Clinical trial NCT02607228
Conditions: Metastatic Castrate-Resistant Prostate Cancer
Sponsor: Gilead Sciences
Start date: 2015-12-08; Completion date: 2019-09-03
Enrollment: 31 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study consists of two phases: Dose Escalation (Phase 1b) and Dose Expansion (Phase 2)

The Dose Escalation phase will characterize the safety, tolerability, and determine the maximum tolerated dose (MTD) of alobresib as a single agent and in combination with enzalutamide, in participants with metastatic castrate-resistant prostate cancer (mCRPC).

The Dose Expansion phase will evaluate the following:

* In group 1, the efficacy of alobresib as a single agent in participants with mCRPC who have progressed while receiving enzalutamide (may have also received abiraterone)
* In group 2, the efficacy of alobresib combined with enzalutamide in participants with mCRPC who have progressed while receiving treatment with abiraterone (may not have previously received enzalutamide)
* In group 3, the efficacy of alobresib combined with enzalutamide in participants with mCRPC who have had prostate specific antigen (PSA) progression, but not radiographic progression, while receiving treatment with enzalutamide (participants may have also previously received abiraterone)

Detailed description:

Arms: arm 1: Participants who have progressed on either abiraterone and/or enzalutamide will be enrolled to receive increasing doses of alobresib up to 9 mg to determine the MTD. arm 2: Following a two week lead-in with enzalutamide once daily, participants who have progressed on abiraterone will receive less than or equal to MTD of alobresib in combination with enzalutamide 160 mg once daily. Based on observed pharmacokinetics (PK) interaction, toxicity, and tolerability observed in the single agent dose escalation, the dose of alobresib may be increased. arm 3: Participants will receive a dose less than or equal to MTD of alobresib (based on safety, pharmacodynamics (PD), and tolerability). arm 4: Participants will receive a dose less than or equal to MTD of alobresib plus enzalutamide (based on safety, PD, and tolerability). arm 5: Participants will receive alobresib plus enzalutamide (dose will be equivalent to the dose chosen for Group 2).
Interventions: intervention 1: Alobresib intervention 2: Enzalutamide
Intervention descriptions: intervention 1: Tablet administered orally once daily. intervention 2: Capsules administered orally once daily.

Protocol documents:
Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Clinical Program 
Manager: 
Gilead Medical Monitor: 
Protocol Version/Date: 
GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 1 b/2 Study to Evaluate the Safety, Tolerability, 
Phaim acokinetics, and Phaim acodynamics of GS-5829 as a 
Single Agent and In Combination with Enzalutamide in Subjects 
with Metastatic Castrate-Resistant Prostate Cancer 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
124032 
2015-003741-26 
NCT02607228 
Metastatic Castrate-Resistant Prostate Cancer 
GS-US-350-1604 
Name: 
Telephone: 
Email: 
Name: 
Telephone: 
Fax: 
Mobile: 
Email: 
Original: 
Amendment 1: 
Amendment 2: 
IPIPD 
IPIPD 
PPU 
IPIPD 
IPIPD 
IPIPD 
IPIPD 
PPU 
22 April 2015 
16 September 2015 
30 June 2016 
CONFIDENTIALITY STATEMENT 
The info1mation contained in this doclllllent, 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 infonnation 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........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................20
1.
INTRODUCTION ..............................................................................................................................................22
1.1.
Background ............................................................................................................................................22
1.2.
GS-5829 .................................................................................................................................................23
1.2.1.
General Information .............................................................................................................23
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................24
1.2.3.
Clinical Trials of GS-5829 ...................................................................................................25
1.2.4.
Information about Enzalutamide..........................................................................................25
1.3.
Rationale for This Study ........................................................................................................................26
1.3.1.
Rationale for the Dose Selection..........................................................................................27
1.4.
Compliance ............................................................................................................................................28
1.5.
Risk/Benefit Assessment for the Study..................................................................................................28
2.
OBJECTIVES.....................................................................................................................................................30
3.
STUDY DESIGN................................................................................................................................................32
3.1.
Endpoints ...............................................................................................................................................32
3.2.
Study Design..........................................................................................................................................32
3.2.1.
Study Schema.......................................................................................................................36
3.3.
Study Treatments ...................................................................................................................................37
3.4.
Criteria for Discontinuation of Study Drug............................................................................................37
3.5.
Criteria for Removal from Study............................................................................................................38
4.
SUBJECT POPULATION..................................................................................................................................39
4.1.
Number of Subjects and Subject Selection ............................................................................................39
4.2.
Inclusion Criteria....................................................................................................................................39
4.3.
Exclusion Criteria...................................................................................................................................40
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................43
5.1.
Enrollment..............................................................................................................................................43
5.2.
Description and Handling of GS-5829 and Enzalutamide .....................................................................43
5.2.1.
Formulation..........................................................................................................................43
5.2.2.
Packaging and Labeling .......................................................................................................43
5.2.3.
Storage and Handling...........................................................................................................43
5.3.
Dosage and Administration of GS-5829 and Enzalutamide...................................................................44
5.3.1.
Dose Adjustment of GS-5829 ..............................................................................................45
5.3.2.
Dose Adjustment in Group 2: Combination of Enzalutamide and GS-5829........................45
5.4.
Prior and Concomitant Medications.......................................................................................................47
5.5.
Accountability for GS-5829 and Enzalutamide .....................................................................................48
5.5.1.
GS-5829 and Enzalutamide Return or Disposal...................................................................48
6.
STUDY PROCEDURES ....................................................................................................................................49
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................49
6.2.
Study Procedure Descriptions ................................................................................................................49
6.2.1.
Informed Consent.................................................................................................................50


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6.2.2. 
Medical Histoiy .................................................................................................................... 50 
6.2.3. 
Prior and Concoinitant Medications ..................................................................................... 50 
6.2.4. 
Physical Examination ........................................................................................................... 50 
6.2.5. 
Vital Signs ............................................................................................................................ 51 
6.2.6. 
Electrocardiograin ................................................................................................................ 51 
6.2.7. 
ECOG Perfonnance Status ................................................................................................... 51 
6.2.8. 
Adverse Events ..................................................................................................................... 51 
6. 2. 9. 
Disease Assessments ............................................................................................................ 51 
6.2.10. 
Laborato1y Assess1nents ....................................................................................................... 52 
6.2.11. 
Phamiacokinetic & Pharmacodynamic Samples .................................................................. 53 
6.3. 
Biomarker Testing .................................................................................................................................. 54 
6.3.1. 
Biomarker Sam les to Address the Stud ob·ectives .......................................................... 54 
6.4. 
Preti·eatinent Assessments ...................................................................................................................... 57 
6.4.1. 
Screening Visit. ..................................................................................................................... 57 
6.4.2. 
Re-Screening Criteria ........................................................................................................... 58 
6.5. 
Treatlnent Assess1nents .......................................................................................................................... 58 
6.5.1. 
StudyDayl .......................................................................................................................... 59 
6.5.2. 
Baseline Visit / Cycle 1 Day 1 (ClDl) ................................................................................ 59 
6.5.3. 
Cycle 1 Day 8, Day 15 and Day 22 (ClD8, C1Dl5, and C1D22) ....................................... 60 
6.5.4. 
Cycle 2 Day 1 (C2Dl) and Day 1 of Subsequent Cycles ..................................................... 61 
6.5.5. 
End ofTreatlnent (EOT) Visit .............................................................................................. 62 
6.6. 
Post-Treatment 30-Day Safety Follow-up Visit ..................................................................................... 63 
6.7. 
Long Te1m Survival Follow-Up ............................................................................................................. 63 
6.8. 
Unscheduled Visits ................................................................................................................................. 64 
6.9. 
Criteria for Discont.intiat.ion of Study Treatment.. ................................................................................... 64 
6.10. 
Post Study Care ...................................................................................................................................... 64 
6.11. 
Replace1nent of Subjects ........................................................................................................................ 64 
6.12. 
Protocol Deviations ................................................................................................................................ 64 
6.13. 
End ofStudy ........................................................................................................................................... 64 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................................................... 65 
7 .1. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events ................................. 65 
7 .1.1. 
Adverse Events ..................................................................................................................... 65 
7.1.2. 
Serious Adverse Events ........................................................................................................ 65 
7.1.3. 
Clinical Laborat.01y Abnonnalities and Other Abno1mal Assessments as 
Adverse Events or Serious Adverse Events ......................................................................... 67 
7.2. 
Assessment of Adverse Events and Serious Adverse Events ................................................................. 67 
7.2.1. 
Assessment. of Causality for Study Drngs and Procedw-es ................................................... 67 
7.2.2. 
Assess1nent. ofSeverity ........................................................................................................ 67 
7.3. 
Investigator Requirements and Inst111ct.ions for Repo1t ing Adverse Events and Serious 
Adverse Events to Gilead ....................................................... ................................................................ 68 
7 .3 .1. 
Requirements for Collect.ion Prior to Study Drng Initiation: ............................................... 68 
7.3.2. 
Adverse Events ..................................................................................................................... 68 
7.3.3. 
Serious Adverse Events ........................................................................................................ 69 
7 .3 .4. 
Electi·onic Serious Adverse Event ( eSAE) Repo1ting Process ............................................. 69 
7 .4. 
Gilead Repo1t ing Requirements ............................................................................................................. 70 
7.4.1. 
Reporting of Adverse Events Relating to the Prima1y Endpoint and Other 
Anticipated Medical Events in the Study Population ........................................................... 70 
7.5. 
Toxicity Management ............................................................................................................................ 70 
7.6. 
Special Situations Repo1ts ...................................................................................................................... 71 
7.6.1. 
Definitions of Special Situations .......................................................................................... 71 
7 .6.2. 
Instluctions for Reporting Special Situations ....................................................................... 72 
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8.
STATISTICAL CONSIDERATIONS................................................................................................................73
8.1.
Analysis Objectives and Endpoints........................................................................................................73
8.1.1.
Analysis Objectives..............................................................................................................73
8.1.2.
Primary Endpoint .................................................................................................................74
8.1.3.
Secondary Endpoint .............................................................................................................74
8.1.4.
Exploratory Endpoints..........................................................................................................75
8.2.
Analysis Conventions.............................................................................................................................75
8.2.1.
Analysis Sets ........................................................................................................................75
8.3.
Data Handling Conventions ...................................................................................................................76
8.4.
Demographic Data and Baseline Characteristics ...................................................................................76
8.5.
Efficacy Analysis ...................................................................................................................................76
8.6.
Safety Analysis.......................................................................................................................................76
8.6.1.
Extent of Exposure...............................................................................................................76
8.6.2.
Adverse Events.....................................................................................................................77
8.6.3.
Laboratory Evaluations ........................................................................................................77
8.7.
Pharmacokinetic Analysis......................................................................................................................78
8.8.
Biomarker Analysis................................................................................................................................78
8.9.
Sample Size............................................................................................................................................78
9.
RESPONSIBILITIES..........................................................................................................................................80
9.1.
Investigator Responsibilities ..................................................................................................................80
9.1.1.
Good Clinical Practice..........................................................................................................80
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................80
9.1.3.
Informed Consent.................................................................................................................81
9.1.4.
Confidentiality......................................................................................................................81
9.1.5.
Study Files and Retention of Records ..................................................................................81
9.1.6.
Case Report Forms...............................................................................................................83
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................83
9.1.8.
Inspections............................................................................................................................83
9.1.9.
Protocol Compliance............................................................................................................83
9.2.
Sponsor Responsibilities ........................................................................................................................84
9.2.1.
Protocol Modifications.........................................................................................................84
9.2.2.
Study Report and Publications .............................................................................................84
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................85
9.3.1.
Payment Reporting...............................................................................................................85
9.3.2.
Access to Information for Monitoring..................................................................................85
9.3.3.
Access to Information for Auditing or Inspections ..............................................................85
9.3.4.
Study Discontinuation..........................................................................................................85
10.
REFERENCES ...................................................................................................................................................86
11.
APPENDICES ....................................................................................................................................................89
Appendix 1.
Investigator Signature Page....................................................................................................90
Appendix 2.
Study Procedures Table – Phase 1b and 2 Monotherapy........................................................91
Appendix 3.
Study Procedures Table – Phase 1b and 2 Combination Therapy..........................................94
Appendix 4.
Criteria of Progression for Trial Eligibility by Disease Manifestation (PCWG2, 
JCO 2008)...............................................................................................................................98
Appendix 5.
On Study Outcome/Efficacy Criteria (PCWG2, JCO 2008) ..................................................99
Appendix 6.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03..................................100
Appendix 7.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................101
Appendix 8.
Performance Status Scoring System (ECOG) ......................................................................103


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Appendix 9.
Enzalutamide (Xtandi®) Prescribing Information.................................................................104
LIST OF IN-TEXT TABLES
Table 3-1.
Dose Escalation ......................................................................................................................32
Table 5-1.
Dose Reduction of GS-5829...................................................................................................45
Table 5-2.
Dose Reduction in Group 2: Combination of Enzalutamide and GS-5829 ............................46
Table 5-3.
Examples of Concomitant Medications Prohibited in this Study ...........................................47
Table 6-1.
Analytes..................................................................................................................................53
Table 7-1.
Grading of Adverse Event Severity........................................................................................68
LIST OF IN-TEXT FIGURES
Figure 1-1.
Mechanism of Action of GS-5829 to Reduce Transcription of MYC and AR Target 
Genes in Cancer Cells ............................................................................................................23
Figure 3-1.
Study Design and Treatment Schema.....................................................................................36


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 1b/2 Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of GS-5829 as a 
Single Agent and in Combination with Enzalutamide in Subjects with 
Metastatic Castrate-Resistant Prostate Cancer
IND Number:
EudraCT Number:
Clinical Trials.gov
Identifier:
124032
2015-003741-26
NCT02607228
Study Centers 
Planned:
Phase 1b: Approximately 4 centers in the United States
Phase 2:  Approximately  11 centers in the United States and 4 in the 
European Union
Objectives:
The primary objectives of this study are as follows:
Phase 1b Dose Escalation

To characterize the safety and tolerability of GS-5829 as a 
single agent and in combination with enzalutamide in subjects 
with metastatic castrate-resistant prostate cancer (mCRPC)

To determine the maximum tolerated dose (MTD) of GS-5829 as 
a single agent and in combination with enzalutamide in subjects 
with mCRPC
Phase 2 Dose Expansion

Group 1: To evaluate the efficacy of GS-5829 as a single agent in 
subjects with mCRPC  who have progressed while receiving 
enzalutamide (may have also received abiraterone) as measured 
by Progression Rate at Week 24 according to Prostate Cancer 
Working Group 2 (PCWG2) Criteria

Group 2: To evaluate the efficacy of GS-5829 combined with 
enzalutamide in subjects with mCRPC who have progressed while 
receiving treatment with abiraterone (may not have previously 
received enzalutamide) as measured by Progression Rate at 
Week 24 according to PCWG2 Criteria


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Protocol GS-US-350-1604 
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• 
Group 3: To evaluate the efficacy of GS-5829 combined with 
enzalutamide in subjects with mCRPC who have had Prostate 
Specific Antigen (PSA) progression, but not radiographic 
progression, while receiving treatment with enzalutamide 
(subjects may have also previously received abiraterone) as 
measured by Progression Rate at Week 24 according to PCWG2 
Criteria 
The secondaiy objectives of this study are as follows: 
Phase 1 b Dose Escalation 
• 
To evaluate the phannacokinetics (PK) of GS-5829 as a single 
agent and in combination with enzalutamide in subjects with 
mCRPC 
• 
To evaluate the efficacy of GS-5829 as a single agent and in 
combination with enzalutamide in subjects with mCRPC as 
measured by PCWG2 Criteria 
Phase 2 Dose Expansion 
• 
To evaluate the safety and tolerability of GS-5829 as a 
single agent and in combination with enzalutamide in subjects 
withmCRPC 
• 
Group 1: To evaluate the efficacy of GS-5829 in subjects with 
mCRPC who have progressed while receiving enzalutamide as 
measured by PSA at Week 12, progression-free survival (PFS) 
and overall survival (OS) 
• 
Group 2: To evaluate the efficacy of GS-5829 combined with 
enzalutamide in subjects with mCRPC who have progressed while 
receiving abiraterone as measured by PSA at Week 12, PFS and 
OS 
• 
Group 3: To evaluate the efficacy of GS-5829 combined with 
enzalutamide in subjects with mCRPC who have had PSA 
progression, but not radiographic progression, while receiving 
enzalutamide as measured by PSA at Week 12, PFS and OS 
The explorato1y objectives of this study are as follows: 
I 
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Study Design:
Phase 1b: This is an open-label, multicenter, sequential 
dose-escalation study to evaluate the safety, tolerability, PK, and 
pharmacodynamics (PD) of GS-5829 as a single agent, and combined 
with enzalutamide in subjects with metastatic castrate-resistant 
prostate cancer (mCRPC).
Dose Escalation of GS-5829
Subjects with mCRPC who have progressed on either abiraterone 
and/or enzalutamide will be sequentially enrolled at progressively 
higher dose levels to receive oral GS-5829 as a single agent 
once daily. Dose escalation [3+3] will be performed with cohort sizes 
of 3 to 6 subjects. Initially 3-4 subjects will be enrolled into each 
dose level. The study will be initiated at a dose level that has been 
demonstrated to be safe and tolerable in the ongoing Phase 1 study in 
patients with solid tumors and lymphomas (Study GS-US-350-1599).
Subjects will return to the clinic for frequent evaluation and 
monitoring as per Appendix 2 and Appendix 3.The doses for each 
monotherapy dose level are shown in the table below. 
Dose Level
Single agent GS -5829 (once daily)
1*
1.4 mg
2
2 mg
3
3 mg
4
4 mg
5
6 mg
6
9 mg
*
The initial dose level may be higher than dose level 1, depending on results in Study 
GS-US-350-1599
Dose levels may be modified based on emerging safety, PK, PD, and 
efficacy results.  
If a dose limiting toxicity (DLT) occurs within 28 days at the 
first dose level, this level will be expanded to enroll 2-3 additional 
subjects (6 subjects total). If ≥ 2 DLTs occur in the first dose level 
tested, then one dose level lower will be opened to enroll 3-4 
additional subjects.  If no DLT occurs in 3-4 subjects or < 2 DLTs 
occur in up to 6 subjects at the lower dose level, then this dose level 
will be the MTD of single agent GS-5829. 


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The safety and tolerability of each dose level will be assessed by a 
Safety Review Team (SRT) after all subjects in the cohort have been 
followed for at least 28 days after the first dose of monotherapy 
GS-5829. If no DLTs occur in 3-4 subjects or < 2 DLTs occur in up 
to 6 subjects on the first dose level after 28 days on treatment, the 
second dose level will open.  Each subsequent dose level will open if 
the dose level preceding has no DLTs in 3-4 subjects or < 2 DLTs in 
up to 6 subjects.
If a subject is enrolled in a dose level but does not complete the 
pharmacokinetic (PK) or pharmacodynamics (PD) analysis in the 
first 28 days of dosing, they may continue on study but an additional 
subject may be enrolled at that dose level.
The MTD of monotherapy is the highest dose level with a subject
incidence of 0 DLTs in 3-4 subjects or < 2 DLTs in 6 subjects during
the first 28 days of study drug dosing. A minimum of 3 subjects need 
to be treated in a cohort before this dose level is deemed as the MTD. 
If the lowest dose evaluated is deemed the MTD, then the lower dose 
cohort may be enrolled to explore the relationship between exposure 
and efficacy and safety.  
The combination dose escalation may initiate prior to identification of 
the MTD of single agent GS-5829 using a starting dose of GS-5829 
that has been determined to be safe and tolerable in the single agent 
dose escalation.
Dose Escalation of GS-5829 and enzalutamide
The first 3-4 subjects to enroll will receive GS-5829 at a dose less 
than or equal to the previously determined single agent MTD 
(or a monotherapy dose that has been determined to be safe) 
combined with enzalutamide.  Enzalutamide is a strong CYP3A4 
inducer, which is expected to decrease the exposure of GS-5829 and 
therefore a higher dose of GS-5829 may be required to achieve target 
coverage compared to the single agent dose. Subjects will administer 
enzalutamide 160 mg once daily as a single agent starting on Study 
Day 1 through Cycle 1, Day 1. On Cycle 1 Day 1 (approximately 
14 days after Study Day 1), subjects will administer GS-5829 
once daily in combination with enzalutamide 160 mg once daily in 
order to evaluate the interaction of the 2 agents. Depending on the 
observed PK interaction, toxicity and tolerability observed in the 
single agent dose escalation, the dose escalation may continue beyond 
a dose which has been identified to be safe and tolerable in the 
single agent arm. Any increase in the dose of GS-5829 will not be by 
more than 100% in the next cohort.


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Similar to the single agent dose escalation, the available safety,
tolerability and pharmacokinetics data for each combination therapy 
dose level will be assessed by a Safety Review Team (SRT) after all 
subjects in the cohort have been followed for at least 28 days after 
their first dose of GS-5829. If no DLTs occur in 3-4 subjects or 
< 2 DLTs occur in up to 6 subjects on the first combination dose level 
after 28 days on treatment (C1D28), the second dose level will open.  
Each subsequent dose level will open if the dose level preceding has 
no DLTs in 3-4 subjects or < 2 DLTs in up to 6 subjects.  The dose 
escalation intended is similar to that for single agent GS-5829 
(see the previous table).  Depending on the exposure observed, the 
data (including PK, tolerability, safety and PSA response) will be 
evaluated to determine the appropriate GS-5829 dose in combination 
with enzalutamide.  The dose of GS-5829 for the next combination 
therapy dose level will be communicated to the sites by 
administrative letter. 
If a subject is enrolled in a dose level but does not complete the PK or 
PD analysis in the first 28 days of GS-5829 dosing, they may 
continue on study but an additional subject may be enrolled at that 
dose level.
The MTD of the combination therapy is the highest dose level with a
subject incidence of 0 DLTs in 3-4 subjects or < 2 DLTs in 6 subjects 
during the first 28 days of study drug dosing. A minimum of 
3 subjects need to be treated at a dose level before this dose level can 
be deemed as the MTD.  Based on tolerability, PK, PD, efficacy and 
emerging data from other studies using GS-5829, dose escalation may 
be discontinued prior to reaching the MTD.
Dose Limiting Toxicity Definition
A DLT is a toxicity defined below and considered possibly related to 
GS-5829 occurring during the DLT assessment window (Day 1 
through Day 28) in each monotherapy or combination therapy cohort:

Grade ≥ 4 neutropenia (absolute neutrophil count [ANC] 
< 500/mm3

Grade ≥3 neutropenia (ANC < 1000/mm3) with fever (a single 
temperature of > 38.3°C or a sustained temperature of ≥38°C for
more than one hour)

Grade ≥ 3 thrombocytopenia 

Grade ≥ 2 bleeding (e.g. gastrointestinal, respiratory, epistaxis, 
purpura)


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
Grade ≥3 or higher non-hematologic toxicity, except:
Grade 3 nausea or emesis with maximum duration of 48 hours 
on adequate medical therapy
Grade 3 diarrhea which persists for < 72 hours in the absence 
of maximal medical therapy.

Grade ≥ 2 non-hematologic treatment-emergent adverse event 
(TEAE) that in the opinion of the investigator is of potential 
clinical significance such that further dose escalation would 
expose subjects to unacceptable risk

Treatment interruption of ≥7 days due to unresolved toxicity
For certain toxicities, such as laboratory assessments without a clear 
clinical correlate, a discussion between the Investigator and Medical 
Monitor may take place to determine if this adverse event (AE) 
should be assessed as a DLT. However, any Grade 3 or Grade 4 
elevation in aspartate transaminase (AST) or alanine transaminase 
(ALT) associated with a Grade 2 elevation in bilirubin that is at least 
possibly related to study drug will be considered a DLT.
Phase 2 Dose Expansion:
Group 1: A dose that is less than or equal to the MTD of GS-5829 
monotherapy (based on safety, PD and tolerability) will be chosen for 
an expansion phase. Approximately 20 subjects with mCRPC who 
have had radiographic disease progression despite adequate 
testosterone suppression and treatment with enzalutamide will be 
enrolled. These subjects may have previously received abiraterone.  
Enrollment into this group may initiate as soon as the MTD of 
single agent GS-5829 has been identified. 
Group 2: A dose that is less than or equal to the MTD of GS-5829 + 
enzalutamide (based on safety, PD and tolerability) will be chosen for 
an expansion phase.  Approximately 20 subjects with mCRPC who 
have had radiographic disease progression despite adequate 
testosterone suppression and treatment with abiraterone will be 
enrolled.  These subjects may not have previously received 
enzalutamide. Enzalutamide will be initiated on Study Day 1 and 
GS-5829 will initiate on Cycle 1, Day 1 (approximately 15 days 
later).


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Group 3:  A dose equivalent to the dose chosen for Group 2 will be 
chosen for an expansion phase.  A maximum of 20 subjects with 
mCRPC who have had PSA only progression, but not radiographic 
progression, despite adequate testosterone suppression and treatment 
with enzalutamide, will be enrolled.  These subjects may have 
received prior abiraterone (similar to Group 1).   These subjects will 
continue on the enzalutamide therapy they have been receiving 
(must be receiving continuous enzalutamide for at least 12 weeks 
prior to Cycle 1, Day 1) and GS-5829 will initiate on Cycle 1, Day 1.
The choice of enrolling a subject into a specific dose escalation 
cohort or dose expansion group will be based on the treatment slots 
open at the time of screening, inclusion/exclusion enrollment criteria
and the discretion of the investigator.
Number of Subjects 
Planned:
Phase 1b Dose Escalation: Approximately 72 subjects will be 
enrolled
Phase 2 Dose Expansion: Up to 60 subjects will be enrolled
Target Population:
Adult subjects with histologically or cytologically confirmed mCRPC 
who are chemo-naïve, and have documented disease progression 
while receiving enzalutamide and/or abiraterone therapy.
Duration of 
Treatment:
Treatment will continue in the absence of disease progression,
unacceptable toxicity, withdrawal of consent, or other reasons
specified in Section 3.4.  
Diagnosis and Main 
Eligibility Criteria:
Inclusion Criteria:
Subjects must meet all of the following inclusion criteria to be 
eligible for participation in this study:
1) Male 18 years of age
2) Histologically or cytologically confirmed prostate cancer 
(subjects with primary neuroendocrine carcinoma of prostate are 
excluded)

Phase 1b Monotherapy Dose Escalation:  Subject must have 
documented progressive disease by meeting at least one of 
the PCWG2 criteria (Appendix 4) despite treatment with 
abiraterone and/or enzalutamide

Phase 1b Combination Therapy Escalation and Phase 2 
Combination Dose Expansion (Group 2):  Subjects must have 
documented progressive disease by meeting at least one of 
the PCWG2 criteria, despite treatment with abiraterone.  
They may not have received prior enzalutamide or 
chemotherapy for mCRPC


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
Phase 1b Combination Therapy Escalation and Phase 2 
Combination Dose Expansion (Group 2):  Subjects must have 
documented progressive disease by meeting at least one of 
the PCWG2 criteria, despite treatment with abiraterone.  
They may not have received prior enzalutamide or 
chemotherapy for mCRPC

Phase 2 Monotherapy Dose Expansion (Group 1): Subjects 
must have documented progressive disease by meeting at 
least one of the PCWG2 criteria, despite treatment with 
enzalutamide.  They may have received prior abiraterone, 
but not prior chemotherapy, for mCRPC

Phase 2 Combination Therapy Dose Expansion (Group 3): 
Subjects must have documented progressive disease by 
meeting the PCWG2 criteria for PSA progression, but not 
radiographic progression, despite treatment with 
enzalutamide.  They may have received prior abiraterone, 
but not prior chemotherapy, for mCRPC (similar to Group 1); 
however, they must also have been on continuous 
enzalutamide therapy for at least 12 weeks prior to Cycle 1, 
Day 1.
3) Castration-resistant disease defined as ongoing androgen 
deprivation therapy with GnRH analogue or bilateral orchiectomy 
and serum testosterone level ≤ 1.73 nmol/L (50 ng/dL) at the 
screening visit. Subjects who have not had a bilateral orchiectomy 
must have a plan to maintain effective GnRH-analogue therapy 
for the duration of the trial
4) Metastatic disease documented by bone lesions on bone scan or 
by measurable soft tissue disease by CT/MRI. Subjects whose 
disease spread is limited to regional pelvic lymph nodes are not 
eligible.
5) All acute toxic effects of any prior antitumor therapy resolved to
Grade ≤ 1 before the start of study drug dosing (with the exception
of alopecia [Grade 1 or 2 permitted] and neurotoxicity [Grade 1 or
2 permitted])
6) Eastern Cooperative Oncology Group (ECOG) Performance
Status of ≤ 1
7) Life expectancy of ≥3 months, in the opinion of the Investigator


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8) Adequate organ function defined as follows:
a) Hematologic:  Platelets ≥ 100 x 109/L; Hemoglobin 
≥9.0 g/dL; ANC ≥ 1.5 x 109/L (without platelet transfusion or 
any granulocytic growth factors within previous 7 days of the 
hematologic laboratory values obtained at screening visit)
b) Hepatic: AST / ALT ≤ 2.5 x upper limit of normal (ULN) 
(if liver metastases are present, ≤ 5 x ULN); total or 
conjugated bilirubin ≤ 1.5 x ULN
c) Renal: Serum Creatinine ≤ 1.5 x ULN or creatinine clearance 
(CrCl) ≥ 60 mL/min as calculated by the Cockroft-Gault 
method
9) Coagulation: International Normalized Ratio (INR) ≤1.2
10) Male subjects of reproductive potential who engage in 
heterosexual intercourse must agree to use protocol-specified 
method(s) of contraception as described in Appendix 7 and refrain 
from sperm donation for at least 90 days 
11) Able and willing to provide written informed consent to 
participate in the study
Exclusion Criteria:
Subjects who meet any of the following exclusion criteria are not to 
be enrolled in this study:
1) History or evidence of clinically significant disorder, condition, or 
disease that, in the opinion of the Investigator or Medical Monitor 
would pose a risk to subject safety or interfere with the study 
evaluations, procedures, or completion
2) Known brain metastasis or leptomeningeal disease
3) Uncontrolled intercurrent illness including, but not limited to, 
active uncontrolled infection, active or chronic bleeding event 
within 28 days prior to first dose of study drug, uncontrolled 
cardiac arrhythmia, or psychiatric illness/social situation that
would limit compliance with study requirements as judged by 
treating physician
4) A history of seizure, underlying brain injury with loss of 
consciousness, transient ischemic attack within the past 
12 months, cerebral vascular accident and brain arteriovenous 
malformation are excluded from combination therapy with 
enzalutamide.  


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5) Myocardial infarction, symptomatic congestive heart failure 
(New York Heart Association Classification > Class II), unstable
angina, or serious uncontrolled cardiac arrhythmia within the
last 6 months of Cycle 1 Day 1
6) Major surgery, defined as any surgical procedure that involves 
general anesthesia and a significant incision (ie, larger than what 
is required for placement of central venous access, percutaneous 
feeding tube, or biopsy) within 28 days of the first dose of study 
drug
7) Impairment of gastrointestinal (GI) function or GI disease that 
may significantly alter the absorption of GS-5829, including any 
unresolved nausea, vomiting, or diarrhea that is Common 
Terminology Criteria for Adverse Events (CTCAE) Grade > 1
8) Minor surgical procedure(s) within 7 days of enrollment or 
randomization, or not yet recovered from prior surgery 
(placement of central venous access device, fine needle aspiration, 
or endoscopic biliary stent ≥ 1 day before enrollment or 
randomization is acceptable)
9) Anti-tumor therapy (chemotherapy, antibody therapy, molecular 
targeted therapy) within 21 days or 5 half-lives, whichever is 
longer, of study drug dosing (6 weeks for nitrosoureas, mitomycin 
C, or molecular agents with t1/2 > 10 days); concurrent use of an 
LHRH agonist is permitted for all subjects and ongoing 
enzalutamide is required in Group 3.
10) History of a concurrent or second malignancy, except for: 
adequately treated local basal cell or squamous cell carcinoma of 
the skin; cervical carcinoma in situ; superficial bladder cancer; 
breast carcinoma in situ; adequately treated Stage 1 or 2 cancer 
currently in complete remission; any other cancer that has been in 
complete remission for ≥ 5 years
11) History of long QT syndrome or whose corrected QT interval 
(QTc) measured (Fridericia method) at screening is prolonged 
(> 450 ms). Subjects who screen fail due to this criterion are not 
eligible to be re-screened
12) Prior exposure to bromodomain (BET) inhibitors
13) Clinically significant bleeding within 28 days of Cycle 1 Day 1
14) Known human immunodeficiency virus (HIV) infection
15) HBsAg positive
16) HCV antibody positive


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17) Use of moderate/strong cytochrome P450 (CYP)3A4 inhibitors or 
moderate/strong CYP3A4 inducers within 2 weeks prior to the 
first dose of study drug (with the exception of enzalutamide in the 
combination arms)
18) Evidence of bleeding diathesis
19) History of hemoptysis of ≥2.5 mL/1 teaspoon within 6 months of 
Cycle 1 Day 1
20) History of high grade esophageal or gastric varices
21) Anticoagulation therapy within 7 days of Cycle 1 Day 1, 
including acetylsalicylic acid, low molecular weight heparin, or 
warfarin.
Study Procedures/
Frequency:
Screening:
Screening will commence with obtaining the subject’s signed
informed consent and will occur up to 28 days prior to the first dosing
of study drug on Study Day 1/Cycle 1 Day 1. Screening procedures
will include the following: medical history review, physical exam,
vital signs, 12-lead electrocardiogram (ECG), ECOG Performance
Status, prior/concomitant medication review, chemistry, hematology
and coagulation, PSA, adverse event (AE) assessment, and computed 
tomography (CT) or magnetic resonance imaging (MRI) (scans that 
meet protocol requirements that are obtained as part of standard
medical practice up to 28 days prior to Study Day 1/Cycle 1 Day 1 are
acceptable) and bone scan. Baseline tumor lesions will be measured
and characterized prior to Study Day 1/Cycle 1 Day 1 to assess the
subject disease status prior to beginning treatment.
Treatment:
Subjects who meet eligibility criteria will receive GS-5829 as a 
single agent and combined with enzalutamide orally once daily. Each 
cycle will consist of 28 days.  Safety and efficacy assessments will
occur on an outpatient basis including an assessment of tumor
response, physical exam, vitals, ECG, collection of blood samples
(for routine safety labs, GS-5829 PK, PD markers, and biomarkers at 
applicable visits), and assessment of AEs. In addition, subjects will
undergo a bone scan and CT (or MRI) scan every 12 weeks. A subject
who does not show evidence of disease progression may continue
receiving GS-5829 or GS-5829 plus enzalutamide once daily until
disease progression (clinical or radiographic), unacceptable toxicity,
withdrawal of consent, or other reasons specified in Section 3.4.  
Subjects who have progressive disease by PSA measurements alone 
may continue study drug.


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After discontinuation of study treatment, subjects will be followed for 
safety for 30 days.
Phase 1b Monotherapy Dose Escalation 
PK and PD samples for GS-5829 will be collected on Day 8 of 
Cycle 1 at pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose as well 
as pre-dose and 1-4 hours after GS-5829 administration on Day 1 and 
Day 15 of Cycle 1 and anytime on Day 1 of Cycles 2 through 6.  
At one or more dose levels, PK samples will be collected on Day 1 of 
Cycle 2 at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post-dose. 
GS-5829 dose will be administered in fed state on Day 1 of Cycle 2.
Phase 1b Dose Escalation with enzalutamide
PK and PD samples for GS-5829 will be collected on Day 1 and 
Day 15 of Cycle 1 at pre-dose 0.5, 1, 2, 3, 4, 6, 8 and 24 hours
post-dose and anytime on Day 1 of Cycles 2 through 6.  
Phase 2 Dose Expansion (Group 1)
PK and PD samples will be collected on Day 8 of Cycle 1 at pre-dose 
and 1, 2, 4, and 6 hours post-dose. Sparse PK and PD samples will be 
collected at pre-dose and 1 - 4 hours post-dose on Cycle 1 Day 1 and 
Day 15 and anytime on Day 1 of Cycles 2 through 6.
Phase 2 Dose Expansion (Group 2)
PK and PD samples will be collected on Cycle 2, Day 1 at pre-dose 
and 1, 2, 4, and 6 hours post-dose. Sparse PK and PD samples will be 
collected at pre-dose and 1 - 4 hours post-dose on Cycle 1, Day 1 and 
Day 15 and anytime on Day 1 of Cycles 3 through 6.
Phase 2 Dose Expansion (Group 3)
PK and PD samples will be collected on Cycle 2, Day 1 at pre-dose 
and 1, 2, 4, and 6 hours post-dose. Sparse PK and PD samples will be 
collected at pre-dose and 1 - 4 hours post-dose on Cycle 1, Day 1 and 
Day 15 and anytime on Day 1 of Cycles 3 through 6.
Test Product, Dose, 
and Mode of 
Administration:
GS-5829 tablets will be self-administered orally once daily, beginning 
on Cycle 1 Day 1 of the study and thereafter at approximately the 
same time each day until end of treatment.  GS-5829 is supplied as 
0.2 mg, 1 mg, 5 mg, and 10 mg tablets.
Enzalutamide capsules will be self-administered orally once daily 
beginning on Study Day 1 of the Dose Escalation portion and Dose 
Expansion portion (Group 2).  Enzalutamide will be supplied as 
40 mg capsules; subjects will self-administer 160 mg (4 × 40 mg 
capsules) once daily.


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Reference Therapy, 
Dose, and Mode of 
Administration:
Not Applicable
Criteria for 
Evaluation:
Phase 1b and Phase 2
Safety:
Safety will be evaluated by assessment of clinical laboratory tests, 
physical examination, 12-lead ECG, vital signs measurements, and 
the documentation of AEs
Efficacy
Disease progression will be assessed according to PCWG2 criteria. 
Progression/Non-progression rate at Week 12, Progression free 
survival defined by the time from Study Day 1 to the date of death 
from any cause or the date of progressive disease which one is earlier, 
and overall survival will be measured.  
Pharmacokinetics:
The following PK parameters for GS-5829 will be calculated as 
applicable: Cmax, AUClast, AUCtau, Ctau, and Tmax
Statistical Methods:
Analysis Methods
The Full Analysis Set (FAS) will be used in the analyses of subject 
characteristics and efficacy endpoints. The FAS consists of all 
subjects who receive ≥ 1 dose of study drug. A Safety Analysis Set 
for this study will be the same as FAS since this study is a 
non-randomized study. Other analysis sets (DLT evaluable and 
PK/PD analysis sets) will be used for additional analyses as well.
Subject characteristics and study results will be described and
summarized by dose level and assessment for the relevant analysis
sets. Descriptive summaries will be prepared to show sample size,
mean, standard deviation (StD), 90% confidence intervals (CIs) on
the mean, median, minimum and maximum for continuous variables, 
and counts, percentages and 90% CIs on the percentage for 
categorical variables.
Efficacy endpoints: Estimates of progression/non-progression rate at 
Week 12 will be present with 90% exact CIs: PFS and OS will be 
visualized using Kaplan-Meier plot, and median survival time 
estimate will be listed.
Based on the Safety Analysis Set, information regarding study drug 
administration, study drug compliance and safety variables will be 
described and summarized.


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Using data from the PK and PD Analysis Sets, GS-5829 plasma 
concentrations and PK parameters and whole blood PD markers will 
also be described and summarized. Plasma concentrations of 
GS-5829 metabolite(s) may also be determined and PK explored.
Sample Size
The sample size is not determined by statistical hypothesis testing.  
The sample size of phase 1b monotherapy phase will be determined 
based on the number of dose levels evaluated and the emerging 
GS-5829-related toxicities. The phase 1b study will consist of up to 
72 subjects.  The phase 2 part will enroll up to 60 subjects to help 
understand the efficacy effect of GS-5829 as a monotherapy and 
combination therapy with enzalutamide.  The expectation is that at 
24 weeks, the non-progression rate will be > 30% with GS-5829 
monotherapy in subjects who have progressed on enzalutamide 
(may have received abiraterone) and/or with GS-5829 combined with 
enzalutamide in subjects who have progressed on abiraterone only. 
If the true non-progression rate is above 50%, and we do observe 
more than 10 non-progression subjects from 20 treated subjects per 
group, it will guarantee that the lower bound of the 90% confidence 
interval of the estimated rate will be larger than 30%.
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
AE
adverse event
ALT
alanine transaminase
ANC
absolute neutrophil count
AR
androgen receptor
AR-V7
AR splice variant 7
AST
aspartate transaminase
AUClast
area under the plasma concentration-time curve from time zero to the time of the last 
quantifiable concentration
AUCtau
area under the plasma concentration-time curve
BCRP
breast cancer resistance protein
BET
bromodomain and extra-terminal
BRD
bromodomain
Cmax
maximum concentration observed
Ctau
concentration at the end of the dosing interval
CFR
Code of Federal Regulations
CI
confidence interval
CR
complete response
CrCl
creatinine clearance
CRF
case report form
CRO
contract research organization
CRPC
castrate-resistant prostate cancer
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DDI
drug-drug interaction
DLBCL
diffuse large B-cell lymphoma
DLT
dose limiting toxicity
DNA
deoxyribonucleic acid
DSPH
Drug Safety and Public Health
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
ER
estrogen receptor
eSAE
electronic serious adverse events
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal
HBsAg
Hepatitis B surface Antigen


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HIV
Human Immunodeficiency Virus
HNSTD
highest non-severely toxic dose
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IP
investigational product
IRB
Institutional Review Board
IxRS
Interactive voice/web Response System
LHRH
luteinizing hormone releasing hormone
mCRPC
metastatic castrate-resistant prostate cancer
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
ORR
overall response rate
OS
overall survival
PCWG
Prostate Cancer Working Group
PD
pharmacodynamics
PFS
progression-free survival
PK
pharmacokinetics
PR
partial response
PSA
prostate-specific antigen
QD
every day
QTc
corrected QT interval
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RNAPII
RNA polymerase II
SADR
serious adverse drug reaction
SAE
serious adverse event
StD
standard deviation
SOC
system organ class
SOP
standard operating procedure
STD
severely toxic dose
SUSAR
suspected unexpected serious adverse reactions
t1/2
terminal phase half-life
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
US
United States
WBC
white blood cell


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1.
INTRODUCTION
1.1.
Background
GS-5829 is a small-molecule inhibitor of the highly conserved bromodomain pockets of the 
bromodomain and extraterminal (BET) proteins. Bromodomain and extraterminal proteins 
regulate specific gene expression by enhancing ribonucleic acid (RNA) polymerase II 
(RNAPII)-mediated transcription. Signal transduction pathways recruit BET proteins to target 
genes through posttranslational modification of histone proteins in the form of lysine acetylation 
{Belkina et al 2012, Hargreaves et al 2009}. The tandem bromodomain motifs of BET proteins 
specifically recognize acetylated histones and, in turn, recruit protein factors that regulate 
RNAPII {Shi et al 2014}. The BET family includes bromodomain-containing proteins 2, 3, 4, and 
T (BRD2, 3, 4, and T). BRD2, 3 and 4 are widely expressed and regulate gene transcription in 
diverse cell types, including malignant cells, whereas BRDT expression is restricted to the testes.  
BRD2, 3, 4 are essential regulators of the expression or activity of several key oncogenic 
transcription factors, including v-myc avian myelocytomatosis viral oncogene homolog (MYC) 
and the androgen receptor (AR) {Shi et al 2014}. Transcription of the MYC gene is dependent on 
BET proteins in many cells {Mertz et al 2011} (Figure 1-1). Androgen receptor-dependent 
transcription of target genes requires BET proteins in prostate cancer cells {Asangani et al 2014}. 
Cancer cells addicted to MYC and AR are highly sensitive to BET protein inhibition {Asangani et 
al 2014, Delmore et al 2011, Mertz et al 2011}, which provides the basic therapeutic rationale for 
BET inhibition with GS-5829 for the treatment of cancer.
MYC promotes cell proliferation, cell survival, and metabolic adaptation and is frequently 
overexpressed in human cancers {Dang 2012}. Data generated at Gilead demonstrated MYC 
overexpression to be prevalent in 76% of prostate cancer (n = 60), 67% of diffuse large B-cell 
lymphoma (DLBCL) (n = 98), 65% of multiple myeloma (MM, n=30), 73% of colorectal cancer 
(n = 60), and 80% of ovarian cancer (n = 60) cases examined (PC-350-2083). These data are
consistent with literature that reports a high incidence of MYC expression in these and other 
cancers {Affer et al 2014, Barrans et al 2010, Chesi et al 2008, Chng et al 2011, Glitza et al 2014, 
Hawksworth et al 2010, Nesbit et al 1999, Nupponen et al 1998, Perry et al 2014}. The AR is a nuclear 
hormone receptor that is nearly ubiquitously expressed in prostate cancer (PC-350-2083) and 
activates growth and survival signals both by binding to androgen, its natural ligand, and through 
androgen-independent mechanisms {Yuan et al 2014}.
A number of orally administered, BET-directed compounds (TEN-010, CPI-0610, OTX015, 
ZEN-3365, and GSK525762) are currently in early-stage clinical development for the treatment 
of solid tumors or hematologic cancers. Initial evidence of clinical activity at tolerated doses has 
been reported for the BET inhibitor OTX015 in patients with refractory hematological cancers 
{Herait et al 2014}. GS-5829 is an orally available small-molecule inhibitor of BET proteins that 
is being developed by Gilead Sciences, Inc. for the treatment of solid tumors, including 
castrate-resistant prostate cancer (CRPC), and hematologic malignancies. In nonclinical studies, 
GS-5829 inhibited cell growth and induced apoptosis of solid tumor and hematological cancer 
cells by inhibiting BET protein-dependent transcription of MYC and other oncogenic pathways, 
including transcription mediated by the AR in prostate cancer cells.


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Additionally, enzalutamide-resistant LNCaP-AR and VACP tumors in murine xenograft models 
displayed significantly higher AR expression and signaling relative to controls yet maintained 
sensitivity to BET inhibitors.  The AR-v7 splice variant of CRPC, which has been reported to be 
associated with resistance to anti-androgen treatments, was elevated in enzalutamide-resistant 
cells and was markedly repressed by BET inhibitors particularly when combined with continued 
exposure to enzalutamide {Asangani et al 2016}.
Figure 1-1.
Mechanism of Action of GS-5829 to Reduce Transcription of MYC 
and AR Target Genes in Cancer Cells
Bromodomain and extraterminal proteins, including BRD4, are recruited to the MYC promoter and enhancer elements through an 
interaction between the tandem bromodomains and acetylated histone proteins in chromatin (top panel). BRD4 recruits the 
positive transcription elongation factor b (pTEFb) complex to the MYC gene, which phosphorylates RNAPII to increase 
transcription of the MYC gene. GS-5829 binds to the bromodomains of BET proteins, thereby blocking the interaction with 
acetylated histone proteins and leading to a reduction of MYC transcription. GS-5829 similarly functions to inhibit the 
transcription of AR target genes in prostate cancer cells, including the kallikrein-related peptidase 3 (KLK3) gene that encodes 
prostate specific antigen (bottom panel). 
1.2.
GS-5829
1.2.1.
General Information
For further information on GS-5829, refer to the current investigator’s brochure for GS-5829.
.
GS-5829 
MYC 
-
.
GS-5829 -
AR targets 
• KLK2 
• KLK3 (PSA) 
• TMPRSS2 
• SLC45A3 


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1.2.2.
Preclinical Pharmacology and Toxicology
1.2.2.1.
Absorption, Distribution, Metabolism, and Elimination 
GS-5829 shows moderate plasma protein binding and volumes of distribution in nonclinical 
species that are similar to or slightly higher than total body water.  Systemic clearance in 
nonclinical species is generally well predicted from the rates of metabolism by hepatocytes.  
Since GS-5829 has high metabolic stability with human hepatic material in vitro, it is likely to 
show low clearance in humans.  The major route of metabolism of GS-5829 involves 
hydroxylation of the 5-methyl moiety on the 3,4-dimethly isoxazole ring catalyzed primarily by
CYP3A4 and CYP3A5 enzymes in humans.  
Consistent with the moderate to high bioavailability seen in nonclinical species, GS-5829 shows 
high forward permeability across Caco-2 monolayers, and low efflux, but GS-5829 is a substrate
of human P-p and BCRP.
GS-5829 has relatively high unbound fraction in cell culture medium containing fetal bovine 
serum.  Competitive dialysis between cell culture median and human, dog and mouse plasma 
yielded a ratio of unbound fractions of 5.7, 15.2 and 13.2 respectively.  
GS-5829 is unlikely to cause clinical interaction through inhibition of CYP1A2, CYP2C9, 
CYP2C19, or CYP2D6, CYP2B6, CYP2C8, CYP3A or UGT1A1, so the potential for causing 
drug interactions through inhibition of those enzymes is low.  GS-5829 is also a weak inhibitor 
of the human efflux transporters, P-gp and BCRP, and the uptake transporters, OATP1B1 and 
OATP1B3. 
1.2.2.2.
Nonclinical Toxicology
Nonclinical safety pharmacology and toxicology studies have characterized the safety of 
GS-5829 through repeat dose toxicology studies.  All pivotal toxicology studies were conducted 
in full compliance with Good Laboratory Practice regulations (21 CFR 58).  The scope of the 
nonclinical safety evaluation is consistent with the guidance issued by the International 
Conference on Harmonisation (ICH). 
In nonclinical pharmacology studies, GS-5829 showed no significant adverse effects on central 
nervous, respiratory or cardiovascular system functioning at the projected exposure and human 
target dose of 25 mg once daily.  
The following target organs/systems were identified in the nonclinical toxicology studies: 
hematopoietic and male reproductive system (mice and dogs), the adrenal and skin (mice), and 
the gastrointestinal tract, respiratory and cardiac (dogs).  With the exception of the adrenals in 
the mouse and the respiratory and cardiac hemorrhages observed in dogs, target organs are as 
expected based on the known pharmacology.  The dog was the more sensitive species, with the 
no-observed-adverse-effect levels in the mouse and dog being 10 and 0.03 mg/kg/day 
respectively.  The severely toxic dose in 10% of mice and the highest non-severely toxic dose
(HNSTD) in dogs were 25 and 0.1 mg/kg/day, respectively.  


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Hematopoietic effects include decreases in white blood cells, lymphocytes, platelets and 
reticulocyte counts as well as mild reduced cellularity in the marrow in mice at doses of 
≥10 mg/kg/day.  Minimal to marked decrease in bone marrow cellularity, decrease in 
lymphocytes in the lymphoid tissues (spleen, thymus, lymph nodes and gastrointestinal 
associated lymphoid tissue), decrease in neutrophils and platelets were observed at 
0.3 mg/kg/day in dogs.  Elevated fibrinogen was also noted at 0.3 mg/kg/day in dogs. 
Mild to moderate alveolar (lung) hemorrhage was observed at ≥ 0.1 mg/kg/day in dogs.  Mild 
hemorrhage in the left atrioventricular valve of the heart was seen at 0.3 mg/kg/day in 1 of 
6 dogs.  The mechanism for the hemorrhage is not known.  Prothrombin time and partial 
thromboplastin time measurements were normal. The anatomic pattern of the hemorrhage in the 
lung field and microscopy was considered potentially consistent with pneumonia, however 
bacteria were not identified.  
In the male reproductive system, decreased testes weight with oligospermia/aspermia were 
observed in both mouse and dog studies at 25 and 0.3 mg/kg/day respectively.  Minimal to 
moderate vacuolation of the seminiferous tubules occurred at ≥ 0.1 mg/kg/day in the dog. These 
changes are consistent with the known effects of a bromodomain inhibitor on the testes.
The gastrointestinal findings in the dog included minimal to mild mucosal atrophy, mucosal 
hemorrhage and crypt hyperplasia in the stomach or intestines at ≥ 0.1 mg/kg/day.  Adrenal 
gland weight decreases were noted at 25 mg/kg/day and cytoplasmic vacuolation at 
≥10 mg/kg/day in the mouse studies, of unknown cause. QT prolongation is not expected based 
on hERG, rodent and dog studies.  
1.2.3.
Clinical Trials of GS-5829
As of 02 June 2016, two clinical studies evaluating GS-5829 have been initiated (including this 
ongoing study). One study (Protocol GS-US-350-1599) includes subjects with advanced solid 
tumors, ER+Her2- breast cancer, and lymphomas. This study is an ongoing open-label, 
multicenter, sequential dose-escalation study to evaluate the safety, tolerability, 
pharmacokinetics (PK), and PD of GS-5829 in subjects with advanced solid tumors and 
lymphomas. This study includes a cohort of subjects with advanced stage breast cancer who will 
receive GS-5829 combined with exemestane and fulvestrant. Doses planned for this study are 
0.6, 1.4, 2, 3, 4, 6, 9, and 12 mg once daily. Pharmacokinetic data are available from 4 dose 
levels of the single agent GS-5829 in Study GS-US-350-1599 (0.6, 1.4, 2 mg, and 3 mg once 
daily). GS-5829 is well-absorbed with higher than predicted plasma exposures in humans. No 
clinically detectable trend in laboratory abnormalities in relationship to dose has been observed. 
A Grade 3 thrombocytopenia that was considered a DLT was observed in 1 of 6 subjects at 
3.0 mg.
Please refer to the current GS-5829 Investigator’s Brochure for additional details. 
1.2.4.
Information about Enzalutamide
Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen 
receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen 
binding to androgen receptors and inhibit androgen receptor nuclear translocation and interaction 


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with DNA. A major metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to 
enzalutamide. Enzalutamide decreased proliferation and induced cell death of prostate cancer 
cells in vitro and decreased tumor volume in a mouse prostate cancer xenograft model. In the 
US, enzalutamide is approved as a single agent for mCRPC.  For current information about 
enzalutamide (XTANDI®) {Astellas Pharma US Inc. 2014}, refer to the regional prescribing 
information (Appendix 9) or the summary of product characteristics in the pharmacy binder.
1.3.
Rationale for This Study
In 2014, it was estimated that 233,000 new cases of prostate cancer and 29,480 deaths due to 
prostate cancer would occur in the US {National Cancer Institute 2014}. The majority of men 
(approximately 90%) are diagnosed with loco-regional disease that is treated surgically and/or 
with radiation therapy; 5-year survival approaches 100% for these patients. However, despite the 
availability of a variety of therapies, including pharmacological inhibitors of AR activity, 
immunotherapy, radiation, and chemotherapy, metastatic prostate cancer has a 5-year survival of 
only 30%, with most patients dying from prostate cancer. 
In patients with advanced prostate cancer who have progressed while receiving therapy with 
chemical or surgical castration, the androgen/androgen receptor (AR) axis remains the target of 
current standard of care agents, abiraterone {Janssen Biotech Inc. 2015} and enzalutamide. Primary 
and acquired resistance to such agents occurs when the AR is activated in an 
androgen-independent manner, most notably through the expression of the constitutively active 
AR splice variant 7 (AR-V7) {Antonarakis et al 2014, Guo et al 2009}. In nonclinical studies, 
GS-5829 inhibited growth and induced apoptosis in prostate cancer cell lines by inhibiting MYC 
expression and AR-target gene expression in both AR- and AR-V7-expressing prostate cancer 
cell lines.
Although GS-5829 has the potential for activity in mCRPC at all points of treatment, first line 
therapies with enzalutamide and abiraterone are relatively well tolerated and demonstrated 
improvements in PFS and OS compared with placebo.  Abiraterone is a CYP17 inhibitor 
indicated in combination with prednisone for the treatment of patients with mCRPC who are 
chemotherapy-naïve based on demonstrating an improvement in OS from 30.1 to 35.3 months 
compared with placebo (Hazard Ratio [HR]  0.782 [95% confidence interval (CI); 0.655, 0.956]).  
Enzalutamide is an androgen receptor inhibitor indicated for the treatment of patients with 
mCRPC who are chemotherapy-naïve based on demonstrating an improvement in OS from 
30.3 to 32.4 months compared with placebo (HR  0.71 [95% CI; 0.60, 0.84]) {Astellas Pharma US 
Inc. 2014}.
Based on limited data, once a patient has received abiraterone or enzalutamide, the response to 
the other agent is in the range of 10-26% and median radiographic/clinical progression is 
3.6 to 6.6 months {Azad et al 2015, Brasso et al 2014, Noonan et al 2013}. One mechanism of 
resistance which may explain part of this cross-resistance has been identification of the AR-V7
splice variant, which is estimated to occur in 30-40% of patients who have received abiraterone 
and/or enzalutamide {Antonarakis et al 2014}. Due to its downstream inhibition of AR-V7 
transcription, however, pre-clinical models suggest tumors cells with the AR-V7 splice variant 
are still sensitive to BET inhibition.


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In addition, preclinical data has demonstrated that the combination of GS-5829 and enzalutamide 
increases the inhibition of AR-mediated transcription and growth of prostate cancer cell lines 
compared to either agent alone.  These results suggests an additive effect of the two agents, 
which may provide a beneficial option for patients who have failed abiraterone and would 
otherwise have soon proceeded to chemotherapy.  
Chemotherapy (docetaxel, cabazitaxel) is the systemic treatment option after failure of 
abiraterone and enzalutamide, but it does not offer a potential for cure and use is limited due to 
its cumulative toxicity in this relatively elderly patient population.  One of the greatest unmet 
needs for patients with mCRPC is to prolong the time from the development of mCRPC to the 
initiation of chemotherapy.
This is a phase 1b/2 dose escalation and dose expansion study designed to evaluate the single 
agent safety and activity of GS-5829 in subjects who have progressive disease despite receiving 
abiraterone and/or enzalutamide.  A second group of subjects will evaluate the safety and activity 
of the combination of GS-5829 and enzalutamide in subjects who have failed abiraterone.  A 
third group of subjects will evaluate the safety and activity of adding GS-5829 to enzalutamide 
in subjects who have progressed by PSA criteria alone while receiving enzalutamide.
1.3.1.
Rationale for the Dose Selection
The starting dose of GS-5829 in this study will be a dose that has been demonstrated to be safe 
and tolerable in the ongoing Phase 1 study (GS-US-350-1599) in patients with solid tumors and 
lymphomas. Based on the systemic concentrations of GS-5829 measured in the repeat dose 
toxicity studies in mice and dogs, the margins of exposure at the severely toxic dose in 10% of 
rodents (STD10) in mice and highest non-severely toxic dose (HNSTD) in dog are 
approximately 6.3- and 1-fold, respectively, at a plasma exposure (AUCtau) of 2.5 h.µg/mL 
which is anticipated to provide clinical efficacy based on in vivo preclinical data and anticipated 
target inhibition.  Preliminary PK data from a limited number of patients in the ongoing Phase 1 
study (GS-US-350-1599) indicate plasma exposures are higher than predicted; observed AUCtau
at 0.6 and 1.8 h.ug/mL respectively.  Thus, it is anticipated that a clinically efficacious exposure 
will be achieved at a lower dose than previously predicted and the dose escalation plan has been 
modified to reflect this emerging data.
For the single agent dose escalation, PK and PD results from the 28 day continuous dosing will 
be evaluated to explore the dose/exposure-response relationship.  Continuation of the study, 
according to the proposed dose escalation Phase 1b, will require that available data supports the 
potential to achieve an effective dose of GS-5829 in humans which will be safe and tolerable. 
Due to the narrow therapeutic index observed in dogs, the percentage dose increment 
sequentially decreases at each dose level.
The combination dose escalation may initiate prior to identification of the MTD of single agent 
GS-5829 using a starting dose of GS-5829 that has been determined to be safe and tolerable in 
the single agent dose escalation. Subjects who have mCRPC and have progressive disease 
despite treatment with abiraterone will be enrolled to receive GS-5829 and enzalutamide.  


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Enzalutamide is a strong CYP3A4 inducer, which has been demonstrated to decrease the AUC of 
a CYP3A4 substrate (midazolam) by 86%; therefore further dose escalation of the combination 
therapy will be performed in these subjects prior to initiation Phase 2 Dose Expansion.  As the 
concern is for decreased GS-5829 exposure, the initial dose level of the combination therapy will 
be 160 mg of enzalutamide combined with a starting dose of GS-5829 that has been determined 
to be safe and tolerable in the single agent dose escalation.  Enzalutamide dosing will begin 
approximately 2 weeks prior to GS-5829 dosing to achieve near maximal CYP3A4 induction to 
reduce changes in GS-5829 exposure over the first cycle. PK evaluations will be performed and 
if indicated and supported by PK, safety and tolerability, additional cohorts with higher doses 
and/or more frequent dosing (ie, twice daily) of GS-5829 in combination with enzalutamide may 
be tested.  The total daily dose will not increase by more than 100% in the next cohort.
1.4.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.
1.5.
Risk/Benefit Assessment for the Study
Based on the systemic concentrations of GS-5829 measured in the repeat dose toxicity studies in 
mice and dogs, the margins of exposure at the severely toxic dose in 10% of rodents (STD10) in 
mice and HNSTD in dog are approximately 6.3- and 1-fold, respectively, at the anticipated 
clinically efficacious exposure.  Another bromodomain inhibitor in development has identified 
thrombocytopenia as the earliest signs of toxicity in human studies, a toxicity which may be
easily monitored.  
Target organs identified in the repeat-dose toxicity studies included the hematopoietic and male 
reproductive systems (mice and dogs), the adrenal glands (mice), and the GI tract and respiratory 
system (dogs). With the exception of the adrenal glands in the mouse and the respiratory system 
in dogs, all other target organs are expected based on the known pharmacology of GS-5829 to 
inhibit BET proteins. The effects on the hematopoietic system, male reproductive tract, adrenal 
glands, and GI tract were considered reversible and can be monitored in the clinic.
As of 17 June 2016, the 3 mg dose level has been found to be safe and tolerable as single agent 
dosing in the First-In-Human Study GS-US-350-1599 and the 2 mg dose level has been found to 
be safe and tolerable in the prostate cancer Study GS-US-350-1604, respectively.  Two subjects 
in the First-In-Human Study (GS-US-350-1599) experienced 3 serious adverse events (SAEs) 
which were considered by the investigator to be Grade 3 and not related to study drug 
(cholangitis and sepsis in 1 subject at 0.6 mg and thrombocytopenia in 1 subject at 1.4 mg).  The 
following AEs were considered related to study drug: fatigue (1 subject, 0.6-mg group and 
1 subject, 1.4-mg group), nausea (1 subject, 0.6-mg group and 1 subject, 1.4-mg group), 
splenomegaly (1 subject, 1.4-mg group), and dizziness (1 subject, 1.4-mg group). No AEs led to 
discontinuation of study drug. After the most recent data cut (12 October 2015), a DLT of 
adrenal hemorrhage was reported in a subject receiving 4 mg of GS-5829. The subject had 
normal coagulation parameters and a platelet count higher than normal at baseline which did not 
change at the time of the event. An additional DLT of Grade 3 thrombocytopenia was reported in 


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a subject receiving 3 mg of GS-5829.  To minimize the risk of excessive toxicity, the dose 
escalation of GS-5829 in this protocol will increase at a proportionally smaller percentage at 
each subsequent dose level. 
Assessments for AEs and monitoring for laboratory abnormalities are specified in the protocol 
and include symptom and AE assessment on Days 1, 8, 15, 22 of the first 28 day cycle and then 
every 28 days, until end of treatment followed by a 30 day Safety Follow-Up visit. Physical 
examinations will occur on Day 1of each 28-day cycle, until end of treatment followed by a 
30-day safety follow-up visit.
The safety monitoring frequency is considered sufficient to identify potential AEs as they 
emerge. In addition, mitigation strategies are incorporated into the study design. The inclusion 
and exclusion criteria are designed to ensure subjects have acceptable organ function to be 
eligible for this study such that confounding significant co-morbidities are excluded. Study 
medications will continue until disease progression, unacceptable toxicity, consent withdrawal, 
or subject’s refusal of treatment.
Enzalutamide is an approved drug for prostate cancer and has known toxicities of seizure, 
fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flushes, upper 
respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decrease, 
headache, hypertension and dizziness/vertigo. Subjects with a history of seizure will be 
excluded from receiving enzalutamide.  
Potential Benefits
The primary potential benefit of BET inhibition alone or combined with androgen inhibition is 
that therapy may delay progression or improve overall survival over the current standard of care 
which is either enzalutamide alone or chemotherapy. Participants are informed that their 
involvement in the study may offer benefits to other current or future patients with metastatic 
prostate cancer by enhancing knowledge relating to the disease course and treatment of prostate 
cancer.


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2.
OBJECTIVES
The primary objectives of this study are as follows:
Phase 1b Dose Escalation

To characterize the safety and tolerability of GS-5829 as a single agent and in combination 
with enzalutamide in subjects with mCRPC

To determine the maximum tolerated dose (MTD) of GS-5829 as a single agent and in 
combination with enzalutamide in subjects with mCRPC
Phase 2 Dose Expansion

Group 1: To evaluate the efficacy of GS-5829 as a single agent in subjects with mCRPC  
who have progressed while receiving enzalutamide (may have also received abiraterone) as 
measured by Progression Rate at Week 24 according to Prostate Cancer Working Group 2 
(PCWG2) Criteria

Group 2: To evaluate the efficacy of GS-5829 combined with enzalutamide in subjects with 
mCRPC who have progressed while receiving treatment with abiraterone (subjects may not
have previously received enzalutamide) as measured by Progression Rate at Week 24 
according to PCWG2 Criteria

Group 3:  To evaluate the efficacy of GS-5829 combined with enzalutamide in subjects with 
mCRPC who have had Prostate-Specific Antigen (PSA) progression, but not radiographic 
progression, while receiving treatment with enzalutamide (may have also previously 
received abiraterone), as measured by Progression Rate at Week 24 according to PCWG2 
Criteria
The secondary objectives of this study are as follows: 
Phase 1b Dose Escalation

To evaluate the pharmacokinetics (PK) of GS-5829 as a single agent and in combination with 
enzalutamide in subjects with mCRPC

To evaluate the efficacy of GS-5829 as a single agent and in combination with enzalutamide 
in subjects with mCRPC as measured by PCWG2 Criteria


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• 
To evaluate the safety and tolerability of GS-5829 as a single agent and in combination with 
enzalutamide in subjects with mCRPC 
• 
Group 1: To evaluate the efficacy of GS-5829 in subjects with mCRPC who have progressed 
while receiving abiraterone as measured by prostate specific antigen (PSA) at Week 12, 
progression-free survival (PFS) and overall survival (OS) 
• 
Group 2: To evaluate the efficacy of GS-5829 combined with enzalutamide in subjects with 
mCRPC who have progressed while receiving abiraterone as measured by PSA at Week 12, 
PFS and OS 
• 
Group 3: To evaluate the efficacy of GS-5829 combined with enzalutamide in subjects with 
mCRPC who have had PSA progression, but not radiographic progression, while receiving 
enzalutamide, as measured by PSA at Week 12, PFS and OS 
The explorato1y objectives of this study are as follows: 
I 
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3.
STUDY DESIGN
3.1.
Endpoints
The endpoints for this study are described in Section 8.
3.2.
Study Design
Phase 1b Dose Escalation: This is an open-label, multicenter, sequential dose-escalation study 
to evaluate the safety, tolerability, PK, and PD of GS-5829 as a single agent and in combination
with enzalutamide in subjects with mCRPC.
Dose Escalation of GS-5829
Subjects with mCRPC who have progressed on either abiraterone and/or enzalutamide will be 
sequentially enrolled at progressively higher dose levels to receive oral GS-5829 as single agent 
once daily.  Dose escalation [3+3] will be performed with cohort sizes of 3 to 6 subjects. 
Initially 3-4 subjects will be enrolled into each dose level.  The study will be initiated at a dose 
level that has been demonstrated to be safe and tolerable in the ongoing Phase 1 study
(GS-US-350-1599) in patients with solid tumors and lymphomas. Subjects will return to the 
clinic for frequent evaluation and monitoring as per the Study Procedures Table found in
Appendix 2 and Appendix 3.
The doses for each monotherapy dose level are shown in the table below. 
Table 3-1.
Dose Escalation
Dose Level
GS -5829 (once daily)
1*
1.4 mg
2
2 mg
3
3 mg
4
4 mg
5
6mg
6
9 mg
*
The initial dose level may be higher than dose level 1, depending on results in Study GS-US-350-1599
Dose levels may be modified based on emerging safety, PK, PD, and efficacy results.
If a DLT occurs within 28 days at the first dose level, this level will be expanded to enroll
2-3 additional subjects (6 subjects total).  If ≥ 2 DLTs occur in the first dose level tested, then 
one dose level lower will be opened to enroll 3-4 additional subjects.  If no DLT occurs in 
3-4 subjects or < 2 DLTs occur in up to 6 subjects at the lower dose level, then this dose level 
will be the MTD of single agent GS-5829. 


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The safety and tolerability of each dose level will be assessed by a Safety Review Team (SRT) after
all subjects in the cohort have been followed for at least 28 days after the first dose of GS-5829. 
If no DLTs occur in 3-4 subjects or < 2 DLTs occur in up to 6 subjects on the first dose level 
after 28 days on treatment, the second cohort will open.  Each subsequent cohort will open if the 
dose level preceding has no DLTs in 3-4 subjects or < 2 DLTs in up to 6 subjects.
The SRT will consist of at least one investigator and the following: 
Gilead Sciences, Inc. (Gilead) study team members: the Medical Monitor, representatives from 
Drug Safety and Public Health (DSPH), Clinical Operations and Biostatistics. Others may be 
invited to participate as members of the SRT if additional expertise is desired. The Medical 
Monitor serves as the chair of the SRT.
If a subject is enrolled in a cohort but does not complete the PK or PD analysis in the 
first 28 days of dosing, they may continue on study but an additional subject may be enrolled at
that dose level.
The MTD of monotherapy is the highest dose level with a subject incidence of 0 DLTs in 
3-4 subjects or < 2 DLTs in 6 subjects during the first 28 days of study drug dosing. A minimum of 
3 subjects need to be treated in a cohort before this dose level is deemed as the MTD.  If we do 
not determine the MTD of single agent GS-5829, the dose selected for expansion phase will be 
the highest administered monotherapy dose.   If the lowest dose evaluated is deemed the MTD, 
then the lower dose cohort may be enrolled to explore the relationship between exposure and 
efficacy and safety.
The combination dose escalation may initiate prior to identification of the MTD of single agent 
GS-5829 using a starting dose of GS-5829 that has been determined to be safe and tolerable in 
the single agent dose escalation.
Dose Escalation of GS-5829 and enzalutamide
The first 3-4 subjects to enroll will receive GS-5829 at a dose level less than or equal to the 
previously determined MTD (or a monotherapy dose that has been determined to be safe), 
combined with enzalutamide.  Enzalutamide is a strong CYP3A4 inducer, which is expected to 
decrease the exposure of GS-5829 and therefore a higher dose of GS-5829 may be required to 
achieve target coverage compared to the single agent dose.  Subjects will administer 
enzalutamide 160 mg once daily as a single agent starting on Study Day 1 through Cycle 1 
Day 1.  On Cycle 1 Day 1 (approximately 14 days after Study Day 1), subjects will administer 
GS-5829 once daily in combination with enzalutamide 160 mg once daily in order to evaluate 
the interaction of the 2 agents. Depending on the observed PK interaction, toxicity and 
tolerability observed in the single agent dose escalation, the dose escalation may continue 
beyond a dose which has been identified to be safe and tolerable in the single agent arm.  Any 
increase in the dose of GS-5829 will not be more than 100% in the next cohort.
Similar to the single agent dose escalation, the available safety, tolerability and PK data for each 
combination therapy cohort will be assessed by an SRT after all subjects in the cohort have been 
followed for at least 28 days after the first dose of GS-5829. If no DLTs occur in 3-4 subjects or 


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< 2 DLTs occur in up to 6 subjects on the first dose level after 28 days on treatment (C1D28), the 
second dose level will open.  Each subsequent dose level will open if the dose level preceding 
has no DLTs in 3-4 subjects or < 2 DLTs in up to 6 subjects.  The dose escalation intended is 
similar to that of the single agent GS-5829 (see Table 3-1).  Depending on the exposure 
observed, the data (including PK, tolerability, safety and PSA response) will be evaluated to 
determine the appropriate GS-5829 dose in combination with enzalutamide.  The dose of 
GS-5829 for the next combination therapy cohort will be communicated to the sites by 
administrative letter.
If a subject is enrolled in a cohort but does not complete the PK or PD analysis in the 
first 28 days of GS-5829 dosing, they may continue on study but an additional subject may be 
enrolled at that dose level.
The MTD of the combination therapy is the highest dose level with a subject incidence of 0 DLTs
in 3-4 subjects or < 2 DLTs in 6 subjects during the first 28 days of study drug dosing. A minimum 
of 3 subjects need to be treated at a dose level before this dose level can be deemed as the MTD.
Based on tolerability, PK, PD, efficacy and emerging data from other studies using GS-5829, 
dose escalation may be discontinued prior to reaching the MTD.
Dose Limiting Toxicity Definition
A DLT is a toxicity defined below, considered possibly related to GS-5829, occurring during the
DLT assessment window (Day 1 through Day 28) in each cohort:

Grade ≥ 4 neutropenia (absolute neutrophil count [ANC] < 500/mm3)

Grade ≥3 neutropenia (ANC < 1000/mm3) with fever (a single temperature of > 38.3°C or a 
sustained temperature of ≥38°C for more than one hour)

Grade ≥ 3 thrombocytopenia 

Grade ≥ 2 bleeding (e.g. gastrointestinal, respiratory, epistaxis, purpura)

Grade ≥3 or higher non-hematologic toxicity, except:
Grade 3 nausea or emesis with maximum duration of 48 hours on adequate medical 
therapy
Grade 3 diarrhea which persists for < 72 hours in the absence of maximal medical 
therapy

Grade ≥ 2 non-hematologic treatment-emergent adverse event (TEAE) that in the opinion of 
the investigator is of potential clinical significance such that further dose escalation would 
expose subjects to unacceptable risk

Treatment interruption of  ≥7 days due to unresolved toxicity


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For certain toxicities, such as laboratory assessments without a clear clinical correlate, a 
discussion between the investigator and medical monitor may take place to determine if this 
adverse event (AE) should be assessed as a DLT necessitating dose reduction. However, any 
Grade 3 or Grade 4 elevation in AST or ALT associated with a Grade 2 elevation in bilirubin that 
is at least possibly related to study drug will be considered a DLT.
Phase 2 Dose Expansion:
Group 1: A dose that is less than or equal to the MTD of GS-5829 monotherapy (based on 
safety, PD and tolerability) will be chosen for the expansion phase. Approximately 20 subjects 
with mCRPC who have had radiographic disease progression despite adequate testosterone 
suppression and treatment with enzalutamide will be enrolled. These subjects may have 
previously received abiraterone.  Enrollment into this group may initiate as soon as the MTD of 
single agent GS-5829 has been identified.
Group 2: A dose that is less than or equal to the MTD of GS-5829 + enzalutamide (based on 
safety, PD and tolerability) will be chosen for the expansion phase.  Approximately 20 subjects 
with mCRPC who have had radiographic disease progression despite adequate testosterone 
suppression and treatment with abiraterone will be enrolled.  These subjects may not have 
previously received enzalutamide. Enzalutamide will be initiated on Study Day 1 and GS-5829 
will initiate on Cycle 1, Day 1.
Group 3: A dose equivalent to the dose chosen for Group 2 will be chosen for an expansion 
phase. A maximum of 20 subjects with mCRPC who have had PSA only progression, but not 
radiographic progression, despite adequate testosterone suppression and treatment with 
enzalutamide will be enrolled.  These subjects may have received prior abiraterone (similar to 
Group 1).  These subjects will continue on the enzalutamide therapy they have been receiving 
(must be receiving continuous enzalutamide for at least 12 weeks prior to Cycle 1, Day 1) and 
GS-5829 will initiate on Cycle 1, Day 1) and GS-5829 will initiate on Cycle 1, Day 1.
The choice of enrolling a subject into a specific dose escalation cohort or dose expansion group 
will be based on the treatment slots open at the time of screening, inclusion/exclusion enrollment 
criteria and the discretion of the investigator.


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3.2.1.
Study Schema
Figure 3-1 provides the study schema
Figure 3-1.
Study Design and Treatment Schema
Stud Desi n and Treatment Schema 
Phase 1b - DOSE ESCALATION 
GS-5829 
N = 3 to 6 / cohort 
9 mg PO GS-5829 
Daily dosing 
6 mg PO GS-5829 
Daily dosing 
4 mg PO GS-5829 
Daily dosino 
3 mg PO GS-5829 
Daily dosing 
2 mg PO GS-5829 
Dailv dosina 
1.4 mg PO GS-5829 
Daily dosino 
G S-5829 + enzalutam ide 
N = 3 to 6 / cohort 
9 mg PO GS-5829 
Daily dosing plus enzalutamide daily 
6 mg PO GS-5829 
Daily dosing plus enzalutamide daily 
4 mg PO GS-5829 
Daily dosina plus enzalutamide daily 
3 mg PO GS-5829 
Daily dosing plus enzalutamide daily 
2 mg PO GS-5829 
Dailv dosina olus enzalutamide dailv 
1.4 mg PO GS-5829 
Dailvdosina plus enzalutamide daily 
3 + 3 Dose Escalation Design 
(n = 3 to 6 per cohort) 
Intermediate doses may be explored 
GS-5829 administered daily. Enzalutamide dosing begins on 
Study Day 1 for the combination therapy 
On days when GS-5829 and enzalutamide are both 
administered, both drugs should be administered at the same 
time. 
6 nominal dose levels 
DLT window is 28 days 
Dose escalation combination therapy may begin prior to the 
monotherapyMTD is determined. 


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3.3.
Study Treatments
Subjects who meet eligibility criteria will receive GS-5829 as a single agent or combined with 
enzalutamide orally once daily.  Each cycle will consist of 28 days.  Safety and efficacy 
assessments will occur on an outpatient basis including assessment of tumor response, physical 
exam, vitals, electrocardiogram (ECG), collection of blood samples (for routine safety labs, 
GS-5829 PK, PD markers, and biomarkers at applicable visits), and assessment of AEs. In 
addition, subjects will undergo a bone scan and CT (or MRI) every 12 weeks.
A subject who does not show evidence of disease progression may continue receiving GS-5829 
as a single agent or combined with enzalutamide once daily until disease progression (clinical or 
radiographic), unacceptable toxicity, withdrawal of consent, or other reasons specified in 
Section 3.4.  Subjects who have progressive disease by PSA measurements alone may continue 
study drug.  
Following treatment, subjects will be followed for safety for 30 days and for survival.
3.4.
Criteria for Discontinuation of Study Drug
Study medication may be discontinued in the following instances:

Documented progression of malignant disease

Death

Investigator discretion 

Non-compliance with study drug

Important protocol deviation
Phase 2 - DOSE EXPANSION 
• Dose expansion will begin after completion of t he corresponding dose-escalation phase t reatment 
o 
Group 1: GS-5829 
o 
Group 2: GS-5829 + enzalut amide 
o 
Group 3: GS-5829 + e nzalut amide 
• Dose level based upon results fro m the dose-escalation phase 
• Up to 20 additional subjects in each arm 


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
Subject decision

Lost to follow-up

Study termination by the sponsor

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree

Unacceptable toxicity, as defined in the toxicity management section of the protocol, or 
toxicity that, in the judgment of the investigator, compromises the ability to continue 
study-specific procedures or is considered to not be in the subject’s best interest
3.5.
Criteria for Removal from Study
Subjects may be removed from the study for the following reasons:

Documented progression of malignant disease

Death

Investigator discretion 

Non-compliance with study drug

Subject never dosed with study drug

Important protocol deviation 

Withdrawal of consent 

Lost to follow-up

Study termination by the sponsor

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree

Unacceptable toxicity, as defined in the toxicity management section of the protocol, or 
toxicity that, in the judgment of the investigator, compromises the ability to continue 
study-specific procedures or is considered to not be in the subject’s best interest


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Up to 72 subjects who meet the eligibility criteria will be enrolled in the phase 1b dose escalation 
portion of the study.
Up to 60 subjects who meet the eligibility criteria will be enrolled in the phase 2 dose expansion 
portion of the study.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Male 18 years of age
2) Histologically or cytologically confirmed prostate cancer (subjects with primary 
neuroendocrine carcinoma of prostate are excluded)

Phase 1b Monotherapy Escalation:  Subjects must have documented progressive disease 
by meeting at least one of the PCWG2 criteria (Appendix 4) despite treatment with 
abiraterone and/or enzalutamide

Phase 1b Combination Therapy Dose Escalation and Phase 2 Combination Dose 
Expansion (Group 2): Subjects must have documented progressive disease by meeting at 
least one of the PCWG2 criteria, despite treatment with abiraterone.  They may not have 
received prior enzalutamide or chemotherapy for mCRPC

Phase 2 Monotherapy Dose Expansion (Group 1): Subjects must have documented 
progressive disease by meeting at least one of the PCWG2 criteria, despite treatment with 
enzalutamide.  They may have received prior abiraterone, but not prior chemotherapy, for 
mCRPC

Phase 2 Combination Therapy Dose Expansion (Group 3): Subjects must have 
documented progressive disease by meeting the PCWG2 criteria for PSA progression, but 
not radiographic progression, despite treatment with enzalutamide.  They may have 
received prior abiraterone, but not prior chemotherapy, for mCRPC (similar to Group 1);
however, they must also have been on continuous enzalutamide therapy for at least 
12 weeks days prior to Cycle 1, Day 1.
3) Castration-resistant disease defined as ongoing androgen deprivation therapy with GnRH 
analogue or bilateral orchiectomy and serum testosterone level ≤ 1.73 nmol/L (50 ng/dL) at 
screening visit.   Subjects who have not had a bilateral orchiectomy must have a plan to 
maintain effective GnRH-analogue therapy for the duration of the trial.


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4) Metastatic disease documented by bone lesions on bone scan or by measurable soft tissue 
disease by CT/MRI. Patients whose disease spread is limited to regional pelvic lymph nodes 
are not eligible
5) All acute toxic effects of any prior antitumor therapy resolved to Grade ≤ 1 before the start of
study drug dosing (with the exception of alopecia [Grade 1 or 2 permitted] and neurotoxicity
[Grade 1 or 2 permitted])
6) Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1
7) Life expectancy of ≥3 months, in the opinion of the Investigator
8) Adequate organ function defined as follows:
a) Hematologic:  Platelets ≥ 100 x 109/L; Hemoglobin ≥9.0 g/dL; ANC ≥1.5 x 109/L 
(without platelet transfusion or any growth factors within previous 7 days of the 
hematologic laboratory values obtained at screening visit)
b) Hepatic: Aspartate transaminase (AST) / Alanine transaminase (ALT) ≤2.5 x upper limit 
of normal (ULN) (if liver metastases are present, ≤ 5 x ULN); total or conjugated 
bilirubin ≤ 1.5 x ULN
c) Renal: Serum Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥60 mL/min as 
calculated by the Cockroft-Gault method
9) Coagulation: International Normalized Ratio (INR) ≤1.2  
10) Male subjects of childbearing potential who engage in heterosexual intercourse must agree 
to use protocol-specified method(s) of contraception as described in Appendix 7  and refrain 
from sperm donation for at least 90 days
11) Able and willing to provide written informed consent to participate in the study
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) History or evidence of clinically significant disorder, condition, or disease that, in the opinion 
of the Investigator or Medical Monitor would pose a risk to subject safety or interfere with 
the study evaluations, procedures, or completion
2) Known brain metastasis or leptomeningeal disease
3) Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, 
active or chronic bleeding event within 28 days prior to first dose of study drug, uncontrolled 
cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with 
study requirements as judged by treating physician


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4) History of seizure, underlying brain injury with loss of consciousness, transient ischemic 
attack within the past 12 months, cerebral vascular accident and brain arteriovenous 
malformation are excluded from combination therapy with enzalutamide.  
5) Myocardial infarction, symptomatic congestive heart failure (New York Heart Association
Classification > Class II), unstable angina, or serious uncontrolled cardiac arrhythmia within
the last 6 months of Cycle 1 Day 1
6) Major surgery, defined as any surgical procedure that involves general anesthesia and a 
significant incision (ie, larger than what is required for placement of central venous access, 
percutaneous feeding tube, or biopsy) within 28 days of the first dose of study drug
7) Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of GS-5829, including any unresolved nausea, vomiting, or diarrhea that is 
Common Terminology Criteria for Adverse Events (CTCAE) Grade > 1
8) Minor surgical procedure(s) within 7 days of enrollment, or not yet recovered from prior 
surgery (placement of central venous access device, fine needle aspiration, or endoscopic 
biliary stent ≥ 1 day before enrollment is acceptable)
9) Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy) within 
21 days or 5 half-lives, whichever is longer, of study drug dosing (6 weeks for nitrosoureas, 
mitomycin C, or molecular agents with t1/2 > 10 days); concurrent use of an LHRH agonist is 
permitted for all subjects and ongoing enzalutamide is required in Group 3.
10) History of a concurrent or second malignancy, except for: adequately treated local basal cell 
or squamous cell carcinoma of the skin; cervical carcinoma in situ; superficial bladder 
cancer; breast carcinoma in situ; adequately treated Stage 1 or 2 cancer currently in complete 
remission; any other cancer that has been in complete remission for ≥ 5 years
11) History of long QT syndrome or whose corrected QT interval (QTc) measured 
(Fridericia method) at screening is prolonged (> 450 ms). Subjects who screen fail due to this 
criterion are not eligible to be re-screened
12) Prior exposure to bromodomain (BET) inhibitors
13) Clinically significant bleeding within 28 days of Cycle 1 Day 1
14) Known human immunodeficiency virus (HIV) infection
15) HBsAg positive
16) HCV antibody positive
17) Use of moderate/strong cytochrome P450 (CYP)3A4 inhibitors or moderate/strong CYP3A4 
inducers within 2 weeks prior to the first dose of study drug (with the exception of 
enzalutamide in the combination arms)


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18) Evidence of bleeding diathesis
19) History of hemoptysis of ≥2.5 mL/1 teaspoon within 6 months of Cycle 1 Day 1
20) History of high grade esophageal or gastric varices
21) Anticoagulation/antiplatelet therapy within 7 days of Cycle 1 Day 1, including low molecular 
weight heparin, or warfarin.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Enrollment
This is an open-label study.  All baseline tests and procedures must be completed prior to the 
administration of the first dose of study drug on Day 1.  It is the responsibility of the Investigator 
to ensure that subjects are eligible for the study prior to enrollment.  A subject will be considered 
enrolled once he or she has started treatment.
5.2.
Description and Handling of GS-5829 and Enzalutamide
5.2.1.
Formulation
GS-5829 will be supplied as GS-5829-02 (phosphate salt form of GS-5829) and is available as 
round, plain-faced tablets containing 1, 5, or 10 mg GS-5829. The 1, and 10 mg tablets are 
film-coated gray and the 5 mg tablets are film-coated orange.
In addition to the active ingredient, 1, and 10 mg tablets contain the following commonly used 
excipients: microcrystalline cellulose, lactose monohydrate, crospovidone, magnesium stearate, 
polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide black.  
In addition to the active ingredient, 5 mg GS-5829 tablets contain the following commonly used 
excipients: microcrystalline cellulose, lactose monohydrate, crospovidone, magnesium stearate, 
polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, FD&C yellow #6, and iron oxide 
yellow. Refer to the enzalutamide package insert Appendix 9 for the enzalutamide formulation.
5.2.2.
Packaging and Labeling
GS-5829 tablets are in white, high density polyethylene bottles with desiccant and polyester 
packing material. Each bottle contains 30 tablets and is enclosed with a white, continuous thread, 
child-resistant screw cap with an induction-sealed, aluminum-faced liner.
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice – Annex 13 (Investigational Medicinal 
Products), and/or other local regulations.
Refer to Appendix 9 for the enzalutamide packaging information.
5.2.3.
Storage and Handling
GS-5829 tablets should be stored at controlled room temperature until required for 
administration.  Controlled room temperature is defined as 25°C (77°F); excursions are permitted 
between 15°C and 30°C (59°F and 86°F). Storage conditions are specified on the label. 


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Until dispensed to the subjects, all bottles of study drug should be stored in a securely locked 
area, accessible only to authorized site personnel. The study center will be required to maintain a 
log of daily temperature readings in the storage area for the duration of the study. To ensure the 
stability and proper identification, the drug product should not be stored in a container other than 
the container in which it was supplied. Consideration should be given to handling, preparation, 
and disposal through measures that minimize drug contact with the body. Appropriate 
precautions should be followed to avoid direct eye contact or exposure through inhalation when 
handling GS-5829 tablets.
Refer to Appendix 9 for enzalutamide storage and handling information.
5.3.
Dosage and Administration of GS-5829 and Enzalutamide
GS-5829 tablets will be provided by Gilead Sciences, Inc. and will be taken orally. Initiation of 
treatment with the study drug will take place after enrollment and cohort assignment. Subjects 
will take their dose of study drug at approximately 24-hour intervals.  To reduce inter-subject 
variability on efficacy and safety, subjects will be instructed to take GS-5829 approximately
1 hour before or 2 hours after a meal, unless otherwise specified by protocol.  Grapefruit juice is 
prohibited while on study drug. In one or more monotherapy dose levels or in the monotherapy 
expansion (Group 1), on Day 1 of Cycle 2, approximately 10 subjects may be asked to
administer GS-5829 in fed state with a standardized meal (~500 to 600 calories and ~30% of 
calories from fat). If evaluation of food effect cannot be performed on Cycle 2, Day 1, it may be 
performed at a visit after Cycle 2, Day 1 (where subject has taken at least 7 consecutive days of 
GS-5829), if necessary.
XTANDI® (enzalutamide) will be supplied as 40 mg capsules for oral administration. Subjects 
assigned to receive enzalutamide in combination with GS-5829 in this study will orally 
self-administer 4 capsules of enzalutamide (160 mg total daily dose) once daily at approximately 
24-hour intervals beginning on Study Day 1 and GS-5829 will start, at the assigned dose, 14 days 
(± 3 day window) later on Cycle 1 Day 1. Subjects enrolled into Group 3 should be on at least 
12 weeks of continuous enzalutamide treatment prior to starting Cycle 1 Day 1. Capsules should 
be swallowed whole and may be taken with or without food. Refer to Appendix 9 for further 
details.
If the subject misses a dose, he should be instructed to take the study drug as soon as he 
remembers, unless more than 8 hours have elapsed since the scheduled time of the missed dose. 
In this case, the subject should be instructed to wait and take the next dose at the regularly 
scheduled time. Subjects should not take more than 1 dose of study drug at a time.
If a subject vomits within 5 minutes of dosing and the tablet is visible, the subject should be 
instructed to re-dose.  If a subject vomits more than 5 minutes after dosing or if the tablet is not 
visible, the subject should be instructed to wait and take the next dose at the regularly scheduled 
time.


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5.3.1.
Dose Adjustment of GS-5829
In the event of a Grade 3 or 4 hematologic or any non-hematologic toxicity that the investigator 
considers related to GS-5829 and is clinically significant, GS-5289 will be interrupted for a 
maximum of 28 days until the toxicity resolves to ≤ Grade 1 or returns to baseline level.  
Following resolution of the toxicity or the toxicity returns to baseline level, treatment may be 
restarted at a reduced dose as per Table 5-1.  If the toxicity does not resolve or return to baseline, 
study drug(s) GS-5829 and enzalutamide will be permanently discontinued and the subject will 
return for an End of Treatment and a 30 day Safety Follow-Up visit.  
No dose reduction of GS-5829 below 1.0 mg is allowed.  
Table 5-1.
Dose Reduction of GS-5829
Dose at time of toxicity (mg)
Restarting dose level (mg)
6
5
5
4
4
3
3
2
2
1.0
If a subject develops a recurrence of the same Grade 3 or 4 hematologic or any non-hematologic 
toxicity that the investigator considers related to GS-5829 and is clinically significant at the 
lower dose, then the subject should be permanently discontinued from all study drug(s).
After the 28 day DLT period in the Dose Escalation Phase and at any time in the Dose Expansion 
Phase, in the event of a Grade 2 hematologic or non-hematologic toxicity the investigator 
considers related to GS-5829, GS-5829 may be interrupted per the investigator’s discretion for a 
maximum of 28 days and resumed at either the same or a lower dose per Table 5-1.
Subjects who dose interrupt for a non-drug related toxicity for up to 28 days, and are deemed by 
the investigator to be clinically benefiting from GS-5829 prior to dose interruption, may resume 
GS-5829 treatment.  Non-drug related dose interruptions for longer than 28 days in subjects who 
do not have disease progression may be considered for resumption of GS-5829 after discussion 
with the Medical Monitor.
5.3.2.
Dose Adjustment in Group 2: Combination of Enzalutamide and GS-5829
Due to the CYP3A4 interaction of the two study drugs, discontinuing enzalutamide for more 
than 2 weeks may lead to a clinically significant increase in GS-5829 exposure. Therefore, in the 
event of any hematologic or non-hematologic toxicity in the combination arm, even if the 
toxicity is attributed by the investigator only to enzalutamide, both enzalutamide and GS-5829 
may need to be interrupted or discontinued according to Table 5-2.


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Table 5-2.
Dose Reduction in Group 2: Combination of Enzalutamide and 
GS-5829
Considered related to 
enzalutamide
Considered related to 
GS-5829
Considered potentially 
related to both enzalutamide 
and GS-5829 or unknown 
relationship
Grade 4 toxicity
Interrupt dosing of 
enzalutamide for at least 
7 days and not longer than 
17 days until symptoms 
improve to ≤ Grade 2, then 
resume at 120 mg. If subject is 
already at 120 mg, or it takes 
longer than 17 days to improve 
≤ Grade 2, then permanently 
discontinue both enzalutamide 
and GS-5829.
Permanently discontinue 
both enzalutamide and 
GS-5829
Permanently discontinue both 
enzalutamide and GS-5829
Grade 3 toxicity
Interrupt dosing of 
enzalutamide for at least 
7 days and a maximum of 
17 days until symptoms 
improve to ≤ Grade 2, then 
resume at 120 mg. If subject is 
already at 120 mg, or it takes 
longer than 17 days to improve 
≤Grade 2, then permanently 
discontinue both enzalutamide 
and GS-5829.
Interrupt GS-5289 for a 
maximum of 28 days until 
the toxicity resolves to 
≤Grade 1 or returns to 
baseline level. Following 
resolution of the toxicity or 
the toxicity returns to 
baseline level, treatment 
may be restarted at a 
reduced dose as per 
Table 5-1.
Enzalutamide dosing does 
not need to be interrupted 
or dose reduced.
Interrupt both enzalutamide 
and GS-5829 for at least 
7 days and a maximum of 
17 days until symptoms 
improve to ≤ Grade 1 or return 
to baseline level at which time 
subjects may resume 
enzalutamide at either 120 mg 
or 160 mg and resume 
GS-5829 at a reduced dose per 
Table 5-1. If a subject is 
already at 120 mg of 
enzalutamide, they must 
discontinue.
Intolerable 
Grade 2 Toxicity
Interrupt dosing a maximum of 
17 days until symptoms 
improve to ≤ Grade 2, then
resume at either 160 mg or 
120 mg. If subject is already at 
120 mg, or it takes longer than 
17 days to improve ≤ to 
Grade 1 then permanently 
discontinue.
Interrupt GS-5829 for a 
maximum of 28 days until 
the toxicity resolves to 
≤Grade 1 or returns to 
baseline level. Following 
resolution of the toxicity or 
the toxicity returns to 
baseline level, treatment 
may be restarted at either 
the same dose or a reduced 
dose as per Table 5-1.
Interrupt both enzalutamide 
and GS-5829 for a maximum 
of 17 days until symptoms 
improve to ≤Grade 1 or return 
to baseline level, at which 
time subjects may resume 
enzalutamide at either 120 mg 
or 160 mg and GS-5829 at the 
same dose or a reduced dose 
per Table 5-1. A subject may 
not dose reduce enzalutamide 
to less than 120 mg once daily
If a subject develops a recurrence of the same Grade 3 or 4 hematologic or non-hematologic 
toxicity that the investigator considers related to GS-5829 and is clinically significant at the 
lower dose of GS-5829, then the subject should be permanently discontinued from all study 
drug(s).


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Subjects whose dose of enzalutamide is interrupted for a non-drug related toxicity for up to 
17 days, or whose dose of GS-5829 is interrupted for up to 28 days and are deemed by the 
investigator to be clinically benefiting from the combination treatment prior to dose interruption, 
may resume combination treatment. Non-drug related dose interruptions for longer than 17 days 
(enzalutamide) or 28 (GS-5829) days in patients who do not have disease progression may be 
considered for resumption of study drugs after discussion with the Medical Monitor.
5.4.
Prior and Concomitant Medications
Subjects who have not had a bilateral orchiectomy must be receiving androgen deprivation 
therapy with a GnRH analogue prior to enrollment and must continue on GnRH-analogue 
therapy for the duration of the study.
Abiraterone and chemotherapy are prohibited while on study drug.
Phase 1b Monotherapy: Subjects must have previously received abiraterone and/or enzalutamide.
Phase 2 Monotherapy Dose Expansion (Group 1): Subjects must have previously received 
enzalutamide. Subjects must not have previously received chemotherapy for mCRPC.
Phase 1b Combination Therapy Dose Escalation and Phase 2 Combination Dose Expansion 
(Group 2): Subjects must have previously received abiraterone, but must not have previously 
received enzalutamide or chemotherapy for mCRPC.
Phase 2 Combination Therapy Dose Expansion (Group 3):  Subjects must have previously 
received enzalutamide and have been on continuous enzalutamide for the 12 weeks prior to 
Cycle 1, Day 1.  Subjects must not have previously received chemotherapy for mCRPC. Subjects 
must not have previously received chemotherapy for mCRPC.
In vitro data indicate GS-5829 is a substrate of CYP3A4. Co-administration of CYP3A4 
inhibitors may increase GS-5829 exposure. As such, co-administration of moderate and strong 
CYP3A4 inhibitors with study drug is prohibited in this study. 
Co-administration of CYP3A4 inducers may decrease GS-5829 exposure. As such, moderate and 
potent CYP3A4 inducers are prohibited while subject is on study drug and ≥2 weeks prior to 
study drug administration except for subjects in Group 2 who may receive enzalutamide as 
described in the protocol. Examples of moderate and strong CYP3A4 inhibitors and inducers are 
provided in the table below.
Table 5-3.
Examples of Concomitant Medications Prohibited in this Study
Moderate
Strong
CYP3A4 Inhibitor
Aprepitant, ciprofloxacin, crizotinib, 
diltiazem, erythromycin, 
fluconazole, imatinib, verapamil
Clarithromycin, conivaptan, 
grapefruit juice, itraconazole, 
ketoconazole, nefazodone, 
posaconazole, telithromycin, 
voriconazole
CYP3A4 Inducer
bosentan, modafinil, nafcillin
carbamazepine, phenytoin, rifampin, 
St. John’s wort


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Toxicology data from dogs demonstrated minimal to moderate gastrointestinal, pulmonary, 
muscular and intracardiac bleeding.  The mechanism for the bleeding is not understood.  
Anticoagulant medications are prohibited on study; this includes vitamin K antagonists 
(eg, warfarin), low molecular weight heparin, Factor Xa inhibitors, thrombin inhibitors and 
aspirin. If anticoagulation therapy needs to be initiated while on study treatment, the Investigator 
should consult with the Medical Monitor to determine if study treatment should be discontinued.
For subjects receiving enzalutamide, CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow 
therapeutic index should be avoided with the exception of study drug, as enzalutamide may 
decrease the plasma exposures of these drugs. Additional INR monitoring should be conducted 
in subjects receiving warfarin and enzalutamide. Strong or moderate CYP3A4 or CYP2C8 
inducers and strong CYP2C8 inhibitors should be avoided. Refer to the prescribing information 
for XTANDI® for more information regarding potential drug interactions. 
5.5.
Accountability for GS-5829 and Enzalutamide
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. This includes acknowledgement of receipt of each shipment of study drug (quantity and 
condition). All used and unused study drug dispensed to subjects must be returned to the site.
Accountability records will be provided to each study site to:

Record the date received and quantity of study drug kits

Record the date, subject number, subject initials, the study drug kit number dispensed

Record the date, quantity of used and unused study drug returned, along with the initials of 
the person recording the information.
5.5.1.
GS-5829 and Enzalutamide Return or Disposal
Study drug should be retrieved from each subject at the end of each dispensing interval. The 
quantity of study drug and the date returned by the subject should be recorded in the study drug 
accountability records. All study drug returned by the subject should be retained for review by 
the study site monitor prior to destruction.
Please see Section 9.1.7 for more information.


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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 Appendix 3 and described in the text below. Additional 
information is provided in the study manual.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
Safety and tolerability assessments will include regular monitoring of AEs, changes from 
baseline in laboratory variables, physical examinations, vital signs, and special safety 
assessments like ECGs. 
From the time of obtaining informed consent through the first administration of investigational 
medicinal product, record all serious adverse events (SAEs), as well as any non-serious AEs 
related to protocol-mandated procedures on the AEs electronic case report form (eCRF). All 
other untoward medical occurrences observed during the Screening period, including 
exacerbation or changes in medical history are to be captured on the medical history eCRF. 
See Section 7 for additional details.
6.1.
Subject Enrollment and Treatment Assignment
Subjects will be assigned a unique screening number at the time of consent.  Subject eligibility 
will be established at the conclusion of the screening evaluations. Once eligibility is confirmed, 
subjects will be assigned a unique subject number. The screening number and/or subject ID will 
be assigned for that individual subject by Gilead. The investigator will submit an enrollment 
form to Gilead for review and approval prior to enrollment of the subject. 
It is the responsibility of the investigator to ensure that each subject is eligible for the study 
before start of treatment. 
6.2.
Study Procedure Descriptions
The sections below describe the individual study procedures outlined in the subsequent sections 
and the Study Procedures Table.  During the treatment period, all visits may be performed within 
the specified window for that study visit.


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6.2.1. 
Informed Consent 
All sub· ects must sign and date th 
I 
I 
I 
Final 
Amendment2 
Subjects who screen fail must re-sign the infonned consent, in the event any screening 
procedures will be perfo1med outside of the 28-day screening window from the time of the 
first infonned consent. 
6.2.2. 
Medical History 
A complete medical histo1y will be obtained by the Investigator or qualified designee prior to 
emollment and recorded on the eCRF. 
6.2.3. 
Prior and Concomitant Medications 
At Screening, all medications taken up to 30 days prior to the screening visit will be recorded on 
the eCRF. In addition, suppo1iive therapies given during the course of the study (e.g. blood 
transfusion, growth factor) should be collected and 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 and 
non-prescription medications, pre-infusion medications (e.g. anti-emetics), and vitamins and 
minerals. 
6.2.4. 
Physical Examination 
The Investigator or qualified designee will perfo1m a complete physical examination at 
Screening and at the End of Treatment visit. Pre-dose abnonnal findings will be repo1ied on the 
medical histo1y page of the eCRF. Any changes from the pre-dose baseline physical examination 
that represent a clinically significant deterioration will be documented on the AE page of the 
eCRF. 
Weight (without shoes) should be measured with each physical examination. 
Height (without shoes) should be measured at Screening only. 
Beginning at ClDl , a modified physical examination will be perfonned to monitor for any 
changes, and will also include weight and assessment of disease-related clinical signs and 
symptoms. 
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6.2.5.
Vital Signs
Vital signs will include blood pressure, respiratory rate, pulse, oxygen saturation and 
temperature. 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.  Measurements of blood pressure should be taken per institutional 
guidelines. 
6.2.6.
Electrocardiogram 
Triplicate 12-lead ECGs reporting ventricular rate, PR, QRS, QT, and QTc intervals will be 
obtained at the applicable study visits and transferred to a central vendor for storage.  ECGs 
should always be collected prior to PK (or any other blood draw) if they are to be collected at the 
same nominal time point. Subjects should be resting quietly and free of distraction 
(e.g. tv, conversation) for 10 minutes prior to ECG collection and ECGs should be collected over 
a 5 minute window at each time point.
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.  
6.2.7.
ECOG Performance Status
The Eastern Cooperative Oncology Group (ECOG) Performance Status is an investigator 
assessment of the impact of the disease on the subject’s activities of daily living.  ECOG will be 
scored using the scale index in Appendix 8.
6.2.8.
Adverse Events
Subjects will be assessed for adverse events (AEs) per guidelines in the National Cancer Institute 
(NCI) CTCAE (version 4.03) at the time points outlined in Appendix 2 and Appendix 3. Any 
AEs reported after informed consent is obtained and throughout the study will be recorded on the 
eCRF with appropriate source documentation.  The subject will be assessed for AEs 
approximately 30 days after the last dose of study drug.  Please refer to Appendix 6 for CTCAE 
grading criteria.  
Please refer to Section 7 for additional information on AE reporting.
6.2.9.
Disease Assessments
6.2.9.1.
Bone Scans
Subjects will undergo radionuclide bone scan at Screening [within 8 weeks before Cycle 1 Day 1 
(or Study Day 1 if in the combination therapy) if the scan was performed as part of standard 
medical practice] and every 12 weeks during the treatment period.  Scans at the End of 
Treatment visit are not necessary if the prior scan was performed within 4 weeks prior to the 
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6.2.9.2.
CT or MRI
Subjects will be assessed by CT scan with contrast (or MRI, if unable to tolerate CT contrast) of 
the chest, abdomen and pelvis to document metastatic disease, identify target lesions and to 
assess response as per PCWG2 guidelines.  
In subjects who cannot tolerate iodinated contrast, a CT of the lung without contrast and MRI of 
the abdomen should be performed.  Imaging by CT scan (with contrast) or MRI or applicable 
scan will be performed at Screening (within 8 weeks before Cycle 1 Day 1 if the scan was 
performed as part of standard medical practice) and every 12 weeks during the treatment period 
regardless of cycle number or dose interruption.  During the treatment, scans may be performed 
at time points other than 12 weeks, as clinically indicated, to assess tumor progression.
Tumor burden will be characterized at baseline and subsequent response assessments will be 
carried out according to the PCWG2 Criteria. The same radiographic procedure and specification 
(eg, the same contrast agent, slice thickness, etc.) used to define measurable lesions at baseline 
must be used throughout the study for each subject. 
Please refer to Appendix 5 for additional information on PCWG2 study progression criteria.
6.2.10.
Laboratory Assessments
Screening laboratory samples should be obtained within 28 days prior to Study Day 1/Cycle 1 
Day 1 dose (GS-5829). Local laboratory CBC assessments may be collected as required for dose 
adjustments throughout the study.  Local laboratory assessments resulting in a dose change will 
be reported on the eCRF.
The central laboratory will be responsible for chemistry, hematology, coagulation, and urinalysis 
testing per Table 6-1 and storage of other study samples. If central laboratory results are not 
available, local laboratories may be used for dosing decision. Other tests listed in Table 6-1 will 
be performed by Gilead or a designated laboratory.  Any sample collected per the Schedule of 
Assessments (Appendix 2 and Appendix 3) may be analyzed for any tests necessary to ensure 
subject safety. Specific instructions for processing, labeling, and shipping samples will be 
provided in the central laboratory manual.  The date and time of sample collection will be 
recorded in the subject’s source documentation and reported to the central laboratory.
The date and time of previous GS-5829 dose will be recorded in the subject’s source 
documentation on days where PK is collected. White blood cell (WBC) differentials will be 
reported as absolute counts. All laboratory tests must be reviewed for clinical significance by the 
Investigator or qualified designee.  Eligibility will be based on central laboratory assessments
and will be collected within 7 days of Study Day 1/C1D1.
Study Day 1 and/or Cycle 1 Day 1 pre-dose samples may be drawn up to 2 days prior to the visit.
The analytes listed in Table 6-1 will be tested.


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Table 6-1.
Analytes
Serum Chemistry
Hematology
Other
Sodium
Potassium
Chloride
Glucose
BUN
Creatinine
Creatinine Clearancea
ALT
AST
Alkaline phosphatase
Total bilirubinb
Total protein
Albumin
Calcium
Magnesium
Phosphate
AAG
White Blood Cell (WBC) Count
Hemoglobin
Hematocrit
Platelet Count
Neutrophils (ANC)
Lymphocytes
Monocytes
Basophils
Eosinophils
GS-5829 concentration
Concentrations of 
GS-5829 metabolite(s), 
enzalutamide and 
enzalutamide metabolites, 
as applicable, may be 
determined
Serum and Plasma 
Hepatitis B surface 
antigen
Hepatitis C antibody
PSA
Total testosterone
Coagulation
PT/INR
aPTT
Fibrinogen
Factor VII
Fibrinogen Depredation Products
Urine
Urinalysis
a
Cockcroft-Gault using Actual Body Weight: CRCL (mL/min) = [(140-age(years)) * weight(kg)] / (serum creatinine 
(mg/dL)*72)
b
Includes direct bilirubin
c
At Screening only
6.2.11.
Pharmacokinetic & Pharmacodynamic Samples
PK samples will be collected at the timepoints listed below. GS-5829 plasma concentrations will 
be determined using a validated assay. Plasma concentrations of GS-5829 metabolites and/or 
enzalutamide and/or enzalutamide metabolites may be determined. Plasma protein binding of 
analytes may be evaluated. PD samples may be modified based on the emerging data.
Phase 1b Dose Escalation:
Monotherapy Dose Escalation
PK and PD samples for GS-5829 will be collected on Day 8 of Cycle 1 at pre-dose, 0.5, 1, 2, 3, 
4, 6, 8, and 24 hours post-dose, as well as pre-dose and 1-4 hours after GS-5829 administration 
on Day 1 and Day 15 of Cycle 1 and anytime on Day 1 of Cycles 2 through 6.  
At one or more dose levels, PK samples may be collected on Day 1 of Cycle 2 at pre-dose and 
0.5, 1, 2, 3, 4, 6, 8, and 24 hours post-dose after GS-5829 has been administered in the fed state. 
If evaluation of food effect cannot be performed on Cycle 2, Day 1, it may be performed at a 
visit after Cycle 2, Day 1, if necessary.
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Dose Escalation with Enzalutamide
PK and PD samples for GS-5829 will be collected on Day 1 and Day 15 of Cycle 1 at pre-dose 
0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose and anytime on Day 1 of Cycles 2 through 6.  
Phase 2 Dose Expansion:
Group 1
PK and PD samples will be collected on Day 8 of Cycle 1 at pre-dose and 1, 2, 4, and 6 hours 
post-dose. Sparse PK and PD samples will be collected at pre-dose and 1 - 4 hours post-dose on 
Cycle 1 Day 1 and Day 15 and anytime on Day 1 of Cycles 2 through 6.  PK samples may be 
collected on Day 1 of Cycle 2 at pre-dose and 1, 2, 4, and 6 hours post-dose after GS-5829 has 
been administered in the fed state.  If evaluation of food effect cannot be performed on Cycle 2, 
Day 1, it may be performed at a visit after Cycle 2, Day 1 if necessary.
Group 2
PK and PD samples will be collected on Cycle 2, Day 1 at pre-dose and 1, 2, 4, and 6 hours 
post-dose. Sparse PK and PD samples will be collected at pre-dose and 1 - 4 hours post-dose on 
Cycle 1, Day 1 and Day 15 and anytime on Day 1 of Cycles 3 through 6.
Group 3
PK and PD samples will be collected on Cycle 2, Day 1 at pre-dose and 1, 2, 4, and 6 hours 
post-dose. Sparse PK and PD samples will be collected at pre-dose and 1 - 4 hours post-dose on 
Cycle 1, Day 1 and Day 15 and anytime on Day 1 of Cycles 3 through 6.
6.3.
Biomarker Testing
6.3.1.
Biomarker Samples to Address the Study Objectives
Biological specimens detailed below will be collected in this study and will be used to evaluate 
the association of exploratory systemic and/or tissue specific biomarkers with study drug 
response, including efficacy and/or adverse events and to increase knowledge and understanding 
of the biology of disease and/or the validation of a companion diagnostic for GS-5829. The 
specific analyses will include, but will not be limited to, the biomarkers and assays listed below.  
Since biomarker science is a rapidly evolving area of investigation, and adverse events in 
particular are difficult to predict, it is not possible to specify prospectively all tests that will be 
done on the specimens provided.  The testing outlined below is based upon the current state of 
scientific knowledge. It may be modified during or after the end of the study to remove tests no 
longer indicated and/or to add new tests relevant to the study objectives based upon the growing 
state of art knowledge.
Whole blood, plasma and serum biomarkers will be collected in this study as detailed in 
Section 6.3.1.2 and will be used to evaluate the association of exploratory systemic and/or tissue 
specific biomarkers with study drug response, including efficacy and/or AEs and to increase 
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Biomarker specimens will be collected from all subjects. In addition, sampling time points may 
be eliminated based upon emerging data. 
The biomarker sam les will be destrn ed no later than 10 
For sampling procedures, storage conditions, and shipment instrnctions, see the Sample Handling 
and Logistics Manual. 
6.3.1.1. 
Archival Tumor Tissue 
Paraffin embedded blocks from archival tumor tissue or freshly cut unstained slides will be 
requested for all subjects who have tissue available. This is not an optional paii of the study and 
samples should be collected from all paiiicipating subjects with available tissue. Effo1i s to 
acquire a tissue sample should begin on Day 1. The samples will be used to evaluate the 
association of explorato1y biomai·kers with study diug response and may include protein, somatic 
(tumor-specific) DNA and gene expression analysis. 
6.3.1.2. 
Sernm, Plasma and Whole Blood Biomai·kers 
Whole blood for PD biomarkers will be collected at the time points listed in Appendix 2 and 
Appendix 3. Sernm collected for PSA will also be assessed. Whole blood and plasma for 
Circulating Tumor Cells (CTCs), exosome, circulating proteins and circulating tumor DNA may 
also be collected to evaluate for the presence of AR-V7 variant and for other explorato1y 
biomai·ker analysis. In addition, any remaining plasma samples obtained to measure GS-5829 
levels may also be used to measure the explorato1y PD biomarkers described above. 
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6.4. 
6.4.1. 
Pretreatment Assessments 
Screening Visit 
Final 
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The screening date will be defined as the date the subject signs the infonned consent. Subjects 
will be screened within 28 days of emolhnent to detennine eligibility for paiiicipation in the 
study. Screening laborato1y results for chemistiy, hematology, coagulation and minalysis should 
be obtained from centi·al laborato1y. Subjects must meet all eligibility criteria in order to be 
emolled. Subjects who do not emoll within the 28 day screening window will be screen failed. 
Re-screening is allowed (see Section 6.2.1). 
The following will be perfonned and documented dming Screening: 
• 
Obtain written info1med consent 
• 
Obtain medical histo1y, including prior/concomitant medication review 
• 
Complete physical examination including body weight and height 
• 
Vital Signs 
• 
Triplicate 12-lead ECG 
• 
ECOG Perfonnance Status 
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
Laboratory assessments 
Chemistry
Complete blood count (CBC) with differential 
Total testosterone
Coagulation
Urinalysis

Bone Scan

CT scan with contrast or MRI (scans taken as part of standard medical practice up to 
8 weeks prior to C1D1 are acceptable)

Record any adverse events (occurring after signing of the consent form)

Complete subject/visit information on enrollment form
Subjects meeting all of the inclusion criteria and none of the exclusion criteria, as approved by 
Gilead, will return to the clinic within 28 days after screening for enrollment into the study.
From the time of obtaining informed consent through the Cycle 1 Day 1 dose, record all serious 
adverse events (SAEs), as well as any adverse events related to protocol-mandated procedures on 
the AE eCRF. All other untoward medical occurrences observed during the screening period, 
including exacerbation or changes in medical history are to be captured on the medical history 
eCRF.  See Section 7 Adverse Events and Toxicity Management for additional details. 
6.4.2.
Re-Screening Criteria
Subjects who do not enroll within 28 days of screening will be screen failed.
Re-screening may be allowed. Subjects who are re-screened will be re-consented with new 
screening number, and will repeat the screening assessments. Gilead is to be informed prior to a 
subject re-screening.
6.5.
Treatment Assessments
Each on-study visit will be scheduled relative to C1D1. Visits will follow the schedule of 
assessments in Appendix 2 and Appendix 3.
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6.5.1.
Study Day 1
Only subjects enrolled into a combination therapy and who have met all eligibility criteria will 
return to the clinic on Study Day 1 to perform baseline assessments. 
The following baseline assessments will be conducted prior to the first dose of enzalutamide:

Physical examination, including weight

Vital signs, within 15 minutes prior to the enzalutamide dose 

ECOG performance status

Laboratory assessments and blood sampling (refer to Table 6-1)
Chemistry
CBC with differential
Urinalysis
Coagulation 

Record any adverse events 

Concomitant medications review

IP accountability and dispensing of Enzalutamide and Dosing Diary.     
6.5.2.
Baseline Visit / Cycle 1 Day 1 (C1D1)
Subjects in a monotherapy treatment who have met all eligibility criteria will return to the clinic 
on C1D1 to perform baseline assessments. C1D1 is defined as the date of the first dose of 
GS-5829, and may occur within 3 days following enrollment. 
The following baseline assessments will be conducted prior to the first dose of GS-5829:

Physical examination, including weight

Vital signs, within 15 minutes prior to the GS-5829 dose 

Triplicate 12-lead ECG

ECOG performance status


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
Laboratory assessments and blood sampling (refer to Table 6-1)
Chemistry
CBC with differential
Coagulation
Request archival tumor tissue specimen: Efforts to acquire tissue sample should begin 
on C1D1 for all subjects
Urinalysis
GS-5829 PK (see Appendix 2 and Appendix 3)
Pharmacodynamics (see Appendix 2 and Appendix 3)
PSA

Record any adverse events 

Concomitant medications review

IP accountability and dispensing of IP and Dosing Diary.    
The site will train the subject on the dosing schedule for the IP and the Dosing Diary at the time 
of dispensing. 
The following assessments will be conducted after the first dose of GS-5829:

Triplicate ECG (see Appendix 2 and Appendix 3)

Vital signs (2 and 4 hours post GS-5829 dose [±15 minutes])

GS-5829 PK (see Appendix 2 and Appendix 3)

Pharmacodynamics (see Appendix 2 and Appendix 3)
6.5.3.
Cycle 1 Day 8, Day 15 and Day 22 (C1D8, C1D15, and C1D22)
The following assessments will be conducted:

Physical exam, including weight

Vital signs
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
ECOG Performance Status (Days 8 and 22 only)

Laboratory assessments and blood sampling (refer to Table 6-1, Appendix 2 and Appendix 3)
Chemistry
CBC with differential
Coagulation (D8 only)
GS-5829 PK (see Appendix 2 and Appendix 3)
Pharmacodynamics (C1D8 and C1D15)
Urinalysis (C1D8 only)

Triplicate 12-lead ECG (see Appendix 2 and Appendix 3)

Record any adverse events 

Concomitant medications review
6.5.4.
Cycle 2 Day 1 (C2D1) and Day 1 of Subsequent Cycles
On-study visits during the treatment period may be completed within a window of 7 days. The 
following procedures will be completed on Day 1 of each subsequent cycle:

Physical examination, including weight

Vital signs 

Triplicate 12-lead ECG

ECOG Performance Status

Laboratory assessments and blood sampling (refer to Table 6-1)
Chemistry 
CBC with differential
GS-5829 PK (see Appendix 2 and Appendix 3)
Pharmacodynamics  (see Appendix 2 and Appendix 3)
Urinalysis 
PSA
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
Record any adverse events 

Concomitant medications review

IP accountability and dispensing of IP and Dosing Diary
6.5.5.
End of Treatment (EOT) Visit
The following procedures will be conducted when a subject discontinues GS-5829, with a 
window of ± 7 days, and prior to initiating a new anti-cancer regimen: 

Complete Physical examination, including weight

Vital signs (pre-dose only)

Triplicate 12-lead ECG

ECOG performance status

Laboratory assessments and blood sampling
Chemistry
CBC with differential
Coagulation
Urinalysis
PSA

Bone scan (not necessary if restaging scan was performed within the prior 4 weeks) 

CT with contrast or MRI (not necessary if restaging scan was performed within the prior 
4 weeks) 

Record any adverse events 

Concomitant medications review

IP/Dosing Diary accountability
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6.6.
Post-Treatment 30-Day Safety Follow-up Visit
All subjects will complete the 30-Day Safety Follow-Up visit.  For Phase 1b Dose Escalation 
subjects, the 30-Day Safety Follow-Up will be the final study visit.  Phase 2 Dose Expansion 
subjects will complete the 30-Day Safety Follow-Up Visit and proceed to Long Term Survival 
Follow-Up.
The following procedures will be completed 30 days after the subject’s last dose of IP, within a 
window of 7 days:

Physical examination, including weight

Vital signs

ECOG performance status

Laboratory assessments
Chemistry
CBC with differential
Urinalysis

Concomitant medications review

Record any adverse events (30 days post last dose of IP)
For subjects who come off study treatment for reasons other than disease progression, the 
Investigator should also obtain information on the subject’s post-study anti-cancer therapies, 
surgeries, and date of definitive disease progression (if known).
6.7.
Long Term Survival Follow-Up
Phase 2 Dose Expansion subjects will participate in long term survival follow-up.  These 
subjects will be contacted via phone call every 3 months for determination of long term survival
status and record of any other anti-cancer therapy for up to 2 years after the last dose of IP.  For 
subjects who discontinued the study for reasons other than disease progression, the Investigator 
should obtain information on the subject’s post-study anti-cancer therapies, surgeries, and date of 
definitive disease progression (if known).
Subjects who are alive at the time the sponsor has made the determination the study will be
ended will receive a final follow-up phone call to assess survival status and communicate the
sponsor’s decision. These subjects will be censored on the date the subject was last contacted.
The investigator will make every effort to contact the subject or a close relative or caretaker by
phone to collect survival information. The investigator should show due diligence by
documenting in the source documents steps taken to contact the subject i.e., dates of phone calls,
registered letters, etc.


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6.8.
Unscheduled Visits
Unscheduled procedures may occur at any time during the study. Vital Signs, ECOG, 12-lead 
ECG, bone scan and CT or MRI, may be conducted at these visits and recorded on the applicable 
eCRFs.
6.9.
Criteria for Discontinuation of Study Treatment
See Section 3.4 for discontinuation criteria.  
6.10.
Post Study Care
If a subject has discontinued the study treatment due to toxicity, he/she should not have 
withdrawal of consent recorded as the reason for discontinuation. Instead, the reason for
discontinuation must be recorded as due to adverse event.
Every attempt should be made to keep the subject in the study and continue collecting CT or
MRI scans for tumor assessment at every 12 weeks until disease progression or initiation of 
systemic anti-tumor therapy other than treatment per protocol. If this is not possible or 
acceptable to the subject or investigator, the subject may be withdrawn from the study. The 
subject will be asked to attend the post-treatment follow-up assessment visit above when 
discontinuing from the study treatment.
6.11.
Replacement of Subjects
If a subject is withdrawn from the study for any reason other than a DLT prior to completion of 
the DLT assessment window, a replacement subject will be enrolled at the same dose level as the 
replaced subject. To be evaluable for the DLT observation, a subject must receive at least 
21 doses of GS-5829, complete all safety procedures through Day 28, or experience a DLT prior 
to Day 28.
6.12.
Protocol Deviations
Gilead’s policy prohibits exemptions from protocol inclusion/exclusion criteria. In the event of a 
significant deviation related to gross non-compliance from the protocol or incidences that impose 
significant risk to subject safety, the investigator or designee must notify the sponsor and/or its 
designee immediately. The site will be required to document deviations in accordance with 
Gilead’s procedures and in accordance with the site’s procedures and processes.
6.13.
End of Study
End of study for a subject is defined as the date of the last study-related procedure or the date of
death for an on-study subject.


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal product, which does not necessarily have a causal relationship with the
treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. AEs may also include pre- or post-treatment complications that occur as a 
result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse reports, or 
occupational exposure. Preexisting events that increase in severity or change in nature during or 
as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an AE and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see Section 7.6.1)

Any medical condition or clinically significant laboratory abnormality with an onset date 
before the consent form is signed and not related to a protocol-associated procedure is not an 
AE. It is considered to be pre-existing and should be documented on the medical history 
CRF.
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) or serious adverse drug reaction (SADR) is defined as an event 
that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)


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
In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is reportable under 
expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
Clarification of 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 study drug 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

“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


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7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, ECG, 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 7.1.1 and 7.1.2. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result (ie, decreased 
hemoglobin).
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to study 
drug therapy using clinical judgment and the following considerations:

No: Evidence exists that the AE has an etiology other than the study drug. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the study drug.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The AE occurred as a result of protocol procedures, (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity of AEs will be graded using the CTCAE, Version 4.03 (Appendix 6).
For each episode, the highest severity grade attained should be reported.


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If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or 
Grade 5 (fatal) to describe the maximum intensity of the AE. For purposes of consistency with 
the CTCAE, these intensity grades are defined in Table 7-1.
Table 7-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1
Mild
Sign or symptom is present, but it is easily tolerated, is not expected to have a 
clinically significant effect on the subject’s overall health and well-being, does 
not interfere with the subject’s usual function, and is not likely to require medical 
attention.
Grade 2
Moderate
Sign or symptom causes interference with usual activity or affect clinical status, 
and may require medical intervention.
Grade 3
Severe
Sign or symptom is incapacitating or significantly affects clinical status and 
likely requires medical intervention and/or close follow-up.
Grade 4
Life-threatening
Sign or symptom results in a potential threat to life.
Grade 5
Fatal
Sign or symptom results in death.
The distinction between the seriousness and the severity of an 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 in Section 7.1.2.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead 
7.3.1.
Requirements for Collection Prior to Study Drug Initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the eCRF: all SAEs and AEs related to protocol-mandated procedures.
7.3.2.
Adverse Events
Following the initiation of study medication, all AEs (regardless of cause or relationship) until
30 days after last administration of study drug, must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the AE is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.


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Serious Adverse Events 
Final 
Amendment2 
All SAEs, regardless of cause or relationship that occur after the subject first consents to 
paiiicipate in the study (ie, signing the info1m ed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported in the 
eCRF database and to Gilead Dmg Safety and Public Health (DSPH) as instru cted. This also 
includes any SAEs resulting from protocol-associated procedures perfo1med after infonned 
consent is signed. 
Any SAEs and deaths that occur after the post tl'eatment follow-up visit but within 30 days of the 
last dose of study dmg, regardless of causality, should also be repo1ied. 
Investigators ai·e not obligated to actively seek SAEs after the 30-day period However, if the 
investigator leains of any SAEs that occur after study paiiicipation has concluded and the event 
is deemed relevant to the use of study diug, he/she should promptly document and repo1i the 
event to Gilead DSPH. 
All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
7.3.4. 
Electronic Serious Adverse Event ( eSAE) Reporting Process 
• 
Site personnel record all SAE data in the eCRF database and from there tr·ansmit the SAE 
info1mation 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 info1mation electr·onically, ie, the eCRF 
database is not functioning, record the SAE on the paper SAE repo1iing f01m and submit 
within 24 hours of the investigator's knowledge of the event to: 
Gilead DSPH: 
• 
As soon as it is possible to do so, any SAE repo1ied via paper must be tl'anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repo1ied via a paper fonn because the eCRF database has been locked, no 
fuiiher action is necessa1y. 
• 
For fatal or life-threatening events, copies of hospital case repo1is, autopsy repo1is, and other 
documents ai·e also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the tl'aceability of a document to the subject identifiers. 
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
Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, SADRs, or suspected unexpected serious 
adverse reactions (SUSARs). In accordance with the EU Clinical Trials Directive (2001/20/EC), 
Gilead or a specified designee will notify worldwide regulatory agencies and the relevant IEC in 
concerned Member States of applicable SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.4.1.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population
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 drug will not be considered SAEs:

Progression of underlying disease (mCRPC)

Death related to progression of underlying disease (mCRPC)
Disease progression and death from disease progression should be reported as SAEs by the 
investigator only if it is assessed that the study drug 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.
7.5.
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.


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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.
7.6.
Special Situations Reports
7.6.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of AEs associated with product complaints, and pregnancy reports regardless of an associated 
AE.  Reports of adverse reactions in infants following exposure from breastfeeding, and reports 
of adverse reactions associated with product complaints and reports arising from occupational 
exposure are also considered special situation reports.

A pregnancy report is used to report any pregnancy in female partners of male subjects on 
study

Medication error is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product while in the control of the health care provider, subject, or consumer

Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by 
a subject

Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information

An overdose is defined as an accidental or intentional administration of a quantity of a 
medicinal product given per administration or cumulatively which is above the maximum 
recommended dose as per protocol or in the product labelling (as it applies to the daily dose 
of the subject in question). In cases of a discrepancy in drug accountability, overdose will be 
established only when it is clear that the subject has taken the excess dose(s). Overdose 
cannot be established when the subject cannot account for the discrepancy except in cases in 
which the investigator has reason to suspect that the subject has taken the additional dose(s)

Product complaint is defined as complaints arising from potential deviations in the 
manufacture, packaging, or distribution of the medicinal product


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7.6.2. 
7.6.2.1. 
Instructions for Reporting Special Situations 
Instiuctions for Repo1iing Pregnancies 
Final 
Amendment2 
Pregnancies of female paiiners of male study subjects exposed to Gilead or other study diugs 
must be repo1ied and relevant info1mation should be submitted to Gilead DSPH using the 
pregnancy and pregnancy outcome fo1ms within 24 hours. Monitoring should continue until the 
conclusion of the pregnancy. If the end of the pregnancy occurs after the study has been 
completed, the outcome should be repo1ied directly to Gilead DSPH. 
Gilead DSPH contact infonnation is as 
follows: 
Fax:PPD 
Email: PU 
Refer to Appendix 7 for Pregnancy Precautions, Definition for Female of Childbeai·ing Potential, 
and Contl'aceptive Requirements. 
7.6.2.2. 
Repo1iing Other Special Situations 
All other special situation repo1i s must be repo1ied on the special situations repo1i fonn and 
fo1wai·ded to Gilead DSPH within 24 hours of the investigator becoming awai·e of the situation. 
These repo1is must consist of situations that involve study diug and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications do not need to be repo1ied on 
the special situations report fo1m; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be repo1ied on the AE fonn. 
Any inappropriate use of concomitant medications prohibited by this protocol should be 
appropriately documented as a protocol deviation. 
Refer to the eCRF completion guidelines for full instiuctions on the mechanism of special 
situations repoliing. 
All clinical sequelae in relation to these special situation repo1i s will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE repo1i fonn. Details of the symptoms and 
signs, clinical management, and outcome will be repo1ied, when available. 
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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objectives of this study are:
Phase 1b Dose Escalation

To characterize the safety and tolerability of GS-5829 as a single agent an in combination 
with enzalutamide in subjects with mCRPC

To determine the maximum tolerated dose (MTD) of GS-5829 as a single agent and in 
combination with enzalutamide  in subjects with mCRPC
Phase 2 Dose Expansion

Group 1: To evaluate the efficacy of GS-5829 as a single agent in subjects with mCRPC  
who have progressed while receiving enzalutamide (may have also received abiraterone) as 
measured by Progression Rate at Week 24 according to PCWG2 Criteria

Group 2: To evaluate the efficacy of GS-5829 combined with enzalutamide in subjects with 
mCRPC who have progressed while receiving treatment with abiraterone (may not have
previously received enzalutamide) as measured by Progression Rate at Week 24 according to 
PCWG2 Criteria

Group 3: To evaluate the efficacy of GS-5829 combined with enzalutamide in subjects with 
mCRPC who have had PSA progression, but not radiographic progression, while receiving 
treatment with enzalutamide (subjects may have also previously received abiraterone) as 
measured by Progression Rate at Week 24 according to PCWG2 Criteria
The secondary objectives of this study are:
Phase 1b Dose Escalation

To evaluate the pharmacokinetics (PK) of GS-5829 as a single agent and in combination with 
enzalutamide in subjects with mCRPC

To evaluate the efficacy of GS-5829 as a single agent and in combination with enzalutamide 
in subjects with mCRPC as measured by PCWG2 Criteria


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• 
To evaluate the safety and tolerability of GS-5829 as a single agent and in combination with 
enzalutamide in subjects with mCRPC 
• 
Group 1: To evaluate the efficacy of GS-5829 in subjects with mCRPC who have progressed 
while receiving enzalutamide as measured by PSA at Week 12, PFS and OS 
• 
Group 2: To evaluate the efficacy of GS-5829 combined with enzalutamide in subjects with 
mCRPC who have progressed while receiving abiraterone as measured by PSA at Week 12, 
PFS and OS 
• 
Group 3: To evaluate the efficacy of GS-5829 combined with enzalutamide in subjects with 
mCRPC who have had PSA progression, but not radiographic progression, while receiving 
enzalutamide as measured by PSA at Week 12, PFS and OS 
The explorato1y objectives of this study are: 
I 
8.1.2. 
Primary Endpoint 
Primary endpoints of this study are: 
Phase lb Dose Escalation: 
The prima1y endpoint of this study is incidence ofDLT as defined in Section 3.2. 
Phase 2 Dose Expansion: 
The prima1y endpoint is efficacy assessed as non-progression/progression rate at Week 24 
according to PCWG2 Criteria. 
8.1.3. 
Secondary Endpoint 
Secondary endpoints of this study are: 
Phase lb Dose Escalation: 
• 
Dose escalation subjects: PK parameters (Cmax, Ctau, AUC1ast, AUCtau, and Tmax) for GS-5829 
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Phase 1b Dose Escalation and Phase 2 Dose Expansion:

PSA response: ≥ 30% decline in PSA from baseline at 12 weeks for Groups 1, 2 and 3

Progression free survival (PFS) defined as the interval from first dose date of study drug to 
the earlier of the first documentation of definitive disease progression (assessed per PCWG2) 
or death from any cause.
Phase 2 Dose Expansion:

Overall survival (OS) defined as the interval from first dose date of study drug to death from 
any cause.
8.1.4.
Exploratory Endpoints
 
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Full Analysis Set (FAS)
The FAS includes all subjects who receive ≥ 1 dose of study drug. This analysis set will be used 
for subject characteristics and efficacy endpoints.
8.2.1.2.
Safety Analysis Set
The Safety Analysis Set for this study will be the same as FAS since this study is a 
non-randomized study. This analysis set will be used for safety endpoints, study treatment 
administration and post-study therapy.
8.2.1.3.
DLT-Evaluable Analysis Set
The DLT-Evaluable Analysis Set includes all subjects in the Safety Analysis Set who complete 
all treatment and safety procedures through Day 29, or experienced a DLT prior to Day 29. 
Determination of the MTD will be in DLT-Evaluable Analysis Set.
8.2.1.4.
Pharmacodynamic and Pharmacokinetic Analysis Sets
The PD and PK Analysis Sets consist of all subjects in the FAS who have the necessary baseline 
and on-study measurements to provide interpretable results for the specific parameters of 
interest.
CCI
I 


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8.3.
Data Handling Conventions
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 (StD), 90% confidence intervals (CIs) on the 
mean, median, minimum, and maximum. Summary tables for categorical variables will include: 
N, n, percentage, and 90% CIs on the percentage. Unless otherwise indicated, 90% CIs for binary 
variables will be calculated using the binomial distribution (exact method) and will be 2-sided. 
Data will be described and summarized by relevant dose level, analysis set, and time point. As 
appropriate, changes from baseline to each subsequent time point will be described and 
summarized by dose level. Similarly, as appropriate, the best change from baseline during the 
study will also be described and summarized by dose level. Graphical techniques (eg, waterfall 
plots, Kaplan-Meier curves, line plots) may be used when such methods are appropriate and 
informative.
The baseline value 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.
8.4.
Demographic Data and Baseline Characteristics
Subject demographic and baseline characteristics will be listed and summarized by dose level for 
the Safety Analysis Set.
8.5.
Efficacy Analysis
Estimates of progression/non-progression rate at Week 12 will be present with 90% exact CIs.
PFS and OS will be visualized using Kaplan-Meier plot, and median survival time estimate will 
be listed.
8.6.
Safety Analysis
All safety data collected on or after the date that study drug was first dispensed up to the date of 
last dose of study drug plus 30 days will be summarized by dose level. Data for the pretreatment 
will be included in data listings.
8.6.1.
Extent of Exposure
Descriptive information will be provided by dose level regarding the number of doses of study 
drug prescribed, the total number of doses taken, the percent of expected doses taken, the number 
of days of study drug, and the number and timing of prescribed dose modification and 
interruptions.
Compliance will be described by dose level 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 modification and interruptions).


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8.6.2.
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 drug to 30 days after the last dose of study drug.
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
http://www.meddramsso.com) with descriptions by System Organ Class (SOC), 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 IP will be categorized as related or unrelated.
TEAEs will be summarized by dose level. 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 SOC) is counted only once for that Preferred Term (or SOC) using the worst severity grade. 
AE descriptions will be presented by decreasing frequency for a given SOC and 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
8.6.3.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed data. 
The focus of laboratory data summarization will be on treatment-emergent laboratory 
abnormalities. A treatment-emergent laboratory abnormality is defined as an abnormality that, 
compared to baseline, worsens by ≥ 1 grade in the period from the first dose of study drug to 
30 days after the last dose of study drug. If baseline data are missing, then any graded 
abnormality (ie, an abnormality that is Grade ≥ 1 in severity) will be considered treatment 
emergent.
Hematological, serum biochemistry, and urine data will be programmatically graded according 
to CTCAE severity grade, when applicable. For parameters for which a CTCAE scale does not 
exist, reference ranges from the central laboratory will be used to determine programmatically if 


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a laborato1y parameter is below, within, or above the nonnal range for the subject's age, sex, etc. 
Hematological and sernm biochemistiy and their changes from baseline will be summarized by 
dose level, by visit. Summaiy tables will be presented for each relevant assay to show the 
number of subjects by CTCAE severity grade with conesponding percentages. For pai·ameters 
for which a CTCAE scale does not exist, the frequency of subjects with values below, within, 
and above the nonnal ranges will be summai·ized. Subjects will be chai·acterized only once for a 
given assay, based on their worst severity grade observed during a period of interest ( eg, during 
the study or from baseline to a pa1ticular visit). 
Shift tables for hematology and sernm biochemistiy will also be presented by showing change in 
CTCAE severity grade from baseline to the worst grade post-baseline. For parameters for which 
a CTCAE scale does not exist, shift tables will be presented showing change in results from 
baseline to the worst grade post baseline. Separate listings and summai·ies will be prepai·ed for 
laborato1y abno1malities that are Grade~ 3 in severity. 
8.7. 
Pharmacokinetic Analysis 
The plasma concenti·ation of GS-5829 will be summai·ized by nominal sampling time using 
descriptive statistics. PK pai·ameters (Cmax, Ciau, AUC1ast, AUCtau, and Tmax, as applicable), will 
be listed and summarized using descriptive statistics ( eg, sample size, arithmetic mean, 
geometi·ic mean, coefficient ofvai·iation (%) StD, median, minimum, and maximum). Plasma 
concenti·ations over time will be plotted in semi-logai·ithmic and lineai· fo1mats as mean± StD, 
and median (QI, Q3) if applicable. 
8.8. 
Biomarker Analysis 
Descriptive statistics of baseline and change in biomarkers will be provided at each sampling 
time for all subjects, and by dose. 
8.9. 
Sample Size 
The study will consist of up to 132 subjects. The sample size of the phase 1 b pa1t of the study 
will be dete1mined based on the number of dose levels evaluated and the emerging 
GS-5829-related toxicities, and will be up to 72 subjects. 
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In patients who have progressed on abiraterone the expected PSA response rate to enzalutamide 
is approximately 10%-26% and median radiographic/clinical progression is 4.6 to 6.6 months
{Azad et al 2015, Brasso et al 2014}.  Similarly, although data is limited, patients who have 
progressed on enzalutamide have a low PSA response to abiraterone (approximately 10%) and 
short median time to progression of approximately 15 weeks {Noonan et al 2013}.
The expectation is that at 24 weeks the non-progression rate will be > 30% with GS-5829 
monotherapy in subjects who have progressed on enzalutamide (may have received abiraterone) 
and/or with GS-5829 combined with enzalutamide in subjects who have progressed on 
abiraterone only. If the true non-progression rate is above 50%, and we do observe more than 
10 non-progression subjects from 20 treated subjects per group, it will guarantee us that lower 
bound of the 90% confidence interval of the estimated rate will be larger than 30%.


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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), 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 (GCP) Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of GCP, as outlined in 
21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 1998, 
and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, 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) to an IRB. The investigator will not begin any study subject activities until 
approval from the IRB has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC on any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial approval, with the exception of those necessary to reduce 
immediate risk to study subjects.


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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 use the most current IRB-approved consent form for documenting written 
informed consent. Each informed consent (or assent as applicable) will be appropriately signed 
and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by local 
requirements. The consent form will inform subjects about genomic testing and sample retention, 
and their right to receive clinically relevant genomic analysis results.
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, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the sponsor, IRB, or laboratory. Laboratory specimens 
must be labeled in such a way as to protect subject identity while allowing the results to be 
recorded to the proper subject. Refer to specific laboratory instructions. 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. Subject data will be processed in accordance with all applicable 
regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the study drug, and any other study information, 
remain the sole and exclusive property of Gilead 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. 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, and 
governmental approval with correspondence, informed consent, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence.


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The required source data 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)

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number)

Study discussed and date of informed consent

Dates of all visits

Documentation that protocol specific procedures were performed

Results of efficacy parameters, as required by the protocol

Start and end date (including dose regimen) of study drug, including dates of dispensing and 
return

Record of all AEs and other safety parameters (start and end date, and including causality 
and severity)

Concomitant medication (including start and end date, dose if relevant; dose changes)

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, US, Europe, or Japan) and until there are no pending or planned marketing 
applications in an ICH region; or, if no application is filed or if the application is not approved 
for such indication, until 2 years after the investigation is discontinued and regulatory authorities 
have been notified. Investigators may be required to retain documents longer if specified by 
regulatory requirements, by local regulations, or by an agreement with Gilead. The investigator 
must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from 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. Electronic CRF
should be completed on the day of the subject visit to enable the sponsor to perform central 
monitoring of safety data.  The Eligibility Criteria eCRF should be completed only after all data 
related to eligibility have been received. 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 capture 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.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused study drug supplies be destroyed at sites if they have 
applicable standard operating procedure (SOP) to do so. The study monitor will evaluate each 
study center’s study drug disposal procedures and provide appropriate instruction for destruction 
of unused study drug supplies, as needed. If the site has an appropriate SOP for drug destruction
as determined by Gilead Clinical Operations or designee (per SOP-CR-23035), the site may 
destroy used (empty or partially empty) and unused study drug supplies in accordance with that
site’s approved SOP. A copy of the site’s approved SOP will be obtained for central files. If the 
site does not have an acceptable SOP to destroy, or cannot due to other regulatory reasons, 
Gilead will provide instruction for the return if the study drug for disposal/destruction.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs, or to regulatory authority or health authority 
inspectors.
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.


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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. The investigator must submit all protocol modifications to the in 
accordance with local requirements and receive documented approval before modifications can 
be implemented.
9.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency. Gilead 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.
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 in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years.
The investigator will submit to Gilead 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. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s 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.


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9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, eg, attendance at Investigator's Meetings.  If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF 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 eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead 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 medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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Amendment 2
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10.
REFERENCES
Affer M, Chesi M, Chen WD, Keats JJ, Demchenko YN, Tamizhmani K, et al. Promiscuous 
rearrangements of the MYC locus  hijack enhancers but mostly super-enhancers 
to dysregulate MYC expression in multiple myeloma. Leukemia 2014:1-43.
Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance 
to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014;371 
(11):1028-38.
Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, et al. Therapeutic targeting 
of BET bromodomain proteins in castration-resistant prostate cancer. Nature 
2014;510 (7504):278-82.
Asangani IA, Wilder-Romans K, Dommeti VL, Krishnamurthy PM, Apel IJ, Escara-Wilke J, et 
al. BET Bromodomain Inhibitors Enhance Efficacy and Disrupt Resistance to AR 
Antagonists in the Treatment of Prostate Cancer. Molecular cancer research : 
MCR 2016.
Astellas Pharma US Inc. XTANDI® (enzalutamide) capsules for oral use. US Prescribing 
Information. Revised: September 2014:
Azad AA, Eigl BJ, Murray RN, Kollmannsberger C, Chi KN. Efficacy of enzalutamide 
following abiraterone acetate in chemotherapy-naive metastatic castration-
resistant prostate cancer patients. European urology 2015;67 (1):23-9.
Barrans S, Crouch S, Smith A, Turner K, Owen R, Patmore R, et al. Rearrangement of MYC is 
associated with poor prognosis in patients with diffuse large B-cell lymphoma 
treated in the era of rituximab. J Clin Oncol 2010;28 (20):3360-5.
Belkina AC, Denis GV. BET domain co-regulators in obesity, inflammation and cancer. Nature 
reviews. Cancer 2012;12 (7):465-77.
Brasso K, Thomsen FB, Schrader AJ, Schmid SC, Lorente D, Retz M, et al. Enzalutamide 
Antitumour Activity Against Metastatic Castration-resistant Prostate Cancer 
Previously Treated with Docetaxel and Abiraterone: A Multicentre Analysis. 
European urology 2014.
Chesi M, Robbiani DF, Sebag M, Chng WJ, Affer M, Tiedemann R, et al. AID-dependent 
activation of a MYC transgene induces multiple myeloma in a conditional mouse 
model of post-germinal center malignancies. Cancer cell 2008;13 (2):167-80.
Chng WJ, Huang GF, Chung TH, Ng SB, Gonzalez-Paz N, Troska-Price T, et al. Clinical and 
biological implications of MYC activation: a common difference between MGUS 
and newly diagnosed multiple myeloma. Leukemia 2011;25 (6):1026-35.


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Dang CV. MYC on the path to cancer. Cell 2012;149 (1):22-35.
Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, et al. BET bromodomain 
inhibition as a therapeutic strategy to target c-Myc. Cell 2011;146 (6):904-17.
Glitza IC, Lu G, Shah R, Bashir Q, Shah N, Champlin RE, et al. Chromosome 8q24.1/c-MYC 
abnormality: a marker for high-risk myeloma. Leuk Lymphoma 2014:1-6.
Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, et al. A novel androgen receptor splice 
variant is up-regulated during prostate cancer progression and promotes androgen 
depletion-resistant growth. Cancer Res 2009;69 (6):2305-13.
Hargreaves DC, Horng T, Medzhitov R. Control of inducible gene expression by signal-
dependent transcriptional elongation. Cell 2009;138 (1):129-45.
Hawksworth D, Ravindranath L, Chen Y, Furusato B, Sesterhenn IA, McLeod DG, et al. 
Overexpression of C-MYC oncogene in prostate cancer predicts biochemical 
recurrence. Prostate cancer and prostatic diseases 2010;13 (4):311-5.
Herait PE, Berthon C, Thieblemont C, Raffoux E, Magarotto V, Stathis A, et al. BET-
bromodomain inhibitor OTX015 shows clinically meaningful activity at nontoxic 
doses: interim results of an ongoing phase I trial in hematologic malignancies 
[Abstract CT231]. American Association for Cancer Research Annual Meeting 
(AACR); 2014 April 5-9; San Diego, CA. 
Janssen Biotech Inc. ZYTIGA ® (abiraterone acetate) tablets for oral use. US Prescribing 
Information. Revised: January 2015:
Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, Mele DA, et al. Targeting 
MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad 
Sci U S A 2011;108 (40):16669-74.
National Cancer Institute. SEER Stat Fact Sheets: Prostate Cancer. Available at: 
http://seer.cancer.gov/statfacts/html/prost.html. Accessed: 11 November 2014.
Nesbit CE, Tersak JM, Prochownik EV. MYC oncogenes and human neoplastic disease. 
Oncogene 1999;18 (19):3004-16.
Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN. Clinical activity of 
abiraterone acetate in patients with metastatic castration-resistant prostate cancer 
progressing after enzalutamide. Ann Oncol 2013;24 (7):1802-7.
Nupponen NN, Kakkola L, Koivisto P, Visakorpi T. Genetic alterations in hormone-refractory 
recurrent prostate carcinomas. Am J Pathol 1998;153 (1):141-8.


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Perry AM, Alvarado-Bernal Y, Laurini JA, Smith LM, Slack GW, Tan KL, et al. MYC and 
BCL2 protein expression predicts survival in patients with diffuse large B-cell 
lymphoma treated with rituximab. Br J Haematol 2014;165 (3):382-91.
Shi J, Vakoc CR. The mechanisms behind the therapeutic activity of BET bromodomain 
inhibition. Mol Cell 2014;54 (5):728-36.
Yuan X, Cai C, Chen S, Yu Z, Balk SP. Androgen receptor functions in castration-resistant 
prostate cancer and mechanisms of resistance to new agents targeting the 
androgen axis. Oncogene 2014;33 (22):2815-25.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table – Phase 1b and 2 Monotherapy
Appendix 3.
Study Procedures Table – Phase 1b and 2 Combination Therapy
Appendix 4.
Criteria of Progression for Trial Eligibility by Disease Manifestation (PCWG2, 
JCO 2008)
Appendix 5.
On Study Outcome/Efficacy Criteria (PCWG2, JCO 2008)
Appendix 6.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03
Appendix 7.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 8.
Performance Status Scoring System (ECOG)
Appendix 9.
Enzalutamide (Xtandi®) Prescribing Information


GS-5829 
Protocol GS-US-350-1604 
Final 
Gilead Sciences, Inc. 
Amendment 2 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase lb/2 Study to Evaluate the Safety, Tolerability, Pharmacok.inetics, and 
Pharmacodynamics of GS-5829 as a Single Agent and In Combination with Enzalutamide in 
Subjects with Metastatic Castrate-Resistant Prostate Cancer 
GS-US-350-1604, Protocol Amendment 2, 30 June 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
Name (Printed) 
Author 
Date 
/ 
PPD 
S1gna re 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page90 
30 June 2016 


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Appendix 2.
Study Procedures Table – Phase 1b and 2 Monotherapy
Study Phase
Screening
First 28 Days
Cycle  2 Day 1 
and Every 
4 weeks
Every 
12 weeks
EOT
30-day 
Safety 
Follow-up18
Survival 
Follow-Up20
Cycle Day
Day -28
Cycle 1
Day 1*
Day 8
Day 15
Day 22
Window (day)
-28
±1
±2
±3
±7
±7
±7
±7
Informed Consent
X
Medical and Medication 
History1
X
Physical Examination2
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
Vital Signs3
X
X
X
X
X
X
X
X
Triplicate 12-lead ECG4
X
X
X
X
X
Adverse events/Concomitant 
medications7
X
X
X
X
X
X
X
X
X
GS-5829 Accountability 
and/or Dispensing5  
X
X
X
Dosing Diary Accountability 
and/or Dispensing
X
X
X
Enrollment
X
CBC with Differential
X8
X
X
X
X
X
X
X
Chemistry21
X8
X
X
X
X
X
X
X
Coagulation9
X8
X
X
X
Urinalysis 
X8
X
X
X
X
X
GS-5829 Intensive PK10
X
X
X
GS-5829 Sparse PK10
X
X
X


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Amendment 2
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Study Phase
Screening
First 28 Days
Cycle  2 Day 1 
and Every 
4 weeks
Every 
12 weeks
EOT
30-day 
Safety 
Follow-up18
Survival 
Follow-Up20
Cycle Day
Day -28
Cycle 1
Day 1*
Day 8
Day 15
Day 22
Window (day)
-28
±1
±2
±3
±7
±7
±7
±7
GS-5829 
pharmacodynamic11
X
X
X
X
Tumor Markers PSA13
X
X
X
Archival Tumor Tissue14
X
CT/MRI16
X
X
X
Radionuclide Bone Scan17
X
X
X
Treatment Response 
Assessment19
X
X
Phone call 
X
*
Day 1 pre GS-5829 lab samples may be drawn up to two days prior to the Day 1 visit.
1.
Medical history includes significant past medical events (eg, prior hospitalizations or surgeries), a review of the disease under study, prior anti-cancer therapies, historical PSA 
levels and any concurrent medical illnesses.
2.
Screening and End of Treatment Physical Examinations (PE) will be a complete PE. Beginning at C1D1, a modified physical examination will be performed.  Weight 
(without shoes) should be measured at each PE.  Height (without shoes) is measured at Screening only.
3.
C1D1 Vital Signs will be taken within 15 min pre-GS-5829 dose and 2 and 4 hours post dose (+/- 15 min); vital signs will be taken pre-dose only at all subsequent visits.  
Oxygen saturation will be tested with a pulse oximeter.
4.
Triplicate ECG will be collected at any time during Screening window, Day 1 of Cycles 2-6 (at pre-dose), and at EOT. In Phase 1b monotherapy, triplicate ECGs will be 
collected on C1D1 at pre-dose and 1-4 hrs post-dose and on C1D8 at pre-dose, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, and 8 hours post dose (+/- 20 min). In Phase 2 dose 
expansion, triplicate ECGs will be collected on C1D1 at pre-dose and 1-4 hrs post-dose and on C1D8 at pre-dose, 1 hour, 2 hours, 4 hours, and 6 hours post dose 
(+/- 20 min). ECGs should preferably be collected prior to PK (or any other blood draw) if they are to be collected at the same nominal time point. Subjects should be resting 
quietly and free of distraction (eg, TV, conversation) for 10 minutes prior to ECG collection and ECGs should be collected over a 5 minute window at each time point.
5.
Administer GS-5829 in a fed state on C2D1 in selected dose level.
6.
Beginning on C1D1, subjects will receive GS-5829 daily. 
CCI
CCI
--------------------------------------------------------------


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7.
Adverse event reporting period begins once the Informed Consent Form has been signed.  AEs will be assessed using NCI CTCAE (v 4.03) criteria at pre- and post-GS-5829 
dosing during applicable clinic visits. Subjects will also return to clinic at 30-day post last IP dose to assess AEs and SAEs.  At screening, all medications taken up to 30 days 
prior to screening will be documented in the eCRF.
8.
Screening chemistry, hematology, coagulation, and urinalysis to be collected within 7 days of C1D1 for central lab assessment.
9.
Coagulation assessment includes PT/PTT, fibrinogen, Factor VII, fibrinogen degradation products (FDP).
10. In Phase 1b monotherapy: plasma samples for GS-5829 PK will be collected on Day 8 of Cycle 1 at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post-dose as well as pre-dose 
and 1-4 hours after GS-5829 administration on Day 1 and Day 15 of Cycle 1 and anytime on Day 1 of Cycles 2 through 6.  At one or more dose levels, PK samples will be 
collected on Day 1 of Cycle 2 at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post-dose. (C2D1: If intensive PK is collected for that cohort, then sparse PK does not need to 
be collected.)  In Phase 2 dose expansion Group 1:  PK samples will be collected on Day 8 of Cycle 1 at pre-dose and 1, 2, 4, and 6 hours post dose.  Sparse PK samples will 
be collected at pre-dose and 1 - 4 hours post-dose on Cycle 1 Day 1 and Day 15 and anytime on Day 1 of Cycles 2 through 6.  
11. In Phase 1b monotherapy: PD biomarker sampling will be collected at pre-dose, 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose relative to GS-5829 administration on Cycle 1 
Day 8.  PD samples will also be collected pre-dose and 1-4 hours post dose on Cycle 1 Day 1 and Cycle 1 Day 15.  Additional PD samples will be collected at anytime on 
Day 1 of Cycles 2 through 6.In phase 2 dose expansion Group 1: PD samples will be collected on Day 8 of Cycle 1 at pre-dose and 1, 2, 4, and 6 hrs post-dose. Sparse PD will 
be collected at pre-dose and 1 - 4 hours post-dose on Cycle 1 Day 1 and Day 15 and anytime on Day 1 of Cycles 2 through 6.  
 
13. Tumor markers PSA will be collected on C1D1 at pre-dose and on Day 1 of every subsequent Cycle at pre-dose.
14. If available, paraffin embedded archival tumor tissue block for shipment to Gilead or its designee will be requested at C1D1.
16. Tumor evaluation by CT/MRI or applicable scan will be performed during screening (within 8 weeks of Cycle 1 Day 1) and every 12 weeks thereafter. The same radiographic
procedure used to define measurable lesions must be used throughout the study for each subject. CT/MRI to be done at EOT visit if not done within the previous 4 weeks. 
17. Subjects will also undergo a bone scan. Scan at EOT visit is not necessary if the previous scan is performed within 4 weeks of the EOT. 
18. For Phase 1b Dose Escalation subjects, the 30-Day Safety Follow-Up will be the final study visit.  Phase 2 Dose Expansion subjects will complete the 30-Day Safety 
Follow-Up Visit and proceed to Long Term Survival Follow-Up.
19. Tumor burden as assessed by PCWG2 Guidelines.
20. LTFU will begin for subjects participating in phase 2 after the 30 day Safety Follow Up visit for up to 2 years after the last dose of IP.
21. AAG will be collected at Screening, pre-dose on C1D1 and C1D8 only.
CCI
CCI


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Amendment 2
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Appendix 3.
Study Procedures Table – Phase 1b and 2 Combination Therapy
Study Phase
Screening
Study 
Day 1
First 28 Days
Cycle 2 Day 1
and Every 
4 weeks
Every 
12 weeks
EOT
30-day 
Safety 
Follow-
up18
Survival 
Follow-Up20
Cycle Day
Day -28
Cycle 1
Day 1*
Day 8
Day 15
Day 22
Window (day)
-28
-3
±3
±1
±2
±3
±7
±7
±7
±7
Informed Consent
X
Medical and Medication 
History1
X
Physical Examination2
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
Vital Signs3
X
X
X
X
X
X
X
X
X
Triplicate 12-lead ECG4
X
X
X
X
X
Adverse 
events/Concomitant 
medications7
X
X
X
X
X
X
X
X
X
X
GS-5829 Accountability 
and/or Dispensing  
X
X
X
Enzalutamide
Accountability and/or 
Dispensing6  
X
X
X
X
Dosing Diary 
Accountability and/or 
Dispensing
X
X
X
Enrollment
X


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Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
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30 June 2016
Study Phase
Screening
Study 
Day 1
First 28 Days
Cycle 2 Day 1
and Every 
4 weeks
Every 
12 weeks
EOT
30-day 
Safety 
Follow-
up18
Survival 
Follow-Up20
Cycle Day
Day -28
Cycle 1
Day 1*
Day 8
Day 15
Day 22
Window (day)
-28
-3
±3
±1
±2
±3
±7
±7
±7
±7
CBC with Differential
X8
X
X
X
X
X
X
X
X
Chemistry5
X8
X
X
X
X
X
X
X
X
Coagulation9
X8
X
X
X
X
Urinalysis 
X8
X
X
X
X
X
X
GS-5829 Intensive PK10
X
X
X
GS-5829 Sparse PK10
X
X
X
GS-5829 
pharmacodynamic11
X
X
X
X
Tumor Markers PSA13
X
X
X
Archival Tumor Tissue14
X
CT/MRI16
X
X
X
Radionuclide Bone Scan17
X
X
X
Treatment Response 
Assessment19
X
X
CCI
CCI


GS-5829
Protocol GS–US-350-1604
Final
Gilead Sciences, Inc.
Amendment 2
CONFIDENTIAL
Page 96
30 June 2016
Study Phase
Screening
Study 
Day 1
First 28 Days
Cycle 2 Day 1
and Every 
4 weeks
Every 
12 weeks
EOT
30-day 
Safety 
Follow-
up18
Survival 
Follow-Up20
Cycle Day
Day -28
Cycle 1
Day 1*
Day 8
Day 15
Day 22
Window (day)
-28
-3
±3
±1
±2
±3
±7
±7
±7
±7
Phone call 
X
*
Day 1 pre GS-5829 lab samples may be drawn up to two days prior to the Day 1 visit.
1.
Medical history includes significant past medical events (eg, prior hospitalizations or surgeries), a review of the disease under study, prior anti-cancer therapies, historical PSA 
levels and any concurrent medical illnesses.
2.
Screening and End of Treatment Physical Examinations (PE) will be a complete PE. Beginning at C1D1, a modified physical examination will be performed.  Weight 
(without shoes) should be measured at each PE.  Height (without shoes) is measured at Screening only.
3.
Study Day 1 vital signs will be take 15 min pre-enzalutamide dose.  C1D1 Vital Signs will be taken within 15 min pre-GS-5829 dose and 2 and 4 hours post dose 
(+/- 15 min); vital signs will be taken pre-dose only at all subsequent visits.  Oxygen saturation will be tested with a pulse oximeter.
4.
Triplicate ECG will be collected at any time during Screening window, Day 1 of Cycles 2-6 (at pre-dose), and at EOT. In Phase 1b dose escalation with enzalutamide, 
triplicate ECGs will be collected on Cycle 1, Day 1 and Day 15 at pre-dose, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, and 8 hours post dose (+/- 20 min). In Phase 2 dose 
expansion, triplicate ECGs will be collected on C1D1 and C1D15 at pre-dose and 1-4 hrs post-dose and on C2D1 at pre-dose, 1 hour, 2 hours, 4 hours, and 6 hours post dose 
(+/- 20 min). ECGs should preferablyu be collected prior to PK (or any other blood draw) if they are to be collected at the same nominal time point. Subjects should be resting 
quietly and free of distraction (eg, TV, conversation) for 10 minutes prior to ECG collection and ECGs should be collected over a 5 minute window at each time point.
5.
AAG will be collected at Screening, pre-dose on C1D1 and C1D8 only
6.
Subjects in phase 1b dose escalation with enzalutamide and Phase 2 Group 2 or Group 3 receive enzalutamide alone beginning on Study Day 1, then in combination with 
GS-5829 beginning C1D1.
7.
Adverse event reporting period begins once the Informed Consent Form has been signed.  AEs will be assessed using NCI CTCAE (v 4.03) criteria at pre- and post-GS-5829 
dosing during applicable clinic visits. Subjects will also return to clinic at 30-day post last IP dose to assess AEs and SAEs.  At screening, all medications taken up to 30 days 
prior to screening will be documented in the eCRF.
8.
Screening chemistry, hematology, coagulation, and urinalysis to be collected within 7 days of C1D1 for central lab assessment.
9.
Coagulation assessment includes PT/PTT, fibrinogen, Factor VII, fibrinogen degradation products (FDP).
10. In Phase 1b dose escalation with enzalutamide: PK samples will be collected on Day 1 and Day 15 of Cycle 1 at pre-dose 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose and 
anytime on Day 1 of Cycles 2 through 6. In Phase 2 dose expansion Group 2: PK samples will be collected on Cycle 2, Day 1 at pre-dose and 1, 2, 4, and 6 hours post-dose. 
Sparse PK will be collected at pre-dose and 1 - 4 hours post-dose on Cycle 1 Day 1 and Day 15 and anytime on Day 1 of Cycles 3 through 6. In Phase 2 dose expansion 
Group 3: PK  samples will be collected on Cycle 2, Day 1 at pre-dose and 1, 2, 4, and 6 hours post-dose. Sparse PK and PD samples will be collected at pre-dose and 
1 - 4 hours post-dose on Cycle 1, Day 1 and Day 15 and anytime on Day 1 of Cycles 3 through 6.
11. In Phase 1b dose escalation with enzalutamide: PD biomarker samples will be collected on Day 1 and Day 15 of Cycle 1 at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours 
post-dose and anytime on Day 1 of Cycles 2 through 6. In Phase 2 dose expansion Group 2: PD samples will be collected on Day 15 of Cycle 1 at pre-dose and 1, 2, 4, and 
6 hrs post-dose. Spare PD will be collected at pre-dose and 1-4 hours post-dose on Cycle 1 Day 1 and Day 8 and anytime on Day 1 of Cycles 2 through 6. In Phase 2 dose 
expansion Group 3: PD samples will be collected on Cycle 2, Day 1 at pre-dose and 1, 2, 4, and 6 hours post-dose. Sparse PK and PD samples will be collected at pre-dose 
and 1 - 4 hours post-dose on Cycle 1, Day 1 and Day 15 and anytime on Day 1 of Cycles 3 through 6.


GS-5829 
Protocol GS-US-350-1604 
Gilead Sciences, Inc. 
Final 
Amendment2 
The same radiographic 
procedure used to define measurable lesions must be used throughout the study for each subject. CT/MRI to be done at EOT visit if not done within the previous 4 weeks. 
17. Subjects will also undergo a bone scan. Scan at EOT visit is not necessa1y if the previous scan is pe1fo1med within 4 weeks of the EOT. 
18. For Phase lb Dose Escalation subjects, the 30-Day Safety Follow-Up will be the final study visit. Phase 2 Dose Expansion subjects will complete the 30 Day Safety 
Follow-Up Visit and proceed to Long Te1m Survival Follow-Up. 
19. Tumor burden as assessed by PCWG2 Guidelines. 
20. LTFU will begin for subjects participating in phase 2 after the 30 day Safety Follow Up visit for up to 2 years after the last dose ofIP. 
CONFIDENTIAL 
Page 97 
30 June 2016 


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Final
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Amendment 2
CONFIDENTIAL
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Appendix 4.
Criteria of Progression for Trial Eligibility by Disease Manifestation 
(PCWG2, JCO 2008)
Variable
Criteria
PSA
Obtain sequence of rising values at a minimum of 1-week intervals
2.0 ng/mL minimum starting value

Estimate pre-therapy PSA-Doubling Time if 3 or more values available 4 or 
more weeks apart
Target lesions
Nodal or visceral progression sufficient for trial entry independent of PSA
RECIST to record soft-tissue (nodal and visceral) lesions as target or non-target
Only lymph nodes ≥ 2 cm in diameter should be used to asses for a change in 
size
Prostate
Directed pelvic imaging (CT, MRI, PET/CT, endorectal MRI, transrectal 
ultrasound) to document presence of absence of disease
Bone
Progression = appearance of 2 or more new lesions
Confirm ambiguous results by other imaging modalities (eg, CT or MRI)
Other sites
Patients with treated epidural lesions and no other epidural progression are 
eligible


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Appendix 5.
On Study Outcome/Efficacy Criteria (PCWG2, JCO 2008)
Variable
Criteria
PSA
Ignore early rises (prior to 12 weeks) in determining PSA response
For control/relieve/eliminate endpoints: 

Percent change from baseline at 12 weeks and maximal change at any time 
using a waterfall plot. 
For progression endpoints: 

Decline from baseline: record start of therapy to first PSA increase that is 
≥25% and ≥ 2 ng/mL above the nadir and confirmed by a second value 3 or 
more weeks later.

No decline from baseline: PSA progression ≥ 25% and ≥ 2 ng/mL after 
12 weeks
Soft tissue
Use RECIST with caveats:

Only report changes in lymph nodes that were ≥ 2 cm in diameter at 
baseline

Record changes in nodal and visceral soft tissue sites separately

Record complete elimination of disease at any site separately

Confirm favorable change with second scan
Bone
The appearance of ≥ 2 new lesions, and, for the first reassessment only, a 
confirmatory scan performed ≥ 6 weeks later that shows ≥ 2 additional new 
lesions
The date of progression is the date of the first scan that shows the change


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Amendment 2
CONFIDENTIAL
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Appendix 6.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03
CTCAE v 4.03 can be accessed from the link below: 
http://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf


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Amendment 2
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Appendix 7.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1. Pregnancy and Contraception Requirements for Males and Females of Childbearing 
Potential 
The risks of treatment with GS-5829 during pregnancy have not been evaluated. Enzalutamide 
treatment of pregnant mice resulted in an increased incidence of embryo-fetal deaths and 
external and skeletal changes, and is contraindicated in pregnant women and women of 
child-bearing potential. Females will not be enrolled in this study. 
1) Definitions
a
Definition of Childbearing Potential pertaining to Female Partners of Male 
Study Subjects
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. 
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.
b
Definition of Male Fertility
For the purposes of this study, a male born subject is considered to be fertile after the 
initiation of puberty unless permanently sterile by bilateral orchidectomy or medical 
documentation.
c
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.


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GS-5829 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.
Male subjects must also refrain from sperm donation during treatment and until at 
least 90 days after the end of relevant systemic exposure.
2) 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.
3) Procedures to be Followed in the Event of Pregnancy
Subjects whose partner has become pregnant or suspects she is pregnant during the study 
must report the information to the investigator.  
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are 
outlined in Section 7.6.2.1.


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Amendment 2
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Appendix 8.
Performance Status Scoring System (ECOG)
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead


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Appendix 9.
Enzalutamide (Xtandi®) Prescribing Information
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203415lbl.pdf

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 1b/2 Study to Evaluate the Safety, Tolerability,
Pharmacokinetics, and Pharmacodynamics of GS-5829 as a
Single Agent and In Combination with Enzalutamide in 
Subjects with Metastatic Castrate-Resistant Prostate Cancer
Name of Test Drug:
GS-5829
Study Number:
GS-US-350-1604
Protocol Version (Date):
Amendment 2 (30 June 2016)
Analysis Type:
CSR
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
21 November 2019
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r) GILEAU 


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF TABLES.........................................................................................................................................................4
LIST OF ABBREVIATIONS........................................................................................................................................5
PHARMACOKINETIC ABBREVIATIONS................................................................................................................7
1.
INTRODUCTION ................................................................................................................................................8
1.1.
Study Objectives ......................................................................................................................................8
1.2.
Study Design..........................................................................................................................................10
1.3.
Sample Size and Power..........................................................................................................................11
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................12
2.1.
Interim Analyses ....................................................................................................................................12
2.2.
Final Analysis ........................................................................................................................................12
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................13
3.1.
Analysis Sets..........................................................................................................................................13
3.1.1.
All Enrolled Analysis Set.....................................................................................................13
3.1.2.
Full Analysis Set ..................................................................................................................13
3.1.3.
Safety Analysis Set...............................................................................................................13
3.1.4.
Dose-Limiting Toxicity (DLT) Analysis Set........................................................................13
3.1.5.
Pharmacokinetic Analysis Set..............................................................................................14
3.2.
Subject Grouping ...................................................................................................................................14
3.3.
Strata and Covariates..............................................................................................................................14
3.4.
Examination of Subject Subgroups........................................................................................................14
3.5.
Multiple Comparisons............................................................................................................................14
3.6.
Missing Data and Outliers......................................................................................................................14
3.6.1.
Missing Data ........................................................................................................................14
3.6.2.
Outliers.................................................................................................................................15
3.7.
Data Handling Conventions and Transformations .................................................................................15
3.8.
Analysis Visit Windows.........................................................................................................................16
3.8.1.
Definition of Study Day .......................................................................................................16
3.8.2.
Analysis Visit Windows.......................................................................................................16
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window................................................................................................................................17
4.
SUBJECT DISPOSITION ..................................................................................................................................18
4.1.
Subject Enrollment and Disposition.......................................................................................................18
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................18
4.2.1.
Duration of Exposure to GS-5829........................................................................................18
4.2.2.
Adherence to GS-5829.........................................................................................................19
4.2.2.1.
On-Treatment Adherence ...............................................................................19
4.3.
Protocol Deviations................................................................................................................................20
5.
BASELINE CHARACTERISTICS....................................................................................................................21
5.1.
Demographics and Baseline Characteristics ..........................................................................................21
5.2.
Other Baseline Characteristics ...............................................................................................................21
5.3.
Medical History......................................................................................................................................21
5.4.
Prior Anticancer Therapy.......................................................................................................................21
6.
EFFICACY ANALYSES ...................................................................................................................................22


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6.1.
Primary Efficacy Endpoint.....................................................................................................................22
6.1.1.
Definition of the Primary Efficacy Endpoint .......................................................................22
6.1.2.
Analysis of the Primary Efficacy Endpoint..........................................................................24
6.2.
Secondary Efficacy Endpoints ...............................................................................................................25
6.2.1.
Definition of Secondary Efficacy Endpoints........................................................................25
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints..........................................................25
7.
SAFETY ANALYSES........................................................................................................................................26
7.1.
Adverse Events and Deaths....................................................................................................................26
7.1.1.
Adverse Event Dictionary ....................................................................................................26
7.1.2.
Adverse Event Severity........................................................................................................26
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................26
7.1.4.
Serious Adverse Events........................................................................................................26
7.1.5.
Treatment-Emergent Adverse Events...................................................................................26
7.1.5.1.
Definition of Treatment-Emergent Adverse Events .......................................26
7.1.5.2.
Incomplete Dates ............................................................................................27
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................27
7.1.6.1.
Summaries of AE Incidence by Severity Grades............................................27
7.1.6.2.
Summary of Deaths ........................................................................................29
7.1.7.
Additional Analysis of Adverse Events ...............................................................................29
7.1.7.1.
Dose Limiting Toxicity...................................................................................29
7.1.7.2.
Treatment-Emergent Adverse Events (TEAE) of Interest..............................29
7.2.
Laboratory Evaluations ..........................................................................................................................29
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................30
7.2.2.
Graded Laboratory Values ...................................................................................................30
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities.............................................30
7.2.2.2.
Summaries of Laboratory Abnormalities........................................................31
7.2.3.
Liver-related Laboratory Evaluations...................................................................................31
7.2.4.
Shifts Relative to the Baseline Value ...................................................................................32
7.3.
Vital Signs..............................................................................................................................................32
7.4.
Prior and Concomitant Medications.......................................................................................................32
7.4.1.
Prior Medications .................................................................................................................32
7.4.2.
Concomitant Medications.....................................................................................................32
7.5.
Electrocardiogram Results .....................................................................................................................33
7.5.1.
Corrected QT Intervals.........................................................................................................33
7.5.2.
PR and QRS Intervals...........................................................................................................34
7.6.
ECOG Performance Status.....................................................................................................................34
7.7.
Other Safety Measures ...........................................................................................................................35
7.8.
Changes From Protocol-Specified Safety Analyses...............................................................................35
8.
PHARMACOKINETIC ANALYSES ................................................................................................................36
8.1.
PK Sample Collection............................................................................................................................36
8.2.
PK Analyses Related to Intensive PK Sampling....................................................................................36
8.2.1.
Estimation of Pharmacokinetic Parameters..........................................................................36
8.2.2.
Pharmacokinetic Parameters ................................................................................................36
8.2.3.
PK/PD Analyses...................................................................................................................38
9.
REFERENCES ...................................................................................................................................................39
10.
SOFTWARE.......................................................................................................................................................40
11.
SAP REVISION..................................................................................................................................................41
12.
APPENDICES ....................................................................................................................................................42


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Appendix 1.
Schedule of Assessments........................................................................................................42
LIST OF TABLES
Table 6-1.
Event/Censoring Scheme of Analysis for PFS .......................................................................23
Table 8-1.
Pharmacokinetic Parameters for Each Analyte ......................................................................37


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LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
CI
confidence interval
CRF
case report form
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DLT
dose-limiting toxicity
ECG
electrocardiogram
ET
early termination
FAS
Full Analysis Set
HLT
high-level term
LTT
lower-level term
LOQ
limit of quantitation
mCRPC
metastatic castrate-resistant prostate cancer
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
OS
overall survival
PFS
progression-free survival
PK
pharmacokinetics
PSA
prostate specific antigen
PT
preferred term
Q1, Q3
first quartile, third quartile
QRS
electrocardiographic deflection between the beginning of the Q wave and termination of the 
S wave representing time for ventricular depolarization
QT
electrocardiographic interval between the beginning of the Q wave and termination of the 
T wave representing the time for both ventricular depolarization and repolarization to occur
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RR
electrocardiographic interval representing the time measurement between the R wave of one 
heartbeat and the R wave of the preceding heartbeat
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
StD
standard deviation
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings


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ULN
upper limit of normal
VR
ventricular rate
WHO
World Health Organization


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PHARMACOKINETIC ABBREVIATIONS
AUClast
area under the concentration versus time curve from time zero to the last quantifiable 
concentration
AUCtau
area under the concentration versus time curve over the dosing interval
%AUCexp
percentage of AUC extrapolated between AUClast and AUCinf
AUCx xx
partial area under the plasma/serum concentration versus time curve from time “x” to time “xx”
Clast
last observed quantifiable concentration of the drug 
Cmax
maximum observed concentration of drug 
Ctau
observed drug concentration at the end of the dosing interval
CLss/F
apparent oral clearance after administration of the drug:
at steady state: CLss/F = Dose/AUCtau, where “Dose” is the dose of the drug
Vz/F
apparent volume of distribution during terminal phase after non-intravenous administration of the 
drug
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural log of 
2 by the terminal elimination rate constant (z)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
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
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-350-1604. This SAP is based on the study protocol amendment 2 dated 
30 June 2016 and the electronic case report form (eCRF). The SAP will be finalized before 
database finalization for the CSR analysis. Any changes made after the finalization of the SAP 
will be documented in the CSR.
The original study included two phases in the design: phase 1b dose escalation and phase 2 dose 
expansion. It was decided by the sponsor during the dose escalation phase that this study would 
be discontinued without moving forward to the phase 2 dose expansion. All subjects who were 
enrolled in phase 1b have discontinued study drug and conducted the safety follow-up visit. 
1.1.
Study Objectives
This study has two phases: Phase 1b dose escalation and Phase 2 dose expansion. The primary 
objective of this study is as follows:
Phase 1b Dose Escalation

To characterize the safety and tolerability of GS-5829 as a single agent and in combination 
with enzalutamide in subjects with metastatic castrate-resistant prostate cancer (mCRPC)

To determine the maximum tolerated dose (MTD) of GS-5829 as a single agent and in 
combination with enzalutamide in subjects with mCRPC
Phase 2 Dose Expansion

Group 1: To evaluate the efficacy of GS-5829 as a single agent in subjects with mCRPC who 
have progressed while receiving enzalutamide (may have also received abiraterone) as 
measured by Progression Rate at Week 24 according to Prostate Cancer Working Group 2 
(PCWG2) Criteria

Group 2: To evaluate the efficacy of GS-5829 combined with enzalutamide in subjects with 
mCRPC who have progressed while receiving treatment with abiraterone (may not have 
previously received enzalutamide) as measured by Progression Rate at Week 24 according to 
PCWG2 Criteria


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• 
Group 3: To evaluate the efficacy of GS-5829 combined with enzalutamide in subjects with 
mCRPC who have had Prostate Specific Antigen (PSA) progression, but not radiographic 
progression, while receiving treatment with enzalutamide (subjects may have also previously 
received abiraterone) as measured by Progression Rate at Week 24 according to PCWG2 
Criteria 
The secondary objectives of this study are as follows: 
Phase lb Dose Escalation 
• 
To evaluate the pharmacokinetics (PK) of GS-5829 as a single agent and in combination with 
enzalutamide in subjects with mCRPC 
• 
To evaluate the efficacy of GS-5829 as a single agent and in combination with enzalutamide 
in subjects with mCRPC as measured by PCWG2 Criteria 
Phase 2 Dose Expansion 
• 
To evaluate the safety and tolerability of GS-5829 as a single agent and in combination with 
enzalutamide in subjects with mCRPC 
• 
Group 1: To evaluate the efficacy of GS-5829 in subjects with mCRPC who have progressed 
while receiving enzalutamide as measured by PSA at Week 12, progression-free survival 
(PFS) and overall survival (OS) 
• 
Group 2: To evaluate the efficacy of GS-5829 combined with enzalutamide in subjects with 
mCRPC who have progressed while receiving abiraterone as measured by PSA at Week 12, 
PFS and OS 
• 
Group 3: To evaluate the efficacy of GS-5829 combined with enzalutamide in subjects with 
mCRPC who have had PSA progression, but not radiographic progression, while receiving 
enzalutamide as measured by PSA at Week 12, PFS and OS 
The exploratory objectives of this study are as follows: 
I 
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1.2.
Study Design
This study has two phases: Phase 1b dose escalation and Phase 2 dose expansion.
Phase 1b: This is an open-label, multicenter, sequential dose-escalation study to evaluate the 
safety, tolerability, PK, and pharmacodynamics (PD) of GS-5829 as a single agent, and
combined with enzalutamide in subjects with metastatic castrate-resistant prostate cancer 
(mCRPC).
Dose Escalation of GS-5829
Subjects with mCRPC who have progressed on either abiraterone and/or enzalutamide will be 
sequentially enrolled at progressively higher dose levels to receive oral GS-5829 as a single 
agent once daily. Dose escalation [3+3] will be performed with cohort sizes of 3 to 6 subjects. 
Initially 3-4 subjects will be enrolled into each dose level. The study will be initiated at a dose 
level that has been demonstrated to be safe and tolerable in the ongoing Phase 1 study in patients 
with solid tumors and lymphomas (Study GS-US-350-1599).
The dose levels for single agent GS-5829 once daily are 2, 3, 4, 6 and 9mg. Dose levels may be 
modified based on emerging safety, PK, PD, and efficacy results.
Dose Escalation of GS-5829 and enzalutamide
The combination dose escalation using 3+3 design may initiate prior to identification of the 
MTD of single agent GS-5829 using a starting dose of GS-5829 that has been determined to be 
safe and tolerable in the single agent dose escalation. The first 3-4 subjects to enroll will receive 
GS-5829 at a dose less than or equal to the previously determined single agent MTD (or a 
monotherapy dose that has been determined to be safe) combined with enzalutamide. 
Enzalutamide is a strong CYP3A4 inducer, which is expected to decrease the exposure of 
GS-5829 and therefore a higher dose of GS-5829 may be required to achieve target coverage 
compared to the single agent dose. Subjects will administer enzalutamide 160 mg once daily as a 
single agent starting on Study Day 1 through Cycle 1, Day 1. On Cycle 1 Day 1 (approximately
14 days after Study Day 1), subjects will administer GS-5829 once daily in combination with 
enzalutamide 160 mg once daily in order to evaluate the interaction of the 2 agents. Depending 
on the observed PK interaction, toxicity and tolerability observed in the single agent dose 
escalation, the dose escalation may continue beyond a dose which has been identified to be safe 
and tolerable in the single agent arm. Any increase in the dose of GS-5829 will not be by more 
than 100% in the next cohort.
Phase 2 Dose Expansion:
Group 1: A dose that is less than or equal to the MTD of GS-5829 monotherapy (based on safety, 
PD and tolerability) will be chosen for an expansion phase. Approximately 20 subjects with 
mCRPC who have had radiographic disease progression despite adequate testosterone 
suppression and treatment with enzalutamide will be enrolled. These subjects may have 


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previously received abiraterone. Enrollment into this group may initiate as soon as the MTD of 
single agent GS-5829 has been identified.
Group 2: A dose that is less than or equal to the MTD of GS-5829 + enzalutamide (based on 
safety, PD and tolerability) will be chosen for an expansion phase. Approximately 20 subjects 
with mCRPC who have had radiographic disease progression despite adequate testosterone 
suppression and treatment with abiraterone will be enrolled. These subjects may not have 
previously received enzalutamide. Enzalutamide will be initiated on Study Day 1 and GS-5829 
will initiate on Cycle 1, Day 1 (approximately 15 days later).
Group 3: A dose equivalent to the dose chosen for Group 2 will be chosen for an expansion 
phase. A maximum of 20 subjects with mCRPC who have had PSA only progression, but not 
radiographic progression, despite adequate testosterone suppression and treatment with 
enzalutamide, will be enrolled. These subjects may have received prior abiraterone (similar to 
Group 1). These subjects will continue the enzalutamide therapy they have been receiving (must 
be receiving continuous enzalutamide for at least 12 weeks prior to Cycle 1, Day 1) and GS-5829 
will initiate on Cycle 1, Day 1. 
The choice of enrolling a subject into a specific dose escalation cohort or dose expansion group 
will be based on the treatment slots open at the time of screening, inclusion/exclusion enrollment 
criteria and the discretion of the investigator.
1.3.
Sample Size and Power
Number of subjects planned:

Phase 1b Dose Escalation: Approximately 72 subjects will be enrolled

Phase 2 Dose Expansion: Up to 60 subjects will be enrolled
The sample size is not determined by statistical hypothesis testing. The sample size of phase 1b 
monotherapy phase will be determined based on the number of dose levels evaluated and the 
emerging GS-5829-related toxicities. The phase 1b study will consist of up to 72 subjects. The 
phase 2 part will enroll up to 60 subjects to help understand the efficacy effect of GS-5829 as a 
monotherapy and combination therapy with enzalutamide. The expectation is that at 24 weeks, 
the non-progression rate will be > 30% with GS-5829 monotherapy in subjects who have 
progressed on enzalutamide (may have received abiraterone) and/or with GS-5829 combined 
with enzalutamide in subjects who have progressed on abiraterone only. If the true non-
progression rate is above 50%, and we do observe more than 10 non-progression subjects from 
20 treated subjects per group, it will guarantee that the lower bound of the 90% confidence
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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analyses
No formal interim analyses are planned.
2.2.
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.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
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 were 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.
For each analysis set, the number and percentage of subjects eligible for inclusion will be 
summarized by treatment group.
A listing of reasons for exclusion from analysis sets will be provided by subject.
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.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all subjects who took at least 1 dose of study drug with 
treatment group designated according to the planned treatment. This is the primary analysis set 
for efficacy analyses. Throughout this SAP, study drug is defined as any drug in the therapy (GS-
5829 or enzalutamide) unless specified otherwise.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who took at least 1 dose of study drug. This is the 
primary analysis set for safety analyses.
3.1.4.
Dose-Limiting Toxicity (DLT) Analysis Set
The DLT Analysis Set includes all subjects in the Safety Analysis Set who complete all or at 
least 21-day study treatment and have safety assessment through Day 28 of GS-5829, inclusive, 
or experienced a DLT prior to Day 28, exclusive. During the DLT assessment window, if a 
subject who fails to receive GS-5829 for at least 21 days for reasons other than DLT, another 


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subject will be enrolled at the same dose level for replacement. For subjects who are replaced but 
received at least 1 dose of study drug, they will be included in the Safety Analysis Set and not in 
the DLT Analysis Set.
3.1.5.
Pharmacokinetic Analysis Set
The Pharmacokinetic (PK) Analysis Set will include all enrolled subjects who took at least 
1 dose of study drug and have at least 1 nonmissing postdose concentration value reported by the 
PK laboratory. This is the primary analysis set for all PK analyses.
3.2.
Subject Grouping
For analyses based on the FAS, subjects will be grouped according to the treatment to which 
they were assigned. For analyses based on the Safety Analysis Set, subjects will be grouped 
according to actual treatment received. The actual treatment received will differ from the 
assigned treatment only when their actual treatment differs from assigned treatment for the entire 
treatment duration. 
For the PK Analysis Set, subjects will be grouped according to the actual treatment they 
received.
3.3.
Strata and Covariates
This study does not use a stratified randomization schedule when enrolling subjects. 
No covariates will be included in efficacy and safety analyses.
3.4.
Examination of Subject Subgroups
There are no prespecified subject subgroupings for efficacy and safety analyses.
3.5.
Multiple Comparisons
Adjustments for multiplicity will not be made, because no formal statistical testing will be 
performed in this study.
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.
For missing last dosing date of study drug, imputation rules are described in Section 4.2.1. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.5.2, and for
prior and concomitant medications in Section 7.4.


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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 on the date of the first dose of study drug will be used for 
analyses and presentation in listings. If age at Day 1 is not available for a subject, then 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 any study drug, the enrollment date will be used instead of the first dosing 
date of study drug. For screen failures, the date the first informed consent was signed will be 
used for 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 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).
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data or nonparametric analysis methods may be used, 
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Natural logarithm transformation will be used for plasma/blood concentrations and analysis of 
PK parameters. Plasma 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 postbaseline time points, where 
LOQ is corrected for the dilution factor (ie, reported LOQ/dilution factor) for determination of 
summary and order statistics.
The following conventions will be used for the presentation of summary and order statistics:

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ.”

If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”

If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”

If more than 75% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”

If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
PK parameters that are BLQ will be imputed as one-half LOQ before log transformation or 
statistical model fitting.
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 postdose 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.
3.8.2.
Analysis Visit Windows
The nominal visit as recorded on the CRF will be used when data are summarized by visit. Any 
data relating to unscheduled visits will not be assigned to a particular visit or time point. 


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However, the following exceptions will be made:

An unscheduled visit prior to the first dosing of study drug may be included in the calculation 
of the baseline value, if applicable.

Unscheduled visits after the first dosing of study drug will be included in determining the 
maximum postbaseline toxicity grade.

For subjects who prematurely discontinue from the study, early termination (ET) data will be 
assigned to what would have been the next scheduled visit where the respective data were 
scheduled to be collected.

Data collected on a follow-up visit will be summarized as a separate visit and labeled 
“Follow-up Visit.”

Data obtained after the follow-up visit or last dose date plus 30 days (whichever is later) will 
be excluded from the summaries but will be included in the listings.
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.
If multiple, valid nonmissing measurements exist in an analysis window, records will be chosen 
based on the following rules if a single value is needed:

For baseline, the last nonmissing value on or prior to the first dosing date of study drug (GS-
5829 or enzalutamide) will be selected, unless specified differently. If there are multiple 
records with the same time or no time recorded on the same day, the baseline value will be 
the average of the measurements for continuous data, or the measurement with the lowest 
severity (eg, normal will be selected over abnormal for safety electrocardiogram [ECG] 
findings) for categorical data.

For postbaseline visits:
The record closest to the nominal day for that visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken for 
continuous data and the worse severity will be taken for categorical data, unless 
otherwise specified.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by treatment group for each investigator and 
overall. 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 by treatment group. This summary will 
present the number of subjects screened, the number of subjects enrolled, and the number of 
subjects in each of the categories listed below:

Full Analysis Set

Safety Analysis Set

Discontinued GS-5829 with reasons for discontinuation 

Discontinued Enzalutamide with reasons for discontinuation 

Discontinued the study with reasons for discontinuation of study
For the status of study drug (GS-5829 and Enzalutamide) and study completion and reasons for 
premature discontinuation, the number and percentage of subjects in each category will be 
provided. The denominator for the percentage calculation will be the total number of subjects in 
the Full Analysis Set corresponding to that column.
The following by-subject listings will be provided by subject identification (ID) number in 
ascending order to support the above summary tables:

Reasons for premature study drug or study discontinuation
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to GS-5829 will be examined by assessing the total duration of exposure to 
GS-5829 and the level of adherence to the GS-5829 specified in the protocol.
4.2.1.
Duration of Exposure to GS-5829
Total duration of exposure to GS-5829 will be defined as last dosing date of GS-5829 minus first 
dosing date plus 1, regardless of any temporary interruptions in GS-5829 administration and will 
be expressed in weeks using up to 1 decimal place (eg, 4.5 weeks). 


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If the last GS-5829 dosing date is missing, the latest date among the GS-5829 end date, clinical 
visit date, laboratory sample collection date, and vital signs assessment date that occurred during 
the on-treatment period will be used.
Partial dose start or stop dates for each dosing period will be imputed using the following 
algorithm:

For dose stop date: If day and month are missing but year is available, then the imputed 
day and month will be the earliest from the following dates: 31 DEC, death date, end of 
GS-5829 treatment (EOT) date, and (start date of the next dosing period -1); If day is missing 
but the month and year are available, then the imputed day will be the earliest from the 
following dates: last day of the month, death date, EOT date, and (start date of the next 
dosing period 1).

For dose start date: If day and month are missing but year is available, then the imputed day 
and month will be the earliest from the following dates: later of (01 JAN, and (stop date of 
the previous dosing period + 1)), and stop date of the associated dosing period; If day is 
missing but the month and year are available, then the imputed day will be the earliest from 
the following dates: later of (first day of the month, and (stop date of the previous dosing 
period + 1)), and stop date of the associated dosing period.
The total duration of exposure to GS-5829 will be summarized using descriptive statistics and 
percentage of subjects exposed through the following time periods: 1 day, 4 weeks, 8 weeks, 
16 weeks, 24 weeks, 36 weeks, 48 weeks and 60 weeks. Summaries will be provided by 
treatment group for the Safety Analysis Set.
4.2.2.
Adherence to GS-5829
The total amount of doses administered in mg will be summarized using descriptive statistics. 
The presumed total amount of doses administered to a subject will be determined by the data 
collected on the drug accountability CRF using the following formula:
Total Amount of Doses Administered 
(∑	
.   
 
 ) −(∑	
.   	
 
 )
4.2.2.1.
On-Treatment Adherence
The level of on-treatment adherence to GS-5829 will be determined by the total amount of study 
drug administered relative to the total amount of GS-5829 expected to be administered during a 
subject’s actual on-treatment period. Investigator-prescribed interruption and reductions as 
specified in the protocol will be taken into account.


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The level of on-treatment adherence will be expressed as a percentage using the following 
formula:
Total Amount of Study Drug Administered
On-Treatment Adherence (%)  
 x 100
Study Drug Expected to be Administered on Treatment






If there are treatment periods that bottles are not returned, or the return information is missing, 
these periods will be excluded from the on-treatment adherence calculation for both total amount
of study drug administered, and study drug expected to be administered. If subjects never 
returned any bottle, the adherence will be set as missing.
Descriptive statistics for the level of on-treatment adherence with the number and percentage of 
subjects belonging to adherence categories (< 75%, ≥ 75%) will be provided by treatment group 
for the Safety Analysis Set.
A by-subject listing of study drug administration and drug accountability will be provided 
separately for GS-5829 by subject ID number (in ascending order) and visit (in chronological 
order). Separate listing of enzalutamide administration will also be provided.
4.3.
Protocol Deviations
Subjects who did not meet the eligibility criteria for study entry but enrolled in the study will be 
summarized regardless of whether they were exempted by the sponsor or not. The summary will 
present the number and percentage of subjects who did not meet at least 1 eligibility criterion and 
the number of subjects who did not meet specific criteria by treatment group based on the All 
Enrolled Analysis Set. A by-subject listing will be provided for those subjects who did 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 did not meet and related comments, if 
collected.
Protocol deviations occurring after subjects entered 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 by treatment group for the All Enrolled Analysis Set. A by-subject listing 
will be provided for those subjects with any important protocol deviation.


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5.
BASELINE CHARACTERISTICS
5.1.
Demographics and Baseline Characteristics
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 by 
treatment group and overall 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 All Enrolled Analysis Set.
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
Not applicable.
5.3.
Medical History
Medical history will be collected at screening for disease-specific and general conditions 
(ie, conditions not specific to the disease being studied).
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, time since the completion of last regimen, and specific prior 
treatment (enzalutamide, abiraterone, and chemotherapy) will be summarized by treatment group 
using descriptive statistics based on the Full Analysis Set. A partial completion date will be 
imputed using the algorithm defined below.
All partial dates of the completion of 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.
A by-subject listing will be provided for prior anticancer therapies, on-study anticancer therapies, 
prior and on-study radiation therapy, and prior and on-study surgery and procedures each 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 non-progression rate at Week 24 defined as the 
proportion of subjects who don’t progress by Week 24. The progression is determined by the 
investigators based on Prostate Cancer Working Group 2 (PCWG2) Criteria for lesion scans, 
bone scans and PSA assessments together. Subjects will be considered as having definitive 
disease progression if any of three progression criteria meets.  Progression-free survival (PFS), 
defined as the interval from start of study drug to the earlier of the first documentation of 
definitive disease progression or death from any cause. Definitive disease progression is 
determined by investigator based on PCWG2 criteria.
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 tumor assessments after the last tumor assessment. Non-evaluable (NE) 
and no disease (ND) are considered as not adequate.
Subjects will be censored on the date of Study Day 1 if 

no adequate baseline target lesion assessment nor bone scan is available (note: baseline PSA 
assessment missing is allowed) 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 Day 1 
if the last post-baseline adequate tumor assessment doesn’t exist, for the following situations: 

who do not have documented progression or die, or 

who start new anticancer therapy before documented progression, or

who start new anticancer therapy before death without documented progression, or

who have ≥ 2 consecutive missing post-baseline tumor assessments immediately before 
documented progression, or

who have ≥ 2 consecutive missing post-baseline tumor assessments immediately before death 
without documented progression


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Table 6-1 below provides detailed event/censoring scheme for PFS derivation and the derivation
diagram provides all decisions on event/censoring indicators and time. 
Table 6-1.
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 
Date of death
Event


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PFS 
Derivation Step
Situation
Date of Progression 
or Censoring
Outcome
consecutive missing post-baseline 
tumor assessments immediately 
before death
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
4
Start new anticancer 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 anticancer therapy start 
date and/or the consecutive 
missing
2) Study Day 1 
Censored
When the date of initiation of anticancer 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.
Every attempt will be made to ensure that complete death dates are recorded. In those rare 
instances where complete death dates are not recorded, the following algorithm will be used:

If day is missing but the month and year are available, then the imputed date will be the 1st 
day of the month or the last known alive date + 1, whichever is later.

If day and month are missing but year is available, then the imputed date will be 01Jan of 
that year or the last known alive date + 1, whichever is later.
6.1.2.
Analysis of the Primary Efficacy Endpoint
The non-progression rate at Week 24 and 95% confidence interval (CI) will be estimated using 
Kaplan-Meier method through PFS analysis. The number and percentage of subject who had no 
progressive disease at Week 24 by counting will also be provided for each treatment group. 
The analysis of PFS will be performed using the Kaplan-Meier method for the Full Analysis Set. 
Medians, Q1, Q3, the proportion of subjects who have no progression or death events at 24 and 


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48 weeks from the first dosing date will be provided along with corresponding 95% CIs. Kaplan-
Meier curves for PFS will be provided by treatment group. 
6.2.
Secondary Efficacy Endpoints
6.2.1.
Definition of Secondary Efficacy Endpoints
PSA response, defined as ≥ 30% decline in PSA from baseline at 12 weeks. 
Overall response by lesion scan only:  subjects will be categorized based on PCWG2 criteria of 
lesion scans (same with RECIST v. 1.1 for lesion scans) as complete response (CR), partial 
response (PR), stable disease (SD), non-complete response or non-progressive disease, 
progressive disease (PD) or not evaluable (NE) at each visit of assessment. 
Overall survival (OS), defined as the interval from start of study drug to death from any cause. 
Subjects who are lost to follow-up or survived until the end of the study will be censored at the 
last date that they were known to be alive.
6.2.2.
Analysis Methods for Secondary Efficacy Endpoints
Number of subjects with ≥ 30% or ≥ 50% PSA reduction from baseline at 12 weeks and during 
the whole treatment period will be summarized separately. 
The number and percentage of subjects in each overall response category by lesion scans (eg, 
CR, PR, SD, and PD) will be summarized by treatment group for the FAS.
The analysis of OS will be performed using the Kaplan-Meier method for the FAS Analysis Set. 
Medians, Q1, Q3, the proportion of subjects who have no events at 24 weeks and 48 weeks from 
the first dosing date will be provided along with corresponding 95% CIs. Kaplan-Meier curves 
for OS will be provided by treatment group. 


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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. 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.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE case report form 
(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 SAE 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

Any AEs leading to premature discontinuation of study drug.


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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 Grades  
The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC, HLT PT, and treatment group. For other AEs described below, summaries 
will be provided by SOC, PT, and treatment group:

TEAEs

TEAEs with Grade 3 or higher 

TEAEs related to GS-5829

TE SAEs


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
TE SAEs related to GS-5829

TEAEs leading to premature discontinuation of GS-5829

TEAEs leading to death 

TEAEs leading to temporary interruption of GS-5829

TEAEs leading to dose reduction of GS-5829
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 HLT within each SOC (if applicable), 
and then by PT in descending order of total frequency within each SOC. For summaries by 
severity grade, the most severe grade will be used for those AEs that occurred more than once in 
an individual subject during the study. 
In addition to the above summary tables, all TEAEs and TE SAEs will be summarized by PT 
only, in descending order of total frequency. All TEAEs and TEAEs related to GS-5829 will be 
summarized by SOC, PT and severity.
In addition, data listings will be provided for the following:

All AEs, indicating whether the event is treatment emergent

All AEs with Grade 3 or higher

All SAEs

All deaths

All AEs leading to death

AEs leading to premature discontinuation of GS-5829

AEs leading to temporary interruption of GS-5829

AEs leading to dose reduction of GS-5829


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7.1.6.2.
Summary of Deaths
A summary (number and percentage of subjects) of deaths will be provided by treatment group. 
Summary will include the following categories:

All deaths

Deaths within 30 days of the last dosing of study drug

Deaths beyond 30 days of the last dosing of study drug 
7.1.7.
Additional Analysis of Adverse Events
7.1.7.1.
Dose Limiting Toxicity
A listing of the DLT AEs will be provided following the standard AE listing format.
7.1.7.2.
Treatment-Emergent Adverse Events (TEAE) of Interest
The following AEs of interest defined by the medical search term (MST) provided by Gilead 
Pharmacovigilance and Epidemiology (PVE) Department will be summarized similarly to 
TEAEs by treatment group. 

Decreased Platelets 

Diarrhoea  

Haemorrhage
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. 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, serum chemistry, coagulation and urinalysis separately. 
Values falling outside of the relevant reference range and/or having a severity grade of 1 or 
higher on the CTCAE severity grade will be flagged in the data listings, as appropriate.


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7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided by treatment group for each laboratory test specified in the 
study protocol as follows:

Baseline values 

Values at each postbaseline visit

Change and percentage change from baseline at each postbaseline visit
A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
values will be displayed to the reported number of digits; StD values will be displayed to the 
reported number of digits plus 1.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. In the event that both central and local lab results are collected in the 
clinical database, only central lab results will be included in the summary by visits. All central 
and local laboratory values will be listed.
7.2.2.
Graded Laboratory Values
The CTCAE Version 4.03 will be used for assigning 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 central lab normal ranges with in-house macro. In the event that both central 
and local lab results are collected in the clinical database, the worst toxicity grade will be used 
for the summary of lab toxicities. All central and local laboratory values will be listed.
7.2.2.1.
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. 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.


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7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit.
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by lab test and treatment group; subjects will be categorized 
according to the most severe postbaseline abnormality grade for a given lab test:

Baseline grade (Grade 0 to 4 separately, Grade 3 or 4, and Grade 1 to 4)

Worst treatment-emergent laboratory abnormalities postbaseline grade (Grade 1 to 4 
separately, Grade 3 or 4, and Grade 1 to 4)
For all summaries of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after the last dosing date.
7.2.3.
Liver-related Laboratory Evaluations
Liver-related abnormalities after initial study drug dosing will be examined and summarized 
using the number and percentage of subjects who were reported to have the following laboratory 
test values for postbaseline measurements:

Aspartate aminotransferase (AST): (a) > 3 times of the upper limit of reference range
(ULN); (b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x ULN

Alanine aminotransferase (ALT): (a) > 3 x ULN; (b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x 
ULN

AST or ALT: (a) > 3 x ULN; (b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x ULN

Total bilirubin: (a) > 1 x ULN ; (b) > 2 x ULN

Alkaline phosphatase (ALP) > 1.5 x ULN

AST or ALT > 3 x ULN and total bilirubin: (a) > 1.5 x ULN; (b) > 2 x ULN

AST or ALT > 3 x ULN and total bilirubin > 2 x ULN and ALP < 2 x ULN
The summary will include data from all postbaseline visits up to 30 days after the last dose of 
study drug. For individual laboratory tests, subjects will be counted once based on the most 
severe postbaseline values. For both the composite endpoint of AST or ALT and total bilirubin, 
subjects will be counted once when the criteria are met at the same postbaseline visit date. The 
denominator is the number of subjects in the Safety Analysis Set who have nonmissing 
postbaseline values of all relevant tests at the same postbaseline visit date. A listing of subjects 
who met at least 1 of the above criteria will be provided.


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7.2.4.
Shifts Relative to the Baseline Value 
Shift tables will be presented by showing change in severity grade from baseline to the worst 
postbaseline grade. 
7.3.
Vital Signs
Descriptive statistics will be provided by treatment group for vital signs as follows:

Baseline value

Values at each postbaseline visit

Change from baseline at each postbaseline visit
A baseline value will be defined as the last available value collected on or prior to the date/time 
of first dose of study drug. Change from baseline to a postbaseline visit will be defined as the 
postbaseline value minus the baseline value. Vital signs measured at unscheduled visits will be 
included for the baseline value selection.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. 
A by-subject listing of 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.
A summary of general prior medications will not be provided. Prior medications will be included 
in a listing together with concomitant medications.
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 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 by preferred term in descending 
overall frequency. For drugs with the same frequency, sorting will be done alphabetically.


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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. 
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 Results
Electrocardiogram (ECG) analysis results are intended to identify meaningful changes in the QT 
interval. If potential abnormalities of interest are identified, further analyses may be conducted. 
Summaries of ECG data will be provided for the Safety Analysis Set for each scheduled time
point based on central ECG results. The local ECG assessment results will be used in the data 
summary if only local ECG measurements are available at a visit/time point. No formal 
statistical testing is planned.
A by-subject listing for ECG assessment results will be provided by subject ID number and visit
in chronological order.
7.5.1.
Corrected QT Intervals
The QT interval (measured in millisecond [msec]) is a measure of the time between the start of 
the Q wave and the end of the T wave in the heart’s electrical cycle. The QT interval represents 
electrical depolarization and repolarization of the ventricles. The QT interval is affected by heart 
rate, and a number of methods have been proposed to correct QT for heart rate. 
Corrected QT (QTc) intervals will be derived using Fridericia’s correction (QTcF) as follows:


√

where QT is measured in msec; RR
60/Heart Rate (beats per min [bpm]) and RR is 
measured in seconds


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The maximum postdose QTcF interval values obtained during the study will be summarized 
within the following categories:

> 450 msec

> 480 msec

> 500 msec
The maximum postdose change in QTcF interval values obtained during the study will also be 
summarized within the following categories:

> 30 msec

> 60 msec
QTcF and uncorrected QT values at each visit and time point and change from baseline at each 
visit and time point will be summarized for the Safety Analysis Set by treatment group using 
descriptive statistics.
7.5.2.
PR and QRS Intervals
The PR interval (measured in msec) is a measure of the time between the start of the P wave (the 
onset of atrial depolarization) and the beginning of the QRS complex (the onset of ventricular 
depolarization). The QRS interval measures the duration of the QRS complex. The maximum 
ventricular rate (VR) and PR and QRS intervals observed during the study will be categorized. 
The number and percentage of subjects having values in the following ranges will be presented 
by treatment group:

VR > 100 bpm

PR interval > 200 msec

QRS interval > 110 msec
In addition, VR, PR, RR, and QRS values at each visit and time point and change from baseline 
at each visit will be summarized for the Safety Analysis Set by treatment group using descriptive 
statistics.
7.6.
ECOG Performance Status
A by-subject listing will be provided for ECOG Performance Status assessments by subject ID 
number and visit in chronological order.


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7.7.
Other Safety Measures
No additional safety measures are specified in the protocol.
7.8.
Changes from Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC ANALYSES
8.1.
PK Sample Collection
PK samples will be collected at the time points listed in Protocol 6.2.11. 
8.2.
PK Analyses Related to Intensive PK Sampling
Concentrations of GS-5829 and its metabolite in plasma will be determined using validated 
bioanalytical assays. The first dose and steady-state PK will be determined in subjects in the PK 
analysis set.
8.2.1.
Estimation of Pharmacokinetic Parameters
Pharmacokinetic (PK) parameters will be estimated using Phoenix WinNonlin® software using 
standard noncompartmental methods. The linear/log trapezoidal rule will be used in conjunction 
with the appropriate noncompartmental model, with input values for dose level, dosing time, 
plasma concentration, and corresponding real-time values, based on drug dosing times whenever 
possible.
All predose sample times before time-zero will be converted to 0.
For area under the curve (AUC), samples BLQ of the bioanalytical assays occurring prior to the 
achievement of the first quantifiable concentration will be assigned a concentration value of 0 to 
prevent overestimation of the initial AUC. Samples that are BLQ at all other time points will be 
treated as missing data in WinNonlin. The nominal time point for a key event or dosing interval 
(τ) may be used to permit direct calculation of AUC over specific time intervals. The 
appropriateness of this approach will be assessed by the PK scientist on a profile-by-profile
basis.
Pharmacokinetic parameters such as AUCtau, λz and t1/2 are dependent on an accurate estimation 
of the terminal elimination phase of drug. The appropriateness of calculating these parameters 
will be evaluated upon inspection of PK data on a profile-by-profile basis by the PK scientist.
8.2.2.
Pharmacokinetic Parameters
Pharmacokinetic parameters will be generated for all subjects in the PK analysis set for whom 
PK parameters can be derived. The analytes presented in Table 8-1 will be evaluated if data are 
available. 


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Table 8-1.
Pharmacokinetic Parameters for Each Analyte
GS-5829
GS-697412
Cycle 1 Day 1
(enzalutamide combination groups)
Cmax, Tmax, AUC0-24h, AUClast, 
C24h, Clast, Tlast, λz, T1/2
Cmax, Tmax, AUC0-24h,
AUClast, C24h, Clast, Tlast, λz, T1/2,
Cycle 1 Day 8
(monotherapy group, fasted)
Cycle 2 Day 1 (monotherapy 
group, fed)
Cmax, Tmax, AUCtau, AUClast, Ctau, 
Clast, Tlast, λz, T1/2, Vz F, CLss F
Cmax, Tmax, AUCtau AUClast,
Ctau, Clast, Tlast, λz, T1/2,
Cycle 1 Day 15
(enzalutamide combination group)
Cmax, Tmax, AUCtau, AUClast, Ctau, 
Clast, Tlast, λz, T1/2, Vz F, CLss F
Cmax, Tmax, AUCtau AUClast, 
Ctau, Clast, Tlast, λz, T1/2,
Individual subject concentration data and individual subject PK parameters will be listed and 
summarized using descriptive statistics by treatment. Summary statistics (n, mean, StD, 
coefficient of variation [%CV], median, min, max, Q1, and Q3) will be presented for both 
individual subject concentration data by time point and individual subject PK parameters by 
treatment. Moreover, the geometric mean, 95% CI, and the mean and StD of the natural log-
transformed values will be presented for individual subject PK parameter data. 
Individual concentration data listings and summaries will include all subjects with concentration 
data. 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.
Individual PK parameter data listings and summaries will include all subjects for whom PK 
parameter(s) can be derived. The sample size for each PK parameter will be based on the number 
of subjects with nonmissing data for that PK parameter.
The following tables will be provided for each analyte by treatment:

Individual subject concentration data and summary statistics

Individual subject plasma PK parameters and summary statistics
The following figures may be provided for each analyte by treatment:

Mean (± StD) concentration data versus time (on linear and semilogarithmic scales)

Median (Q1, Q3) concentration data versus time (on linear and semilogarithmic scales)
Individual, mean, and median postdose concentration values that are ≤LLOQ will not be 
displayed in the figures and remaining points connected.


GS-5829
Protocol GS–US-350-1604
Final
Gilead Sciences, Inc. 
Version 1.0
CONFIDENTIAL
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21 November 2019
PK sampling details by subject, including procedures, differences in scheduled and actual draw 
times, and sample age will be provided in listings.
8.2.3.
PK/PD Analyses
Not applicable.


GS-5829
Protocol GS–US-350-1604
Final
Gilead Sciences, Inc. 
Version 1.0
CONFIDENTIAL
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21 November 2019
9.
REFERENCES
Koch GG, Carr GJ, Amara IA, Stokes ME, Uryniak TJ. Categorical Data Analysis. Chapter 13 in 
Berry, D.A. (ed.). Statistical Methodology in the Pharmaceutical Sciences. New 
York: Marcel Dekker, Inc., 1989:pp. 414-21.
Nehls G, Akland G. Procedures for Handling Aerometric Data. Journal of the Air Pollution 
Control Association 1973;23 (3):180-4.
Chan IS, Zhang Z. Test-based exact confidence intervals for the difference of two binomial 
proportions. Biometrics 1999;55 (4):1202-9.
Wiens BL, Dmitrienko A. The fallback procedure for evaluating a single family of hypotheses. J 
Biopharm Stat 2005;15 (6):929-42.
LaVange LM, Koch GG. Randomization-Based Nonparametric (ANCOVA). In: D'Agostino Sr. 
RB, Sullivan LM, Massaro JM, eds. Wiley Encyclopedia of Clinical Trials. John 
Wiley & Sons, Inc.; 2008: 31-8. vol 4).
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER). Guidance for Industry. Bioavailability and 
Bioequivalence Studies for Orally Administered Drug Products - General 
Considerations (Revision 1).  March, 2003.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER). Guidance for Industry. Statistical Approaches 
to Establishing Bioequivalence.  January, 2001.


GS-5829
Protocol GS–US-350-1604
Final
Gilead Sciences, Inc. 
Version 1.0
CONFIDENTIAL
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21 November 2019
10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.
nQuery Advisor(R) Version 8.3. Statistical Solutions, Cork, Ireland.


GS-5829
Protocol GS–US-350-1604
Final
Gilead Sciences, Inc. 
Version 1.0
CONFIDENTIAL
Page 41
21 November 2019
11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


GS-5829 
Protocol GS-US-350- 1604 
Gilead Sciences, Inc. 
12. 
APPENDICES 
Appendix 1. 
Schedule of Assessments 
Study Procedures Table - Phase lb and 2 Monotherapy 
Study Phase 
Screening 
First 28 Days 
Day 
Cycle 1 
Day 
Day 
Day 
Cycle Day 
-28 
Day 1* 
8 
15 
22 
Window (day) 
-28 
±1 
±2 
±3 
Infom1ed Consent 
X 
Medical and Medication 
X 
History• 
Physical Examination2 
X 
X 
X 
X 
X 
ECOG Perfom1ance Status 
X 
X 
X 
X 
Vital Signs3 
X 
X 
X 
X 
X 
Triplicate 12 lead ECG4 
X 
X 
X 
Adverse events/Concomitant 
X 
X 
X 
X 
X 
medications7 
GS 5829 Accountability 
X 
and/or Dispensing5 
Dosing Diary Accountability 
X 
and/or Dispensing 
Enrollment 
X 
CBC with Differential 
xs 
X 
X 
X 
X 
CONFIDENTIAL 
Page 42 
Cycle 2 Day 
1 a nd Every 
Every 
4 weeks 
12 weeks 
±7 
±7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EOT 
±7 
X 
X 
X 
X 
X 
X 
X 
X 
30-day 
Safety 
Final 
Version 1.0 
Survival 
Follow-up18 
Follow-Up2G 
±7 
X 
X 
X 
X 
X 
21 November 2019 


GS-5829 
Protocol GS-US-350- 1604 
Final 
Gilead Sciences, Inc. 
Version 1.0 
Cycle 2 Day 
30-day 
1 and Every 
Every 
Safety 
Survival 
Study Phase 
Screening 
First 28 Days 
4 weeks 
12 weeks 
EOT 
Follow-up18 
Follow-Up2G 
Day 
Cycle 1 
Day 
Day 
Day 
Cycle Day 
-28 
Day 1* 
8 
15 
22 
Window (day) 
-28 
±1 
±2 
±3 
±7 
±7 
±7 
±7 
Chemistry 
xs 
X 
X 
X 
X 
X 
X 
X 
Coagulation9 
xs 
X 
X 
X 
Urinalysis 
xs 
X 
X 
X 
X 
X 
GS 5829 Intensive PK10 
X 
X 
X 
GS 5829 Sparse PK10 
X 
X 
X 
GS 5829 pham1ac.odynamic11 
X 
X 
X 
X 
Radionuclide Bone Scan17 
X 
X 
X 
CONFIDENTIAL 
Page 43 
21 November 2019 


GS-5829 
Protocol GS-US-350- 1604 
Gilead Sciences, Inc. 
Final 
Version 1.0 
* 
2 
3 
4 
5 
6 
7 
Cycle 2 Day 
30-day 
1 and Every 
Every 
Safety 
Survival 
Study Phase 
Screening 
First 28 Days 
4 weeks 
12 weeks 
EOT 
Follow-up18 
Follow-Up2G 
Day 
Cycle 1 
Day 
Day 
Day 
Cycle Day 
-28 
Day 1* 
8 
15 
22 
Window (day) 
-28 
±1 
±2 
±3 
±7 
±7 
±7 
±7 
Treatment Response 
X 
X 
Assessment19 
Phone call 
X 
Day I pre GS 5829 lab samples may be drawn up to two days prior to the Day I visit. 
Medical history includes significant past medical events (eg, prior hospitalizations or surgeries), a review of the disease under study, prior anti cancer therapies, historical PSA 
levels and any concurrent medical illnesses. 
Screening and End of Treatment Physical Examinations (PE) will be a complete PE. Beginning at C ID I, a modified physical examination will be perfornied. Weight 
(without shoes) should be measured at each PE. Height (without shoes) is measured at Screening only. 
CID I Vital Signs will be taken within 15 min pre GS 5829 dose and 2 and 4 hours post dose ( +/ 15 min); vital signs will be taken pre dose only at all subsequent visits. 
Oxygen saturation will be tested with a pulse oximeter. 
Triplicate ECG will be collected at any time during Screening window, Day I of Cycles 2 6 (at pre dose), and at EOT. In Phase I b monotherapy, triplicate ECGs will be 
collected on C ID I at pre dose and I 4 hrs post dose and on C I 08 at pre dose, I hour, 2 hours, 3 hours, 4 hours, 6 hours, and 8 hours post dose ( +/ 20 min). In Phase 2 dose 
expansion, triplicate ECGs will be collected on C ID I at pre dose and I 4 hrs post dose and on C I 08 at pre dose, I hour, 2 hours, 4 hours, and 6 hours post dose 
(+/ 20 min). ECGs should always be collected prior to PK (or any other blood draw) if they are to be collected at the same nominal time po int. Subjects should be resting 
quietly and free of distraction (eg, TV, conversation) for 10 minutes prior to ECG collection and ECGs should be collected over a 5 minute window at each time point. 
Administer GS 5829 in a fed state on C2O I in selected dose level. 
Beginning on C ID I, subjects will receive GS 5829 daily. 
Adverse event reporting period begins once the Infornied Consent Forni has been signed. AEs will be assessed using NCI CTCAE (v 4.03) criteria at pre and post GS 5829 
dosing during applicable clinic visits. Subjects will also return to clinic at 30 day post last IP dose to assess AEs and SAEs. At screening, all medications taken up to 30 days 
prior to screening will be documented in the eCRF. 
8 
9 
10 
Screening chemistry, hematology, coagulation, and urinalysis to be collected within 7 days of C ID I for central lab assessment. 
Coagulation assessment includes PT/PTT, fibrinogen, Factor VII, fibrinogen degradation products (FOP). 
In Phase I b monotherapy: plasma samples for GS 5829 PK will be collected on Day 8 of Cycle I at pre dose, 0.5, I, 2, 3, 4, 6, 8, and 24 hours post dose as well as pre dose 
and I 4 hours after GS 5829 administration on Day I and Day 15 of Cycle I and anytime on Day I of Cycles 2 through 6. At one or more dose levels, PK samples will be 
collected on Day I of Cycle 2 at pre dose and 0.5, I, 2, 3, 4, 6, 8, and 24 hours post dose. (C2O I: If intensive PK is collected for that cohort, then sparse PK does not need to 
be collected.) In Phase 2 dose expansion Group I: PK samples will be collected on Day 8 of Cycle I at pre dose and I, 2, 4, and 6 hours post dose. Sparse PK samples will 
be collected at pre dose and I 4 hours post dose on Cycle I Day I and Day 15 and anytime on Day I of Cycles 2 through 6. 
CON FIDE NTIAL 
Page 44 
21 November 2019 


GS-5829
Protocol GS–US-350-1604
Final
Gilead Sciences, Inc. 
Version 1.0
CONFIDENTIAL
Page 45
21 November 2019
11
In Phase 1b monotherapy: PD biomarker sampling will be collected at pre dose, 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post dose relative to GS 5829 administration on Cycle 1 
Day 8.  PD samples will also be collected pre dose and 1 4 hours post dose on Cycle 1 Day 1 and Cycle 1 Day 15.  Additional PD samples will be collected at anytime on 
Day 1 of Cycles 2 through 6.In phase 2 dose expansion Group 1: PD samples will be collected on Day 8 of Cycle 1 at pre dose and 1, 2, 4, and 6 hrs post dose. Sparse PD will 
be collected at pre dose and 1 4 hours post dose on Cycle 1 Day 1 and Day 15 and anytime on Day 1 of Cycles 2 through 6.  
 
13
Tumor markers PSA will be collected on C1D1 at pre dose and on Day 1 of every subsequent Cycle at pre dose.
14
If available, paraffin embedded archival tumor tissue block for shipment to Gilead or its designee will be requested at C1D1.
16
Tumor evaluation by CT/MRI or applicable scan will be performed during screening (within 8 weeks of Cycle 1 Day 1) and every 12 weeks thereafter. The same radiographic
procedure used to define measurable lesions must be used throughout the study for each subject. CT/MRI to be done at EOT visit if not done within the previous 4 weeks. 
17
Subjects will also undergo a bone scan. Scan at EOT visit is not necessary if the previous scan is performed within 4 weeks of the EOT. 
18
For Phase 1b Dose Escalation subjects, the 30 Day Safety Follow Up will be the final study visit.  Phase 2 Dose Expansion subjects will complete the 30 Day Safety Follow
Up Visit and proceed to Long Term Survival Follow Up.
19
Tumor burden as assessed by PCWG2 Guidelines.
20
LTFU will begin for subjects participating in phase 2 after the 30 day Safety Follow Up visit for up to 2 years after the last dose of IP.
CCI
CCI


GS-5829 
Protocol GS-US-350- 1604 
Gilead Sciences, Inc. 
Study Procedures Table - Phase lb and 2 Combination Therapy 
Study 
Study Phase 
Screening 
Day 1 
First 28 Days 
Day 
Cycle l 
Day 
Day 
Cycle Day 
-28 
Day 1* 
8 
15 
Window (day) 
-28 
3 
±3 
±1 
±2 
Infom1ed Consent 
X 
Medical and Medication 
X 
I-Iistory1 
Physical Examination2 
X 
X 
X 
X 
X 
ECOG Perfom1anc.e 
X 
X 
X 
X 
Status 
Vital Signs3 
X 
X 
X 
X 
X 
Triplicate 12 lead ECG4 
X 
X 
X 
Adverse 
X 
X 
X 
X 
X 
events/Concomitant 
medications7 
GS 5829/enzalutamide 
X 
Ac.countability and/or 
Dispensing5 
Enzalutamide 
X 
X 
Ac.countability and/or 
Dispensing'> 
Dosing Diary 
X 
Ac.countability and/or 
Dispensing 
CONFIDENTIAL 
Page 46 
Cycle 2 Day 1 
and Every 
Every 
4 weeks 
12 weeks 
Day 
22 
±3 
±7 
±7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EOT 
±7 
X 
X 
X 
X 
X 
X 
X 
X 
30-day 
Safety 
Follow-
up•a 
±7 
X 
X 
X 
X 
Final 
Version 1.0 
Survival 
Follow-Up20 
21 November 2019 


GS-5829 
Protocol GS-US-350- 1604 
Final 
Gilead Sciences, Inc. 
Version 1.0 
30-day 
Cycle 2 Day 1 
Safety 
Study 
and Every 
Every 
Follow-
Survival 
Study Phase 
Screening 
Day 1 
First 28 Days 
4 weeks 
12 weeks 
EOT 
up•a 
Follow-Up20 
Day 
Cycle l 
Day 
Day 
Day 
Cycle Day 
-28 
Day 1* 
8 
15 
22 
Window (day) 
-28 
3 
±3 
±1 
±2 
±3 
±7 
±7 
±7 
±7 
Enrollment 
X 
CBC with Differential 
xs 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
xs 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation9 
xs 
X 
X 
X 
X 
Urinalysis 
xs 
X 
X 
X 
X 
X 
X 
GS 5829 Intensive PK10 
X 
X 
X 
GS 5829 Sparse PK10 
X 
X 
X 
GS 5829 
X 
X 
X 
X 
pham1ac.odynamic11 
CONFIDENTIAL 
Page 47 
21 November 2019 


GS-5829 
Protocol GS-US-350- 1604 
Gilead Sciences, Inc. 
Final 
Version 1.0 
30-day 
Cycle 2 Day 1 
Safety 
Study 
and Every 
Every 
Follow-
Survival 
Study Phase 
Screening 
Day 1 
First 28 Days 
4 weeks 
12 weeks 
EOT 
up•a 
Follow-Up20 
Day 
Cycle l 
Day 
Day 
Day 
Cycle Day 
-28 
Day 1* 
8 
15 
22 
Window (day) 
-28 
3 
±3 
±1 
±2 
±3 
±7 
±7 
±7 
±7 
Radionuclide Bone Scan17 
X 
X 
X 
Treatment Response 
X 
X 
Assessment19 
Phone call 
X 
* 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Day I pre GS 5829 lab samples may be drawn up to two days prior to the Day I visit. 
Medical history includes significant past medical events (eg, prior hospitalizations or surgeries), a review of the disease under study, prior anti cancer therapies, historical PSA 
levels and any concurrent medical illnesses. 
Screening and End of Treatment Physical Examinations (PE) will be a complete PE. Beginning at C ID I, a modified physical examination will be perfom1ed. Weight 
(without shoes) should be measured at each PE. Height (without shoes) is measured at Screening only. 
Study Day I vital signs will be take 15 min pre enzalutamide dose. C ID I Vital Signs will be taken within 15 min pre GS 5829 dose and 2 and 4 hours post dose 
(+/ 15 min); vital signs will be taken pre dose only at all subsequent visits. Oxygen saturation will be tested with a pulse oximeter. 
Triplicate ECG will be collected at any time during Screening window, Day I of Cycles 2 6 (at pre dose), and at EOT. In Phase I b dose escalation with enzalutamide, 
triplicate ECGs will be collected on Cycle I, Day I and Day 15 at pre dose, I hour, 2 hours, 3 hours, 4 hours, 6 hours, and 8 hours post dose ( +/ 20 min). In Phase 2 dose 
expansion triplicate ECGs will be collected on C ID I and C ID 15 at pre dose and I 4 hrs post dose and on C2O I at pre dose, I hour, 2 hours, 4 hours, and 6 hours post dose 
(+/ 20 min). ECGs should always be collected prior to PK (or any other blood draw) if they are to be collected at the same nominal time po int. Subjects should be resting 
quietly and free of distraction (eg, TV, conversation) for 10 minutes prior to ECG collection and ECGs should be collected over a 5 minute window at each time point. 
Administer GS 5829 in a fed state on C2O I in selected dose level. 
Subjects in phase I b dose escalation with enzalutamide and Phase 2 Group 2 receive enzalutamide alone beginning on Study Day I, then in combination with GS 5829 
beginning C ID I. 
Adverse event reporting period begins once the Infomied Consent Fom1 has been signed. AEs will be assessed using NCI CTCAE (v 4.03) criteria at pre and post GS 5829 
dosing during applicable clinic visits. Subjects will also return to clinic at 30 day post last IP dose to assess AEs and SAEs. At screening, all medications taken up to 30 days 
prior to screening will be documented in the eCRF. 
Screening chemistry, hematology, coagulation, and urinalysis to be collected within 7 days of C ID I for central lab assessment. 
Coagulation assessment includes PT/PTT, fibrinogen, Factor VII, fibrinogen degradation products (FOP). 
In Phase I b dose escalation with enzalutamide: PK samples will be collected on Day I and Day 15 of Cycle I at pre dose 0.5, I, 2, 3, 4, 6, 8 and 24 hours post dose and 
anytime on Day I of Cycles 2 through 6. In Phase 2 dose expansion Group 2: PK samples will be collected on Cycle 2, Day I at pre dose and I, 2, 4, and 6 hours post dose. 
Sparse PK will be collected at pre dose and I 4 hours post dose on Cycle I Day I and Day 15 and anytime on Day I of Cycles 3 through 6. 
CONFIDENTIAL 
Page 48 
21 November 2019 


GS-5829
Protocol GS–US-350-1604
Final
Gilead Sciences, Inc. 
Version 1.0
CONFIDENTIAL
Page 49
21 November 2019
11
In Phase 1b dose escalation with enzalutamide: PD biomarker samples will be collected on Day 1 and Day 15 of Cycle 1 at pre dose, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post
dose and anytime on Day 1 of Cycles 2 through 6. In Phase 2 dose expansion Group 2: PD samples will be collected on Day 15 of Cycle 1 at pre dose and 1, 2, 4, and 6 hrs 
post dose. Spare PD will be collected at pre dose and 1 4 hours post dose on Cycle 1 Day 1 and Day 8 and anytime on Day 1 of Cycles 2 through 6.
 
13
Tumor markers PSA will be collected on C1D1 at pre dose and on Day 1 of every subsequent Cycle at pre dose.
14
If available, paraffin embedded archival tumor tissue block for shipment to Gilead or its designee will be requested at C1D1.
16
Tumor evaluation by CT/MRI or applicable scan will be performed during screening (within 8 weeks of Cycle 1 Day 1) and every 12 weeks thereafter. The same radiographic
procedure used to define measurable lesions must be used throughout the study for each subject. CT/MRI to be done at EOT visit if not done within the previous 4 weeks. 
17
Subjects will also undergo a bone scan. Scan at EOT visit is not necessary if the previous scan is performed within 4 weeks of the EOT. 
18
For Phase 1b Dose Escalation subjects, the 30 Day Safety Follow Up will be the final study visit.  Phase 2 Dose Expansion subjects will complete the 30 Day Safety Follow
Up Visit and proceed to Long Term Survival Follow Up.
19
Tumor burden as assessed by PCWG2 Guidelines.
20
LTFU will begin for subjects participating in phase 2 after the 30 day Safety Follow Up visit for up to 2 years after the last dose of IP.
CCI
CCI