Clinical trial NCT02392611
Conditions: Solid Tumors and Lymphomas
Keywords: Estrogen Receptor Positive Breast Cancer
Sponsor: Gilead Sciences
Start date: 2015-03-16; Completion date: 2017-10-11
Enrollment: 33 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of this study are to characterize the safety and tolerability and determine the maximum tolerated dose (MTD) or recommended dose for phase 2 study (RDP2) of alobresib as a monotherapy in participants with advanced solid tumors and lymphomas, and in combination with exemestane or fulvestrant in participants with advanced estrogen receptor positive breast cancer.

Detailed description:

Arms: arm 1: Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 0.6 mg to determine the MTD. arm 2: Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 1.4 mg to determine the MTD. arm 3: Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 2 mg to determine the MTD. arm 4: Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 3 mg to determine the MTD. arm 5: Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 4 mg to determine the MTD. arm 6: Participants with advanced solid tumors and lymphomas who have failed or are intolerant to standard therapy or for whom no standard therapy exists, will receive alobresib at a dose of 6 mg to determine the MTD. arm 7: Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy exists, will receive alobresib at a dose of 2 mg in combination with exemestane 25 mg. arm 8: Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy exists, will receive alobresib at a dose of 2 mg in combination with fulvestrant 500 mg. arm 9: Participants with advanced stage estrogen receptor positive breast cancer for whom no standard curative therapy exists, will receive alobresib at a dose of 3 mg in combination with fulvestrant 500 mg.
Interventions: intervention 1: Alobresib intervention 2: Exemestane intervention 3: Fulvestrant
Intervention descriptions: intervention 1: Tablet administered orally once daily on Study Day 1 through Cycle 1 Day 28 of 28 days cycle intervention 2: Tablets administered orally once daily on Cycle 1 Day 1 of 28 days cycle intervention 3: Administered intramuscularly on Cycle 1 Day 1 of 28 days cycle and every 28 days

Protocol documents:
Prot_000.pdf: 
Study Title: 
Sponsor: 
IND Number: 
EudraCT Number: 
Clinical Trials.gov 
Identifier: 
Indication: 
Protocol ID: 
Clinical Program 
Manager: 
Gilead Medical Monitor: 
Protocol Version/Date: 
GILEAU 
CLINICAL STUDY PROTOCOL 
A Phase 1 Study to Evaluate the Safety, Tolerability, 
Phaim acokinetics, and Phaim acodynamics of GS-5829 as a 
Monotherapy in Subjects with Advanced Solid Tumors and 
Lymphomas and in Combination with Exemestane or Fulvestrant 
in Subjects with Estrogen Receptor Positive Breast Cancer 
Gilead Sciences, Inc. 
333 Lakeside Drive 
Foster City, CA 94404 
124032 
2016-001912-39 
NCT02392611 
Solid tumors and lymphomas 
GS-US-350-1599 
Name: 
Telephone: 
Email: 
Name: 
Telephone: 
Fax: 
Mobile: 
Email: 
Original: 
Amendment 1: 
Amendment 2: 
Amendment 3: 
Amendment 4: 
Amendment 5: 
Amendment 6: 
IPIPD 
IPIPD 
IPIPD 
IPIPD 
IPIPD 
IPIPD 
IPIPD 
IPIPD 
10 December 2014 
26 Januaiy 2015 
06 April 2015 
04 November 2015 
21 Mai·ch 2016 
24May2016 
20 June 2016 
CONFIDENTIALITY STATEMENT 
The info1m ation contained in this document, paiiiculai·ly unpublished data, is the prope1iy or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
Institutional Review Boai·d or Independent Ethics Committee. The infonnation is only to be used 
by you in connection with authorized clinical studies of the investigational diug described in the 
protocol. You will not disclose any of the info1mation to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessaiy to obtain info1m ed consent from those 
persons to whom the di11g may be adininistered. 


GS-5829
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Gilead Sciences, Inc.
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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...........................................................................25
1.2.3.
Clinical Trials of GS-5829 ...................................................................................................26
1.2.4.
Information on Exemestane..................................................................................................26
1.2.5.
Information on Fulvestrant...................................................................................................27
1.3.
Rationale for Development of GS-5829 in Advanced Solid Tumors and Lymphomas 
(Group 1)................................................................................................................................................27
1.3.1.
Rationale for Development of GS-5829 in Combination with Exemestane 
or Fulvestrant for the Treatment of Estrogen Receptor Positive Breast 
Cancer (Group 2)..................................................................................................................28
1.3.2.
Rationale to Evaluate GS-5829 in Specific Aggressive Non-Hodgkin’s 
Lymphoma: DLBCL and PTCL (Group 3)..........................................................................30
1.3.3.
Rationale for the Dose Selection..........................................................................................30
1.4.
Compliance ............................................................................................................................................31
1.5.
Risk/Benefit Assessment for the Study..................................................................................................31
2.
OBJECTIVES.....................................................................................................................................................33
3.
STUDY DESIGN................................................................................................................................................34
3.1.
Endpoints ...............................................................................................................................................34
3.2.
Study Design..........................................................................................................................................34
3.3.
Study Treatments ...................................................................................................................................38
3.4.
Criteria for Discontinuation of Study Drug............................................................................................38
3.5.
Criteria for Removal from Study............................................................................................................39
4.
SUBJECT POPULATION..................................................................................................................................40
4.1.
Number of Subjects and Subject Selection ............................................................................................40
4.2.
Inclusion Criteria....................................................................................................................................40
4.3.
Exclusion Criteria...................................................................................................................................41
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................44
5.1.
Enrollment..............................................................................................................................................44
5.2.
Description and Handling of GS-5829, Exemestane and Fulvestrant ....................................................44
5.2.1.
Formulation..........................................................................................................................44
5.2.2.
Packaging and Labeling .......................................................................................................44
5.2.3.
Storage and Handling...........................................................................................................45
5.3.
Dosage and Administration of GS-5829, Exemestane and Fulvestrant..................................................45
5.4.
Prior and Concomitant Medications.......................................................................................................46
5.5.
Accountability for GS-5829...................................................................................................................46
5.5.1.
GS-5829 Return or Disposal ................................................................................................47


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6. 
STUDY PROCEDURES .................................................................................................................................... 48 
6.1. 
Study Procedw·e Descriptions ................................................................................................................ 48 
6 .1.1. 
Info1med Consent ................................................................................................................. 48 
6.1.2. 
Medical & Medication Histoiy ............................................................................................. 48 
6.1.3. 
Physical Examination ........................................................................................................... 49 
6.1.4. 
Vital Signs ............................................................................................................................ 49 
6.1.5. 
Electrocardiogra1n Assess1nent ............................................................................................ 49 
6.1.6. 
Echocardiograrn ................................................................................................................... 49 
6.1.7. 
ECOG Perfonnance Status ................................................................................................... 49 
6.1.8. 
Prior and Concomitant Medications ..................................................................................... 50 
6.1.9. 
Adverse Events ..................................................................................................................... 50 
6.1.10. 
CT or MRI ............................................................................................................................ 50 
6.1.11. 
Bone Scans (Group 2) Only ................................................................................................. 51 
6.1.12. 
PET/CT Scan ........................................................................................................................ 51 
6.1.13. 
Blood and Urine Sa1nples ..................................................................................................... 51 
6.1.14. 
Pregnancy Test for Females of Childbearing Potential ........................................................ 52 
6.2. 
Vitamin D Assessment for Patients in Group 2 ...................................................................................... 52 
6.2.1. 
Pha1macokinetic Sain les ..................................................................................................... 53 
6.3.4. 
Unscheduled Procedw·es ...................................................................................................... 56 
6.4. 
Post-treatment Assessments ................................................................................................................... 56 
6.4.1. 
Post-Study Phone Call .......................................................................................................... 56 
6.5. 
Criteria for Discontinuation of Study Treatment. ................................................................................... 56 
6.6. 
Replace1nent of Subjects ........................................................................................................................ 56 
6.7. 
Dose Intenuption and Reduction ........................................................................................................... 57 
6.7.1. 
GS-5829 ............................................................................................................................... 57 
7. 
ADVERSE EVENTS AND TOXICITY MANAGEMENT ............................................................................... 60 
7 .1. 
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events ................................. 60 
7 .1.1. 
Adverse Events ..................................................................................................................... 60 
7.1.2. 
Serious Adverse Events ........................................................................................................ 60 
7.1.3. 
Clinical Laborato1y Abnonnalities and Other Abno1mal Assessments as 
Adverse Events or Serious Adverse Events ......................................................................... 61 
7 .2. 
Assessment of Adverse Events and Serious Adverse Events ................................................................. 62 
7.2.1. 
Assessment of Causality for Study Drngs and Procedw-es ................................................... 62 
7.2.2. 
Assess1nent of Severity ........................................................................................................ 62 
7.3. 
Investigator Requirements and Instiuctions for Repo1t ing Adverse Events and Serious 
Adverse Events to Gilead ....................................................................................................................... 63 
7 .3 .1. 
Requirements for Collection Prior to Study Drng Initiation: ............................................... 63 
7.3.2. 
Adverse Events ..................................................................................................................... 63 
7.3.3. 
Serious Adverse Events ........................................................................................................ 63 
7 .3 .4. 
Electi·onic Serious Adverse Event ( eSAE) Repo1ting Process ............................................. 64 
7 .4. 
Gilead Repo1t ing Requirements ............................................................................................................. 65 
7.4.1. 
Reporting of Adverse Events Relating to the Prima1y Endpoint and Other 
Anticipated Medical Events in the Study Population ........................................................... 65 
7.5. 
Toxicity Management ............................................................................................................................ 65 
7 .6. 
Special Situations Repo1ts ...................................................................................................................... 66 
7.6.1. 
Definitions of Special Situations .......................................................................................... 66 
7 .6.2. 
Instiuctions for Reporting Special Situations ....................................................................... 66 
8. 
STATISTICALCONSIDERATIONS ................................................................................................................ 68 
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8.1.
Analysis Objectives and Endpoints........................................................................................................68
8.1.1.
Analysis Objectives..............................................................................................................68
8.1.2.
Primary Endpoint .................................................................................................................68
8.1.3.
Secondary Endpoint .............................................................................................................68
8.2.
Analysis Conventions.............................................................................................................................69
8.2.1.
Analysis Sets ........................................................................................................................69
8.3.
Data Handling Conventions ...................................................................................................................69
8.4.
Demographic Data and Baseline Characteristics ...................................................................................70
8.5.
Efficacy Analysis ...................................................................................................................................70
8.6.
Safety Analysis.......................................................................................................................................70
8.6.1.
Extent of Exposure...............................................................................................................70
8.6.2.
Adverse Events.....................................................................................................................70
8.6.3.
Laboratory Evaluations ........................................................................................................71
8.7.
Pharmacokinetic Analysis......................................................................................................................72
8.9.
Sample Size............................................................................................................................................72
9.
RESPONSIBILITIES..........................................................................................................................................73
9.1.
Investigator Responsibilities ..................................................................................................................73
9.1.1.
Good Clinical Practice..........................................................................................................73
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................73
9.1.3.
Informed Consent.................................................................................................................73
9.1.4.
Confidentiality......................................................................................................................74
9.1.5.
Study Files and Retention of Records ..................................................................................74
9.1.6.
Case Report Forms...............................................................................................................75
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................76
9.1.8.
Inspections............................................................................................................................76
9.1.9.
Protocol Compliance............................................................................................................76
9.2.
Sponsor Responsibilities ........................................................................................................................76
9.2.1.
Protocol Modifications.........................................................................................................76
9.2.2.
Study Report and Publications .............................................................................................77
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................77
9.3.1.
Payment Reporting...............................................................................................................77
9.3.2.
Access to Information for Monitoring..................................................................................77
9.3.3.
Access to Information for Auditing or Inspections ..............................................................78
9.3.4.
Study Discontinuation..........................................................................................................78
10.
REFERENCES ...................................................................................................................................................79
11.
APPENDICES ....................................................................................................................................................83
Appendix 1.
Investigator Signature Page....................................................................................................84
Appendix 2.
Study Procedures Table..........................................................................................................85
Appendix 3.
RECIST 1.1 ............................................................................................................................89
Appendix 4.
Criteria for Progression in Castration-Resistant Prostate Cancer...........................................90
Appendix 5.
Lymphoma Efficacy Assessments..........................................................................................91
Appendix 6.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03....................................98
Appendix 7.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................99
Appendix 8.
Performance Status Scoring System (ECOG) ......................................................................102
Appendix 9.
Exemestane (Aromasin®) Prescribing Information ..............................................................103
Appendix 10.
Fulvestrant (Faslodex®) Prescribing Information.................................................................104
CCI
CCI
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LIST OF IN-TEXT TABLES
Table 3-1.
Group 1: Single Agent GS-5829 ............................................................................................34
Table 3-2.
Group 2: Combination of GS-5829 in Breast Cancer.............................................................36
Table 3-3.
Group 3: Single agent expansion in aggressive lymphomas ..................................................37
Table 5-1.
Examples of Concomitant Medications Prohibited in this Study ...........................................46
Table 6-1.
Blood and Urine Samples Collected During the Course of the Study....................................52
Table 6-2.
Dose Reduction of GS-5829...................................................................................................58
Table 7-1.
Grading of Adverse Event Severity........................................................................................63
LIST OF IN-TEXT FIGURES
Figure 1-1.
Mechanism of Action of GS-5829 to Reduce Transcription of MYC and AR Target 
Genes in Cancer Cells ............................................................................................................24
Figure 1-2.
Mechanism of Action of GS-5829 to Reduce Transcription of ER Target Genes in 
Cancer Cells ...........................................................................................................................29


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title:
A Phase 1 Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of GS-5829 as a 
Monotherapy in Subjects with Advanced Solid Tumors and 
Lymphomas and in Combination with Exemestane or Fulvestrant in 
Subjects with Estrogen Receptor Positive Breast Cancer
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
124032
2016-001912-39
NCT02392611
Study Centers Planned:
Approximately 5 centers in the United States and approximately 
10 centers in France
Objectives:
The primary objectives of this study are as follows:

Characterize the safety and tolerability of GS-5829 as a 
monotherapy in subjects with advanced solid tumors and 
lymphomas

Determine the maximum tolerated dose (MTD) or 
recommended dose for phase 2 (RDP2) of GS-5829 as a 
monotherapy in subjects with advanced solid tumors and 
lymphomas

Characterize the safety and tolerability of GS-5829 in 
combination with exemestane or fulvestrant in subjects with 
advanced estrogen receptor positive breast cancer 

Determine the MTD or RDP2 of GS-5829 in combination with 
exemestane or fulvestrant in subjects with advanced estrogen 
receptor positive breast cancer 
The secondary objective of this study is: 

Evaluate the pharmacokinetics (PK) of GS-5829 alone in 
subjects with advanced solid tumors and lymphomas and in 
combination with exemestane or fulvestrant in subjects with 
advanced estrogen receptor positive breast cancer 


GS-5829 
Protocol GS-US-350-1599 
Gilead Sciences, Inc. 
Study Design: 
CONFIDENTIAL 
Final 
Amendment6 
This is an open-label, multicenter, sequential dose-escalation study 
to evaluate the safety, tolerability, PK, and PD of GS-5829 as a 
single agent in subjects with advanced solid tumors and lymphomas 
and in combination with exemestane or fulvestrnnt in subjects with 
advanced estrngen receptor positive breast cancer. 
Group 1: Single agent GS-5829 in solid tumors and lymphomas 
Coh01ts of subjects with advanced solid tumors and lymphomas 
who have failed or are intolerant to standard therapy or for whom no 
standard therapy exists will be sequentially enrolled at progressively 
higher dose levels to receive oral GS-5829 as monotherapy 
once daily (QD). The starting dose will be 0.6 mg. Each dose level 
will enroll 1 subject until a ~ Grade 2 treatment-related toxicity is 
observed within the initial dosing period (Study Day 1 through 
C1D28 for all coho1ts). At Dose Level 5 or if a~ Grade 2 
treatment-related toxicity is obse1ved (whichever occurs first), the 
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dose level will be expanded to 3 subjects. (Note: subjects enrolled 
with Grade 2 hemoglobin [Hb] must have Hb worsen by at least 
1 grade from baseline to be considered for expansion of the cohort 
to 3 subjects).
Once a dosing level has been expanded to 3 subjects, a standard 
3+3 study design will begin and, dose escalation [3+3] will be 
performed at every subsequent dose level with cohort sizes of 
3 to 6 subjects. Subjects in the first 3 cohorts will receive a 
single dose and then approximately
7 days later, initiate dosing once daily. Subjects will return to the 
clinic for frequent evaluation and monitoring as per Appendix 2.
The doses for each Dose Level are shown in the table below. 
Group 1: Single Agent GS-5829
Dose Level
GS-5829*
1
0.6 mg
2
1.4 mg
3
2 mg
4
3 mg
5
4 mg
6
6 mg
7
9 mg
8
12 mg
*
Dose Levels may be modified based on emerging safety and PK results.
If a dose limiting toxicity (DLT) occurs within the 28 day DLT 
period at any dose level, this level will be expanded to enroll 
3 additional subjects. 
The safety and tolerability of each dose level will be assessed by a 
safety review team (SRT) after all subjects in the cohort have been 
followed for at least 28 days after the first dose of GS-5829. If no 
DLTs occur in up to 3 subjects or < 2 DLTs occur in up to 
6 subjects on any Dose Level after 28 days on treatment, the next 
Dose Level will open. Each subsequent Dose Level will open if the 
Dose Level preceding has no DLTs in 3 subjects or < 2 DLTs in up 
to 6 subjects.
Prior to initiating enrollment for Dose Level 4 in Group 1, an 
analysis of all available safety, PK, and PD data from previous 
cohorts will be reviewed.
If a subject is enrolled in a dose level but does not complete the PK 
or PD analysis, they may continue on study but an additional 
subject may be enrolled at that dose level.


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The MTD is the highest dose level with a subject incidence of 
≤1 DLTs during the first 28 days of study drug dosing of 6 subjects. 
A minimum of 6 subjects need to be treated at a dose level before 
this dose level can be deemed as the MTD.
Group 2: Combination therapy of GS-5829 with exemestane or 
fulvestrant in patients with advanced stage estrogen receptor 
positive breast cancer
Cohorts of subjects with advanced stage estrogen receptor positive
breast cancer 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 full standard doses of exemestane or fulvestrant. 
The starting dose of GS-5829 will be 2.0 mg QD, which is a dose 
level that has been demonstrated to be safe and tolerable (no 
Grade 2 or higher drug related toxicity) as a single agent in patients 
with solid tumors. Dose escalation will continue with cohort sizes 
of 3-6 subjects in parallel arms: Group 2A will initiate with 2.0 mg 
of GS-5829 orally once daily on Cycle 1 Day 1 combined with 
25 mg of exemestane administered once daily beginning on Cycle 1 
Day 1. The subject may initiate exemestane any time prior to, or on, 
Cycle 1 Day 1. Group 2B will initiate with 2.0 mg of GS-5829 
orally once daily on Cycle 1 Day 1 with 500 mg fulvestrant 
administered intramuscularly (Cycle 1 Day 1 and then every 
28 days (+/-3 days). If Cycle 1 Day 1 is the subject’s first dose of 
fulvestrant, a one-time additional dose of fulvestrant should be
administered on Cycle 1 Day 15.
The candidate doses of GS-5829 for each Dose Level for Group 2 
are shown in the table below. 
Group 2: Combination of GS-5829 in Breast Cancer
Dose Level
GS-5829*
Group 2A Exemestane
Group 2B Fulvestrant
1
2 mg
25 mg orally once daily
500 mg intramuscularly 
day 1, 29 and then 
every 28 days**
2
3 mg
3
4 mg
4
6 mg
5
9 mg
6
12 mg
*
Dose Levels may be modified based on emerging safety and PK results.
**
Subjects initiating fulvestrant on this study should receive a single additional dose of 
fulvestrant on Cycle 1 Day 15.


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Group 2A and Group 2B will dose escalate independent of each 
other. In both Groups 2A and Group 2B, each cohort will consist of 
3 newly enrolled subjects who will be treated at the specified dose 
level. After all subjects in each cohort have been followed for at 
least 28 days after the first dose of GS-5829, a dose-DLT model 
(Bayesian logistic regression model) utilizing all available GS-5829 
safety data will be built, and will provide estimates of DLT rates at 
all dose levels.
The dose-DLT model recommended dose for the next cohort will 
be the one having 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%.
Group 3 Lymphoma expansion:
In addition to the minimum 6 subjects in Group 1 with solid tumors
or lymphomas who will be enrolled to confirm the MTD, an 
additional minimum of 6 subjects with aggressive NHL (DLBCL, 
or PTCL) may be enrolled at a dose no higher than the MTD and 
complete a 28 day safety period. If ≤1 of these 6 subjects reports a 
DLT within this 28 day safety period, then up to an additional 
34 subjects may be enrolled to evaluate the efficacy and tolerability 
of GS-5829 in lymphoma (a maximum total of 40 subjects with 
lymphoma enrolled). A minimum of 20 DLBCL and 5 PTCL 
subjects will be enrolled into this group. If ≥ 2 of 6 subjects report a 
DLT, then an additional 6 subjects will be enrolled at a lower dose 
level, or at an alternative dosing schedule, which decreases the total 
amount of GS-5829 administered over a 28-day period to at least 
25% less than the previous cohort (eg 14 days on and 7 days off).
The final dose escalation decisions will be made by the SRT, 
following a review of the model recommendation and all relevant 
data available including safety information, PK, biomarkers, 
clinical data from evaluable patients.
Group 3: Single agent expansion in aggressive lymphomas
Dose 
Level
GS-5829*
# of subjects 
enrolled initially
Total number of subjects
1
≤ MTD determined 
by Group 1
6 subjects
If no DLT in first 6 subjects 
expand to maximum total of 
40 (approx 34 additional 
subjects)
-1
is ≥25% less total 
GS-5829 
administered over a 
28 day period
6 subjects
If no DLT in 6 subjects at 
this dose level, then expand 
to maximum total of all 
Group 3 subjects of 40 
(approx 28 additional 
subjects)


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Sites in France will be limited to Group 3 enrollment only.
Dose escalation in Group 1 will continue until identification of the 
MTD, or a suitable lower recommended dose, for Phase II studies. 
At least 6 subjects should be treated and evaluated at the GS-5829 
dose level recommended for Phase II studies.
A DLT in Group 1 or 2 is a toxicity defined below considered
possibly related to GS-5829 occurring during the DLT assessment
window (Study Day 1 through C1D28) in each cohort:

Grade ≥ 4 neutropenia (absolute neutrophil count [ANC] 
< 500/mm3)

Grade ≥ 3 neutropenia (ANC < 1000/mm3) with fever (a single 
temperature of > 38.3°C or a sustained temperature of ≥38°C 
for more than one hour)

Grade ≥ 3 thrombocytopenia 

Grade ≥ 2 bleeding (e.g. gastrointestinal, respiratory, epistaxis, 
purpura)

Grade ≥ 3 or higher non-hematologic toxicity, except:
Grade 3 nausea or emesis with maximum duration of 
48 hours on adequate medical therapy

Grade 3 diarrhea which persists for < 72 hours in the absence of 
maximal medical therapy.

Grade ≥ 2 non-hematologic treatment-emergent adverse event 
(TEAE) that in the opinion of the investigator is of potential 
clinical significance such that further dose escalation would 
expose subjects to unacceptable risk

Treatment interruption of ≥7 days due to unresolved toxicity
For certain toxicities, such as laboratory assessments without a 
clear clinical correlate, a discussion between the investigator and 
medical monitor, may take place to determine if this adverse event 
(AE) should be assessed as a DLT necessitating dose reduction. 
However, any Grade 3 or Grade 4 elevation in AST or ALT 
associated with a Grade 2 elevation in bilirubin that is at least 
possibly related to study drug will be considered a DLT.


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Amendment 6
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Group 3: For the first 6 subjects enrolled in the aggressive 
lymphoma group (Group 3), a modification of the DLT assessment 
for hematologic toxicity will be:

Grade ≥ 4 neutropenia (absolute neutrophil count [ANC] 
< 500/mm3) which persist for > 3 days upon interruption of 
GS-5829 (administration of growth factors not allowed 
concurrently, but allowed during GS-5829 interruption)

Grade ≥ 4 thrombocytopenia (< 25,000/mm3)

Grade ≥ 3 thrombocytopenia (< 50,000/mm3 to 25,000/mm3
which persists for > 7 days upon interruption of GS-5829
Number of Subjects 
Planned:
Up to 160 subjects will be enrolled
Target Population:
Adult subjects with a histologically or cytologically confirmed
advanced malignant solid tumor or lymphoma that is refractory to or 
intolerant of standard therapy or for which no standard therapy is 
available (Group 1) and post-menopausal women with advanced 
stage estrogen receptor positive breast cancer who are candidates 
for exemestane or fulvestrant (Group 2A and Group 2B). The 
Group 3 lymphoma expansion is limited to DLBCL or PTCL.
Duration of Treatment:
Treatment will continue in the absence of disease progression,
unacceptable toxicity, withdrawal of consent, or other reasons
specified in 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) Male or female ≥18 years of age. Subjects in Group 2 must be 
female.
2) Group 1: Histologically or cytologically confirmed advanced 
malignant solid tumor or lymphoma (any subtype) that is 
refractory to or intolerant of standard therapy or for which no 
standard therapy is available. 


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3) Group 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. Prior chemotherapy for 
advanced/metastatic disease is allowed.
a.
Documentation of ER positive (≥ 1% positive stained cells 
by local standards) based on the most recent tumor biopsy, 
unless bone only disease.
b. 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)
c.
Post, pre or peri-menopausal subjects considered to be in the 
post-menopausal state as defined by one of the following:
i.
Age ≥ 60 years
ii. 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 FSH level within 
the post menopausal range
iii. Prior bilateral oophorectomy
iv. Pre/perimenopausal women can be enrolled if amenable 
to be treated with the LHRH agonist goserelin. Patients 
must have commenced treatment with goserelin or an 
alternative LHRH agonist at least 4 weeks prior to 
first dose of study drug. If patients have received an 
alternative LHRH agonist prior to study entry they must 
switch to goserelin for the duration of the study.
4) Group 3 lymphoma expansion: Subjects with lymphoma are 
limited to diffuse large B-cell lymphoma or peripheral T-cell 
lymphoma that are refractory to or intolerant of standard 
therapy or for which no standard therapy is available.
5) All acute toxic effects of any prior antitumor therapy resolved to
Grade ≤ 1 before the start of study drug dosing (with the 
exception of alopecia [Grade 1 or 2 permitted] and neurotoxicity
[Grade 1 or 2 permitted])
6) Eastern Cooperative Oncology Group (ECOG) Performance
Status of ≤ 1


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7) Life expectancy of ≥3 months, in the opinion of the Investigator
8) Adequate organ function defined as follows:
a.
Hematologic: Platelets ≥ 100 x 109/L; Hemoglobin 
≥9.0 g/dL; ANC ≥ 1.5 x 109/L (without platelet transfusion 
or any growth factors within previous 7 days of the 
hematologic laboratory values obtained at screening visit). 
Patients in the Group 3 lymphoma expansion may be 
enrolled with an ANC of ≥ 1.0 x 109/L; Platelets ≥75 x 
109/L. 
b. Hepatic: Aspartate transaminase (AST) / Alanine 
transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN) 
(if liver metastases are present, ≤ 5 x ULN); Total or 
conjugated bilirubin ≤1.5 x ULN
c.
Renal: Serum Creatinine ≤ 1.5 x ULN or creatinine 
clearance (CrCl) ≥ 60 mL/min as calculated by the 
Cockroft-Gault method
9) Coagulation: International Normalized Ratio (INR) ≤1.2
10) Negative serum pregnancy test for female subjects 
(Appendix 7)
11) Male subjects and female subjects of childbearing potential who 
engage in heterosexual intercourse must agree to use 
protocol-specified method(s) of contraception as described in 
Appendix 7.
12) Females who are nursing must agree to discontinue nursing
before the first dose of GS-5829 
13) Able and willing to provide written informed consent to 
participate in the study
Exclusion Criteria:
Subjects who meet any of the following exclusion criteria are not to 
be enrolled in this study:
1) History or evidence of clinically significant disorder, condition, 
or disease that, in the opinion of the Investigator or Medical 
Monitor would pose a risk to subject safety or interfere with the 
study evaluations, procedures, or completion
2) Pregnant 
3) Known brain metastasis or leptomeningeal disease


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4) 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
5) Myocardial infarction, symptomatic congestive heart failure 
(New York Heart Association Classification > Class II), 
unstable angina, or serious uncontrolled cardiac arrhythmia 
within the last 6 months of study Day 1
6) Major surgery, defined as any surgical procedure that involves 
general anesthesia and a significant incision (ie, larger than 
what is required for placement of central venous access, 
percutaneous feeding tube, or biopsy) within 28 days of the 
first dose of study drug
7) Impairment of gastrointestinal (GI) function or GI disease that 
may significantly alter the absorption of GS-5829, including 
any unresolved nausea, vomiting, or diarrhea that is Common 
Terminology Criteria for Adverse Events (CTCAE) Grade > 1
8) Minor surgical procedure(s) within 7 days of enrollment or 
randomization, or not yet recovered from prior surgery 
(placement of central venous access device, fine needle 
aspiration, or endoscopic biliary stent ≥ 1 day before enrollment 
or randomization is acceptable)
9) Anti-tumor therapy (chemotherapy, antibody therapy, molecular 
targeted therapy) within 21 days or 5 half-lives, whichever is 
longer, of study drug dosing (6 weeks for nitrosoureas, 
mitomycin C, or molecular agents with t1/2 > 10 days); 
concurrent use of hormone therapy for prostate cancer is 
permitted , and concurrent use of exemestane or fulvestrant (and 
goserelin for pre/perimenopausal breast cancer as per inclusion 
criteria 2.c.iv) for subjects enrolled in Group 2 (advanced breast 
cancer) is permitted.
10) History of long QT syndrome or whose corrected QT interval 
(QTc) measured (Fridericia method) at screening is prolonged 
(> 450 ms for males and > 470 ms for females). Subjects who 
screen fail due to this criterion are not eligible to be re-screened
11) Prior exposure to bromodomain (BET) inhibitors
12) Clinically significant bleeding within 28 days of study Day 1
13) Known human immunodeficiency virus (HIV) infection


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14) HBsAg positive
15) HCV antibody positive
16) 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
17) Evidence of bleeding diathesis
18) History of hemoptysis of ≥2.5 mL/1 teaspoon within 6 months
of study Day 1
19) History of high grade esophageal or gastric varices
20) No anticoagulation therapy within 7 days of study Day 1, 
including acetylsalicylic acid, low molecular weight heparin, or 
warfarin.
Study Procedures/
Frequency:
Screening:
Screening will commence with obtaining the subject’s signed
informed consent and will occur up to 28 days prior to the first
dosing of study drug on Study Day 1/C1D1. Screening procedures
will include the following: medical history review, physical exam,
vital signs, 12-lead electrocardiogram (ECG), ECOG Performance
Status, prior/concomitant medication review, blood collection for
pregnancy test (females of child bearing potential), chemistry and 
hematology and coagulation (chemistry, hematology and 
coagulation to be collected within 7 days of Study Day 1/C1D1),
AE assessment, and computed tomography (CT) or magnetic
resonance imaging (MRI) (scans that meet protocol requirements 
that are obtained as part of standard medical practice up to 28 days
prior to Study Day 1/C1D1 are acceptable). Subjects who are 
enrolled in Group 2 will also undergo a baseline radionuclide bone 
scan. Subjects who are enrolled in Group 3 will undergo a baseline 
PET/CT in the place of a CT scan if available. Baseline tumor
lesions will be measured and characterized prior to Study 
Day 1/C1D1 to assess the subject disease status prior to beginning
treatment.
Treatment:
Subjects who meet eligibility criteria will receive GS-5829 orally 
once daily. Subjects in the first 3 cohorts of Group 1 will receive a 
single dose of GS-5829 and then approximately 7 days later start 
their first 28 day cycle of GS-5829 once daily. Each cycle will 
consist of 28 days. Safety and efficacy assessments will occur on an
outpatient basis including assessment of tumor response, physical


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exam, vitals, ECG, collection of blood samples (for routine safety
labs, GS-5829 PK, PD markers, and biomarkers at applicable visits),
urine pregnancy test (every 4 weeks while receiving GS-5829 in
female of childbearing potential), and assessment of AEs. In
addition, subjects will undergo CT/MRI or applicable scans every 
8 weeks for the first year and then every 12 weeks. Subjects in 
Group 3 will undergo a PET/CT if available instead of a CT scan 
alone at week 16.  A subject who does not show evidence of disease
progression by clinical assessment or by CT/MRI or applicable scan 
may continue receiving GS-5829 once daily until disease 
progression (clinical or radiographic), unacceptable toxicity,
withdrawal of consent, or other reasons specified in Section 3.5.
Plasma samples for GS-5829 PK will be collected (± 10 minutes) in 
cohorts 1-3 of Group 1 on Study Day 1 at pre-dose (0hr), 0.5, 1, 2, 
3, 4, 6, 8, 12, and 24 hours post-dose and in cohorts 4-8 of Group 1 
and all cohorts of Group 2 on Cycle 1 Day 1 at pre-dose (0 hr), 0.5, 
1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose. Additional samples will 
be collected at 48 and 72 hours post-dose in cohorts 1 – 3 of 
Group 1 relative to first dose of GS-5829. Plasma samples for 
GS-5829 PK will be collected in all cohorts (Group 1 and Group 2) 
at pre-dose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose 
relative to GS-5829 administration on Cycle 1 Day 8. Sparse PK 
samples will be collected in all cohorts (Group 1 and Group 2) at 
trough (20-26 hours post-dose) on Cycle 1 Day 4, 2 - 4 hours 
post-dose on Cycle 1 Day 15, and anytime post-dose on Day 1 of 
Cycles 2 through 6. In one or more cohorts, PK samples will be 
collected on Day 1 of Cycle 2 at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 
and 24 hours post-dose. GS-5829 dose will be administered in fed 
state on Day 1 of Cycle 2.
Urine will be collected for GS-5829 PK in Group 1 cohorts 1-3 on 
Study Day 1 and in Group 1 cohorts 4-8 on Cycle 1 Day 1 at 
pre-dose, 0-6 hours, 6-12 hours, and 12-24 hours post-dose relative 
to first dose of GS-5829.
Subjects in the Group 3 lymphoma expansion will have PK drawn 
at pre-dose, 1, 2, 4, 6, and 24 hours post-dose on Cycle 1, Day 8. 
PK samples will also be drawn at pre-dose on Day 1 of 
Cycles 2, 4, and 6.
After discontinuation of treatment, subjects will be followed for 
safety for 30 days.


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Test Product, Dose, and 
Mode of Administration:
GS-5829 tablets will be self-administered orally once daily, 
beginning on Cycle 1 Day 1 of the study and thereafter at 
approximately the same time each day until end of treatment.
Subjects in the first 3 Dose Levels will be administered GS-5829 in 
the clinic as a single dose and then 7 days later will self-administer 
GS-5829 orally once daily. GS-5829 is supplied as 0.2, 1, 5, and 
10 mg tablets.
For subjects in Group 2A, exemestane tablets will be 
self-administered orally once daily, beginning on Cycle 1 Day 1 of 
the study and thereafter at approximately the same time each day 
until the end of treatment.
For subjects in Group 2B, fulvestrant will be administered 
intramuscularly by the clinic staff on Cycle 1 Day 1, Cycle 1 
Day 15 and Cycle 2 Day 1 of the study and thereafter at 
approximately every 28 days (+/- 3 days) until the end of treatment.
Reference Therapy, 
Dose, and Mode of 
Administration:
Not Applicable
Criteria for Evaluation:
Safety:
Safety will be evaluated by assessment of clinical laboratory tests, 
physical examination, 12-lead ECG, vital signs measurements, and 
the documentation of AEs
Efficacy
Efficacy will be evaluated by overall response rate (ORR) 
(complete response [CR] + partial response [PR], assessed as per 
RECIST v1.1 or appropriate evaluation such as Cheson Criteria for 
lymphoma or based on the Prostate Cancer Working Group 
[PCWG] for prostate cancer) and progression-free survival (PFS), 
defined as the interval from first dose date of study drug to the 
earlier of the first documentation of definitive disease progression 
or death from any cause.
Pharmacokinetics:
The following PK parameters for GS-5829 will be calculated as 
applicable: Cmax, AUClast, AUCtau, Ctau, Tmax, and t1/2


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Statistical Methods:
Analysis Methods
The Full Analysis Set (FAS) will be used in the analyses of subject 
characteristics and efficacy endpoints. The FAS consists of all 
subjects who receive ≥ 1 dose of study drug. A Safety Analysis Set 
for this study will be the same as FAS since this study is a 
non-randomized study. Other analysis sets (DLT-Evaluable and 
PK/PD analysis sets) will be used for additional analyses as well.
Subject characteristics and study results will be described and 
summarized by group (Group 1, Group 2A and Group 2B, Group 3 
lymphoma expansion), dose level, and assessment for the relevant 
analysis sets. Descriptive summaries will be prepared to show 
sample size, mean, standard deviation (StD), 90% confidence 
intervals (CIs) on the mean, median, minimum and maximum for 
continuous variables, and counts, percentages and 90% CIs on the 
percentage for categorical variables.
Efficacy endpoints, ORR and PFS, will be listed only.
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 PK and PD Analysis Sets, GS-5829 plasma 
concentrations and PK parameters and whole blood PD markers 
will also be described and summarized. Plasma concentrations of 
GS-5829 metabolite(s) may also be determined and PK explored.
Sample Size
The sample size of the study will be determined based on the 
number of dose levels evaluated and the emerging GS-5829-related 
toxicities. The study will consist of up to 160 subjects.
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
AAG
Alpha-1 Acid Glycoprotein
ABC
activated B-cell
AE
adverse event
AI
aromatase inhibitor
ALT
alanine transaminase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
APTT
Activated partial thromboplastin time
AR
androgen receptor
AR-V7
AR splice variant 7
AST
aspartate transaminase
AUC
area under the concentration versus time curve
BCL
B-cell lymphoma
BCRP
breast cancer resistance protein
BET
bromodomain and extra-terminal
BRD
bromodomain
CA 15-3
cancer antigen 15-3
CA 19-9
carbohydrate antigen 19-9
CA 27.29
cancer antigen 27.29
CA-125
cancer antigen-125
CDK 4/6
cyclin-dependent kinase 4/6
CEA
carcinoembryonic antigen
CP17
centromeric probe for chromosome 17
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


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E2
estradiol
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic CRF
ER
estrogen receptor
eSAE
electronic SAE
FAS
full analysis set
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
GCP
good clinical practice
GI
gastrointestinal
Hb
hemoglobin
HBsAg
Hepatitis B surface Antigen
hCG
human chorionic gonadotropin
HCV
hepatitis c virus
HED
human equivalent dose
HER2
human epidermal growth factor receptor 2
HIV
Human Immunodeficiency Virus
HNSTD
highest non-severely toxic dose
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IP
investigational product
IRB
Institutional Review Board
IUD
intrauterine device
IxRS
Interactive voice/web Response System
LD
longest diameter
LHRH
lutenizing hormone-releasing hormone
LPD
longest perpendicular diameter
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCI
National Cancer Institute
ORR
overall response rate
PCWG
Prostate Cancer Working Group
PD
pharmacodynamics
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetics
PR
partial response


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PSA
prostate-specific antigen
PT
prothrombin time
PTCL
peripheral T cell lymphoma
QD
every day
QTc
corrected QT interval
R-CHOP
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone
RDP2
Recommended dose for phasae 2
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RNAPII
RNA polymerase II
SADR
serious adverse drug reaction
SAE
serious adverse event
SOC
system organ class
SOP
standard operating procedure
SPD
sum of the product
SRT
safety review team
STD
severely toxic dose
StD
standard deviation
SUSAR
suspected unexpected serious adverse reactions
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 2014a}. 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 2014a}. Transcription of the MYC gene is dependent 
on BET proteins in many cells {Mertz et al 2011} (Figure 1-1). Androgen receptor-dependent 
transcription of target genes requires BET proteins in prostate cancer cells {Asangani et al 2014}.
Cancer cells addicted to MYC and AR are highly sensitive to BET protein inhibition {Asangani et 
al 2014, Delmore et al 2011, Mertz et al 2011}, which provides the basic therapeutic rationale for 
BET inhibition with GS-5829 for the treatment of cancer.
MYC promotes cell proliferation, cell survival, and metabolic adaptation and is frequently 
overexpressed in human cancers {Dang 2012}. Data generated at Gilead demonstrated MYC 
overexpression to be prevalent in 76% of prostate cancer (n = 60), 67% of diffuse large B-cell 
lymphoma (DLBCL) (n = 98), 65% of multiple myeloma (MM, n=30), 73% of colorectal cancer 
(n = 60), and 80% of ovarian cancer (n = 60) cases examined (PC-350-2083). These data are 
consistent with literature that reports a high incidence of MYC expression in these and other 
cancers {Affer et al 2014, Barrans et al 2010, Chesi et al 2008, Chng et al 2011, Glitza et al 2014, 
Hawksworth et al 2010, Nesbit et al 1999, Nupponen et al 1998, Perry et al 2014}. The AR is a 
nuclear hormone receptor that is nearly ubiquitously expressed in prostate cancer (PC-350-2083) 
and activates growth and survival signals both by binding to androgen, its natural ligand, and 
through androgen-independent mechanisms {Yuan et al 2014}.
A number of orally administered, BET-directed compounds (TEN-010, CPI-0610, OTX015, 
ZEN-3365, and GSK525762) are currently in early-stage clinical development for the treatment 
of solid tumors or hematologic cancers. Initial evidence of clinical activity at tolerated doses has 
been reported for the BET inhibitor OTX015 in patients with refractory hematological cancers 
{Herait et al 2014}. GS-5829 is an orally available small-molecule inhibitor of BET proteins that 
is being developed by Gilead Sciences, Inc. for the treatment of solid tumors, including 
castrate-resistant prostate cancer (CRPC), estrogen receptor positive advanced stage breast 
cancer and hematologic malignancies. In nonclinical studies, GS-5829 inhibited cell growth and 


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induced apoptosis of solid tumor and hematological cancer cells by inhibiting BET 
protein-dependent transcription of MYC and other oncogenic pathways, including transcription 
mediated by the AR in prostate cancer cells and the ER in breast cancer cells. 
Figure 1-1.
Mechanism of Action of GS-5829 to Reduce Transcription of MYC 
and AR Target Genes in Cancer Cells
Bromodomain and extraterminal proteins, including BRD4, are recruited to the MYC promoter and enhancer elements through an 
interaction between the tandem bromodomains and acetylated histone proteins in chromatin (top panel). BRD4 recruits the 
positive transcription elongation factor b (pTEFb) complex to the MYC gene, which phosphorylates RNAPII to increase 
transcription of the MYC gene. GS-5829 binds to the bromodomains of BET proteins, thereby blocking the interaction with 
acetylated histone proteins and leading to a reduction of MYC transcription. GS-5829 similarly functions to inhibit the 
transcription of AR target genes in prostate cancer cells, including the kallikrein-related peptidase 3 (KLK3) gene that encodes 
prostate specific antigen (bottom panel). 
1.2.
GS-5829
1.2.1.
General Information
For further information on GS-5829, refer to the current investigator’s brochure for GS-5829.
.
GS-5829 
MYC 
.. 
.
GS-5829 .. 
AR targets 
• KLK2 
• KLK3 (PSA) 
• TMPRSS2 
• SLC45A3 


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


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Hematopoietic effects include decreases in white blood cells, lymphocytes, platelets and 
reticulocyte counts as well as mild reduced cellularity in the marrow in mice at doses of 
≥10 mg/kg/day. Minimal to marked decrease in bone marrow cellularity, decrease in 
lymphocytes in the lymphoid tissues (spleen, thymus, lymph nodes and gastrointestinal 
associated lymphoid tissue), decrease in neutrophils and platelets were observed at 
0.3 mg/kg/day in dogs. Elevated fibrinogen was also noted at the 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 the 0.3 mg/kg/day in 1 of 
6 dogs. The mechanism for the hemorrhage is not known. Protime and partial thromboplastin 
time measurements were normal. The anatomic pattern of the hemorrhage in the lung field and 
microscopy appears were 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 mg 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
Study GS-US-350-1604, a Phase 1b/2 study to evaluate the safety, tolerability, PK and 
pharmacodynamics of GS-5829 as a single agent and in combination with enzalutamide in 
subjects with CRPC, initiated in November 2015 and is actively enrolling.
1.2.4.
Information on 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 postmenoapusal 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 prescribing information (Appendix 9) or the summary of product characteristics in the 
pharmacy binder.


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1.2.5.
Information on 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 downregulates 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 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 antiestrogen therapy. For current information about
fulvestrant (Faslodex®), refer to the prescribing information (Appendix 10) or the summary of 
product characteristics in the pharmacy binder
1.3.
Rationale for Development of GS-5829 in Advanced Solid Tumors and 
Lymphomas (Group 1)
In 2014, it is estimated that over 500,000 people will die from cancer in the United States (US)
alone, with the vast majority due to progression of advanced stage solid tumors {National Cancer 
Institute 2014}. Strong evidence exists that the MYC oncogene family plays a critical role in the 
pathogenesis of many of these cancers. Overexpression or amplification of MYC has been 
observed in prostate, breast, colorectal, gastric, melanoma, non-small cell lung, small cell lung, 
medullary thyroid cancer, rhabdomyosarcoma, multiple myeloma, and aggressive non-Hodgkin’s 
lymphomas such as Burkett’s and DLBCL {He et al 2014, Koh et al 2010, Lin et al 2010, 
Molyneux et al 2012, Nair et al 2014, Nesbit et al 1999, Odia et al 2013, Petrich et al 2014, van 
Dam et al 1994, Yoo et al 2004}. GS-5829 is expected to have broad activity in tumors that 
overexpress MYC by decreasing the transcription of MYC RNA. GS-5829 also has potential for 
activity in tumor types that are highly dependent on the activity of other oncogenic transcription 
factors regulated by BET proteins. These include the AR in prostate cancer {Asangani et al 2014}, 
the estrogen receptor and Twist in breast cancer {Feng et al 2014, Shi et al 2014b}, FOS-like 
antigen 1 in nonsmall cell lung cancer and pancreatic cancer {Lockwood et al 2012, Sahai et al 
2014}, and Smoothened in basal cell carcinoma and medulloblastoma {Tang et al 2014}. 
In 2014, it is estimated that there will be 233,000 new cases of prostate cancer and 29,480 deaths 
due to prostate cancer in the US {National Cancer Institute 2014}. The majority of men 
(approximately 90%) are diagnosed with loco-regional disease that is treated surgically and/or 
with radiation therapy; 5-year survival approaches 100% for these patients. However, despite the 
availability of a variety of therapies, including pharmacological inhibitors of AR activity, 
immunotherapy, radiation, and chemotherapy, metastatic prostate cancer has a 5-year survival of 
only 30%, with most patients dying from prostate cancer. 
In patients with advanced prostate cancer who have progressed while receiving therapy with 
chemical or surgical castration, the androgen/AR axis remains the target of current standard of 
care agents abiraterone and enzalutamide. Primary and acquired resistance to such agents occurs 
when the AR is activated in an androgen-independent manner, most notably through the 
expression of the constitutively active AR splice variant 7 (AR-V7) {Antonarakis et al 2014, 
Guo et al 2009}. In nonclinical studies, GS-5829 inhibited growth and induced apoptosis in 


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prostate cancer cell lines by inhibiting MYC expression and AR-target gene expression in both 
AR- and AR-V7-expressing prostate cancer cell lines.
Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin’s lymphoma, 
accounting for approximately 30% of all lymphoma diagnoses {Morton et al 2006}. Currently, 
the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone 
(R-CHOP) is considered to be the standard of care for DLBCL. While approximately half of 
patients with DLBCL achieve durable remissions, patients who relapse or who are refractory to 
primary therapy have a poorer outcome. For patients who are not transplant eligible, salvage 
therapies, which generally include chemotherapy with or without rituximab, offer little chance of 
prolonged disease control. Response rates range from 30% to 60%, with overall survival 
less than 12 months {Vacirca et al 2014}.
GS-5829 is being developed for the treatment of DLBCL based on the known role of BET 
proteins to regulate the transcription of key oncogenic pathways related to MYC, B-cell 
lymphoma 6 (BCL6), and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-B) 
{Ceribelli et al 2014, Chapuy et al 2013}. In nonclinical studies, GS-5829 reduces the 
transcription of MYC in DLBCL cell lines vitro and in vivo, resulting in potent cell growth 
inhibition and/or apoptosis. GS-5829 exhibits equivalent potent activity in DLBCL cell lines 
irrespective of known poor prognosis factors for patients, including activated B-cell (ABC) 
subclass or MYC/B-cell lymphoma 2 (BCL2) coexpression.
1.3.1.
Rationale for Development of GS-5829 in Combination with Exemestane or 
Fulvestrant for the Treatment of Estrogen Receptor Positive Breast Cancer
(Group 2)
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 anti-estrogen 
therapy significantly improves progression-free survival (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 


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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}.
We hypothesize that 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 (Figure 1-2). 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 cell breast cancer lines in vitro and to inhibit growth of patient-derived ER-positive 
breast cancer xenografts in mice. 
Figure 1-2.
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. 
••• 
A romatase lnhitlilor __J ! 
(First lin.e) -----i •• 
Tamoxifen ---I l 
{First Ii rte} 
Fulvestrant 
1 •• 1 
{Secan.rl I ine} 
. l 
ER 
-L 
• 
ER deg:radation 
Nucreus 
Cytoplasm 


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1.3.2.
Rationale to Evaluate GS-5829 in Specific Aggressive Non-Hodgkin’s 
Lymphoma: DLBCL and PTCL (Group 3)
Specific subtypes of aggressive lymphoma may have a greater potential for sensitivity to BETi.
DLBCL and PTCL are included in this category and are also notable for poor OS for patients in 
the relapsed and/or refractory setting who are not bone marrow transplant candidates; 9-12 
months for relapsed DLBCL {Nagle et al 2013} and 5.5 months for PTCL {Mak et al 2013}.
These dismal OS rates highlight an urgent need for improved therapeutic options.
In mature T-cell lymphomas, such as PTCL, BET inhibition may be a favorable target. Cell cycle 
arrest and reduction of MYC mRNA levels in five out of seven anaplastic large-cell T-cell 
lymphoma cell lines has been reported with the BETi, OTX-015 {Bonetti et al 2012}.
Data supporting the single agent evaluation of BETi in treating DLBCL have been discussed in 
Section 1.3.1.
1.3.3.
Rationale for the Dose Selection
The starting dose of 0.6 mg GS-5829 was selected based on preclinical repeat-dose toxicology 
data, where this dose represented 1/6 the highest non-severely toxic dose (HNSTD) in dog, the 
most sensitive nonclinical species tested. This dose is commensurate with the recommendation 
outlined in the ICH Guidance for Industry, “S9 Nonclinical Evaluation for Anticancer 
Pharmaceuticals” (March 2010). The starting dose of 0.6 mg GS-5829 once daily provided
margins of approximately 203-fold of the severely toxic dose (STD10) in the mouse 
(25 mg/kg/day) and 5.5-fold of the HNSTD in the dog (0.1 mg/kg/day) on a human equivalent 
dose (HED) basis as determined in the repeat dose toxicity studies. 
PK data from the first 3 dose levels suggests that exposure in humans is higher than initially 
predicted and therefore additional intermediate dose levels have been added.
Based on preliminary pharmacokinetic data in the early dose levels of this study, the potentially 
clinically efficacious exposure (AUC 2.5 h.µg/mL) in humans is anticipated to be achieved with 
once daily dosing of 3 to 4 mg of GS-5829, which is anticipated to achieve adequate target 
inhibition for a portion of the dosing interval as supported by in vivo preclinical data.  
Dose Levels of 0.6, 1.4, 2.0 and 3.0 enrolled a single subject with the plan to expand to at least 
3 subjects if a ≥ Grade 2 treatment-related toxicity was observed within the initial dosing period 
(Study Day 1 through C1D28). No drug related toxicities were observed at Dose Levels 
0.6 through 2.0 mg. Should a ≥ Grade 2 treatment-related toxicity be observed in the subject 
receiving 3.0 mg, then a standard 3+3 study design will initiate at the 3.0 mg dose. Should no 
≥Grade 2 treatment-related toxicity be observed in the subject receiving 3.0 mg dose, the next 
dose to be enrolled, Dose Level 4.0 mg will expand enrollment to at least 3 subjects and the 
study will proceed with a standard 3 + 3 study design. The study will proceed until MTD is 
identified.
Due to the narrow therapeutic index observed in dogs, the percentage dose increment 
sequentially decreases at each dose level.


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The breast cancer arm of the study (Group 2A and 2B) will initiate at 2.0 mg which has been 
demonstrated to be safe and tolerable in patients with advanced stage solid tumors and 
lymphoma in Group 1 of this study. No drug interactions or overlapping toxicities are expected 
between GS-5829 and exemestane or fulvestrant. Group 2 will not dose escalate beyond the 
single agent MTD of GS-5829.
The Group 3 lymphoma expansion arm will initiate at a dose ≤ to the MTD as determined in 
Group 1; e.g. a dose that has been demonstrated to be safe and tolerable in patients with 
advanced stage solid tumors and lymphoma in Group 1 of this study.  
1.4.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.
1.5.
Risk/Benefit Assessment for the Study
Based on the systemic concentrations of GS-5829 measured in the repeat dose toxicity studies in 
mice and dogs, the margins of exposure at the severely toxic dose in 10% of rodents (STD10) in 
mice and HNSTD in dog are approximately 6.3- and 1-fold, respectively, at the anticipated 
clinically efficacious exposure.  Another bromodomain inhibitor in development has identified 
thrombocytopenia as the earliest sign of toxicity in human studies, a toxicity which may be easily 
monitored. 
Target organs identified in the repeat-dose toxicity studies included hematopoietic and male 
reproductive systems (mice and dogs), the adrenal glands (mice), and the GI tract and respiratory 
system (dogs). With the exception of the adrenal glands in the mouse and the respiratory system 
in dogs, all other target organs are expected based on the known pharmacology of GS-5829 to 
inhibit BET proteins. The effects on the hematopoietic system, male reproductive tract, adrenal 
glands, and GI tract were considered reversible and can be monitored in the clinic.
As of a data cutoff of 12 October 2015, in this First-In-Human study GS-US-350-1599 no deaths 
resulting from adverse events (AEs) have occurred.  Two subjects experienced 3 serious adverse 
events (SAEs) which were considered by the investigator to be Grade 3 and not related to study 
drug (cholangitis and sepsis in 1 subject at 0.6 mg and thrombocytopenia in 1 subject at 1.4 mg). 
The following AEs were considered related to study drug: fatigue (1 subject, 0.6-mg group and 
1 subject, 1.4-mg group), nausea (1 subject, 0.6-mg group and 1 subject, 1.4-mg group), 
splenomegaly (1 subject, 1.4-mg group), and dizziness (1 subject, 1.4-mg group). No AEs lead to 
discontinuation of study drug.  After the data cut, a DLT of adrenal hemorrhage was reported in 
a subject receiving 4 mg of GS-5829.   The subject had normal coagulation parameters and a 
platelet count higher than normal at baseline which did not change at the time of the event.  An 
additional DLT of Grade 3 thrombocytopenia was reported in a subject receiving 3 mg of 
GS-5829.
Assessments for AEs and monitoring for laboratory abnormalities are specified in the protocol 
and include symptom and AE assessment on Days 1, 8, 15, 22 of the first 28 day cycle and then 


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every 28 days, until end of treatment followed by a 30-day Safety Follow-Up Visit. Physical 
examinations will occur on Day 1of each 28-day cycle until end of treatment, followed by a 
30-day Safety Follow-Up visit.
The safety monitoring frequency is considered sufficient to identify potential AEs as they 
emerge. In addition, mitigation strategies are incorporated into the study design. The inclusion 
and exclusion criteria are designed to ensure subjects have acceptable organ function to be 
eligible for this study such that confounding significant co-morbidities are excluded. 
Study medications will continue until disease progression, unacceptable toxicity, consent 
withdrawal, or subject’s refusal of treatment.
Potential Benefits
The primary potential benefit of BET inhibition is that therapy may delay progression or improve 
overall survival in patients with lymphoma or solid tumor who do not have alternative therapies 
which have been demonstrated to provide significant clinical benefit. For patients with breast 
cancer, the potential benefit of BET inhibition administered in combination with standard 
anti-estrogen therapy is to delay progression or improve overall survival.  
Participants are informed that their involvement in the study may offer benefits to other current 
or future cancer patients by enhancing knowledge relating to treatment.


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2. 
OBJECTIVES 
The prima1y objectives of this study are: 
Final 
Amendment6 
• 
Characterize the safety and tolerability of GS-5829 as a monotherapy in subjects with 
advanced solid tumors and lymphomas 
• 
Detennine the MTD or recommended dose for phase 2 study (RDP2) of GS-5829 as a 
monotherapy in subjects with advanced solid tumors and lymphomas 
• 
Characterize the safety and tolerability of GS-5829 in combination with exemestane or 
fulvestrant in subjects with advanced estrogen receptor positive breast cancer 
• 
Detennine the MTD or RDP2 of GS-5829 in combination with exemestane or fulvestrant in 
subjects with advanced estrogen receptor positive breast cancer 
The secondaiy objective of this study is: 
• 
Evaluate the PK of GS-5829 alone in subjects with advanced solid tumors and lymphomas 
and in combination with exemestane or fulvestrant in subjects with advanced estrogen 
receptor positive breast cancer 
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3.
STUDY DESIGN
3.1.
Endpoints
The endpoints for this study are described in Section 8.
3.2.
Study Design
This is an open-label, multicenter, sequential dose-escalation study to evaluate the safety,
tolerability, PK, and PD of GS-5829 as a single agent in subjects with advanced solid tumors and 
lymphomas and in combination with exemestane or fulvestrant in subjects with advanced 
estrogen receptor positive breast cancer.  
Group 1: Single agent GS-5829 in solid tumors and lymphomas
Cohorts of subjects with advanced solid tumors and lymphomas who have failed or are intolerant
to standard therapy or for whom no standard therapy exists will be sequentially enrolled at
progressively higher dose levels to receive oral GS-5829 as monotherapy once daily (QD). The 
starting dose will be 0.6 mg. Each dose level will enroll 1 subject until a ≥Grade 2 
treatment-related toxicity is observed within the initial dosing period (Study Day 1 through 
C1D28 for all cohorts). At Dose Level 5 or if a ≥ Grade 2 treatment-related toxicity is observed
(whichever occurs first), the dose level will be expanded to 3 subjects. (Note: subjects enrolled 
with a Grade 2 hemoglobin [Hb] must have Hb worsen by at least 1 grade from baseline to be 
considered for expansion of the cohort to 3 subjects). Once a dosing level has been expanded to 
3 subjects, a standard 3+3 study design will begin and, dose escalation [3+3] will be performed
with cohort sizes of 3 to 6 subjects. Subjects in the first 3 cohorts will receive a single dose and 
then approximately 7 days later, initiate dosing once daily.  Subjects will return to the clinic for 
frequent evaluation and monitoring as per Appendix 2.
The doses for each candidate dose level in Group 1 are shown in Table 3-1.
Table 3-1.
Group 1: Single Agent GS-5829
Dose Level
GS-5829*
1
0.6 mg
2
1.4 mg
3
2 mg
4
3 mg
5
4 mg
6
6 mg
7
9 mg
8
12 mg
*
Dose levels may be modified based on emerging safety and PK results.


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If a DLT occurs within the 28 day DLT period at any dose level, this level will be expanded to 
enroll 3 additional subjects.
The safety and tolerability of each dose level will be assessed by a safety review team (SRT) after
all subjects in the cohort have been followed for at least 28 days after the first dose of GS-5829. 
If no DLTs occur in up to 3 subjects or < 2 DLTs occur in up to 6 subjects on any Dose Level 
after 28 days on treatment, the next Dose Level will open.  Each subsequent Dose Level will 
open if the Dose Level preceding has no DLTs in 3 subjects or < 2 DLTs in up to 6 subjects.
The SRT will consist of at least one investigator and the following: 
Gilead Sciences, Inc. (Gilead) study team members: the medical monitor, representatives from 
Drug Safety and Public Health (DSPH), Clinical Operations, and Biostatistics. Others may be 
invited to participate as members of the SRT if additional expertise is desired. The medical 
monitor serves as the chair of the SRT.
Prior to initiating enrollment for Dose Level 4 in Group 1, an analysis of all available safety, PK, 
and PD data from previous cohorts will be reviewed.
If a subject is enrolled in a dose level but does not complete the PK or PD analysis, they may 
continue on study but an additional subject may be enrolled at that dose level.
The MTD is the highest dose level with a subject incidence of ≤ 1 DLT during the first 28 days of
study drug dosing of 6 subjects. A minimum of 6 subjects need to be treated at a dose level 
before this dose level can be deemed as the MTD. 
Group 2: Combination therapy of GS-5829 with exemestane or fulvestrant in patients with 
advanced stage estrogen receptor positive breast cancer
Cohorts of subjects with advanced estrogen receptor positive breast cancer 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 full standard 
doses of exemestane or fulvestrant. The starting dose of GS-5829 will be 2.0 mg QD, which is a
dose level that has been demonstrated to be safe and tolerable (no Grade 2 or higher drug related 
toxicity) in patients with solid tumors and prostate cancer.  Dose escalation will continue with 
cohort sizes of 3-6 subjects in parallel arms:  Group 2A will initiate with 2.0 mg of GS-5829 
orally once daily on Cycle 1 Day 1 combined with 25 mg of exemestane once daily beginning on 
Cycle 1 Day 1.  The subject may initiate exemestane anytime prior to, or on, Cycle 1 Day 1. 
Group 2B will initiate with 2.0 mg of GS-5829 orally once daily on Cycle 1 Day 1 with 500 mg 
fulvestrant administered intramuscularly (Cycle 1 Day 1 and then every 28 days (+/- 3 days).  If 
Cycle 1 Day 1 is the subject’s first dose of fulvestrant, a one-time additional dose of fulvestrant 
should be administered on Cycle 1 Day 15).  


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The doses for each candidate dose level in group 2 are shown in Table 3-2.  
Table 3-2.
Group 2: Combination of GS-5829 in Breast Cancer
Dose Level
GS-5829*
Group 2A Exemestane
Group 2B Fulvestrant
1
2 mg
25 mg orally once daily
500 mg intramuscularly day 1,
29 and then every 28 days**
2
3 mg
3
4 mg
4
6 mg
5
9 mg
6
12 mg
*
Dose Levels may be modified based on emerging safety and PK results.
**
Subjects initiating fulvestrant on this study should receive a single additional dose of fulvestrant on Cycle 1 Day 15.
Group 2A and Group 2B will dose escalate independent of each other. In both Group 2A and 
Group 2B, each cohort will consist of 3 newly enrolled subjects who will be treated at the 
specified dose level. After all subjects in each cohort have been followed for at least 28 days after 
the first dose of GS-5829, a dose-DLT model (Bayesian logistic regression model) utilizing all 
available GS-5829 safety data will be built and will provide estimates of DLT rates at all dose 
levels. The dose-DLT model recommended dose for the next cohort will be the one having the 
highest chance that the DLT rate will fall in the target interval [16%, 33%) and a probability of 
<25% that the DLT rate exceeds 33%.
Group 3 Lymphoma expansion:
In addition to the minimum 6 subjects in Group 1 with solid tumors or lymphomas who will be 
enrolled to confirm the MTD, an additional minimum of 6 subjects with aggressive NHL 
(DLBCL or PTCL) may be enrolled at a dose no higher than the MTD and complete a 28 day 
safety period.  If ≤1 of these 6 subjects reports a DLT within this 28 day safety period, then up 
to an additional 34 subjects may be enrolled to evaluate the efficacy and tolerability of GS-5829 
in lymphoma (a maximum total of 40 subjects with lymphoma enrolled). A minimum of 20 
DLBCL and 5 PTCL subjects will be enrolled into this group.  If ≥ 2 of 6 subjects report a DLT, 
then an  additional 6 subjects will be enrolled at a lower dose level, or at an alternative dosing 
schedule, which decreases the total amount of GS-5829 administered over a 28-day period to at 
least 25% less than the previous cohort (eg 14 days on and 7 days off).  
The final dose escalation decisions will be made by the SRT, following a review of the model 
recommendation and all relevant data available including safety information, PK, 
 
clinical data from evaluable patients.
CCI-


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Table 3-3.
Group 3: Single agent expansion in aggressive lymphomas  
Dose 
Level
GS-5829*
# of subjects 
enrolled initially
Total number of subjects
1
≤ MTD determined by Group 1
6 subjects
If no DLT in first 6 subjects expand to
maximum total of 40 
(approx. 34 additional subjects)
-1
is ≥25% less total GS-5829 
administered over a 28 day period
6 subjects
If no DLT in 6 subjects at this dose 
level, then expand to maximum total of 
all Group 3 subjects of 40 
(approx. 28 additional subjects)
Sites in France will be limited to Group 3 enrollment only.
Dose escalation in Group 1 will continue until identification of the MTD, or a suitable lower 
recommended dose, for Phase II studies. At least 6 subjects should be treated and evaluated at 
the GS-5829 dose level recommended for Phase II studies.
A DLT in Group 1 or 2 is a toxicity defined below considered possibly related to GS-5829
occurring during the DLT assessment window (Study Day 1 through C1D28) in each cohort.

Grade ≥ 4 neutropenia (absolute neutrophil count [ANC] < 500/mm3) 

Grade ≥ 3 neutropenia (ANC < 1000/mm3) with fever (a single temperature of > 38.3°C or a 
sustained temperature of ≥ 38°C for more than one hour)

Grade ≥3 thrombocytopenia 

Grade ≥2 bleeding (e.g. gastrointestinal, respiratory, epistaxis, purpura)

Grade ≥3 or higher non-hematologic toxicity, except:
Grade 3 nausea or emesis with maximum duration of 48 hours on adequate medical 
therapy
Grade 3 diarrhea which persists for < 72 hours in the absence of maximal medical 
therapy

Grade ≥ 2 non-hematologic treatment-emergent adverse event (TEAE) that in the opinion of 
the investigator is of potential clinical significance such that further dose escalation would 
expose subjects to unacceptable risk

Treatment interruption of ≥7 days due to unresolved toxicity

For certain toxicities such as laboratory assessments without a clear clinical correlate, 
a discussion between the Investigator and Medical Monitor may take place to determine if 


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this AE should be assessed as a DLT necessitating dose reduction. However, any Grade 3 or 
Grade 4 elevation in AST or ALT associated with a Grade 2 elevation in bilirubin that is at 
least possibly related to study drug will be considered a DLT.
Group 3: For the first 6 subjects enrolled in the aggressive lymphoma group (Group 3), a 
modification of the DLT assessment for hematologic toxicity will be:

Grade ≥ 4 neutropenia (absolute neutrophil count [ANC] < 500/mm3) which persist for 
> 3 days upon interruption of GS-5829 (administration of growth factors not allowed 
concurrently, but allowed during GS-5829 interruption)

Grade ≥ 4 thrombocytopenia (< 25,000/mm3)

Grade ≥ 3 thrombocytopenia  (< 50,000/mm3 to 25,000/mm3 which persists for > 7 days 
upon interruption of GS-5829
3.3.
Study Treatments
Subjects who meet eligibility criteria will receive GS-5829 orally once daily.  Subjects in the 
first 3 cohorts will receive a single dose of GS-5829 and then approximately 7 days later start 
their first 28 day cycle of GS-5829 once daily.  Each cycle will consist of 28 days.  Safety and 
efficacy assessments will occur on an outpatient basis including assessment of tumor response, 
physical exam, vitals, electrocardiogram (ECG), collection of blood samples (for routine safety 
labs, GS-5829 PK, 
 at applicable visits), urine pregnancy (every 
4 weeks while receiving GS-5829 in females of childbearing potential), and assessment of AEs. 
In addition, subjects will undergo computed tomography (CT)/magnetic resonance imaging 
(MRI) or applicable scans every 8 weeks for the first year and then every 12 weeks. Subjects in 
Group 3 will undergo a PET/CT if available instead of a CT scan alone at week 16.
A subject who does not show evidence of disease progression by clinical assessment or by 
CT/MRI or applicable scan may continue receiving GS-5829 once daily day until disease 
progression (clinical or radiographic), unacceptable toxicity, withdrawal of consent, or other 
reasons specified in Section 3.4.
For subjects in Group 2, a radionuclide bone scan (whole body) is also required at screening and 
then as clinically indicated or to confirm a complete response. 
Study drug dosing will continue in the absence of disease progression or toxicity warranting 
discontinuation of therapy.
3.4.
Criteria for Discontinuation of Study Drug
Study medication may be discontinued in the following instances:

Documented progression of malignant disease

Pregnancy
CCI


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


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Up to 160 subjects who meet the eligibility criteria will be enrolled.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.
1) Male or female ≥ 18 years of age. Subjects in Group 2 must be female.
2) Group 1: Histologically or cytologically confirmed advanced malignant solid tumor or 
lymphoma (any subtype) that is refractory to or intolerant of standard therapy or for which no 
standard therapy is available. 
3) Group 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.  
Prior chemotherapy for advanced/metastatic disease is allowed.
a.
Documentation of ER positive (≥ 1% positive stained cells by local standards) based on 
the most recent tumor biopsy, unless bone only disease.
b. 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)
c.
Post, pre or peri-menopausal subjects to be in the post-menopausal state as defined by 
one of the following:
i.
Age ≥60 years
ii. 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 FSH level within the post-menopausal range
iii. Prior bilateral oophorectomy
iv. Pre/perimenopausal women can be enrolled if amenable to be treated with the LHRH 
agonist goserelin. Patients must have commenced treatment with goserelin or an 
alternative LHRH agonist at least 4 weeks prior to first dose of study drug. If patients 
have received an alternative LHRH agonist prior to study entry they must switch to 
goserelin for the duration of the study.


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4) Group 3 lymphoma expansion: Subjects with lymphoma are limited to diffuse large B-cell 
lymphoma or peripheral T-cell lymphoma that are refractory to or intolerant of standard 
therapy or for which no standard therapy is available
5) All acute toxic effects of any prior antitumor therapy resolved to Grade ≤ 1 before the start of 
study drug dosing (with the exception of alopecia [Grade 1 or 2 permitted] and neurotoxicity 
[Grade 1 or 2 permitted])
6) ECOG Performance Status of ≤ 1
7) Life expectancy of > 3 months, in the opinion of the Investigator
8) Adequate organ function defined as follows:
a.
Hematologic: Platelets ≥ 100 x 109/L; Hemoglobin ≥ 9.0 g/ dL; ANC ≥ 1.5 x 109/L 
(without platelet transfusion or any growth factors within previous 7 days of the 
hematologic laboratory values obtained at screening visit).  Patients in the Group 3 
lymphoma expansion may be enrolled with an ANC of ≥ 1.0 x 109/L; 
Platelets ≥75 x 109/L.
b. Hepatic: Aspartate transaminase (AST) / Alanine transaminase (ALT) ≤2.5 x upper limit of 
normal (ULN) (if liver metastases are present, ≤5 x ULN); Total or conjugated bilirubin 
≤1.5 x ULN
c.
Renal: Serum Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥60 ml/min as 
calculated by the Cockroft-Gault method
9) Coagulation: International Normalized Ratio (INR) ≤ 1.2 
10) Negative serum pregnancy test for female subjects (Appendix 7)
11) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 7.
12) Females who are nursing must agree to discontinue nursing before the first dose of GS-5829
13) Able and willing to provide written informed consent to participate in the study
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) History or evidence of clinically significant disorder, condition, or disease that, in the opinion
of the Investigator or Medical Monitor would pose a risk to subject safety or interfere with the
study evaluations, procedures, or completion
2) Pregnant 
3) Known brain metastasis or leptomeningeal disease


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4) 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
5) Myocardial infarction, symptomatic congestive heart failure (New York Heart Association
Classification > Class II), unstable angina, or serious uncontrolled cardiac arrhythmia within
the last 6 months of study Day 1
6) Major surgery, defined as any surgical procedure that involves general anesthesia and a 
significant incision (ie, larger than what is required for placement of central venous access, 
percutaneous feeding tube, or biopsy) within 28 days of first dose of study drug
7) Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of GS-5829, including any unresolved nausea, vomiting, or diarrhea that is 
Common Terminology Criteria for Adverse Events (CTCAE) Grade >1
8) Minor surgical procedure(s) within 7 days of enrollment or randomization, or not yet 
recovered from prior minor surgery (placement of central venous access device, fine needle 
aspiration, or endoscopic biliary stent ≥ 1 day before enrollment or randomization is 
acceptable)
9) Anti-tumor therapy (chemotherapy, antibody therapy, molecular targeted therapy) within
21 days or 5 half-lives, whichever is longer, of study drug dosing (6 weeks for nitrosoureas,
mitomycin C, or molecular agents with t½ > 10 days); concurrent use of hormone therapy for 
prostate cancer is permitted, and concurrent use of exemestane or fulvestrant (and goserelin 
for pre/perimenopausal breast cancer as per inclusion criteria 2.c.iv) for subjects enrolled in 
Group 2 (advanced breast cancer) is permitted
10) History of long QT syndrome or whose corrected QT interval (QTc) measured 
(Fridericia method) at screening is prolonged (> 450 ms for males and > 470 ms for females). 
Subjects who screen-fail due to this criterion are not eligible to be re-screened
11) Prior exposure to BET inhibitors
12) Clinically significant bleeding within 28 days of study Day 1
13) Known human immunodeficiency virus (HIV) infection
14) HBsAg positive
15) HCV antibody positive
16) Use of strong/moderate CYP3A4 inhibitors or strong/moderate CYP3A4 inducers within 
2 weeks prior to the first dose of study drug
17) Evidence of bleeding diatheses


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18) History of hemoptysis of ≥ 2.5 mL/1 teaspoon within 6 months of study Day 1
19) History of high grade esophageal or gastric varices
20) No active anticoagulation within 7 days of study Day 1; including acetylsalicylic acid, 
low molecular weight heparin, or warfarin.


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Enrollment
It is the responsibility of the Investigator to ensure that subjects are eligible for the study prior to 
enrollment. Subjects will be assigned a unique screening number at the time of consent.
Once eligibility is confirmed subjects will be assigned a unique subject number. 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. Once a subject number is assigned to a subject, it will not be reassigned 
to another subject.
Sites in France will be limited to Group 3 enrollment only.
5.2.
Description and Handling of GS-5829, Exemestane and Fulvestrant
5.2.1.
Formulation
GS-5829 will be supplied as gray, plain-faced, film-coated, round tablets containing either 
0.2, 1, or 10 mg GS-5829 (0.24, 1.22 or 12.20 mg GS-5829-02, phosphate salt form of GS-5829, 
respectively). Also, GS-5829 will be supplied as orange, plain-faced, film-coated, round tablets 
containing 5 mg GS-5829 (6.10 mg GS-5829-02, phosphate salt form of GS-5829). In addition to 
the active ingredient, 0.2 mg, 1 mg, and 10 mg tablets contain the following commonly used 
excipients: microcrystalline cellulose, lactose monohydrate, crospovidone, magnesium stearate, 
polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide black. In addition 
to the active ingredient, 5 mg 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. 
Exemestane and fulvestrant are commercially sourced. Information regarding the formulation 
can be found in the current prescribing information. 
5.2.2.
Packaging and Labeling
GS-5829 tablets (0.2, 1, 5, and 10 mg) are packaged 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.
GS-5829 bottles 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.
Sufficient quantities of GS-5829 tablets will be shipped to the investigator or qualified designee 
from Gilead Sciences Clinical Supplies Management (or its designee).


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Exemestane and fulvestrant will 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. The study center will be required to maintain a 
log of daily temperature readings in the storage area for the duration of the study. To ensure the 
stability and proper identification, the drug product should not be stored in a container other than 
the container in which they were supplied. Consideration should be given to handling, 
preparation, and disposal through measures that minimize drug contact with the body. 
Appropriate precautions should be followed to avoid direct eye contact or exposure through 
inhalation when handling GS-5829 tablets.
Exemestane and fulvestrant are commercially sourced. Information regarding the storage 
condition can be found in the current prescribing information.
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. The first
3 cohorts of subjects will take a single dose of GS-5829 and then approximately 7 days later take 
their dose of study drug at approximately 24-hour intervals. Subjects in dose levels 4-8 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.
At one or more dose levels, GS-5829 dose will be administered in fed state with a standardized 
meal (~500 to 600 calories and ~30% of calories from fat) on Day 1 of Cycle 2.
If the subject misses a dose, he/she should be instructed to take the study drug as soon as he/she 
remembers, unless more than 8 hours has elapsed since the scheduled time of the missed dose. In 
this case, the subject should be instructed to wait and take the next dose at the regularly 
scheduled time. Subjects should not take more than 1 dose of study drug at a time.
If a subject vomits within 5 minutes of dosing and the tablet is visible, the subject should be 
instructed to re-dose.  If a subject vomits more than 5 minutes after dosing or if the tablet is not 
visible, the subject should be instructed to wait and take the next dose at the regularly scheduled 
time.


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Aromasin® (exemestane) will be supplied as 25 mg tablets for oral administration.  Subjects 
assigned to receive exemestane in combination with GS-5829 in the study will self-administer 
exemestane orally once daily, beginning on or before Cycle 1 Day 1 of the study and thereafter at 
approximately the same time each day until the end of treatment.  Refer to Appendix 9 for 
further details.
Faslodex® (fulvestrant) is supplied as 50 mg/mL for intramuscular administration.  Subjects 
assigned to receive fulvestrant in combination with GS-5829 in this study will receive fulvestrant 
on Cycle 1 Day 1 and every 28 days (+/- 3 days) until the end of treatment. For subjects initiating 
fulvestrant on this study, a single additional dose of fulvestrant 500 mg should be administered 
on Cycle 1 Day 15 (+/- 3 days).  Fulvestrant should be administered intramuscularly into the 
buttocks slowly (1 – 2 minutes per injection) as two 5mL injections, one in each buttock.  Refer 
to Appendix 10 for further details.
5.4.
Prior and Concomitant Medications
In vitro data indicate GS-5829 is a substrate of CYP3A4. Co-administration of CYP3A4 
inhibitors may increase GS-5829 exposure. As such, co-administration of moderate and strong 
CYP3A4 inhibitors with study drug is prohibited in this study. Co-administration of CYP3A4 
inducers may decrease GS-5829 exposure. As such, moderate and potent CYP3A4 inducers are 
prohibited while subject is on study drug and within 2 weeks prior to study drug administration. 
Examples of moderate and strong CYP3A4 inhibitors and inducers are provided in the table 
below.
Table 5-1.
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 
(eg, warfarin), low molecular weight heparin, Factor Xa inhibitors, thrombin inhibitors and 
acetylsalicylic acid. If anticoagulation therapy needs to be initiated while on study treatment, the 
Investigator should consult with the Medical Monitor to determine if study treatment should be 
discontinued.
5.5.
Accountability for GS-5829
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. This includes acknowledgement of receipt of each shipment of study drug (quantity and 
condition). All used and unused study drug dispensed to subjects must be returned to the site.


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GS-5829 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, and the quantity of study drug 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 Return or Disposal
Study drug should be retrieved from each subject at the end of each dispensing interval. 
The quantity of study drug and the date returned by the subject should be recorded in the study 
drug accountability records. All study drug returned by the subject should be retained for review 
by the study site monitor prior to destruction.
Please see Section 9.1.7 for more information.


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6. 
STUDY PROCEDURES 
Final 
Amendment6 
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular fonn in Appendix 2 and described in the text below. 
The investigator must doclllllent 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 laborato1y variables, physical examinations, vital signs, and special safety assessment 
like ECGs. 
From the time of obtaining info1med 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 repo1i fonn (eCRF). 
All other untoward medical occunences observed during the Screening period, including 
exacerbation or changes in medical histo1y are to be captured on the medical histo1y eCRF. 
See Section 7 for additional details. 
6.1. 
Study Procedure Descriptions 
During the treatment period, all visits may be performed within the specified window for that 
study visit (see Appendix 2). A subject is considered enrolled into the study once enrollment in 
the IxRS system is completed. 
6.1.1. 
Informed Consent 
Subjects who screen fail must re-sign the info1med consent, if any screening procedures will be 
perfo1med outside of the 28-day screening window from the time of the first info1med consent. 
6.1.2. 
Medical & Medication History 
A complete medical histo1y will be obtained by the Investigator or designee. Medical histo1y will 
include infonnation on the subject's significant past medical events (eg, prior hospitalizations or 
surgeries), a review of the disease under study, prior anti-cancer therapies, and any concunent 
illnesses. 
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6.1.3.
Physical Examination
The Investigator or qualified designee will perform a physical examination at Screening and 
timepoints outlined in the Study Procedures Tables (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 which represent a clinically significant deterioration will be 
documented on the AE page of the eCRF.
Weight (without shoes) should be measured with each physical examination.
Height (without shoes) should be measured at Screening only.
6.1.4.
Vital Signs
Vital signs, including blood pressure, respiratory rate, pulse, and temperature will be measured at 
the time points listed in the Study Procedures Tables in Appendix 2. All measurements will be 
recorded on the appropriate eCRF page with appropriate source documentation. Any abnormal 
measurements may be repeated and reported as AEs if appropriate.  All measures of blood 
pressure will be performed using standard sphygmomanometry.  Measurements of blood 
pressure should be taken per institutional guidelines. 
6.1.5.
Electrocardiogram Assessment
Triplicate 12-lead ECGs reporting ventricular rate, PR, QRS, QT, and QTc intervals will be 
obtained at the timepoints outlined in the Study Procedures Tables (Appendix 2) and transferred 
to a central vendor for storage.  ECGs should always be collected prior to PK (or any other blood 
draw) if they are to be collected at the same nominal timepoint. 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 timepoint.
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.
6.1.6.
Echocardiogram
Echocardiograms will be performed at the timepoints listed in the Study Procedures Tables 
(Appendix 2).  
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. 
6.1.7.
ECOG Performance Status
The Eastern Cooperative Oncology Group (ECOG) Performance Status will be performed at the 
timepoints listed in the Study Procedures Tables (Appendix 2).  ECOG will be scored using the 
scale index in Appendix 8.


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6.1.8.
Prior and Concomitant Medications
At Screening, all medication taken up to 30 days prior to the screening visit will be recorded on 
the eCRF.  At each study visit, the site will capture any and all medications taken by the subject 
since the last visit or during the visit (as applicable). Concomitant medications include 
prescription and non-prescription medications, pre-infusion medications (eg, anti-emetics), and 
vitamins and minerals.
In addition, supportive therapies given during the course of the study (eg, blood transfusion, 
growth factor) should be collected and recorded on the eCRF. 
6.1.9.
Adverse Events
Subjects will be assessed for adverse events (AEs) per guidelines in the National Cancer Institute 
(NCI) CTCAE (version 4.03) at the timepoints outlined in the Study Procedures Tables 
(Appendix 2). Any AEs reported after informed consent is obtained and throughout the study 
will be recorded on the eCRF with appropriate source documentation.  The site will contact the 
study subject by phone approximately 30 days after the last dose of study drug to assess AEs.  
Please refer to Appendix 6 for CTCAE grading criteria.
Please refer to Section 7 for additional information on AE reporting.
6.1.10.
CT or MRI
CT scans will be obtained to document metastatic disease, identify target lesions as described in 
RECIST (version 1.1), and to assess response and disease progression. Patients with lymphoma 
will be assessed by Cheson Criteria (Appendix 5). Patients with Prostate Cancer will be assessed 
by radionuclide bone scan and CT scan (or MRI) of the chest, abdomen and pelvis.  Response 
and disease progression for patients with prostate cancer will be assessed based on PCWG
criteria (Appendix 4). In subjects who cannot tolerate iodinated contrast, a CT of the lung 
without contrast and MRI of the abdomen should be performed.  Imaging by CT scan 
(with contrast) or MRI or applicable scan will be performed at Screening (within 8 weeks before 
Day 1 if the scan was performed as part of standard medical practice) and at the timepoints 
outlined in the Study Procedures Tables (Appendix 2).  Please refer to Appendix 3-Appendix 5
for additional information on RECIST (version 1.1), Cheson Criteria and PCWG2 Criteria.
The same radiographic procedure and specification (eg, the same contrast agent, slice thickness, 
etc.) used to define measurable lesions must be used throughout the study for each subject. Any 
subject with symptoms suggestive of disease progression should be evaluated for tumor response 
at the time the symptoms occur. Tumor burden will be characterized at Baseline and subsequent 
response assessments will be carried out according to the RECIST (version 1.1) criteria (solid 
tumors), Cheson Criteria (lymphoma) and PCWG Criteria (prostate).
For subjects in whom a radiologic CR is determined, a bone marrow biopsy may be required for 
complete assessment. In a subject who has a baseline bone marrow involvement with lymphoma 
or does not have a baseline bone marrow examination, declaration of an on-study CR requires 
bone marrow biopsy documentation of the absence of bone marrow lymphoma. In a subject who 


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has a baseline bone marrow biopsy showing no evidence of lymphoma, declaration of an 
on-study CR does not require bone marrow examination as long as other criteria for CR are met. 
The bone marrow biopsy will be performed at the local lab.
6.1.11.
Bone Scans (Group 2) Only
Subjects in Group 2 (breast cancer) will undergo radionuclide bone scan at Screening, as 
clinically indicated or to confirm complete response during the treatment period and at the end of 
treatment for sites of disease identified at Screening (unless disease progression has been 
confirmed elsewhere). 
Group 2 Tumor Assessment Requirements:
Method
Screening
Treatment Period
End of Treatment Visit
CT or MRI of chest, 
abdomen, and pelvis
Required
Required
Required if not done within 4 weeks
CT or MRI of any other 
site of disease, as 
clinically indicated
Required
Required for sites of 
disease identified at 
screening
Required if not done within 4 weeks. 
Required for sites of disease identified 
at screening, unless disease progression 
has been confirmed elsewhere
Radionuclide bone scan 
(whole body) and 
confirmatory imaging in 
case of any hots spots 
(CT, MRI, or X-ray)
Required
As clinically indicated or 
to confirm complete 
response
Required if not done within 4 weeks.
Required for sites of disease identified 
at screening, unless disease progression 
has been confirmed elsewhere
Photographs of all 
superficial lesions as 
applicable
Required
Required for sites of 
disease identified at 
screening
Required if not done within 4 weeks.
Required for sites of disease identified 
at screening, unless disease progression 
has been confirmed elsewhere
6.1.12.
PET/CT Scan
Subjects who are enrolled in Group 3 (DLBCL or PTCL) will undergo a positron emission 
tomography (PET) and CT scan at Screening and at Week 16 to evaluate response, unless the 
subject has demonstrated disease progression prior to this date.  
6.1.13.
Blood and Urine Samples
Blood and urine for laboratory safety tests will be collected according to the Study Procedures 
Tables (Appendix 2). The date and time of blood and urine collection will be recorded in the 
subject’s source documentation. The date and time of previous GS-5829 dose will be recorded in 
the subject’s source documentation on days where PK is collected. The tests will be analyzed 
using standard procedures. White blood cell (WBC) differentials will be reported as absolute 
counts. All laboratory tests must be reviewed for clinical significance by the Investigator or 
qualified designee.  Eligibility will be based on central laboratory assessments and will be 
collected within 7 days of Study Day 1 / C1D1.


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Day 1 pre-dose samples may be drawn up to 2 days prior to the Day 1 visit.
The analytes listed in Table 6-1 will be tested.
Table 6-1.
Blood and Urine Samples Collected During the Course of the Study
Serum Chemistry
Hematology
Other
Sodium
Potassium
Chloride
Glucose
BUN
Creatinine
ALT
AST
Alkaline phosphatase
Total bilirubina
Total protein
Albumin
Calcium
Magnesium
Phosphate
Lactate dehydrogenase
AAG
White Blood Cell (WBC) Count
Hemoglobin
Hematocrit
Platelet Count
Neutrophils (ANC)
Lymphocytes
Monocytes
Basophils
Eosinophils
GS-5829 concentration
Serum and Plasma 
Hepatitis B surface 
antigen (HBsAg)
Hepatitis C (HCV) 
antibody
25-hydroxyvitamin D
Coagulation
PT/INR
aPTT
Platelet Activationb
Pregnancy Testing
Urine
Serum Qualitative -human chorionic 
gonadotropin (hCG) (females)
Urine Pregnancy (females)
Urinalysis
a
Includes direct bilirubin
b
platelet activation testing to be performed at specified sites
6.1.14.
Pregnancy Test for Females of Childbearing Potential
All female subjects of childbearing potential (as defined in Appendix 7) will have a serum 
pregnancy test at Screening and a urine pregnancy test prior to Day 1 dosing, every 28 days 
thereafter, and at the EOT visit. The results must be confirmed as negative prior to continued 
administration of study drug.
6.2.
Vitamin D Assessment for Patients in Group 2
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
CCI-


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6.2.1. 
Pharmacokinetic Samples 
Final 
Amendment6 
Plasma samples for GS-5829 PK will be collected(± 10 minutes) in coho1is 1-3 of Group 1 on 
Study Day 1 at pre-dose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose and in coho1is 4-8 
of Group 1 and all coho1is of Group 2 on Cycle 1 Day 1 at pre-dose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 
12, and 24 hours post-dose. Additional samples will be collected at 48 and 72 hours post-dose in 
dose levels 1 - 3 of Group 1 relative to first dose of GS-5829. Plasma samples for GS-5829 PK 
will be collected in all coho1is (Group 1 and Group 2) at pre-dose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, 
and 24 hours post-dose relative to GS-5829 administration on Cycle 1 Day 8. Sparse PK samples 
will be collected in all coho1is (Group 1 and Group 2) at trough (20-26 hours post-dose) on 
Cycle 1 Day 4, 2 - 4 hours post-dose on Cycle 1 Day 15, and anytime post-dose on Day 1 of 
Cycles 2 through 6. 
At one or more dose levels, PK samples will be collected on Day 1 of Cycle 2 at pre-dose (0 hr) 
and 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post-dose. GS-5829 dose will be administered in fed state 
on Day 1 of Cycle 2. 
Urine will be collected for GS-5829 PK in Group 1 cohorts 1-3 on Study Day 1 and in Group 1 
coho1is 4-8 on Cycle 1 Day 1 at pre-dose, 0-6 hours, 6-12 hours, and 12-24 hours post-dose 
relative to first dose of GS-5829. 
Subjects in the Group 3 lymphoma expansion will have PK drawn at pre-dose, 1, 2, 4, 6, and 
24 hours post-dose on Cycle 1, Day 8. PK samples will also be drawn at pre-dose on Day 1 of 
Cycles 2, 4, and 6. 
Plasma and urine concentrations of GS-5829 will be detennined and PK evaluated. Plasma and 
urine concentrations of GS-5829 metabolite(s) maybe detennined and PK explored. Unbound 
concentrations of GS-5829 and/or metabolites may be detennined. Plasma concentrations of 
fulvestrant, exemestane, or metabolites may be detennined and PK explored. 
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6.3.4. 
Unscheduled Procedures 
Final 
Amendment6 
Unscheduled procedures, including, but not limited to, vital signs, 12-lead ECG, and CT or MRI, 
will be recorded on the applicable eCRFs. 
6.4. 
6.4.1. 
Post-treatment Assessments 
Post-Study Phone Call 
Subjects will be contacted by phone 30 days(± 7 days) after the last dose of GS-5829 to assess 
for AEs. For subjects who come off study for reasons other than disease progression, the site 
should also obtain infonnation post-study anti-cancer therapies, surgeries, and date of definitive 
disease progression (if known). 
6.5. 
Criteria for Discontinuation of Study Treatment 
See Sections 3.4 and 3.5 for discontinuation criteria. 
6.6. 
Replacement of Subjects 
If a subject is withdrawn from the study for any reason other than a DL T 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. 
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6.7.
Dose Interruption and Reduction
The following are the guidelines for dose interruption and/or reduction.  If an AE is attributed to 
study drug, the investigator’s discretion will be used to determine if the drug not attributed to the 
AE will be withheld based on the investigator’s assessment of risk-benefit of withholding the 
study drug.
6.7.1.
GS-5829
For subjects without lymphoma, if at any time in the study a subject experiences a toxicity 
consistent with a Grade 4 DLT (see Section 3.2 for the definition of a DLT), GS-5829 treatment 
will be discontinued permanently, with the exception of Grade 4 neutropenia or 
thrombocytopenia. If a subject experiences Grade 4 neutropenia or thrombocytopenia or any 
other < Grade 4 toxicity consistent with a DLT (per 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.  
For subjects with lymphoma, if the toxicity is neutropenia or thrombocytopenia consistent with 
the definition of a DLT, the dose may be resumed at either one lower dose level, or the same 
dose with an alternative dosing schedule, which decreases the total amount of GS-5829 
administered over a 28 day period to at least 25% less than the previous cohort (eg 14 days on 
and 7 days off). If the subject experiences a recurrence of a non-hematologic toxicity meeting 
criteria for DLT after restarting study drug at a lower dose or if the toxicity does not resolve 
within 28 days, treatment with GS-5829 will be discontinued.  For subjects with lymphoma, if 
the recurrent toxicity is hematologic a second dose decrease is allowed (lowest dose allowed 
1.0 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% after discussion with the 
Gilead Medical Monitor.


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Table 6-2.
Dose Reduction of GS-5829
NCI CTCAE Grade
Recommendation
Group 1 and 2: Non-lymphoma 
GS-5829
Group 3: Lymphoma 
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 ≤1. If the 
toxicity resolves to ≤1 within 28 days, 
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
Hold dosing with GS-5829 until the 
toxicity is resolved to ≤1. If the toxicity 
resolves to ≤1 within 4 days, the subject 
may resume dosing of GS-5829 at the 
same dose or a dose lower. 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. GCSF 
is allowed during dose interruption, but is 
not to be administered on the same day as 
GS-5829
Thrombocytopenia
Grade ≤ 2 
Thrombocytopenia
Maintain current dose level and schedule.
Grade 3 Thombocytopenia 
Hold dosing with GS-5829 until the 
toxicity is resolved to ≤1. If the 
toxicity resolves to ≤1 within 28 days, 
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
Hold dosing with GS-5829 until the 
toxicity is resolved to ≤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.
If the toxicity takes > 7 days to resolve to 
≤ Grade 1, then the drug must be resumed 
at a lower dose or 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 ≤1. If the 
toxicity resolves to ≤1 within 28 days, 
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.
If it takes > 28 days, then GS-5829 will 
be permanently discontinued
Hold dosing with GS-5829 until the 
toxicity is resolved to ≤1 at which time
the subject may either resume at a dose 
with is 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.


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NCI CTCAE Grade
Recommendation
Group 1 and 2: Non-lymphoma 
GS-5829
Group 3: Lymphoma 
GS-5829 
NON-HEMATOLOGICAL ADVERSE EVENTS
Hepatic Adverse Events (elevations in ALT, AST or bilirubin)
Grade 1
(ALT/AST ≤ 3xULN)
(Bilirubin ≤ 1.5xULN)
Maintain current dose level and schedule.
Grade 2
(ALT/AST > 3-5xULN)
(Bilirubin>1.5 -≤ 3xULN)
Maintain current dose level and schedule. Monitor ALT, AST, ALP, and bilirubin at 
least 1x per week.
Grade 3 
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 and or by a 
change in schedule which decreases total GS-5829 administered over a 28 day 
dosing period
Grade 4
Permanently discontinue GS-5829
If the subject was not receiving GS-5829 at the time disease progression was documented 
(eg, due to reversible toxicity), after discussion with the Gilead Sciences Medical Monitor, 
GS-5829 may be re-started if the criteria for resuming treatment as described in Section 6.7.1 are 
met and the Investigator feels it is in the subject’s best interest to do so.


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


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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.
Clarification of Serious Adverse Events

Death is an outcome of an AE, and not an AE in itself

An SAE may occur even if the subject was not on study drug at the time of occurrence of the 
event. Dosing may have been given as treatment cycles or interrupted temporarily before the 
onset of the SAE

“Life-threatening” means that the subject was at immediate risk of death from the event as it 
occurred. This does not include an event that might have led to death if it had occurred with 
greater severity

Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is a SAE

“In-patient hospitalization” means the subject is formally admitted to a hospital for medical 
reasons, for any length of time. This may or may not be overnight. It does not include 
presentation and care within an emergency department

The investigator should attempt to establish a diagnosis of the event on the basis of signs, 
symptoms and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE and/or SAE and not the individual signs/symptoms
7.1.3.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, ECG, x-rays, vital signs) that are associated with 


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signs and/or symptoms must be recorded as an AE or SAE if they meet the definition of an AE 
or SAE as described in Sections 7.1.1 and 7.1.2. If the laboratory abnormality is part of a 
syndrome, record the syndrome or diagnosis (eg, anemia), not the laboratory result (ie, decreased 
hemoglobin).
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to study 
drug therapy using clinical judgment and the following considerations:

No: Evidence exists that the AE has an etiology other than the study drug. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the study drug.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting. 
The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The AE occurred as a result of protocol procedures, (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity of AEs will be graded using the CTCAE, Version 4.03 (Appendix 6). For each 
episode, the highest severity grade attained should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives: 
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or 
Grade 5 (fatal) to describe the maximum intensity of the AE. For purposes of consistency with 
the CTCAE, these intensity grades are defined in Table 7-1.


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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 1 of the 
criteria for serious events listed in Section 7.1.2.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead 
7.3.1.
Requirements for Collection Prior to Study Drug Initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the eCRF: all SAEs and AEs related to protocol-mandated procedures.
7.3.2.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 30 days after last administration of study drug must be reported to the eCRF database as 
instructed.
All AEs should be followed up until resolution or until the AE is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow up 
period.
7.3.3.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported in the 
eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed.


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Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study diug, regardless of causality, should also be repo1ied. 
Investigators are not obligated to actively seek SAEs after the 30-day period However, if the 
investigator learns of any SAEs that occur after study paiiicipation has concluded and the event 
is deemed relevant to the use of study diug, he/she should promptly document and repo1i the 
event to Gilead DSPH. 
All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
7.3.4. 
Electronic Serious Adverse Event ( eSAE) Reporting Process 
• 
Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
infonnation 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 infonnation electr·onically, ie, the eCRF 
database is not functioning, record the SAE on the paper SAE reporting fo1m and submit 
within 24 hours of the investigator's knowledge of the event to: 
Gilead DSPH: 
• 
As soon as it is possible to do so, any SAE reported via paper must be tr·anscribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been repo1ied via a paper fonn because the eCRF database has been locked, no 
fuither action is necessaiy. 
• 
All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline. 
• 
For fatal or life-threatening events, copies of hospital case repo1is, autopsy repo1is, and other 
documents ai·e also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the tr·aceability of a document to the subject identifiers. 
• 
Additional infonnation may be requested to ensure the timely completion of accurate safety 
repo1is. 
• 
Any medications necessaiy for tr·eatinent of the SAE must be recorded onto the concomitant 
medication section of the subject's eCRF and the event description section of the SAE fonn 
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7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, SADRs, or suspected unexpected serious 
adverse reactions (SUSARs). In accordance with the EU Clinical Trials Directive (2001/20/EC), 
Gilead or a specified designee will notify worldwide regulatory agencies and the relevant IEC in 
concerned Member States of applicable SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the investigator’s brochure or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports associated 
with any study drug. The investigator should notify the IRB or IEC of SUSAR reports as soon as 
is practical, where this is required by local regulatory agencies, and in accordance with the local 
institutional policy. 
7.4.1.
Reporting of Adverse Events Relating to the Primary Endpoint and Other 
Anticipated Medical Events in the Study Population
Given the endpoints of the study, in order to maintain the integrity of the study, the following 
events that are assessed as unrelated to study drug will not be considered SAEs:

Progression of disease

Death related to progression of disease
Disease progression and death from disease progression should be reported as SAEs by the 
investigator only if it is assessed that the study drug caused or contributed to the disease 
progression (ie, by a means other than lack of effect). Unrelated disease progression should be 
captured on the eCRF.
7.5.
Toxicity Management 
Treatment-emergent toxicities will be noted by the Investigator and brought to the attention of 
the Gilead Sciences Medical Monitor or designee. Whether or not considered treatment-related, 
all subjects experiencing AEs must be monitored periodically until symptoms subside, any 
abnormal laboratory values have resolved or returned to baseline levels or they are considered 
irreversible, or until there is a satisfactory explanation for the changes observed.
Grade 3 or 4 clinically significant laboratory abnormalities should be confirmed by repeat testing 
as soon as practical to do so, and preferably within 3 calendar days after receipt of the original 
test results. Any questions regarding toxicity management should be directed to the 
Gilead Sciences Medical Monitor or designee.


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


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Any premature termination of pregnancy ( eg, a spontaneous abo1iion, an induced therapeutic 
abo1i ion due to complications or other medical reasons) must be repo1ied within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE te1m. 
A spontaneous abo1i ion is always considered to be an SAE and will be repo1ied as such. 
Furthe1more, any SAE occun ing 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 repo1ied to Gilead DSPH using the pregnancy outcome repo1i 
f01m. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead DSPH. 
Pregnancies of female paiiners of male study subjects exposed to Gilead or other study diugs 
must also be repo1i ed and relevant info1mation should be submitted to or Gilead DSPH using the 
pregnancy and pregnancy outcome fo1ms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead DSPH. 
Gilead DSPH: 
Fax:IPIPD 
Email: IPD 
Refer to Appendix 7 for Pregnancy Precautions, Definition for Female of Childbeai·ing Potential, 
and Contraceptive Requirements. 
7.6.2.2. 
Repo1i ing Other Special Situations 
All other special situation repo1i s must be repo1i ed on the special situations repo1i fonn and 
fo1wai·ded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These repo1is must consist of situations that involve study diug and/or Gilead conc01nitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead conc01nitant medications does not need to be repo1i ed on 
the special situations repo1i f01m; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be repo1i ed on the AE fonn. 
Any inappropriate use of conc01nitant medications prohibited by this protocol should not be 
repo1i ed as "inisuse," but may be more appropriately documented as a protocol deviation. 
Refer to the eCRF completion guidelines for full instructions on the mechanism of special 
situations repo1i ing. 
All clinical sequelae in relation to these special situation repo1i s will be repo1ied as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE repo1i fonn. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available. 
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8. 
8.1. 
8.1.1. 
STATISTICAL CONSIDERATIONS 
Analysis Objectives and Endpoints 
Analysis Objectives 
The prima1y objectives of this study are: 
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• 
Characterize the safety and tolerability of GS-5829 as a monotherapy in subjects with 
advanced solid tumors and lymphomas 
• 
Detennine the MTD or RDP2 of GS-5829 as a monotherapy in subjects with advanced stage 
solid tumors and lymphomas 
• 
Characterize the safety and tolerability of GS-5829 in combination with exemestane or 
fulvestrant in subjects with advanced estrogen receptor positive breast cancer 
• 
Detennine MID or RDP2 of GS-5829 in combination with exemestane or fulvestrant in 
subjects with advanced estrogen receptor positive breast cancer 
8.1.2. 
Primary Endpoint 
The prima1y endpoint of this study is incidence of DLT as defined in Section 3.2. 
8.1.3. 
Secondary Endpoint 
Secondary endpoints of this study are: 
• 
PK parameters (Cmax, Ctau, AUC1ast, AUCtau, Tmax, and t½) for GS-5829. 
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8.2. 
8.2.1. 
8.2.1.1. 
Analysis Conventions 
Analysis Sets 
Full Analysis Set (FAS) 
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The FAS includes all subjects who receive::::: 1 dose of study drng (GS-5829, exemestane or 
fulvestrant). This analysis set will be used for subject characteristics and efficacy endpoints. 
8.2.1.2. 
Safety Analysis Set 
The Safety Analysis Set for this study will be the same as FAS since this study is a 
non-randomized study. This analysis set will be used for safety endpoints, study treatment 
administration and post-study therapy. 
8.2.1.3. 
DLT-Evaluable Analysis Set 
The DLT-Evaluable Analysis Set includes all subjects in the Safety Analysis Set who complete 
all treatment and safety procedures through Day 29, or experienced a DLT prior to Day 29. 
Detennination of the MID will be in DLT-Evaluable Analysis Set. 
8.2.1.4. 
Phaimacodynamic and Pha1macokinetic Analysis Sets 
The-
PK Analysis Sets consist of all subjects in the FAS who have the necessaiy baseline 
and on-study measurements to provide interpretable results for the specific parameters of 
interest. 
8.3. 
Data Handling Conventions 
By-subject listings will be created for impo1iant variables from each eCRF module. 
Summaiy tables for continuous vai·iables will contain the following statistics: N (nmnber in 
population), n (nmnber with data), mean, standai·d deviation (StD), 90% confidence intervals 
(Cls) on the mean, median, minimmn, and maximum. Summa1y tables for categorical vai·iables 
will include: N, n, percentage, and 90% Cls on the percentage. Unless othe1w ise indicated, 90% 
Cls for binaiy vai·iables will be calculated using the binomial distribution ( exact method) and 
will be 2-sided. Data will be described and sUilllllarized by relevant study group, dose level, 
analysis set, and time point. As appropriate, changes from baseline to each subsequent time point 
will be described and sUilllllai·ized by study group and dose level. Similarly, as appropriate, the 
best change from baseline during the study will also be described and summarized by study 
group and dose level. Graphical techniques (eg, waterfall plots, Kaplan-Meier curves, line plots) 
may be used when such methods ai·e appropriate and info1mative. 
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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 study group 
and dose level for the Safety Analysis Set.
8.5.
Efficacy Analysis
ORR and PFS will be listed only.
8.6.
Safety Analysis
All safety data collected on or after the date that study drug (GS-5829, exemestane or 
fulvestrant) was first dispensed up to the date of last dose of study drug plus 30 days will be 
summarized by study group and dose level. Data for the pretreatment will be included in data 
listings.
8.6.1.
Extent of Exposure
Descriptive information will be provided by study group and dose level regarding the number of 
doses of study drug prescribed (GS-5829, exemestane or fulvestrant), the total number of doses 
taken, the percent of expected doses taken, the number of days of study drug, and the number 
and timing of prescribed dose modification and interruptions.
GS-5829 compliance will be described by study group and dose level in terms of the proportion 
of study drug actually taken based on returned pill count relative to the amount that was 
dispensed (taking into account physician-prescribed modification and interruptions).
8.6.2.
Adverse Events
All AEs will be listed. The focus of AE summarization will be on treatment-emergent AEs. 
A treatment-emergent AE is defined as an AE that occurs or worsens in the period from the 
first dose of study drug (GS-5829, exemestane or fulvestrant) to 30 days after the last dose of 
study drug.
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
http://www.meddramsso.com) with descriptions by System Organ Class (SOC), High-Level 
Group Term, High-Level Term, Preferred Term, and Lower-Level Term. The severity of AEs 
will be graded by the investigator according to the CTCAE, Version 4.03, whenever possible. If 
a CTCAE criterion does not exist for a specific type of AE, the grade corresponding to the 
appropriate adjective will be used by the investigator to describe the maximum intensity of the 
AE: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life threatening), 
or Grade 5 (fatal). The relationship of the AE to the IP will be categorized as related or unrelated.


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TEAEs will be summarized by dose level. Summary tables will be presented to show the number 
of subjects reporting treatment-emergent AEs by severity grade and corresponding percentages. 
A subject who reports multiple treatment-emergent AEs within the same Preferred Term 
(or SOC) is counted only once for that Preferred Term (or SOC) using the worst severity grade. 
AE descriptions will be presented by decreasing frequency for a given SOC and Preferred Term. 
Separate listings and summaries will be prepared for the following types of treatment emergent 
AEs:

Study-drug-related (GS-5829, exemestane or fulvestrant) AEs

AEs that are Grade ≥ 3 in severity

AEs leading to study drug (GS-5829, exemestane or fulvestrant) interruption and/or dose 
modification

AEs leading to study drug (GS-5829, exemestane or fulvestrant) discontinuation

SAEs
8.6.3.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed data. 
The focus of laboratory data summarization will be on treatment-emergent laboratory 
abnormalities. A treatment-emergent laboratory abnormality is defined as an abnormality that, 
compared to baseline, worsens by ≥ 1 grade in the period from the first dose of study drug 
(GS-5829, exemestane or fulvestrant) to 30 days after the last dose of study drug. If baseline data 
are missing, then any graded abnormality (ie, an abnormality that is Grade ≥1 in severity) will 
be considered treatment emergent.
Hematological, serum biochemistry, and urine data will be programmatically graded according 
to CTCAE severity grade, when applicable. For parameters for which a CTCAE scale does not 
exist, reference ranges from the central laboratory will be used to determine programmatically if 
a laboratory parameter is below, within, or above the normal range for the subject’s age, sex, etc. 
Hematological and serum biochemistry and their changes from baseline will be summarized by 
study group, dose level, and visit. Summary tables will be presented for each relevant assay to 
show the number of subjects by CTCAE severity grade with corresponding percentages. For 
parameters for which a CTCAE scale does not exist, the frequency of subjects with values 
below, within, and above the normal ranges will be summarized. Subjects will be characterized 
only once for a given assay, based on their worst severity grade observed during a period of 
interest (eg, during the study or from baseline to a particular visit).
Shift tables for hematology and serum biochemistry will also be presented by showing change in 
CTCAE severity grade from baseline to the worst grade post-baseline. For parameters for which 
a CTCAE scale does not exist, shift tables will be presented showing change in results from 
baseline to the worst grade post baseline. Separate listings and summaries will be prepared for 
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Pharmacokinetic Analysis 
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The concentrntion data of GS-5829 will be summarized by nominal sampling time using 
descriptive statistics. PK parameters (Cmax, Ciau, AUC1ast, AUCtau, Tmax, and t½), will be listed and 
summarized using descriptive statistics ( eg, sample size, arithmetic mean, geometi·ic mean, 
coefficient of variation(%) StD, median, minimum, and maximum). Plasma concenh'ations over 
time will be plotted in semi-logarithmic and linear fonnats as mean± StD, and median (QI, Q3) 
if applicable. 
8.9. 
Sample Size 
The sample size of the study will be detennined based on the number of dose levels evaluated 
and the emerging GS-5829-related toxicities. The study will consist of up to160 subjects. 
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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), ICH guidelines, or with the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the study subject. 
These standards are consistent with the European Union Clinical Trials Directive 2001/20/EC 
and Good Clinical Practice (GCP) Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of GCP, as outlined in 
21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 1998, 
and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the 
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB. The investigator will not begin any study subject activities until 
approval from the IRB has been documented and provided as a letter to the investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB/IEC on any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial approval, with the exception of those necessary to reduce 
immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must use the most current IRB-approved consent form for documenting written 


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informed consent. Each informed consent (or assent as applicable) will be appropriately signed 
and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by local 
requirements. The consent form will inform subjects about genomic testing and sample retention, 
and their right to receive clinically relevant genomic analysis results.
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject initials, date of birth, another 
unique identifier (as allowed by local law) and an identification code will be recorded on any 
form or biological sample submitted to the Sponsor, IRB, or laboratory. Laboratory specimens 
must be labeled in such a way as to protect subject identity while allowing the results to be 
recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The investigator 
must keep a screening log showing codes, names, and addresses for all subjects screened and for 
all subjects enrolled in the trial. Subject data will be processed in accordance with all applicable 
regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, CRF/eCRF, the study drug, and any other study information, 
remain the sole and exclusive property of Gilead during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Gilead. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, and 
governmental approval with correspondence, informed consent, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender)

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria)


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
Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number)

Study discussed and date of informed consent

Dates of all visits

Documentation that protocol specific procedures were performed

Results of efficacy parameters, as required by the protocol

Start and end date (including dose regimen) of study drug, including dates of dispensing and 
return

Record of all AEs and other safety parameters (start and end date, and including causality 
and severity)

Concomitant medication (including start and end date, dose if relevant; dose changes)

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, US, Europe, or Japan) and until there are no pending or planned marketing 
applications in an ICH region; or, if no application is filed or if the application is not approved 
for such indication, until 2 years after the investigation is discontinued and regulatory authorities 
have been notified. Investigators may be required to retain documents longer if specified by 
regulatory requirements, by local regulations, or by an agreement with Gilead. The investigator 
must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. Subsequent to data entry, a study monitor will perform source data verification 


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within the EDC system. Original entries as well as any changes to data fields will be stored in the 
audit trail of the system. Prior to database lock (or any interim time points as described in the 
clinical data management plan), the investigator will use his/her log in credentials to confirm that 
the forms have been reviewed, and that the entries accurately reflect the information in the 
source documents. The eCRF capture the data required per the protocol schedule of events and 
procedures. System-generated or manual queries will be issued to the investigative site staff as 
data discrepancies are identified by the monitor or internal Gilead staff, who routinely review the 
data for completeness, correctness, and consistency. The site coordinator is responsible for 
responding to the queries in a timely manner, within the system, either by confirming the data as 
correct or updating the original entry, and providing the reason for the update (eg, data entry 
error). At the conclusion of the trial, Gilead will provide the site with a read-only archive copy of 
the data entered by that site. This archive must be stored in accordance with the records retention 
requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused study drug supplies be destroyed at sites if they have 
applicable standard operating procedure (SOP) to do so. The study monitor will evaluate each 
study center’s study drug disposal procedures and provide appropriate instruction for destruction 
of unused study drug supplies, as needed. If the site has an appropriate SOP for drug destruction 
as determined by Gilead Clinical Operations or designee (per SOP-CR-23035), the site may 
destroy used (empty or partially empty) and unused study drug supplies in accordance with that 
site’s approved SOP. A copy of the site’s approved SOP will be obtained for central files.  If the 
site does not have an acceptable SOP to destroy, or cannot due to other regulatory reasons, 
Gilead will provide instruction for the return if the study drug for disposal/destruction.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the in 
accordance with local requirements and receive documented approval before modifications can 
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9.2.2.
Study Report and Publications
A clinical study report will be prepared and provided to the regulatory agency. Gilead will ensure 
that the report meets the standards set out in the ICH Guideline for Structure and Content of 
Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in certain 
cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
The results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, eg, attendance at Investigator's Meetings.  If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical trial payments, meal, travel 
expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.


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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 e protection of the subjects’ interests.


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10.
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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. 
Koh CM, Bieberich CJ, Dang CV, Nelson WG, Yegnasubramanian S, De Marzo AM. MYC and 
Prostate Cancer. Genes & cancer 2010;1 (6):617-28.
Lin CP, Liu CR, Lee CN, Chan TS, Liu HE. Targeting c-Myc as a novel approach for 
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Lockwood WW, Zejnullahu K, Bradner JE, Varmus H. Sensitivity of human lung 
adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling 
proteins. Proc Natl Acad Sci U S A 2012;109 (47):19408-13.


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Mak V, Hamm J, Chhanabhai M, Shenkier T, Klasa R, Sehn LH, et al. Survival of patients with 
peripheral T-cell lymphoma after first relapse or progression: spectrum of disease 
and rare long-term survivors. J Clin Oncol 2013;31 (16):1970-6.
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 
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Molyneux EM, Rochford R, Griffin B, Newton R, Jackson G, Menon G, et al. Burkitt's 
lymphoma. Lancet 2012;379 (9822):1234-44.
Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma 
incidence patterns by WHO subtype in the United States, 1992-2001. Blood 
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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.
Nagle SJ, Woo K, Schuster SJ, Nasta SD, Stadtmauer E, Mick R, et al. Outcomes of patients 
with relapsed/refractory diffuse large B-cell lymphoma with progression of 
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Hematol 2013;88 (10):890-4.
Nair R, Roden DL, Teo WS, McFarland A, Junankar S, Ye S, et al. c-Myc and Her2 cooperate to 
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http://seer.cancer.gov/statfacts/html/prost.html. Accessed: 11 November 2014.
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Perry AM, Alvarado-Bernal Y, Laurini JA, Smith LM, Slack GW, Tan KL, et al. MYC and 
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
RECIST 1.1
Appendix 4.
Criteria for Progression in Castration-Resistant Prostate Cancer
Appendix 5.
Lymphoma Efficacy Assessments
Appendix 6.
Common Terminology Criteria for Adverse Events (CTCAE) v4.03
Appendix 7.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 8.
Performance Status Scoring System (ECOG)
Appendix 9.
Exemestane (Aromasin®) Prescribing Information
Appendix 10.
Fulvestrant (Faslodex®) Prescribing Information


GS-5829 
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Gilead Sciences, Inc. 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
Final 
Amendment6 
A Phase 1 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of GS-5829 as a Monotherapy in Subjects with Advanced Solid Tumors 
and Lymphomas and in Combination with Exemestane or Fulvestrant in Subjects with 
Estrogen Receptor Positive Breast Cancer 
GS-US-350-1599, Amendment 6, 20 June 2016 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
PD 
PD 
Date 
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I will provide all study _personnel under my supervision copies of the protocol and access to all 
information provided by Gilead Sciences, Inc. I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
Principa] Investigator Name (Printed) 
Signature 
Date 
Site Number 
co:NFIDENTIAL 
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Appendix 2.
Study Procedures Table
Study Phase Cycle Day
Screening 
Day 28
Study 
Day 1a
First 28 Days
Cycle 2 
Day 1 and 
Every 
2 weeks*
Cycle 2 
Day 1 
and 
Every 
4 weeks
Every 
8 weeks
EOT
30 day 
Safety 
Follow-upk
Cycle 1 
Day 1b
Day 2
Day 4
Day 8
Day 11
Day 15
Day 22
Window (day)
-28
±0
±3
±0
±0
±1
±1
±2
±3
±7
±7
±7
±7
±7
Informed Consent
X
Medical and Medication 
Historyc
X
Physical Examinationd
X
X
X
X
X
X
X
X
X
X
X
Vital Signse
X
X
X
X
X
X
X
X
X
X
X
Oxygen saturationf
X
X
X
X
X
X
X
X
X
X
X
Echocardiogramr
X
X
X
Triplicate 12-lead ECGg
X
X
X
X
X
X
Adverse events/
Concomitant medicationsh
X
X
X
X
X
X
X
X
X
X
X
X
IP Dispensing  
Xi
X
X
Exemestane or Fulvestrantw
(Group 2 only)
X
X
X
Dosing Diary Accountability 
X
X
X
X
X
X
X
X
IXRS Registration
X
X
Xj
X
X
CBC with differential
Xs
X
X
X
X
X
X
X
X
X
Chemistryy
Xs
X
X
X
X
X
X
X
X
X
Coagulationq
Xs
X
X
X
X
25-hydroxy vitamin D
(Group 2 only)
X
Urinalysis and Urine 
Chemistry
X
X
X
X
X
X


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Study Phase Cycle Day
Screening 
Day 28
Study 
Day 1a
First 28 Days
Cycle 2 
Day 1 and 
Every 
2 weeks*
Cycle 2 
Day 1 
and 
Every 
4 weeks
Every 
8 weeks
EOT
30 day 
Safety 
Follow-upk
Cycle 1 
Day 1b
Day 2
Day 4
Day 8
Day 11
Day 15
Day 22
Window (day)
-28
±0
±3
±0
±0
±1
±1
±2
±3
±7
±7
±7
±7
±7
Pregnancy Testl
X
X
Xj
X
X
GS-5829 Intensive PKm
X
X
X
Xv
GS-5829 Sparse PKm
X
X
Xv
Biopsies for Group 3
lymphoma expansionx
X
Xx
X
CT Scan w/Contrast or MRIP
X
X
XP
PET Scan (Group 3 only)z
X
Bone Scan(Group 2 only)
X
X
ECOG Performance Status
X
X
X
X
X
X
X
Treatment Response 
Assessmentt
X
X
*
Day 1 of subsequent cycles.
a
Study Day 1 is applicable to Cohorts 1-3 only of Group 1.
b
Cycle 1 Day 1 occurs on Study Day 7 for subjects in Cohorts 1-3 of Group 1 and must occur at least 5 days, but no more than 9 days after Study Day 1. For Group 1 Cohorts 4 
and higher and all cohorts of Group 2 the first day of study is Cycle 1 Day 1.
c
Medical history includes significant past medical events (eg, prior hospitalizations or surgeries), a review of the disease under study, prior anti-cancer therapies, and any 
concurrent medical illnesses.
d
Screening and End of Treatment Physical Examinations (PE) will be a complete PE. Beginning at Study Day 1 (Group 1 Cohorts 1-3) and C1D1 (all groups), a modified 
physical examination will be performed to monitor for any changes (e.g. lymph nodes, lung, cardiac, abdomen, skin, neurologic, and any systems, as clinically indicated).  
Weight (without shoes) should be measured at each PE.  Height (without shoes) should be measured at screening only.
e
Study Day 1 (Cohorts 1-3 of Group 1) and C1D1 (all groups) vital signs will be taken within 15 min pre-GS-5829 dose.  C1D1 vitals will also be collected at 2 and 4 hours 
post dose (+/- 15 min); vital signs will be taken pre-dose only at all subsequent visits.
CCI
CCI
CCI


GS-5829 
Protocol GS-US-350-1599 
Gilead Sciences, Inc. 
f 
Oxygen saturation will be tested with a pulse oximeter. 
Final 
Amendment6 
g 
ECG: At Screening, at predose on Day 1 of each Cycle sta1ting with Cycle 2, and at EOT, a triplicate 12-lead ECG will be collected at a single timepoint. On Study 
Day l(Coho1ts 1-3 only) and ClDl (Coho1ts 4-8 only and all coho1ts of Group 2), C1D8 (all coho1ts) (at predose, 1 hour, 2 hom·s, 3 hotu-s, 4 hom·s, 6 hotu-s, 8 hom·s, and 
12 hotu'S post fu-st dose +/- 20 min) and Day 1 of cycles 2-6 (at pre-dose). Subjects in the Group 3 lymphoma expansion will have ECGs collected at pre-dose, 1, 2, 4, 6, and 
24 hotu'S post-dose on Cycle 1, Day 8. ECGs will also be collected at pre-dose on Day 1 of Cycles 2, 4, and 6. ECGs should always be collected prior to PK (or any other 
blood draw) if they are to be collected at the same nominal timepoint. Subjects should be resting quietly and free of distraction (eg, TV, conversation) for 10 minutes prior to 
ECG collection and ECGs should be collected over a 5 minute window at each timepoint. 
h 
Adverse events will be assessed at pre- and post-GS-5829 dosing dtuing applicable clinic visits. Subjects will also rettun to clinic at 30-day post last IP dose, to assess AEs 
andSAEs. 
Coho1ts 1-3 of Group 1 will receive one dose of GS-5829 on Study Day 1, which will be administered in the clinic. 
J 
Not applicable to subjects in Coho1t 1-3 of Group 1. 
k 
Subjects who miss the 30 day Safety Follow-up visit will be contacted by phone 30 days(± 2 days) after the last dose of GS-5829 to assess AEs. 
I 
If applicable (females of child bearing potential). Serum pregnancy will be conducted at Screening. U1ine pregnancy will be conducted pre-dose on Study Day 1/ClDl of 
each cycle and at EOT. 
m 
Plasma samples for GS-5829 PK will be collected(± 10 minutes) in coho1ts 1-3 of Group lon Study Day 1 at pre-dose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hom·s post-dose, 
and in coho1ts 4-8 of Group 1 and all coho1ts of Group 2 on Cycle 1 Day 1 at pre-dose (0 hr), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose. Additional samples will be 
collected at 48 and 72 hotu'S post-dose in coho1ts 1 - 3 of Group 1 relative to first dose of GS-5829. Plasma samples for GS-5829 PK will be collected in all cohorts (Group 1 
and Group 2) at pre-dose (0 Ju'), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hotu'S post-dose relative to GS-5829 administration on Cycle 1 Day 8. Spa1-se PK samples will be collected in 
all coho1ts (Group 1 and Group 2) at trough (20-26 hom·s post-dose) on Cycle 1 Day 4, 2 - 4 hotu-s post-dose on Cycle 1 Day 15, and anytime post-dose on Day 1 of Cycles 2 
through 6. Urine will be collected for GS-5829 PK in Group 1 cohorts 1-3 on Study Day 1 and in Group lcoho1ts 4-8 on Cycle 1 Day 1 at pre-dose (0 hr), 0-6 hotu·s, 
6-12 hotu-s, and 12-24 hotu'S post-dose relative tofu-st dose ofGS-5829. Subjects in the Group 3 lymphoma expansion will have PK drawn at pre-dose, 1, 2, 4, 6, and 24 hotu·s 
I' 
ost-dose on 
cle 1, Da 8. PK sam !es will also be drawn at re-dose on Da 1 ofC des 2, 4, and 6 
I' 
p 
q 
r 
Echocardiogram will be pe1formed at screening, C2Dl , and EOT. MUGA is acceptable. The same modality must be used throughout study pa1ticipation. 
s 
Screening chemistty, hematology and coagulation to be collected within 7 days of Study Day 1/ClDl. 
Bone man'Ow biopsy is only to be pe1fon11ed to assess suspected CR, and only if the subject had lymphoma involvement of the man·ow at baseline ( or did not have a baseline 
matTow biopsy). After CR is detem1ined, there is no need for any fiuther bone matTow biopsy assessments. 
CONFIDENTIAL 
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GS-5829 
Protocol GS-US-350-1599 
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r 
Final 
Amendment6 
v 
At one or more ose evels, GS-5829 will be administered in fed state on Day 1 of Cycle 2 and PK samples will be collected at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, and 24 hours 
post-dose. In subjects where intensive PK is collected on Cycle 2, Day 1, sparse PK samples do not need to be collected at that visit. 
w 
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 Cycle 1 Day 1 
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 Cycle 1 Day 1 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). 
x 
Biopsies are requested from subjects with accessible disease and should be core needle or excision biopsies. The pre-treatment biopsy can be obtained any time after the last 
line of therapy and prior to the first dose, the Cycle 2 Day 15 biopsy can be obtained anytime between Cycle 2 Day 1 and Cycle 2Day 21. The EOT biopsy should be collected 
at progression only for subjects with progressive disease. 
y 
AAG will be collected at Screening, pre-dose on ClDl and C1D8 only. Fen-itin and CRP will be collected pre-dose on ClDl and Day 1 of every subsequent cycle. 
z 
Subjects who are enrolled in Group 3 will undergo a baseline PET/CT scan and at Week 16 in the place of a CT scan if available. 
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Appendix 3.
RECIST 1.1


EUROPEAN JOURNAL Of CANCER 45 (2009) 228 247 
a vail a ble at www.sciencedirect.co m 
- ,,1 
•;;,. ScienceDirect 
ELSEVIER 
journs l homepage: www. ejconline.com 
New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1) 
E.A. Eisenhauera,•, P. Therasse0, } . Bogaertsc, L.H. Schwartzd, D. Sargente, R. Fordf, 
J. Dancey9, s. Arbuckh, s. Gwytheri, M. Mooney9, L. Rubinstein9, L. Shankar9, L. Dodd9, 
R. Kaplani, D. Lacombec, }. Verwei? 
•National Cancer Institute of Canada 
Clinical Trials Group, 10 Stu.art Street, Queen's University, Kin9swn, ON, Canada 
bG!axoSmithKline Biologicals, Rixensart, Belgium 
cEuropean Organisation for Research and Jreatment of Cancer, Data Centre, Brussels, Belgium 
dMemorial Sloan Kettering Cancer Center, New York, NY, USA 
"Mayo Clinic, Rochester, MN, USA 
fRadPhann, Princeton, NJ, USA 
8Division of Cancer 1reatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA 
bSchering Plough, Kenilworth, NJ, USA 
;East Surrey Hospital, Redhill, Surrey, UK 
iNational Cancer Research Network, Leeds, UK 
kErasmus University Medical Center, Rotterdam, The Netherlands 
ARTICLE INFO 
Article history: 
Received 17 October 2008 
Accepted 29 October 2008 
Keywords: 
Response criteria 
Solid tumours 
Guidelines 
ABSTRACT 
Background: Assessment of the change in tumour burden is an important feature of the 
clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) 
and disease progression are useful endpoints in clinical trials. Since RECISTwas published 
in 2000, many investigators, cooperative groups, industry and government authorities have 
adopted these criteria in the assessment of treatment outcomes. However, a number of 
questions and issues have arisen which have led to the development of a revised RECIST 
guideline (version 1.1). Evidence for changes, summarised in separate papers in this special 
issue, has come from assessment of a large data warehouse (>6500 patients), simulation 
studies and literature reviews. 
Highlights of revised R.ECIST 1.1: Major changes i nc;!ude: Number of 12,;ions to be assessed: based 
on evidence from numerous trial databases merged into a data warehouse for analysis pur 
poses, the number of lesions required to assess tumour burden for response determination 
has been reduced from a maximum of lOto a maximum of five total (and from five to two 
per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes 
with a short axis of ;a, 15 mm are considered measurable and assessable as target lesions. 
The short axis measurement should be included in the sum of lesions in calculation of 
tumour response. Nodes that shrink to <10 mm short axis are considered normal. Conjirma 
tion of response is required for trials with response primary endpoint but is no longer 
required in randomised studies since the control arm serves as appropriate means of inter 
pretation of data. Disease progrnssion is clarified in several aspects: in addition to the previ 
ous definition of progression in target disease of 20% increase in sum, a 5 mm absolute 
increase is now required as well to guard against over calling PD when the total sum is very 
• Corresponding author: Tel: PPD 
fax: ._iP_P_D ____ ,. 
E mail address: PD 
(£.A. Eisenhauer). 
0959 8049/$ see front matter © 2008 Elsevier Ltd. All rights reserved. 
doi:10.1016/j.ejca.2008.10.026 


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
2 4 7
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.
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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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EUROPEAN JOURNAL OF CANCER 45 (2009) 228 247 
235 
Table 1 - Time point response: patients with target(+/-
non-target) disease. 
Target lesions Non target lesions 
New 
Overall 
lesions 
response 
CR 
CR 
No 
CR 
CR 
Non CR/non PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non PD or 
No 
PR 
not all evaluated 
SD 
Non PD or 
No 
SD 
not all evaluated 
Not all 
Non PD 
No 
NE 
evaluated 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, 
PD = progressive disease, and NE = inevaluable. 
Table 2 - Time point response: patients with non-target 
disease only. 
Non target lesions 
CR 
Non CR/non PD 
Not all evaluated 
Unequivocal PD 
Any 
New lesions 
No 
No 
No 
Yes or No 
Yes 
CR = complete 
~esponse, 
PD = progressive 
NE = inevaluable. 
Overall response 
CR 
Non CR/non PD" 
NE 
PD 
PD 
disease, 
and 
a 'Non CR/non PD' is preferred over 'stable disease' for non target 
disease since SD is increasingly used as endpoint for assessment 
of efficacy in some trials so to assign this category when no 
lesions can be measured is not advised. 
Best response determination in trials where confirmation of com 
plete or partial response IS required: Complete or partial re 
sponses may be claimed only if the criteria for each are met 
at a subsequent time point as specified in the protocol (gener 
ally 4 weeks later). In this circumstance, the best overall re 
sponse can be interpreted as in '!'able 3. 
4.4.4. 
Special notes on response assessment 
When nodal disease is included in the sum of target lesions 
and the nodes decrease to 'normal' size (<10 mm), they may 
still have a measurement reported on scans. This measure 
ment should be recorded even though the nodes are normal 
in order not to overstate progression should it be based on 
increase in size of the nodes. As noted earlier, this means that 
patients with CR may not have a total sum of 'zero' on the 
case report form (CRF). 
In trials where confirmation of response is required, re 
peated 'NE' time point assessments may complicate best re 
sponse determination. The analysis plan for the trial must 
address how missing data/assessments will be addressed in 
determination of response and progression. For example, in 
most trials it is reasonable to consider a patient with time 
point responses of PR NE PR as a confirmed response. 
Patients with a global deterioration of health status requir 
ing discontinuation of treatment without objective evidence 
of disease progression at that time should be reported as 
'symptomatic deterioration'. Every effort should be made to 
document objective progression even after discontinuation 
of treatment. Symptomatic deterioration is not a descriptor 
of an objective response: it is a reason for stopping study ther 
apy. The objective response status of such patients is to be 
determined by evaluation of target and non target disease 
as shown in Tables 1 3. 
Conditions that define 'early progression, early death and 
inevaluability' are study specific and should be clearly de 
scribed in each protocol (depending on treatment duration, 
treatment periodicity). 
In some circumstances it may be difficult to distinguish 
residual disease from normal tissue. When the evaluation of 
complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine 
Table 3 - Best overall response when confirmation of CR and PR required. 
Overall response 
First time point 
CR 
CR 
CR 
CR 
CR 
PR 
PR 
PR 
PR 
PR 
NE 
Overall response 
Subsequent time point 
CR 
PR 
SD 
PD 
NE 
CR 
PR 
SD 
PD 
NE 
NE 
BEST overall response 
CR 
SD, PD or PR" 
SD provided minimum criteria for SD duration met, otherwise, PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
SD provided minimum criteria for SD duration met, otherwise NE 
PR 
PR 
SD 
SD provided minimum criteria for SD duration met, otherwise, PD 
SD provided minimum criteria for SD duration met, otherwise NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = inevaluable. 
a lf a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR criteria relative to baseline, 
makes the disease PD at that point (since disease must have reappeared after CR). Best response would depend on whether minimum duration 
for SD was met. However, sometimes 'CR' may be claimed when subsequent scans suggest small lesions were likely still present and in fact the 
patient had PR, not CR at the first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR. 


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 PET and 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 survivalareinﬂuencedby 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
236
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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.
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
2 4 7
237


Appendix I. Summary of m ajor changes RECIST 1.0 to RECIST 1.1 
Minimum size measurable 
lesions 
S~cial considerations on 
lesion measurability 
Overall tumour burden 
Response criteria target 
disease 
Response criteria non target 
disease 
New lesions 
Overall response 
RECJST 1.0 
CT. 10 mµi spiral 
20 mm non spiral 
Clinical: 20 mm 
Lymph node: not mentioned 
10 lesions (5 per organ) 
CR lymph node not mentioned 
PD 20% increase over smallest sum on 
study or new 1esions 
RECIST 1.1 
CT 10 mm; delete reference to 
spiral scan 
Clinical: 10 mm (must be 
measurable with calipers) 
CT 
mm short a.xis, for target 
<15mm for non target 
<10 mm is non pathological 
Notes included on bone 
lesions, cystic lesions 
5 lesions (2 per organ) 
CR lymph nodes must be 
<10 mm short axis 
PD 20% increase over smallest 
sum on study (including 
baseline if that is smallest) and 
at least 5 mm increase or new 
lesions 
'unequivocal progression' considered as PD 
More detailed description of 
'un~uivocal progression' to 
indicate that it should not 
normally trump target disease 
status. It must be 
representative of overall 
disease status change. not a 
single lesion increase 
Table integrated target and non target 
lesions 
New section on New lesions 
1wo tables: one integrating 
tar~t and non target and the 
other of non target only 
Rationale 
Reference in special issue 
(if applicable) 
Most scans used have 5 mm or less slice 
thickness Clearer to give instruction based on 
slice interval ii it is greater than s mm 
caliper measurement will make this reliable 
Since nodes are normal structure need to define 
pathological enlargement Short axis is most 
sensitive 
Clarify frequently asked questions 
Data warehouse analysis shows. no loss of 
information if lesion number reduced from 10 to 
5. A maximum of 2 lesions per organ yii,lds 
sufficient representation per disease site 
In keeping with normal size of nodes 
Clarification that if baseline measurement is 
smaller than any on study measurement, it is 
reference against which PD is assessed 
5 mm absolute increase to guard against over 
calling PD when total sum is veiy small and 20% 
increase is within measurement EITOr 
Confusion with RECIST 1.0 where some were 
consideringPDif'increase' in any non target 
lesion, even when target disease is stable or 
responding 
To provide guidance on when a lesion is 
considered new (and thus PD) 
To account for the fact that RECJST criteria are 
now being used in trials where PFS is the 
endpoint and not all patients have measurable 
(target) disease at baseline 
Schwartz et al.15 
Bogaerts et al. 10 
Schwartz et al 15 
"' 
c:: 
"' 
0 .,, 
"' 
> z 
0 
C: ,., 
z 
> 
r-
e 
n > 
z n 
"' "' 
-4> 
V, 
..., 
0 
0 
'D 
..., 
..., 
00 
I ..., 
-4> 
...... 


Confirmatory measure 
Progression free survival 
Reporting of response 
results 
Response in phase Ill 
trials 
Imaging appendix 
New appendices 
For CR and PR: criteria 
must be met again 4 
weeks after initial 
documentation 
General comments only 
9 categories suggested for 
reporting phase n results 
More relaxed guidelines 
possible if protocol specified 
Appendix I 
Special notes: 
How to assess and measure 
lymph nodes 
CR in face of residual tissue 
Discussion of 'equivocal' 
progression 
Retain this requirement ONLY 
for 
non randomised trials with 
primary endpoint of response 
More specific comments on 
use of PFS (or proportion 
progression free) as 
phase 11 endpoint 
Greater detail on PFS 
assessment in phase l1I trials 
Divided into phase n and phase 
Ill 
9 categories collapsed into 5 
In phase Ill, guidance given 
about reporting response 
This section removed and 
referenced in section 
above: no need to have 
different criteria for phase II 
andm 
Appendix Il: updated with 
detailed guidance on 
use of MRI; PET/CT 
Other practical guidance 
included 
Appendix I: comparison of 
RECIST 1.0 and 1.1 
Appendix Ill: frequently asked 
questions 
Frequently asked questions on these topics 
Data warehouse shows that response rates 
rise when confirmation is eliminated, but 
the only circumstance where this is 
important is in trials where there is no 
concurrent comparative control and where 
this measure is the primary endpoint 
Increasing use of PFS in phase Ill trials 
requires guidance on assessment of PD in 
patients with non measurable disease 
Simplifies reporting and clarifies !how to 
report phase n and Ill data consistently 
Simplification of response assessment by 
reducing number of lesions and eliminating 
need for confirmation in randomised 
studies where response is not the primary 
endpoint makes separate 'rules' 
unnecessary 
Evolving use of newer modalities addressed. 
Enhanced guidance in response to frequent 
questions and from radiology review 
experience 
Bogaerts et al. m 
Dancey et al. 21 
"' 
c:: ,., 
0 .., 
"' > 
z 
0 
c:: ,., 
z 
> 
.... 
0 .., 
r, 
> z 
r, 
"' "' 
-I' 
V1 
» 
0 
0 
\() 


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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EUROPEAN JOURNAL OF CANCER 45 (2009) 228 247 
241 
should additionally investigate areas that may be 
involved based on signs and symptoms of individual 
patients. Because a lesion later identified in a body part 
not scanned at baseline would be considered as a new 
lesion representing disease progression, careful consid 
eration should be given to the extent of imaging coverage 
at baseline- and at subsequent follow up time points. 
This will enable better consistency not only of tumour 
measurements but also identification of new disease. 
b. N contrast administration: Optimal visualisation and 
measurement of metastases in solid tumours requires 
consistent administration (dose and rate) of IV contrast 
as well as timing of scanning. 1ypically, most abdomi 
nal imaging is performed during the portal venous 
phase and (optimally) about the same time frame after 
injection on each examination (see Fig. 1 for impact of 
different phase of IV contrast on lesion measurement). 
Most solid tumours may be scanned with a single 
phase after administration of contrast. While triphasic 
CT scans are sometimes performed on other types of 
vascular tumours to improve lesion conspicuity, for 
consistency and uniformity, we would recommend tri 
phasic CT for hepatocellular and neuroendocrine 
tumours for which this scanning protocol is generally 
standard of care, and the improved temporal resolution 
of the triphasic scan will enhance the radiologists' abil 
ity to consistently and reproducibly measure these 
lesions. The precise dose and rate of N contrast is 
dependent upon the CT scanning equipment. CT acqui 
sition protocol, the type of contrast used, the available 
venous access and the medical condition of the 
patient. Therefore, the method of administration of 
intravenous contrast agents is variable . . Rather than 
try to institute rigid rules regarding methods for 
administering contrast agents and the volume injected, 
it is appropriate to suggest that an adequate volume of 
a suitable contrast agent should be given so that the 
metastases. are demonstrated to best effect and a con 
sistent method is used on subsequent examinations for 
any given patient (ideally, this would be specified in 
the protocol or for an institution). It is very important 
that the same technique be used at baseline and on fol 
low up examinations for a given patient. 1'his will 
greatly enhance the reproducibility of the tumour mea 
surements. If prior to enrolment it is known a patient is 
not able to undergo CT scans with N contrast due to 
allergy or renal insufficiency, the decision as to 
whether a non contrast CT or MRI (with or without N 
contrast) should be used to evaluate the subject at 
baseline and follow up should be guided by the tumour 
type under investigation and the anatomic location of 
the disease. For patients who develop contraindica 
tions to contrast after baseline contrast CT is done, 
the decision as to whether non contrast CT or MRI 
(enhanced or non enhanced) should be performed 
should also be based on the tumour type, anatomic 
location of the disease and should be optimised to 
allow for comparison to the prior studies if possible. 
Each case should be discussed with the radiologist to 
determine if substitution of these other approaches is 
possible and, if not, the patient should be considered 
not evaluable from that point forward. Care must be 
taken in measurement of target lesions on a different 
modality and interpretation of non target disease or 
new lesions, since the same lesion may appear to have 
a different size using a new modality (see Fig. 2 for a 
comparison of CT and MRI of the same lesion). Oral 
contrast is recommended to help visualise and differ 
entiate structures in the abdomen. 
c. Slice thickness and reconstruction interual: RECIST measure 
ments may be performed at most clinically obtained 
slice thicknesses. It is recommended that CT scans be 
performed at 5 mm contiguous slice thickness or less 
and indeed this guideline presumes a minimum 5 mm 
thickness in recommendations for measurable lesion 
definition. Indeed, variations in slice thickness can have 
an impact on lesion measurement and on detection of 
new lesions. However, consideration should also be 
given for minimising radiation exposure. With these 
patameters, a minimum 10 mm lesion is considered 
measurable at baseline. Occasionally, institutions may 
perform medically acceptable scans at slice thicknesses 
greater than s mm. If this occurs, the minimum size of 
measurable lesions at baseline should be twice the slice 
Fig. 1 - Difference in measurement/visualisation with different phases of IV contrast administration. Hypervascular 
metastases imaged in the arterial phase Qeft) and the portal venous phase (right). Note that the number of lesions visible 
differs greatly between the two phases of contrast administration as does any potential lesion measurement. Consistent CT 
scan acquisition, including phase of contrast administration, is important for optimal and reproducible tumour 


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EUROPEAN JOURNAL OF CANCER 45 (2009} 228 247 
Fig. 2 - CT versus MRI of same lesions showing apparent 'progression' d ue only to differing m e1hod of measurement. 
thickness of the baseline scans. Most contemporary CT 
scanners are multidetector which have many imaging 
options for these acquisition parameters.23 The equip 
ment vendor and scanning manual should be reviewed 
if there are any specific system questions. 
d. Alternative contrast agents: There are a number of other, 
new contras.t agents, some organ specific.24 They may 
be used as part of patient care for instance, in liver 
lesion assessment, or lymph node characterisation25, 
but should not as yet be used in clinical trials. 
FOG PET has gained acceptance as a valuable tool for 
detecting, staging and restagi.ng several malignancies. Criteria 
for incorporating (or substituting) FDG PET into anatomical 
assessment of tumour response in phase II trials are not :yet 
available, though much research is ongoing. Nevertheless, 
FOG PET is being used in many drug development trials both 
as a tool to assess therapeutic efficacy and also in assessment 
of progression. If FDG PET scans are included in a protocol, by 
consensus, an FOG uptake period of 60 min prior to imaging 
has been decided as the most appropriate for imaging of pa 
tients with malignancy.26 Whole body acquisition is impor 
tant since this allows for sampling of all areas of interest 
and can assess if new lesions have appeared thus determining 
the possibility of interval progression of disease. Images from 
the base of the skull to the level of the mid thigh should be ob 
tained 60 min post injection. PET camera specifications are 
variable and manufacturer specific, so every attempt should 
be made to use the same scanner, or the same model scanner, 
for serial scans on the same patient Whole body acquisitions 
can be performed in either 2 or 3 dimensional mode with 
attenuation correction, but the method chosen should be con 
sistent across all patients and serial scans in the clinical trial. 
PET/CT scans: Combined modality scanning such as with 
PET CT is increasingly used in clinical care, and is a modal 
ity/technology that is in rapid evolution; therefore, the recom 
mendations in this paper may change rather quickly with 
time. At present, low dose or attenuation correction CT por 
tions ofa combined PET CTare oflimited use in anatomically 
based efficacy assessments and it is therefore suggested that 
they should not be substituted for dedicated diagnostic con 
trast enhanced CT scans for anatomically based RECISI' mea 
surernents. However, if a site can document that the CT 
performed as part of a PET CT is of identical diagnostic qual 
ity to a diagnostic CT (with N and oral contrast) then the CT 
portion of the PET CT can be used for RECIST measurements. 
Note, however, that the PET portion of the CT introduces addi 
tional data which may bias an investigator if it is not routinely 
or serially performed. 
Ultrasound examinations should not be used in clinical trials 
to measure tumour regression or progression of lesions be 
cause the examination is necessarily subjective and operator 
dependent. The reasons for this are several: Entire examina 
tions cannot be reproduced for independent review at a later 
date, and it must be assumed, whether or not it is the case, 
that the hard copy films available represent a true and accu 
rate reflection of events. Furthermore, if, for example, the 
only measurable lesion is in the para aortic region of the 
abdomen and if gas in the bowel overlies the lesion, the lesion 
will not be detected because the ultrasound beam cannot 
penetrate the gas. Accordingly, the disease staging (or restag 
ing for treatment evaluation} for this patient will not be 
accurate. 
While evaluation of lesions by physical examination is also 
of limited reproducibility, it is permitted when lesions are 
superficial, at least 10mm size, and can be assessed using 
calipers. In general, it is preferred if patients on clinical trials 
have at least one lesion that is measurable by CT. Other skin 
or palpable lesions may be measured on physical examina 
tion and be considered target lesions. 
Use of MRI remains a complex issue. MRI has excellent 
contrast, spatial and temporal resolution; however, there 
are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity and mea 
surement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be 
optimised for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow up 
should be the same as was used at baseline and the lesions 
should be measured/assessed on the same pulse sequence. 
Generally, axial imaging of the abdomen and pelvis with Tl 
and T2 weighted imaging along with gadolinium enhanced 
imaging should be performed. The field of view, matrix, 
number of excitations, phase encode steps, use of fat sup 
pression and fast sequences should be optimised for the spe 


EUROPEAN JOURNAL OF CANCER 45 (2009) 228 247 
243 
cific body part being imaged as well as the scanner utilised. It 
is beyond the scope of this document or appendix to pre 
scribe specific MRI pulse sequence parameters for all scan 
ners, body parts and diseases. Ideally, the same type of 
scanner should be used and the image acquisition protocol 
should be followed as closely as possible to prior scans. Body 
scans should be performed with breath hold scanning tech 
niques if possible. 
Selection of target lesions: In general, the largest lesions rep 
resentative of involved organs (up to a maximum of two per 
organ and five total) are selected to follow as target lesions. 
However, in some cases, the largest lesions may not be easily 
measured and are not suitable for follow up because of their 
configuration. In these cases, identification of the largest most 
reproducible lesions is advised. Fig. 3 provides an illustrative 
example where the largest lesion is not the most reproducible 
and another lesion is better to select and follow: 
Measurement of lesions 
The longest diameter of selected lesions should be measured 
in the plane in which the images were acquired. For body CT, 
this is the axial plane. In the event isotropic reconstructions 
are pertormed, measurements can be made on these recon 
structed images; however, it should be cautioned that not 
all radiology sites are capable of producing isotropic recon 
structions. This -could lead to the undesirable situation of 
measurements in the axial plane at one assessment point 
and in a different plane at a subsequent assessment There 
are some tumours, for instance paraspinal lesions, which 
are better measured in the coronal or sagittal plane. It would 
be acceptable to measure these lesions in these planes if the 
reconstructions in those planes were isotropic or the images 
were acquired with MRI in those planes. Using the same plane 
of evaluation, the maximal diameter of each target lesion 
should always be measured at subsequent follow up time 
points even if this results in measuring the lesion at a differ 
ent slice level orin a different orientation or vector compared 
with the baseline study. Software tools that calculate the 
maximal diameter for a perimeter of a tumour may be em 
ployed and may even reduce variability. 
The only exception to the longest diameter rule is lymph 
node measurement. Because malignant nodes are identifi.ed 
by the length of their short axis, this is the guide used to 
determine not only whether they are pathological but is also 
the dimension measured for adding into the sum of target le 
sions. Fig. 4 illustrates this point: the large arrow identifies a 
malignant node: the shorter perpendicular axis is ;;,,15 mm 
and will be recorded. Close by (small arrow) there is a normal 
node: note here the long axis is greater than 10 mm but the 
short axis is well below 10 mm. This node should be consid 
ered non pathological. 
If a lesion disappears and reappears at a subsequent time 
point it should continue to be measured. However, the pa 
tient's response at the point in time when the lesion reap 
pears will depend upon the status of his/her other lesions. 
For example, if the patient's tumour had reached a CR status 
and the lesion reappeared, then the patient would be consid 
ered PD at the time ofreappearance. In contrast, if the tumour 
status was a PR or SD and one lesion which had disappeared 
then reappears, its maximal diameter should be added to the 
sum of the remaining lesions for a calculated response: in 
other words, the reappearance of an apparently 'disappeared' 
single lesion amongst many which remain is not in itself en 
Fig. 3 - Largest lesion may not be most reproducible: most reproducible should be selected as target. In this example, the 
primary gastric lesion (circled at baseline and at follow-up in the top two images) may be able to be measured with thin 
section volumetric CTwith the same degree of gastric distention at baseline and follow-up. However, this is potentially 
challenging to reproduce in a multicentre trial and if attempted should be done with careful imaging input and analysis. The 
most reproducible lesion is a lymph node (circled at baseline and at follow-up in the bottom two images). 


244 
EUROPEAN JOURNAL OF CANCER 45 (2009} 228 247 
Fig. 4 - Lymph node assessment: large arrow illustrates a 
pathological node with the short axis shown as a solid line 
which should be measured and followed. Small arrow illus-
trates a non-pathological node which has a short axis 
<10mm. 
ough to qualify for: PD: that requires the sum of all lesions to 
meet the PD criteria. The rationale for such a categorisation is 
based upon the realisation that most lesions do not actually 
'disappear' but are not visualised because they are beyond 
the resolving power of the imaging modality employed. 
The identification of the precise bounda:iy definition of a 
lesion may be difficult especially when the lesion is embed 
ded in an organ with a similar contrast such as the liver, pan 
creas, kidney, adrenal or spleen. Additionally, peritumoural 
oedema may surround a lesion and may be difficult to dis tin 
guish on certain modalities between this oedema and actual 
tumour. In fact, pathologically, the presence of tumour cells 
within the oedema region is variable. Therefore, it is most 
critical that the measurements be obtained in a reproducible 
manner from baseline and all subsequent follow up time 
points. This is also a strong reason to consistently utilise 
the same imaging modality. 
When lesions 'fragment', the individual lesion diameters 
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 individual lesion. If the le 
sions have truly coalesced such that they are no longer sep 
arable, the vector of the longest diameter in this instance 
should be the maximal longest diameter for the 'merged 
lesion'. 
Progression of non-target lesions 
To achieve 'unequivocal progression' there must be an overal! 
level of substantial worsening in non target disease that is of 
a magnitude that, even in the presence of SD or PR in target 
disease, the treating physician would feel it important to 
change therapy. Examples of unequivocal progression are 
shown in Pigs. S and 6. 
Fig. 5 - Example of unequivocal progression in non-target lesions in liver. 
Fig. 6 - Example of unequivocal progression in non-target lesion (nodes~ 


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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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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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
cancer]. Gynecologic Cancer Intergroup. J Natl Cancer Inst
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 4.
Criteria for Progression in Castration-Resistant Prostate Cancer
Variable
Criteria
PSA
Ignore early rises (prior to 12 weeks) in determining PSA response
For control/relieve/eliminate endpoints: Percent change from baseline at 12 weeks and maximal 
change at any time using a waterfall plot.
Progression:
Decline from baseline: record start of therapy to first PSA increase that is ≥25% and ≥2 ng/mL 
above the nadir and confirmed by a second value 3 or more weeks later.
No decline from baseline: PSA progression ≥ 25% and ≥ 2 ng/mL after 12 weeks
Soft tissue
Use RECIST with caveats:
Only report changes in lymph nodes that were ≥ 2 cm in diameter at baseline
Record changes in nodal and visceral soft tissue sites separately
Record complete elimination of disease at any site separately
Confirm favorable change with second scan
Bone
The appearance of ≥ 2 new lesions, and, for the first reassessment only, a confirmatory scan 
performed 6 or more weeks later that shows a minimum of 
2 or more additional new lesions
The date of progression is the date of the first scan that shows the change


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Appendix 5.
Lymphoma Efficacy Assessments
Tumor Status Assessments
The determination of lymphoma response and progression will be based on standardized criteria 
{Cheson et al 2007, Owen et al 2013} as specifically modified for this study to reflect the 
biology of the diseases under study. During the course of the study, investigators will 
periodically assess the status of each subject’s lymphoma. 
Method of Assessment
In addition to clinical examination, imaging-based evaluation will be used in this study in all 
subjects enrolled. CT scan is the preferred method for radiographic tumor assessment. MRI 
scanning may be used at the investigator’s discretion in subjects for whom this may be a 
preferred alternative to CT scanning; however, if MRI is performed, a non-contrast CT of the 
chest should also be performed. Contrast-enhanced scanning is preferred, but iodine-containing 
or gadolinium contrast material may be omitted in subjects for whom use of a contrast agent 
would be medically contraindicated. If available, positron emission tomography (PET) scan data 
will be considered in response and progression assessment; however, PET scanning will not be a 
required component of assessment in this study.  As appropriate, bone marrow aspirate/biopsy 
information (eg, for confirmation of CR) will be also be considered. Clinical palpation, chest 
x-ray, ultrasound, endoscopy, laparoscopy, radionuclide scan, or tumor markers will not be 
considered for response assessment.
For radiographic assessments, the same method of assessment and the same technique 
(eg, scan type, scanner, subject position, dose of contrast, injection/scan interval) should be used 
to characterize each identified and reported lesion at baseline, while on study drug treatment and 
during follow-up. Furthermore, the use of IV contrast should be consistent across time points. In 
the event that the screening/baseline CT scan of the neck, chest, abdomen, and pelvis is 
performed without IV contrast, follow-up time points should also be performed without 
IV contrast.
All relevant radiographic and clinical information required to make each tumor status assessment 
must be made available for source verification and for submission to the IRC.
Timing of Assessments
During screening, clinical and imaging-based tumor assessments should be performed within the 
specified screening period. On-study CT/MRI tumor assessments should be performed as 
indicated in Section 6.1.10. An end-of-study CT/MRI tumor assessment should be performed 
unless the subject already has radiographic confirmation of disease progression 4 weeks prior to 
study discontinuation. If a subject permanently discontinues study drug prior to objective 
documentation of lymphoma progression, investigators should continue further follow-up at 
~8-week intervals until lymphoma progression is documented.


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Identification and Follow-up of Tumor Lesions and Organomegaly
Index Lesions
Up to 6 lesions (eg, lymph nodes, liver or spleen nodules, and/or other circumscribed 
extra-nodal masses) should be selected as index lesions that will be used to quantitate the status 
of the disease during study. Ideally, the index lesions should be located in disparate regions of 
the body and include mediastinal, abdominal, and retroperitoneal areas of disease whenever these 
sites are involved. 
Index lesions will be measured and recorded at baseline and at the stipulated intervals. The 
cross-sectional dimensions (the largest cross-sectional diameter, ie, the longest diameter 
[LD] × the longest perpendicular diameter [LPD]) will be recorded (in cm) for each index lesion. 
Using the LD and LPD, the product of the perpendicular diameters (PPD) for each index lesion 
will be calculated. The sum of the products (SPDs) for all index lesions will be calculated and 
recorded. The baseline SPDs will be used as references by which objective tumor response will 
be characterized during treatment. The nadir LDs of individual lesions and the nadir SPDs will 
be used as references by which objective tumor progression will be characterized during study. 
All PPD and SPD measurements will be reported in centimeters squared.
Nodal Index Lesions
A nodal mass may be selected as a nodal index lesion if it is both abnormal and measurable at 
baseline. A lymph node lesion is considered abnormal if it has a single diameter that is 1.0 cm 
and is considered measurable if it has 2 perpendicular diameters that can be accurately measured 
in cross section with the LD being 1.0 cm and the LPD also being 1.0 cm.
Abnormal, measurable nodal lesions will be subcategorized as either large or small.

Large nodal lesions have an LD that is >1.5 cm and an LPD that is 1.0 cm.

Small nodal lesions have an LD that is >1.0 cm and 1.5 cm and an LPD that is >1.0 cm.
Index lesions measuring >1.5 cm in the LD, regardless of the measurement of the LPD, will be 
prioritized during baseline index lesion selection.
At follow-up time points, the SPD of all nodal index lesions will be considered. Because nodal 
index lesions that have one or both diameters >0 cm and 1.0 cm cannot be reliably measured, a 
default value of 1.0 cm will be assigned for each diameter that meets these criteria and the 
resulting PPD will be used in SPD calculations. Based on this convention, a CR may be achieved 
even if an SPD value is >0 cm2 (ie, if all lymph nodes measure <1.0 cm2).
New or enlarging nodal lesions that are still 1.0 cm by 1.0 cm will not be considered to 
represent recurrent disease or PD. A new node that measures >1.5 cm in any diameter or a new 
node that measures >1.0 cm to 1.5 cm in the LD and measures >1.0 cm in the LPD will be 
considered PD.


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In cases in which a large lymph node mass has split into multiple components, only those 
elements that are >1.0 cm in at least 1 diameter will be considered abnormal and used in 
calculating the SPD. Components that are ≤1.0 cm in the LD are assumed to be normal lymph 
node structures. PD will not be based on the growth of a lesion sub-component until it meets the 
criteria for abnormal. Lesion sub-components that are abnormal (>1.0 cm in 1 diameter) will 
have the true PPDs calculated with the result used only for calculating an accurate nadir. Lesion 
sub-components that are normal (1.0 cm in the LD) will have the default PPD of 1.0 cm2
(1.0 cm x 1.0 cm) stored only for the purposes of calculating the nadir value. 
If lesions merge, a boundary between the lesions will be established so the LD of each individual 
lesion can continue to be measured. If the lesions have merged in a way that they can no longer 
be separated by this boundary, the newly merged lesion will be measured bi-dimensionally.
Extra-Nodal Index Lesions
An extra-nodal mass may be selected as an index lesion if it is both abnormal and measurable at 
baseline. An extra-nodal mass of any size is considered abnormal. It is considered measurable at 
baseline if it has 2 perpendicular diameters that can be accurately measured in cross section with 
the LD being 1.0 cm and the LPD also being 1.0 cm.
At follow-up time points, the PPD of each single extra-nodal index lesion and the SPD of all 
extra-nodal index lesions will be considered. Because extra-nodal index lesions that have one or 
both diameters >0 cm and < 1.0 cm cannot be reliably measured, a default value of 1.0 cm will 
be assigned for each diameter that meets these criteria and the resulting PPD will be used in SPD 
calculations. If an extra-nodal lesion is no longer clearly visible, it will be considered resolved 
and its PPD will be defined as 0 cm2. 
If an extra-nodal lesion that had resolved (ie, had a PPD of 0 cm2) subsequently reappears 
unequivocally, the subject will be considered to have PD. A new unequivocal extra-nodal lesion 
of any size that appears at a site that was not previously involved with lymphoma and is 
discernible to the radiologist by CT scan will be considered PD.
Non-Index Lesions
Any other measurable and abnormal nodal or extra-nodal lesions not selected for quantitation as 
index lesions may be considered non-index lesions. In addition, non-measurable evidence of 
lymphoma such as abnormal, non-measurable nodal lesions, extra-nodal lesions with both 
diameters <1.0 cm, bone lesions, leptomeningeal disease, ascites, pleural or pericardial effusions, 
lymphangitis of the skin or lung, abdominal masses that are not confirmed and followed by 
imaging techniques, cystic lesions, previously irradiated lesions, or lesions with artifacts may be 
considered as non-index disease. 
If present at baseline, up to 6 non-index lesions should be recorded. Measurements are not 
required. 


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Non-index disease will be used as a general reference to further characterize regression or 
progression of lymphoma during assessments of the objective tumor response during treatment. 
These lesions should be followed as “present” or “absent”.
Spleen and Liver
Qualitative assessments of the sizes of the spleen and liver will be performed. In addition, the 
presence or absence of splenic and/or hepatic nodules will be recorded. 
Bone Marrow
Bone marrow assessments will be based on morphologic evaluation of bone marrow biopsies. 
Immunohistochemistry may be used to assess response if the sample is indeterminate by 
morphology.
In a subject who has a baseline bone marrow biopsy showing bone marrow involvement with 
lymphoma or does not have a baseline bone marrow examination, declaration of an on-study CR 
requires bone marrow biopsy documentation of the absence of bone marrow lymphoma. In a 
subject who has a baseline bone marrow biopsy showing no evidence of lymphoma, declaration 
of an on-study CR does not require bone marrow examination as long as other criteria for CR are 
met.
Definitions of Tumor Response and Progression
Responses will be categorized as complete response (CR), partial response (PR), stable disease 
(SD), or progressive disease (PD). In addition, a response category of not evaluable (NE) is 
provided for situations in which there is inadequate information to otherwise categorize response 
status. 
The best overall response will be determined. The best overall response is the best response 
recorded from the start of study drug until PD/recurrence (taking as reference for PD the smallest 
measurements recorded since study drug started). Subjects with a best overall response of NE 
will be included in the denominators in calculations of tumor response rate.
Response Categories
Complete Response
To satisfy criteria for CR, all of the following criteria must be met:

No evidence of new disease

Regression of all index nodal lesions to normal size (≤1.5 cm in the LD for nodes that were 
considered large at baseline and < 1.0 cm in the LD and ≤1.0 cm in the LPD for nodes that 
were considered small at baseline) (see Nodal Index Lesions section for definitions of 
large and small nodes)

Regression to normal of all nodal non-index disease 


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
Disappearance of all detectable extra-nodal index and non-index disease

Normal spleen and liver size by imaging studies, no hepatic or splenic lymphoma nodules, 
and no new liver or spleen enlargement

Morphologically negative bone marrow based on an adequate unilateral core biopsy if the 
sample is indeterminate by morphology, it should be negative by immunohistochemistry 

If PET performed (not required), no evidence of residual disease
Partial Response
To satisfy criteria for PR, all of the following criteria must be met as noted below:

No evidence of new disease

A 50% decrease from baseline in the SPD of the index lesions

No increase in the size of non-index disease

No increase in the size of the liver or spleen and no new liver or spleen enlargement

Persistence of bone marrow involvement in a subject who meets other criteria for CR based 
on the disappearance of all nodal and extra-nodal masses

If PET performed (not required): 
Typically FDG-avid lymphoma: if no baseline PET scan or if the PET scan was positive 
before initiating study drug(s), the on-treatment PET is positive in 1 previously involved 
site. If baseline PET was performed and was negative, there is no new PET evidence of 
disease
Variably FDG-avid lymphoma/FDG-avidity unknown: if no pretreatment PET scan or if 
the pretreatment PET scan was negative for lymphoma, CT criteria should be used in 
assessing the tumor during study. If the PET scan was positive before initiating study 
drug(s), the on-treatment PET is positive in 1 previously involved site.
Stable Disease
To satisfy criteria for SD, all of the following criteria must be met:

No evidence of new disease

Neither sufficient tumor shrinkage from baseline to qualify for PR nor sufficient evidence of 
tumor growth to qualify for PD
Progressive Disease
The occurrence of any of the following events indicates progressive disease (PD):


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
Evidence of any new disease that was not present at baseline:
A new node that measures >1.5 cm in LD and > 1.0 cm in the LPD.
A new node that measures >1.0 cm to <1.5 cm in the LD and >1.0 cm in the LPD
Unequivocal reappearance of  an extra-nodal lesion that had resolved (ie, had previously 
been assigned a PPD of 0 cm2)
A new unequivocal extra-nodal lesion of any size
New non-index disease (eg, effusions, ascites, or other organ abnormalities) of any size 
unequivocally attributable to lymphoma (usually requires PET, biopsy, cytology, or other 
non-radiologic confirmation to confirm disease attributable to lymphoma). 
Note: Isolated new effusions, ascites, or bone lesions are not sufficient evidence alone of 
PD unless histologically confirmed. In subjects with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are usually benign. Thus, a declaration of 
PD should not be made if this is the only manifestation of an apparently new lesion.
New or recurrent bone marrow involvement with lymphoma if the last prior bone marrow 
biopsy performed as part of the study (baseline or on-study) was negative for lymphoma

Evidence of worsening of nodal or extra-nodal index lesions:
Increase from the nadir by 50% in the SPD of index lesions
Increase from the nadir by 50% in the LD of an individual node or extra-nodal mass that 
now has an LD of >1.5 cm and an LPD of > 1.0 cm

Unequivocal increase in the size of non-index disease

If PET performed (not required):
The appearance of any new lesion compatible with lymphoma with confirmation by other 
radiographic or histological modalities
The reappearance of any activity in a pre-existent lesion that meets size criteria for a new 
lesion on CT


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Note: If there is uncertainty regarding whether there is definitive lymphoma progression, the 
subject should continue study drug and remain under close observation (eg, evaluated at 
scheduled intervals. In particular, worsening of constitutional symptoms in the absence of 
objective evidence of worsening lymphoma will not be considered definitive disease progression; 
in such subjects, both lymphoma -related and non-lymphoma -related causes for the 
constitutional symptoms should be considered. Transient worsening of disease during temporary 
interruption of study drug(s) (eg, for intercurrent illness) may also not indicate definitive disease 
progression. In these instances, CT/MRI should be attempted in order to document whether 
definitive disease progression has occurred. If subsequent evaluations suggest that the subject 
has experienced persistent definitive disease progression, then the date of progression will be the 
time point at which progression was first objectively documented.
Non-Evaluable
In a subject who does not have evidence of PD, the occurrence of any of the following conditions 
indicates a response status of NE:

There are no images or inadequate or missing images.
Note: A time-point will be considered to have a response of NE if any index lesion is missing. PD 
may be assigned at any time point regardless of the extent of missing index or non-index lesions. 
Missing non-index lesions will not impact the ability to assess for response or disease 
progression. 


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


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Appendix 7.
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.  
Except in Group 2, 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, Group 2 subjects (breast cancer) who are pre/perimenopausal women are considered 
in a postmenopausal state due to treatment with the LHRH agonist goserelin. Patients 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 male born subject is considered to be fertile after the initiation 
of puberty unless permanently sterile by bilateral orchidectomy 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 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
Essure micro-insert system (provided confirmation of success 3 months after procedure)
Vasectomy in the male partner (provided that the partner is the sole sexual partner and 
had confirmation of surgical success 3 months after procedure)
Female subjects must also refrain from egg donation and in vitro fertilization during treatment 
and until at least 30 days after the end of relevant systemic exposure.
3) Contraception Requirements for Male Subjects
It is theoretically possible that a relevant systemic concentration may be achieved in a female 
partner from exposure of the male subject’s seminal fluid.  Therefore, male subjects with female 
partners of childbearing potential must use condoms during treatment and until 90 days after the 
end of relevant systemic exposure.  Additional contraception recommendations should also be 
considered if the female partner is not pregnant.
Male subjects must also refrain from sperm donation during treatment and until at least 90 days 
after the end of relevant systemic exposure.
4) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 


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only, and lactational amenorrhea method (LAM).  Female condom and male condom should not 
be used together.
5) 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 she is pregnant during the study must report the information to 
the investigator.  Instructions for reporting pregnancy, partner pregnancy, and pregnancy 
outcome are outlined in Section 7.6.2.1.


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


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Appendix 9.
Exemestane (Aromasin®) Prescribing Information
http://www.pfizer.com/products/product-detail/aromasin


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Appendix 10.
Fulvestrant (Faslodex®) Prescribing Information
http://www.faslodexhcp.com/home.html

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 1 Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of GS-5829 as a 
Monotherapy in Subjects with Advanced Solid Tumors and 
Lymphomas and in Combination with Exemestane or Fulvestrant 
in Subjects with Estrogen Receptor Positive Breast Cancer
Name of Test Drug:
GS-5829
Study Number:
GS-US-350-1599
Protocol Version (Date):
Amendment 6 (20 June 2016)
Analysis Type:
Final Analysis
Analysis Plan Version:
1.0
Analysis Plan Date:
03 January 2018
Analysis Plan Author(s):
CONFIDENTIAL AND PROPRIETARY INFORMATION
 
 
PPD


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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN..............................................................................................................................1
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF TABLES.........................................................................................................................................................3
PHARMACOKINETIC ABBREVIATIONS................................................................................................................6
1.
INTRODUCTION ................................................................................................................................................7
1.1.
Study Objectives ......................................................................................................................................7
1.2.
Study Design............................................................................................................................................8
1.3.
Sample Size and Power..........................................................................................................................10
2.
TYPE OF PLANNED ANALYSIS ....................................................................................................................11
2.1.
Interim Analyses ....................................................................................................................................11
2.2.
Final Analysis ........................................................................................................................................11
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES............................................................................12
3.1.
Analysis Sets..........................................................................................................................................12
3.1.1.
All Enrolled Analysis Set.....................................................................................................12
3.1.2.
Full Analysis Set ..................................................................................................................12
3.1.3.
Pharmacokinetic Analysis Set..............................................................................................12
3.2.
Subject Grouping ...................................................................................................................................12
3.3.
Strata and Covariates..............................................................................................................................13
3.4.
Examination of Subject Subgroups........................................................................................................13
3.5.
Multiple Comparisons............................................................................................................................13
3.6.
Missing Data and Outliers......................................................................................................................13
3.6.1.
Missing Data ........................................................................................................................13
3.6.2.
Outliers.................................................................................................................................13
3.7.
Data Handling Conventions and Transformations .................................................................................13
3.8.
Analysis Visit Windows.........................................................................................................................14
3.8.1.
Definition of Study Day .......................................................................................................14
3.8.2.
Analysis Visit Windows.......................................................................................................15
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window................................................................................................................................15
4.
SUBJECT DISPOSITION ..................................................................................................................................16
4.1.
Subject Enrollment and Disposition.......................................................................................................16
4.2.
Extent of Study Drug Exposure and Adherence.....................................................................................16
4.2.1.
Duration of Exposure to Study Drug....................................................................................16
4.2.2.
Adherence to GS-5829.........................................................................................................17
4.3.
Protocol Deviations................................................................................................................................17
5.
BASELINE CHARACTERISTICS....................................................................................................................18
5.1.
Demographics ........................................................................................................................................18
5.2.
Other Baseline Characteristics ...............................................................................................................18
5.3.
Medical History......................................................................................................................................18
5.4.
Prior Anticancer Therapy.......................................................................................................................18
6.
EFFICACY ANALYSES ...................................................................................................................................20
6.1.
Efficacy Endpoint...................................................................................................................................20
6.1.1.
Definition of Efficacy Endpoints..........................................................................................20
6.1.2.
Analysis Methods for Efficacy Endpoints............................................................................21


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7.
SAFETY ANALYSES........................................................................................................................................22
7.1.
Adverse Events and Deaths....................................................................................................................22
7.1.1.
Adverse Event Dictionary ....................................................................................................22
7.1.2.
Adverse Event Severity........................................................................................................22
7.1.3.
Relationship of Adverse Events to Study Drug....................................................................22
7.1.4.
Serious Adverse Events........................................................................................................22
7.1.5.
Treatment-Emergent Adverse Events...................................................................................22
7.1.6.
Summaries of Adverse Events and Deaths...........................................................................23
7.1.7.
Additional Analysis of Adverse Events ...............................................................................25
7.2.
Laboratory Evaluations ..........................................................................................................................25
7.2.1.
Summaries of Numeric Laboratory Results .........................................................................25
7.2.2.
Graded Laboratory Values ...................................................................................................26
7.2.3.
Liver-related Laboratory Evaluations...................................................................................27
7.2.4.
Shifts Relative to the Baseline Value ...................................................................................27
7.3.
Body Weight and Vital Signs.................................................................................................................27
7.4.
Prior and Concomitant Medications.......................................................................................................28
7.4.1.
Prior Medications .................................................................................................................28
7.4.2.
Concomitant Medications.....................................................................................................28
7.5.
Electrocardiogram Results .....................................................................................................................29
7.5.1.
Corrected QT Intervals.........................................................................................................29
7.5.2.
PR and QRS Intervals...........................................................................................................30
7.6.
Other Safety Measures ...........................................................................................................................30
7.7.
Changes From Protocol-Specified Safety Analyses...............................................................................30
8.
PHARMACOKINETIC (PK) ANALYSES........................................................................................................31
8.1.
PK Sample Collection............................................................................................................................31
8.1.1.
Estimation of PK Parameters ...............................................................................................31
8.1.2.
PK Parameters......................................................................................................................31
9.
REFERENCES ...................................................................................................................................................34
10.
SOFTWARE.......................................................................................................................................................35
11.
SAP REVISION..................................................................................................................................................36
12.
APPENDICES ....................................................................................................................................................37
Appendix 1.
Schedule of Assessments........................................................................................................37
Appendix 2.
List of Medical Search Terms for Decreased Platelets...........................................................41
Appendix 3.
List of Medical Search Terms for Haemorrhage ....................................................................42
Appendix 4.
List of Medical Search Terms for Diarrhoea..........................................................................61
LIST OF TABLES
Table 1.
PK Parameters for Analytes ...................................................................................................32


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LIST OF ABBREVIATIONS
AE
adverse event
AEI
adverse event of interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BLQ
below the limit of quantitation
BMI
body mass index
BOR
best overall response
CI
confidence interval
CR
complete response
CRF
case report form
CSR
clinical study report
CTCAE
Common Toxicity Criteria for Adverse Events
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DMC
data monitoring committee
ECG
electrocardiogram
ET
early termination
FAS
Full Analysis Set
Hb
hemoglobin
HLT
high-level term
ICH
International Conference on Harmonization (of Technical Requirements for Registration of 
Pharmaceuticals for Human Use)
LTT
lower-level term
LOQ
limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
NE
not evaluable
ORR
overall response rate
PD
progressive disease
PFS
progression-free survival
PK
pharmacokinetics
PR
partial response
PT
preferred term
Q1, Q3
first quartile, third quartile
QRS
electrocardiographic deflection between the beginning of the Q wave and termination of the 
S wave representing time for ventricular depolarization
QT
electrocardiographic interval between the beginning of the Q wave and termination of the T wave 
representing the time for both ventricular depolarization and repolarization to occur
QTc
QT interval corrected for heart rate
QTcF
QT interval corrected for heart rate using Fridericia’s formula


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RP2D
recommended phase 2 dose
RR
electrocardiographic interval representing the time measurement between the R wave of one 
heartbeat and the R wave of the preceding heartbeat
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
StD
standard deviation
SI (units)
international system of units
SOC
system organ class
TEAE
treatment-emergent adverse event
TFLs
tables, figures, and listings
ULN
upper limit of normal
VR
ventricular rate
WHO
World Health Organization


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PHARMACOKINETIC ABBREVIATIONS
AUClast
area under the concentration versus time curve from time zero to the last quantifiable concentration
AUCtau
area under the concentration versus time curve over the dosing interval
Clast
last observed quantifiable concentration of the drug 
Cmax
maximum observed concentration of drug 
Ctau
observed drug concentration at the end of the dosing interval
CLss/F
apparent oral clearance after administration of the drug:
at steady state: CLss/F = Dose/AUCtau , where “Dose” is the dose of the drug
t1/2
estimate of the terminal elimination half-life of the drug, calculated by dividing the natural log of 2 
by the terminal elimination rate constant (z)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination phase 
of the concentration of drug versus time curve




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1.2.
Study Design
This is an open-label, multicenter, sequential dose-escalation study to evaluate the safety,
tolerability, PK, and PD of GS-5829 as a single agent in subjects with advanced solid tumors and 
lymphomas and in combination with exemestane or fulvestrant in subjects with advanced 
estrogen receptor positive breast cancer.
Group 1: Single agent GS-5829 in solid tumors and lymphomas
Cohorts of subjects with advanced solid tumors and lymphomas who have failed or are intolerant 
to standard therapy or for whom no standard therapy exists will be sequentially enrolled at 
progressively higher dose levels to receive oral GS-5829 as monotherapy once daily (QD). The 
starting dose will be 0.6 mg. Each dose level will enroll 1 subject until a ≥Grade 2 treatment 
related toxicity is observed within the initial dosing period (Study Day 1 through Cycle 1 Day 28 
for all cohorts). At Dose Level 5 or if a ≥ Grade 2 treatment related toxicity is observed 
(whichever occurs first), the dose level will be expanded to 3 subjects. (Note: subjects enrolled 
with Grade 2 hemoglobin [Hb] must have Hb worsen by at least 1 grade from baseline to be 
considered for expansion of the cohort to 3 subjects).
Once a dosing level has been expanded to 3 subjects, a standard 3+3 study design will begin 
and, dose escalation [3+3] will be performed at every subsequent dose level with cohort sizes of 
3 to 6 subjects. Subjects in the first 3 cohorts will receive a single dose and then approximately
7 days later, initiate dosing once daily. 
The doses for each Dose Level are shown in the table below.
Group 1: Single Agent GS-5829
Dose Level
GS-5829*
1
0.6 mg
2
1.4 mg
3
2 mg
4
3 mg
5
4 mg
6
6 mg
7
9 mg
8
12 mg
*  
Dose Levels may be modified based on emerging safety and PK results.
If a dose limiting toxicity (DLT) occurs within the 28 day DLT period at any dose level, this 
level will be expanded to enroll 3 additional subjects. 


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The safety and tolerability of each dose level will be assessed by a safety review team (SRT) 
after all subjects in the cohort have been followed for at least 28 days after the first dose of 
GS-5829. If no DLTs occur in up to 3 subjects or < 2 DLTs occur in up to 6 subjects on any dose 
level after 28 days on treatment, the next dose level will open. Each subsequent dose level will 
open if the dose level preceding has no DLTs in 3 subjects or < 2 DLTs in up to 6 subjects.
Group 2: Combination therapy of GS-5829 with exemestane or fulvestrant in patients with 
advanced stage estrogen receptor positive breast cancer 
Cohorts of subjects with advanced stage estrogen receptor positive breast cancer 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 
full standard doses of exemestane or fulvestrant. The starting dose of GS-5829 will be 2.0 mg 
QD, which is a dose level that has been demonstrated to be safe and tolerable (no Grade 2 or 
higher drug related toxicity) as a single agent in patients with solid tumors. Dose escalation will 
continue with cohort sizes of 3-6 subjects in parallel arms: Group 2A will initiate with 2.0 mg of 
GS-5829 orally once daily on Cycle 1 Day 1 combined with 25 mg of exemestane administered 
once daily beginning on Cycle 1 Day 1. The subject may initiate exemestane any time prior to, or 
on, Cycle 1 Day 1. Group 2B will initiate with 2.0 mg of GS-5829 orally once daily on Cycle 1 
Day 1 with 500 mg fulvestrant administered intramuscularly Cycle 1 Day 1 and then every 
28 days (+/- 3 days). If Cycle 1 Day 1 is the subject’s first dose of fulvestrant, a one-time
additional dose of fulvestrant should be administered on Cycle 1 Day 15. 
The candidate doses of GS-5829 for each Dose Level for Group 2 are shown in the table below.
Group 2: Combination of GS-5829 in Breast Cancer
Dose Level
GS-5829*
Group 2A Exemestane
Group 2B Fulvestrant
1
2 mg
25 mg orally once daily
500 mg intramuscularly day 1, 29 
and then every 28 days**
2
3 mg
3
4 mg
4
6 mg
5
9 mg
6
12 mg
*  
Dose Levels may be modified based on emerging safety and PK results.
** Subjects initiating fulvestrant on this study should receive a single additional dose of fulvestrant on Cycle 1 Day 15.
Group 2A and Group 2B will dose escalate independent of each other. In both Groups 2A and 
Group 2B, each cohort will consist of 3 newly enrolled subjects who will be treated at the 
specified dose level. After all subjects in each cohort have been followed for at least 28 days 
after the first dose of GS-5829, a dose-DLT model (Bayesian logistic regression model) utilizing 
all available GS-5829 safety data will be built, and will provide estimates of DLT rates at all 
dose levels.


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1.3.
Sample Size and Power
The sample size of the study is determined based on the number of dose levels evaluated and the 
emerging GS-5829-related toxicities. The study will consist of up to 120 subjects.
A total of 33 subjects were enrolled when the study was completed.


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2.
TYPE OF PLANNED ANALYSIS
2.1.
Interim Analyses
This study does not have a data monitoring committee (DMC). Therefore, no analyses will be 
conducted for the DMC.
No formal interim efficacy analysis, which may lead to early termination for efficacy or futility,
is planned.
2.2.
Final Analysis
After all subjects have completed the study, outstanding data queries have been resolved or 
adjudicated as unresolvable, and the data have been cleaned and finalized, the final analysis of 
the data will be performed.


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3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (StD) or standard error (SE), median, first 
quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the All Enrolled Analysis Set and sorted 
by subject ID number, visit date, and time (if applicable). Data collected on log forms, such as
adverse events, will be presented in chronological order within the subject. The study group and 
dose level to which subjects were initially assigned will be used in the listings. Age, sex at birth, 
race, and ethnicity will be included in the listings, as space permits.
3.1.
Analysis Sets
Analysis sets define the subjects to be included in an analysis. Analysis sets and their definitions 
are provided in this section. The analysis set will be identified and included as a subtitle of each 
table, figure, and listing.
For each analysis set, the number and percentage of subjects eligible for inclusion, as well as the 
number and percentage of subjects who were excluded, will be summarized by study group and 
dose level.
A listing of reasons for exclusion from analysis sets will be provided by subject.
3.1.1.
All Enrolled Analysis Set
All Enrolled Analysis Set includes all subjects who received a study subject identification 
number in the study after screening.
3.1.2.
Full Analysis Set
The Full Analysis Set (FAS) includes all subjects who took at least 1 dose of study drug. This is 
the primary analysis set for efficacy analyses and safety analyses.
3.1.3.
Pharmacokinetic Analysis Set
The Pharmacokinetic (PK) Analysis Set will include all enrolled subjects who took at least 
1 dose of study drug and have at least 1 nonmissing postdose value reported by the PK 
laboratory. This is the primary analysis set for all PK analyses.
3.2.
Subject Grouping
For analyses based on the FAS, subjects will be grouped according to the actual treatment 
received. 
For the PK Analysis Set, subjects will be grouped according to the actual treatment they 
received.


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3.3.
Strata and Covariates
This study does not use a stratified randomization schedule when enrolling subjects. 
No covariates will be included in safety analyses.
3.4.
Examination of Subject Subgroups
There are no prespecified subject subgroupings for safety analyses.
3.5.
Multiple Comparisons
Adjustments for multiplicity will not be made, because no formal statistical testing will be 
performed in this study.
3.6.
Missing Data and Outliers
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in this document.
For missing last dosing date of study drug, imputation rules are described in Section 4.2.1. The 
handling of missing or incomplete dates, for adverse event (AE) onset is described in 
Section 7.1.5.2, and for prior and concomitant medications in Section 7.4.
3.6.2.
Outliers
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.7.
Data Handling Conventions and Transformations
In general, age (in years) on the date of the first dose of study drug will be used for analyses and 
presentation in listings. If an enrolled subject was not dosed with any study drug, the enrollment
date will be used instead of the first dosing date of study drug. For screen failures, the date the 
informed consent was signed will be used for age calculation. If only the birth year is collected 
on the CRF, “01 July” will be used for the unknown birth day and month for the purpose of age 
calculation. If only birth year and month are collected, “01” will be used for the unknown birth 
day.
Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ)
or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “x” (where x is considered the LOQ). For example, if the 
values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or < 0.1, 
etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to 
calculate summary statistics.


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
A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “> x” (where x is considered the LOQ). Values with decimal 
points will follow the same logic as above.

The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of 
“≤ x” or “≥ x” (where x is considered the LOQ).
If methods based on the assumption that the data are normally distributed are not adequate, 
analyses may be performed on transformed data or nonparametric analysis methods may be used, 
as appropriate.
Natural logarithm transformation will be used for plasma/blood concentrations and analysis of 
PK parameters. Plasma concentration values that are below the limit of quantitation (BLQ) will 
be presented as “BLQ” in the concentration data listing. Values that are BLQ will be treated as 
0 at predose time points, and one-half the value of the LOQ at postbaseline time points.
The following conventions will be used for the presentation of summary and order statistics:

If at least 1 subject has a concentration value of BLQ for the time point, the minimum value 
will be displayed as “BLQ.”

If more than 25% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum and Q1 values will be displayed as “BLQ.”

If more than 50% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, and median values will be displayed as “BLQ.”

If more than 75% of the subjects have a concentration data value of BLQ for a given time 
point, the minimum, Q1, median, and Q3 values will be displayed as “BLQ.”

If all subjects have concentration data values of BLQ for a given time point, all order 
statistics (minimum, Q1, median, Q3, and maximum) will be displayed as “BLQ.”
PK parameters that are BLQ will be imputed as one-half LOQ before log transformation or 
statistical model fitting.
3.8.
Analysis Visit Windows
3.8.1.
Definition of Study Day
Study day will be calculated from the first dosing date of study drug and derived as follows:

For postdose study days: Assessment Date – First Dosing Date + 1

For days prior to the first dose: Assessment Date – First Dosing Date
Therefore, study day 1 is the day of the first dose of study drug administration.


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3.8.2.
Analysis Visit Windows
The nominal visit as recorded on the CRF will be used when data are summarized by visit. Any 
data relating to unscheduled visits will not be assigned to a particular visit or time point. 
However, the following exceptions will be made:

An unscheduled visit prior to the first dosing of study drug may be included in the calculation 
of the baseline value, if applicable.

Unscheduled visits after the first dose of study drug will be included in determining the 
maximum postbaseline toxicity grade.

For subjects who prematurely discontinue from the study, early termination (ET) data will be 
assigned to what would have been the next scheduled visit where the respective data were 
scheduled to be collected.

Data collected on a follow-up visit will be summarized as a separate visit, and labeled 
“Follow-up Visit.”

Data obtained after the follow-up visit or last dose date plus 30 days (whichever is later) will 
be excluded from the summaries, but will be included in the listings.
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window.
If multiple valid, nonmissing, continuous measurements exist in an analysis window, records 
will be chosen based on the following rules if a single value is needed:

In general, the baseline value will be the last nonmissing value on or prior to the first dosing 
date of study drug, unless specified differently. If multiple measurements occur on the same 
day, the last nonmissing value prior to the time of first dosing of study drug will be 
considered as the baseline value. If these multiple measurements occur at the same time or 
the time is not available, the last measurements (for continuous data) will be considered the 
baseline value.

For postbaseline values:
The record closest to the nominal day for that visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken, unless 
otherwise specified.


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4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject disposition will be provided by study group and dose level. This summary 
will present the number of subjects screened, the number of subjects enrolled, and the number of 
subjects in each of the categories listed below for each study group:

Full Analysis Set

Discontinued study drug with reasons for premature discontinuation of study drug

Completed study

Discontinued the study with reasons for premature discontinuation of study
For the status of study drug and study completion and reasons for premature discontinuation, the 
number and percentage of subjects in each category will be provided. The denominator for the 
percentage calculation will be the total number of subjects in the FAS corresponding to that 
column.
The following by-subject listing will be provided by subject identification (ID) number in 
ascending order to support the above summary tables:

Reasons for premature study drug or study discontinuation
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to GS-5829 will be examined by assessing the total duration of exposure to 
study drug and the level of adherence to the study drug specified in the protocol.
4.2.1.
Duration of Exposure to Study Drug
Total duration of exposure to GS-5829 will be defined as last dosing date minus first dosing date 
plus 1, regardless of any temporary interruptions in study drug administration, and will be 
expressed in weeks using up to 1 decimal place (eg, 4.5 weeks). 
If the last study drug dosing date is missing, 

If the study drug is permanently withdrawn, the latest date among the study drug end date, 
clinical visit date, laboratory sample collection date, and vital signs assessment date that 
occurred during the on-treatment period will be used.

If the study drug completion status is unknown, the earlier of the date of death or data cutoff 
date for analysis will be used.


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The total duration of exposure to GS-5829 will be summarized using descriptive statistics and
using the number (ie, cumulative counts) and percentage of subjects exposed through the 
following time periods: 1 day, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 36 weeks, 48 weeks, and 
60 weeks. Summaries will be provided by study group and dose level for the FAS.
No formal statistical testing is planned.
4.2.2.
Adherence to GS-5829
The total number of tablets administered will be summarized using descriptive statistics. 
The presumed total number of tablets administered to a subject will be determined by the data 
collected on the drug accountability CRF using the following formula:
Total Number of Doses Administered =
No. of Doses Dispensed
No. of Doses Returned















4.2.2.1.
On-Treatment Adherence
The level of on-treatment adherence to GS-5829 will be determined by the total amount of study 
drug administered relative to the total amount of study drug expected to be administered during a 
subject’s actual on-treatment period based on the study drug regimen. Investigator-prescribed 
interruption, reductions and escalations as specified in the protocol will be taken into account.
The level of on-treatment adherence will be expressed as a percentage using the following 
formula:
Descriptive statistics for the level of on-treatment adherence with the number and percentage of 
subjects belonging to adherence categories (eg, < 75%, ≥ 75) will be provided by dose level for 
the FAS. 
A by-subject listing of study drug administration and drug accountability will be provided 
separately by subject ID number (in ascending order) and visit (in chronological order).
No formal statistical testing is planned.
4.3.
Protocol Deviations 
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation reason (eg, nonadherence to study drug, violation of select inclusion/exclusion criteria) 
will be summarized by study group and dose level for the All Enrolled Analysis Set. A 
by-subject listing will be provided for those subjects with important protocol deviation.
Total Amount of Study Drug Administered
On-Treatment Adherence (%) = 
 x 100
Study Drug Expected to be Administered on Treatment








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5.
BASELINE CHARACTERISTICS
5.1.
Demographics
Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized by dose 
level, overall and study group using descriptive statistics for age, and using number and 
percentage of subjects for sex, race, and ethnicity. The summary of demographic data will be 
provided for the FAS.
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order.
5.2.
Other Baseline Characteristics
Other baseline characteristics include body weight (in kg), height (in cm), and body mass index 
(BMI; in kg/m2). These baseline characteristics will be summarized by dose level, overall and 
study group using descriptive statistics for continuous variables and using number and 
percentage of subjects for categorical variables. The summary of baseline characteristics will be 
provided for the FAS. No formal statistical testing is planned.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order.
5.3.
Medical History
Medical history will be collected at screening for disease-specific and general conditions 
(ie, conditions not specific to the disease being studied).
General medical history data will not be coded, but will be listed only.
A by-subject listing of disease-specific and general medical history will be provided by subject 
ID number in ascending order.
5.4.
Prior Anticancer Therapy
Number of prior regimens and time since the completion of last regimen will be summarized by 
study group and dose level using descriptive statistics based on the FAS. A partial completion 
date will be imputed as follows:

If day and month are missing but year is available, then the imputed day and month will be 
01 Jan.

If day is missing but the month and year are available, then the imputed day will be the first 
day of the month.

Partial date will not be imputed if the year is missing.


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The regimens and prior therapies that the subjects received will be summarized. The last regimen 
subjects received prior to study entry and the best response to the last regimen will be 
summarized.
Number of subjects who received prior radiation therapy will be listed.


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6.
EFFICACY ANALYSES
6.1.
Efficacy Endpoint
6.1.1.
Definition of Efficacy Endpoints
6.1.1.1.
Progression-free Survival
Progression-free survival is defined as the interval from first dosing date of study drug to the 
earlier of the first documentation of definitive disease progression or death from any cause. 
Definitive disease progression is determined based on RECIST v1.1 for solid tumors
{Eisenhauer 2009} or Cheson Criteria {Cheson 2007} for lymphoma or PCWG2 for prostate 
cancer.
The date of definitive progression will be the time point at which progression is first identified 
by relevant radiographic, imaging, or clinical data. Data will be censored on the date of last 
adequate tumor assessment for subjects:

who do not have documented progression or die, or 

who start new anticancer therapy before documented progression, or

who start new anticancer therapy before death without documented progression, or

who have ≥ 2 consecutive missing tumor assessments before documented progression, or

who have ≥ 2 consecutive missing tumor assessments before death without documented 
progression
If a subject does not have a baseline tumor assessment, then PFS will be censored at Study 
Day 1, regardless of whether or not definitive progression or death has been observed.
When the date of initiation of anticancer therapy other than the study treatment is incomplete or 
missing, the following algorithm will be followed:

If the day is missing but the month and year are available, then the imputed day will be the 
last day of the month.

If day and month are missing but year is available, then the imputed day and month will be 
01Jan or the last day of the month for the last adequate disease assessment if they have the 
same year, whichever is later.


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6.1.1.2.
Overall Response Rate
Overall response rate is defined as the proportion of subjects who achieve best overall response
(BOR) of complete response (CR) or partial response (PR) during study. The response definition 
of each response category is based on RECIST v1.1 for solid tumors, and Cheson Criteria for 
lymphoma. Subjects, who do not have sufficient baseline or on-study tumor status information to 
be adequately assessed for response status (ie, those with best overall response of not evaluable 
[NE]) or received anticancer therapy other than the study treatment prior to achieving CR or PR, 
will be considered as nonresponders and will be included in the denominators in calculations of 
response rates.
6.1.2.
Analysis Methods for Efficacy Endpoints
6.1.2.1.
Progression-free Survival
Progression-free survival based on investigators’ assessments will be summarized using 
descriptive statistics by study group and dose level.
6.1.2.2.
Overall Response Rate
Overall response rate based on investigators’ assessments will be calculated along with its 95% 
CIs based on exact method. In the analyses of ORR, the BOR will be summarized by study 
group, dose level, and each response category as CR, PR, SD, PD, and NE.


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


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7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the first dosing date of 
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of study drug 
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
If the onset of the AE is incomplete and needs to be imputed, the following algorithm will be 
followed:

If the day is missing but the month and year are available, then the imputed day will be the 
first day of the month or the first dosing date if they have the same month and year, 
whichever is later.

If the day and month are missing but year is available, then the imputed day and month will 
be 01Jan or the first dosing date if they have the same year, whichever is later.
7.1.6.
Summaries of Adverse Events and Deaths
Treatment-emergent AEs will be summarized based on the FAS.
7.1.6.1.
Summaries of AE incidence by Severity
The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by SOC, PT, dose level, and study group. For other AEs described below, 
summaries will be provided by SOC, PT, maximum severity, dose level, and study group:

TEAEs

TEAEs of Grade 3 or higher

TE GS-5829-related AEs

TE GS-5829-related AEs of Grade 3 or higher 


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
TE SAEs

TE GS-5829-related SAEs 

TEAEs leading to premature discontinuation of GS-5829

TEAEs leading to death

TEAEs leading to temporary interruption of GS-5829

TEAEs leading to dose reduction of GS-5829
A brief, high-level summary of AEs described above will be provided by study group and dose 
level and by the number and percentage of subjects who experienced the above AEs.
Multiple events will be counted only once per subject in each summary. Adverse events will be 
summarized and listed first in alphabetic order of SOC and HLT within each SOC (if applicable), 
and then by PT in descending order of total frequency within each SOC. For summaries by 
severity grade, the most severe grade will be used for those AEs that occurred more than once in 
an individual subject during the study. 
In addition to the above summary tables, TEAEs, TEAEs of Grade 3 or higher, TE treatment-
related AEs, and TE SAEs will be summarized by PT only in descending order of total 
frequency.
In addition, data listings will be provided for the following:

All AEs, indicating whether the event is treatment emergent

All AEs of Grade 3 or higher

SAEs

Deaths

AEs leading to death

AEs leading to premature discontinuation of GS-5829

AEs leading to temporary interruption of GS-5829

AEs leading to dose reduction of GS-5829


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7.1.7.
Additional Analysis of Adverse Events
7.1.7.1.
Dose Limiting Toxicity
A listing of the DLT AEs will be provided by study group and cohort including cohort number 
with dose level, subject identification, DLT term from investigator as well as CTCAE term and 
associated severity grade, if available.
7.1.7.2.
Treatment-Emergent Adverse Events (TEAE) of Interest
The treatment-emergent AEs of interest (AEI) include:

Decreased Platelets (Preferred terms are defined in Appendix 2 of this SAP)

Haemorrhage (Preferred terms are defined in Appendix 3 of this SAP)

Diarrhoea (Preferred terms are defined in Appendix 4 of this SAP)
The AEIs will be summarized similarly to TEAE by study group and dose level cohort.
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the FAS
and will include data collected up to the last dose of study drug plus 30 days for subjects who 
have permanently discontinued study drug. The analysis will be based on values reported in 
conventional units. When values are below the LOQ, they will be listed as such, and the closest 
imputed value will be used for the purpose of calculating summary statistics as specified in 
Section 3.7.
A by-subject listing for laboratory test results will be provided by subject ID number and visit in 
chronological order for hematology, serum chemistry, coagulation, and urinalysis separately. 
Values falling outside of the relevant reference range and/or having a severity grade of 1 or 
higher on the CTCAE severity grade will be flagged in the data listings, as appropriate.
No formal statistical testing is planned.
7.2.1.
Summaries of Numeric Laboratory Results
Descriptive statistics will be provided by study group and dose level for each laboratory test 
specified in the study protocol as follows:

Baseline values 

Values at each postbaseline visit

Change from baseline at each postbaseline visit


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A baseline laboratory value will be defined as the last measurement obtained on or prior to the 
date/time of first dose of study drug. Change from baseline to a postbaseline visit will be defined 
as the visit value minus the baseline value. The mean, median, Q1, Q3, minimum, and maximum 
values will be displayed to the reported number of digits; StD values will be displayed to the 
reported number of digits plus 1.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3.
7.2.2.
Graded Laboratory Values
The CTCAE, Version 4.03, will be used to assign toxicity grades (0 to 4) to laboratory results for 
analysis. Grade 0 includes all values that do not meet the criteria for an abnormality of at least 
Grade 1. For laboratory tests with criteria for both increased and decreased levels, analyses for 
each direction (ie, increased, decreased) will be presented separately. Local labs will be graded
based on central lab normal ranges with in-house macro. In the event that both central and local 
lab results are collected in the clinical database, the worst toxicity grade will be used for the 
summary of lab toxicities. All central and local laboratory values will be listed.
7.2.2.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days for subjects who permanently discontinued study drug, or the 
last available date in the database snapshot for subjects who were still on treatment at the time of 
an interim analysis. If the relevant baseline laboratory value is missing, any abnormality of at 
least Grade 1 observed within the time frame specified above will be considered treatment 
emergent.
7.2.2.2.
Summaries of Laboratory Abnormalities
Laboratory data that are categorical will be summarized using the number and percentage of 
subjects in the study with the given response at baseline and each scheduled postbaseline visit.
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by lab test, dose level, and study group; subjects will be 
categorized according to the most severe postbaseline abnormality grade for a given lab test:

Graded laboratory abnormalities
For all summaries of laboratory abnormalities, the denominator is the number of subjects in the 
FAS.
A by-subject listing of treatment-emergent laboratory abnormalities will be provided by subject 
ID number and visit in chronological order. This listing will include all test results that were 
collected throughout the study for the lab test of interest, with all applicable severity grades
displayed.


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7.2.3.
Liver-related Laboratory Evaluations
Liver-related abnormalities after initial study drug dosing will be examined and summarized 
using the number and percentage of subjects who were reported to have the following laboratory 
test values for postbaseline measurements:

Aspartate aminotransferase (AST): (a) > 3 times of the upper limit of reference range
(ULN); (b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x ULN

Alanine aminotransferase (ALT): (a) > 3 x ULN; (b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x 
ULN

AST or ALT: (a) > 3 x ULN; (b) > 5 x ULN; (c) > 10 x ULN; (d) > 20 x ULN

Total bilirubin: (a) > 1 x ULN; (b) > 2 x ULN

Alkaline phosphatase (ALP) > 1.5 x ULN

AST or ALT > 3 x ULN: (a) total bilirubin > 1.5 x ULN; (b) total bilirubin > 2 x ULN; 
(c) total bilirubin > 2 x ULN and ALP < 2 x ULN
The summary will include data from all postbaseline visits up to 30 days after the last dose of 
study drug. For individual laboratory tests, subjects will be counted once based on the most 
severe postbaseline values. For both the composite endpoint of AST or ALT and total bilirubin, 
subjects will be counted once when the criteria are met at the same postbaseline visit date. The 
denominator is the number of subjects in the FAS who have nonmissing postbaseline values of 
all relevant tests at the same postbaseline visit date. 
In addition, a listing of subjects who met at least 1 of the above criteria will be provided.
7.2.4.
Shifts Relative to the Baseline Value
Shift tables will be presented by showing change in severity grade from baseline to the worst 
grade postbaseline.
7.3.
Body Weight and Vital Signs
Descriptive statistics will be provided by study group and dose level for body weight and vital 
signs as follows:

Baseline value

Values at each postbaseline visit

Change from baseline at each postbaseline visit


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A baseline value will be defined as the last available value collected on or prior to the date of 
first dose of study drug. Change from baseline to a postbaseline visit will be defined as the 
postbaseline value minus the baseline value. Body weight and vital signs measured at 
unscheduled visits will be included for the baseline value selection.
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. No formal statistical testing is planned.
A by-subject listing of vital signs will be provided by subject ID number and visit in 
chronological order. Body weight will be included in the vital signs listing, if space permits. If 
not, they will be provided separately.
7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization (WHO) Drug dictionary.
7.4.1.
Prior Medications
Prior medications are defined as any medications taken before a subject took the first study drug.
A summary of prior medications will not be provided. 
7.4.2.
Concomitant Medications
Concomitant medications are defined as medications taken while a subject took study drug. Use 
of concomitant medications will be summarized by preferred name using the number and 
percentage of subjects for each study group and dose level. A subject reporting the same 
medication more than once will be counted only once when calculating the number and 
percentage of subjects who received that medication. The summary will be ordered by preferred 
term in descending overall frequency. For drugs with the same frequency, sorting will be done 
alphabetically.
For the purposes of analysis, any medications with a start date prior to or on the first dosing date 
of study drug and continued to be taken after the first dosing date, or started after the first dosing 
date but prior to or on the last dosing date of study drug will be considered concomitant 
medications. Medications started and stopped on the same day as the first dosing date or the last 
dosing date of study drug will also be considered concomitant. Medications with a stop date prior 
to the date of first dosing date of study drug or a start date after the last dosing date of study drug 
will be excluded from the concomitant medication summary. If a partial stop date is entered, any 
medication with the month and year (if day is missing) or year (if day and month are missing) 
prior to the date of first study drug administration will be excluded from the concomitant 
medication summary. If a partial start date is entered, any medication with the month and year (if 
day is missing) or year (if day and month are missing) after the study drug stop date will be 
excluded from the concomitant medication summary. Medications with completely missing start 
and stop dates will be included in the concomitant medication summary, unless otherwise 
specified. Summaries will be based on the FAS. No formal statistical testing is planned.


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7.5.2.
PR and QRS Intervals
The PR interval (measured in msec) is a measure of the time between the start of the P wave (the 
onset of atrial depolarization) and the beginning of the QRS complex (the onset of ventricular 
depolarization). The QRS interval measures the duration of the QRS complex. The maximum 
ventricular rate (VR) and PR and QRS intervals observed during the study will be categorized. 
The number and percentage of subjects having values in the following ranges will be presented 
by study group and dose level:

VR > 100 bpm

PR interval > 200 msec

QRS interval > 110 msec
In addition, VR, PR, RR, and QRS values at each visit and time point and change from baseline 
at each visit and time point will be summarized for the FAS by study group and dose level using 
descriptive statistics.
7.6.
Other Safety Measures
No additional safety measures are specified in the protocol.
7.7.
Changes From Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


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8.
PHARMACOKINETIC (PK) ANALYSES
8.1.
PK Sample Collection
Plasma samples for GS-5829 PK will be collected in cohorts 1 - 3 of Group 1 on Study Day 1 at 
predose, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours postdose and in cohorts 4 - 6 of Group 1 and all 
cohorts of Group 2 on Cycle 1 Day 1 at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours postdose. 
Additional samples will be collected at 48 and 72 hours postdose in cohorts 1 - 3 of Group 1 
relative to first dose of GS-5829. Plasma samples for GS-5829 PK will be collected in all cohorts
at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours post dose relative to GS-5829 administration on 
Cycle 1 Day 8. Sparse PK samples will be collected in all cohorts at trough (20 - 26 hours 
postdose) on Cycle 1 Day 4, 2 - 4 hours post dose on Cycle 1 Day 15, and anytime postdose on 
Day 1 of Cycles 2 through 6. In one or more cohorts, PK samples will be collected on Day 1 of 
Cycle 2 at pre-dose and 0.5, 1, 2, 3, 4, 6, 8, and 24 hours post dose. 
8.1.1.
Estimation of PK Parameters
PK parameters will be estimated using Phoenix WinNonlin® software using standard 
noncompartmental methods. The linear/log trapezoidal rule will be used in conjunction with the 
appropriate noncompartmental model, with input values for dose level, dosing time, plasma 
concentration, and corresponding real-time values, based on drug dosing times whenever 
possible.
All predose sample times before time-zero will be converted to 0.
For area under the curve (AUC), samples BLQ of the bioanalytical assays occurring prior to the 
achievement of the first quantifiable concentration will be assigned a concentration value of 0 to 
prevent overestimation of the initial AUC. Samples that are BLQ at all other time points will be 
treated as missing data in WinNonlin. The nominal time point for a key event or dosing interval 
(τ) may be used to permit direct calculation of AUC over specific time intervals. The 
appropriateness of this approach will be assessed by the PK scientist on a profile-by-profile 
basis.
Pharmacokinetic parameters such as AUCtau, λz and t1/2 are dependent on an accurate estimation 
of the terminal elimination phase of drug. The appropriateness of calculating these parameters 
will be evaluated upon inspection of PK data on a profile-by-profile basis by the PK scientist.
8.1.2.
PK Parameters
PK parameters will be generated for all subjects in the PK analysis set. The analytes presented in 
Table 1 will be evaluated if data are available.


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Table 1.
PK Parameters for Analytes
GS-5829
GS-697412
Metabolite/parent ratio
Study Day 1/ Cycle 1 Day 1
(Study Day 1 only applies to 
Group 1 cohort 1-3)
Cmax, Tmax, AUC0-24h, 
AUClast, AUCinf, C24h, 
Clast, Tlast, λz, T1/2, 
Vz_F_obs, CL_F_obs
Cmax, Tmax, AUC0-24h, 
AUClast, AUCinf, C24h, Clast, 
Tlast, λz, T1/2
Cmax, AUC0-24h, and C24h
Cycle 1 Day 8
Cmax, Tmax, AUCtau, 
AUClast, AUCinf, Ctau, 
Clast, Tlast, λz, T1/2, Vz_F, 
CLss_F
Cmax, Tmax, AUCtau, 
AUClast, AUCinf, Ctau, Clast, 
Tlast, λz, T1/2
Cmax, AUCtau, and Ctau
Individual subject concentration data and individual subject PK parameters for GS-5829 and its 
metabolite GS-697412 will be listed and summarized using descriptive statistics by treatment. 
Summary statistics (n, mean, StD, coefficient of variation [%CV], median, min, max, Q1, and 
Q3) will be presented for both individual subject concentration data by time point and individual 
subject PK parameters by dose level. Moreover, the geometric mean, 95% CI, and the mean and 
StD of the natural log-transformed values will be presented for individual subject PK parameter 
data. 
Individual metabolite to parent ratios will be calculated for AUC0-24h, Cmax, and C24h on Study 
Day 1 and Cycle 1 Day 1, and for AUCtau, Cmax, and Ctau on Cycle 1 Day 8, when available, and 
summarized similarly to the PK parameters.
Individual concentration data listings and summaries will include all subjects with concentration 
data. The sample size for each time point will be based on the number of subjects with 
nonmissing concentration data at that time point. The number of subjects with concentration 
BLQ will be presented for each time point. For summary statistics, BLQ values will be treated as 
0 at predose and one-half of the lower limit of quantitation (LLOQ) for postdose time points.
Individual PK parameter data listings and summaries will include all subjects for whom PK 
parameter(s) can be derived. The sample size for each PK parameter will be based on the number 
of subjects with nonmissing data for that PK parameter.
The following tables will be provided by dose level:

Individual subject concentration data and summary statistics

Individual subject plasma PK parameters and summary statistics

Individual metabolite to parent ratios for AUC0-24h, Cmax, and C24h on Study Day 1 and Cycle 
1 Day 1, and for AUCtau, Cmax, and Ctau, on Cycle 1 Day 8 and its summary statistics.


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The following figures may be provided by dose level:

Mean (± StD) concentration data versus time (on linear and semilogarithmic scales)

Median (Q1, Q3) concentration data versus time (on linear and semilogarithmic scales)
Individual, mean, and median postdose concentration values that are ≤LLOQ will not be 
displayed in the figures and remaining points connected.
PK sampling details by subject, including procedures, differences in scheduled and actual draw 
times, and sample age will be provided in listings.


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9.
REFERENCES
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol 2007;25 (5):579-86.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New Response 
Evaluation Criteria in Solid Tumours: Revised RECIST Guideline (Version 1.1). 
Eur J Cancer 2009;45 (2):228-47.
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, 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 (7):1148-59.


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10.
SOFTWARE
SAS® Software Version 9.4. SAS Institute Inc., Cary, NC, USA.


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11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


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12.
APPENDICES
Appendix 1.
Schedule of Assessments
Study Phase Cycle Day
Screening 
Day 28
Study 
Day 1a
First 28 Days
Cycle 2 
Day 1 and 
Every 
2 weeks*
Cycle 2 
Day 1 
and 
Every 
4 weeks
Every 
8 weeks
EOT
30 day 
Safety 
Follow-upk
Cycle 1 
Day 1b
Day 2
Day 4
Day 8
Day 11
Day 15
Day 22
Window (day)
-28
±0
±3
±0
±0
±1
±1
±2
±3
±7
±7
±7
±7
±7
Informed Consent
X
Medical and Medication 
Historyc
X
Physical Examinationd
X
X
X
X
X
X
X
X
X
X
X
Vital Signse
X
X
X
X
X
X
X
X
X
X
X
Oxygen saturationf
X
X
X
X
X
X
X
X
X
X
X
Echocardiogramr
X
X
X
Triplicate 12-lead ECGg
X
X
X
X
X
X
Adverse events/ 
Concomitant medicationsh
X
X
X
X
X
X
X
X
X
X
X
X
IP Dispensing  
Xi
X
X
Exemestane or Fulvestrantw 
(Group 2 only)
X
X
X
Dosing Diary Accountability 
X
X
X
X
X
X
X
X
IXRS Registration
X
X
Xj
X
X
CBC with differential
Xs
X
X
X
X
X
X
X
X
X
Chemistryy
Xs
X
X
X
X
X
X
X
X
X
Coagulationq
Xs
X
X
X
X
25-hydroxy vitamin D 
(Group 2 only)
X


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Study Phase Cycle Day
Screening 
Day 28
Study 
Day 1a
First 28 Days
Cycle 2 
Day 1 and 
Every 
2 weeks*
Cycle 2 
Day 1 
and 
Every 
4 weeks
Every 
8 weeks
EOT
30 day 
Safety 
Follow-upk
Cycle 1 
Day 1b
Day 2
Day 4
Day 8
Day 11
Day 15
Day 22
Window (day)
-28
±0
±3
±0
±0
±1
±1
±2
±3
±7
±7
±7
±7
±7
Urinalysis and Urine 
Chemistry
X
X
X
X
X
X
Pregnancy Testl
X
X
Xj
X
X
GS-5829 Intensive PKm
X
X
X
Xv
GS-5829 Sparse PKm
X
X
Xv
Biopsies for Group 3 
lymphoma expansionx
X
Xx
X
CT Scan w/Contrast or MRIP
X
X
XP
PET Scan (Group 3 only)z
X
Bone Scan(Group 2 only)
X
X
ECOG Performance Status
X
X
X
X
X
X
X
Treatment Response 
Assessmentt
X
X
*  
Day 1 of subsequent cycles.
a
Study Day 1 is applicable to Cohorts 1-3 only of Group 1.
b
Cycle 1 Day 1 occurs on Study Day 7 for subjects in Cohorts 1-3 of Group 1 and must occur at least 5 days, but no more than 9 days after Study Day 1. For Group 1 Cohorts 4 
and higher and all cohorts of Group 2 the first day of study is Cycle 1 Day 1.
c
Medical history includes significant past medical events (eg, prior hospitalizations or surgeries), a review of the disease under study, prior anti-cancer therapies, and any 
concurrent medical illnesses.
d
Screening and End of Treatment Physical Examinations (PE) will be a complete PE. Beginning at Study Day 1 (Group 1 Cohorts 1-3) and C1D1 (all groups), a modified 
physical examination will be performed to monitor for any changes (e.g. lymph nodes, lung, cardiac, abdomen, skin, neurologic, and any systems, as clinically indicated).  
Weight (without shoes) should be measured at each PE.  Height (without shoes) should be measured at screening only.
CCI
CCI
CCI




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w
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 Cycle 1 Day 1 
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 Cycle 1 Day 1 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).
x
Biopsies are requested from subjects with accessible disease and should be core needle or excision biopsies. The pre-treatment biopsy can be obtained any time after the last 
line of therapy and prior to the first dose, the Cycle 2 Day 15 biopsy can be obtained anytime between Cycle 2 Day 1 and Cycle 2Day 21. The EOT biopsy should be collected 
at progression only for subjects with progressive disease. 
y
AAG will be collected at Screening, pre-dose on C1D1 and C1D8 only.  Ferritin and CRP will be collected pre-dose on C1D1 and Day 1 of every subsequent cycle.
z
Subjects who are enrolled in Group 3 will undergo a baseline PET/CT scan and at Week 16 in the place of a CT scan if available.  


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Appendix 2.
List of Medical Search Terms for Decreased Platelets
MEDDRA Term Name
MEDDRA Code
Amegakaryocytic thrombocytopenia
10076744
Cutaneovisceral angiomatosis with thrombocytopenia
10069098
HELLP syndrome
10049058
Immune thrombocytopenic purpura
10074667
Platelet production decreased
10035540
Thrombocytopenia
10043554
Thrombocytopenic purpura
10043561
Thrombotic thrombocytopenic purpura
10043648
Severe fever with thrombocytopenia syndrome
10078387
Acquired amegakaryocytic thrombocytopenia
10076747
Megakaryocytes decreased
10027119
Platelet count decreased
10035528
Platelet maturation arrest
10035537
Platelet production decreased
10035540
Platelet toxicity
10059440
Thrombocytopenia
10043554
Megakaryocytes abnormal
10027118
Platelet count abnormal
10035526
Platelet disorder
10035532
Plateletcrit abnormal
10064785
Plateletcrit decreased
10064784
Thrombocytopenia neonatal
10043557


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Appendix 3.
List of Medical Search Terms for Haemorrhage
MEDDRA Term Name
MEDDRA Code
Haemorrhagic adrenal infarction
10079902
Eye haematoma
10079891
Spontaneous hyphaema
10080110
Anal fissure haemorrhage
10079765
Paranasal sinus haemorrhage
10080108
Peripheral artery aneurysm rupture
10079908
Aortic annulus rupture
10079586
Abdominal wall haematoma
10067383
Abdominal wall haemorrhage
10067788
Abnormal clotting factor
10049862
Abnormal withdrawal bleeding
10069195
Acquired dysfibrinogenaemia
10051122
Acquired haemophilia
10053745
Acquired haemophilia with anti FVIII, XI, or XIII
10056496
Acquired protein S deficiency
10068370
Acquired Von Willebrand's disease
10069495
Activated partial thromboplastin time abnormal
10000631
Activated partial thromboplastin time prolonged
10000636
Activated partial thromboplastin time ratio abnormal
10075284
Activated partial thromboplastin time ratio fluctuation
10075286
Activated partial thromboplastin time ratio increased
10075287
Acute haemorrhagic leukoencephalitis
10058994
Acute haemorrhagic ulcerative colitis
10075634
Administration site bruise
10075094
Administration site haematoma
10075100
Administration site haemorrhage
10075101
Adrenal haematoma
10059194
Adrenal haemorrhage
10001361
Anal haemorrhage
10049555
Anal ulcer haemorrhage
10063896
Anastomotic haemorrhage
10056346


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MEDDRA Term Name
MEDDRA Code
Anastomotic ulcer haemorrhage
10002244
Aneurysm ruptured
10048380
Angina bullosa haemorrhagica
10064223
Anorectal varices haemorrhage
10068925
Anti factor IX antibody positive
10058748
Anti factor V antibody positive
10058745
Anti factor VII antibody positive
10058746
Anti factor VIII antibody positive
10049013
Anti factor X activity abnormal
10077670
Anti factor X activity increased
10077671
Anti factor X antibody positive
10058747
Anti factor XI antibody positive
10058749
Anti factor XII antibody positive
10058750
Antithrombin III increased
10051115
Aortic aneurysm rupture
10002886
Aortic dissection rupture
10068119
Aortic intramural haematoma
10067975
Aortic perforation
10075729
Aortic rupture
10060874
Aponeurosis contusion
10075330
Application site bruise
10050114
Application site haematoma
10068317
Application site haemorrhage
10072694
Application site purpura
10050182
Arterial haemorrhage
10060964
Arterial intramural haematoma
10074971
Arterial ligation
10003165
Arterial perforation
10075732
Arterial rupture
10003173
Arteriovenous fistula site haematoma
10055150
Arteriovenous fistula site haemorrhage
10055123
Arteriovenous graft site haematoma
10055152


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MEDDRA Term Name
MEDDRA Code
Arteriovenous graft site haemorrhage
10055126
Atrial rupture
10048761
Auricular haematoma
10003797
Basal ganglia haematoma
10077031
Basal ganglia haemorrhage
10067057
Basilar artery perforation
10075736
Benign familial haematuria
10060876
Bladder tamponade
10062656
Bleeding time abnormal
10049227
Bleeding time prolonged
10005140
Bleeding varicose vein
10005144
Blood blister
10005372
Blood fibrinogen abnormal
10005518
Blood fibrinogen decreased
10005520
Blood thrombin abnormal
10005818
Blood thrombin decreased
10005820
Blood thromboplastin abnormal
10005824
Blood thromboplastin decreased
10005826
Blood urine
10005863
Blood urine present
10018870
Bloody discharge
10057687
Bloody peritoneal effluent
10067442
Bone contusion
10066251
Bone marrow haemorrhage
10073581
Brain contusion
10052346
Brain stem haematoma
10073230
Brain stem haemorrhage
10006145
Brain stem microhaemorrhage
10071205
Breast haematoma
10064753
Breast haemorrhage
10006254
Broad ligament haematoma
10006375
Bronchial haemorrhage
10065739


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MEDDRA Term Name
MEDDRA Code
Bronchial varices haemorrhage
10079163
Bursal haematoma
10077818
Capillary fragility abnormal
10007192
Capillary fragility increased
10007194
Capillary permeability increased
10007200
Cardiac contusion
10073356
Carotid aneurysm rupture
10051328
Carotid artery perforation
10075728
Catheter site bruise
10063587
Catheter site haematoma
10055662
Catheter site haemorrhage
10051099
Central nervous system haemorrhage
10072043
Cephalhaematoma
10008014
Cerebellar haematoma
10061038
Cerebellar haemorrhage
10008030
Cerebellar microhaemorrhage
10071206
Cerebral aneurysm perforation
10075394
Cerebral aneurysm ruptured syphilitic
10008076
Cerebral arteriovenous malformation haemorrhagic
10008086
Cerebral artery perforation
10075734
Cerebral haematoma
10053942
Cerebral haemorrhage
10008111
Cerebral haemorrhage foetal
10050157
Cerebral haemorrhage neonatal
10008112
Cerebral microhaemorrhage
10067277
Cervix haematoma uterine
10050020
Cervix haemorrhage uterine
10050022
Chest wall haematoma
10076597
Choroidal haematoma
10068642
Choroidal haemorrhage
10008786
Chronic gastrointestinal bleeding
10050399
Chronic pigmented purpura
10072726


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MEDDRA Term Name
MEDDRA Code
Ciliary body haemorrhage
10057417
Circulating anticoagulant
10053627
Clot retraction abnormal
10009669
Clot retraction time prolonged
10009675
Coagulation disorder neonatal
10009732
Coagulation factor decreased
10009736
Coagulation factor deficiency
10067787
Coagulation factor IX level abnormal
10061770
Coagulation factor IX level decreased
10009746
Coagulation factor mutation
10065442
Coagulation factor V level abnormal
10061771
Coagulation factor V level decreased
10009754
Coagulation factor VII level abnormal
10061772
Coagulation factor VII level decreased
10009761
Coagulation factor VIII level abnormal
10061773
Coagulation factor VIII level decreased
10009768
Coagulation factor X level abnormal
10061774
Coagulation factor X level decreased
10009775
Coagulation factor XI level abnormal
10061775
Coagulation factor XI level decreased
10009779
Coagulation factor XII level abnormal
10061776
Coagulation factor XII level decreased
10009783
Coagulation factor XIII level abnormal
10061777
Coagulation factor XIII level decreased
10009787
Coagulation time abnormal
10009791
Coagulation time prolonged
10009799
Coagulopathy
10009802
Coital bleeding
10065019
Colonic haematoma
10009996
Congenital coagulopathy
10063563
Congenital dysfibrinogenaemia
10051123
Conjunctival haemorrhage
10010719


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MEDDRA Term Name
MEDDRA Code
Contusion
10050584
Corneal bleeding
10051558
Cullen's sign
10059029
Cystitis haemorrhagic
10011793
Deep dissecting haematoma
10074718
Diarrhoea haemorrhagic
10012741
Dilutional coagulopathy
10060906
Disseminated intravascular coagulation
10013442
Diverticulitis intestinal haemorrhagic
10013541
Diverticulum intestinal haemorrhagic
10013560
Duodenal ulcer haemorrhage
10013839
Duodenitis haemorrhagic
10013865
Dysfunctional uterine bleeding
10013908
Ear haemorrhage
10014009
Ecchymosis
10014080
Encephalitis haemorrhagic
10014589
Endometriosis
10014778
Enterocolitis haemorrhagic
10014896
Epidural haemorrhage
10073681
Epistaxis
10015090
Ethanol gelation test positive
10062650
Exsanguination
10015719
Extra-axial haemorrhage
10078254
Extradural haematoma
10015769
Extravasation blood
10015867
Eye contusion
10073354
Eye haemorrhage
10015926
Eyelid bleeding
10053196
Eyelid contusion
10075018
Eyelid haematoma
10064976
Factor I deficiency
10016075
Factor II deficiency
10016076


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MEDDRA Term Name
MEDDRA Code
Factor III deficiency
10052473
Factor IX deficiency
10016077
Factor V deficiency
10048930
Factor VII deficiency
10016079
Factor VIII deficiency
10016080
Factor X deficiency
10052474
Factor Xa activity abnormal
10078667
Factor Xa activity decreased
10078676
Factor XI deficiency
10016082
Factor XII deficiency
10051806
Factor XIII deficiency
10016083
Femoral artery perforation
10075739
Femoral vein perforation
10075745
Fibrin abnormal
10016575
Fibrin D dimer decreased
10016579
Fibrin D dimer increased
10016581
Fibrin decreased
10016584
Fibrin degradation products
10016585
Fibrin degradation products increased
10016588
Fibrinolysis abnormal
10016604
Fibrinolysis increased
10016607
Foetal-maternal haemorrhage
10016871
Gardner-Diamond syndrome
10078888
Gastric haemorrhage
10017788
Gastric occult blood positive
10067855
Gastric ulcer haemorrhage
10017826
Gastric ulcer haemorrhage, obstructive
10017829
Gastric varices haemorrhage
10057572
Gastritis alcoholic haemorrhagic
10017857
Gastritis haemorrhagic
10017866
Gastroduodenal haemorrhage
10053768
Gastroduodenitis haemorrhagic
10048712


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MEDDRA Term Name
MEDDRA Code
Gastrointestinal angiectasia
10078142
Gastrointestinal angiodysplasia haemorrhagic
10017929
Gastrointestinal haemorrhage
10017955
Gastrointestinal organ contusion
10078655
Gastrointestinal polyp haemorrhage
10074437
Gastrointestinal ulcer haemorrhage
10056743
Genital contusion
10073355
Genital haemorrhage
10061178
Gingival bleeding
10018276
Graft haemorrhage
10063577
Grey Turner's sign
10075426
Haemarthrosis
10018829
Haematemesis
10018830
Haematochezia
10018836
Haematocoele
10018833
Haematoma
10018852
Haematoma evacuation
10060733
Haematoma infection
10051564
Haematosalpinx
10050468
Haematospermia
10018866
Haematotympanum
10063013
Haematuria
10018867
Haematuria traumatic
10018871
Haemobilia
10058947
Haemophilia
10061992
Haemophilia A with anti factor VIII
10056492
Haemophilia A without inhibitors
10056493
Haemophilia B with anti factor IX
10056494
Haemophilia B without inhibitors
10056495
Haemophilic arthropathy
10065057
Haemophilic pseudotumour
10073770
Haemoptysis
10018964


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MEDDRA Term Name
MEDDRA Code
Haemorrhage
10055798
Haemorrhage coronary artery
10055803
Haemorrhage foetal
10061191
Haemorrhage in pregnancy
10018981
Haemorrhage intracranial
10018985
Haemorrhage neonatal
10061993
Haemorrhage subcutaneous
10018999
Haemorrhage subepidermal
10019001
Haemorrhage urinary tract
10055847
Haemorrhagic anaemia
10052293
Haemorrhagic arteriovenous malformation
10064595
Haemorrhagic ascites
10059766
Haemorrhagic breast cyst
10077443
Haemorrhagic cerebral infarction
10019005
Haemorrhagic cyst
10059189
Haemorrhagic diathesis
10062713
Haemorrhagic disease of newborn
10019008
Haemorrhagic disorder
10019009
Haemorrhagic erosive gastritis
10067786
Haemorrhagic hepatic cyst
10067796
Haemorrhagic infarction
10019013
Haemorrhagic necrotic pancreatitis
10076058
Haemorrhagic ovarian cyst
10060781
Haemorrhagic pneumonia
10077933
Haemorrhagic stroke
10019016
Haemorrhagic thyroid cyst
10072256
Haemorrhagic transformation stroke
10055677
Haemorrhagic tumour necrosis
10054096
Haemorrhagic urticaria
10059499
Haemorrhagic varicella syndrome
10078873
Haemorrhagic vasculitis
10071252
Haemorrhoidal haemorrhage
10054787


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MEDDRA Term Name
MEDDRA Code
Haemostasis
10067439
Haemothorax
10019027
Henoch-Schonlein purpura
10019617
Hepatic haemangioma rupture
10054885
Hepatic haematoma
10019676
Hepatic haemorrhage
10019677
Hereditary haemorrhagic telangiectasia
10019883
Hermansky-Pudlak syndrome
10071775
Hyperfibrinolysis
10074737
Hyphaema
10020923
Hypocoagulable state
10020973
Hypofibrinogenaemia
10051125
Hypoprothrombinaemia
10021085
Hypothrombinaemia
10058517
Hypothromboplastinaemia
10058518
Iliac artery perforation
10075731
Iliac artery rupture
10072789
Iliac vein perforation
10075744
Immune thrombocytopenic purpura
10074667
Implant site bruising
10063850
Implant site haematoma
10063780
Implant site haemorrhage
10053995
Incision site haematoma
10059241
Incision site haemorrhage
10051100
Increased tendency to bruise
10021688
Induced abortion haemorrhage
10052844
Inferior vena cava perforation
10075742
Infusion site bruising
10059203
Infusion site haematoma
10065463
Infusion site haemorrhage
10065464
Injection site bruising
10022052
Injection site haematoma
10022066


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MEDDRA Term Name
MEDDRA Code
Injection site haemorrhage
10022067
Instillation site bruise
10073630
Instillation site haematoma
10073609
Instillation site haemorrhage
10073610
Internal haemorrhage
10075192
International normalised ratio abnormal
10022592
International normalised ratio increased
10022595
Intestinal haematoma
10069829
Intestinal haemorrhage
10059175
Intestinal varices haemorrhage
10078058
Intra-abdominal haematoma
10056457
Intra-abdominal haemorrhage
10061249
Intracerebral haematoma evacuation
10062025
Intracranial haematoma
10059491
Intracranial tumour haemorrhage
10022775
Intraocular haematoma
10071934
Intrapartum haemorrhage
10067703
Intraventricular haemorrhage
10022840
Intraventricular haemorrhage neonatal
10022841
Iris haemorrhage
10057418
Joint microhaemorrhage
10077666
Kidney contusion
10023413
Lacrimal haemorrhage
10069930
Large intestinal haemorrhage
10052534
Large intestinal ulcer haemorrhage
10061262
Laryngeal haematoma
10070885
Laryngeal haemorrhage
10065740
Lip haematoma
10066304
Lip haemorrhage
10049297
Liver contusion
10067266
Lower gastrointestinal haemorrhage
10050953
Lower limb artery perforation
10075730


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MEDDRA Term Name
MEDDRA Code
Lymph node haemorrhage
10074270
Mallory-Weiss syndrome
10026712
Mediastinal haematoma
10049941
Mediastinal haemorrhage
10056343
Medical device site bruise
10075570
Medical device site haematoma
10075577
Medical device site haemorrhage
10075578
Melaena
10027141
Melaena neonatal
10049777
Meningorrhagia
10052593
Menometrorrhagia
10027295
Menorrhagia
10027313
Mesenteric haematoma
10071557
Mesenteric haemorrhage
10060717
Metrorrhagia
10027514
Mouth haemorrhage
10028024
Mucocutaneous haemorrhage
10076048
Mucosal haemorrhage
10061298
Muscle contusion
10070757
Muscle haemorrhage
10028309
Myocardial haemorrhage
10048849
Myocardial rupture
10028604
Naevus haemorrhage
10062955
Nail bed bleeding
10048891
Nasal septum haematoma
10075027
Neonatal gastrointestinal haemorrhage
10074159
Nephritis haemorrhagic
10029132
Nipple exudate bloody
10029418
Occult blood positive
10061880
Ocular retrobulbar haemorrhage
10057571
Oesophageal haemorrhage
10030172
Oesophageal intramural haematoma
10077486


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MEDDRA Term Name
MEDDRA Code
Oesophageal ulcer haemorrhage
10030202
Oesophageal varices haemorrhage
10030210
Oesophagitis haemorrhagic
10030219
Optic disc haemorrhage
10030919
Optic nerve sheath haemorrhage
10030941
Oral contusion
10078170
Oral mucosa haematoma
10074779
Osteorrhagia
10051937
Ovarian haematoma
10033263
Ovarian haemorrhage
10065741
Palpable purpura
10056872
Pancreatic contusion
10078654
Pancreatic haemorrhage
10033625
Pancreatitis haemorrhagic
10033650
Papillary muscle haemorrhage
10059164
Paranasal sinus haematoma
10069702
Parathyroid haemorrhage
10059051
Parotid gland haemorrhage
10051166
Pelvic haematoma
10054974
Pelvic haematoma obstetric
10034248
Pelvic haemorrhage
10063678
Penile contusion
10073352
Penile haematoma
10070656
Penile haemorrhage
10034305
Peptic ulcer haemorrhage
10034344
Pericardial haemorrhage
10034476
Perineal haematoma
10034520
Periorbital haematoma
10034544
Periorbital haemorrhage
10071697
Periosteal haematoma
10077341
Peripartum haemorrhage
10072693
Perirenal haematoma
10049450


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MEDDRA Term Name
MEDDRA Code
Peritoneal haematoma
10058095
Peritoneal haemorrhage
10034666
Periventricular haemorrhage neonatal
10076706
Petechiae
10034754
Pharyngeal haematoma
10068121
Pharyngeal haemorrhage
10034827
Pituitary haemorrhage
10049760
Placenta praevia haemorrhage
10035121
Plasminogen activator inhibitor
10059620
Plasminogen activator inhibitor decreased
10059619
Plasminogen decreased
10035493
Plasminogen increased
10035495
Platelet factor 4 decreased
10060220
Polymenorrhagia
10064050
Post abortion haemorrhage
10036246
Post procedural contusion
10073353
Post procedural haematoma
10063188
Post procedural haematuria
10066225
Post procedural haemorrhage
10051077
Post transfusion purpura
10072265
Postmenopausal haemorrhage
10055870
Postpartum haemorrhage
10036417
Post-traumatic punctate intraepidermal haemorrhage
10071639
Procedural haemorrhage
10071229
Proctitis haemorrhagic
10036778
Prostatic haemorrhage
10036960
Protein C increased
10060230
Protein S abnormal
10051736
Protein S increased
10051735
Prothrombin level abnormal
10037048
Prothrombin level decreased
10037050
Prothrombin time abnormal
10037057


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MEDDRA Term Name
MEDDRA Code
Prothrombin time prolonged
10037063
Prothrombin time ratio abnormal
10061918
Prothrombin time ratio increased
10037068
Pulmonary alveolar haemorrhage
10037313
Pulmonary contusion
10037370
Pulmonary haematoma
10054991
Pulmonary haemorrhage
10037394
Puncture site haemorrhage
10051101
Purpura
10037549
Purpura fulminans
10037556
Purpura neonatal
10037557
Purpura non-thrombocytopenic
10057739
Purpura senile
10037560
Putamen haemorrhage
10058940
Radiation associated haemorrhage
10072281
Rectal haemorrhage
10038063
Rectal ulcer haemorrhage
10038081
Renal artery perforation
10075737
Renal cyst haemorrhage
10059846
Renal haematoma
10038459
Renal haemorrhage
10038460
Respiratory tract haemorrhage
10038727
Respiratory tract haemorrhage neonatal
10038728
Retinal aneurysm rupture
10079121
Retinal haemorrhage
10038867
Retinopathy haemorrhagic
10051447
Retroperitoneal haematoma
10058360
Retroperitoneal haemorrhage
10038980
Retroplacental haematoma
10054798
Ruptured cerebral aneurysm
10039330
Russell's viper venom time abnormal
10059759
Scleral haemorrhage
10050508


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MEDDRA Term Name
MEDDRA Code
Scrotal haematocoele
10061517
Scrotal haematoma
10039749
Shock haemorrhagic
10049771
Skin haemorrhage
10064265
Skin neoplasm bleeding
10060712
Skin ulcer haemorrhage
10050377
Small intestinal haemorrhage
10052535
Small intestinal ulcer haemorrhage
10061550
Soft tissue haemorrhage
10051297
Spermatic cord haemorrhage
10065742
Spinal cord haematoma
10076051
Spinal cord haemorrhage
10048992
Spinal epidural haematoma
10050162
Spinal epidural haemorrhage
10049236
Spinal subarachnoid haemorrhage
10073564
Spinal subdural haematoma
10050164
Spinal subdural haemorrhage
10073563
Spleen contusion
10073533
Splenic artery perforation
10075738
Splenic haematoma
10041646
Splenic haemorrhage
10041647
Splenic varices haemorrhage
10068662
Splinter haemorrhages
10041663
Spontaneous haematoma
10065304
Spontaneous haemorrhage
10074557
Stoma site haemorrhage
10074508
Stomatitis haemorrhagic
10042132
Subarachnoid haematoma
10076701
Subarachnoid haemorrhage
10042316
Subarachnoid haemorrhage neonatal
10042317
Subchorionic haematoma
10072596
Subchorionic haemorrhage
10071010


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MEDDRA Term Name
MEDDRA Code
Subclavian artery perforation
10075740
Subclavian vein perforation
10075743
Subcutaneous haematoma
10042345
Subdural haematoma
10042361
Subdural haematoma evacuation
10042363
Subdural haemorrhage
10042364
Subdural haemorrhage neonatal
10042365
Subgaleal haematoma
10069510
Subretinal haematoma
10071935
Superior vena cava perforation
10075741
Testicular haemorrhage
10051877
Thalamus haemorrhage
10058939
Third stage postpartum haemorrhage
10043449
Thoracic haemorrhage
10062744
Thrombin time abnormal
10051319
Thrombin time prolonged
10051390
Thrombin-antithrombin III complex abnormal
10053972
Thrombin-antithrombin III complex increased
10053968
Thrombocytopenic purpura
10043561
Thrombotic thrombocytopenic purpura
10043648
Thyroid haemorrhage
10064224
Tongue haematoma
10043959
Tongue haemorrhage
10049870
Tonsillar haemorrhage
10057450
Tooth pulp haemorrhage
10072228
Tooth socket haemorrhage
10064946
Tracheal haemorrhage
10062543
Traumatic haematoma
10044522
Traumatic haemorrhage
10053476
Traumatic haemothorax
10074487
Traumatic intracranial haematoma
10079013
Traumatic intracranial haemorrhage
10061387


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MEDDRA Term Name
MEDDRA Code
Tumour haemorrhage
10049750
Ulcer haemorrhage
10061577
Umbilical cord haemorrhage
10064534
Umbilical haematoma
10068712
Umbilical haemorrhage
10045455
Upper gastrointestinal haemorrhage
10046274
Ureteric haemorrhage
10065743
Urethral haemorrhage
10049710
Urinary bladder haemorrhage
10046528
Urogenital haemorrhage
10050058
Uterine haematoma
10063875
Uterine haemorrhage
10046788
Vaccination site bruising
10069484
Vaccination site haematoma
10069472
Vaccination site haemorrhage
10069475
Vaginal haematoma
10046909
Vaginal haemorrhage
10046910
Varicose vein ruptured
10046999
Vascular access site bruising
10077767
Vascular access site haematoma
10077647
Vascular access site haemorrhage
10077643
Vascular access site rupture
10077652
Vascular graft haemorrhage
10077721
Vascular pseudoaneurysm ruptured
10053949
Vascular purpura
10047097
Vascular rupture
10053649
Vein rupture
10077110
Venous haemorrhage
10065441
Venous perforation
10075733
Ventricle rupture
10047279
Vertebral artery perforation
10075735
Vessel puncture site bruise
10063881


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GS-US-350-1599 Statistical Analysis Plan 
Version 1.0
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03 January 2018
MEDDRA Term Name
MEDDRA Code
Vessel puncture site haematoma
10065902
Vessel puncture site haemorrhage
10054092
Vitreous haematoma
10071936
Vitreous haemorrhage
10047655
Von Willebrand's disease
10047715
Von Willebrand's factor antibody positive
10066358
Von Willebrand's factor multimers abnormal
10055165
Vulval haematoma
10047756
Vulval haematoma evacuation
10047757
Vulval haemorrhage
10063816
White nipple sign
10078438
Withdrawal bleed
10047998
Wound haematoma
10071504
Wound haemorrhage
10051373


GS-5829
GS-US-350-1599 Statistical Analysis Plan 
Version 1.0
CONFIDENTIAL
Page 61
03 January 2018
Appendix 4.
List of Medical Search Terms for Diarrhoea
MEDDRA Term Name
MEDDRA Code
Defaecation urgency
10012110
Diarrhoea
10012735
Diarrhoea haemorrhagic
10012741
Diarrhoea neonatal
10012743
Frequent bowel movements
10017367
Gastrointestinal hypermotility
10052402
Post procedural diarrhoea
10057585
Abnormal faeces
10000133
Allergic gastroenteritis
10075308
Anal incontinence
10077605
Antidiarrhoeal supportive care
10055660
Bowel movement irregularity
10063541
Change of bowel habit
10008399
Colitis
10009887
Colitis erosive
10058358
Colitis ischaemic
10009895
Colitis microscopic
10056979
Colitis psychogenic
10053397
Culture stool negative
10011630
Encopresis
10014643
Enteritis
10014866
Enteritis leukopenic
10014877
Enterocolitis
10014893
Enterocolitis haemorrhagic
10014896
Eosinophilic colitis
10057271
Faecal containment device insertion
10073732
Faecal volume increased
10049939
Faeces discoloured
10016100
Gastroenteritis
10017888
Gastroenteritis eosinophilic
10017902
Gastroenteritis radiation
10017912
Gastrointestinal inflammation
10064147


GS-5829
GS-US-350-1599 Statistical Analysis Plan 
Version 1.0
CONFIDENTIAL
Page 62
03 January 2018
MEDDRA Term Name
MEDDRA Code
Gastrointestinal motility disorder
10061173
Gastrointestinal toxicity
10059024
Gastrointestinal tract irritation
10070840
Intestinal angioedema
10076229
Intestinal transit time abnormal
10074724
Intestinal transit time decreased
10074598
Irritable bowel syndrome
10023003
Low anterior resection syndrome
10080023
Neutropenic colitis
10062959
Radiation proctitis
10037766