and Epidemiology Department before data finalization.
7.1.5.
Treatment-Emergent Adverse Events
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug


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
Any AEs leading to premature discontinuation of study drug.
7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the first dosing date of 
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of study drug 
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
In case when the AE onset date is incomplete and needs to be imputed, the following algorithm 
will be followed:

If the day is missing but the month and year are available, then the imputed day will be the 
first day of the month or the first dosing date if they have the same month and year, 
whichever is later.

If the day and month are missing but year is available, then the imputed day and month will 
be 01Jan or the first dosing date if they have the same year, whichever is later.
7.1.6.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the Safety Analysis Set.
7.1.6.1.
Summaries of AE Incidence by Severity
The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC, and PT. For the AE categorizes described below, summaries will be 
provided by SOC, PT, and maximum severity (if applicable):

TEAEs

TEAEs of Grade 3 or higher

TE treatment-related AEs

TE Treatment-related AEs with Grade 3 or higher


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
TE SAEs

TE treatment-related SAEs

TEAEs leading to discontinuation of study drug

TEAEs leading to death

TEAEs leading to dose interruption of study drug

TEAEs leading to dose reduction of study drug
A brief, high-level summary of AEs described above will be provided by treatment group and by 
the number and percentage of subjects who experienced the above AEs.
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC and then by PT in descending order of 
total frequency within each SOC. For summaries by severity, the most severe severity will be 
used for those AEs that occurred more than once in a given subject during the study.
In addition to the above summary tables, TEAEs, TEAEs of Grade 3 or higher, TE 
treatment-related AEs, and TE SAEs will be summarized by PT only in descending order of total 
frequency.
In addition, data listings will be provided for the following:

All AEs, indicating whether the event is treatment emergent

All SAEs

Deaths

All AEs leading to death

All AEs leading to discontinuation of study drug

All AEs leading to dose interruption of study drug

All AEs leading to dose reduction of study drug
7.1.6.2.
Summary of Deaths
A summary (number and percentage of subjects) of deaths will be provided by presenting the 
following categories:

All deaths

Deaths within 30 days of the last dosing of study drug

Deaths beyond 30 days of the last dosing of study drug


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7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days 
for subjects who have permanently discontinued study drug, or all available data at the time of 
the database snapshot for subjects who were ongoing at the time of an interim analysis. The 
analysis will be based on values reported in conventional units. When values are below the LOQ, 
they will be listed as such, and the closest imputed value will be used for the purpose of 
calculating summary statistics as specified in Section 3.7. Hemolized test results will not be 
included in the analysis, but they will be listed in by-subject laboratory listings.
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology and serum chemistry separately. Values falling outside of the 
relevant reference range and/or having a severity grade of 1 or higher on CTCAE severity grade 
will be flagged in the data listings, as appropriate.
7.2.1.
Graded Laboratory Values
CTCAE Version 4.03 will be used to assign toxicity grades (0 to 4) to laboratory results for 
analysis. Grade 0 includes all values that do not meet the criteria for an abnormality of at least 
Grade 1. For laboratory tests with criteria for both increased and decreased levels, analyses for 
each direction (ie, increased, decreased) will be presented separately. Local labs will be graded
based on the central lab normal ranges with in-house macro. For the event that both central and 
local lab results are collected in the clinical database, the worst toxicity grade will be used for the 
summary of lab toxicities. All central and local laboratory values will be listed.
7.2.1.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days for subjects who permanently discontinued study drug, or the 
last available date in the database snapshot for subjects who were still on treatment at the time of 
an interim analysis. If the relevant baseline laboratory value is missing, any abnormality of at 
least Grade 1 observed within the time frame specified above will be considered treatment 
emergent.
7.2.1.2.
Summaries of Laboratory Abnormalities
The following summaries (number and percentage of subjects) for laboratory abnormalities will 
be provided by lab test:

Baseline grade (Grade 0 to 4 separately, Grade 3 or 4, Grade 1 to 4, and Missing)

Worst treatment-emergent laboratory abnormalities postbaseline grade (Grade 1 to 
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The summary of the baseline abnormalities will use the number of subjects in the Safety 
Analysis Set as the denominator. The summary of the worst treatment-emergent laboratory 
abnormalities postbaseline is the number of subjects with nonmissing postbaseline values up to 
30 days after the last dosing date of the study drug. 
A by-subject listing of treatment-emergent Grade 3 or 4 laboratory abnormalities will be 
provided by subject ID number and visit in chronological order. This listing will include all test 
results that were collected throughout the study for the lab test of interest, with all applicable 
severity grades displayed.
7.2.2.
Shift in Relative to the Baseline
Shift tables will be presented by showing change in severity grade from baseline to the worst 
grade postbaseline.
7.3.
Body Weight and Vital Signs
A by-subject listing of body weight and vital signs will be provided by subject ID number and 
visit in chronological order. High or low values for vital signs will be flagged.
7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary.
7.4.1.
Prior Medications
Prior medications are defined as any medications taken before a subject took the first study drug.
Prior medications will be summarized by Anatomical Therapeutic Chemical (ATC) drug class 
Level 2 and preferred name using the number and percentage of subjects for each treatment 
group and overall. A subject reporting the same medication more than once will be counted only 
once when calculating the number and percentage of subjects who received that medication. The 
summary will be ordered alphabetically by ATC medical class and then by preferred term in 
order of descending overall frequency within each ATC medical class. For drugs with the same 
frequency, sorting will be done alphabetically.
For the purposes of analysis, any medication with a start date prior to the first dosing date of 
study drug will be included in the prior medication summary regardless of when the stop date is. 
If a partial start date is entered the medication will be considered prior unless the month and year 
(if day is missing) or year (if day and month are missing) of the start date are after the first 
dosing date. Medications with a completely missing start date will be included in the prior 
medication summary, unless otherwise specified.
Summaries will be based on the Safety Analysis Set. No formal statistical testing is planned.


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7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a subject took study drug. Use 
of concomitant medications will be summarized by ATC drug class Level 2 and preferred name 
using the number and percentage of subjects for each treatment group. A subject reporting the 
same medication more than once will be counted only once when calculating the number and 
percentage of subjects who received that medication. The summary will be ordered 
alphabetically by ATC medical class and then by preferred term in descending overall frequency 
within each ATC medical class. For drugs with the same frequency, sorting will be done 
alphabetically.
For the purposes of analysis, any medications with a start date prior to or on the first dosing date 
of study drug and continued to be taken after the first dosing date, or started after the first dosing 
date but prior to or on the last dosing date of study drug will be considered concomitant 
medications. Medications started and stopped on the same day as the first dosing date or the last 
dosing date of study drug will also be considered concomitant. Medications with a stop date prior 
to the date of first dosing date of study drug or a start date after the last dosing date of study drug 
will be excluded from the concomitant medication summary. If a partial stop date is entered, any 
medication with the month and year (if day is missing) or year (if day and month are missing) 
prior to the date of first study drug administration will be excluded from the concomitant 
medication summary. If a partial start date is entered, any medication with the month and year 
(if day is missing) or year (if day and month are missing) after the study drug stop date will be 
excluded from the concomitant medication summary. Medications with completely missing start 
and stop dates will be included in the concomitant medication summary, unless otherwise 
specified. Summaries will be based on the Safety Analysis Set. No formal statistical testing is 
planned.
All concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.  
All prior and concomitant medications (other than per-protocol study drugs) will be provided in a 
by-subject listing sorted by subject ID number and administration date in chronological order.
7.5.
Electrocardiogram (ECG) Results
Twelve (12)-lead ECGs reporting ventricular rate, PR, QRS, QT, and QTc intervals will be 
obtained at screening, safety monitoring visits and, if clinically indicated, during the course of 
the study.
ECG data including heart rate-corrected QT intervals (ie. corrected by Bazett’s formula (QTcB) 
and Fridericia’s formula (QTcF), will be presented in a by-subject listing sorted by subject ID 
number and exam date in chronological order. QTcB and QTcF will be derived as following 
formulas:

Bazett formula: QTcB
QT / (RR)1/2

Fridericia formula: QTcF
QT / (RR)1/3


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where QT is measured in milliseconds, and RR  60/Heart Rate (beats/min).
A by-subject listing of ECG results will be provided by subject ID number and visit in 
chronological order.
7.6.
Post Treatment Anti-Cancer Therapies
All post treatment anti-cancer therapies (other than those allowed per-protocol) will be provided 
in a by-subject listing sorted by subject ID number and administration date in chronological 
order.
A summary of post treatment anti-cancer therapies will not be provided.
7.7.
Changes from Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC (PK) ANALYSES
Plasma samples will be collected for concentrations of ENTO at protocol specified time points. 
Concentration of ENTO in plasma will be determined using a validated bioanalytical assay.
8.1.
Statistical Analysis Methods
8.1.1.
Plasma Concentration
Individual subject concentration data will be listed and summarized using descriptive statistics. 
Summary statistics (n, mean, StD, coefficient of variation [%CV], median, min, max, Q1, and 
Q3) will be presented by time point. Moreover, the geometric mean, 95% CI of the natural 
log-transformed values will be presented.
Individual concentration data listings and summaries will include all subjects in PK Analysis 
Set. The sample size for each time point will be based on the number of subjects with 
nonmissing concentration data at that time point. The number of subjects with concentration 
BLQ will be presented for each time point. For summary statistics, BLQ values will be treated as 
0 at predose and one-half of the lower LOQ for postdose time points. 
The listing of PK plasma concentrations sampling details by subject including deviations in 
scheduled and actual draw time and procedures will be provided.


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PHARMACODYNAMIC (PD) ANALSES 
In the synoptic CSR, the following exploratory endpoints of PD will not be provided: 
I 
I 
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10.
REFERENCES
U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse
Events (CTCAE). Version 4.0 (Published: May 28, 2009). v4.03 (Published: June 14, 2010) NIH 
Publication No. 09-5410. 2010.
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol 2007;25 (5):579-86.
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, et al. Guidelines 
for the diagnosis and treatment of chronic lymphocytic leukemia: a report from 
the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 
updating the National Cancer Institute-Working Group (NCI-WG) 1996 
guidelines. Blood 2008;111 (12):5446-56.
Rourke M, Anderson KC, Ghobrial IM. Review of clinical trials conducted in Waldenstrom 
macroglobulinemia and recommendations for reporting clinical trial responses in 
these patients. Leuk Lymphoma 2010;51 (10):1779-92.


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11.
SOFTWARE
SAS® Software Version 9.4 or higher, SAS Institute Inc., Cary, NC, USA.


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12.
SAP REVISION
Revision Date
(dd month, yyyy)
Section
Summary of Revision
Reason for Revision


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13.
APPENDICES
Appendix 1.
Schedule of Assessments
Study Phase
Screening
Cycle 1
(28 days)
Subsequent 
Cycles
(28 days)
Safety 
Monitoring 
Visits
Tumor Response 
Assessments
Disease 
Progression or 
EOSc
30-Day 
Follow Up
Cycle Day
Screening
1
1
Variesa
Q8 or 12 wks or 
6 monthsb
N/A
Window
-35
±2 days
±2 days
N/A
Study Assessments
Informed Consent
X
Medical History
X
Physical Examd
X
X
X
X
X
Vital Signse
X
X
X
X
X
12-lead ECG
X
X
Karnofsky Performance Status
X
X
X
X
X
Prior/Concomitant Meds
X
X
X
X
X
AEsf
X
X
X
X
X
X
CT or MRI
Xg
Xh
Xi
Bone Marrow Biopsy and Aspirate
Xj
Xj
DLBCL Subtypingk
X
Collect Archival Tumor Tissue (if available)
Xl
Complete Subject/Visit info in IxRS
X
X
X
X


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Study Phase
Screening
Cycle 1
(28 days)
Subsequent 
Cycles
(28 days)
Safety 
Monitoring 
Visits
Tumor Response 
Assessments
Disease 
Progression or 
EOSc
30-Day 
Follow Up
Cycle Day
Screening
1
1
Variesa
Q8 or 12 wks or 
6 monthsb
N/A
Window
-35
±2 days
±2 days
N/A
Sample Collection
Chemistry
X
X
Xx
X
X
Beta-2-microglobulin
X
X
X
Hematology 
X
X
Xx
X
X
Coagulation
X
X
Xx
X
X
Urinalysis
X
X
X
HBV, HCV and HIV Virology
X
Pregnancy Testn
X
X
X
X
X
GS-9973 Plasma Concentrationo, p, v
X
X
X
X
Buccal Swabu
X
Serum monoclonal IgM SPEP/IFE and 
cryoglobulin testingq
X
X
Study Drug Dosing 
GS-9973 up to 800 mg BID Fasting or 100, 
200 or 400 mg GS-9973 SDD BID Fasting
X
X
Dispense Study Drug
X
X
Study Drug Compliancer
X
X
X
Collect Used/Unused Study Drugw
X
X
For CLL, SLL and MCL subjects only
CCI
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Study Phase
Screening
Cycle 1
(28 days)
Subsequent 
Cycles
(28 days)
Safety 
Monitoring 
Visits
Tumor Response 
Assessments
Disease 
Progression or 
EOSc
30-Day 
Follow Up
Cycle Day
Screening
1
1
Variesa
Q8 or 12 wks or 
6 monthsb
N/A
Window
-35
±2 days
±2 days
N/A
Cytokines and Chemokines
Xm
Xm
Xm
X
CTC Molecular Characterization
X
Xs
X
CTC RNAw
Xw
Xw
Xw
CLL ONLY:  Pharmacodynamic 
Measurements (BAT Assay)
Xt
CLL ONLY: Pharmacogenomic Testing
X
Xs
X
a
Days 8, 15, and 22 of Cycle 1 and Day 15 of Cycle 2
b
Tumor assessments will be performed every 8 weeks during the first 24 weeks of the study and then every 12 weeks thereafter regardless of cycle number and regardless of 
dose interruptions.  Tumor assessments may be performed at other timepoints during the treatment phase as clinically indicated (to assess tumor progression).  After week 72 
scans will occur at least every 6 months (± 4 weeks).  The same evaluation procedures must be used throughout the study for each subject.  Scans should be of high quality
and digitalized in the DICOM format to allow for reading at a centralized facility.
c
If a subject stops study drug for a reason other than progressive disease and consistent with good medical practice, they will be followed as per the scheduled imaging in 
Section 6.5 with additional CBC (hematology) at time of assessments.
d
Complete physical examination will be performed at Screening and at Disease Progression or EOS. A modified physical examination capturing changes from prior exams will 
be performed at other visits. Weight should be measured (in kilograms) at each physical examination. Height will be measured (in centimeters) at Screening only.
e
Vital signs (including blood pressure, respiratory rate, pulse, oxygen saturation by pulse oximetry and temperature) should be taken after the subject has been sitting for at 
least 5 minutes.
f
Adverse events will be assessed once ICF is signed, pre and post dose during applicable clinic visits, and 30 (±7) days following completion of the subject’s last dose of 
study drug.  Subjects should be contacted by phone (or in person, if necessary) 30 days (± 7 days) after the subject’s last dose of study drug to assess AEs.  Subjects should 
specifically be asked about the development of any adverse events since stopping the study.
g
CT or MRI scans of neck, chest, abdomen, and pelvis taken as part of standard medical practice up to 35days prior to Day 1 of Cycle 1 visit are acceptable for use at the 
Screening.  Subjects with LPL/WM who previously failed screening for this study, due to an absence of lymphadenopathy on CT or MRI scans, do not need to be re scanned 
if the scans were performed within 16 weeks of first study drug administration to meet eligibility criteria.
h
At all timepoints after Screening imaging of the chest, abdomen, and pelvis will be required.  Imaging of the neck is required at each follow up time point if the neck scan was 
positive at baseline or if palpable neck lymphadenopathy appears during the course of the study.
i
Tumor evaluations should be conducted at the End of Study Visit if not conducted in the previous 4 weeks. If a subject permanently discontinues study drug prior to objective 
documentation of progression, investigators should continue further follow up at the ~8 or ~12 week intervals until progression is documented.
j
A bone marrow biopsy and aspirate will be collected for all subjects who achieve a CR for confirmatory purpose.  For CLL subjects a bone marrow biopsy/aspirate will be 
collected to confirm a PD.  If the subject does not otherwise meet criteria for CR or if the nature of PD does not require bone marrow confirmations, it is not necessary to 
obtain a bone marrow biopsy/aspirate (See Sections 6.18 and 6.20).


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k
If the subject has DLBCL, subtyping is required.  Submission of 15 unstained slides is required for subtyping if the subtype is not already known.  Subjects for whom tissue is 
not available but the subtype is already known may be included if approved by the Medical Monitor following discussion with the investigator.
l
Fifteen recently prepared unstained slides from archival tumor tissues will be collected. Efforts to acquire tissue sample should begin on Day 1 of Cycle 1.
m
Collect on Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1 and Cycle 12, Day 1 only
n
For females of childbearing potential, a serum pregnancy test will be performed at Screening and urine pregnancy tests will be performed on Days 1 of each Cycle and Day 15 
of Cycles 1 & 2 and at EOS.
o
Record the approximate number of hours between the last 2 doses of GS 9973 and the time the blood samples for plasma concentration were obtained
p
GS 9973: PK samples will be collected on Day 1 of Cycle 1 pre dose, 1.5 hours post dose and 4 hours post dose; on Day 1 of Cycles 2 6 pre dose (12 hours post last dose).
q
GS 9973 SDD: PK samples will be collected on Day 1 of Cycle 1 pre dose, 1.5 hours post dose and 4 hours post dose; on Day 8 of Cycle 1 pre dose, 1.5 hours post dose and 
4 hours post dose; on Days 15 and 22 of Cycle 1 pre dose and 1.5 hours post dose; and on Day 1 of subsequent cycles pre dose and 1.5 hours post dose.
r
Subjects with LPL/WM only.  This procedure should be conducted on the Day 1 visit occurring during the week window allotted for tumor response assessments.
s
Includes date/time of last dose of GS 9973 (excluding Day 1 of Cycle 1)
t
Collect on Cycle 2, Day 15 only
u
On Day 1 of Cycle 1, samples will be collected pre dose, 1.5 hours post dose (± 10 minutes) and 4 hours post dose ((± 10 minutes); on cycle 1 day 8 (predose and 4 hours 
post dose) and cycle 1 day 15 (predose)
v
For CLL dose ranging, CLL prior BTK inhibitor exposure, or CLL prior PI3K inhibitor exposure cohorts only
w
Excluding subjects off study drug at time of progression
x
Samples will be collected pre dose on Cycle 1 Day 1, Cycle 12 Day 1 and at Disease Progression or EOS only
y
May be collected up to 2 days prior to the Day 1 visit


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Appendix 2.
PFS Definition and Derivation Diagram
Progression-free survival (PFS) is defined as the interval from the first dosing date of study drug 
to the earlier of the first documentation of definitive disease progression or death from any cause. 
Definitive disease progression for NHL is defined in the Protocol Section 6.20 based on 
standardized criteria {Cheson 2007, Rourke 2010} as specifically modified for this study to 
reflect the biology of the diseases under study and the pharmacology of study drug and the 
methods to be used in evaluation. The determination of CLL response and progression is defined 
in the Protocol Section 6.21 based on standardized IWCLL criteria {Hallek 2008} as specifically 
modified for this study considering the pharmacology of ENTO and the methods to be used in 
evaluation. The progression should be identified by relevant radiographic imaging assessments
and pertinent clinical data by IRC and investigators. For this study, the IRC assessments will be 
used as primary PFS analyses. The date of definitive progression will be the time point at which 
progression is first identified. The death from any cause to be considered as PFS event should 
occur within the time window of 2 consecutive scheduled post-baseline tumor assessments after 
the last tumor assessment. 
Subjects without progression or death will be censored at the last adequate post-baseline tumor 
assessment time. The adequate tumor assessments for determining censoring dates include 
complete response (CR), partial response (PR), minor response (MR), stable disease (SD), 
progressive disease (PD), and very good partial response (VGPR) or minor response (MR) for 
subjects with LPL/WM. Non-evaluable (NE), not assessed, and not applicable are considered as 
not adequate. 
Subjects will be censored on the date of Study Day 1 if

no adequate baseline tumor assessment is available and subject didn’t die before or on the 
2nd scheduled post-baseline tumor assessment without receiving anti-cancer therapy; 

or if no adequate post-baseline tumor assessment is available and subjects didn’t die

or if no adequate post-baseline tumor assessment is available and subjects died after the 2nd
scheduled tumor assessment. 
Subjects will be censored on the date of last adequate post-baseline tumor assessment, or Study 
Day 1 if the last adequate post-baseline tumor assessment doesn’t exist, for the following 
situations:

who do not have documented progression or die, or 

who start new anti-cancer therapy before documented progression, or

who start new anti-cancer therapy before death without documented progression, or

who have ≥ 2 consecutive missing post-baseline tumor assessments immediately before 
documented progression, or


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
who have ≥ 2 consecutive missing post-baseline tumor assessments immediately before death 
without documented progression
Table 13-1 below lists detailed event/censoring scheme for PFS derivation and the derivation
diagram lists all decisions on event/censoring indicators and time. 
Table 13-1.
Event/Censoring Scheme of Analysis for PFS
PFS 
Derivation 
Step
Situation
Date of 
Progression or 
Censoring
Outcome
1
No adequate baseline tumor assessments and subjects didn’t 
die before or on the 2nd scheduled post-baseline tumor 
assessment
Study Day 1*
Censored 
1
No adequate baseline tumor assessments and subjects died 
before or on the 2nd scheduled post-baseline tumor assessment 
without receiving anti-cancer therapy
Date of death
Event
1
No adequate baseline tumor assessments, subjects died before 
or on the 2nd scheduled post-baseline tumor assessment and
received anti-cancer therapy
Study Day 1*
Censored 
2
No adequate post-baseline tumor assessments and subjects did 
not die 
Study Day 1
Censored
2
No adequate post-baseline tumor assessments and subjects 
died after the 2nd scheduled post-baseline tumor assessment
Study Day 1
Censored
2
No adequate post-baseline tumor assessments and subjects 
died before or on the 2nd scheduled post-baseline tumor 
assessment without receiving anti-cancer therapy
Date of death
Event
2
No adequate post-baseline tumor assessments, subjects died 
before the 2nd scheduled post-baseline tumor assessment and 
received anti-cancer therapy
Study Day 1
Censored
3
Documented progression and didn’t receive anti-cancer 
therapy or have ≥ 2 consecutive missing post-baseline tumor 
assessments immediately before documented progression
Date of the first 
documented 
progression
Event
3
Death without progression and within the time window of 
2 consecutive scheduled post-baseline tumor assessments after 
the last tumor assessment and didn’t receive anti-cancer 
therapy or have ≥ 2 consecutive missing post-baseline tumor 
assessments immediately before death
Date of death
Event
3
No documented progression or death and 
didn’t receive anti-cancer therapy or have ≥ 2 consecutive 
missing post-baseline tumor assessments 
Date of the last 
adequate 
post-baseline 
tumor 
assessment
Censored


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PFS 
Derivation 
Step
Situation
Date of 
Progression or 
Censoring
Outcome
4
Start new anti-cancer therapy without or before documented 
progression or death or have ≥ 2 consecutive missing 
post-baseline tumor assessments immediately before 
documented progression or death
The later one 
of
1) Date of the 
last adequate 
post-baseline 
tumor 
assessment 
on/prior to the 
new 
anti-cancer 
therapy start 
date and/or the 
consecutive 
missing
2) Study Day 1
Censored
* Study Day 1 is the day of first dose of study drug administration.
When the date of initiation of anti-cancer therapy other than the study treatment is incomplete or 
missing, the following algorithm will be followed:

If the day is missing but the month and year are available, then the imputed day will be the 
first day of the month.

If day and month are missing but year is available, then the imputed day and month will be 
01Jan or the last day of the month for the last adequate disease assessment if they have the 
same year, whichever is later.


Entospletinib
GS-US-339-0102 Statistical Analysis Plan
Version 1.0
CONFIDENTIAL
Page 42
16SEP2019
Progression 
nd/or Death* 
Yes 
No 
Indicator =Event; 
Set ADT+ as the earlier 
date of progression 
and/or death* 
Indicator= Censor; 
Set ADT as the last 
adequate post-
baseline tumor 
assessment date; If 
there is no such date, 
set as Study Day 1" 
Progression Free Survival Derivation Diagram 
Apply to both events 
and censors; 
Set the indicator to 
censor and ADT to 
Study Day 1 
Yes 
No adequate 
baseline tumor assessment 
and didn't die before or on the 
2nd scheduled post-baseline 
tumor assessment? 
No 
Apply to both events 
and censors; 
Set the indicator to 
censor and ADT to the 
last adequate 
post-baseline tumor 
assessment date 
before anti-cancer 
therapy; if there is no 
such date, set as 
Study Day 1 
, 
Yes 
Received anti-cancer 
therapy before the current 
ADT? 
No 
Only apply to events; 
Change the indicator 
to censor and ADT to 
the last adequate 
post-baseline tumor 
assessment date 
before >= 2 
consecutive missing; 
if there is no such 
date, set as 
Study Day 1 
, 
Yes 
Have >=2 
consecutive missing post-
baseline tumor assessments 
immediately before 
rogression/ death (i.e., 
ADT for events)? 
* Death should occur within the time window of 2 consecutive scheduled post-baseline tumor assessments from the last tumor assessment. 
+ ADT: Analysis date 
/\ Study Day 1 is the randomization date of the randomized studies, or the 1st dosing date of the non-randomized studies. 


GS-US-339-0102 CSR Statistical Analysis Plan_v1.0
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Research eSigned 17-Sep-2019
17:37:29
Biostatistics eSigned
17-Sep-2019
21:25:26
PPD
PPD-