A Phase 1b/2 Study of GS-5829 in Combination With Fulvestrant or Exemestane in Subjects With Advanced Estrogen Receptor Positive, HER2 Negative-Breast Cancer
Phase: PHASE1
Conditions: Advanced Estrogen Receptor Positive HER2- Breast Cancer
Sponsor: Gilead Sciences

CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1b Study Followed by an Open label, Parallel, Randomized 
Phase 2 Study Evaluating the Safety, Tolerability and Efficacy of
GS-5829 in Combination with Exemestane or Fulvestrant Comparing 
with Exemestane or Fulvestrant Alone in Subjects with Advanced 
Estrogen Receptor Positive HER2- Breast Cancer
Sponsor:
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City CA, 94404
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
124032 
2016-002365-63
TBD
Indication:
Estrogen Receptor Positive Breast Cancer
Protocol ID:
GS-US-350-1937
Clinical Program 
Manager:
Name:
Telephone:
Email:
Gilead Medical 
Monitor:
Name:
Work:
Cell:
Fax:
Email:
Protocol Version/Date:
Original:
17 June 2016
Amendment 1: 
10 August 2016
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
PPD
PPD
PPD
PPD
PPD
PPD
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PPD

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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 ..............................................................................................................................................23
1.1.
Background ............................................................................................................................................23
1.2.
GS-5829 .................................................................................................................................................24
1.2.1.
General Information .............................................................................................................24
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................24
1.2.3.
Clinical Trials of GS-5829 ...................................................................................................25
1.2.4.
Information about Exemestane.............................................................................................26
1.2.5.
Information about Fulvestrant..............................................................................................26
1.3.
Rationale for This Study ........................................................................................................................27
1.3.1.
Rationale for Dose Selection................................................................................................28
1.4.
Risk/Benefit Assessment for the Study..................................................................................................29
1.5.
Potential Benefits ...................................................................................................................................30
1.6.
Compliance ............................................................................................................................................30
2.
OBJECTIVES.....................................................................................................................................................31
3.
STUDY DESIGN................................................................................................................................................33
3.1.
Endpoints ...............................................................................................................................................33
3.2.
Study Design..........................................................................................................................................33
3.3.
Study Treatments ...................................................................................................................................36
3.4.
Duration of Treatment............................................................................................................................36
3.5.
Criteria for Discontinuation of Study Drug............................................................................................37
3.6.
Criteria for Removal from Study............................................................................................................37
4.
SUBJECT POPULATION..................................................................................................................................38
4.1.
Number of Subjects and Subject Selection ............................................................................................38
4.2.
Inclusion Criteria....................................................................................................................................38
4.3.
Exclusion Criteria...................................................................................................................................40
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................42
5.1.
Enrollment..............................................................................................................................................42
5.2.
Description and Handling of GS-5829...................................................................................................42
5.2.1.
Formulation..........................................................................................................................42
5.2.2.
Packaging and Labeling .......................................................................................................42
5.2.3.
Storage and Handling...........................................................................................................43
5.3.
Dosage and Administration of GS-5829, Exemestane and Fulvestrant..................................................43
5.3.1.
Dose Adjustment of GS-5829 ..............................................................................................44
5.3.2.
Dose Adjustment of Fulvestrant...........................................................................................46
5.3.3.
Dose Adjustment of Exemestane..........................................................................................47
5.4.
Prior and Concomitant Medications.......................................................................................................47
5.5.
Accountability for GS-5829, Exemestane and Fulvestrant ....................................................................48
5.5.1.
GS-5829, Exemestane and Fulvestrant Investigational Medicinal Product 
Return or Disposal................................................................................................................48

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6.
STUDY PROCEDURES ....................................................................................................................................49
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................49
6.2.
Study Procedures Descriptions...............................................................................................................49
6.2.1.
Informed Consent.................................................................................................................49
6.2.2.
Medical History....................................................................................................................50
6.2.3.
Prior and Concomitant Medications.....................................................................................50
6.2.4.
Physical Examination...........................................................................................................50
6.2.5.
Vital Signs............................................................................................................................50
6.2.6.
Electrocardiogram................................................................................................................51
6.2.7.
Echocardiogram ...................................................................................................................51
6.2.8.
ECOG Performance Status...................................................................................................51
6.2.9.
Adverse Events.....................................................................................................................52
6.2.10.
Disease Assessments............................................................................................................52
6.2.11.
Laboratory Assessments.......................................................................................................53
6.2.12.
Pregnancy Test for Females of Childbearing Potential ........................................................54
6.2.13.
Vitamin D Assessment.........................................................................................................55
6.2.14.
Pharmacokinetic & Pharmacodynamic Samples..................................................................55
6.3.
Biomarker Testing..................................................................................................................................55
6.3.1.
Biomarker Samples to Address the Study Objectives:.........................................................55
6.3.2.
Biomarker Samples for Optional Future Research...............................................................57
6.3.3.
Biomarker Samples for Optional Genomic Research...........................................................58
6.4.
Re-Screening Criteria.............................................................................................................................58
6.5.
Treatment Assessments..........................................................................................................................59
6.6.
Post-treatment Assessments ...................................................................................................................59
6.7.
Long-Term Survival Follow-Up ............................................................................................................60
6.8.
Unscheduled Visits.................................................................................................................................60
6.9.
Assessments for Premature Discontinuation from Study.......................................................................60
6.10.
Criteria for Discontinuation of Study Treatment....................................................................................60
6.11.
Post Study Care......................................................................................................................................60
6.12.
Replacement of Subjects........................................................................................................................61
6.13.
Protocol Deviations................................................................................................................................61
6.14.
End of Study...........................................................................................................................................61
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................62
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................62
7.1.1.
Adverse Events.....................................................................................................................62
7.1.2.
Serious Adverse Events........................................................................................................62
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events .........................................................................63
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................64
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................64
7.2.2.
Assessment of Severity ........................................................................................................64
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................65
7.4.
Gilead Reporting Requirements.............................................................................................................67
7.5.
Toxicity Management ............................................................................................................................67
7.6.
Special Situations Reports......................................................................................................................67
7.6.1.
Definitions of Special Situations..........................................................................................67
7.6.2.
Instructions for Reporting Special Situations.......................................................................68
8.
STATISTICAL CONSIDERATIONS................................................................................................................70
8.1.
Analysis Objectives and Endpoints........................................................................................................70
8.1.1.
Analysis Objectives..............................................................................................................70

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8.1.2.
Primary Endpoint .................................................................................................................71
8.1.3.
Secondary Endpoint .............................................................................................................71
8.2.
Analysis Conventions.............................................................................................................................72
8.2.1.
Analysis Sets ........................................................................................................................72
8.3.
Data Handling Conventions ...................................................................................................................73
8.4.
Demographic Data and Baseline Characteristics ...................................................................................73
8.5.
Efficacy Analysis ...................................................................................................................................73
8.5.1.
Primary Analysis..................................................................................................................73
8.5.2.
Secondary Analyses .............................................................................................................74
8.6.
Safety Analysis.......................................................................................................................................74
8.6.1.
Extent of Exposure...............................................................................................................74
8.6.2.
Adverse Events.....................................................................................................................74
8.6.3.
Laboratory Evaluations ........................................................................................................75
8.6.4.
Other Safety Evaluations......................................................................................................76
8.7.
Pharmacokinetic Analysis......................................................................................................................76
8.8.
Biomarker Analysis................................................................................................................................76
8.9.
Sample Size............................................................................................................................................77
9.
RESPONSIBILITIES..........................................................................................................................................78
9.1.
Investigator Responsibilities ..................................................................................................................78
9.1.1.
Good Clinical Practice..........................................................................................................78
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................78
9.1.3.
Informed Consent.................................................................................................................79
9.1.4.
Confidentiality......................................................................................................................79
9.1.5.
Study Files and Retention of Records ..................................................................................79
9.1.6.
Case Report Forms...............................................................................................................81
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................81
9.1.8.
Inspections............................................................................................................................82
9.1.9.
Protocol Compliance............................................................................................................82
9.2.
Sponsor Responsibilities ........................................................................................................................82
9.2.1.
Protocol Modifications.........................................................................................................82
9.2.2.
Study Report and Publications .............................................................................................82
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................83
9.3.1.
Payment Reporting...............................................................................................................83
9.3.2.
Access to Information for Monitoring..................................................................................83
9.3.3.
Access to Information for Auditing or Inspections ..............................................................83
9.3.4.
Study Discontinuation..........................................................................................................83
10.
REFERENCES ...................................................................................................................................................84
11.
APPENDICES ....................................................................................................................................................86
Appendix 1.
Investigator Signature Page....................................................................................................87
Appendix 2.
Study Procedures Table..........................................................................................................88
Appendix 3.
Pharmacokinetics, Pharmacodynamic Time Point Collection Tables ....................................92
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03....................................94
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................95
Appendix 6.
Performance Status Scoring System (ECOG) ........................................................................97
Appendix 7.
RECIST 1.1 ............................................................................................................................98
Appendix 8.
Exemestane (Aromasin®) Prescribing Information ................................................................99
Appendix 9.
Fulvestrant (Faslodex®) Prescribing Information.................................................................100
Appendix 10.
Bayesian Logistic Regression Model ...................................................................................101

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LIST OF IN-TEXT TABLES
Table 3-1.
Phase 1b Dose Escalation: Combination of GS-5829 with exemestane or fulvestrant 
in subjects with advanced ER+/HER2- BrCa.........................................................................33
Table 5-1.
Dose Reduction of GS-5829...................................................................................................44
Table 5-2.
Dose Reduction of GS-5829...................................................................................................46
Table 5-3.
Examples of Concomitant Medications Prohibited in this Study ...........................................47
Table 6-1.
Analytes..................................................................................................................................54
Table 7-1.
Grading of Adverse Event Severity........................................................................................65
LIST OF IN-TEXT FIGURES
Figure 1-1.
Mechanism of Action of GS-5829 to Reduce Transcription of ER Target Genes in 
Cancer Cells ...........................................................................................................................28
Figure 3-1.
Randomized Phase 2 Dose Expansion....................................................................................36

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City CA, 94404
Study Title: 
A Phase 1b Study Followed by a Parallel Randomized Phase 2 Study 
Evaluating the Safety, Tolerability and Efficacy of GS-5829 in 
Combination with Exemestane or Fulvestrant Comparing with 
Exemestane or Fulvestrant alone in Subjects with Advanced Estrogen 
Receptor Positive HER2-Negative Breast Cancer
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
124032
2016-002365-63
TBD
Study Centers 
Planned:
Approximately 50 centers in the USA and Europe
Objectives:
The primary objective:
Phase 1b Dose Escalation

To characterize the safety and tolerability of GS-5829 in 
combination with exemestane or fulvestrant in subjects with 
advanced estrogen receptor positive Her2-negative breast cancer 
(ER+/HER2- BrCa)

To determine the Maximum Tolerated Dose (MTD), if not already 
determined from Study GS-US-350-1599, or the recommended 
Phase 2 Dose (RP2D) of GS-5829 in combination with exemestane 
or fulvestrant in subjects with advanced ER+/HER2- BrCa
Randomized Phase 2 Dose Expansion

To evaluate the efficacy of GS-5829 in combination with 
exemestane compared to exemestane alone in subjects with 
advanced ER+/HER2- BrCa, as measured by progression-free 
survival (PFS)

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
To evaluate the efficacy of GS-5829 in combination with 
fulvestrant compared to fulvestrant alone in subjects with advanced 
ER+/HER2- BrCa, as measured by PFS
Secondary objectives: 
Phase 1b Dose Escalation

To evaluate the pharmacokinetics (PK) of GS-5829 in combination
with exemestane or fulvestrant in subjects with advanced 
ER+/HER2- BrCa
Randomized Phase 2 Dose Expansion

To evaluate the efficacy of GS-5829 in combination with 
exemestane compared to exemestane alone in subjects with 
advanced ER+/HER2- BrCa, as measured by overall response rate 
(ORR) and clinical benefit rate (CBR) evaluated according to 
Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1.
ORR is defined as the proportion of subjects with response 
(complete response [CR], or partial response [PR]). CBR is defined 
as proportion of subjects with CR, PR, or stable disease (SD) that 
lasts for ≥ 24 weeks

To evaluate the efficacy of GS-5829 in combination with 
fulvestrant compared to fulvestrant alone in subjects with advanced 
ER+/HER2- BrCa, as measured by ORR and CBR

To evaluate the safety and tolerability of GS-5829 in combination 
with exemestane compared to exemestane alone in subjects with 
advanced ER+/HER2- BrCa

To evaluate the safety and tolerability of GS-5829 in combination 
with fulvestrant compared to fulvestrant alone in subjects with 
advanced ER+/HER2- BrCa

To evaluate the overall survival (OS) for subjects with advanced 
ER+/HER2- BrCa who receive GS-5829 in combination with 
exemestane or fulvestrant compared to exemestane or fulvestrant 
alone
Exploratory objectives:
 
 
PPD

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Study Design:
Phase 1b Dose Escalation: 
Cohorts of postmenopausal women with advanced ER+/HER2- BrCa,
for whom no standard curative therapy exists and who are candidates 
for exemestane or fulvestrant, will be sequentially enrolled at 
progressively higher dose levels of oral GS-5829 in combination with 
standard doses of exemestane or fulvestrant. Up to 60 subjects will be 
enrolled for the Phase 1b Dose Escalation portion of the study. The 
starting dose of GS-5829 will be either 3 mg once daily or a dose level 
that has been demonstrated to be safe and tolerable based on other 
ongoing studies (GS-US-350-1599, GS-US-350-1604).   
Eligible subjects will be assigned to either Group A or B based on prior 
treatment and the investigators’ decision. Group A will initiate with 
GS-5829 orally once daily on Cycle 1 Day 1 (C1D1) combined with 
25 mg of exemestane administered orally once daily (or in accordance 
with locally approved labeling). The subject may initiate exemestane 
any time prior to, or on, C1D1. Group B will initiate GS-5829 orally 
once daily on C1D1 with fulvestrant administered intramuscularly (in 
accordance with locally approved labeling) every 28 days (± 3 days).  
The subject may initiate fulvestrant any time prior to, or on, C1D1. If 
C1D1 is the subject’s first dose of fulvestrant, a one-time additional 
dose of fulvestrant should be administered on Cycle 1 Day 15 (C1D15).  
The doses of GS-5829 for each Dose Level are shown in the table
below. 
Phase 1b Dose Escalation: Combination of GS-5829 with 
exemestane or fulvestrant in subjects with advanced ER+/HER2-
BrCa
Dose Level
GS-5829
(once daily)
Group A 
(Exemestane)
Group B 
(Fulvestrant)**
1*
3 mg
25 mg orally once 
daily
(or in accordance
with locally 
approved labeling)
500 mg 
intramuscularly 
day 1, 29 and then 
every 28 days
(or in accordance
with locally approved 
labeling)
2
4 mg
3
6 mg
4
9 mg
* The initial dose level may be higher (e.g., 4 mg) than Dose Level 1, depending on results 
from ongoing studies and emerging PK data.
** Subjects initiating fulvestrant on this study on C1D1and not having received any prior dose 
of fulvestrant should receive a single additional dose of fulvestrant on C1D15.

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Group A and Group B will dose escalate independently of each other; 
each cohort will consist of 3 newly enrolled subjects who will be 
treated at the specified dose level. Dose escalation will continue until 
identification of the MTD of GS-5829, or a RP2D is reached. 
After all the subjects in each cohort have been followed for at least 
28 days after the first dose of GS-5829, a dose limiting toxicity (DLT) 
model (see Appendix 10) utilizing all available GS-5829 safety data 
will be built and will provide estimates of DLT rates at all dose levels. 
The recommended dose from the dose-DLT model for the next cohort 
will have the highest probability that the DLT rate will fall in the target 
interval (16%, 33%), and a probability of < 25% that the DLT rate 
exceeds 33%.
The dose escalation decision and the final decision for the RP2D will 
be made by the Safety Review Team (SRT), following a review of the 
model recommendation and all relevant data including safety 
information, PK, biomarkers, clinical data from evaluable subjects. 
The recommended dose of GS-5829 to be combined with exemestane 
or fulvestrant in the Randomized Phase 2 Dose Expansion part of this 
study will be determined based on the data available in the Phase 1b 
Dose Escalation portion of this study and from studies 
GS-US-350-1599 and GS-US-350-1604. The recommended dose will 
not exceed the MTD identified by either the Phase 1b Dose
Escalation from this study or from studies GS-US-350-1599 and 
GS-US-350-1604, whichever dose is higher. At least 6 subjects should 
have already been treated and evaluated at that dose level prior to 
enrolling subjects in the Randomized Phase 2 Dose Expansion.
Dose Limiting Toxicity (DLT) Definition
A DLT is a toxicity defined below and considered possibly related to 
GS-5829 if occurring during the DLT assessment window (Day 1 
through Day 28) in each 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 ≥ 4 thrombocytopenia (platelet count < 25,000/μL)

Grade ≥ 3 thrombocytopenia (platelet count <50,000/μL but 
>25,000/μL) lasting > 7 days despite GS-5829 drug interruption

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 the Gilead 
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. See 
Section 3.2 for details.
Randomized Phase 2 Dose Expansion:
Approximately 120 female subjects who are post-menopausal with 
ER+/HER2- BrCa and who have had disease progression following 
anti-estrogen therapy will be enrolled.

Approximately 60 subjects who have not previously received 
exemestane will be randomized in a 2:1 ratio to receive exemestane 
+ GS-5829 or exemestane alone in Group 1.  

Approximately 60 subjects who have not previously received 
fulvestrant will be randomized in a 2:1 ratio to receive fulvestrant + 
GS-5829 or fulvestrant alone in Group 2.  
GS-5829 and the anti-estrogen therapy (exemestane for Group 1 or 
fulvestrant for Group 2) will be initiated on C1D1.

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Study Schema: Randomized Phase 2 Dose Expansion:
Number of 
Subjects Planned:
Phase 1b Dose Escalation: Up to 60 subjects will be enrolled
Randomized Phase 2 Dose Expansion: Approximately 120 subjects will 
be enrolled, with 60 subjects in Group 1 (GS-5829+exemestane vs. 
exemestane alone) and 60 subjects in Group 2 (GS-5829+fulvestrant
vs. fulvestrant alone).  
Target Population:
Postmenopausal women with histologically or cytologically confirmed
ER+/HER2- BrCa who have progressed after treatment with an 
anti-estrogen or an aromatase inhibitor (AI) therapy and are 
candidates for fulvestrant or exemestane therapy.  
Duration of 
Treatment:
Subjects may continue receiving GS-5829 once daily until disease 
progression (clinical or radiographic), unacceptable toxicity, withdrawal
of consent, or death whichever comes first (Section 3.5).
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) 18 years of age, female
2) Histologically or cytologically confirmed breast cancer with 
evidence of metastatic or locally advanced disease not amenable to 
resection or radiation therapy with curative intent and who have 
progressed during treatment with at least one prior hormonal 
therapy. Note: In referring to prior hormonal therapy; targeted 
therapies, such as palbociclib and/or everolimus or investigative 
targeted therapies which were administered as part of a prior 
hormonal therapy regimen are allowed after the washout period has 
been reached.
a.
Phase 1b Dose Escalation - Subjects may have had unlimited 
prior hormonal therapy and a total of 2 prior chemotherapy 
regimens (adjuvant chemotherapy is considered 1 regimen). 

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Subjects may have progressed on fulvestrant or exemestane as 
a single agent
b. Randomized Phase 2 Dose Expansion - Subjects may have had 
unlimited prior hormonal therapy, only one adjuvant 
chemotherapy is permitted (no prior chemotherapy for 
metastatic disease is allowed). Subject enrolling in Group 1 
must be exemestane naïve and subjects enrolling in Group 2 
must be fulvestrant naïve. If a subject is naïve to both 
exemestane and fulvestrant, it is the investigator’s decision for 
which Group to enroll
3) Documentation of ER positive (≥ 1% positive stained cells by local 
standards) based on the most recent tumor biopsy, unless bone-only 
disease
4) Documented HER2-negative tumor based on local testing on most 
recent tumor biopsy (immunohistochemistry score 0/1+ or negative 
by in situ hybridization HER2/CP17 ratio < 2 or for single probe 
assessment HER2 copy number < 4)
5) Post-menopausal subjects considered to be in the post-menopausal 
state as defined by one of the following:
a.
Age ≥60 years
b. Age < 60 years and cessation of regular menses for at least 
12 consecutive months in the absence of chemotherapy, 
tamoxifen, toremifene, or ovarian suppression and serum 
estradiol and follicle-stimulating hormone (FSH) level within 
the post-menopausal range
c.
Prior bilateral oophorectomy
d. Pre-/peri-menopausal women can be enrolled if amenable to be 
treated with the luteinizing-hormone releasing hormone 
(LHRH) agonist, goserelin. Subjects must have commenced 
treatment with goserelin or an alternative LHRH agonist at 
least 4 weeks prior to first dose of study drug. If subjects have 
received an alternative LHRH agonist prior to study entry, they 
must switch to goserelin on or before C1D1 for the duration of 
the study
6) Measurable disease defined per RECIST v. 1.1, or bone-only 
disease must have a lytic or mixed lytic blastic lesion that can be 
accurately assessed by computed tomography (CT) or magnetic
resonance imaging (MRI). Subjects with bone-only disease and 
blastic-only metastases are not eligible

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7) 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])
8) Eastern Cooperative Oncology Group (ECOG) Performance Status
of  ≤ 1
9) Life expectancy of ≥3 months, in the opinion of the investigator
10) 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
11) Coagulation: International Normalized Ratio (INR) ≤1.2 
12) Negative serum pregnancy test (Appendix 5)
13) Female subjects of childbearing potential who engage in 
heterosexual intercourse must agree to use protocol specified 
method(s) of contraception as described in Appendix 5
14) Females who are nursing must agree to discontinue nursing before 
the first dose of GS-5829
15) 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 the Gilead 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

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cardiac arrhythmia, or psychiatric illness/social situation that would 
limit compliance with study requirements as judged by treating 
physician
4) 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 C1D1
5) Major surgery, defined as any surgical procedure that involves 
general anesthesia and a significant incision (i.e., larger than what is 
required for placement of central venous access, percutaneous 
feeding tube) within 28 days of the first dose of study drug
6) 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
7) 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)
8) 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; 
adequately treated Stage 1 or 2 cancer currently in complete 
remission; any other cancer that has been in complete remission for 
≥ 5 years
9) Anti-tumor therapy (chemotherapy, chemoradiation, radiation, 
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); 5 half-lives 
of any investigational drug; concurrent use of goserelin for 
pre-/peri-menopausal breast cancer and exemestane or fulvestrant
per the protocol are permitted
10) History of long QT syndrome or whose corrected QT interval 
(QTc) measured (Fridericia method) at screening is prolonged 
(> 470 ms). Subjects who screen fail due to this criterion are not 
eligible to be re-screened
11) Prior exposure to any bromodomain (BET) inhibitors  

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12) Immunotherapy within 6 months of C1D1
13) Evidence of bleeding diathesis or clinically significant 
bleeding, within 28 days of C1D1 or history of hemoptysis of 
> 2.5mL/1 teaspoon within 6 months of C1D1
14) Anticoagulation therapy within 7 days of C1D1, including 
acetylsalicylic acid, low molecular weight heparin, or warfarin
15) Known human immunodeficiency virus (HIV) infection
16) Hepatitis B surface Antigen (HBsAg) positive
17) Hepatitis C virus (HCV) antibody positive with HCV RNA positive
18) 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 
19) History of high grade esophageal or gastric varices
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 C1D1. Screening procedures will include the following:
medical history review, physical exam, vital signs, 12-lead
electrocardiogram (ECG), echocardiogram (ECHO), ECOG
Performance Status, prior/concomitant medication review, chemistry, 
hematology and coagulation, hepatitis B and hepatitis C virus 
(HBV)/(HCV) testing, human immunodeficiency virus (HIV) testing, 
serum pregnancy β-HCG (serum estradiol and FSH for subjects 
< 60 years old and who have been amenorrheic for at least 
12 consecutive months), and CT or MRI and bone scans. Scans that 
meet protocol requirements that are obtained as part of standard
medical practice up to 28 days prior to C1D1 are acceptable as long as:
(1) tests were performed using the method requirements outlined in 
RECIST v.1.1, (2) the same technique/modality can be used to follow 
identified lesions throughout the trial for a given subject, and 
(3) appropriate documentation indicating that these radiographic tumor 
assessments were performed as standard of care is available in the
subject’s source notes. Baseline tumor lesions will be measured and
characterized prior to C1D1 to assess the subject’s disease status prior
to beginning treatment.

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Treatment:
Phase 1b Dose Escalation with Exemestane or Fulvestrant 
Subjects who meet eligibility criteria will receive GS-5829 orally once 
daily combined with either 25 mg of exemestane orally once daily 
or fulvestrant intramuscularly on Day 1, 15 (for whom C1D1 is the 
subject’s first dose of fulvestrant), 29 and then every 28 days 
(± 3 days). Subjects in the Phase 1b Dose Escalation portion may 
initiate exemestane (Group A) or fulvestrant (Group B) any time prior 
to, or on, C1D1. 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 computed tomography (CT) scan (or magnetic 
resonance imaging [MRI]) scan every 8 weeks for the first year, then 
every 12 weeks. A subject who does not show evidence of disease
progression may continue receiving GS-5829 once daily and 
exemestane (Group A) or fulvestrant (Group B) until disease 
progression (clinical or radiographic), unacceptable toxicity, withdrawal
of consent, or death whichever comes first.
Following treatment discontinuation, subjects will be followed for 
safety for 30 days from the last dose of study drug. 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.  
Randomized Phase 2 Dose Expansion
Sparse PK and PD samples will be collected at pre-dose and anytime 
between 1 to 4 hours post-dose on Day 1 and Day 15 of Cycle 1 and at 
pre-dose on Day 1 of Cycles 3 and 6. Note: PK samples will only be 
collected for subjects who are randomized to a GS-5829 combination 
arm.
Subjects in the Randomized Phase 2 Dose Expansion portion of the 
study will also be followed for up to two years for OS. 

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Test Product, Dose, 
and Mode of 
Administration:
GS-5829 will be supplied as GS-5829-02 and is available as round, 
plain-faced tablets containing 1 mg or 5 mg GS-5829. GS-5829 tablets 
will be self-administered orally once daily, beginning on C1D1 of the 
study and thereafter at approximately the same time each day until end 
of treatment (EOT).  
For subjects in Group A of the Phase 1b Dose Escalation or subjects in 
Group 1 of the Randomized Phase 2 Dose Expansion, 25 mg 
exemestane tablets will be self-administered orally once daily (or in 
accordance with locally approved labeling), beginning on C1D1 of the 
study and thereafter at approximately the same time each day until the 
EOT.  
For subjects in Group B of the Phase 1b Dose Escalation or subjects in 
Group 2 of the Randomized Phase 2 Dose Expansion, fulvestrant will 
be administered intramuscularly (in accordance with locally approved 
labeling) by the clinic staff approximately every 28 days (± 3 days) 
until the EOT. 
For subjects in the Phase 1b Dose Escalation or subjects in the 
Randomized Phase 2 Dose Expansion part of the study for whom C1D1
is the subject’s first dose of fulvestrant, a one-time additional dose of 
fulvestrant will be administered on Cycle 1, Day 15 (± 3 days).
Reference Therapy, 
Dose, and Mode of 
Administration:
The reference therapy in the Randomized Phase 2 Dose Expansion 
portion of the study is exemestane alone and fulvestrant alone.
For subjects in Group 1 of the Randomized Phase 2 Dose Expansion, 
exemestane 25 mg tablets will be self-administered orally once daily
(or in accordance with locally approved labeling), beginning on C1D1
of the study and thereafter at approximately the same time each day 
until the EOT.  
For subjects in Group 2 of the Randomized Phase 2 Dose Expansion, 
fulvestrant will be administered intramuscularly (in accordance with 
locally approved labeling) by the clinic staff approximately every 
28 days (±3 days) until the EOT. For all subjects in the dose expansion 
Phase and for subjects in the dose escalation phase for whom C1D1 is 
the subject’s first dose of fulvestrant, a one-time additional dose of 
fulvestrant will be administered on Cycle 1 Day 15 (± 3 days).
Criteria for 
Evaluation:
Phase 1b Dose Escalation and Randomized Phase 2 Dose 
Expansion
Safety:
Safety will be evaluated by assessment of clinical laboratory tests, 
physical examination, 12-lead ECG, vital signs measurements, and the 
documentation of AEs

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Efficacy:
PFS – defined as the interval from date of randomization to the earlier 
of the first documented confirmed disease progression or death from 
any cause
ORR – defined as the proportion of subjects who achieve a CR or PR
CBR - defined as the proportion of subjects who achieve a CR or PR or 
SD that lasts for ≥ 24 weeks
OS - defined as interval from date of randomization to date of death 
from any cause
Pharmacokinetics:
Phase 1b Dose Escalation: The PK parameters for GS-5829 will be 
calculated as applicable: [e.g., Cmax, and AUCtau ]
Statistical Methods:
Analysis Methods
Phase 1b Dose Escalation: The incidence of DLTs, AEs, serious 
adverse events (SAEs), and clinically significant laboratory 
abnormalities in subjects treated with GS-5829 in combination with 
exemestane or fulvestrant will be evaluated.
Randomized Phase 2 Dose Expansion: The Intent-to-Treat (ITT) 
analysis set includes all subjects who are randomized, regardless of 
whether subjects receive any study drug(s) or receive a different 
regimen from the regimen they were randomized to. Treatment 
assignment will be designated according to randomization. The analysis 
of PFS based on the ITT analysis set will be considered the primary 
analysis of the study. 
The Per-Protocol (PP) analysis set includes data from subjects in the 
ITT analysis set who meet the general criteria defining the target 
population for this study: those who are adherent to the protocol, are 
compliant with study drug treatment, and are evaluable for relevant 
efficacy endpoints. Treatment assignment will be designated according 
to the actual treatment received. The PP analysis set will be used in 
sensitivity analyses of efficacy endpoints.
A Safety Analysis Set for this study consists of all subjects who receive 
≥ 1 dose of study drug. Other analysis sets (DLT evaluable analysis set,
PK analysis set, and biomarker analysis set) will be used for the 
corresponding analyses.
Subject characteristics and study results will be described and 
summarized by dose level and by study visit 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 
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The log-rank test will be used for the analyses of PFS. Kaplan-Meier 
estimates and plots will be provided. ORR will be calculated along with 
the 95% CIs based on exact method and compared between treatment 
arms by Fisher’s exact test. Based on the Safety Analysis Set, 
information regarding study drug administration, study drug 
compliance and safety variables will be described and summarized.
Using data from the relevant Analysis Sets, GS-5829 plasma 
concentrations will be summarized. PD markers will also be described 
and summarized. Plasma concentrations of GS-5829 metabolite(s), 
fulvestrant and/or exemestane may also be determined.
Sample Size
Up to approximately 60 subjects will be enrolled in the Phase1b Dose 
Escalation portion of the study.
Total enrollment will be approximately 120 subjects in Randomized 
Phase 2 Dose Expansion portion. In Group 1 of the Randomized Phase 
2 Dose Expansion portion of the study, approximately 60 subjects will 
be randomized to receive GS-5829 in combination with exemestane or 
exemestane alone in a 2:1 ratio. Similarly, in Group 2 of the
Randomized Phase 2 Dose Expansion portion of the study, 
approximately 60 subjects will be randomized to receive GS-5829 in 
combination with fulvestrant or fulvestrant alone in a 2:1 ratio. The 
sample size of 60 subjects in each group (40 in the combination arm 
and 20 in the exemestane alone or fulvestrant alone arm) will provide 
37 events in total and greater than 80% power to detect the difference 
in PFS between GS-5829 in combination with exemestane and 
exemestane alone and between GS-5829 in combination with 
fulvestrant and fulvestrant alone with 0.1 two-sided significance level, 
assuming a median PFS of 5 months for subjects who receive 
exemestane alone or fulvestrant alone, a median PFS of 12.5 months in 
subjects who receive GS-5829 in combination with exemestane or 
fulvestrant, accrual period of 6 months and total study duration of 
18 months and a drop-out rate of 10% by 12 months. An interim 
analysis may be performed separately when 22 events have been 
reached in each group. The purpose of this analysis is to have an early 
evaluation of the safety and efficacy of GS-5829 in combination with 
exemestane or fulvestrant. The interim analysis will assess either an 
expansion or study stop on any one of the arms independent of one 
another. The trial will continue after the interim analysis.
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
AI
aromatase inhibitor
ALT
alanine transaminase
ANC
absolute neutrophil count
AR
androgen receptor
AST
aspartate transaminase
AUCtau
area under the plasma concentration-time curve
BCRP
breast cancer resistance protein
BET
bromodomain and extra-terminal
BRD
bromodomain
CBC
complete blood count
CBR
Clinical benefit rate
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
CTC
circulating tumor cells
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
ECHO
echocardiogram
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOT
end of treatment
ER
estrogen receptor
eSAE
electronic serious adverse events
FAS
full analysis set

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FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
gastrointestinal
HBsAg
Hepatitis B surface Antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human Immunodeficiency Virus
HNSTD
highest non-severely toxic dose
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
INR
IP
International Normalized Ratio
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
MYC
myelocytomatosis viral oncogene homolog
MUGA
multigated acquisition scan
NCI
National Cancer Institute
ORR
overall response rate
OS
overall survival
PD
pharmacodynamics
PFS
progression-free survival
PK
pharmacokinetics
PR
partial response
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
SD
stable disease
StD
standard deviation
SOC
system organ class
SOP
standard operating procedure

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SRT
safety review team
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}. 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 subjects 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 

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cells by inhibiting BET protein-dependent transcription of MYC and other oncogenic pathways, 
including transcription mediated by the AR in prostate cancer cells.
1.2.
GS-5829
1.2.1.
General Information
For further information on the GS-5829, refer to the current investigator’s brochure for GS-5829.
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-glycoprotein (P-gp) and breast cancer resistance protein (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 single and 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.  

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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 of GS-5829. 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.  
Hematopoietic effects include decreases in white blood cells (WBC), 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 22 July 2016, two clinical studies evaluating GS-5829 have been initiated and are actively 
enrolling subjects. One study (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
pharmacodynamics (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 

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detectable trend in laboratory abnormalities in relationship to dose has been observed. In study 
GS-US-350-1599, two DLTs were reported as of 22 July 2016: a DLT of Grade 3 
thrombocytopenia was reported in 1 of 6 evaluable subjects at 3 mg, and a second DLT of 
adrenal hemorrhage was reported in 1 out of 2 evaluable subjects at 4 mg.
A second clinical study (GS-US-350-1604) in subjects with metastatic castrate-resistant prostate 
cancer (mCRPC) has completed the cohorts of enrollment with 4 evaluable subjects at the 2 mg 
and 4 evaluable subjects at 3 mg as single agent dose of GS-5829. No DLT has been reported as 
of 22 July 2016. This study 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 combined with 
enzalutamide in subjects with mCRPC. Doses planned for this study are 1.4, 2, 3, 4, 6, and 9 mg
once daily.
Please refer to the current GS-5829 investigator’s brochure for additional details.
1.2.4.
Information about Exemestane
Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural 
substrate androstenedione. It acts as a false substrate for the aromatase enzyme and is processed 
to an intermediate that binds irreversibly to the active site of the enzyme, causing its inactivation, 
an effect also known as “suicide inhibition.” Exemestane significantly lowers circulating 
estrogen concentrations in post-menopausal women. In the US, exemestane is approved for the 
treatment of advanced breast cancer in postmenopausal women whose disease has progressed 
following tamoxifen therapy. For current information about exemestane (Aromasin ®) refer to 
the regional prescribing information Appendix 8 or the summary of product characteristics in the 
pharmacy binder.
1.2.5.
Information about Fulvestrant
Fulvestrant is an estrogen receptor antagonist that binds to the estrogen receptor in a competitive 
manner with affinity comparable to that of estradiol and down-regulates the ER protein in human 
breast cancer cells. In vitro studies demonstrated that fulvestrant is a reversible inhibitor of the 
growth of tamoxifen resistant as well as estrogen sensitive human breast cancer cell lines. In vivo 
tumor studies demonstrated that fulvestrant delayed the establishment of tumors from xenografts 
of human breast cancer MCF-7 cells in nude mice. Fulvestrant inhibited the growth of 
established MCF7 xenografts and of tamoxifen resistant breast tumor xenografts. In the US, 
fulvestrant is approved for the treatment of hormone receptor positive metastatic breast cancer in 
postmenopausal women with disease progression following anti-estrogen therapy. For current 
information about fulvestrant (Faslodex®), refer to Appendix 9 or the summary of product 
characteristics in the pharmacy binder.

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1.3.
Rationale for This Study
Approximately 75% of breast cancers express the estrogen receptor (ER), a nuclear hormone 
receptor and transcription factor that promotes the expression of genes involved in cell growth 
and survival {Clark et al 1984}. Anti-estrogen endocrine therapies, such as aromatase inhibitors 
(AIs) and tamoxifen, are the primary treatments for early stage ER-positive breast cancers but 
many women relapse during or after completing these adjuvant hormonal therapies. In the 
metastatic setting, single-agent treatment with AIs, tamoxifen, or the selective ER degrader, 
fulvestrant, has limited benefit. When combined with other targeted therapies such as the 
Cyclin-Dependent Kinase (CDK) 4/6 inhibitor, palbociclib, the benefit of first-line antiestrogen 
therapy significantly improves PFS. Standard of care includes sequential administration of 
endocrine therapies until hormone resistance occurs, at which time patients are usually 
transitioned to chemotherapy and eventually die. Therefore, the development of effective 
therapies that improve response to endocrine therapy and prevent or reverse resistance continues 
to be of clinical importance. 
Resistance to endocrine therapy is mediated by several mechanisms that enable reactivation of 
ER-driven transcription under conditions of low estrogen (i.e. estrogen-independent transcription 
by the ER). These mechanisms include ER overexpression, activating ER mutations, increased 
expression of ER co-activators, or increased expression of ER-target genes such as MYC and 
cyclin D1 {Osborne et al 2011}. Importantly, BET proteins are required for both 
estrogen-dependent and estrogen-independent transcription by the ER receptor. BRD4 and 
BRD3 are recruited to ER target genes, including MYC, where they promote transcription by 
RNA polymerase II. In preclinical studies, the BET inhibitor, JQ1, decreased ER-mediated gene 
transcription and inhibited the growth of ER-positive tumors {Nagarajan et al 2014, Sengupta et 
al 2015}. In addition, combination of JQ1 with fulvestrant significantly increased time to disease 
progression in an endocrine-resistant ER-positive xenograft mouse breast tumor {Feng et al 
2014}.
The combination of GS-5829 and an anti-estrogen such as fulvestrant or an AI such as 
exemestane may increase the efficacy of endocrine therapy in patients with advanced 
ER-positive breast cancer by targeting orthogonal mechanisms. The combination is expected to 
lead to overall greater inhibition of ER-dependent transcription by blocking distinct aspects of 
ER signaling (reduced ligand-dependent ER activation with AI, reduced ER protein stability with 
fulvestrant, and reduced BET-dependent transcription of ER target genes with GS-5829). By 
directly inhibiting the transcription of ER target genes such as MYC, GS-5829 is hypothesized to 
block established mechanisms of resistance to endocrine therapy. BET proteins also promote 
transcription of several ER-independent cell cycle genes, including CDK 6, which may 
additionally contribute to the combination activity in ER+ breast cancer cells. Preliminary Gilead 
data has demonstrated a synergistic effect of fulvestrant and GS-5829 to inhibit growth of 
ER-positive breast cancer cell lines in vitro and to inhibit growth of patient-derived ER-positive 
breast cancer xenografts in mice. 

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Figure 1-1.
Mechanism of Action of GS-5829 to Reduce Transcription of ER 
Target Genes in Cancer Cells
Overall, the pre-clinical studies demonstrate that GS-5829 is a potent and selective inhibitor of 
BET proteins and support the use of GS-5829 to treat solid tumors and hematological cancers. 
1.3.1.
Rationale for Dose Selection
As of 22 July 2016, a total of 20 subjects have been dosed with single agent GS-5829 once daily 
and are evaluable for DLT assessment: 2 subjects at 0.6 mg, 1 subject at 1.4 mg, 5 subjects at 2 
mg, 10 subjects at 3 mg and 2 subject at 4 mg. A DLT of thrombocytopenia at 3 mg dose level
and a DLT of adrenal hemorrhage at 4 mg dose level have been reported. No drug interactions or 
overlapping toxicities are expected between GS-5829 and exemestane or fulvestrant. Based on a 
dose limiting toxicity (DLT) model (see Appendix 10) utilizing GS-5829 safety data from 
different dose levels collected so far, the probabilities of underdosing (DLT rate<16%) (see 
Appendix 10 for results), falling in the target interval of DLT rate (between 16% and 33%) and 
overdosing (DLT rate>33%) will be about 68% , 30% and 2% , respectively, if the next cohort is 
at 3 mg. The probabilities of underdosing, falling in the target interval of DLT rate and 
overdosing will be about 95%, 5% , and 0.1%, respectively, if the next cohort is at 2 mg. 
Because there is a high (95%) chance of underdosing at 2 mg and a low (2%) chance of 
overdosing at 3 mg, the starting dose of GS-5829 is planned as 3 mg for both Groups A and B in 
the Phase 1b Dose Escalation portion of this study. The starting dose level will be at 3 mg once 
daily. If a higher dose has been demonstrated to be both safe and tolerable in studies 
GS-US-350-1599 and GS-US-350-1604, the new dose level will be selected prior to initiating 
dosing in this study.

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The recommended dose of GS-5829 to be combined with exemestane or fulvestrant in the 
Randomized Phase 2 Dose Expansion part of this study will not exceed the maximum tolerated 
dose (MTD) identified by either Phase 1b dose escalation from this study or from 
GS-US-350-1599, whichever dose is higher. A lower dose may be chosen for the Randomized 
Phase 2 Dose Expansion study based on emerging safety, PK, pharmacodynamics (PD), and 
efficacy results from this study and including additional safety data generated from other 
ongoing Phase 1 and 2 studies with GS-5829.
1.4.
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.  
As of 22 July 2016, the 3 mg has been determined to be safe as single agent dosing in both the 
First-In-Human study GS-US-350-1599 and prostate cancer study GS-US-350-1604 respectively
In addition, to minimize the risk of excessive toxicity, the dose escalation of GS-5829 in this 
protocol will not increase at > 50% 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, and 15 of the first two 28 day cycles, Day 1
of the third 28 day cycle, and then every 28 days until end of treatment (EOT) which will be
followed by a 30-day Safety Follow-Up Visit. Physical examinations will occur on Day 1 of each 
28-day cycle until EOT which will be 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.
Exemestane and fulvestrant have been approved for treatment of advanced breast cancer in 
postmenopausal women whose disease has progressed either following tamoxifen or 
anti-estrogen therapy. The known toxicities for exemestane for this patient population are hot 
flushes, nausea, fatigue, increase sweating, increased appetite (Appendix 8). The know toxicities 
for fulvestrant are increased hepatic enzymes (ALT, AST and ALP), injection side pain, nausea, 
bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, vomiting, 
anorexia, asthenia, musculoskeletal pain, cough, dyspnea and constipation (Appendix 9).

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1.5.
Potential Benefits
The combination of GS-5829 with exemestane and fulvestrant is expected to lead to overall 
greater inhibition of ER-dependent transcription by blocking distinct aspects of ER signaling 
(reduced ligand-dependent ER activation with AI such as exemestane, reduced ER protein 
stability with fulvestrant, and reduced BET-dependent transcription of ER target genes with 
GS-5829). By directly inhibiting the transcription of ER target genes such as MYC, GS-5829 is 
hypothesized to block established mechanisms of resistance to endocrine therapy.  
1.6.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.

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2.
OBJECTIVES
The primary objectives:
Phase 1b Dose Escalation

To characterize the safety and tolerability of GS-5829 in combination with exemestane or 
fulvestrant in subjects with advanced estrogen receptor positive Her2-negative breast cancer 
(ER+/HER2- BrCa)

To determine the MTD if not already determined from GS-US-350-1599, or the 
recommended Phase 2 dose (RP2D) of GS-5829 in combination with exemestane or 
fulvestrant in subjects with advanced ER+/HER2- BrCa
Randomized Phase 2 Dose Expansion

To evaluate the efficacy of GS-5829 in combination with exemestane compared to 
exemestane alone in subjects with advanced ER+/HER2- BrCa, as measured by PFS

To evaluate the efficacy of GS-5829 in combination with fulvestrant compared to fulvestrant
alone in subjects with advanced ER+/HER2- BrCa, as measured by PFS
The secondary objectives:
Phase 1b Dose Escalation

To evaluate the PK of GS-5829 in combination with exemestane or fulvestrant in subjects 
with advanced ER+/HER2- BrCa
Randomized Phase 2 Dose Expansion

To evaluate the efficacy of GS-5829 in combination with exemestane compared to 
exemestane alone in subjects with advanced ER+/HER2- BrCa, as measured by overall 
response rate (ORR) and clinical benefit rate (CBR) evaluated according to Response 
Evaluation Criteria in Solid Tumors (RECIST) v. 1.1. ORR is defined as the proportion of 
subjects with response (complete response [CR], or partial response [PR]). CBR is defined as 
the proportion of subjects with CR, PR, or stable disease (SD) that lasts for ≥24 weeks

To evaluate the efficacy of GS-5829 in combination with fulvestrant compared to fulvestrant
alone in subjects with advanced ER+/HER2- BrCa, as measured by ORR or CBR

To evaluate the safety and tolerability of GS-5829 in combination with exemestane compared 
to exemestane alone in subjects with advanced ER+/HER2- BrCa

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
To evaluate the safety and tolerability of GS-5829 in combination with fulvestrant compared 
to fulvestrant alone in subjects with advanced ER+/HER2- BrCa

To evaluate the overall survival (OS) for subjects with advanced ER+/HER2-BrCa who 
receive GS-5829 in combination with exemestane or fulvestrant comparing to exemestane or 
fulvestrant alone
The exploratory objectives:
 
PPD

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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: 
Cohorts of postmenopausal women with (ER+/HER2- BrCa), for whom no standard curative 
therapy exists and who are candidates for exemestane or fulvestrant, will be sequentially enrolled 
at progressively higher dose levels of oral GS-5829 in combination with standard doses of 
exemestane or fulvestrant. Up to 60 subjects will be enrolled in the Phase 1b Dose Escalation
portion of the study. The starting dose of GS-5829 will be the either 3 mg once daily or a dose 
level that has been demonstrated to be safe and tolerable based on other ongoing studies
(GS-US-350-1599, GS-US-350-1604).     
Eligible subjects will be assigned to either Group A or Group B based on prior treatment and the 
investigators’ decision. Group A will initiate with GS-5829 orally once daily on Cycle 1 Day 1 
(C1D1) combined with 25 mg of exemestane administered orally once daily (or in accordance 
with locally approved labeling). The subject may initiate exemestane any time prior to, or on, 
C1D1. Group B will initiate GS-5829 orally once daily on C1D1 with fulvestrant administered 
intramuscularly every 28 days (± 3 days) (or in accordance with locally approved labeling). The 
subject may initiate fulvestrant any time prior to, or on, C1D1. If C1D1 is the subject’s first dose 
of fulvestrant, a one-time additional dose of fulvestrant should be administered on Cycle 1 
Day 15 (C1D15).  
The doses of GS-5829 for each Dose Level are shown in the following table.
Table 3-1.
Phase 1b Dose Escalation: Combination of GS-5829 with exemestane
or fulvestrant in subjects with advanced ER+/HER2- BrCa
Dose Level
GS-5829 (once daily)
Group A Exemestane
Group B Fulvestrant**
1*
3 mg
25 mg orally once daily
(or in accordance with locally 
approved labeling)
500 mg intramuscularly day 1, 
29 and then every 28 days
(or in accordance with locally 
approved labeling)
2
4 mg
3
6 mg
4
9 mg
*
The initial dose level may be higher (e.g., 4 mg) than Dose Level 1, depending on results from ongoing studies and 
emerging PK data. 
**
Subjects initiating fulvestrant on this study on C1D1 and not having received any prior dose of fulvestrant should receive a 
single additional dose of fulvestrant on Cycle 1 Day 15.

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Group A and Group B will dose escalate independently of each other; each cohort will consist of 
3 newly enrolled subjects who will be treated at the specified dose level. Dose escalation will 
continue until identification of the MTD of GS-5829, or until a RP2D is reached.
After all the subjects in each cohort have been followed for at least 28 days after the first dose of 
GS-5829, a DLT model (Bayesian logistic regression model, see Appendix 10) utilizing all 
available GS-5829 safety data will be built and will provide estimates of DLT rates at all dose 
levels. The recommended dose from the dose-DLT model for the next cohort will have the 
highest probability that the DLT rate will fall in the target interval (16%, 33%), and a probability 
of < 25% that the DLT rate exceeds 33%.
The dose escalation decision and the final decision for the RP2D will be made by the Safety 
Review Team (SRT), following a review of the model recommendation and all relevant data 
including safety information, PK, biomarkers, clinical data from evaluable subjects. 
The SRT will consist of at least one investigator and the following Gilead Sciences, Inc. (Gilead) 
study team members: the Gilead medical monitor, representatives from Drug Safety and Public 
Health (DSPH) and Biostatistics. Others may be invited to participate as members of the SRT if 
additional expertise is desired. The Gilead medical monitor serves as the chair of the SRT.
The recommended dose of GS-5829 to be combined with exemestane or fulvestrant in the 
Randomized Phase 2 Dose Expansion part of this study will be determined based on the data 
available in the Phase 1b Dose Escalation portion of this study and from studies 
GS-US-350-1599 and GS-US-350-1604. The recommended dose will not exceed the MTD 
identified by either the Phase 1b dose escalation from this study or from studies 
GS-US-350-1599 and 1604, whichever dose is higher. At least 6 subjects should have already 
been treated and evaluated at that dose level prior to enrolling subjects in the Randomized Phase 
2 Dose Expansion.
Dose Limiting Toxicity (DLT) Definition
A DLT is a toxicity defined below and considered possibly related to GS-5829 if occurring during
the DLT assessment window (Day 1 through Day 28) in each 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 ≥ 4 thrombocytopenia (platelet count < 25,000/μL)

Grade ≥ 3 thrombocytopenia (platelet count <50,000/μL but >25,000/μL) lasting > 7 days 
despite GS-5829 drug interruption

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 the Gilead medical monitor may take place to determine 
if this 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.
Randomized Phase 2 Dose Expansion:
Approximately 120 female subjects who are post-menopausal with ER+/HER2- BrCa and who 
have had disease progression following anti-estrogen therapy will be enrolled.  

Approximately 60 subjects who have not previously received exemestane will be randomized 
in a 2:1 ratio to receive exemestane + GS-5829 or exemestane alone in Group 1.  

Approximately 60 subjects who have not previously received fulvestrant will be randomized
in a 2:1 ratio to receive fulvestrant + GS-5829 or fulvestrant alone in Group 2.
GS-5829 and the anti-estrogen therapy (exemestane for Group 1 or fulvestrant for Group 2) will 
be initiated on C1D1.

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Figure 3-1.
Randomized Phase 2 Dose Expansion
3.3.
Study Treatments
Subjects who meet eligibility criteria will receive GS-5829 orally once daily combined with either 
25 mg of exemestane orally once daily or fulvestrant intramuscularly on Day 1, 15 (for whom 
C1D1 is the subject’s first dose of fulvestrant), 29 and then every 28 days (± 3 days). Subjects in 
the Phase 1b Dose Escalation portion may initiate exemestane (Group A) or fulvestrant 
(Group B) any time prior to, or on, C1D1. 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 CT scan (or MRI) scan every 8 weeks for the first year, then every 12 weeks. 
Subjects who do not show evidence of disease progression may continue receiving GS-5829 
combined with either exemestane (Group A or Group 1) or fulvestrant (Group B or Group 2)
until disease progression (clinical or radiographic), unacceptable toxicity, withdrawal of consent, 
or death, whichever comes first.  
Following treatment discontinuation, subjects will be followed for safety for 30 days from last 
dose of study drug. Subjects in the Randomized Phase 2 Dose Expansion portion of the study 
will also be followed for up to two years for OS.
3.4.
Duration of Treatment
Subjects may continue receiving GS-5829 once daily until disease progression (clinical or 
radiographic), unacceptable toxicity, withdrawal of consent or death, whichever comes first. See 
Section 3.5 for criteria for study drug discontinuation.  

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3.5.
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 

Pregnancy

Subject decision

Lost to follow-up

Study termination by the sponsor

Adverse Event
3.6.
Criteria for Removal from Study
Subjects may be removed from the study for the following reasons:

Documented progression of malignant disease

Death

Investigator discretion 

Withdrawal of consent 

Lost to follow-up

Important protocol deviation

Pregnancy

Study termination by the sponsor

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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Up to 60 subjects who meet the eligibility criteria will be enrolled in the Phase 1b Dose 
Escalation portion of the study. 
Up to 120 subjects who meet the eligibility criteria will be enrolled in the Randomized 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) 18 years of age, female
2) Histologically or cytologically confirmed breast cancer with evidence of metastatic or locally 
advanced disease not amenable to resection or radiation therapy with curative intent and who 
have progressed during treatment with at least one prior hormonal therapy. Note: In referring 
to prior hormonal therapy; targeted therapies, such as palbociclib and/or everolimus or 
investigative targeted therapies which were administered as part of a prior hormonal therapy 
regimen are allowed after the washout period has been reached
a.
Phase 1b Dose Escalation - Subjects may have had unlimited prior hormonal therapy and 
a total of 2 prior chemotherapy regimens (adjuvant chemotherapy is considered 1 
regimen). Subjects may have progressed on fulvestrant or exemestane as a single agent
b. Randomized Phase 2 Dose Expansion - Subjects may have had unlimited prior hormonal 
therapy, only one adjuvant chemotherapy is permitted (no prior chemotherapy for 
metastatic disease is allowed). Subject enrolling in Group 1 must be exemestane naïve 
and subjects enrolling in Group 2 must be fulvestrant naïve. If a subject is naïve to both 
exemestane and fulvestrant, it is the investigator’s decision for which Group to enroll
3) Documentation of ER positive (≥ 1% positive stained cells by local standards) based on the 
most recent tumor biopsy, unless bone-only disease
4) Documented HER2-negative tumor based on local testing on most recent tumor biopsy 
(immunohistochemistry score 0/1+ or negative by in situ hybridization HER2/CP17 ratio < 2 
or for single probe assessment HER2 copy number < 4)

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5) Post -menopausal subjects considered to be in the post-menopausal state as defined by one of 
the following:
a.
Age ≥60 years
b. Age < 60 years and cessation of regular menses for at least 12 consecutive months in the 
absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and serum
estradiol and Follicle-stimulating hormone (FSH) level within the post-menopausal range
c.
Prior bilateral oophorectomy
d. Pre-/peri-menopausal women can be enrolled if amenable to be treated with the
luteinizing-hormone releasing hormone (LHRH) agonist goserelin. Subjects must have 
commenced treatment with goserelin or an alternative LHRH agonist at least 4 weeks 
prior to first dose of study drug. If subjects have received an alternative LHRH agonist 
prior to study entry, they must switch to goserelin on or before C1D1 for the duration of 
the study
6) Measurable disease defined per RECIST v. 1.1 or bone-only disease must have a lytic or 
mixed lytic blastic lesion that can be accurately assessed by CT or MRI. Subjects with 
bone-only disease and blastic-only metastases are not eligible
7) 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])
8) Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1
9) Life expectancy of ≥3 months, in the opinion of the investigator
10) 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
11) Coagulation: International Normalized Ratio (INR) ≤1.2 
12) Negative serum pregnancy test (Appendix 5)

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13) Female subjects of childbearing potential who engage in heterosexual intercourse must agree 
to use protocol specified method(s) of contraception as described in Appendix 5
14) Females who are nursing must agree to discontinue nursing before the first dose of GS-5829
15) 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 the Gilead 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) 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 C1D1
5) Major surgery, defined as any surgical procedure that involves general anesthesia and a 
significant incision (i.e., larger than what is required for placement of central venous access, 
percutaneous feeding tube) within 28 days of the first dose of study drug
6) 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 
CTCAE Grade > 1
7) 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)
8) 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; adequately treated Stage 1 or 2 cancer currently in complete remission; any other 
cancer that has been in complete remission for ≥ 5 years
9) Anti-tumor therapy (chemotherapy, chemoradiation, radiation, antibody therapy, molecular 
targeted therapy) within 21 days of study drug dosing (6 weeks for nitrosoureas, mitomycin 
C, or molecular agents with t1/2 > 10 days); 5 half-lives of any investigational drug; 

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concurrent use of goserelin for pre-/peri-menopausal breast cancer and exemestane or 
fulvestrant per the protocol are permitted
10) History of long QT syndrome or whose corrected QT interval (QTc) measured (Fridericia 
method) at screening is prolonged (> 470 ms). Subjects who screen fail due to this criterion 
are not eligible to be re-screened
11) Prior exposure to any bromodomain (BET) inhibitors
12) Immunotherapy within 6 months of C1D1
13) Evidence of bleeding diathesis or clinically significant bleeding, within 28 days of C1D1 or 
history of hemoptysis of > 2.5mL/1 teaspoon within 6 months of C1D1
14) Anticoagulation therapy within 7 days of C1D1, including acetylsalicylic acid, low 
molecular weight heparin, or warfarin
15) Known human immunodeficiency virus (HIV) infection
16) Hepatitis B surface Antigen (HBsAg) positive
17) Hepatitis C virus (HCV) antibody positive with HCV RNA positive
18) 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 
19) History of high grade esophageal or gastric varices

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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. 
Up to 60 subjects will be enrolled in the Phase 1b Dose Escalation portion of the study, each 
subject will be assigned to either Group A (exemestane+GS5829) or B (fulvestrant+GS5829) 
based on prior treatment and the investigators’ decision. 
Approximately 120 eligible subjects will be enrolled in the Phase 2 portion of the study based on 
prior treatment:

Approximately 60 subjects who have not previously received exemestane will be randomized 
in a 2:1 ratio to receive exemestane + GS-5829 or exemestane alone in Group 1.  

Approximately 60 subjects who have not previously received fulvestrant will be randomized 
in a 2:1 ratio to receive fulvestrant + GS-5829 or fulvestrant alone in Group 2.  
A subject will be considered enrolled once they have been registered in the Interactive Web 
Response System (IxRS).
5.2.
Description and Handling of GS-5829
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 mg or 5 mg. The 1 mg tablet is film-coated gray and the 5 
mg tablet is film-coated orange.
In addition to the active ingredient, 1 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.
5.2.2.
Packaging and Labeling
GS-5829 tablets are provided 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.

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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.
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. 
Until dispensed to the subjects, all bottles of study drug should be stored in a securely locked 
area, accessible only to authorized site personnel. 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 when handling GS-5829 tablets.
Commercially available product of exemestane and fulvestrant will be used for the study.  
Further information regarding formulation is available in the Prescribing Information for 
commercial products.
5.3.
Dosage and Administration of GS-5829, Exemestane and Fulvestrant
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. Grapefruit juice is prohibited while on study drug.
GS-5829 tablets will be self-administered orally once daily, beginning on C1D1 of the study and 
thereafter at approximately the same time each day until EOT.
For subjects in Group A (Phase 1b) and Group 1 (Phase 2), exemestane 25 mg tablets will be 
self-administered orally once daily (or in accordance with locally approved labeling), beginning 
on C1D1 of the study and thereafter at approximately the same time each day until the EOT.
Exemestane will be dispensed to subjects at visits on the first day of each cycle.
For subjects in Group B (Phase 1b) and Group 2 (Phase 2), fulvestrant will be administered 
intramuscularly (in accordance with locally approved labeling) by the clinic staff approximately 
every 28 days (± 3 days) until the EOT. 
For all subjects in the Randomized Phase 2 Dose Expansion phase and for subjects in the
Phase 1b Dose Escalation for whom C1D1 is the subject’s first dose of fulvestrant, a one-time 
additional dose of fulvestrant will be administered on C1D15 (± 3 days).

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5.3.1.
Dose Adjustment of GS-5829
If at any time in the study, a subject experiences a toxicity consistent with a Grade 4 AE that is 
deemed to be related to GS-5829, GS-5829 treatment will be discontinued permanently, with the 
exception of Grade 4 neutropenia, thrombocytopenia, or alopecia. If a subject experiences
non-hematologic Grade 3 toxicity consistent with a DLT (See Section 3.2), dosing with GS-5829 
will be postponed until the toxicity is resolved to Grade 0 or 1 (as defined by the CTCAE, 
version 4.03) or returns to the subject’s baseline value. If the toxicity resolves to Grade 0 or 1 or 
returns to the subject’s baseline value within 28 days from the start of the event, the subject may 
resume dosing of GS-5829 at a dose that is at least one dose level lower after discussion with the 
Gilead medical monitor (See Table 5-1).
If the subject experiences a recurrence of the toxicity after restarting study drug at a lower dose 
or if the toxicity does not resolve within 28 days, treatment with GS-5829 will be permanently 
discontinued.
If a subject has Grade 4 neutropenia, Grade 3 neutropenia with fever, or Grade 3 
thrombocytopenia, GS-5829 should be interrupted for up to 28 days and/or until the toxicity 
resolves to < Grade 1. If the Grade 4 neutropenia or Grade 3 fever and neutropenia resolves 
within 4 days (7 days for Grade 3 thrombocytopenia), then the subject may resume dosing at the 
same dose. If the Grade 4 neutropenia or Grade 3 fever and neutropenia takes > 4 days (> 7 days 
for Grade 3 thrombocytopenia), but within 28 days to recover, then the dose of GS-5829 must be 
resumed at a lower dose. If the Grade 4 neutropenia, Grade 3 fever and neutropenia or Grade 3 or 
higher thromboctyopenia takes longer than 28 days to recover then GS-5829 must be 
permanently discontinued. Grade 4 thrombocytopenia observed at any time must be followed by 
a dose reduction.
If the recurrent toxicity is hematologic a second dose decrease is allowed (lowest dose allowed 
1 mg) in either total daily dose or by a change in schedule such that the total amount of GS-5829 
administered over a 28 day period is decreased by at least 25%.
Table 5-1.
Dose Reduction of GS-5829
HEMATOLOGICAL ADVERSE EVENTS
Neutropenia
Grade ≤ 3 Neutropenia
Maintain current dose level and schedule.
Grade 4 neutropenia (or occurrence of 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) or infection
Hold dosing with GS-5829 until the toxicity is resolved to ≤ Grade 
1. If the toxicity resolves to ≤Grade 1 within 4 days, the subject 
may resume dosing of GS-5829 at the same dose. If recovery to 
Grade ≤1 takes > 4 days, but within 28 days, then the subject may 
resume dosing of GS-5829 at a dose that is at least one dose level 
lower after discussion with the Gilead medical monitor.  
Granulocyte colony-stimulating factor (GCSF) is allowed (but not 
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HEMATOLOGICAL ADVERSE EVENTS
Thrombocytopenia
Grade ≤ 2 Thrombocytopenia
Maintain current dose level and schedule.
Grade 3 Thrombocytopenia 
Hold dosing with GS-5829 until the toxicity is resolved to 
≤Grade 1. If the toxicity resolves within 7 days, the subject may 
either resume at the same dose or a dose with is one level lower or at 
an intermittent dosing schedule (at least 25% less GS-5829 in a 
28 day dosing period) after discussion with the Gilead medical 
monitor. If the thrombocytopenia takes 7-28 days to recover then the 
subject must resume at a dose one level lower or at an intermittent 
dosing schedule after discussion with the Gilead medical monitor.
Grade 4 Thrombocytopenia
Hold dosing with GS-5829 until the toxicity is resolved to 
≤Grade 1. If the toxicity resolves within 28 days, the subject may 
either resume at a dose with is at least one level lower, or at 
intermittent dosing schedule (at least 25% less GS-5829 in a 28 day 
dosing period) after discussion with the Gilead medical monitor.
NON-HEMATOLOGICAL ADVERSE EVENTS
Hepatic Adverse Events (elevations in ALT or AST and/or bilirubin)
Grade 1
(ALT/AST ≤ 3 x ULN)
(Bilirubin ≤ 1.5 x ULN)
Maintain current dose level and schedule.
Grade 2
(ALT/AST > 3-5 x ULN)
(Bilirubin>1.5 -≤ 3 x ULN)
Maintain current dose level and schedule. Monitor ALT, AST, ALP, 
and bilirubin at least once a week.
Grade 3 
Hold dosing until ≤ Grade 2. 
Permanently discontinue if any Grade 3 or Grade 4 elevation in AST 
or ALT associated with a Grade 2 elevation in bilirubin
Grade 4
Permanently discontinue GS-5829
Non-Hepatic, Non-Hematologic Adverse Events
Grade ≤ 2
No change in dosing required. Dosing may be interrupted until 
Grade ≤ 1 or baseline
Grade 3
Hold dosing until ≤ Grade 1 and decrease dose by at least one dose 
level lower or at intermittent dosing schedule (at least 25% less 
GS-5829 in a 28 day dosing period) after discussion with the Gilead 
medical monitor.
Grade 4
Permanently discontinue GS-5829
If the toxicity does not resolve or return to baseline, study drug(s) GS-5829 and exemestane or 
GS-5829 and fulvestrant will be permanently discontinued and the subject will return for an EOT
and a 30-day Safety Follow-Up visit.  

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If the subject was not receiving GS-5829 at the time disease progression was documented 
(e.g., due to reversible toxicity), after discussion with the Gilead medical monitor, GS-5829 may 
be re-started if the criteria for resuming treatment are met and the investigator feels it is in the 
subject’s best interest to do so.
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 Phase 1b Dose Escalation and at any time in the Randomized 
Phase 2 Dose Expansion, 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 3-1.
Subjects whose dose of either exemestane or fulvestrant is interrupted for a non-drug related 
toxicity for up to 15 or 28 days respectively, 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 15 or 28 days (exemestane or fulvestrant respectively), or longer 
than 28 days for GS-5829 in subjects who do not have disease progression may be considered for 
resumption of study drugs after discussion with the Gilead medical monitor.
No dose reduction of GS-5829 below 2 mg is allowed.  
Table 5-2.
Dose Reduction of GS-5829
Dose at time of toxicity (mg)
Restarting dose level (mg)
9
6
6
4
4
3
3*
2**
*
Dose level 1
**    Dose level -1
5.3.2.
Dose Adjustment of Fulvestrant
Since there is no anticipated drug-drug interaction between GS-5829 and fulvestrant, the dose, 
route and schedule for administration of fulvestrant in Group A is provided in package insert 
included in Appendix 9. Dose adjustment for GS-5829 is provided in Section 5.3.1.

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5.3.3.
Dose Adjustment of Exemestane 
Since there is no anticipated drug-drug interaction between GS-5829 and exemestane, the dose, 
route and schedule for administration of exemestane in Group B is provided in package insert 
included in Appendix 8. Dose adjustment for GS-5829 is provided in Section 5.3.1.
5.4.
Prior and Concomitant Medications
Pre-/peri-menopausal subjects must have commenced treatment with goserelin or an alternative 
LHRH agonist at least 4 weeks prior to first dose of study drug. If subjects have received an 
alternative LHRH agonist prior to study entry, they must switch to goserelin for the duration of 
the study on or before C1D1.
Subjects enrolling in the Phase 1b Dose Escalation portion of the study may have progressed on 
fulvestrant or exemestane as a single agent.
Subjects enrolling in the Randomized Phase 2 Dose Expansion portion of the study may not have 
received prior exemestane (Group 1) or fulvestrant (Group 2).
In vitro data indicates 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 within 2 weeks prior to study drug. 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
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 
(e.g., 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 Gilead medical monitor to determine if study treatment should be 
discontinued.

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5.5.
Accountability for GS-5829, Exemestane and Fulvestrant
The investigator is responsible for ensuring adequate accountability of all used and unused 
investigational medicinal products (IMP). This includes acknowledgement of receipt of each 
shipment of IMP (quantity and condition). All used and unused IMP dispensed to subjects must 
be returned to the site.
Study drug (GS-5829, exemestane and fulvestrant) 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, Exemestane and Fulvestrant Investigational Medicinal Product
Return or Disposal
Study drugs 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. Whenever possible, study drug returned by the subject should be retained 
for review by the study site monitor prior to destruction.
For additional information about study drug accountability, return and disposal, refer to 
Section 9.1.7.

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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 described in the text that follows. Additional information is 
provided in the study procedures 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 and/or designee 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 Procedures Descriptions
6.2.1.
Informed Consent
All subjects must sign and date the most recent Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) approved informed consent form before any study procedures are 
performed.
 
PPD

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Subjects who screen fail must re-sign the informed consent, in the event any screening 
procedures will be performed outside of the 28-day screening window from the time of the first 
informed consent.
6.2.2.
Medical History
A complete medical history will be obtained by the investigator or qualified designee at 
screening and recorded on the eCRF. Medical history will include information on the subject’s 
significant past medical events (e.g., prior hospitalizations or surgeries), a review of the disease 
under study, prior anti-cancer therapies, and any concurrent illnesses. 
6.2.3.
Prior and Concomitant Medications
All medications taken up to 30 days prior to the screening visit will be recorded on the eCRF. In 
addition, supportive 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 perform a complete physical examination at 
designated time points during the study (Refer to Appendix 2). Pre-dose abnormal findings will 
be reported on the medical history 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. Screening and End of Treatment (EOT) physical examinations will be 
complete physical examinations. Beginning at C1D1, a modified physical examination will be 
performed to monitor for any changes, and will also include weight and assessment of disease-
related clinical signs and symptoms.
Weight (without shoes) should be measured with each physical examination.
Height (without shoes) should be measured at Screening only.
6.2.5.
Vital Signs
Vital signs will include blood pressure, respiratory rate, pulse, 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.

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C1D1 vital signs will be taken within 15 min pre-GS-5829 dose and 2 and 4 hours post dose 
(+/- 15 min). At all subsequent visits, vital signs will be taken pre-GS-5829 dose only.
6.2.6.
Electrocardiogram 
12-lead electrocardiograms (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. 
Triplicate ECGs will be collected at any time during the Screening window, C1D1, Day 1 of 
Cycles 2-6 (at pre-dose), and at EOT. In the Phase 1b Dose Escalation phase of the study, 
triplicate ECGs will be collected on C1D1 at pre-dose and 1-4 hrs post-dose and on C1D15 at 
pre-dose, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, and 8 hours post dose (+/- 20 min). In the 
Randomized Phase 2 Dose Expansion phase of the study, triplicate ECGs will be collected on 
C1D1 at pre-dose and 1-4 hrs post-dose and on C1D15 at pre-dose, 1 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 point. Subjects should be resting quietly and free of 
distraction (e.g., television, 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.
Echocardiogram
Echocardiograms will be performed at the time points listed in the Study Procedures Table 
(Appendix 2). Multigated acquisition (MUGA) scans are also acceptable. However, the same 
modality must be used throughout study participation.
Abnormal echocardiogram findings that are considered clinically significant by the investigator 
should be reported as AEs and recorded in the AE eCRF if the finding meets the definition of an 
AE. 
6.2.8.
ECOG Performance Status
ECOG Performance Status is an investigator assessment of the impact of the disease on the 
subject’s activities of daily living. ECOG assessments will be performed at the time points listed 
in the Study Procedures Table (Appendix 2). ECOG will be scored using the scale index in
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6.2.9.
Adverse Events
Subjects will be assessed for AEs per guidelines in the National Cancer Institute (NCI) CTCAE 
(version 4.03) at the time points outlined in Appendix 4. 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 4 CTCAE grading criteria.  
Please refer to Section 7 for additional information on AE reporting.
6.2.10.
Disease Assessments
6.2.10.1.
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 RECIST 1.1 (refer to Appendix 7). The same assessment methods should 
be used for the subject throughout all treatment cycles. CT, or MRI scans will be obtained at the 
applicable study visits per the Study Procedures Table (Appendix 2) and transferred to a central 
vendor for storage.
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 28 days before C1D1 if the scan was performed as 
part of standard medical practice) and every 8 weeks for the first year and then 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 RECIST v. 1.1 (refer to Appendix 7). The same radiographic 
procedure and specification (e.g., the same contrast agent, slice thickness, etc.) used to define 
measurable lesions at baseline must be used throughout the study for each subject. 
Subjects who discontinue study treatment for reasons other than disease progression will
continue to have tumor assessments performed during the follow up visits every 8 weeks for the 
first year and then every 12 weeks until disease progression, initiation of new anti-cancer 
therapy, or discontinuation from the overall study participation (death, subject’s request, lost to 
follow-up) whichever happens first. Every effort should be made to perform a last tumor 
assessment before starting a new anti-cancer therapy. Additional unscheduled tumor assessments 
may be performed as clinically indicated at any time.
6.2.10.2.
Bone Scans
All subjects will undergo radionuclide bone scan at Screening (within 12 weeks prior to 
randomization). Bone scans performed before the signing of informed consent as routine 
procedures (but within 12 weeks before randomization) do not need to be repeated and may be 

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used as baseline assessments as long as (1) tests were performed using the method requirements 
outlined in RECIST v.1.1 (2) appropriately documentation indicating that these radiographic 
tumor assessments were performed as standard of care is available in the patient’s source notes. 
Any suspicious abnormalities (i.e., hotspots) identified on the bone scans at baseline and on 
subsequent bone scans MUST be confirmed by X-ray, CT scan with bone windows or MRI. The 
same modality must be used throughout the trial for confirmation for a given lesion/patient. Bone 
lesions identified at baseline will be followed up according to the same assessment schedule and 
every 8 weeks (±7 days) for the first year and then every 12 weeks (±7 days) from the date of 
randomization during the treatment period. Scans at the EOT visit are not necessary if the prior 
scan was performed within 4 weeks prior to the EOT visit date. Bone scans will be obtained at 
the applicable study visits per the Study Procedures Table (Appendix 2) and transferred to a 
central vendor for storage.
Bone lesions imaging:

If bone lesions were identified at baseline as the only sites of a subject’s disease the
following assessment must be performed:
○
CT scan/MRI every 8 weeks (±7 days) for the first year and then every 12 weeks (±7 
days) from the date of randomization and to confirm CR using the same modality used to 
confirm the bone lesions at baseline. Areas that have received palliative radiotherapy on 
study cannot be used to assess response to study treatment.

If no bone lesions were identified at baseline, or if bone is not the only site of a subject’s 
disease, bone scans will only be repeated as clinically indicated (i.e., subject describes new or
worsening bone pain, or has increasing alkaline phosphatase level, or other signs and 
symptoms of new/progressing bone metastases) but are required to confirm CR. 
Abnormalities found on subsequent bone scans shall also be confirmed by X-ray, CT or MRI.
6.2.11.
Laboratory Assessments
Screening laboratory samples should be obtained within 28 days prior to C1D1 dose (GS-5829). 
Local laboratory complete blood count (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, and coagulation 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 Study Procedures Table 
(Appendix 2) 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 
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The date and time of previous GS-5829 dose will be recorded in the subject’s source 
documentation on days where PK is collected. 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 C1D1.
C1D1 pre-dose samples may be drawn up to 2 days prior to the visit.
The analytes listed in Table 6-1 will be tested.
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
CRP
White Blood Cell (WBC) Count
Hemoglobin
Hematocrit
Platelet Count
Neutrophils (ANC)
Lymphocytes
Monocytes
Basophils
Eosinophils
Serum -hCG for pregnancy test
GS-5829 concentration
Concentrations of GS-5829 
metabolite(s), fulvestrant, exemestane, 
and/or metabolites, as applicable, may 
be determined
 
Hepatitis B surface antigend
Hepatitis C antibody
FSH
Serum Estradiol
Hepatitis C RNA Reflex
26- hydroxyvitamin D
HIV
Urine pregnancy test
Coagulation
PT/INRc
aPTTc
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
Collected at Screening and pre-dose of C1D1, C1D15, C2D1
d
HCV RNA Reflex is required
6.2.12.
Pregnancy Test for Females of Childbearing Potential
All female subjects of childbearing potential (as defined in Appendix 5) will have serum 
pregnancy, estradiol and FSH testing throughout the study (refer to Appendix 2). The results 
must be confirmed as negative for pregnancy prior to continued administration of study drug.
Female subjects of childbearing potential must have commenced treatment with goserelin or an 
alternative LHRH agonist at least 4 weeks prior to first dose of study drug. Additionally, subjects 
on goserelin or an alternative LHRH agonist will have serum pregnancy, serum estradiol, and 
FSH checked on the first day of Cycle 1 to Cycle 3, urine pregnancy test will be performed
monthly thereafter.
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6.2.13.
Vitamin D Assessment 
Routine assessment of 25-hydroxy vitamin D levels prior to the start of exemestane and 
fulvestrant treatment should be performed, due to the high prevalence of vitamin D deficiency in 
women with breast cancer. Women with vitamin D deficiency should receive supplementation 
with vitamin D.
6.2.14.
Pharmacokinetic & Pharmacodynamic Samples
PK samples will be collected at the time points listed below for each Phase. GS-5829 plasma 
concentrations will be determined using a validated assay. Plasma concentrations of GS-5829 
metabolites and/or exemestane and/or fulvestrant metabolites may be determined. Plasma protein 
binding of analytes may be evaluated. PD samples may be modified based on the emerging data.
The date and clock time of GS-5829 and exemestane dosing, as applicable, will be collected 
prior to and on the day of PK sampling. The date and clock time of each fulvestrant dose will be 
recorded on eCRF, as applicable.
Phase 1b Dose Escalation 
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. Refer to 
Appendix 3.
Randomized Phase 2 Dose Expansion
Sparse PK and PD samples will be collected at pre-dose and anytime between 1 to 4 hours 
post-dose on Day 1 and Day 15 of Cycle 1 and at pre-dose on Day 1 of Cycles 3 and 6. Refer to 
Appendix 3. Note: PK samples will only be collected for subjects who are randomized to a 
GS-5829 combination arm.
6.3.
Biomarker Testing
6.3.1.
Biomarker Samples to Address the Study Objectives:
 
 
 
 
 
 
 
 
 
 
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6.3.2.
Biomarker Samples for Optional Future Research
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.3.3.
Biomarker Samples for Optional Genomic Research
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.
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. Subjects who do not meet QTc 
criteria are not allowed to re-screen (see Section 4.3). Gilead is to be informed prior to a subject 
re-screening.
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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.
Subjects who meet eligibility criteria will receive GS-5829 orally once daily combined with daily 
orally dosing of either exemestane or injection of fulvestrant intramuscularly on Day 1, Day 28
and then every 28 days (± 3 days). Subjects initiating fulvestrant on C1D1 should receive a 
single additional dose at C1D15. Subjects in the Phase 1b Dose Escalation phase of the study
may initiate exemestane (Group A) or fulvestrant (Group B) any time prior to, or on, C1D1. 
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 CT scan (or MRI) scan every 8 weeks 
for the first year and then every 12 weeks. Bone scans may be repeated as clinically indicated or 
to confirm a CR.  
A subject who does not show evidence of disease progression may continue receiving GS-5829 
once daily and exemestane (Group A or Group 1) or fulvestrant (Group B or Group 2) until
disease progression (clinical or radiographic), unacceptable toxicity, withdrawal of consent, or 
other reasons specified in Section 3.5.
6.6.
Post-treatment Assessments
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. Randomized Phase 2 Dose 
Expansion subjects will complete the 30-Day Safety Follow-Up Visit and proceed to Long Term 
Survival Follow-Up (See Section 6.7).
Subjects who discontinue study treatment for reasons other than disease progression will
continue to have tumor assessments performed during the follow up visits every 12 weeks until
disease progression, initiation of new anti-cancer therapy, or discontinuation from the overall 
study participation (death, subject’s request, lost to follow-up) whichever happens first. Every 
effort should be made to perform a last tumor assessment before starting a new anticancer 
therapy. Additional unscheduled tumor assessments may be performed as clinically indicated at 
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6.7.
Long-Term Survival Follow-Up
Randomized 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.
6.8.
Unscheduled Visits
Unscheduled procedures may occur at any time during the study. Vital Signs, ECOG, ECHO, 
12-lead ECG, bone scan and CT or MRI, may be conducted at these visits and recorded on the 
applicable eCRFs.
6.9.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related 
follow-up and procedures (see Section 6.10, Criteria for Discontinuation of Study Treatment). If 
this is not possible or acceptable to the subject or investigator, the subject may be withdrawn 
from the study.
6.10.
Criteria for Discontinuation of Study Treatment
See Section 3.5 for discontinuation criteria.  
6.11.
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 AEs.
Every attempt should be made to keep the subject in the study and continue collecting CT or 
MRI scans for tumor assessment at every 8 weeks for the first year and then every 12 weeks 
from the date of randomization 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 

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the post-treatment follow-up assessment visit above when discontinuing from the study 
treatment. Randomized 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.
6.12.
Replacement of Subjects
If a subject in the Phase 1b portion of the study 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.
6.13.
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.
6.14.
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. Randomized 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.

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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 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 

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 SAE 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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
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 a 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
7.1.2.1.
Protocol-Specific Serious Adverse Event Instructions
To maintain the integrity of the study, disease progression and death from disease progression 
should be reported as SAEs by the investigator only if it is assessed that the study drugs caused 
or contributed to the disease progression (i.e., by a means other than lack of effect). Unrelated 
disease progression should be captured on the eCRF.
In addition, events that are indicative of the following disease-related SAEs that are assessed as 
unrelated to study drugs will not be reported as expedited reports by Gilead during the study:

Progression of disease

Death related to disease progression
These events will be exempt from global expedited reporting requirements for the duration of the 
study as they are the primary endpoints of this study. They will be reported as appropriate in the 
final clinical study report as well as any relevant aggregate safety report.
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 (e.g., clinical chemistry, hematology) that require medical or 
surgical intervention or lead to IMP interruption, modification, or discontinuation must be 
recorded as an AE, as well as an SAE, if applicable. In addition, laboratory or other abnormal 
assessments (e.g., electrocardiogram, x-rays, vital signs) that are associated with signs and/or 
symptoms must be recorded as an AE or SAE if they meet the definition of an AE or SAE as 
described in Sections 7.1.1 and 7.1.2. If the laboratory abnormality is part of a syndrome, record 
the syndrome or diagnosis (e.g., anemia), not the laboratory result (i.e., decreased hemoglobin).

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For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 5.3.1.
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified sub-investigator 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 sub-investigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the AE has an etiology other than the IMP. For SAEs, an alternative 
causality must be provided (e.g., pre-existing condition, underlying disease, intercurrent 
illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the IMP.
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 (e.g., 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, (e.g., venipuncture).
7.2.2.
Assessment of Severity
The severity of AEs will be graded using the CTCAE, Version 4.03 (Appendix 4).
For each episode, the highest severity grade attained should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or 
Grade 5 (fatal) to describe the maximum intensity of the AE. For purposes of consistency with 
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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 
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 case report form (CRF/eCRF): all SAEs and AEs related to 
protocol-mandated procedures.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30-days after last administration of study IMP 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
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (i.e., signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead DSPH as instructed. This also includes any SAEs resulting from 
protocol-associated procedures performed after informed consent is signed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported.
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period, 
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of IMP, he/she should promptly document and report 
the event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the
eCRF completion guideline. 
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, i.e., the 
eCRF database is not functioning, record the SAE on the paper SAE reporting form and 
submit within 24 hours to:
Gilead DSPH:
Fax: 
Email: 

As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are 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 traceability 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 CRF/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, serious adverse drug reactions (SADRs), or 
suspected unexpected serious adverse reactions (SUSARs). In accordance with the EU Clinical 
Trials Directive (2001/20/EC), Gilead or a specified designee will notify worldwide regulatory 
agencies and the relevant IEC in concerned Member States of applicable SUSARs as outlined in 
current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or the relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study IMP. 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. 
7.5.
Toxicity Management 
Treatment-emergent toxicities will be noted by the investigator and brought to the attention of 
the Gilead medical monitor or designee. Whether or not considered treatment-related, all subjects 
experiencing AEs must be monitored periodically until symptoms subside, any abnormal 
laboratory values have resolved or returned to baseline levels or they are considered irreversible, 
or until there is a satisfactory explanation for the changes observed.
Grade 3 or 4 clinically significant laboratory abnormalities should be confirmed by repeat testing 
as soon as practical to do so, and preferably within 3 calendar days after receipt of the original 
test results. Any questions regarding toxicity management should be directed to the Gilead 
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.  

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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 and 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.  
7.6.2.
Instructions for Reporting Special Situations
7.6.2.1.
Instructions for Reporting Pregnancies
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period, to Gilead DSPH using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.
Refer to eCRF completion guidelines for full instructions on the mechanism of pregnancy 
reporting.
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (e.g., a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Section 7.1.2 Furthermore, any SAE occurring as an adverse pregnancy outcome post study must 
be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 

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be reported directly to Gilead DSPH. Gilead DSPH contact information is as follows: Email: 
 and Fax: 
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
7.6.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to eCRF completion guidelines for full instructions on the mechanism of special situations 
reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.
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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective:
Phase 1b Dose Escalation

To characterize the safety and tolerability of GS-5829 in combination with exemestane or 
fulvestrant in subjects with advanced ER+/HER2- BrCa

To determine the MTD or RP2D of GS-5829 in combination with exemestane or fulvestrant
in subjects with advanced ER+/HER2- BrCa
Randomized Phase 2 Dose Expansion

To evaluate the efficacy of GS-5829 in combination with exemestane compared to 
exemestane alone in subjects with advanced ER+/HER2- BrCa, as measured by PFS

To evaluate the efficacy of GS-5829 in combination with fulvestrant compared to fulvestrant
alone in subjects with advanced ER+/HER2- BrCa, as measured by PFS
Secondary objectives: 
Phase 1b Dose Escalation

To evaluate the PK of GS-5829 in combination with exemestane or fulvestrant in subjects 
with advanced ER+/HER2- BrCa
Randomized Phase 2 Dose Expansion  

To evaluate the efficacy of GS-5829 in combination with exemestane compared to 
exemestane alone in subjects with advanced ER+/HER2- BrCa, as measured by ORR and 
CBR evaluated according to RECIST v. 1.1. ORR is defined as the proportion of subjects 
with response (CR or PR). CBR is defined as proportion of subjects with CR, PR, or SD that 
lasts for ≥ 24 weeks

To evaluate the efficacy of GS-5829 in combination with fulvestrant compared to fulvestrant
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
To evaluate the safety and tolerability of GS-5829 in combination with exemestane compared 
to exemestane alone in subjects with advanced ER+/HER2- BrCa

To evaluate the safety and tolerability of GS-5829 in combination with fulvestrant compared 
to fulvestrant alone in subjects with advanced ER+/HER2- BrCa

To evaluate the OS for subject with advanced ER+ BrCa with exemestane or fulvestrant ±
GS-5829
Exploratory objectives:
 
8.1.2.
Primary Endpoint
Phase 1b Dose Escalation: 

Safety profile and tolerability of the combination of GS-5829 and exemestane or fulvestrant
as assessed by the incidence of dose limiting toxicities (DLTs) through Day 28 at each dose 
level of GS-5829
Randomized Phase 2 Dose Expansion: 

PFS defined as the interval from date of randomization to the earlier of the first documented 
confirmed disease progression or death from any cause
8.1.3.
Secondary Endpoint
Phase 1b Dose Escalation: 

GS-5829 PK parameters (e.g., Cmax, AUCtau)
Randomized Phase 2 Dose Expansion: 

Overall safety profile will be characterized by the type, frequency, severity, timing of onset, 
duration, and relationship to study treatment of any AEs or abnormalities in laboratory tests 
or ECGs 

ORR, defined as the proportion of subjects who achieve CR, PR and SD, based on 
RECIST v. 1.1 study progression criteria
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
CBR, defined as the proportion of subjects who achieve CR, PR or SD that lasts for 
>24 weeks based on RECIST v. 1.1 study progression criteria

Overall survival, defined as interval from date of randomization to date of death from any 
cause
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Intent-to-Treat (ITT) Analysis Set
The ITT analysis set includes all subjects who are randomized in the Randomized Phase 2 Dose 
Expansion phase of the study regardless of whether subjects receive any study drug(s), or receive 
a different regimen from the regimen they were randomized to. Treatment assignment will be 
designated according to randomization.
This analysis set will be used in the analyses of PFS, ORR, and CBR. Subjects in the ITT 
analysis set who do not have sufficient baseline or on-study tumor status information to be 
adequately assessed for response status will be included in the denominators in the calculation of 
ORR and CBR.
8.2.1.2.
The Per-Protocol (PP) analysis set
The PP analysis set includes data from subjects in the ITT analysis set who meet the general 
criteria defining the target population for this study: those who are adherent to the protocol, are 
compliant with study drug treatment, and are evaluable for relevant efficacy endpoints. 
Treatment assignment will be designated according to the actual treatment received. The PP 
analysis set will be used in sensitivity analyses of efficacy endpoints.
8.2.1.3.
Safety Analysis Set
The Safety Analysis Set includes subjects who receive ≥ 1 dose of study drug. This analysis set 
will be used for the analyses of safety endpoints, study treatment administration and study drug 
compliance. 
8.2.1.4.
DLT-Evaluable Analysis Set
The DLT-Evaluable Analysis Set includes all Phase 1b Dose Escalation subjects in the Safety 
Analysis Set who complete all treatment and safety procedures through Day 28, or experienced a 
DLT prior to Day 28. Subjects who are not evaluable for DLT determination may be replaced.
8.2.1.5.
Pharmacokinetics and Pharmacodynamics Analysis Sets
The PK and PD Analysis Sets will consist of all subjects in the Safety Analysis Set who have the 
necessary baseline and on-study measurements to provide interpretable results for the specific 
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8.2.1.6.
Biomarker Analysis Set
The Biomarker Analysis Sets include data from subjects in the Safety analysis set who have the 
necessary baseline and on-study measurements to provide interpretable results for the specific 
parameters of interest.
8.3.
Data Handling Conventions
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, the first and third quartiles, 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 (Phase 1b Dose Escalation), time point and treatment group for the 
corresponding analysis sets. As appropriate, changes from baseline to each subsequent time point 
will be described and summarized by dose level and treatment group. Similarly, as appropriate, 
the best change from baseline during the study will also be described and summarized by dose 
level and treatment group. Graphical techniques (e.g., 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
(Phase 1b Dose Escalation) and by treatment group for the Safety Analysis Set.
8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The difference in PFS between the treatment arms will be assessed in the ITT analysis set using
Kaplan-Meier methods and the log-rank test. Kaplan-Meier estimates and plots, hazard ratios and 
corresponding 95% CIs will be presented. 
Subjects who withdraw from the study or are lost to follow-up without disease progression or 
death will be censored on the date of the last visit when lack of disease progression was 
documented. Subjects who have progression or die after ≥ 2 consecutive missing tumor 
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definitive progression was objectively documented. Subjects without any adequate post-baseline 
disease assessment will be censored on the date of first study dose.
In the sensitivity analysis, PFS will be compared between the treatment arms in the PP analysis 
set using Kaplan-Meier methods and the log-rank test.
8.5.2.
Secondary Analyses
The best overall response will be summarized by each response category as CR, PR, SD and PD 
by treatment arms. Fisher’s exact test will be used to compare ORR and CBR between treatment 
arms. The 2-sided 95% CIs for ORR and CBR will be calculated based on exact method. 
The difference in OS between the treatment arms will be assessed using the log-rank test.
Kaplan-Meier estimates and plots, hazard ratios and corresponding 95% CIs will be presented.
8.6.
Safety Analysis
Safety will be evaluated by assessment of clinical laboratory tests, physical examination, 12-lead 
ECG, vital signs measurements and documented AEs as described in the Study Procedures Table 
(Appendix 2). 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 (Phase 1b 
Dose Escalation) and visit where appropriate and by treatment group for subjects in the Safety 
Analysis Set. AEs occurred in pretreatment will be included in data listings.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to GS-5829, exemestane and fulvestrant will be reported. 
Exposure data and study drug compliance will be summarized by dose level and treatment group 
for subjects in the safety analysis set.
GS-5829 compliance will be described in terms of the amount actually taken based on returned 
pill count relative to the amount that was dispensed (taking into account physician-prescribed 
reductions and interruptions).
Exemestane and fulvestrant compliance will be described in terms of the number of doses 
actually administered relative to the expected number of doses planned.
8.6.2.
Adverse Events
The focus of AE summarization will be on treatment-emergent AEs. Treatment-emergent AEs 
(TEAEs) are events in a given study period that meet one of the following criteria:

Events with onset dates on or after the start of treatment and up to 30 days after the
permanent discontinuation of the study treatment.

AEs resulting in treatment discontinuation after the start of treatment.

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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 (Phase 1b Dose Escalation) and treatment group. Summary 
tables will be presented to show the number of subjects reporting treatment-emergent AEs by 
severity grade and corresponding percentages.
Following summaries (number and percentage of subjects) of TEAEs will be provided:
1. All AEs
2. AEs related to study drug
3. AEs that are Grade ≥ 3 in severity
4. AEs leading to study drug modification (interruption/reduction)
5. AEs leading to study drug discontinuation
6. AEs leading to death
7. SAEs
Summaries of TEAEs (by SOC and PT) will be provided by dose level (Phase 1b Dose 
Escalation) and treatment group. 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.
All AEs will be listed.
8.6.3.
Laboratory Evaluations
All central laboratory results will be listed. Selected laboratory data will be summarized using 
only observed data. Laboratory results and change from baseline at all scheduled time points will 
be summarized.
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, worsened by ≥ 1 grade in the period from the first dose of study treatment 
to 30 days after the last dose of study drug. If baseline measurement is missing, then any graded 
abnormality (i.e., an abnormality that is Grade ≥ 1 in severity) will be considered treatment 
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Hematology and serum biochemistry will be graded according to CTCAE 4.03 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 whether a laboratory value is below, within, or 
above the normal range for the subject’s age, sex, etc.
Hematology and serum biochemistry test results and their changes from baseline will be 
summarized by dose level Phase 1b Dose Escalation, visit and treatment group. Laboratory 
abnormalities will be summarized for each relevant assay to show the number of subjects by 
CTCAE severity grade with corresponding percentages. For parameters for which a CTCAE 
scale does not exist, the frequency of subjects with values below, within, and above the normal 
ranges will be summarized. Subjects will be characterized only once for a given assay, based on 
their worst severity grade observed during a period of interest (e.g., during the study or from 
baseline to a particular visit).
Shift tables for hematology and serum biochemistry will be presented by showing change in 
CTCAE severity grade from baseline to the worst grade post-baseline. Separate listings and 
summaries will be prepared for laboratory abnormalities that are Grade ≥ 3 in severity.
8.6.4.
Other Safety Evaluations
Dose limiting toxicities will be listed for all dose levels. 
8.7.
Pharmacokinetic Analysis
In the Phase 1b Dose Escalation portion of study, the plasma concentration of GS-5829 will be 
summarized by nominal sampling time using descriptive statistics by dose cohorts. 
Pharmacokinetic parameters will be determined using standard non-compartmental methods. PK 
parameters (Cmax and, AUCtau), will be listed and summarized using descriptive statistics (e.g., 
sample size, arithmetic mean, geometric mean, coefficient of variation (%) StD, median, 
minimum, and maximum) by dose cohorts. Plasma concentrations over time will be plotted in 
semi-logarithmic and linear formats as mean ± StD, and median (Q1, Q3) if applicable. In the 
Randomized Phase 2 Dose Expansion portion of study, plasma concentrations will be 
summarized by nominal sampling time using descriptive statistics by treatment arm.
8.8.
Biomarker Analysis
Descriptive statistics of baseline and change in biomarkers will be provided at each sampling 
time for all subjects, and by treatment arms.
 
 
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8.9.
Sample Size
The sample size of the Phase 1b Dose Escalation portion of the study will be determined based 
on the number of dose levels evaluated and the emerging drug-related toxicities, and may enroll 
up to approximately 60 subjects. 
Approximately 120 subjects will be enrolled in the Randomized Phase 2 Dose Expansion portion 
of this study. Approximately 60 subjects will be randomized in Group 1 to receive GS-5829 in 
combination with exemestane or exemestane alone in a 2:1 ratio. Similarly, in Group 2 of the
Randomized Phase 2 Dose Expansion portion of the study, approximately 60 subjects will be 
randomized to receive GS-5829 in combination with fulvestrant or fulvestrant alone in a 2:1 
ratio. The sample size of 60 subjects (40 in the combination arm and 20 in the exemestane alone 
or fulvestrant alone arm) will provide 37 events in total and greater than 80% power to detect the 
difference in PFS between GS-5829 in combination with exemestane and exemestane alone and 
between GS-5829 in combination with fulvestrant and fulvestrant alone with 0.1 two-sided 
significance level. , assuming a median PFS of 5 months for subjects who receive exemestane 
alone or fulvestrant alone, a median PFS of 12.5 months in subjects who receive GS-5829 in 
combination with exemestane or fulvestrant, accrual period of 6 months, total study duration of 
18 months and a drop-out rate of 10% by 12 months. 
An interim analysis may be performed separately when 22 events have been reached in each 
group of Phase 2 dose expansion portion. The purpose of this analysis is to have an early 
evaluation of the safety and efficacy of GS-5829 in combination with exemestane or fulvestrant.
The interim analysis will assess either an expansion or study stop on any one of the arms 
independent of one another. The trial will continue after the interim analysis.
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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 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 sub-investigators 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 sub-investigator’s) participation in the study. The investigator and 
sub-investigator 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/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC 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 any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IEC 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 or IEC 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 IEC, 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, eCRF, the IMP, 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, IRB 
or IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.

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The required source data 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, i.e., 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 IMP, 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 (i.e., United States, 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. eCRFs 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 (e.g. 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
Where possible, study drug(s) should be destroyed at the site. At the start of the study, the study 
monitor will evaluate each study center’s study drug disposal procedures and provide appropriate 
instruction for disposal or return of unused study drug supplies. If the site has an appropriate 
standard operating procedure (SOP) for drug destruction as determined by Gilead Sciences, the 
site may destroy used (empty or partially empty) and unused study drug supplies as long as 
performed in accordance with the site’s SOP. This can occur only after the study monitor has 
performed drug accountability during an on-site monitoring visit. 
A copy of the site’s study drug disposal SOP or written procedure (signed and dated by the PI 
or designee) will be obtained for Gilead site files. If the site does not have acceptable 
procedures in place, arrangements will be made between the site and Gilead Sciences 
(or Gilead Sciences’ representative) for return of unused study drug supplies. 
If study drug is destroyed on site, the investigator must maintain accurate records for all study 
drugs destroyed. Upon study completion, copies of the study drug accountability records must be 
filed at the site. Another copy will be returned to Gilead.
The study monitor will review study drug supplies and associated records at periodic intervals.

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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, IECs, 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.
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 IRB or IEC
in accordance with local requirements and receive documented IRB or IEC approval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). 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.

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 
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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, e.g. 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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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.
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.
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.
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.
Clark GM, Osborne CK, McGuire WL. Correlations between estrogen receptor, progesterone 
receptor, and patient characteristics in human breast cancer. J Clin Oncol 1984;2 
(10):1102-9.
Cytel Inc. East Software Version 6.4 Cambridge, MA: 2016:
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.
Feng Q, Zhang Z, Shea MJ, Creighton CJ, Coarfa C, Hilsenbeck SG, et al. An epigenomic 
approach to therapy for tamoxifen-resistant breast cancer. Cell research 2014;24 
(7):809-19.
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.
Hargreaves DC, Horng T, Medzhitov R. Control of inducible gene expression by signal-
dependent transcriptional elongation. Cell 2009;138 (1):129-45.

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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. 
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.
Nagarajan S, Hossan T, Alawi M, Najafova Z, Indenbirken D, Bedi U, et al. Bromodomain 
protein BRD4 is required for estrogen receptor-dependent enhancer activation and 
gene transcription. Cell reports 2014;8 (2):460-9.
Nesbit CE, Tersak JM, Prochownik EV. MYC oncogenes and human neoplastic disease. 
Oncogene 1999;18 (19):3004-16.
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I 
cancer trials. Stat Med 2008;27 (13):2420-39.
Nupponen NN, Kakkola L, Koivisto P, Visakorpi T. Genetic alterations in hormone-refractory 
recurrent prostate carcinomas. Am J Pathol 1998;153 (1):141-8.
Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 
2011;62:233-47.
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.
Sengupta S, Biarnes MC, Clarke R, Jordan VC. Inhibition of BET proteins impairs estrogen-
mediated growth and transcription in breast cancers by pausing RNA polymerase 
advancement. Breast Cancer Res Treat 2015;150 (2):265-78.
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
Appendix 3.
Pharmacokinetics, Pharmacodynamic Time Point Collection Tables
Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 6.
Performance Status Scoring System (ECOG)
Appendix 7.
RECIST 1.1
Appendix 8.
Exemestane (Aromasin®) Prescribing Information
Appendix 9.
Fulvestrant (Faslodex®) Prescribing Information
Appendix 10.
Bayesian Logistic Regression Model

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5
Triplicate ECGs will be collected at any time during Screening window, C1D1, Day 1 of Cycles 2-6 (at pre-dose), and at EOT. In the Phase 1b Dose Escalation phase of the 
study, triplicate ECGs will be collected on C1D1 at pre-dose and 1-4 hrs post-dose and on C1D15 at pre-dose, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, and 8 hours post dose 
(+/- 20 min). In the Randomized Phase 2 Dose Expansion phase of the study, triplicate ECGs will be collected on C1D1 at pre-dose and 1-4 hrs post-dose and on C1D15 at 
pre-dose, 1 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 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.
6
MUGA is acceptable. The same modality must be used throughout study participation.
7
Day 1 pre GS-5829 lab samples may be drawn up to two days prior to the Day 1 visit. 
8
For Phase 1b Dose Escalation subjects, the 30-Day Safety Follow-Up will be the final study visit. Randomized Phase 2 Dose Expansion subjects will complete the 30-Day 
Safety Follow-Up Visit and proceed to Long Term Survival Follow-Up.
9
LTFU will begin for subjects participating in the Randomized Phase 2 Dose Expansion phase of the study after the 30 day Safety Follow-Up visit for up to 2 years after the 
last dose of IP. A phone call will be made every 3 months to confirm whether subject has had disease progression. 
10
AE 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.  
11
Beginning on C1D1, subjects will receive GS-5829 daily. 
12
Subjects assigned to receive exemestane in combination with GS-5829 in the study will self-administer exemestane orally once daily starting on or before on C1D1 and 
thereafter at approximately the same time each day until the end of treatment. Subjects assigned to receive fulvestrant in combination with GS-5829 in this study will receive 
fulvestrant 500 mg IM on C1D1 and every 28 days (+/- 3 days) until the end of treatment.  For subjects initiating fulvestrant on this study a single dose of fulvestrant 500 mg 
should be administered on Cycle 1 Day 15 (+/- 3 days).
13
Screening chemistry, hematology, coagulation are to be collected within 7 days of C1D1 for central lab assessment. C1D1 pre-dose samples may be drawn up to 2 days prior 
to the visit.
14
Coagulation assessment includes PT/INR, aPTT to be done at Screening and predose of: C1D1, C1D15 and C2D1 
15
Subjects who are on goserelin will have serum pregnancy, serum estradiol, and FSH checked first day of Cycle 1 to Cycle 3, and a urine pregnancy test will be performed
monthly thereafter starting cycle 4
16
HCV RNA Reflex is required
17
If available, paraffin embedded archival tumor tissue block or freshly sectioned unstained slides will be requested to be shipped to Gilead or designee. These samples will be
requested prior to C1D1.
18
Tumor burden as assessed by RECIST v. 1.1 Guidelines (refer to Appendix 7).
19
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. Subjects who discontinue study treatment for reasons other than disease progression will continue to have tumor assessments performed during the follow 
up visits every 12 weeks until disease progression, initiation of new anti-cancer therapy, or discontinuation from the overall study participation (death, subject’s request, lost 
to follow-up) whichever happens first. Every effort should be made to perform a last tumor assessment before starting a new anti-cancer therapy. Additional unscheduled 
tumor assessments may be performed as clinically indicated at any time.

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All subjects will also undergo a bone scan during Screening (within 12 weeks prior to randomization). Bone scans performed before the signing of informed consent as 
routine procedures (but within 12 weeks before randomization) do not need to be repeated and may be used as baseline assessments as long as (1) tests were performed using 
the method requirements outlined in RECIST v.1.1 (2) appropriate documentation indicating that these radiographic tumor assessments were performed as standard of care is 
available in the patient’s source notes. Any suspicious abnormalities identified on the bone scans at baseline and on subsequent bone scans MUST be confirmed by X-ray, CT 
scan with bone windows or MRI. The same modality must be used throughout the trial for confirmation for a given lesion/patient. Bone lesions identified at baseline will be 
followed up according to the same assessment schedule every 8 weeks (±7 days) for the first year and then every 12 weeks (±7 days) from the date of randomization.
21
Subjects who discontinue study treatment for reasons other than disease progression will continue to have tumor assessments performed during the follow up visits every 8 
weeks for the first year and then every 12 weeks until disease progression, initiation of new anti-cancer therapy, or discontinuation from the overall study participation (death, 
subject’s request, lost to follow-up) whichever happens first. Every effort should be made to perform a last tumor assessment before starting a new anticancer therapy. 
Additional unscheduled tumor assessments may be performed as clinically indicated at any time.
 
 
 
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Appendix 4.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03
CTCAE v 4.03 can be assessed from the link below:
http://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf

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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Definitions
a. Definition of Childbearing Potential
For the purposes of this study, a female born subject is considered of childbearing potential 
following the initiation of puberty (Tanner stage 2) until becoming post-menopausal, unless 
permanently sterile or with medically documented ovarian failure.  
Subjects with breast cancer who are also receiving hormonal therapies, women are considered to 
be in a postmenopausal state when they are > 60 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.
In addition, pre/perimenopausal women are considered in a postmenopausal state due to 
treatment with the LHRH agonist goserelin. Subjects must have commenced treatment with 
goserelin or an alternative LHRH agonist at least 4 weeks prior to first dose of study drug, 
leading to a reduction in luteinizing hormone production and consequent reduction of sex steroid 
hormones to castration levels by the time of exposure to study drugs.
b. Definition of Male Fertility
For the purposes of this study, a partner of a female study subject is considered to be fertile after 
the initiation of puberty unless permanently sterile by bilateral orchiectomy or medical 
documentation.
2) Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
GS-5829 is contraindicated in pregnancy as any potential for human teratogenicity/fetotoxicity in 
early pregnancy is currently unknown. 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. Please refer to the latest version of the 
investigator’s brochure for additional information.

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b. Contraception Requirements for Female Subjects of Childbearing Potential
The inclusion of female subjects who are pre/peri-menopausal and treated with goserelin or an 
alternative LHRH agonist starting at least 4 weeks prior to first dose of study drug and 
throughout the duration of the study (per the above definition) of childbearing potential requires 
the use of highly effective contraceptive measures. They must also not rely on 
hormone-containing contraceptives as a form of birth control during the study. They must have a 
negative serum pregnancy test at Screening and a negative pregnancy test on the Baseline/Day 1 
visit prior to initial randomization. Pregnancy tests will be performed at protocol-specified dates 
thereafter. Female subjects must agree to one of the following from Screening until 30 days 
following the end of relevant systemic exposure.

Complete abstinence from intercourse of reproductive potential. Abstinence is an acceptable 
method of contraception only when it is in line with the subject’s preferred and usual 
lifestyle.
Or

Consistent and correct use of 1 of the following methods of birth control listed below. 
Intrauterine device (IUD) with a failure rate of <1% per year
Tubal sterilization
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Subjects must also refrain from egg donation and in vitro fertilization during treatment and until 
at least 30 days after the end of relevant systemic exposure.
3) 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.
4) Procedures to be Followed in the Event of Pregnancy
Subjects will be instructed to notify the investigator if they become pregnant at any time during 
the study, or if they become pregnant within 30 days of last study drug dose. Subjects who 
become pregnant or who suspect that they are pregnant during the study must report the 
information to the investigator and discontinue study drug immediately. Subjects whose partner 
has become pregnant or suspects they are 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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Appendix 6.
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, e.g., 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 7.
RECIST 1.1
E.A. Eisenhauera, et al. New response evaluation criteria in solid tumors:
Revised RECIST guideline (version 1.1). European Journal of Cancer 45 (2009) 228-247.

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small. Furthermore, there is guidance offered on what constitutes ‘unequivocal progres
sion’ of non measurable/non target disease, a source of confusion in the original RECIST
guideline. Finally, a section on detection of new lesions, including the interpretation of
FDG PET scan assessment is included. Imaging guidance: the revised RECIST includes a
new imaging appendix with updated recommendations on the optimal anatomical assess
ment of lesions.
Future work: A key question considered by the RECIST Working Group in developing RECIST
1.1 was whether it was appropriate to move from anatomic unidimensional assessment of
tumour burden to either volumetric anatomical assessment or to functional assessment
with PET or MRI. It was concluded that, at present, there is not sufﬁcient standardisation
or evidence to abandon anatomical assessment of tumour burden. The only exception to
this is in the use of FDG PET imaging as an adjunct to determination of progression. As
is detailed in the ﬁnal paper in this special issue, the use of these promising newer
approaches requires appropriate clinical validation studies.
 2008 Elsevier Ltd. All rights reserved.
1.
Background
1.1.
History of RECIST criteria
Assessment of the change in tumour burden is an important
feature of the clinical evaluation of cancer therapeutics. Both
tumour shrinkage (objective response) and time to the devel
opment of disease progression are important endpoints in
cancer clinical trials. The use of tumour regression as the
endpoint for phase II trials screening new agents for evi
dence of anti tumour effect is supported by years of evi
dence suggesting that, for many solid tumours, agents
which produce tumour shrinkage in a proportion of patients
have a reasonable (albeit imperfect) chance of subsequently
demonstrating an improvement in overall survival or other
time to event measures in randomised phase III studies (re
viewed in [1 4]). At the current time objective response car
ries with it a body of evidence greater than for any other
biomarker supporting its utility as a measure of promising
treatment effect in phase II screening trials. Furthermore,
at both the phase II and phase III stage of drug development,
clinical trials in advanced disease settings are increasingly
utilising time to progression (or progression free survival)
as an endpoint upon which efﬁcacy conclusions are drawn,
which is also based on anatomical measurement of tumour
size.
However, both of these tumour endpoints, objective re
sponse and time to disease progression, are useful only if
based on widely accepted and readily applied standard crite
ria based on anatomical tumour burden. In 1981 the World
Health Organisation (WHO) ﬁrst published tumour response
criteria, mainly for use in trials where tumour response was
the primary endpoint. The WHO criteria introduced the con
cept of an overall assessment of tumour burden by summing
the products of bidimensional lesion measurements and
determined response to therapy by evaluation of change from
baseline while on treatment.5 However, in the decades that
followed their publication, cooperative groups and pharma
ceutical companies that used the WHO criteria often ‘modi
ﬁed’ them to accommodate new technologies or to address
areas that were unclear in the original document. This led
to confusion in interpretation of trial results6 and in fact,
the application of varying response criteria was shown to lead
to very different conclusions about the efﬁcacy of the same
regimen.7 In response to these problems, an International
Working Party was formed in the mid 1990s to standardise
and simplify response criteria. New criteria, known as RECIST
(Response Evaluation Criteria in Solid Tumours), were pub
lished in 2000.8 Key features of the original RECIST include
deﬁnitions of minimum size of measurable lesions, instruc
tions on how many lesions to follow (up to 10; a maximum
ﬁve per organ site), and the use of unidimensional, rather
than bidimensional, measures for overall evaluation of tu
mour burden. These criteria have subsequently been widely
adopted by academic institutions, cooperative groups, and
industry for trials where the primary endpoints are objective
response or progression. In addition, regulatory authorities
accept
RECIST
as
an
appropriate
guideline
for
these
assessments.
1.2.
Why update RECIST?
Since RECIST was published in 2000, many investigators have
conﬁrmed in prospective analyses the validity of substituting
unidimensional for bidimensional (and even three dimen
sional) based criteria (reviewed in [9]). With rare exceptions
(e.g. mesothelioma), the use of unidimensional criteria seems
to perform well in solid tumour phase II studies.
However, a number of questions and issues have arisen
which merit answers and further clarity. Amongst these
are whether fewer than 10 lesions can be assessed without
affecting the overall assigned response for patients (or the
conclusion about activity in trials); how to apply RECIST in
randomised phase III trials where progression, not response,
is the primary endpoint particularly if not all patients have
measurable disease; whether or how to utilise newer imag
ing technologies such as FDG PET and MRI; how to handle
assessment of lymph nodes; whether response conﬁrmation
is truly needed; and, not least, the applicability of RECIST in
trials of targeted non cytotoxic drugs. This revision of the
RECIST guidelines includes updates that touch on all these
points.
E U R O P E A N J O U R N A L O F C A N C E R 4 5 ( 2 0 0 9 ) 2 2 8
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229

1.3.
Process of RECIST 1.1 development
The RECIST Working Group, consisting of clinicians with
expertise in early drug development from academic research
organisations, government and industry, together with imag
ing specialists and statisticians, has met regularly to set the
agenda for an update to RECIST, determine the evidence
needed to justify the various changes made, and to review
emerging evidence. A critical aspect of the revision process
was to create a database of prospectively documented solid
tumour measurement data obtained from industry and aca
demic group trials. This database, assembled at the EORTC
Data Centre under the leadership of Jan Bogaerts and Patrick
Therasse (co authors of this guideline), consists of >6500 pa
tients with >18,000 target lesions and was utilised to investi
gate the impact of a variety of questions (e.g. number of
target lesions required, the need for response conﬁrmation,
and lymph node measurement rules) on response and pro
gression free survival outcomes. The results of this work,
which after evaluation by the RECIST Working Group led to
most of the changes in this revised guideline, are reported
in detail in a separate paper in this special issue.10 Larry Sch
wartz and Robert Ford (also co authors of this guideline) also
provided key databases from which inferences have been
made that inform these revisions.11
The publication of this revised guideline is believed to be
timely since it incorporates changes to simplify, optimise
and standardise the assessment of tumour burden in clinical
trials. A summary of key changes is found in Appendix I. Be
cause the fundamental approach to assessment remains
grounded in the anatomical, rather than functional, assess
ment of disease, we have elected to name this version RECIST
1.1, rather than 2.0.
1.4.
What about volumetric or functional assessment?
This raises the question, frequently posed, about whether it is
‘time’ to move from anatomic unidimensional assessment of
tumour burden to either volumetric anatomical assessment
or to functional assessment (e.g. dynamic contrast enhanced
MRI or CT or (18)F ﬂuorodeoxyglucose positron emission
tomographic (FDG PET) techniques assessing tumour metab
olism). As can be seen, the Working Group and particularly
those involved in imaging research, did not believe that there
is at present sufﬁcient standardisation and widespread avail
ability to recommend adoption of these alternative assess
ment methods. The only exception to this is in the use of
FDG PET imaging as an adjunct to determination of progres
sion, as described later in this guideline. As detailed in paper
in this special issue12, we believe that the use of these prom
ising newer approaches (which could either add to or substitute
for anatomical assessment as described in RECIST) requires
appropriate and rigorous clinical validation studies. This pa
per by Sargent et al. illustrates the type of data that will be
needed to be able to deﬁne ‘endpoints’ for these modalities
and how to determine where and when such criteria/modal
ities can be used to improve the reliability with which truly
active new agents are identiﬁed and truly inactive new agents
are discarded in comparison to RECIST criteria in phase II
screening trials. The RECIST Working Group looks forward
to such data emerging in the next few years to allow the
appropriate changes to the next iteration of the RECIST
criteria.
2.
Purpose of this guideline
This guideline describes a standard approach to solid tumour
measurement and deﬁnitions for objective assessment of
change in tumour size for use in adult and paediatric cancer
clinical trials. It is expected these criteria will be useful in all
trials where objective response is the primary study endpoint,
as well as in trials where assessment of stable disease, tu
mour progression or time to progression analyses are under
taken, since all of these outcome measures are based on an
assessment of anatomical tumour burden and its change on
study. There are no assumptions in this paper about the pro
portion of patients meeting the criteria for any of these end
points which will signal that an agent or treatment regimen is
active: those deﬁnitions are dependent on type of cancer in
which a trial is being undertaken and the speciﬁc agent(s) un
der study. Protocols must include appropriate statistical sec
tions which deﬁne the efﬁcacy parameters upon which the
trial sample size and decision criteria are based. In addition
to providing deﬁnitions and criteria for assessment of tumour
response,
this
guideline
also
makes
recommendations
regarding standard reporting of the results of trials that utilise
tumour response as an endpoint.
While these guidelines may be applied in malignant brain
tumour studies, there are also separate criteria published for
response assessment in that setting.13 This guideline is not in
tended for use for studies of malignant lymphoma since
international guidelines for response assessment in lym
phoma are published separately.14
Finally, many oncologists in their daily clinical practice fol
low their patients’ malignant disease by means of repeated
imaging studies and make decisions about continued therapy
on the basis of both objective and symptomatic criteria. It is
not intended that these RECIST guidelines play a role in that
decision making, except if determined appropriate by the
treating oncologist.
3.
Measurability of tumour at baseline
3.1.
Deﬁnitions
At baseline, tumour lesions/lymph nodes will be categorised
measurable or non measurable as follows:
3.1.1.
Measurable
Tumour lesions: Must be accurately measured in at least one
dimension (longest diameter in the plane of measurement is
to be recorded) with a minimum size of:
• 10 mm by CT scan (CT scan slice thickness no greater than
5 mm; see Appendix II on imaging guidance).
• 10 mm caliper measurement by clinical exam (lesions
which cannot be accurately measured with calipers should
be recorded as non measurable).
• 20 mm by chest X ray.
230
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2 4 7

Malignant lymph nodes: To be considered pathologically en
larged and measurable, a lymph node must be P15 mm in
short axis when assessed by CT scan (CT scan slice thickness
recommended to be no greater than 5 mm). At baseline and in
follow up, only the short axis will be measured and followed
(see Schwartz et al. in this Special Issue15). See also notes be
low on ‘Baseline documentation of target and non target le
sions’ for information on lymph node measurement.
3.1.2.
Non-measurable
All other lesions, including small lesions (longest diameter
<10 mm or pathological lymph nodes with P10 to <15 mm
short axis) as well as truly non measurable lesions. Lesions
considered truly non measurable include: leptomeningeal dis
ease, ascites, pleural or pericardial effusion, inﬂammatory
breast disease, lymphangitic involvement of skin or lung,
abdominal masses/abdominal organomegaly identiﬁed by
physical exam that is not measurable by reproducible imaging
techniques.
3.1.3.
Special considerations regarding lesion measurability
Bone lesions, cystic lesions, and lesions previously treated
with local therapy require particular comment:
Bone lesions:.
• Bone scan, PET scan or plain ﬁlms are not considered ade
quate imaging techniques to measure bone lesions. How
ever,
these
techniques
can
be
used
to
conﬁrm
the
presence or disappearance of bone lesions.
• Lytic bone lesions or mixed lytic blastic lesions, with identi
ﬁable soft tissue components, that can be evaluated by cross
sectional imaging techniques such as CT or MRI can be con
sidered as measurable lesions if the soft tissue component
meets the deﬁnition of measurability described above.
• Blastic bone lesions are non measurable.
Cystic lesions:.
• Lesions that meet the criteria for radiographically deﬁned
simple cysts should not be considered as malignant lesions
(neither measurable nor non measurable) since they are, by
deﬁnition, simple cysts.
• ‘Cystic lesions’ thought to represent cystic metastases can
be considered as measurable lesions, if they meet the deﬁ
nition of measurability described above. However, if non
cystic lesions are present in the same patient, these are pre
ferred for selection as target lesions.
Lesions with prior local treatment:
• Tumour lesions situated in a previously irradiated area, or
in an area subjected to other loco regional therapy, are usu
ally not considered measurable unless there has been dem
onstrated progression in the lesion. Study protocols should
detail the conditions under which such lesions would be
considered measurable.
3.2.
Speciﬁcations by methods of measurements
3.2.1.
Measurement of lesions
All measurements should be recorded in metric notation,
using calipers if clinically assessed. All baseline evaluations
should be performed as close as possible to the treatment
start and never more than 4 weeks before the beginning of
the treatment.
3.2.2.
Method of assessment
The same method of assessment and the same technique
should be used to characterise each identiﬁed and reported
lesion at baseline and during follow up. Imaging based evalu
ation should always be done rather than clinical examination
unless the lesion(s) being followed cannot be imaged but are
assessable by clinical exam.
Clinical lesions: Clinical lesions will only be considered mea
surable when they are superﬁcial and P10 mm diameter as
assessed using calipers (e.g. skin nodules). For the case of skin
lesions, documentation by colour photography including a ru
ler to estimate the size of the lesion is suggested. As noted
above, when lesions can be evaluated by both clinical exam
and imaging, imaging evaluation should be undertaken since
it is more objective and may also be reviewed at the end of the
study.
Chest X ray: Chest CT is preferred over chest X ray, particu
larly when progression is an important endpoint, since CT is
more sensitive than X ray, particularly in identifying new le
sions. However, lesions on chest X ray may be considered
measurable if they are clearly deﬁned and surrounded by aer
ated lung. See Appendix II for more details.
CT, MRI: CT is the best currently available and reproducible
method to measure lesions selected for response assessment.
This guideline has deﬁned measurability of lesions on CT
scan based on the assumption that CT slice thickness is
5 mm or less. As is described in Appendix II, when CT scans
have slice thickness greater than 5 mm, the minimum size
for a measurable lesion should be twice the slice thickness.
MRI is also acceptable in certain situations (e.g. for body
scans). More details concerning the use of both CT and MRI
for assessment of objective tumour response evaluation are
provided in Appendix II.
Ultrasound: Ultrasound is not useful in assessment of lesion
size and should not be used as a method of measurement.
Ultrasound examinations cannot be reproduced in their en
tirety for independent review at a later date and, because
they are operator dependent, it cannot be guaranteed that
the same technique and measurements will be taken from
one assessment to the next (described in greater detail in
Appendix II). If new lesions are identiﬁed by ultrasound in
the course of the study, conﬁrmation by CT or MRI is ad
vised. If there is concern about radiation exposure at CT,
MRI may be used instead of CT in selected instances.
Endoscopy, laparoscopy: The utilisation of these techniques for
objective tumour evaluation is not advised. However, they
can be useful to conﬁrm complete pathological response
when biopsies are obtained or to determine relapse in trials
where recurrence following complete response or surgical
resection is an endpoint.
Tumour markers: Tumour markers alone cannot be used to as
sess objective tumour response. If markers are initially above
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the upper normal limit, however, they must normalise for a
patient to be considered in complete response. Because
tumour markers are disease speciﬁc, instructions for their
measurement should be incorporated into protocols on a
disease speciﬁc basis. Speciﬁc guidelines for both CA 125
response (in recurrent ovarian cancer) and PSA response (in
recurrent prostate cancer), have been published.16–18 In addi
tion, the Gynecologic Cancer Intergroup has developed CA125
progression criteria which are to be integrated with objective
tumour assessment for use in ﬁrst line trials in ovarian
cancer.19
Cytology, histology: These techniques can be used to differenti
ate between PR and CR in rare cases if required by protocol
(for example, residual lesions in tumour types such as germ
cell tumours, where known residual benign tumours can re
main). When effusions are known to be a potential adverse
effect of treatment (e.g. with certain taxane compounds or
angiogenesis inhibitors), the cytological conﬁrmation of the
neoplastic origin of any effusion that appears or worsens dur
ing treatment can be considered if the measurable tumour
has met criteria for response or stable disease in order to dif
ferentiate between response (or stable disease) and progres
sive disease.
4.
Tumour response evaluation
4.1.
Assessment of overall tumour burden and
measurable disease
To assess objective response or future progression, it is nec
essary to estimate the overall tumour burden at baseline and
use this as a comparator for subsequent measurements.
Only patients with measurable disease at baseline should
be included in protocols where objective tumour response
is the primary endpoint. Measurable disease is deﬁned by
the presence of at least one measurable lesion (as detailed
above in Section 3). In studies where the primary endpoint
is tumour progression (either time to progression or propor
tion with progression at a ﬁxed date), the protocol must
specify if entry is restricted to those with measurable disease
or whether patients having non measurable disease only are
also eligible.
4.2.
Baseline documentation of ‘target’ and ‘non-target’
lesions
When more than one measurable lesion is present at baseline
all lesions up to a maximum of ﬁve lesions total (and a max
imum of two lesions per organ) representative of all involved
organs should be identiﬁed as target lesions and will be re
corded and measured at baseline (this means in instances
where patients have only one or two organ sites involved a
maximum of two and four lesions respectively will be re
corded). For evidence to support the selection of only ﬁve tar
get lesions, see analyses on a large prospective database in
the article by Bogaerts et al.10.
Target lesions should be selected on the basis of their size
(lesions with the longest diameter), be representative of all in
volved organs, but in addition should be those that lend
themselves to reproducible repeated measurements. It may be
the case that, on occasion, the largest lesion does not lend it
self to reproducible measurement in which circumstance the
next largest lesion which can be measured reproducibly
should be selected. To illustrate this point see the example
in Fig. 3 of Appendix II.
Lymph nodes merit special mention since they are normal
anatomical structures which may be visible by imaging even
if not involved by tumour. As noted in Section 3, pathological
nodes which are deﬁned as measurable and may be identi
ﬁed as target lesions must meet the criterion of a short axis
of P15 mm by CT scan. Only the short axis of these nodes
will contribute to the baseline sum. The short axis of the
node is the diameter normally used by radiologists to judge
if a node is involved by solid tumour. Nodal size is normally
reported as two dimensions in the plane in which the image
is obtained (for CT scan this is almost always the axial plane;
for MRI the plane of acquisition may be axial, saggital or
coronal). The smaller of these measures is the short axis.
For example, an abdominal node which is reported as being
20 mm · 30 mm has a short axis of 20 mm and qualiﬁes as a
malignant, measurable node. In this example, 20 mm should
be recorded as the node measurement (See also the example
in Fig. 4 in Appendix II). All other pathological nodes (those
with short axis P10 mm but <15 mm) should be considered
non target lesions. Nodes that have a short axis <10 mm
are considered non pathological and should not be recorded
or followed.
A sum of the diameters (longest for non nodal lesions, short
axis for nodal lesions) for all target lesions will be calculated
and reported as the baseline sum diameters. If lymph nodes
are to be included in the sum, then as noted above, only the
short axis is added into the sum. The baseline sum diameters
will be used as reference to further characterise any objective
tumour regression in the measurable dimension of the
disease.
All other lesions (or sites of disease) including pathological
lymph nodes should be identiﬁed as non target lesions and
should also be recorded at baseline. Measurements are not re
quired and these lesions should be followed as ‘present’, ‘ab
sent’, or in rare cases ‘unequivocal progression’ (more details
to follow). In addition, it is possible to record multiple non
target lesions involving the same organ as a single item on
the case record form (e.g. ‘multiple enlarged pelvic lymph
nodes’ or ‘multiple liver metastases’).
4.3.
Response criteria
This section provides the deﬁnitions of the criteria used to
determine objective tumour response for target lesions.
4.3.1.
Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions.
Any pathological lymph nodes (whether target or
non target) must have reduction in short axis to
<10 mm.
Partial Response (PR): At least a 30% decrease in the sum of
diameters of target lesions, taking as reference the
baseline sum diameters.
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Progressive Disease (PD): At least a 20% increase in the sum
of diameters of target lesions, taking as reference
the smallest sum on study (this includes the baseline
sum if that is the smallest on study). In addition to
the relative increase of 20%, the sum must also dem
onstrate an absolute increase of at least 5 mm. (Note:
the appearance of one or more new lesions is also
considered progression).
Stable Disease (SD): Neither sufﬁcient shrinkage to qualify for
PR nor sufﬁcient increase to qualify for PD, taking as
reference the smallest sum diameters while on study.
4.3.2.
Special notes on the assessment of target lesions
Lymph nodes. Lymph nodes identiﬁed as target lesions should
always have the actual short axis measurement recorded (mea
sured in the same anatomical plane as the baseline examina
tion), even if the nodes regress to below 10 mm on study. This
means that when lymph nodes are included as target lesions,
the ‘sum’ of lesions may not be zero even if complete response
criteria are met, since a normal lymph node is deﬁned as having
a short axis of <10 mm. Case report forms or other data collec
tion methods may therefore be designed to have target nodal le
sions recorded in a separate section where, in order to qualify
for CR, each node must achieve a short axis <10 mm. For PR,
SD and PD, the actual short axis measurement of the nodes is
to be included in the sum of target lesions.
Target lesions that become ‘too small to measure’. While on
study, all lesions (nodal and non nodal) recorded at baseline
should have their actual measurements recorded at each sub
sequent evaluation, even when very small (e.g. 2 mm). How
ever, sometimes lesions or lymph nodes which are recorded
as target lesions at baseline become so faint on CT scan that
the radiologist may not feel comfortable assigning an exact
measure and may report them as being ‘too small to measure’.
When this occurs it is important that a value be recorded on
the case report form. If it is the opinion of the radiologist that
the lesion has likely disappeared, the measurement should be
recorded as 0 mm. If the lesion is believed to be present and is
faintly seen but too small to measure, a default value of 5 mm
should be assigned (Note: It is less likely that this rule will be
used for lymph nodes since they usually have a deﬁnable size
when normal and are frequently surrounded by fat such as in
the retroperitoneum; however, if a lymph node is believed to
be present and is faintly seen but too small to measure, a de
fault value of 5 mm should be assigned in this circumstance as
well). This default value is derived from the 5 mm CT slice
thickness (but should not be changed with varying CT slice
thickness). The measurement of these lesions is potentially
non reproducible, therefore providing this default value will
prevent false responses or progressions based upon measure
ment error. To reiterate, however, if the radiologist is able to
provide an actual measure, that should be recorded, even if
it is below 5 mm.
Lesions that split or coalesce on treatment. As noted in Appen
dix II, when non nodal lesions ‘fragment’, the longest diame
ters of the fragmented portions should be added together to
calculate the target lesion sum. Similarly, as lesions coalesce,
a plane between them may be maintained that would aid in
obtaining maximal diameter measurements of each individ
ual lesion. If the lesions have truly coalesced such that they
are no longer separable, the vector of the longest diameter
in this instance should be the maximal longest diameter for
the ‘coalesced lesion’.
4.3.3.
Evaluation of non-target lesions
Thissection provides the deﬁnitionsofthe criteriausedtodeter
mine the tumour response for the group of non target lesions.
While some non target lesions may actually be measurable,
they need not be measured and instead should be assessed only
qualitatively at the time points speciﬁed in the protocol.
Complete Response (CR): Disappearance of all non target le
sions and normalisation of tumour marker level. All
lymph nodes must be non pathological in size
(<10 mm short axis).
Non CR/Non PD: Persistence of one or more non target le
sion(s) and/or maintenance of tumour marker level
above the normal limits.
Progressive Disease (PD): Unequivocal progression (see com
ments below) of existing non target lesions. (Note:
the appearance of one or more new lesions is also
considered progression).
4.3.4.
Special notes on assessment of progression of non-
target disease
The concept of progression of non target disease requires
additional explanation as follows:
When the patient also has measurable disease. In this setting,
to achieve ‘unequivocal progression’ on the basis of the
non target disease, there must be an overall level of substan
tial worsening in non target disease such that, even in pres
ence of SD or PR in target disease, the overall tumour
burden has increased sufﬁciently to merit discontinuation
of therapy (see examples in Appendix II and further details
below). A modest ‘increase’ in the size of one or more non tar
get lesions is usually not sufﬁcient to quality for unequivocal
progression status. The designation of overall progression so
lely on the basis of change in non target disease in the face of
SD or PR of target disease will therefore be extremely rare.
When the patient has only non-measurable disease.This circum
stance arises in some phase III trials when it is not a criterion of
study entry to have measurable disease. The same general con
cepts apply here as noted above, however, in this instance there
is no measurable disease assessment to factor into the inter
pretation of an increase in non measurable disease burden.
Because worsening in non target disease cannot be easily
quantiﬁed (by deﬁnition: if all lesions are truly non measur
able) a useful test that can be applied when assessing patients
for unequivocal progression is to consider if the increase in
overall disease burden based on the change in non measurable
disease is comparable in magnitude to the increase that would
berequiredtodeclarePDformeasurabledisease: i.e.anincrease
in tumour burden representing an additional 73% increase in
‘volume’ (which is equivalent to a 20% increase diameter in a
measurable lesion). Examples include an increase in a pleural
effusion from ‘trace’ to ‘large’, an increase in lymphangitic
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disease from localised to widespread, or may be described in
protocols as ‘sufﬁcient to require a change in therapy’. Some
illustrative examples are shown in Figs. 5 and 6 in Appendix II.
If ‘unequivocal progression’ is seen, the patient should be con
sidered to have had overall PD at that point. While it would be
ideal to have objective criteria to apply to non measurable dis
ease, the very nature of that disease makes it impossible to do
so, therefore the increase must be substantial.
4.3.5.
New lesions
The appearance of new malignant lesions denotes disease
progression; therefore, some comments on detection of new
lesions are important. There are no speciﬁc criteria for the
identiﬁcation of new radiographic lesions; however, the ﬁnd
ing of a new lesion should be unequivocal: i.e. not attributable
to differences in scanning technique, change in imaging
modality or ﬁndings thought to represent something other
than tumour (for example, some ‘new’ bone lesions may be
simply healing or ﬂare of pre existing lesions). This is partic
ularly important when the patient’s baseline lesions show
partial or complete response. For example, necrosis of a liver
lesion may be reported on a CT scan report as a ‘new’ cystic
lesion, which it is not.
A lesion identiﬁed on a follow up study in an anatomical
location that was not scanned at baseline is considered a new
lesion andwill indicate diseaseprogression. An example of this
is the patient who has visceral disease at baseline and while on
study has a CTor MRI brain ordered which reveals metastases.
The patient’s brain metastases are considered to be evidence of
PD even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal, for example because of its
small size, continued therapy and follow up evaluation will
clarify if it represents truly new disease. If repeat scans con
ﬁrm there is deﬁnitely a new lesion, then progression should
be declared using the date of the initial scan.
While FDG PET response assessments need additional
study, it is sometimes reasonable to incorporate the use of
FDG PET scanning to complement CT scanning in assessment
of progression (particularly possible ‘new’ disease). New le
sions on the basis of FDG PET imaging can be identiﬁed
according to the following algorithm:
a. Negative FDG PET at baseline, with a positivel FDG PET
at follow up is a sign of PD based on a new lesion.
b. No FDG PET at baseline and a positive FDG PET at fol
low up:
If the positive FDG PET at follow up corresponds to a
new site of disease conﬁrmed by CT, this is PD.
If the positive FDG PET at follow up is not conﬁrmed as
a new site of disease on CT, additional follow up CT
scans are needed to determine if there is truly progres
sion occurring at that site (if so, the date of PD will be
the date of the initial abnormal FDG PET scan).
If the positive FDG PET at follow up corresponds to a
pre existing site of disease on CT that is not progress
ing on the basis of the anatomic images, this is not PD.
4.4.
Evaluation of best overall response
The best overall response is the best response recorded from
the start of the study treatment until the end of treatment
taking into account any requirement for conﬁrmation. On oc
casion a response may not be documented until after the end
of therapy so protocols should be clear if post treatment
assessments are to be considered in determination of best
overall response. Protocols must specify how any new therapy
introduced before progression will affect best response desig
nation. The patient’s best overall response assignment will
depend on the ﬁndings of both target and non target disease
and will also take into consideration the appearance of new
lesions. Furthermore, depending on the nature of the study
and the protocol requirements, it may also require conﬁrma
tory measurement (see Section 4.6). Speciﬁcally, in non ran
domised trials where response is the primary endpoint,
conﬁrmation of PR or CR is needed to deem either one the
‘best overall response’. This is described further below.
4.4.1.
Time point response
It is assumed that at each protocol speciﬁed time point, a re
sponse assessment occurs. Table 1 on the next page provides
a summary of the overall response status calculation at each
time point for patients who have measurable disease at
baseline.
When patients have non measurable (therefore non tar
get) disease only, Table 2 is to be used.
4.4.2.
Missing assessments and inevaluable designation
When no imaging/measurement is done at all at a particular
time point, the patient is not evaluable (NE) at that time point.
If only a subset of lesion measurements are made at an
assessment, usually the case is also considered NE at that
time point, unless a convincing argument can be made that
the contribution of the individual missing lesion(s) would
not change the assigned time point response. This would be
most likely to happen in the case of PD. For example, if a pa
tient had a baseline sum of 50 mm with three measured le
sions and at follow up only two lesions were assessed, but
those gave a sum of 80 mm, the patient will have achieved
PD status, regardless of the contribution of the missing lesion.
4.4.3.
Best overall response: all time points
The best overall response is determined once all the data for the
patient is known.
Best response determination in trials where conﬁrmation of com
plete or partial response IS NOT required: Best response in these
trials is deﬁned as the best response across all time points (for
example, a patient who has SD at ﬁrst assessment, PR at sec
ond assessment, and PD on last assessment has a best overall
response of PR). When SD is believed to be best response, it
must also meet the protocol speciﬁed minimum time from
baseline. If the minimum time is not met when SD is other
wise the best time point response, the patient’s best response
depends on the subsequent assessments. For example, a pa
tient who has SD at ﬁrst assessment, PD at second and does
not meet minimum duration for SD, will have a best response
of PD. The same patient lost to follow up after the ﬁrst SD
assessment would be considered inevaluable.
l A ‘positive’ FDG PET scan lesion means one which is FDG avid
with an uptake greater than twice that of the surrounding tissue
on the attenuation corrected image.
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needle aspirate/biopsy) before assigning a status of complete
response. FDG PET may be used to upgrade a response to a CR
in a manner similar to a biopsy in cases where a residual
radiographic abnormality is thought to represent ﬁbrosis or
scarring. The use of FDG PET in this circumstance should be
prospectively described in the protocol and supported by dis
ease speciﬁc medical literature for the indication. However, it
must be acknowledged that both approaches may lead to
false positive CR due to limitations of FDG PETand biopsy res
olution/sensitivity.
For equivocal ﬁndings of progression (e.g. very small and
uncertain new lesions; cystic changes or necrosis in existing
lesions), treatment may continue until the next scheduled
assessment. If at the next scheduled assessment, progression
is conﬁrmed, the date of progression should be the earlier
date when progression was suspected.
4.5.
Frequency of tumour re-evaluation
Frequency
of
tumour
re evaluation
while
on
treatment
should be protocol speciﬁc and adapted to the type and sche
dule of treatment. However, in the context of phase II studies
where the beneﬁcial effect of therapy is not known, follow up
every 6 8 weeks (timed to coincide with the end of a cycle) is
reasonable. Smaller or greater time intervals than these could
be justiﬁed in speciﬁc regimens or circumstances. The proto
col should specify which organ sites are to be evaluated at
baseline (usually those most likely to be involved with meta
static disease for the tumour type under study) and how often
evaluations are repeated. Normally, all target and non target
sites are evaluated at each assessment. In selected circum
stances certain non target organs may be evaluated less fre
quently. For example, bone scans may need to be repeated
only when complete response is identiﬁed in target disease
or when progression in bone is suspected.
After the end of the treatment, the need for repetitive tu
mour evaluations depends on whether the trial has as a goal
the response rate or the time to an event (progression/death).
If ‘time to an event’ (e.g. time to progression, disease free
survival, progression free survival) is the main endpoint of
the study, then routine scheduled re evaluation of protocol
speciﬁed sites of disease is warranted. In randomised com
parative trials in particular, the scheduled assessments
should be performed as identiﬁed on a calendar schedule
(for example: every 6 8 weeks on treatment or every 3 4
months after treatment) and should not be affected by delays
in therapy, drug holidays or any other events that might lead
to imbalance in a treatment arm in the timing of disease
assessment.
4.6.
Conﬁrmatory measurement/duration of response
4.6.1.
Conﬁrmation
In non randomised trials where response is the primary end
point, conﬁrmation of PR and CR is required to ensure re
sponses identiﬁed are not the result of measurement error.
This will also permit appropriate interpretation of results in
the context of historical data where response has traditionally
required conﬁrmation in such trials (see the paper by Bogaerts
et al. in this Special Issue10). However, in all other circum
stances, i.e. in randomised trials (phase II or III) or studies
where stable disease or progression are the primary endpoints,
conﬁrmation ofresponseis notrequiredsince itwillnotaddva
lue to theinterpretationoftrial results.However, eliminationof
the requirement for response conﬁrmation may increase the
importance of central review to protect against bias, in partic
ular in studies which are not blinded.
In the case of SD, measurements must have met the SD
criteria at least once after study entry at a minimum interval
(in general not less than 6 8 weeks) that is deﬁned in the
study protocol.
4.6.2.
Duration of overall response
The duration of overall response is measured from the time
measurement criteria are ﬁrst met for CR/PR (whichever is ﬁrst
recorded) until the ﬁrst date that recurrent or progressive dis
ease is objectively documented (taking as reference for progres
sive disease the smallest measurements recorded on study).
The duration of overall complete response is measured
from the time measurement criteria are ﬁrst met for CR until
the ﬁrst date that recurrent disease is objectively documented.
4.6.3.
Duration of stable disease
Stable disease is measured from the start of the treatment (in
randomised trials, from date of randomisation) until the crite
ria for progression are met, taking as reference the smallest
sum on study (if the baseline sum is the smallest, this is the
reference for calculation of PD).
The clinical relevance of the duration of stable disease var
ies in different studies and diseases. If the proportion of pa
tients achieving stable disease for a minimum period of time
is an endpoint of importance in a particular trial, the protocol
should specify the minimal time interval required between
two measurements for determination of stable disease.
Note: The duration of response and stable disease as well as
theprogression free survivalareinﬂuenced by thefrequencyof
follow up after baseline evaluation. It is not in the scope of this
guideline to deﬁne a standard follow up frequency. The fre
quency should take into account many parameters including
disease types and stages, treatment periodicity and standard
practice. However, these limitations of the precision of the
measured endpoint should be taken into account if compari
sons between trials are to be made.
4.7.
Progression-free survival/proportion progression-free
4.7.1.
Phase II trials
This guideline is focused primarily on the use of objective re
sponse endpoints for phase II trials. In some circumstances, ‘re
sponse rate’ may not be the optimal method to assess the
potential anticancer activity of new agents/regimens. In such
cases ‘progression free survival’ (PFS) or the ‘proportion pro
gression free’ at landmark time points, might be considered
appropriate alternatives to provide an initial signal of biologic
effect of new agents. It is clear, however, that in an uncontrolled
trial, these measures are subject to criticism since an appar
ently promising observation may be related to biological factors
such as patient selectionand not theimpactof theintervention.
Thus, phase II screening trials utilising these endpoints are best
designed with a randomised control. Exceptions may exist
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where the behaviour patterns of certain cancers are so consis
tent (and usually consistently poor), that a non randomised
trial is justiﬁable (see for example van Glabbeke et al.20). How
ever, in these cases it will be essential to document with care
the basis for estimating the expected PFS or proportion progres
sion free in the absence of a treatment effect.
4.7.2.
Phase III trials
Phase III trials in advanced cancers are increasingly designed
to evaluate progression free survival or time to progression as
the primary outcome of interest. Assessment of progression
is relatively straightforward if the protocol requires all pa
tients to have measurable disease. However, restricting entry
to this subset of patients is subject to criticism: it may result
in a trial where the results are less likely to be generalisable if,
in the disease under study, a substantial proportion of pa
tients would be excluded. Moreover, the restriction to entry
will slow recruitment to the study. Increasingly, therefore, tri
als allow entry of both patients with measurable disease as
well as those with non measurable disease only. In this cir
cumstance, care must be taken to explicitly describe the ﬁnd
ings which would qualify for progressive disease for those
patients without measurable lesions. Furthermore, in this set
ting, protocols must indicate if the maximum number of re
corded target lesions for those patients with measurable
disease may be relaxed from ﬁve to three (based on the data
found in Bogaerts et al.10 and Moskowitz et al.11). As found in
the ‘special notes on assessment of progression’, these guide
lines offer recommendations for assessment of progression
in this setting. Furthermore, if available, validated tumour mar
ker measures of progression (as has been proposed for ovarian
cancer) may be useful to integrate into the deﬁnition of pro
gression. Centralised blinded review of imaging studies or of
source imaging reports to verify ‘unequivocal progression’
may be needed if important drug development or drug ap
proval decisions are to be based on the study outcome. Finally,
as noted earlier, because the date of progression is subject to
ascertainment bias, timing of investigations in study arms
should be the same. The article by Dancey et al. in this special
issue21 provides a more detailed discussion of the assessment
of progression in randomised trials.
4.8.
Independent review of response and progression
For trials where objective response (CR + PR) is the primary end
point, and in particular where key drug development deci
sions are based on the observation of a minimum number of
responders, it is recommended that all claimed responses be
reviewed by an expert(s) independent of the study. If the study
is a randomised trial, ideally reviewers should be blinded to
treatment assignment. Simultaneous review of the patients’
ﬁles and radiological images is the best approach.
Independent review of progression presents some more
complex issues: for example, there are statistical problems
with the use of central review based progression time in
place of investigator based progression time due to the poten
tial introduction of informative censoring when the former
precedes the latter. An overview of these factors and other
lessons learned from independent review is provided in an
article by Ford et al. in this special issue.22
4.9.
Reporting best response results
4.9.1.
Phase II trials
When response is the primary endpoint, and thus all patients
must have measurable disease to enter the trial, all patients
included in the study must be accounted for in the report of
the results, even if there are major protocol treatment devia
tions or if they are not evaluable. Each patient will be assigned
one of the following categories:
1. Complete response
2. Partial response
3. Stable disease
4. Progression
5. Inevaluable for response: specify reasons (for example: early
death, malignant disease; early death, toxicity; tumour
assessments not repeated/incomplete; other (specify)).
Normally, all eligible patients should be included in the
denominator for the calculation of the response rate for phase
II trials (in some protocols it will be appropriate to include all
treated patients). It is generally preferred that 95% two sided
conﬁdence limits are given for the calculated response rate.
Trial conclusions should be based on the response rate for
all eligible (or all treated) patients and should not be based
on a selected ‘evaluable’ subset.
4.9.2.
Phase III trials
Response evaluation in phase III trials may be an indicator
of the relative anti tumour activity of the treatments eval
uated and is almost always a secondary endpoint. Ob
served differences in response rate may not predict the
clinically relevant therapeutic beneﬁt for the population
studied. If objective response is selected as a primary end
point for a phase III study (only in circumstances where a
direct relationship between objective tumour response and
a clinically relevant therapeutic beneﬁt can be unambigu
ously demonstrated for the population studied), the same
criteria as those applying to phase II trials should be used
and all patients entered should have at least one measur
able lesion.
In those many cases where response is a secondary end
point and not all trial patients have measurable disease, the
method for reporting overall best response rates must be
pre speciﬁed in the protocol. In practice, response rate may
be reported using either an ‘intent to treat’ analysis (all ran
domised patients in the denominator) or an analysis where
only the subset of patients with measurable disease at
baseline are included. The protocol should clearly specify
how response results will be reported, including any subset
analyses that are planned.
The original version of RECIST suggested that in phase III
trials one could write protocols using a ‘relaxed’ interpreta
tion of the RECIST guidelines (for example, reducing the num
ber of lesions measured) but this should no longer be done
since these revised guidelines have been amended in such a
way that it is clear how these criteria should be applied for
all trials in which anatomical assessment of tumour response
or progression are endpoints.
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237

Conﬂict of interest statement
None declared.
Acknowledgements
The RECIST Working Group would like to thank the following
organisations which made data bases available to us in order
to perform the analyses which informed decisions about
changes to this version of the criteria: Amgen; AstraZeneca;
Breast Cancer International Research Group (BCIRG); Bristol
Myers
Squibb; European
Organisation for
Research and
Treatment of Cancer (EORTC) Breast Cancer Group and Gas
trointestinal
Group;
Erasmus
University
Medical
Center,
Rotterdam, The Netherlands; Genentech; Pﬁzer; RadPharm;
Roche; SanoﬁAventis.
We would also like to thank the following individuals from
academic, government, and pharmaceutical organisations for
providing helpful comments on an earlierdraft of these revised
guidelines: Ohad Amit, Phil Murphy, Teri Crofts and Janet Be
gun, GlaxoSmithKline, USA; Laurence H. Baker, Southwest
Oncology Group, USA; Karla Ballman, Mayo Clinic, USA;
Charles Baum, Darrel Cohen, and Mary Ashford Collier, Pﬁzer,
USA; Gary J. Becker, American Board of Radiology, Tucson,
USA; Jean Yves Blay, University Claude Pertrand, Lyon France;
Renzo Canetta, Bristol Myers Squibb, USA; David Chang, Am
gen Inc., USA; Sandra Chica, Perceptive Informations Inc. (PAR
EXEL),
USA;
Martin
Edelman,
University
of
Maryland
Greenbaum Cancer Centre, USA; Gwendolyn Fyfe, Genentech,
USA; Bruce Giantonio, Eastern Cooperative Oncology Group,
USA; Gary Gordon, Abbott Pharmaceuticals, USA; Ronald Gott
lieb, Roswell Park Cancer Institute, USA; Simon Kao, University
of Iowa College of Medicine, USA; Wasaburo Koizumi, Kitasato
University, Japan; Alessandro Riva, Novartis Pharmaceuticals,
USA; Wayne Rackhoff, Ortho Biotech Oncology Research and
Development, USA; Nagahiro Saijo, President Japanese Society
of Medical Oncology, Japan; Mitchell Schnall American College
of Radiology Imaging Network, USA; Yoshik Shimamura, PAR
EXEL International Inc., Japan; Rajeshwari Sridhara, Centre
for Drug Evaluation and Research, Food and Drug Administra
tion, USA; Andrew Stone, Alan Barge, AstraZeneca, United
Kingdom; Orhan Suleiman, Centre for Drug Evaluation and Re
search, Food and Drug Administration, USA; Daniel C. Sullivan,
Duke University Medical Centre, USA; Masakazu Toi, Kyoto
University, Japan; Cindy Welsh, Centre for Drug Evaluation
and Research, Food and Drug Administration, USA.
Finally, the RECIST Working Group would like to thank indi
vidualswho were not permanent members of the group (which
are all acknowledged as co authors) but who attended working
group meetings from time to time and made contributions to
the total process over the past 7 years: Richard Pazdur, Food
and Drug Administration, USA; Francesco Pignatti, European
Medicines Agency, London, UK.
Appendix II.
Speciﬁcations for standard
anatomical radiological imaging
These protocols for image acquisition of computed tomogra
phy (CT) and magnetic resonance imaging (MRI) are recom
mendations intended for patients on clinical trials where
RECIST assessment will be performed. Standardisation of
imaging requirements and image acquisition parameters is
ideal to allow for optimal comparability of subjects within a
study and results between studies. These recommendations
are designed to balance optimised image acquisition proto
cols with techniques that should be feasible to perform glob
ally at imaging facilities in all types of radiology practices.
These guidelines are not applicable to functional imaging
techniques or volumetric assessment of tumour size.
Scanner quality control is highly recommended and should
follow
standard
manufacturer
and
facility
maintenance
schedules using commercial phantoms. It is likely that for RE
CIST unidimensional measurements this will be adequate to
produce reproducible measurements. Imaging quality control
for CT includes an analysis of image noise and uniformity and
CT number as well as spatial resolution. The frequency of
quality control analysis is also variable and should focus on
clinically relevant scanning parameters. Dose analysis is al
ways important and the use of imaging should follow the
ALARA principle, ‘As Low As Reasonably Achievable’, which
refers to making every reasonable effort to maintain radiation
exposures as far below the dose limits as possible.
Speciﬁc notes
Chest X ray measurement of lesions surrounded by pulmon
ary
parenchyma
is
feasible,
but
not
preferable
as
the
measurement represents a summation of densities. Further
more, there is poor identiﬁcation of new lesions within the
chest on X ray as compared with CT. Therefore, measure
ments of pulmonary parenchymal lesions as well as medias
tinal disease are optimally performed with CT of the chest.
MRI of the chest should only be performed in extenuating cir
cumstances. Even if IV contrast cannot be administered (for
example, in the situation of allergy to contrast), a non con
trast CT of the chest is still preferred over MRI or chest X ray.
CT scans: CT scans of the chest, abdomen, and pelvis should
be contiguous throughout all the anatomic region of interest.
As a general rule, the minimum size of a measurable lesion at
baseline should be no less than double the slice thickness and
also have a minimum size of 10 mm (see below for minimum
size when scanners have a slice thickness more than 5 mm).
While the precise physics of lesion size and partial volume
averaging is complex, lesions smaller than 10 mm may be dif
ﬁcult to accurately and reproducibly measure. While this rule
is applicable to baseline scans, as lesions potentially decrease
in size at follow up CT studies, they should still be measured.
Lesions which are reported as ‘too small to measure’ should
be assigned a default measurement of 5 mm if they are still
visible.
The most critical CT image acquisition parameters for opti
mal tumour evaluation using RECIST are anatomic coverage,
contrast administration, slice thickness, and reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most
solid tumours is the chest, abdomen and pelvis. Cover
age should encompass all areas of known predilection
for metastases in the disease under evaluation and
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Appendix III. Frequently asked questions
Question
Answer
What should be done if several unique lesions at
baseline become conﬂuent at a follow up
evaluation?
Measure the longest diameter of the conﬂuent mass and record to add into the sum of
the longest diameters
How large does a new lesion have to be to count
as progression? Does any small subcentimetre
lesion qualify, or should the lesion be at least
measurable?
New lesions do not need to meet ‘measurability criteria’ to be considered valid. If it is
clear on previous images (with the same technique) that a lesion was absent then its
deﬁnitive appearance implies progression. If there is any doubt (because of the
techniques or conditions) then it is suggested that treatment continue until next
scheduled assessment when, generally, all should be clear. Either it gets bigger and the
date of progression is the date of the ﬁrst suspicion, or it disappears and one may then
consider it an artefact with the support of the radiologists
How should one lesion be measured if on
subsequent exams it is split into two?
Measure the longest diameter of each lesion and add this into the sum
Does the deﬁnition of progression depend on
the status of all target lesions or only one?
As per the RECIST 1.1 guideline, progression requires a 20% increase in the sum of
diameters of all target lesions AND a minimum absolute increase of 5 mm in the sum
Are RECIST criteria accepted by regulatory
agencies?
Many cooperative groups and members of pharma were involved in preparing RECIST
1.0 and have adopted them. The FDA was consulted in their development and supports
their use, though they don’t require it. The European and Canadian regulatory
authorities also participated and the RECIST criteria are now integrated in the European
note for guidance for the development of anticancer agents. Many pharmaceutical
companies are also using them. RECIST 1.1 was similarly widely distributed before
publication
What is the criterion for a measurable lesion if
the CT slice thickness is >5 mm?
RECIST 1.1 recommends that CT scans have a maximum slice thickness of 5 mm and the
minimum size for a measurable lesion is twice that: 10 mm (even if slice thickness is
<5 mm). If scanners with slice thickness >5 mm are used, the minimum lesion size must
have a longest diameter twice the actual slice thickness
What should we record when target lesions
become so small they are below the 10 mm
‘measurable’ size?
Target lesion measurability is deﬁned at baseline. Thereafter, actual measurements,
even if <10 mm, should be recorded. If lesions become very small, some radiologists
indicate they are ‘too small to measure’. This guideline advises that when this occurs, if
the lesion is actually still present, a default measurement of 5 mm should be applied. If
in fact the radiologist believes the lesion has gone, a default measurement of 0 mm
should be recorded
If a patient has several lesions which have
decreased in size to meet PR criteria and one
has actually disappeared, does that patient have
PD if the ‘disappeared’ lesion reappears?
Unless the sum meets the PD criteria, the reappearance of a lesion in the setting of PR (or
SD) is not PD. The lesion should simply be added into the sum.
If the patients had had a CR, clearly reappearance of an absent lesion would qualify for
PD
When measuring the longest diameter of target
lesions in response to treatment, is the same
axis that was used initially used subsequently,
even if there is a shape change to the lesion that
may have produced a new longest diameter?
The longest diameter of the lesion should always be measured even if the actual axis is
different from the one used to measure the lesion initially (or at different time point
during follow up)
The only exception to this is lymph nodes: as per RECIST 1.1 the short axis should
always be followed and as in the case of target lesions, the vector of the short axis may
change on follow up
Target lesions have been selected at baseline
and followed but then one of these target
lesions then becomes non evaluable (i.e.
different technique used)
What may be done in such cases is one of the following:
What is the effect this has on the other target
lesions and the overall response?
(a) If the patient is still being treated, call the centre to be sure that future evaluations are
done with the baseline technique so at least SOME courses are fully evaluable
(b) If that is not possible, check if there IS a baseline exam by the same technique which
was used to follow patients...in which case if you retrieve the baseline measures from
that technique you retrieve the lesion evaluability
(c) If neither (a) nor (b) is possible then it is a judgement call about whether you delete
the lesion from all forms or consider the impact of the lesion overall is so important that
its being non evaluable makes the overall response interpretation inevaluable without
it. Such a decision should be discussed in a review panel
It is NOT recommended that the lesion be included in baseline sums and then excluded
from follow up sums since this biases in favour of a response
(continued on next page)
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245

R E F E R E N C E S
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Appendix III – continued
Question
Answer
What if a single non target lesion cannot be reviewed, for
whatever reason; does this negate the overall assessment?
Sometimes the major contribution of a single non target lesion may be in
the setting of CR having otherwise been achieved: failure to examine one
non target in that setting will leave you unable to claim CR. It is also
possible that the non target lesion has undergone such substantial
progression that it would override the target disease and render patient
PD. However, this is very unlikely, especially if the rest of the measurable
disease is stable or responding
A patient has a 32% decrease in sum cycle 2, a 28% decrease cycle
4 and a 33% decrease cycle 6. Does conﬁrmation of PR have to
take place in sequential scans or is a case like this conﬁrmed PR?
It is not infrequent that tumour shrinkage hovers around the 30% mark.
In this case, most would consider PR to have been conﬁrmed looking at
this overall case. Had there been two or three non PR observations
between the two time point PR responses, the most conservative
approach would be to consider this case SD
In the setting of a breast cancer neoadjuvant study, would
mammography not be used to assess lesions? Is CT preferred in
this setting?
Neither CT nor mammography are optimal in this setting. MRI is the
preferred modality to follow breast lesions in a neoadjuvant setting
A patient has a lesion measurable by clinical exam and by CT
scan. Which should be followed?
CT scan. Always follow by imaging if that option exists since it can be
reviewed and veriﬁed
A lesion which was solid at baseline has become necrotic in the
centre. How should this be measured?
The longest diameter of the entire lesion should be followed. Eventually,
necrotic lesions which are responding to treatment decrease in size. In
reporting the results of trials, you may wish to report on this
phenomenon if it is seen frequently since some agents (e.g. angiogenesis
inhibitors) may produce this effect
If I am going to use MRI to follow disease, what is minimum size
for measurability?
MRI may be substituted for contrast enhanced CT for some sites, but not
lung. The minimum size for measurability is the same as for CT (10 mm)
as long as the scans are performed with slice thickness of 5 mm and no
gap. In the event the MRI is performed with thicker slices, the size of a
measurable lesion at baseline should be two times the slice thickness. In
the event there are inter slice gaps, this also needs to be considered in
determining the size of measurable lesions at baseline
Can PET CT be used with RECIST?
At present, the low dose or attenuation correction CT portion of a
combined PET CT is not always of optimal diagnostic CT quality for use
with RECIST measurements. However, if your site has documented that
the CT performed as part of a PET CT is of the same diagnostic quality as
a diagnostic CT (with IV and oral contrast) then the PET CT can be used
for RECIST measurements. Note, however, that the PET portion of the CT
introduces additional data which may bias an investigator if it is not
routinely or serially performed
246
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13. Macdonald DR, Cascino TL, Schold Jr SC, Cairncross JG.
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15. Schwartz LH, Bogaerts J, Ford R, et al. Evaluation of lymph
nodes with RECIST 1.1. Eur J Cancer 2009;45:261 7.
16. Rustin GJ, Quinn M, Thigpen T, et al. Re: New guidelines to
evaluate the response to treatment in solid tumors (ovarian
cancer). J Natl Cancer Inst 2004;96:487 8.
17. Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response
guidelines for phase II clinical trials in androgen independent
prostate cancer: recommendations from the Prostate Speciﬁc
Antigen Working Group. J Clin Oncol 1999;17:3461 7.
18. Scher H, Halabi S, Tannock I, et al. Design and end points of
clinical trials for patients with progressive prostate cancer
and castrate levels of testosterone: recommendations of the
Prostate Cancer Clinical Trials Working Group. J Clin Oncol
2008;26:1148 59.
19. Vergote I, Rustin GJ, Eisenhauer EA, et al. Re: new guidelines
to evaluate the response to treatment in solid tumors [ovarian
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2000;92:1534 5.
20. Van Glabbeke M, Verweij J, Judson I, Nielsen OS. EORTC Soft
Tissue and Bone Sarcoma Group: Progression free rate as the
principal end point for phase II trials in soft tissue sarcomas.
Eur J Cancer 2002;38:543 9.
21. Dancey JE, Dodd LE, Ford R, et al. Recommendations for the
assessment of progression in randomised cancer treatment
trials. Eur J Cancer 2009;45:281 9.
22. Ford R, Schwartz L, Dancey J, et al. Lessons learned
from independent central review. Eur J Cancer 2009;45:
268 74.
23. Catalano C, Francone M, Ascarelli A, Mangia M, Iacucci I,
Passariello R. Optimizing radiation dose and image quality.
Eur Radiol 2007;17(Suppl 6):F26 32.
24. Low RN. Abdominal MRI advances in the detection of liver
tumours and characterization. Lancet Oncol 2007;8(6):525 35.
25. Barrett T, Choyke PL, Kobayashi H. Imaging of the lymphatic
system: new horizons. Contrast Media Mol Imaging
2006;1(6):230 45.
26. Shankar LK, Hoffman JM, Bacharach S, et al. National
Cancer Institute. Consensus recommendations for the use
of 18F FDG PET as an indicator of therapeutic response
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Appendix 8.
Exemestane (Aromasin®) Prescribing Information
http://www.pfizer.com/products/product-detail/aromasin

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Appendix 9.
Fulvestrant (Faslodex®) Prescribing Information
http://www.faslodexhcp.com/home.html

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Appendix 10.
Bayesian Logistic Regression Model
Determination of the MTD will be based on the posterior probability of DLT rate estimated by a 
2-parameter BLRM with overdose control {Neuenschwander et al 2008} and calculated using 
East software {Cytel Inc 2016}.
Let π[di] be the probability of DLT at dose level di of GS-5829. The statistical model describing 
dose-toxicity relationship will have the following form:
ߨሾ݀௜ሿൌ
expሺlog ሺߙሻ൅ߚlog ሺ݀௜
݀∗ሻሻ
1 ൅expሺlog ሺߙሻ൅ߚlog ሺ݀௜
݀∗ሻሻ
where α, β > 0 and d* is the reference dose level. The prior specification of the model parameters 
is provided below. The estimate of parameters will be updated as data are accumulated and the 
toxicity probability at each dose level will be calculated based on the posterior distributions of 
the model parameters. The estimated posterior probability of DLT rate at each dose level will be 
summarized using the following intervals:
Under dosing: [0.00, 0.167)
Targeted toxicity: [0.167, 0.333]
Excessive toxicity: (0.333, 1.00]
The overdose control criterion is set as the posterior probability of excessive toxicity less than 
25%. The dose level recommended for the next cohort will be the dose cohort at which the 
posterior probability for the target toxicity interval is maximum among all dose candidates 
satisfying the overdose control criterion.
Each trial can be stopped if any one of three criteria is met:
1. The posterior probability of targeted toxicity exceeds 70% and at least 6 subjects have 
been allocated at a dose level
2. Maximum number of subjects (N=12) has been treated at a dose level 
3. Maximum number of subjects (N=30) has been reached
1. Planned Dose Levels
The provisional dose levels for GS-5829 are 3 mg, 4 mg, 6 mg and 9 mg once daily.

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2. Prior Specification
The prior distribution for (log(α), log(β)) is assumed to be a bivariate normal distribution. The 
following non-informative prior is used first:

The median DLT rate at 3 mg is assumed to be 15%, i.e. mean(log(α))= -1.73.

A doubling in dose is assumed to double the odds of DLT, i.e. mean(log(β)) = 0

The StD of log(α) is set to 2 and the StD of log(β) to 1.

The correlation between log(α) and log(β) is set to be 0.  
Then the posterior is calculated based on the data collected from other on-going studies 
(GS-US-350-1599 and GS-US-350-1604) and will be updated as more data in these studies are 
collected. The prior for the current study will be based on the posterior calculated based on the 
data from GS-US-350-1599 and GS-US-350-1604 with inflated variance to discount the 
information from GS-US-350-1599 and GS-US-350-1604 considering between-trial variations.
Appendix Table 1.
DLT data collected in GS-US-350-1599 and GS-US-350-1604 as of 
22 July 2016*
QD Dose (mg)
Total number of evaluable subjects
Number of subjects with DLT
0.6
2
0
1.4
1
0
2
5
0
3
10**
1
4
2
1
*
Current data were collected only for subjects with GS-5829 monotherapy
**    A total of 13 subjects dosed, but 10 were evaluable
Appendix Table 2.
Prior for and Posterior from current data collected in 
GS-US-350-1599 and GS-US-350-1604
Parameter
Means
Variances
Correlation
Prior for (log(α), log(β))
(-1.73, 0)
(4, 1)
0
Posterior for (log(α), log(β)) from data in 
Appendix Table 1
(-2.13, 0.52)
(0.56, 1.02)
-0.01
Prior for (log(α), log(β)) used to assess operating 
characteristics by simulation  
(-2.13, 0.52)
(1.12, 2.04)
-0.01

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Appendix Table 3 shows the posterior probabilities of DLT rate based on current data from 
GS-US-1599 and GS-1604. Because there is a high chance of under dosing for 2 mg and low
chance of overdosing for 3 mg, 3 mg once daily of GS-5829 is planned as the starting dose 
for both Group A and Group B in the Phase 1b Dose Escalation portion of this study. The 
starting dose level may be either higher or lower than 3 mg once daily, if either a higher or lower
dose has been demonstrated to be both safe and tolerable in Studies GS-US-350-1599 and 
GS-US-250-1604. The new dose level will be selected prior to initiating dosing in this study.
Appendix Table 3.
Summary of posterior probabilities of DLT based on data from 
GS-US-350-1599 and GS-US-350-1604 as of 22 July 2016
QD Dose (mg)
Pr(DLT)
Prior Probability of
Median
Under
[0%, 16.7%)
Target
[16.7% 33.3%]
Excessive
(33.3%, 100%)
2 
0.05
0.95
0.05
0.001
3 
0.10
0.68
0.30
0.02
4 
0.2
0.43
0.35
0.23
6 
0.34
0.24
0.26
0.50
9 
0.51
0.15
0.20
0.65
3. Operating Characteristics
In order to assess operating characteristics, simulation was performed under 2 hypothetical 
scenarios using East software {Cytel Inc 2016}. A total of 1000 trials were simulated under each 
scenario.
Scenario 1: Only the lowest dose level (2 mg) is safe
Scenario 2: The dose level of 4 mg or below are safe
Appendix Table 4.
True underlying DLT rates in hypothetical scenarios 
QD Dose (mg)
True DLT rate
Scenario 1
Scenario 2
2 
0.30
0.10
3 
0.40
0.20
4 
0.50
0.30
6 
0.60
0.40
9 
0.70
0.50

GS-5829
Protocol GS-US-350-1937
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
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10 August 2016
As shown in Appendix Table 5, the simulations illustrate that the model has reasonable operating 
characteristics. The probabilities of recommending a correct dose level and stopping the study 
with declaring all dose levels to be toxic are 27.9% and 53.1%, respectively, in Scenario 1. The 
probability of recommending a correct dose level in Scenario 2 is 73.8%. The design is not 
aggressive to assign subjects to high toxic dose levels even with strong prior information based 
on the safety data from 20 evaluable subjects from other studies as of July 22, 2016.

GS-5829
Protocol GS-US-350-1937
Final
Gilead Sciences, Inc. 
Amendment 1
CONFIDENTIAL
Page 105
10 August 2016
Appendix Table 5.
Simulation results for operating characteristics in hypothetical 
scenarios
Operating Characteristics
Scenario 1
Scenario 2
Proportion of trials that recommend dose levels with true 
Pr(DLT) in [0.167, 0.333] (Correct decision)
27.9%
73.8%
Proportion of trials that recommend dose levels with true 
Pr(DLT)>0.333 (Patient risk)
19.0%
13.7%
Proportion of trials that recommend dose levels with true 
Pr(DLT)<0.167 
0
3.6%
Proportion of trials which stops early because all dose levels are 
too toxic
53.1%
8.9%
Average number of subjects evaluated
15
20