A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of GS-5745 Combined With mFOLFOX6 as First Line Treatment in Patients With Advanced Gastric or Gastroesophageal Junction Adenocarcinoma
Phase: PHASE3
Conditions: Gastric Adenocarcinoma
Sponsor: Gilead Sciences

CLINICAL STUDY PROTOCOL
Study Title:
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study 
to Evaluate the Efficacy and Safety of GS-5745 Combined with 
mFOLFOX6 as First Line Treatment in Patients with Advanced 
Gastric or Gastroesophageal Junction Adenocarcinoma 
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
EudraCT Number:
Clinical Trials.gov Identifier:
116561
2015-001526-42
NCT02545504
Indication:
Gastric Adenocarcinoma 
Protocol ID:
GS-US-296-1080
Gilead Clinical Program 
Manager:
Name:
Telephone:
Fax:
Email:
Gilead Medical Monitor:
Name:
Telephone:
Email:
Protocol Version/Date:
Original:
02 December 2014
Amendment 1
15 June 2015
Amendment 2
17 August 2015
Amendment 3
14 December 2015
Amendment 4
22 June 2016
Amendment 5
14 December 2016
Amendment 6
06 March 2017
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable 
Institutional Review Board or Independent Ethics Committee. The information is only to be used 
by you in connection with authorized clinical studies of the investigational drug described in the 
protocol. You will not disclose any of the information to others without written authorization 
from Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................16
1.
INTRODUCTION ..............................................................................................................................................19
1.1.
Background ............................................................................................................................................19
1.1.1.
Gastric Adenocarcinoma ......................................................................................................19
1.1.2.
MMP9 Expression in Oncology...........................................................................................21
1.2.
General Information...............................................................................................................................21
1.2.1.
Preclinical Pharmacology and Toxicology...........................................................................21
1.2.2.
Clinical Trials of GS-5745 ...................................................................................................22
1.3.
Rationale for This Study ........................................................................................................................22
1.3.1.
Information about mFOLFOX-6 ..........................................................................................23
1.4.
Risk/Benefit Assessment for the Study..................................................................................................23
1.5.
Compliance ............................................................................................................................................24
2.
OBJECTIVES AND ENDPOINTS ....................................................................................................................25
2.1.
Primary Objective ..................................................................................................................................25
2.2.
Secondary Objectives.............................................................................................................................25
2.3.
Exploratory Objectives...........................................................................................................................25
2.4.
Primary Endpoint ...................................................................................................................................25
2.5.
Secondary and Exploratory Endpoints...................................................................................................25
3.
STUDY DESIGN................................................................................................................................................27
3.1.
Study Design..........................................................................................................................................27
3.2.
Study Treatments ...................................................................................................................................27
3.3.
Duration of Treatment............................................................................................................................27
3.4.
Discontinuation Criteria from Study Treatment.....................................................................................28
3.5.
Premature Discontinuation from Study Treatment.................................................................................28
3.6.
Discontinuation Criteria from Study ......................................................................................................29
3.7.
Long-Term Follow-Up for Overall Survival and Study Completion .....................................................29
3.8.
Source Data............................................................................................................................................30
3.9.
Biomarker Testing..................................................................................................................................30
3.9.1.
Biomarker Samples to Address the Study Objectives ..........................................................30
3.9.2.
Optional Blood Sample for Future Genomic Analysis.........................................................31
3.9.3.
Biologic Samples for Optional Future Research ..................................................................32
4.
SUBJECT POPULATION..................................................................................................................................33
4.1.
Number of Subjects and Subject Selection ............................................................................................33
4.2.
Inclusion Criteria....................................................................................................................................33
4.3.
Exclusion Criteria...................................................................................................................................34
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................37
5.1.
Randomization, Blinding and Treatment Codes ....................................................................................37
5.1.1.
Procedures for Breaking Treatment Codes...........................................................................37
5.2.
Description and Handling of Study Treatments .....................................................................................37
5.2.1.
Formulation..........................................................................................................................37
5.2.2.
Packaging and Labeling .......................................................................................................38
5.2.3.
Storage and Handling...........................................................................................................38

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5.3.
Dosage and Administration of Study Drug and mFOLFOX6................................................................39
5.3.1.
Dose Interruption and Reduction..........................................................................................39
5.4.
Prior and Concomitant Medications.......................................................................................................41
5.5.
Accountability for Study Drug...............................................................................................................41
5.5.1.
Investigational Medicinal Product & mFOLFOX6 Return or Disposal...............................41
6.
STUDY PROCEDURES ....................................................................................................................................42
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................42
6.2.
Study Procedure Descriptions ................................................................................................................42
6.2.1.
Informed Consent.................................................................................................................42
6.2.2.
Re-Screening Criteria...........................................................................................................43
6.2.3.
Medical & Medication History.............................................................................................43
6.2.4.
Physical Examination...........................................................................................................43
6.2.5.
Vital Signs & Weight ...........................................................................................................44
6.2.6.
Electrocardiogram Assessment ............................................................................................44
6.2.7.
Performance Status...............................................................................................................44
6.2.8.
Laboratory Assessments.......................................................................................................44
6.2.9.
Disease and Response Assessment.......................................................................................47
6.2.10.
Patient-reported Outcomes Assessments..............................................................................48
6.2.11.
Study Drug and Chemotherapy Administration ...................................................................48
6.2.12.
Adverse Events.....................................................................................................................48
6.3.
Assessments for Premature Discontinuation from Study.......................................................................49
6.4.
Criteria for Discontinuation of Study Treatment....................................................................................49
6.5.
End of Treatment....................................................................................................................................49
6.6.
End of Study...........................................................................................................................................49
6.7.
Safety Follow-Up...................................................................................................................................49
6.8.
Long-Term Follow-up............................................................................................................................50
6.9.
Unscheduled visits .................................................................................................................................50
6.10.
Protocol Deviations................................................................................................................................50
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................51
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................51
7.1.1.
Adverse Events.....................................................................................................................51
7.1.2.
Serious Adverse Events........................................................................................................51
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................52
7.2.1.
Assessment of Causality for Study Drugs and Procedures...................................................53
7.2.2.
Assessment of Severity ........................................................................................................53
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................53
7.3.1.
Adverse Events.....................................................................................................................54
7.3.2.
Serious Adverse Events........................................................................................................54
7.4.
Gilead Reporting Requirements.............................................................................................................55
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................55
7.6.
Toxicity Management ............................................................................................................................56
7.7.
Special Situations Reports......................................................................................................................56
7.7.1.
Definitions of Special Situations..........................................................................................56
7.7.2.
Instructions for Reporting Special Situations.......................................................................57
8.
STATISTICAL CONSIDERATIONS................................................................................................................59
8.1.
Analysis Objectives................................................................................................................................59
8.1.1.
Primary Objective ................................................................................................................59
8.1.2.
Secondary Objectives...........................................................................................................59
8.1.3.
Exploratory Objectives.........................................................................................................59

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8.2.
Analysis Endpoints.................................................................................................................................59
8.2.1.
Primary Endpoint .................................................................................................................59
8.2.2.
Secondary and Exploratory Endpoints .................................................................................59
8.3.
Analysis Conventions.............................................................................................................................60
8.3.1.
Analysis Sets ........................................................................................................................60
8.4.
Data Handling Conventions ...................................................................................................................60
8.4.1.
General Methods ..................................................................................................................60
8.4.2.
Demographic Data and Baseline Characteristics..................................................................61
8.5.
Efficacy Analysis ...................................................................................................................................62
8.5.1.
Primary Analysis..................................................................................................................62
8.5.2.
Secondary and Exploratory Analyses...................................................................................62
8.5.3.
Control of Type I Error Rate in Efficacy Analyses ..............................................................62
8.6.
Safety Analysis.......................................................................................................................................63
8.6.1.
Extent of Exposure...............................................................................................................63
8.6.2.
Adverse Events.....................................................................................................................63
8.6.3.
Laboratory Evaluations ........................................................................................................63
8.6.4.
Other Safety Evaluations......................................................................................................64
8.7.
Pharmacokinetic Analysis......................................................................................................................64
8.8.
Biomarker Analysis................................................................................................................................64
8.8.1.
Pharmacodynamic and Exploratory Biomarker Analysis Analysis......................................64
8.9.
Patient-Reported Outcomes....................................................................................................................64
8.10.
Interim Analyses ....................................................................................................................................65
8.11.
Sample Size............................................................................................................................................65
8.12.
Data Monitoring Committee ..................................................................................................................66
9.
RESPONSIBILITIES..........................................................................................................................................67
9.1.
Investigator Responsibilities ..................................................................................................................67
9.1.1.
Good Clinical Practice..........................................................................................................67
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................67
9.1.3.
Informed Consent.................................................................................................................67
9.1.4.
Confidentiality......................................................................................................................68
9.1.5.
Study Files and Retention of Records ..................................................................................68
9.1.6.
Case Report Forms...............................................................................................................69
9.1.7.
Investigational Medicinal Product & mFOLFOX6 Accountability and 
Return...................................................................................................................................70
9.1.8.
Inspections............................................................................................................................70
9.1.9.
Protocol Compliance............................................................................................................70
9.2.
Sponsor Responsibilities ........................................................................................................................71
9.2.1.
Protocol Modifications.........................................................................................................71
9.2.2.
Study Report and Publications .............................................................................................71
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................71
9.3.1.
Payment Reporting...............................................................................................................71
9.3.2.
Access to Information for Monitoring..................................................................................72
9.3.3.
Access to Information for Auditing or Inspections ..............................................................72
9.3.4.
Study Discontinuation..........................................................................................................72
10.
REFERENCES ...................................................................................................................................................73
11.
APPENDICES ....................................................................................................................................................76
Appendix 1.
Investigator Signature Page....................................................................................................77
Appendix 2.
Study Procedures Table..........................................................................................................78

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Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements...................................................................................................82
Appendix 4.
ECOG Performance Status.....................................................................................................85
Appendix 5.
Dose Modification Tables for mFOLFOX6 ...........................................................................86
Appendix 6.
Details for Testing Efficacy Endpoints...................................................................................89
Appendix 7.
Revised RECIST Guideline (version 1.1) ..............................................................................94
LIST OF IN-TEXT TABLES
Table 3-1.
Biomarker Objectives and Testing .........................................................................................31
Table 5-1.
Dose Reduction Levelsa for mFOLFOX6...............................................................................40
Table 6-1.
Analytes..................................................................................................................................45
Table 8-1.
Stopping Boundaries for Efficacy Analyses...........................................................................65

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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title:
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of GS-5745 Combined with 
mFOLFOX6 as First Line Treatment in Patients with Advanced 
Gastric or Gastroesophageal Junction  Adenocarcinoma
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
116561
2015-001526-42
NCT02545504
Study Centers 
Planned:
Approximately 188 centers globally
Study Phase:
Phase 3
Objectives:
The primary objective of this study is:

To compare the efficacy of GS-5745 versus placebo in 
combination with mFOLFOX6 as measured by overall survival 
(OS)
The secondary objectives of this study are:

To compare the efficacy of GS-5745 versus placebo in 
combination with mFOLFOX6 as measured by progression-free 
survival (PFS)

To compare the efficacy of GS-5745 versus placebo in 
combination with mFOLFOX6 as measured by objective response 
rate (ORR) per Response Evaluation Criteria In Solid Tumors
Version 1.1 (RECIST v1.1)

To compare the safety of GS-5745 versus placebo in combination 
with mFOLFOX6

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The exploratory objectives of this study are:
Study Design:
This is a Phase 3, randomized, double-blind, multicenter study of 
GS-5745 combined with mFOLFOX6 in subjects with untreated 
gastric and gastroesophageal junction (GEJ) adenocarcinoma. A total 
of 430 eligible subjects with advanced gastric and GEJ 
adenocarcinoma will be randomized in a 1:1 manner to mFOLFOX6
plus GS-5745 or mFOLFOX6 plus placebo. Treatment assignment will 
be stratified by Eastern Cooperative Oncology Group (ECOG) 0 or 1, 
geographic region (Latin America or other participating countries), and 
primary tumor site (gastric or GEJ).
Computed Tomography (CT) or Magnetic Resonance Imaging (MRI)
scans will be performed every 8 weeks to evaluate response to 
treatment by RECIST v1.1.
Dosage and frequency will be as follows:
mFOLFOX6 on Days 1 and 15 of each 28-day treatment cycle 
(1 cycle of mFOLFOX consists of 2 infusions) for a total of 
6 cycles followed by leucovorin (LV) and 5-fluorouracil (5-FU)
dosing on Days 1 and 15 of each 28-day treatment cycle until 
disease progression. The mFOLFOX6 dosing regimen will consist 
of l-LV 200 mg/m2 or dl-LV 400 mg/m2 and oxaliplatin 85 mg/m2
followed by bolus 5-FU 400 mg/m2 and a 46-hour infusion of 5-FU 
2400 mg/m2. Minor modifications to the duration of the infusion 
time are permitted as per institutional standard.  Adjustments to the 
dose of mFOLFOX6 are permitted in response to treatment 
emergent adverse events.  The preferred formula for calculating 
body surface area (BSA) will be the Mosteller formula below and 
rounded to the nearest tenth:
√( [Height (cm) Weight (kg)]/3600)
CCI

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However, institutional guidelines/practice for calculating BSA will 
also be allowed.

GS-5745/placebo 800 mg every 2 weeks, on Days 1 and 15 of each 
28 day cycle, until disease progression
An independent data monitoring committee (DMC) will review the 
progress of the study and perform interim reviews of safety data. The 
first safety review by the DMC will be performed after the equivalent 
of 4 treatment cycles from the time the 60th subject is randomized. 
Thereafter, review of safety data will be performed at regular intervals 
as described in the DMC charter. In addition, the DMC will meet after 
approximately 33.3% and 66.7% of the expected number of events 
have occurred to review the results from the futility and efficacy 
interim analysis, respectively.
Number of 
Subjects Planned:
Approximately 430 subjects
Target Population:
Subjects who are ≥18 years old with histologically confirmed, 
inoperable, locally advanced or metastatic adenocarcinoma of the 
stomach or GEJ and who have received no prior treatment for 
advanced or metastatic gastric cancer.
Duration of 
Treatment:
Eligible subjects will be randomized to receive study drug
(GS-5745/placebo) in combination with mFOLFOX6 until disease 
progression, unacceptable toxicity, or withdrawal of consent.
Duration of Study:
Each cycle will consist of 28 days and will continue in the absence of 
disease progression or unacceptable toxicity. 
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
2) Histologically confirmed adenocarcinoma of the stomach or GEJ 
with inoperable, locally advanced or metastatic disease, not 
amenable to curative therapy 
Adenocarcinoma of the GEJ is defined as tumors that have their 
center within 5 cm proximal and distal of the anatomical 
esophagogastric junction as described in Siewert’s classification 
system
3) Eastern Cooperative Oncology Group (ECOG) ≤ 1

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4) Measurable disease or non-measurable but evaluable disease, 
according to RECIST v1.1. Subjects with peritoneal disease would 
generally be regarded as having evaluable disease and allowed to 
enter the trial
5) Subjects not receiving anticoagulant medication must have an 
international normalized ratio (INR) ≤1.5 and activated partial 
thromboplastin (aPTT) ≤ 1.5 x upper limit of normal (ULN) 
The use of full-dose oral or parenteral anticoagulants is permitted 
as long as the INR or aPTT is within therapeutic limits (according 
to the medical standard in the institution) and the subject has been 
on stable dose of anticoagulants for at least 1 week at the time of 
randomization
6) Adequate hematologic function:
a) neutrophils 2.0 x 109/L
b) platelets 100 x 109/L
c) hemoglobin 9 g/dL
7) Adequate hepatic function:
a) Direct or total bilirubin 1.5 x ULN
b) ALT and AST 2.5 x ULN, in case of liver metastases 
≤5 x ULN
8) Creatinine clearance (CLcr) should be ≥ 30 mL/min based on the 
Cockroft-Gault formula. Subjects with a CLcr just below30 mL/min 
may be eligible if a measured creatinine clearance (based on 
24 hour urine collection or other reliable method) is ≥30 mL/min
9) For female subjects of childbearing potential, willingness to use a 
protocol-recommended method of contraception from the 
screening visit throughout the study treatment period, for 90 days 
following the last dose of study drug (GS-5745/placebo), and for
4 months after the last dose of oxaliplatin or 6 months after the 
last dose of 5-FU whichever occurs later unless the subject chooses
continuous heterosexual abstinence as a lifestyle-choice
(see Appendix 3 for more information)
10) For male subjects of reproductive potential having intercourse with 
females of childbearing potential, willingness to use a protocol 
recommended method of contraception and to refrain from sperm 
donation from the start of study drug, throughout the study 
treatment period, for 90 days after administration of the last dose of 
any study drug, and for 6 months after the last dose of oxaliplatin 
or 6 months following the last dose of 5-FU whichever occurs later
(see Appendix 3)

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11) Breastfeeding females must agree to discontinue nursing before 
study drug administration
12) In the judgment of the investigator, participation in the protocol 
offers an acceptable benefit-to-risk ratio when considering current 
disease status, medical condition, and the potential benefits and 
risks of alternative treatments for the subject’s cancer
13) Willingness to comply with scheduled visits, drug administration 
plan, imaging studies, laboratory tests, other study procedures, and 
study restrictions
14) Evidence of a signed informed consent prior to implementation of 
any protocol specific procedure
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be 
randomized in this study:
1) Previous chemotherapy for locally advanced or metastatic gastric
or GEJ cancer. Subjects may have received prior neoadjuvant or 
adjuvant chemotherapy as long as it was completed at least 
6 months prior to randomization
2) Human Epidermal Growth Factor Receptor 2 (HER2) cancer 
(primary tumor or metastatic lesion). HER2-positivity is defined as 
either IHC3+ or IHC2+/ISH+ (ISH positivity is defined as a 
HER2:CEP17 ratio of ≥2.0.)
3) Patients who have received palliative radiation and have not 
recovered from all acute, reversible effects
4) Uncontrolled intercurrent illness including, but not limited to, 
active uncontrolled infection, active gastrointestinal bleeding, 
uncontrolled cardiac arrhythmia, or psychiatric illness/social 
situation that would limit compliance with study requirements as 
judged by treating physician
5) History of a concurrent or second malignancy except for 
adequately treated local basal cell or squamous cell carcinoma of 
the skin, cervical carcinoma in situ, superficial bladder cancer, 
asymptomatic prostate cancer without known metastatic disease 
and with no requirement for therapy or requiring only hormonal 
therapy and with normal prostate-specific antigen for ≥1 year prior 
to randomization, adequately treated Stage 1 or 2 cancer currently 
in complete remission, or any other cancer that has been in 
complete remission for ≥ 5 years

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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) Known positive status for human immunodeficiency virus (HIV)
8) Known acute or chronic-active infection with hepatitis B virus 
(HBV) or hepatitis C virus (HCV)
9) Peripheral neuropathy ≥ Grade 2 according to National Cancer 
Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) v.4.03
10) Chronic daily treatment with oral corticosteroids 
(dose of > 10 mg/day methylprednisolone equivalent). Inhaled 
steroids and short courses of oral steroids for anti-emesis or as an 
appetite stimulant are allowed
11) Pregnant or breastfeeding women (pregnancy needs to be excluded 
by testing of beta-human chorionic gonadotropin [β-hCG])
12) Known or suspected central nervous system metastases
13) Known dihydropyrimidine dehydrogenase-deficiency 
(special screening not required) 
14) Known alcohol or drug abuse or any other medical or psychiatric 
condition which contraindicates participation in the study
15) Documented myocardial infarction or unstable/uncontrolled 
cardiac disease (ie, unstable angina, congestive heart failure 
[New York Heart Association > Class II]) within 6 months of 
randomization
16) Active tuberculosis or history of latent tuberculosis that has not 
been treated
17) Any chronic medical condition that, in the opinion of the 
Investigator, would make the subject unsuitable for the study or 
would prevent compliance with the study protocol. 
18) Serious systemic fungal, bacterial, viral, or other infection that is 
not controlled or requires intravenous antibiotics
19) Experimental medical treatment within 28 days prior to 
randomization
20) Known hypersensitivity to any of the study drugs or excipients or 
to Chinese hamster ovary cell products or to recombinant human or 
humanized antibodies, or known allergic reactions to products that 
contain platinum

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21) History of long QT syndrome or whose corrected QT interval 
(QTc) measured using Fridericia’s formula (QTcF = QT/RR0.333) at 
screening is prolonged (> 450 ms for males and > 470 ms for 
females)
22) Subjects with potassium, magnesium or calcium less than the lower 
limit of normal (LLN); electrolyte replacement is permitted during 
screening
Study Visits:
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 Day 1. Screening procedures will include the following: 
medical history review, physical exam, vital signs, 12-lead ECG, 
ECOG performance status, prior/concomitant medication review, 
blood collection for pregnancy test (females), chemistry, hematology 
and coagulation, adverse event (AE) assessment, and CT or MRI. 
Baseline tumor lesions will be measured and characterized prior to
randomization to assess the subject’s disease status prior to beginning 
treatment.
Treatment:
Treatment will occur over cycles comprised of 28 days. Subjects who 
meet eligibility will undergo CT or MRI scan performed every 
8 weeks. Beginning with Day 1 of Cycle 1, subjects will receive 
GS-5745 or placebo by intravenous infusion over 30 minutes every 
2 weeks for a total of 2 infusions per cycle (Day 1 and Day 15 of each 
cycle). All subjects will also receive mFOLFOX6 for the first 6 cycles 
and 5-fluorouracil (5-FU) and leucovorin (LV) thereafter administered 
via intravenous infusion after GS-5745 or placebo on Days 1 and 15 of 
each cycle. The mFOLFOX6 dosing regimen will consist of l-LV 
200 mg/m2 or dl-LV 400 mg/m2 and oxaliplatin 85 mg/m2 followed by 
bolus 5-FU 400 mg/m2 and a 46-hour infusion of 5-FU 2400 mg/m2.
Treatment will continue with subsequent 28-day treatment cycles in 
combination with intravenous mFOLFOX6 for a total of 12 infusions 
over 6 cycles via the same regimen defined above. After the subject 
has received 6 cycles of mFOLFOX6, the oxaliplatin component will 
be discontinued, and 5-FU, leucovorin, and GS-5745/placebo will be 
continued as maintenance therapy in the absence of disease 
progression or toxicity warranting discontinuation of therapy. CT or 
MRI for assessment of tumor status will be conducted every 8P
Pweeks. 
However, tumor response may be assessed prior to the specified every 
8-week time point, if clinically indicated.

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Investigational Drug:
Subjects will be administered 800 mg GS-5745/placebo intravenous 
over approximately 30 minutes and in advance of mFOLFOX6 on 
Days 1 and 15 of each cycle.
Reference Therapy, 
Dose, and Mode of 
Administration:
The dosing regimen for each subject will adhere to the protocol 
specifications. mFOLFOX6 will consist of l-LV 200 mg/m2 or 
dl-LV 400 mg/m2 and oxaliplatin 85 mg/m2 followed by bolus 5-FU 
400 mg/m2 and a 46-hour infusion of 5-FU 2400 mg/m2.
Criteria for 
Evaluation:
All subjects meeting the eligibility criteria that have signed a consent 
form and have begun treatment will be evaluated for response.
Efficacy
Overall survival (OS) is the primary endpoint of the study and is 
measured as time from date of randomization to death from any cause.
Progression-free survival (PFS) is measured as the interval of time 
from randomization to the earlier of first documentation of definitive 
disease progression or death from any cause. Subjects who discontinue 
the study drug before disease progression will continue to be
followed-up until they have documented disease progression. 
Objective response is assessed by the RECIST v1.1 as Complete 
Response (CR), Partial Response (PR), Stable Disease (SD)
Non-CR/Non-PD (NN) or Progressive Disease (PD). The response of 
Not Evaluable (NE) will be recorded for subjects who drop out early 
before the scheduled imaging is performed, or for images with poor 
quality. Objective response rate (ORR) is the proportion of subjects 
who achieve a CR or PR.
Safety
The safety evaluation will be based on incidence of adverse events, 
clinically relevant changes in laboratory values and vital signs.
Pharmacokinetics
Blood samples to measure GS-5745 and oxaliplatin/5-FU 
concentrations will be collected at the timepoints specified in the 
protocol.
Blood samples to measure anti-GS-5745 antibodies will also be 
collected at the time points specified in the protocol.
Pharmacodynamic and Exploratory Biomarkers
 
.
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Statistical Methods:
Analysis Methods
The primary efficacy analysis set will be intent-to-treat (ITT). The
ITT analysis set includes all randomized subjects and will be analyzed 
according to treatment assigned.
The Kaplan-Meier method and stratified log-rank test will be used to 
compare the 2 treatment groups for OS and PFS. A Cox proportional 
hazard model will be used to estimate the hazard ratio and 
corresponding 95% confidence interval (CI).
For the analysis of ORR, a Cochran-Mantel-Haenszel (CMH)
Chi-square test will be performed to compare the 2 treatment groups.
In general, count and percent of subjects will summarize categorical 
and ordinal data. Mean, standard deviation, minimum, quartiles, 
median and maximum will summarize continuous data.
Interim Analysis
Two interim analyses are planned: the futility interim will be 
performed at 33.3% information and the efficacy interim at 
66.7% information. The final analysis will occur when 286 OS events 
have been observed.
The Lan-DeMets approach with O’Brien-Fleming type alpha spending 
function will be used for efficacy data monitoring. The stopping 
boundaries at each analysis time are provided in the table below.
Stopping Boundaries for Efficacy Analyses
Efficacy Analysis
Events (%)
Stopping Boundary
Z scale
One-sided 
p-value scale
Interim
191 (66.7%)
2.509
0.006
Final
286 (100%)
1.993
0.023
    
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Sample Size
Assuming a median OS time for the mFOLFOX6 + placebo group of 
11.5 months, 286 events are needed to detect a hazard ratio (HR) of 
0.70 with 85% power at a 1-sided significance level of 0.025. With an 
accrual period of 18 months, minimum follow-up of 18 months, and a 
10% annual dropout rate, a total sample size of 430 subjects 
(215 subjects per treatment group) is needed to observe the required 
286 events within the 36-month time frame.
As the targeted number of deaths is large (~286), if the null hypothesis 
of the primary end point of OS is rejected, it will convincingly 
demonstrate clinical treatment effect and would provide a narrow 
confidence interval. Based on the number of deaths and the assumed 
treatment effect on OS in the protocol, the expected 95% confidence 
interval on the HR of OS between the 2 treatment groups is 
~ (0.627, 0.996). At the time of final analysis and assuming OS is 
significant, PFS will be tested at one-sided type I error of 0.016. 
Assuming that the hazard ratio in PFS is 0.7, which is expected to be 
on par or better than the treatment effect in OS, and that median PFS in 
control is 9 months, a sample size of 430 subjects (322 PFS events) 
will provide 85% power under the planned study enrolment 
(18 months), follow-up duration (18 month) and drop-out rate 
(annually 10%).
This study will be conducted in accordance with the guidelines of Good Clinical Practices 
(GCPs), including archiving of essential documents.

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
β-hCG
beta-human chorionic gonadotropin
λz
terminal elimination rate constant; estimated by linear regression of the terminal elimination 
phase of the log serum/plasma/PBMC concentration versus time curve of the drug
5-FU
5-fluorouracil
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUClast
area under the plasma/serum/PBMC concentration versus time curve from time zero to the 
last quantifiable concentration
AUCtau
area under the plasma/serum/PBMC concentration versus time curve over the dosing interval
BSA
body surface area
Cmax
maximum observed concentration of drug
CFR
Code of Federal Regulations
CI
confidence interval
Clast
last observed quantifiable serum/plasma/PBMC concentration of the drug
CLcr
creatinine clearance
Cmax
maximum observed serum/plasma/PBMC concentration of drug
CR
complete response
CRO
contract research organization
CT
computed tomography
Ctau
observed drug concentration at the end of the dosing interval
CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DOR
duration of response
DSPH
Drug Safety and Public Health
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EORTC
European  Organization for Research and Treatment of Cancer
EOS
end of study
EOT
end of treatment
eSAE
electronic serious adverse event
EU
European Union
FDA
Food and Drug Administration
GCP
good clinical practice

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GEJ
gastroesophageal junction
HBV
hepatitis B virus
HCV
hepatitis C virus
HER2
human epidermal growth factor receptor 2
HIV
human immunodeficiency virus
HLT
high-level term
HR
hazard ratio
IB
investigator’s brochure
IC50
concentration necessary to achieve 50% inhibition of target
ICH
International Conference on Harmonisation
IHC
immunohistochemistry
IMP
investigational medicinal product
INR
international normalized ratio
IRB/IEC
institutional review board or independent ethics committee
ISH
in situ hybridization
ITT
intent-to-treat
IUD
intrauterine device
IWRS
interactive web response system
KM
Kaplan-Meier
LV
leucovorin
LTFU
long term follow up
MMP
matrix metalloproteinases
MRI
magnetic resonance imaging
MSS
musculoskeletal syndrome
ORR
objective response rate
OS
overall survival
PD
progressive disease
PE
physical examination
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
PRO
patient-reported outcomes
QoL
quality of life
RECIST
Response Evaluation Criteria In Solid Tumors
PT
preferred term
RNA
ribonucleic acid
SADR
serious adverse drug reactions
SAE
serious adverse event
SD
stable disease
SOC
system organ class

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SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reactions
t½
estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, calculated 
by dividing the natural log of 2 by the terminal elimination rate constant (λz)
TIMPs
tissue inhibitors of metalloproteinases
Tlast
time (observed time point) of Clast
TTR
time to response
ULN
upper limit of normal

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1.
INTRODUCTION
1.1.
Background
Matrix metalloproteinases (MMP) comprise a family of at least 23 Zn2+-dependent proteases 
which are primarily involved in the degradation and remodeling of the extracellular matrix and 
basement membranes in many normal as well as pathologic biological processes. They are 
typically grouped based on their structure or their primary substrates and include the gelatinases, 
collagenases, stromelysins, matrilysins, an elastase, and membrane-type MMP, a group of cell 
surface tethered proteases {Hu 2007, Mott 2004}. The gelatinases comprise MMP2 and MMP9, 
sometimes referred to as type IV collagenases, which are named for their ability to degrade type 
IV collagen and gelatin, a denatured form of collagen {Chen 2002, Kridel 2001}. The 
contrasting roles of MMP9 and MMP2 have been revealed in a variety of studies which support a 
more ubiquitous expression pattern and associated role for MMP2 in normal tissue homeostasis, 
as compared to disease-induced and pathology-associated expression and activity of MMP9
{Agrawal 2006, Garg 2009, Hu 2007, Itoh 2002, Castaneda 2005, Dubois 1999, Li 2009, 
Miyazaki 2011, Naito 2005, Santana 2006}. Additional substrates have been identified for 
MMP9, and the active enzyme can release cytokines, growth factors, and bioactive fragments 
which in turn modulate inflammation, neovascularization, and matrix remodeling {Hijova 2005}. 
MMP9 is an inducible MMP that is secreted as a zymogen and activated in a “cysteine switch” 
mechanism by the cleavage of the peptidoglycan binding domain {Van Wart 1990}. While 
activation of MMP9 appears to be carried out by other MMPs, the protease’s activity is also 
regulated by the binding of tissue inhibitors of metalloproteinases (TIMPs), primarily by TIMP1
{Imai 1995, Olson 1997, Vempati 2007}. Elevated MMP9 expression in diseased tissue and 
plasma is associated with several human diseases. The health and largely normal development of 
the MMP9 knockout mouse has enabled evaluation in a variety of disease models, and these data 
support a significant role for MMP9 in a variety of inflammatory, fibrotic, and oncologic 
processes {Dubois 1999, Hu 2007, Itoh 2002, Itoh 1999, Opdenakker 2003}.
More recent studies in the MMP field have revealed diversity in the functional roles of MMPs in 
disease and normal homeostasis, suggesting a therapeutic opportunity for selective inhibitors. 
Despite their structural similarities, expression analysis in human disease and data from 
knockout mice reveal contrasting roles for MMP9 and MMP2 regulation and activity in normal 
homeostasis and in disease. MMP9 expression is restricted to limited cell types in healthy tissues
whereas MMP2 is found to be more constitutively expressed {Hu 2007}. The disease-associated 
induction and functions of MMP9 render it an attractive therapeutic target.
1.1.1.
Gastric Adenocarcinoma
Adenocarcinoma of the stomach is the most common gastrointestinal cancer in the world and the 
third leading cause of cancer death worldwide{Ferlay 2013}. Approximately 22,220 patients are 
diagnosed annually in the United States, of whom 10,990 are expected to die. While the 
incidence of distal gastric adenocarcinoma has recently declined in the United States, gastric 
cancer remains quite frequent in certain minority populations and it is still the second most 

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common cause of cancer death worldwide. In addition, adenocarcinoma of the gastroesophageal 
junction (GEJ) is one of the most rapidly increasing solid tumors in the United States and 
Western Europe.
Most patients with gastric cancer in the United States are symptomatic and already have 
advanced incurable disease at the time of presentation. At diagnosis, approximately 50 percent 
have disease that extends beyond locoregional confines, and only one-half of those who appear 
to have locoregional tumor involvement can undergo a potentially curative resection. Surgically 
curable early gastric cancers are usually asymptomatic and only infrequently detected outside the 
realm of a screening program. Screening is not widely performed, except in countries which have 
a very high incidence, such as Japan, Venezuela, and Chile. The common presenting symptoms 
and diagnostic approaches to gastric cancer include weight loss (usually results from insufficient 
caloric intake rather than increased catabolism) and may be attributable to anorexia, nausea, 
abdominal pain, early satiety, and/or dysphagia. Abdominal pain is often present which tends to 
be epigastric, vague and mild early in the disease but more severe and constant as the disease 
progresses. Dysphagia is a common presenting symptom in patients with cancers arising in the 
proximal stomach or at the esophagogastric junction. Patients may also present with nausea or 
early satiety from the tumor mass or in cases of an aggressive form of diffuse-type gastric cancer 
called linitis plastica, from poor distensibility of the stomach. They may also present with a 
gastric outlet obstruction from an advanced distal tumor.
In metastatic disease, multiple single agent studies using drugs such as cisplatin, docetaxel, 
5-fluorouracil (5-FU), and irinotecan among others have demonstrated modest activity. 
Treatment of metastatic HER2 negative cancer in the first line setting consists of combination 
chemotherapy with a triplet or doublet regimen. The triplet regimen of docetaxel/cisplatin/5-FU 
is the only approved combination in the United States. Because of significant toxicity, this 
combination is reserved for patients who are medically fit and have good performance status. 
The National Comprehensive Cancer Network guidelines for the treatment of metastatic disease 
recommend a 2-drug regimen. A common regimen includes a fluoropyrimidine (5-FU or 
capecitabine) and platinum agent (cisplatin or oxaliplatin). The current standard of care for 
patients who progress on front line regimens remains controversial. While many patients are 
treated in the second line setting with taxanes, some are treated with irinotecan either by itself or 
in combination with a taxane. Ramucirumab, an anti-vascular endothelial growth factor receptor 
2 antibody, was recently approved in the United States as monotherapy or in combination with 
paclitaxel to treat gastric and GEJ cancer that has progressed after treatment with a 
fluoropyrimidine- or platinum-containing regimen. While there is no clear standard regimen for 
this disease, there is also a lack of clinical trials addressing this patient population. The majority 
of patients with adenocarcinomas of the esophagus and stomach are diagnosed with either 
stage III or IV disease and the prognosis is very poor with 5-year survival rates between 5-15%. 
Treatment options after first-line therapy are still limited in the metastatic setting. Traditional 
cytotoxic chemotherapy regimens for second and third-line treatment in patients with metastatic 
disease have shown a median overall survival ranging from 3-5 months compared to 
2.4-3.6 months for best supportive care {Ford 2014, Kang 2012, Thuss-Patience 2011}.

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1.1.2.
MMP9 Expression in Oncology
Matrix metalloproteinase 9 is expressed by tumor epithelia as well as infiltrating macrophages,
other inflammatory cells, fibroblastic stroma, and tumor-associated endothelial cells. Expression 
of MMP9 by tumor epithelia in particular has been implicated in many pro-tumorigenic 
processes and is associated either with loss of tumor suppressor or gain of oncogenic activity, as 
a temporal response to oncogenic changes in local tumor environment, or during processes such 
as invasion and proliferation. MMP9 expression by tumor-associated macrophages, neutrophils, 
mesenchymal-derived suppressor cells and other cell types in in the tumor microenvironment is 
also associated with local pro-tumorigenic immunomodulation and angiogenesis {Farina 2014}.
In gastric tumors, MMP9 expression is consistently observed, often in both tumor epithelia and 
stromal compartments.
1.2.
General Information
GS-5745 is a humanized monoclonal antibody that binds with high affinity to human MMP9, but 
not to other human MMPs. GS-5745 was derived from the murine anti-human MMP9 
monoclonal antibody, AB0041, and shares the same binding characteristics. GS-5745 and 
AB0041 cross-react with and inhibit rat and cynomolgus monkey MMP9 but not murine MMP9. 
AB0046, which cross-reacts with and inhibits murine MMP9, was generated via immunization in 
MMP9 knockout mice. Epitope mapping analysis revealed that AB0046 binds a similar region in 
murine MMP9 to that bound by GS-5745 and AB0041 on human MMP9. 
1.2.1.
Preclinical Pharmacology and Toxicology
1.2.1.1.
Pharmacology
The therapeutic potential of inhibitory antibodies targeting human MMP9 (AB0041) and mouse 
MMP9 (AB0046) was evaluated in a surgical orthotopic xenograft mouse model of colorectal 
carcinoma in which tumors were derived from the human tumor cell line HCT116. In this 
treatment model, selective inhibition of MMP9 using a cocktail of anti-human MMP9 and 
anti-mouse MMP9 antibodies significantly reduced growth of the primary tumor and reduced the 
incidence of metastases in multiple independent studies. In xenografts, treatment with either an 
anti-tumor-MMP9 (human) or anti-stromal MMP9 (murine) antibody yielded significant tumor 
growth reduction highlighting important roles for tumor epithelial-derived and stromal-derived
MMP9 in primary tumor outgrowth. However, targeting of stromal MMP9 was necessary for 
maximum efficacy with respect to incidence of metastases, highlighting the disease-associated 
role of other cellular sources of MMP9 in tumorigenesis.
The major dose limiting toxicity observed in clinical studies with pan-MMP inhibitors, such as 
marimastat, was musculoskeletal syndrome (MSS) consisting of tendonitis manifested by joint 
stiffness, edema, reduced mobility, and skin discoloration. A study to evaluate the potential of an 
anti-MMP9 antibody to induce MSS was conducted in Lewis rats. Unlike the pan-MMP 
inhibitor, Marimastat, AB0041 did not induce any evidence of MSS or other toxicities in this
Lewis rat MSS model.

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Further details on the non-clinical pharmacology are available in the GS-5745 
Investigator’s Brochure (IB).
1.2.1.2.
Toxicology
The toxicity profile of GS-5745 has been assessed in rats and monkeys administered GS-5745 
intravenous once weekly for up to 4 weeks (5 doses) at up to 100 mg/kg/dose. Target organs 
identified in the 4-week studies were the physeal bone (rat) and adrenal gland (monkey). The 
physeal hypertrophy in rats is likely directly attributable to inhibition of MMP9 as similar 
findings were observed in MMP9 null mice {Vu 1998} and in children with mutations in MMP9 
and MMP13 {Lausch 2009}. In both mice and children, this is a transient finding that 
spontaneously regresses as the bone matures. The physeal hypertrophy noted in rats is not 
considered relevant to adult humans because the growth plates are closed and longitudinal bone 
growth is no longer ongoing in adults. The relationship of the adrenal gland weight increase to 
MMP9 inhibition is unknown. Both the physeal bone and adrenal gland findings were reversible 
after discontinuing GS-5745 treatment. Because these findings were minimal and/or did not 
impact the overall health of the animals, these findings were not considered adverse. The no 
observed adverse effect levels in both the rat and monkey studies were 100 mg/kg/dose 
intravenous once weekly for 4 weeks (5 doses).
1.2.2.
Clinical Trials of GS-5745
In addition to the clinical development program in solid tumors, GS-5745 is being developed for 
the treatment of rheumatoid arthritis and cystic fibrosis. Details of the clinical studies in these 
diseases can be found in the IB.
Study GS US-296-0101 is a Phase 1, open-label, dose-escalation study to evaluate safety, 
pharmacokinetics (PK), and pharmacodynamics following multiple intravenous administrations 
of GS-5745 every 2 weeks in subjects with advanced solid tumors that are refractory to or 
intolerant of standard treatment, or for which no standard treatment is available. Multiple doses 
between 200 and 1800 mg are being evaluated.
1.3.
Rationale for This Study
The preliminary clinical efficacy data in patients with gastric and GEJ adenocarcinoma treated 
with GS-5745 (800 mg every 2 weeks) and mFOLFOX6 in the Phase 1 study (GS-US-296-0101)
suggests that the combination is well tolerated and has the potential to provide benefit over 
treatment with mFOLFOX6 alone. Serum biomarkers including the collagen neo-epitopes that 
are likely to reflect MMP9 enzymatic activity decrease during the first cycle of treatment with 
these agents. The 800 mg every 2 weeks regimen of GS-5745 is expected to reach linear range of 
pharmacokinetics (ie, saturate target-mediated drug disposition at trough concentrations) and to 
achieve steady trough concentrations greater than 26 g/mL in majority of subjects, which is 
260-fold over the IC50 (0.691 nM or 0.1 g/mL) evaluated in enzymatic inhibitory activities of 
GS-5745 in vitro. Together, these data support the hypothesis that GS-5745 treatment inhibits 
MMP9 activity and that the inhibition may lead to improved clinical outcomes. The study aims 

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to assess in a randomized, blinded fashion whether GS-5745 in combination with mFOLFOX6 
improves therapeutic outcomes in subjects with previously untreated locally advanced or 
metastatic gastric and GEJ adenocarcinoma.
1.3.1.
Information about mFOLFOX-6
Treatment of metastatic HER2 negative esophagogastric adenocarcinoma consists of 
combination chemotherapy with a triplet or doublet cytotoxic regimen. The triplet regimen of 
docetaxel/cisplatin/5-FU is the only approved combination in the US. Because of significant 
toxicity, this combination is reserved for patients who are medically fit and have good 
performance status. The National Comprehensive Cancer Network and European Society of 
Medical Oncology guidelines for the treatment of metastatic disease in the first line setting 
recommend a 2-drug regimen. A common regimen includes a fluoropyrimidine 
(5-FU or capecitabine) and platinum agent (cisplatin or oxaliplatin). There are no definitive 
studies demonstrating the superiority of either fluoropyrimine or platinum. An mFOLFOX6 
regimen is commonly used and is acceptable in the first line setting to treat advanced 
esophagogastric adenocarcinoma and will be evaluated in combination with GS-5745.
1.4.
Risk/Benefit Assessment for the Study
GS-5745 when administered at 800 mg IV every 2 weeks in combination with standard of care 
chemotherapy appears to be safe and well-tolerated. The 800 mg every 2 weeks regimen of 
GS-5745 IV is expected to achieve steady trough concentrations greater than 26 µg/mL in the 
majority of subjects, which is 260-fold over the IC50 (0.691 nM or 0.1 µg/mL) evaluated in 
enzymatic inhibitory activities of GS-5745 in vitro. There were no dose-limiting toxicities 
observed at monotherapy doses up to 1800 mg IV every 2 weeks. The AE profile observed in 
study GS-US-296-0101 is consistent with the profile typically seen in subjects with advanced 
cancers including pancreatic, gastric, or non-small cell lung adenocarcinoma receiving standard 
of care chemotherapy. Preliminary efficacy data indicates that the objective response rate is 58% 
(33 evaluable subjects, data on file as of 11 September 2015) compared to the historical response 
rate of approximately 40% in gastric cancer patients with measurable disease treated with 
mFOLFOX6.
For the treatment of advanced gastric cancer, a common regimen includes a fluoropyrimidine 
(5-FU or capecitabine) and platinum agent (cisplatin or oxaliplatin). There are no definitive 
studies demonstrating the superiority of either fluoropyrimine or platinum. In the EU, in line 
with ESMO recommendations clinical practice guidelines {Waddell 2013}, combination 
regimens based upon a platinum fluoropyrimidne doublet are generally used for the treatment of 
metastatic advanced gastric cancer.
There is no clear or demonstrably superior standard regimen for the treatment of advanced 
gastric cancer and few clinical trials addressing this target patient population. Furthermore, there 
are limited first-line therapy treatment options in the metastatic setting. In addition, prognosis is 
poor in patients with adenocarcinoma of the stomach diagnosed with Stage III or IV disease.

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Thus, the favorable nonclinical and clinical data outweigh the risks associated with 
administration of GS-5745 and hence support the evaluation of GS-5745 in combination with 
mFOLFOX6 as a first-line treatment in patients with advanced gastric or gastroesophageal 
junction adenocarcinoma.
1.5.
Compliance
The sponsor will conduct this study in compliance with this protocol, Good Clinical Practice 
(GCP), and all applicable regulatory requirements.

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2.
OBJECTIVES AND ENDPOINTS
2.1.
Primary Objective

To compare the efficacy of GS-5745 versus placebo in combination with mFOLFOX6 as 
measured by overall survival (OS)
2.2.
Secondary Objectives

To compare the efficacy of GS-5745 versus placebo in combination with mFOLFOX6 as 
measured by progression-free survival (PFS)

To compare the efficacy of GS-5745 versus placebo in combination with mFOLFOX6 as 
measured by objective response rate (ORR) per Response Evaluation Criteria In Solid 
Tumors version 1.1 (RECIST v1.1)

To compare the safety of GS-5745 versus placebo in combination with mFOLFOX6
2.3.
Exploratory Objectives
2.4.
Primary Endpoint

Overall survival (OS) - defined as the time from date of randomization to death from any 
cause
2.5.
Secondary and Exploratory Endpoints
The following secondary endpoints will be defined and analyzed in this study: 

Progression free survival (PFS) – defined as the time from randomization to the earlier of 
first documentation of definitive disease progression or death from any cause
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
Objective response rate (ORR) – defined as the proportion of subjects who achieve a CR or 
PR as assessed by RECIST v1.1 

Safety measurements including incidence of adverse events, clinical relevant changes in 
laboratory values and vital signs. 
The following exploratory endpoints will be defined and analyzed in this study:
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3.
STUDY DESIGN
3.1.
Study Design
This is a Phase 3, randomized, double-blind, multicenter study of GS-5745 combined with 
mFOLFOX6 in subjects with untreated gastric and GEJ adenocarcinoma. A total of 
430 eligible subjects with advanced gastric and GEJ cancer will be randomized in a 1:1 manner 
to mFOLFOX6 plus GS-5745 or mFOLFOX6 plus placebo. Treatment assignment will be 
stratified by ECOG status (0 or 1), geographic region (Latin America or other participating
countries), and primary tumor site (gastric or GEJ).
Computed tomography (CT) or magnetic resonance imaging (MRI) scans will be performed 
every 8 weeks to evaluate response to treatment by RECIST v1.1.
Dosage and frequency will be as follows:

mFOLFOX6 on Days 1 and 15 of each 28-day treatment cycle for a total of 6 cycles
followed thereafter by leucovorin (LV) and 5-fluorouracil (5-FU) dosing on Days 1 and 15 of 
each 28-day treatment cycle until disease progression . The mFOLFOX6 dosing regimen will 
consist of l-LV 200 mg/m2 or dl-LV 400 mg/m2 and oxaliplatin 85 mg/m2 followed by 
bolus 5-FU 400 mg/m2 and a 46-hour infusion of 5-FU 2400 mg/m2.

GS-5745/placebo 800 mg every 2 weeks until disease progression
An independent data monitoring committee (DMC) will review the progress of the study and 
perform interim reviews of safety data. Safety review by the DMC will be performed after the 
equivalent of 4 treatment cycles from the time the 60th subject is randomized. Thereafter, review 
of safety data will be performed at regular intervals as described in the DMC charter. In addition, 
the DMC will meet after approximately 33.3% and approximately 66.7% of the expected number 
of events have occurred to review the results from the futility and efficacy interim analysis, 
respectively.
3.2.
Study Treatments
Subjects will receive study drug (GS-5745/placebo) on Day 1 and Day 15 of each 28 day cycle 
of mFOLFOX6 via intravenous infusion over approximately 30 minutes. One cycle of 
mFOLFOX6 consists of 2 infusions. Administration of mFOLFOX6 will be immediately after 
administration of study drug as described above in Section 3.1.
3.3.
Duration of Treatment
Each cycle will consist of 28 days and will continue in the absence of disease progression or 
unacceptable toxicity, consent withdrawal or subject’s refusal of treatment. There will be a 
screening period of up to 28 days. Following completion of treatment, subjects will be followed 
for safety for 55 days and survival approximately every 3 months for up to 5 years. 

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3.4.
Discontinuation Criteria from Study Treatment
GS-5745/Placebo and all of the components from mFOLFOX6 will be discontinued for any of 
the following reasons:

Adverse events

Pregnancy

Investigator decision to remove the subject from the study treatment, in consultation with 
Gilead Medical Monitor

Disease progression

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree

Initiation of non-study specific anti-neoplastic therapy in the absence of progression

Subject request to discontinue treatment

Withdrawal of consent. 
A subject may withdraw consent solely from active participation in the study but still 
participate in follow up for disease progression and survival

Death

Discontinuation of the study at the request of Gilead, a regulatory agency, or an 
institutional review board or independent ethics committee (IRB/IEC)

Lost to follow up
Should this occur, the corresponding study drug completion CRF should be entered to document 
the reason for discontinuation. In addition, the subject should continue with the rest of the 
treatment regimen and the study related procedures per protocol.
3.5.
Premature Discontinuation from Study Treatment
If a subject has discontinued all study treatments prior to definitive disease progression, the 
subject shall remain on study until at least 1 of the criteria for discontinuation from study is met
(Section 3.6). Every attempt should be made to keep the subject in the study and continue to 
perform tumor evaluation by CT or MRI every 8 weeks until disease progression. If this is not 
possible or acceptable to the subject or investigator, the subject may be withdrawn from the 
study. It is recommended that the investigator consults with the medical monitor prior to 
removing the subject from study for any reason except subject withdrawal of consent.

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3.6.
Discontinuation Criteria from Study
Subject study participation will be ended due to any of the following reasons, and subjects 
should then enter long-term follow-up if applicable:

Initiation of non-study specific anti-neoplastic therapy in the absence of progression

Disease progression

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree

Withdrawal of consent. 
A subject may withdraw consent solely from active participation in the study but 
participate in follow up for survival

Investigator decision to remove the subject from the study, in consultation with 
Gilead Medical Monitor

Death

Discontinuation of the study at the request of Gilead, a regulatory agency, or an IRB/IEC

Lost to follow up
3.7.
Long-Term Follow-Up for Overall Survival and Study Completion
After the End of Study (EOS), long-term follow-up (LTFU) will be initiated for subjects who 
discontinue from study due to reasons other than death. The subject shall remain on LTFU for 
OS until: 

Death 

Withdrawal of consent to participate in LTFU

Lost to follow up

End of LTFU period 
Every attempt should be made to keep the subject in the LTFU for OS.
The end of the trial will be defined as when all subjects have completed LTFU or discontinued 
their participation in the study due to death, withdrawal of consent or lost to follow up.

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3.8.
Source Data
The subject identification number and randomization number captured by the interactive
web response system (IWRS), as well as the patient reported outcomes data captured are 
considered source data.
3.9.
Biomarker Testing
3.9.1.
Biomarker Samples to Address the Study Objectives
The biological specimens described below will be collected in this study and will be used to 
evaluate the association of exploratory systemic and/or tissue specific biomarkers with study 
drug response including efficacy, as well as to increase knowledge and understanding of the 
mechanism of action of drug activity in human tumors, biology of resistance and highlight 
possible new combination opportunities. The specific analyses may include, but will not be 
limited to, the biomarkers and assays listed below. Because biomarker science is a rapidly 
evolving area of investigation, it is not possible to specify prospectively all tests that will be done 
on the specimens provided. Testing may be modified during or after the end of the study to 
remove tests no longer indicated and/or to add new tests based upon the growing state of the art 
knowledge. 
These samples will be destroyed no later than 10 years, or as per local regulations, after the end 
of study unless the subject gives specific consent for the remainder of the samples to be stored 
for optional future research. If the patient provides consent for optional future research, the 
samples will be destroyed no later than 15 years after the end of the study, or as per local 
regulations. 
3.9.1.1.
Pharmacodynamic
 
3.9.1.2.
 
 
 
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Table 3-1.
Biomarker Objectives and Testing 
SAMPLE TYPE
OBJECTIVE
TEST
Blood
To evaluate pharmacodynamics of GS-5745
MMP9 cleavage products (eg, C1M, C4M)
Circulating MMP9 protein
To evaluate the effect of GS-5745 and 
chemotherapy on inflammation
Circulating cytokines and inflammatory 
markers (eg, interleukin-8, interleukin-2 
receptor, interleukin 6, interferon gamma, 
etc)
To evaluate the effect of GS-5745 and 
chemotherapy on circulating immune cells
Immune monitoring assay
To evaluate other biomarkers of GS-5745 
activity
Circulating growth factors (eg, vascular 
endothelial growth factor , epidermal 
growth factor etc)
To evaluate disease burden and identify 
mutations correlated with resistance to 
therapy
Circulating tumor DNA isolation and 
sequencing for disease-specific markers 
(eg, mKRAS, mEGFR, mPIK3CA etc) and 
other genes
Tissue Biopsy: 
Archival Tissue
To evaluate baseline markers that correlate 
with response
MMP9, other MMPs and Immune Cells by
immunohistochemistry (IHC)
Gene expression patterns (RNA)
DNA mutations may be evaluated
Tissue Biopsy: 
At progression
(if medically feasible)
To evaluate markers of response or 
resistance
MMP9, other MMPs and Immune Cells 
by IHC
Gene expression patterns (RNA) and DNA 
mutations may be evaluated and compared 
with data from the archival biopsy
3.9.2.
Optional Blood Sample for Future Genomic Analysis
 
 
 
 
 
 
 
 
 
 
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3.9.3.
Biologic Samples for Optional Future Research
 
 
 
 
 
 
 
 
 
 
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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Approximately 430 subjects will be randomized to receive double-blind study drug. The target 
population is subjects with previously untreated advanced gastric or GEJ adenocarcinoma.
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
2) Histologically confirmed adenocarcinoma of the stomach or GEJ with inoperable, locally 
advanced or metastatic disease, not amenable to curative therapy 
Adenocarcinoma of the GEJ is defined as tumors that have their center within 5 cm proximal 
and distal of the anatomical esophagogastric junction as described in Siewert’s classification 
system
3) Eastern Cooperative Oncology Group (ECOG) ≤ 1
4) Measurable disease or non-measurable but evaluable disease, according to RECIST v1.1. 
Subjects with peritoneal disease would generally be regarded as having evaluable disease and 
allowed to enter the trial
5) Subjects not receiving anticoagulant medication must have an international normalized ratio
(INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤1.5 X upper limit of normal 
(ULN)
The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT 
is within therapeutic limits (according to the medical standard in the institution) and the 
subject has been on stable dose of anticoagulants for at least 1 week at the time of 
randomization.
6) Adequate hematologic function:
a) neutrophils 2.0 x 109/L
b) platelets 100 x 109/L
c) hemoglobin 9 g/dL

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7) Adequate hepatic function:
a) Direct or total bilirubin 1.5 x ULN. 
b) ALT and AST 2.5 x ULN, in case of liver metastases ≤ 5 x ULN
8) Creatinine clearance (CLcr) should be ≥ 30 mL/min based on the Cockroft -Gault formula.  
Subjects with a CLcr just below 30 mL/min may be eligible if a measured CLcr (based on 
24 hour urine collection or other reliable method) is ≥ 30 mL/min
9) For female subjects of childbearing potential, willingness to use a protocol-recommended 
method of contraception from the screening visit throughout the study treatment period, for 
90 days following the last dose of study drug (GS-5745/placebo), and for 4 months after the 
last dose of oxaliplatin or 6 months after the last dose of 5-FU whichever occurs later unless 
the subject chooses continuous heterosexual abstinence as a lifestyle-choice (see Appendix 3
for more information)
10) For male subjects of reproductive potential, willingness to use a protocol-recommended 
method of contraception and to refrain from sperm donation from the start of study drug, 
throughout the study treatment period, for 90 days after administration of the last dose of any 
study drug, and for 6 months after the last dose of oxaliplatin or 6 months following the last 
dose of 5-FU whichever occurs later (see Appendix 3)
11) Breastfeeding females must agree to discontinue nursing before study drug administration 
12) In the judgment of the investigator, participation in the protocol offers an acceptable 
benefit-to-risk ratio when considering current disease status, medical condition, and the 
potential benefits and risks of alternative treatments for the subject’s cancer
13) Willingness to comply with scheduled visits, drug administration plan, imaging studies, 
laboratory tests, other study procedures, and study restrictions
14) Evidence of a signed informed consent prior to implementation of any protocol specific 
procedure
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be randomized in this study.
1) Previous chemotherapy for locally advanced or metastatic gastric or GEJ cancer. Subjects 
may have received prior neoadjuvant or adjuvant chemotherapy as long as it was completed 
at least 6 months prior to randomization
2) Human Epidermal Growth Factor Receptor 2 (HER2)-positive gastric cancer (primary tumor 
or metastatic lesion). HER2-positivity is defined as either IHC3+ or IHC2+/ISH+ (ISH 
positivity is defined as a HER2:CEP17 ratio of ≥2.0.)

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3) Patients who have received palliative radiation and have not recovered from all acute, 
reversible effects. 
4) Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, 
active gastrointestinal bleeding, uncontrolled cardiac arrhythmia, or psychiatric illness/social 
situation that would limit compliance with study requirements as judged by treating 
physician
5) History of a concurrent or second malignancy except for adequately treated local basal cell or 
squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, 
asymptomatic prostate cancer without known metastatic disease and with no requirement for 
therapy or requiring only hormonal therapy and with normal prostate-specific antigen for 
≥1 year prior to randomization, adequately treated Stage 1 or 2 cancer currently in complete 
remission, or any other cancer that has been in complete remission for ≥ 5 years
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) Known positive status for human immunodeficiency virus (HIV)
8) Known acute or chronic-active infection with hepatitis B virus (HBV) or hepatitis C virus 
(HCV)
9) Peripheral neuropathy ≥ Grade 2 according to National Cancer Institute Common 
Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v.4.03)
10) Chronic daily treatment with oral corticosteroids (dose of > 10 mg/day 
methylprednisolone equivalent). Inhaled steroids and short courses of oral steroids for 
anti-emesis or as an appetite stimulant are allowed
11) Pregnant or breastfeeding women (pregnancy needs to be excluded by testing of beta-human 
chorionic gonadotropin [β-hCG])
12) Known or suspected central nervous system metastases
13) Known dihydropyrimidine dehydrogenase-deficiency (special screening not required)
14) Known alcohol or drug abuse or any other medical or psychiatric condition which 
contraindicates participation in the study
15) Documented myocardial infarction or unstable/uncontrolled cardiac disease 
(ie, unstable angina, congestive heart failure [New York Heart Association > Class II]) 
within 6 months of randomization
16) Active tuberculosis or history of latent tuberculosis that has not been treated
17) Any chronic medical condition that, in the opinion of the Investigator, would make the 
subject unsuitable for the study or would prevent compliance with the study protocol. 

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18) Serious systemic fungal, bacterial, viral, or other infection that is not controlled or requires 
intravenous antibiotics
19) Experimental medical treatment within 28 days prior to randomization
20) Known hypersensitivity to any of the study drugs or excipients or to Chinese hamster ovary 
cell products or to recombinant human or humanized antibodies, or known allergic reactions 
to products that contain platinum
21) History of long QT syndrome or whose corrected QT interval (QTc) measured using 
Fridericia’s formula (QTcF = QT/RR0.333) at screening is prolonged (> 450 ms for males and 
> 470 ms for females)
22) Subjects with potassium, magnesium or calcium less than the lower limit of normal (LLN);
electrolyte replacement is permitted during screening  

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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
Randomization to GS-5745 or placebo will be based on a randomization schedule prepared by 
Gilead and/or a designee before the start of the study. Eligible subjects will be randomized via an 
interactive web response system (IWRS).As described in Section 8.5.1, randomization will be 
stratified by ECOG status (0 or 1) at screening, geographic region (Latin America or other 
participating countries), and primary tumor site (gastric or GEJ).
The IWRS will be used to maintain a central log documenting screening, to implement 
randomization, to assess current inventories of study drug, to initiate any necessary resupply of 
study drug, and to document discontinuation of the study drug. 
The IWRS will assign kit numbers and provide instructions for dispensing of blinded study drug 
(GS-5745/placebo). It is anticipated that subjects will usually begin study drug immediately after 
randomization.
5.1.1.
Procedures for Breaking Treatment Codes
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the investigator may obtain treatment assignment directly from the IWRS system 
for that subject. Gilead recommends but does not require that the investigator contact the 
Gilead medical monitor before breaking the blind. Treatment assignment should remain blinded 
unless that knowledge is necessary to determine subject emergency medical care. The rationale 
for unblinding must be clearly explained in source documentation and on the electronic case 
report form (eCRF), along with the date on which the treatment assignment was obtained. The 
investigator is requested to contact the Gilead medical monitor promptly in case of any treatment 
unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead Drug Safety and Public Health (DSPH) may independently unblind cases for expedited 
reporting of suspected unexpected serious adverse reactions (SUSARs).
5.2.
Description and Handling of Study Treatments
5.2.1.
Formulation
5.2.1.1.
GS-5745
GS-5745 is formulated as a sterile, aqueous buffered solution containing acetate at pH 5.0, with 
sucrose and polysorbate 20 added for stabilization. Each 10 mL vial contains 400 mg GS-5745 at 
a concentration of 40 mg/mL.

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5.2.1.2.
Placebo to Match GS-5745
Placebo to match GS-5745 is formulated as a sterile, aqueous buffered solution containing
acetate at pH 5.0, with sucrose and polysorbate 20 added for stabilization in a 10 mL vial.
5.2.1.3.
mFOLFOX6
The mFOLFOX6 dosing regimen will consist of dl-LVor l-LV, oxaliplatin and 5-FU.
5.2.1.3.1.
dl-Leucovorin and l-Leucovorin
dl-Leucovorin and l-LV are commercially sourced. Information regarding the formulation can be 
found in the current prescribing information.
5.2.1.3.2.
Oxaliplatin
Oxaliplatin is commercially sourced. Information regarding the formulation can be found in the 
current prescribing information
5.2.1.3.3.
5-Fluorouracil 
5-Fluorouracil is commercially sourced. Information regarding the formulation can be found in 
the current prescribing information.
5.2.2.
Packaging and Labeling
Study drug (GS-5745/placebo) solution will be supplied in 10 mL glass vials with coated 
elastomeric stoppers and aluminum crimp overseals with a flip-off cap.
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), European Union (EU) guideline to Good Manufacturing Practice - Annex 13 
(investigational medicinal Product(s)), and/or other local requirements. Gilead or designated 
distribution depots will distribute study drug vials to sites as per current Good Manufacturing 
Practices (cGMP) requirements.
mFOLFOX6 will be supplied by Gilead per local country regulations.
5.2.3.
Storage and Handling
Study drug (GS-5745/placebo) should be stored at 2 - 8 ºC. Storage conditions are specified on 
the study drug label. Until dispensed to the subject, all study drug should be stored in a securely 
locked area, accessible only to authorized site personnel. To ensure stability and proper 
identification, the study drug should be stored in the containers in which they were supplied until 
dosing to the subject.
Components of mFOLFOX6 regimen are commercially sourced. Information regarding the 
storage and handling of dl-LV/l-LV, oxaliplatin and 5-FU can be found in the current prescribing 
information

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5.3.
Dosage and Administration of Study Drug and mFOLFOX6
Study drug (GS-5745/placebo) will be administered 800 mg via intravenous infusion over 
approximately 30 (± 5) minutes at the research clinic by a qualified staff member on Days 1 and 
15 of each 28-day treatment cycle of mFOLFOX6. One cycle of mFOLFOX6 consists of 
2 infusions. mFOLFOX6 will be administered immediately following study drug on Days 1 and 
15 of each cycle as well. After 6 cycles of mFOLFOX6, the oxaliplatin component will be
discontinued. Leucovorin and 5-FU will be continued as maintenance therapy, in combination 
with GS-5745/placebo, in the absence of disease progression or toxicity warranting 
discontinuation of therapy. The mFOLFOX6 dosing regimen will consist of l-LV 200 mg/m2 or 
dl-LV 400 mg/m2 and oxaliplatin 85 mg/m2 followed by bolus 5-FU 400 mg/m2 and a 46-hour 
infusion of 5-FU 2400 mg/m2. Minor modifications to the duration of the infusion time are 
permitted as per institutional standard. Adjustments to the dose of mFOLFOX6 are permitted in 
response to treatment emergent adverse events. Refer to the local prescribing information for 
care of subjects including contraindications, subject monitoring, and the medicinal products 
prohibited or to be used with care for all the components of mFOLFOX6.
The Investigator or a qualified designee must be present during the administration of 
GS-5745/placebo. Subjects should be observed following end of infusion and discharged at the 
discretion of the Investigator or qualified designee.
Documentation of the study drug and mFOLFOX6 administration will be noted on the eCRF and 
in the source documentation.
5.3.1.
Dose Interruption and Reduction
If an adverse event is attributed to only 1 drug (ie, GS-5745/placebo or 1 or more component of 
mFOLFOX6), the investigator’s discretion will be used to determine if the drug(s) not attributed 
to the adverse event will be withheld based on the investigator’s assessment of risk-benefit of 
withholding 1 or more drugs (please see sections 5.3.1.1 and 5.3.1.2 for additional guidance).
Careful monitoring must be ensured for subjects with a history of allergic reactions to other 
platinum based chemotherapy agents.  In the event of anaphylactic shock symptoms, interrupt 
infusion immediately and initiate appropriate treatment. Resumption of oxaliplatin treatment 
following anaphylactic reaction is contraindicated.
Clinically significant, abnormal 12-lead safety ECGs should be repeated. Subjects who have 
2 consecutive ECGs showing a new absolute QTc duration > 500 msec, or a QT/QTc > 60 msec 
over the corresponding baseline value must discontinue any medications that could prolong the 
QT interval (including oxaliplatin).  Subject’s concomitant medications should be reviewed to 
determine a potential etiology for the ECG changes.  Appropriate intervention (ie cardiology 
evaluation, telemetry monitoring, management of electrolyte abnormalities) in response to 
treatment emergent QT interval prolongation should be initiated.

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5.3.1.1.
GS-5745/Placebo (Study Drug)
If a subject experiences a Grade 3 or greater toxicity considered secondary to study drug 
(GS-5745/placebo), treatment will be postponed until the toxicity returns to Grade 0-1 
(as defined by NCI CTCAE v 4.03) or returns to the subject’s baseline value. If the toxicity 
returns to Grade 0-1 or the subject’s baseline value, the subject may resume GS-5745 at the 
originally assigned dose level. 
If the event does not resolve to Grade 0-1 or the subject’s baseline within 28 days, treatment with 
study drug (GS-5745/placebo) must be permanently discontinued. If the subject experiences a 
recurrence of the Grade 3 or greater toxicity after restarting study drug, treatment with 
GS-5745/placebo will be discontinued. Subjects who permanently discontinue treatment with 
study drug (GS-5745/placebo) may continue treatment with mFOLFOX6 after consultation with 
the medical monitor. 
Subjects who are not receiving any chemotherapy (mFOLFOX6) should not receive study drug 
(GS-5745/placebo) as monotherapy.  Investigators should contact the Gilead Medical Monitor 
with any questions regarding study drug dose modification, interruption or discontinuation.
5.3.1.2.
mFOLFOX6
Recommended dose reduction for the components of mFOLFOX6 is described in Table 5-1 and 
is based on the adverse event (AE) table described in Appendix 5. Sites may also follow their 
institutional practice for dose reductions. Leucovorin doses may be adjusted per institutional 
guidelines in the event of a supply shortage.
Subjects who interrupt all components of mFOLFOX6 for greater than 28 days secondary to 
drug toxicity(s) that do not resolve should permanently discontinue all study treatment.  
Subjects who permanently discontinue all components of mFOLFOX6 should also discontinue 
GS-5745/placebo.
Investigators should contact the Gilead Medical Monitor with any questions regarding study drug 
dose modification, interruption or discontinuation.
Table 5-1.
Dose Reduction Levelsa for mFOLFOX6
Drug
Dose Level
Starting Dose
-1
-2 b
Oxaliplatin
85 mg/m2
65 mg/m2
50 mg/m2
5-FU bolus
400 mg/m2
OMIT
OMIT
5-FU continuous infusion over 46-48 hours
2400 mg/m2
1900 mg/m2
1500 mg/m2
dl-Leucovorin/l-Leucovorinc
400/200 mg/m2
100%
100%
a
If an AE is believed likely to be due to 1 drug, it is permissible to decrease dose of that drug only.
b
Further dose levels (-3, -4, etc.) will be 20% dose reductions from the previous level for oxaliplatin and 5-FU continuous 
infusion. In addition, the bolus dose of 5-FU will continue to be omitted, and the leucovorin dose will remain unadjusted 
(100%).
c
Dosing of leucovorin will remain fixed at 100% of recommended dose.

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5.4.
Prior and Concomitant Medications
During the course of the clinical trial, study subjects are anticipated to continue the use of 
prescribed medications identified during the screening procedures, consistent with study 
inclusion and exclusion criteria. 
Non-study anticancer chemotherapy or immunotherapy (approved or investigational) are not 
permitted during the trial. If administered, the subject may be removed from the trial.
Concomitant medications that are known to lengthen QTc interval must be used carefully while 
the subject is receiving oxaliplatin.  Please refer to https://www.crediblemeds.org/ for a listing of 
such medications.
5.5.
Accountability for Study Drug
The investigator or designee (eg, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused investigational medicinal product during the study. This includes 
acknowledgement of receipt of each shipment of study drug (quantity and condition) and 
tracking of vials assigned/utilized for subject dosing.
Study drug (GS-5745/placebo) accountability records will be provided to each study site to:

Record the date received and quantity of study drug vials

Record the date, subject number, subject initials, the vial number dispensed

Record the date, quantity of used and unused vials returned, along with the initials of the 
person recording the information.
Dispensing records will include the initials of the person dispensing the study drug or supplies. 
5.5.1.
Investigational Medicinal Product & mFOLFOX6 Return or Disposal
The study drug and mFOLFOX6 should be disposed of at the site as per local standard operating 
procedures. Please see Section 9.1.7 for additional instructions. 

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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. 
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
Safety and tolerability assessments will include regular monitoring of AEs, changes from 
baseline in laboratory variables, physical examinations, vital signs, and special safety assessment 
like ECGs. 
From the time of obtaining informed consent through the first administration of study drug, 
record all serious adverse events (SAEs), as well as any non-serious AEs related to 
protocol-mandated procedures on the AEs eCRF. All other untoward medical occurrences 
observed during the Screening period, including exacerbation or changes in medical history are 
to be captured on the medical history eCRF. 
6.1.
Subject Enrollment and Treatment Assignment
Subject eligibility will be established at the conclusion of the screening evaluations. The 
screening number and/or subject ID will be assigned for that individual subject by the designated 
IWRS. Subject eligibility must be determined by results received from the central lab with 
exceptions made for re-screening and human epidermal growth factor receptor 2 (HER2) testing 
as described in Sections 6.2.2 and 6.2.8.2.
It is the responsibility of the investigator to ensure that each subject is eligible for the study 
before randomization. A subject will be considered enrolled once he or she has completed 
randomization.
Subjects in both treatment arms will undergo all the same procedures. Details regarding 
randomization and treatment assignment are in Section 5.
6.2.
Study Procedure Descriptions
The sections below describe the individual study procedures outlined in subsequent sections and 
the schedule of assessments. During the treatment period, all visits may be performed within the 
windows identified in Appendix 2.
6.2.1.
Informed Consent
All subjects must sign and date the most recent IRB/IEC-approved informed consent form before 
any study specific procedures are performed except where noted in the protocol in relation to 
standard of care procedures.
 
 
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6.2.2.
Re-Screening Criteria
Subjects who do not randomize within 28 days of screening will be screen failed. The screening 
period may be extended beyond 28 days with sponsor approval if the only outstanding eligibility 
criterion is the human epidermal growth factor receptor 2 (HER2) status.
Re-screening may be allowed. Subjects who are re-screened after 30 days, must be re-consented 
with a new screening number, and repeat the screening assessments. For subjects re-screened 
within 30 days, assessments with results that would exclude the subject will need to be repeated.
Subjects with abnormal electrolyte values during screening will be allowed to repeat testing for 
the purposes of study eligibility - replacement therapy is permitted.  If this is the only 
inclusion/exclusion criteria not met, these analytes may be retested (locally or centrally) so that 
values above the lower limit of normal could be achieved without the need to screen fail the 
subject.
Subject eligibility must be determined by results received from the central lab. However, if there 
have been 2 failed attempts to obtain test results from the central lab, eligibility may be 
determined using local lab results, with documentation of failed attempts, local lab results, and 
sponsor approval.
6.2.3.
Medical & Medication History
A complete medical and surgical history will be obtained by the investigator or designee at 
screening, including disease history, and recorded on the eCRF.
All medications taken within 30 days prior to screening and during the screening period will be 
obtained prior to randomization and recorded on the eCRF. At each study visit, the site will 
capture any and all medications taken by the subject since the last visit or during the visit 
(as applicable). Concomitant medications include prescription and non-prescription medications, 
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.
6.2.4.
Physical Examination
A physical examination (PE) will be performed at screening, end of treatment (EOT) and EOS. 
This will include assessment of clinical signs and symptoms. The exam will be performed by a 
physician, a physician’s assistant, or nurse practitioner qualified to perform assessments. Breast, 
genital, and rectal examinations are not required, unless warranted in opinion of the healthcare 
provider. 
A modified physical exam capturing changes from prior exams will be performed at Day 1 of 
each cycle and at the 30-day Safety Follow-Up. Height will be collected at Screening only and 
entered in the CRFs in centimeters. Body surface area (BSA) to determine the dose for 
mFOLFOX6 will be calculated using height and weight; the Mosteller formula: √( [Height (cm) 
Weight (kg)]/3600) is preferred. However, institutional guidelines/practice for calculating BSA 
will also be allowed.

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Amendment 6
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6.2.5.
Vital Signs & Weight
Vital signs ie, blood pressure, heart rate, respiratory rate, and oral temperature, will be measured
by the investigator or qualified designee as per standard institutional guidelines at each study 
visit as indicated in Appendix 2. Weight will be collected at the same visits vital signs are taken
and entered in the CRFs in kilograms. BSA to determine the dose for mFOLFOX6 will be 
calculated using weight in kilograms. The Mostellar formula is preferred for calculating BSA.  
However, institutional guidelines/practice for calculating BSA will also be allowed.
6.2.6.
Electrocardiogram Assessment
A single 12-lead electrocardiogram (ECG) will be collected at Screening, Day 1 of each cycle, at 
the EOT and EOS visits, per standard practice. Additional ECGs following administration of 
oxaliplatin will be collected at visits when oxaliplatin is administered after the infusion is 
completed (i.e., Days 1 and 15 of each cycle, up to a maximum of six 28-day cycles) as required 
per country label guidance regarding cardiac monitoring. The investigator will review all ECGs 
and retain the tracing with the source documents.  ECGs obtained after oxaliplatin infusions must
be reviewed by the investigator/sub investigator before subjects leave the clinic/infusion center.
6.2.7.
Performance Status
Performance status will be scored using the ECOG performance status scale index 
(refer to Appendix 4), at Screening, Day 1 of each cycle, EOT, EOS and 30-day Safety 
Follow-up visits. ECOG used to determine eligibility must be the performance status during the 
screening period. ECOG performance status on Cycle 1 Day 1 may be waived if it was 
conducted during screening within 4 days of Cycle 1 Day 1.
6.2.8.
Laboratory Assessments
The central laboratory will be responsible for chemistry, hematology, coagulation, urinalysis, 
and serum pregnancy testing (per Table 6-1) as well as processing and/or storage of other study 
samples. Specific instructions for processing, labeling, and shipping samples will be provided in 
a central laboratory manual. The date and time of sample collection will be reported to the 
central laboratory.
If central laboratory results are not available, local laboratories may be used for dosing decisions. 
Local laboratory assessments resulting in a dose change or as part of an adverse event 
assessment, which is not supported by central lab results, will be reported on the eCRF.
Urine pregnancy test will be performed at the site. 

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Table 6-1.
Analytes
Chemistry
Urinalysis
Hematology
Other
Albumin
Alkaline phosphatase
ALT 
AST 
Bicarbonate
BUN
Calcium
Chloride
Creatininea
Glucose
Lipase
Magnesium
Phosphorus
Potassium
Sodium
Total bilirubin
Direct bilirubin
Total protein
CA19-9
CEA
Color and appearance
Specific gravity
pH
Occult blood
Protein
Glucose
Bilirubin
Leukocyte esterase
Nitrite
Urobilinogen
Ketones
Microscopicb
WBC
Hemoglobin
Hematocrit
Platelet
ANC
Differential
Eosinophils
Lymphocytes
Monocytes
Neutrophils
Serum β-hCG or urine 
pregnancy testc
Coagulation
PT/INR
aPTT
ANC = absolute neutrophil count; ALT = alanine aminotransferase; aPTT = Activated Partial Thromboplastin Time; 
AST = aspartate aminotransferase; BUN = blood urea nitrogen; CEA=carcinoembryonic antigen; β-hCG = beta-human
chorionic gonadotropin; HER2 = human epidermal growth factor receptor 2; INR = International Normalized Ratio; 
PT = Prothrombin Time; SGOT = Serum Glutamic-Oxaloacetic Transaminase; SGPT = Serum Glutamic-Pyruvic Transaminase; 
WBC = white blood cell
a
Estimated creatinine clearance (CLcr)/glomerular filtration rate will be calculated based on the Cockroft-Gault formula using 
actual body weight: CLcr (mL/min) = (140 – age [years])* weight (kg) / (serum creatinine [mg/dL]*72).  If the subject is 
female, multiply the quantity by 0.85.
b
Reflex testing based on other abnormalities
c
Females of child-bearing potential only. Serum pregnancy will be conducted at Screening. Urine pregnancy will be 
conducted pre-dose on Day 1 of each cycle
Screening laboratory samples should be obtained within 28 days prior to randomization. Blood 
samples will be obtained for hematology, chemistry, coagulation, and pregnancy testing for 
female subjects. A urine sample will also be obtained at screening for urinalysis.
Blood samples for hematology and chemistry will be obtained at pre-dose of Days 1 and 15 of 
each cycle, EOT, EOS, and 30-day Safety Follow-up. A urine sample for urinalysis and 
pregnancy testing for female subjects will also be obtained at Day 1 of each cycle, EOT, EOS,
and 30-day Safety Follow-up (urinalysis only). Blood samples for coagulation will be obtained at 
EOT and EOS.
At any time during the study, abnormal laboratory parameters that are clinically relevant 
(eg, lead to clinical symptoms or signs, require therapeutic intervention), and constitute an AE 
must be recorded in the eCRF.

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Amendment 6
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6.2.8.1.
Pregnancy Test
All females of childbearing potential (see Appendix 3) will have a serum pregnancy test at 
screening. Urine pregnancy tests will be performed on Day 1 of every cycle, EOT, EOS, and 
30-day Safety Follow-up.
6.2.8.2.
Human Epidermal Growth Factor Receptor 2 (HER2) Testing
Prior to randomization, the subject’s tumor should have been tested for HER2 status with 
approved immunohistochemistry (IHC) and in situ hybridization (ISH) kits. HER2 positivity is 
defined as IHC3+ or IHC2+/ISH+ (ISH positivity is defined as HER2:CEP17 ratio of ≥2.0).
Results for HER2 status obtained prior to signing informed consent are acceptable if obtained 
with approved IHC and ISH kits. HER2 status may be determined during screening by testing the 
tumor at the central lab or a local lab with approved IHC and ISH kits.
6.2.8.3.
Archival Tumor Tissue
Archival tumor tissue formalin-fixed paraffin embedded (FFPE) blocks will be collected from all 
subjects for biomarker analysis and shipped to central laboratory for sectioning after Day 1 of 
Cycle 1.  If FFPE blocks are not available, unstained slides are also acceptable (see Covance 
manual for details). If an archival block was submitted for HER2 testing, and the subject is 
randomized, the block will be stored for biomarker analysis. However, if slides were submitted 
for HER2 testing, additional slides will be required after Day 1 of Cycle 1 for biomarker 
analysis. 
6.2.8.4.
Anti-GS-5745 Antibody
Blood samples for anti-GS-5745 antibody will be collected prior to dosing on Day 1 of 
cycles 1, 2, 3, 5, 7, and every 3 cycles thereafter, at the EOT, EOS, and 30-Day Safety Follow 
Up visits. 
6.2.8.5.
GS-5745 Pharmacokinetics
Blood plasma samples will be collected for GS-5745 PK at 30 (± 15) minutes after the end of 
infusion on Cycle 1 Day 1, prior to dosing, and 30 (± 15) minutes after the end of infusion on 
Day 1 of Cycles 2, 3, 5, 7, and every 3 cycles thereafter, at the EOT and EOS visits. 
6.2.8.6.
Optional PK Sub-study
 
 
CCI
I 

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Amendment 6
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6.2.8.7.
Biomarkers
Samples for biomarker analysis as listed on Table 3-1 will be collected as specified below and in 
Appendix 2:

Blood biomarker samples will be collected prior to dosing on Cycle 1 Day 1, Cycle 1 
Day 15, and Day 1 of Cycles 2 and 4, and every 2 cycles thereafter.

A pharmacodynamic biomarker sample and immune-monitoring sample will be collected 
prior to dosing on Cycle 1 Day 1 and Cycle 3 Day 1.

A biomarker sample for circulating tumor DNA will be collected prior to dosing on Cycle 1 
Day 1, Cycle 3 Day 1, and at disease progression.

 
 
6.2.8.8.
Core Biopsy
At disease progression, a core biopsy will be collected (fine needle aspirate is not acceptable) if 
medically feasible. The sample should be collected by the last clinic visit on study, ie, EOS or 
30-Day Safety Follow-up visit.
6.2.9.
Disease and Response Assessment
6.2.9.1.
Tumor Imaging 
Either contrast-enhanced CT or gadolinium-enhanced MRI of the chest, abdomen, and pelvis 
will be performed at screening, every 8 weeks during the study (starting from Cycle 1 Day 1) and 
at the EOS visit if one has not been performed within the last 8 weeks. Tumor burden will be 
evaluated solely based on radiographic imaging per RECIST v 1.1. Chest x-ray, ultrasound, 
endoscopy, laparoscopy, positron-emission tomography, radionuclide scans, or tumor markers 
will not be considered for response assessment.
For radiographic evaluations, the same method of assessment and the same technique 
(eg, scan type, scanner, subject position, dose of contrast, injection/scan interval) should be used 
to characterize each identified and reported lesion at baseline and during study treatment and 
follow-up.
CCI
CCI

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Amendment 6
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Scans taken as part of standard medical practice up to 42 days prior to randomization can be used 
for Screening as long as they meet all study requirements. During the treatment phase, scans may 
be performed at time points other than every 8 weeks as clinically indicated to assess tumor 
progression. 
For subjects who stop study treatment in the absence of disease progression (eg, experienced 
unexpected toxicity), scans should continue to be collected approximately every 8 weeks until 
disease progression or initiation of systemic anti-tumor therapy other than the study treatment, 
whichever is earlier. 
All relevant clinical and radiographic information required to make each assessment must be 
made available for source verification and submission to a central reader. Scans will be 
transferred to a central reader for collection and future analysis. Disease progression will be 
determined by the investigator or qualified designee.
6.2.10.
Patient-reported Outcomes Assessments
Patient-reported outcomes (PRO) will be collected at Day 1 of each cycle, EOT and EOS visits, 
and at the 30 day safety follow up visit prior to any assessments in the clinic.
6.2.10.1.
EuroQol-5D
The EuroQol-5D (EQ-5D) is a general health quality of life self-report instrument that assesses 
5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each 
dimension has 3 levels (EQ-5D-3L), ranging from no health problem, moderate health 
problem(s), and extreme health problem(s). It also includes a single visual analog scale for 
assessment of current general health.
6.2.10.2.
Quality of Life Questionnaire
The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire (QLQ-C30) is a self-report questionnaire consisting of 30 questions assessing
15 sections of the subject’s wellbeing. The accompanying module for gastric cancer,
QLQ-STO22, has an additional 22 questions.
6.2.11.
Study Drug and Chemotherapy Administration
Study drug (GS-5745/placebo) will be dosed on Days 1 and 15 of every 28-day cycle via 
intravenous infusion over approximately 30 (± 5) minutes followed by chemotherapy
(mFOLFOX6) as described in Section 5. One cycle of mFOLFOX6 consists of 2 infusions.
6.2.12.
Adverse Events
From the time of obtaining informed consent through the first administration of study drug, 
record all SAEs as well as any AEs related to protocol-mandated procedures on the AE eCRF.
All other untoward medical occurrences observed during the screening period, including 
exacerbation or changes in medical history are to be captured on the medical history eCRF.

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From the time of the first administration of study drug through 55 days post the last 
administration of treatment (GS-5745/placebo and mFOLFOX6), record any SAEs, and AEs 
including exacerbation or changes in medical history, on the AE eCRF.
See Section 7 Adverse Events and Toxicity Management for additional details.
6.3.
Assessments for Premature Discontinuation from Study
If a subject has discontinued all study treatments prior to definitive disease progression, the 
subject shall remain on study for follow-up for progression-free survival (see Sections 3.5
and 3.6). Every attempt should be made to keep the subject in the study and continue to perform 
tumor evaluation by CT or MRI every 8 weeks. Subjects will remain on study until disease 
progression or initiation of non-study specific anti-neoplastic therapy in the absence of 
progression, whichever occurs earlier.
If it is not possible to keep the subject on study, or acceptable to the subject or investigator, the 
subject may be withdrawn. It is recommended that the investigator consults with the medical 
monitor prior to removing the subject from study for any reason except subject withdrawal of 
consent.
6.4.
Criteria for Discontinuation of Study Treatment
See Sections 3.4 and 3.6 for discontinuation criteria.
6.5.
End of Treatment
End of treatment (EOT) assessments will be completed only by subjects who discontinue all 
treatment prior to disease progression.  These assessments should be completed as soon as
possible after the decision is made. Every attempt should be made to keep the subject in the 
study and continue to perform tumor evaluation by CT or MRI every 8 weeks until disease 
progression.  
6.6.
End of Study
End of study (EOS) assessments will be completed when the subject meets at least 1 of the 
criteria for study discontinuation (Section 3.6).
6.7.
Safety Follow-Up
A follow-up visit will be performed 30 days (7 days) following the last dose of 
GS-5745/placebo or all components of mFOLFOX6, whichever is discontinued later. A 
follow-up phone call will be performed 55 days (± 7 days) following the last dose of 
GS-5745/placebo or all components of mFOLFOX6, whichever is discontinued later to assess 
any AEs and concomitant mediations. 

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6.8.
Long-Term Follow-up
Long-term follow-up (LTFU) for overall survival begins after the EOS visit, or the last visit on 
study if EOS does not occur. Subjects will be contacted via phone call every 3 months for 
determination of long term survival status and record of any other anti-cancer therapy, cancer 
related surgery for up to 5 years after the EOS visit. 
Subjects who are not deceased by the time Gilead has made the determination the study will be 
ended will receive a final follow-up phone call to assess survival status and communicate the 
Sponsor’s decision. 
The investigator will make every effort to contact the subject or a close relative or caretaker by 
phone to collect survival information. The investigator should show due diligence by 
documenting in the source documents steps taken to contact the subject (ie, dates of phone calls, 
registered letters, etc).
See Section 3.7 for reasons for discontinuing long-term follow-up and study completion.
6.9.
Unscheduled visits
Unscheduled visits may occur at any time while the subject is enrolled on study. Vital signs, 
laboratory assessments, ECG, and physical examination may be conducted at these visits. Data 
generated during an unscheduled visit will be collected on the eCRF.
6.10.
Protocol Deviations
Gilead’s policy prohibits exemptions from protocol inclusion/exclusion criteria. In the event of a 
significant deviation related to gross non-compliance from the protocol or incidences that impose 
significant risk to subject safety, the investigator or designee must notify Gilead and/or its 
designee immediately. The site will be required to document deviations in accordance with 
Gilead’s procedures and in accordance with the site’s procedures and processes.

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

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
In-patient hospitalization or prolongation of existing hospitalization (Note: Hospitalization 
for chemotherapy infusion per institutional guidelines will not be considered an SAE.)

Persistent or significant disability/incapacity

A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is a reportable 
under expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.2.1.
Protocol-Specific Serious Adverse Event Instructions
To maintain the integrity of the study, disease progression and death from disease progression 
should be reported as SAEs by the investigator only if it is assessed that the study drugs caused 
or contributed to the disease progression (ie, by a means other than lack of effect). Unrelated 
disease progression should be captured on the eCRF.
In addition, events that are indicative of the following disease-related SAEs that are assessed as 
unrelated to study drugs will not be reported as expedited reports by Gilead during the study:

Progression of gastric cancer

Death related to disease progression
These events will be exempt from global expedited reporting requirements for the duration of the 
study as they are the primary endpoints of this study. They will be reported as appropriate in the 
final clinical study report as well as any relevant aggregate safety report.
7.2.
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.

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7.2.1.
Assessment of Causality for Study Drugs and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to IMP
therapy using clinical judgment and the following considerations:

No: Evidence exists that the adverse event 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 
investigational medicinal product.
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of adverse event 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 adverse event has an etiology other than the study procedure.

Yes: The adverse event occurred as a result of protocol procedures, (eg., venipuncture)
7.2.2.
Assessment of Severity
The severity of AEs will be graded using the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.03 in the study manual.
If an NCI CTCAE term is not available for the AE/SAE, the severity will be graded per the 
General Guidance rules found in the introduction section of the NCI CTCAE , Version 4.03 
document.  
The distinction between the seriousness and the severity of an AE should be noted. Severe is a 
measure of intensity; thus, a severe (Grade 3) reaction is not necessarily a serious adverse event 
(SAE). 
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead
Requirements for collection prior to study drug initiation:
After informed consent, but prior to initiation of study medication, the following types of events 
should be reported on the eCRF: 

All SAEs and adverse events related to protocol-mandated procedures

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7.3.1.
Adverse Events
Following initiation of study medication, collect all AEs, regardless of cause or relationship, 
until 55 days after last administration of GS-5745/placebo or all components of mFOLFOX6, 
whichever is discontinued later.  These must be reported to the eCRF database as instructed.  
All AEs should be followed up until resolution or until the adverse event is stable, if possible. 
Gilead Sciences may request that certain AEs be followed beyond the protocol defined follow-up 
period.
7.3.2.
Serious Adverse Events
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
eCRF database and Gilead DSPH as instructed. This also includes any SAEs resulting from 
protocol-associated procedures performed after informed consent is signed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 55 days of the 
last dose of GS-5745/placebo or all components of mFOLFOX6, whichever is discontinued later, 
regardless of causality, should also be reported. 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period,
however, if the investigator learns of any SAEs that occur after study participation has concluded 
and the event is deemed relevant to the use of study drug, he/she should promptly document and 
report the event to Gilead DSPH.

All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
eCRF completion guideline.

SAEs will be reported using an electronic SAE (eSAE) system. 
7.3.2.1.
Electronic Serious Adverse Event (eSAE) Reporting Process

Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.

If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper serious adverse event reporting 
form and submit within 24 hours to:
Gilead DSPH:
Fax:
Email:
PPD
PPD

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
As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF database according to instructions in the eCRF completion guidelines.

If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.

For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.

Additional information may be requested to ensure the timely completion of accurate safety 
reports.

Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA 
Code of Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant 
updates, and other country-specific legislation or regulations, Gilead may be required to expedite 
to worldwide regulatory agencies reports of SAEs, SADRs, or suspected unexpected serious 
adverse reactions (SUSARs). In accordance with the EU Clinical Trials Directive (2001/20/EC), 
Gilead or a specified designee will notify worldwide regulatory agencies and the relevant IEC in 
concerned Member States of applicable SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the IB 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.
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (eg, clinical chemistry, hematology, and urinalysis) that require medical or surgical 
intervention or lead to interruption or discontinuation of study drug (GS-5745/placebo) or 
mFOLFOX6 must be recorded as an AE, as well as an SAE, if applicable. In addition, laboratory 
or other abnormal assessments (eg, electrocardiogram, X-rays, vital signs) that are associated 
with signs and/or symptoms must be recorded as an AE or SAE if they meet the definition of an 
AE or SAE as described in Sections 7.1.1 and 7.1.2, respectively. If the laboratory abnormality is 
part of a syndrome, record the syndrome or diagnosis (ie, anemia) not the laboratory result 
(ie, decreased hemoglobin).

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Severity should be recorded and graded according to the NCI CTCAE (version 4.03).
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.
7.6.
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. Laboratory abnormalities (eg, thiamine deficiency) identified at screening/baseline 
and during study participation should be treated at the investigators discretion. 
Any questions regarding toxicity management should be directed to the Gilead Sciences 
Medical Monitor or designee.
7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports 
of adverse events associated with product complaints, and pregnancy reports regardless of an 
associated AE.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional and inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).

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Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
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.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported. Furthermore, 
any SAE occurring as an adverse pregnancy outcome post study must be reported to 
Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to or Gilead DSPH using the pregnancy outcome 
report form. 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 partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead DSPH using the 
pregnancy and pregnancy outcome forms 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 contact information is as follows:
Fax:
Email:
Refer to Appendix 3 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Requirements.
PPD
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7.7.2.2.
Emergency Unblinding
In the event of a medical emergency where breaking of the blind is being considered by the 
treating physician, the investigator may break the blind using the IWRS. It is recommended that 
the Gilead Medical Monitor be contacted before the investigator breaks the blind. Please note 
that the treatment assignment should not be unblinded if unblinding will not affect the way the 
subject would be treated. In the event of a medical emergency, where breaking of the blind is 
required per the medical judgment of the investigator, the Gilead Medical Monitor must be 
contacted as soon as possible after the unblinding. The unblinding must be clearly justified and 
explained by a comment in the source documentation, along with the date on which the code was 
broken and the identity of the person authorizing the unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the investigator, the subject will have study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject.
Gilead DSPH may independently unblind cases for expedited reporting of SUSARs.
7.7.2.3.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to Gilead DSPH within 24 hours of the investigator becoming aware of the situation. 
These reports must consist of situations that involve study IMP and/or Gilead concomitant 
medications, but do not apply to non-Gilead concomitant medications. 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situations report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form.
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation.
Refer to the eCRF completion guidelines for full instructions on the mechanism of special 
situations reporting.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available.

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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives 
8.1.1.
Primary Objective
The primary objective is to compare the efficacy of GS-5745 versus placebo in combination with 
mFOLFOX6 as measured by OS.
8.1.2.
Secondary Objectives
The secondary objectives are:

To compare the efficacy of GS-5745 versus placebo in combination with mFOLFOX6 as 
measured by PFS

To compare the efficacy of GS-5745 versus placebo in combination with mFOLFOX6 as 
measured by ORR per RECIST v1.1

To compare the safety profile of GS-5745 versus placebo in combination with mFOLFOX6
8.1.3.
Exploratory Objectives
8.2.
Analysis Endpoints
8.2.1.
Primary Endpoint
The primary endpoint of the study is OS as defined in Section 2.4.
8.2.2.
Secondary and Exploratory Endpoints
The secondary and exploratory endpoints of the study are defined in Section 2.5.
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8.3.
Analysis Conventions
8.3.1.
Analysis Sets
8.3.1.1.
Intent-to-Treat (ITT) Analysis Set
The ITT analysis set includes data from all randomized subjects. Study drug assignment will be 
designated according to randomization.
This analysis set will be used in the analyses of subject characteristics, OS, PFS, ORR and DCR. 
The analysis of OS based on the ITT analysis set will be considered the primary analysis of the 
study.
Subjects in the ITT analysis set who do not have sufficient baseline or on-study tumor status 
information to be adequately assessed for response status (ie, those with best overall responses of 
NE or ND) will be included in the denominators in calculations of response rates and disease 
control rates.
8.3.1.2.
Safety Analysis Set
The safety analysis set will include data from all subjects who receive 1 dose of study 
treatment, with treatment assignments designated according to the actual treatment received.
This analysis set will be used in the analysis of safety variables as well as study treatment 
administration. All data collected up to the last dose of GS-5745/placebo or mFOLFOX6 or 
5-FU and LV, whichever is later, plus 55 days will be included in the safety summaries.
8.3.1.3.
Pharmacodynamic and Pharmacokinetic (PK) Analysis Sets
The pharmacodynamics and PK analysis sets will include data from subjects in the safety 
analysis set who have the necessary baseline and on-study measurements to provide interpretable 
results for the specific parameters of interest.
8.4.
Data Handling Conventions
8.4.1.
General Methods
By-subject listings will be created for important variables from each eCRF module.
Summary tables for continuous variables will contain the following statistics:
N (number in analysis set), n (number with data), mean, standard deviation (std),
95% confidence intervals (CIs) on the mean, median, minimum, and maximum. Summary tables 
for categorical variables will include: N, n, percentage, and 95% CIs on the percentage. Unless 
otherwise indicated, 95% CIs for binary variables will be calculated using the binomial 
distribution (exact method) and will be 2-sided. Data will be described and summarized by 
relevant treatment arm, analysis set, and time point. As appropriate, changes from baseline to 

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each subsequent time point will be described and summarized by treatment arm. Similarly, as 
appropriate, the best change from baseline during the study will also be described and 
summarized by treatment arm. Graphical techniques (eg, waterfall plots, Kaplan-Meier curves,
etc.) may be used when such methods are appropriate and informative.
The baseline value used in each analysis will be the last (most recent) pre-treatment value.
Subjects with discrepancies between the stratification factor values at randomization and the 
actual values as documented on data review will be categorized in the analyses according to the 
actual values. In the situation that there is insufficient information in a stratum (ie, if there are 
< 6 subjects or there are no events in a stratum), that stratum will be pooled with the smallest 
adjacent stratum for stratified analyses; the smallest stratum is defined as that stratum having the 
fewest number of subjects or the fewest number of events in case the former is a tie and the 
adjacent stratum is defined as a stratum having 2 factors of the 3 at the same level. 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.
Unless otherwise specified, all analyses will be 1-sided at the 0.025 level of significance.
The following censoring conventions will be applied to tumor control endpoints:

OS: Data from surviving subjects will be censored at the last time that the subject was known
to be alive.

PFS: Data from surviving, non-progressing subjects will be censored at the earliest of the
time of initiation of antitumor treatment other than the study treatment or the last time that
lack of definitive progression was objectively documented. Data from subjects who have 
disease progression or die after ≥2 consecutive missing tumor assessments will be censored 
at the last time prior to the missing assessments that lack of definitive disease progression 
was objectively documented.

DOR: Data from surviving, non-progressing subjects will be censored at the earliest of the 
time of initiation of antitumor treatment other than the study treatment or the last time that 
lack of definitive disease progression was objectively documented. Data from subjects who 
have disease progression or die after ≥ 2 consecutive missing tumor assessments will be 
censored at the last time prior to the missing assessments that lack of definitive disease 
progression was objectively documented.
8.4.2.
Demographic Data and Baseline Characteristics
Demographic summaries will include sex, race/ethnicity, randomization stratification group, and age.
Baseline characteristics will include a summary of body weight, height, and body mass index.
Demographic and baseline characteristics will be summarized using standard descriptive methods. 

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8.5.
Efficacy Analysis
8.5.1.
Primary Analysis
The null hypothesis is that addition of GS-5745 to mFOLFOX6 will not improve OS in first-line 
patients with advanced gastric cancer. The alternative hypothesis is that addition of GS-5745 to 
mFOLFOX6 will improve OS.
The Kaplan-Meier (KM) method and logrank test stratified by ECOG status (0 or 1), 
geographic region (Latin America or other participating countries), and primary tumor site 
(gastric or GEJ) will be used to compare the 2 treatment groups. A Cox proportional hazard 
model with the same stratification factors will be used to estimate the hazard ratio and 
corresponding 95% confidence interval (CI).
8.5.2.
Secondary and Exploratory Analyses
 
 
 
 
 
8.5.3.
Control of Type I Error Rate in Efficacy Analyses
In the efficacy analyses, the following procedures will be implemented to preserve the overall 
type I error rate across the primary and secondary endpoints of the study, and at interim and final 
analysis, at a 1-sided significance level of 0.025.
The primary endpoint analysis will serve as the gatekeeper for the secondary endpoint analyses, 
ie, the primary efficacy endpoint must be met before the secondary efficacy endpoints can be 
tested. The secondary endpoints included in this sequential testing approach are (1) PFS and 
(2) ORR.
If the primary hypothesis is rejected, the 2 secondary endpoints will be sequentially tested at the 
1-sided 0.016 significance level in the order listed above. If a null hypothesis is not rejected, 
formal sequential testing will be stopped and only nominal significance will be cited for the 
remaining secondary endpoints. Analyses and p-values will be reported for all the efficacy 
endpoints, including the primary endpoint, the secondary endpoints, and all of the exploratory
endpoints.
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8.6.
Safety Analysis
All safety data collected on or after the date that GS-5745/placebo was first administered up to 
the date of last dose of GS-5745/placebo or mFOLFOX6 or 5-FU and LV (whichever is later) 
plus 55 days will be summarized by treatment group (according to the treatment received). Data 
for the pre-treatment and post-treatment follow-up period will be included in data listings.
In general, count and percent of subjects will summarize categorical and ordinal data. 
Mean, standard deviation, minimum, quartiles, median, and maximum will summarize 
continuous data.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to GS-5745 will be generated from the study drug administration 
eCRF page. Exposure data will be summarized by treatment group.
8.6.2.
Adverse Events
Clinical and laboratory adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). System Organ Class (SOC), High-Level Group Term 
(HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term (LLT) will be 
attached to the clinical database.
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event is defined as any adverse event with onset date on or after the date of first dose of 
study drug up to 55 days after permanent study drug discontinuation or any adverse events
leading to premature study drug discontinuation.
Summaries (number and percentage of subjects) of treatment-emergent adverse events 
(by SOC, HLT, and PT) will be provided by treatment group.
8.6.3.
Laboratory Evaluations
Selected laboratory data (using conventional units) will be summarized using only observed data. 
Data and change from baseline at all scheduled time points will be summarized.
Graded laboratory abnormalities will be defined using the NCI CTCAE (version 4.03). 
Maximum post-baseline grade will be summarized by count and percent of subjects with each 
grade.
Incidence of treatment-emergent laboratory abnormalities, defined as values that increase at least 
1 toxicity grade from baseline at any time post-baseline, will be summarized by treatment group. 
If baseline data are missing, then any graded abnormality (ie, at least a Grade 1) will be 
considered treatment-emergent.
Laboratory abnormalities that occur before the first dose of study drug will be included in data 
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8.6.4.
Other Safety Evaluations
Similar general approaches to the AE and clinical laboratory data will be utilized to summarize 
other safety measures.
8.7.
Pharmacokinetic Analysis
The plasma concentration data of GS-5745, oxaliplatin, and 5-FU (and metabolite, if applicable) 
will be summarized by nominal sampling time using descriptive statistics (eg, sample size, 
arithmetic mean, geometric mean, coefficient of variation (%) standard deviation, median, 
minimum, and maximum). PK parameters (Cmax, Tmax, Clast, Tlast, Ctau, λz, AUClast, AUCtau, and t½, 
as applicable) will be listed and summarized using descriptive statistics. Plasma concentrations 
over time may also be plotted in semi-logarithmic and linear formats as mean ± standard 
deviation, and median (Q1, Q3). Exposures (Cmax and AUC) of oxaliplatin and 5-FU with or 
without co-administration of GS-5745 will be compared to evaluate if GS-5745 treatment alters 
the PK of oxaliplatin/5-FU. 
Exposure-response analysis may be explored as appropriate.
The number and percentage of positive or negative anti-GS-5745 antibody values at each 
specified timepoint will be summarized. The effect of anti-GS-5745 antibody on GS-5745 PK, 
safety, and efficacy may be evaluated.
8.8.
Biomarker Analysis
8.8.1.
Pharmacodynamic and Exploratory Biomarker Analysis Analysis
 
 
 
 
 
8.9.
Patient-Reported Outcomes
The values and change from baseline for EQ-5D-3L index scores and the visual analog scale 
(VAS) will be summarized by descriptive statistics by visit for each treatment arm. 
The EORTC QLQ-C30 and QLQ-STO22 questionnaire will be scored according to EORTC 
guidelines, such that all scales from 0 to 100, with higher functioning and global scores 
representing better QoL and higher symptom scores representing greater symptom burden. The 
values and change from baseline for QLQ-C30 and QLQ-STO22 scores will be summarized by 
descriptive statistics by visit for each treatment arm. 
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The time to QLQ-C30 and QLQ-STO22 deterioration is defined as the time from randomization 
to the first deterioration of ≥10 points from baseline. If no deterioration was observed, censoring 
occurs at the date of the last assessment. The hazard ratio and the 95% CI comparing the 
treatment and placebo arm will be provided using the Cox proportional hazard model. 
The QLQ-C30 and QLQ-STO22 analysis will also characterize each post baseline assessment as 
Improved if the improvement from baseline is ≥10 points, and Stable if the change from 
baseline is within +/-10 points, exclusive. The proportion of subjects in each treatment arm with 
Improved/Stable scores will be summarized at each time point and overall. The odds ratio and 
the 95% CI comparing the treatment and placebo arm will be provided.
8.10.
Interim Analyses
Two formal interim analyses (detailed in Appendix 6) are planned: the futility interim will be 
performed at approximately 33.3% information and the efficacy interim at 66.7% information. 
The final analysis will occur when 286 OS events have been observed. 
The Lan-DeMets approach with O’Brien-Fleming type alpha spending function will be used to 
control the type I error rate for testing. The stopping boundaries at each efficacy analysis time 
are provided in Table 8-1.
Table 8-1.
Stopping Boundaries for Efficacy Analyses
Efficacy Analysis
Events (%)
Stopping Boundary
Z scale
One-sided p-value scale
Interim
191 (66.7%)
2.509
0.006
Final
286 (100%)
1.993
0.023
Given significance of OS at either the interim or final analysis, the secondary endpoints of PFS 
and ORR will sequentially tested at the 1-sided 0.016 significance level.
If the DMC sees substantial evidence of benefit of the GS-5745 + mFOLFOX6 combination,
(ie, OS is significantly better in Arm A compared to Arm B), Gilead personnel who are not 
involved with the study may perform an unblinded review of the integrated interim data, and 
may decide to stop the study and offer GS-5745 treatment to those subjects who are still enrolled
in Arm B.
8.11.
Sample Size
Assuming a median OS time for the mFOLFOX6 + placebo group of 11.5 months, 286 events 
are needed to detect a hazard ratio (HR) of 0.70 with 85% power at a 1-sided significance level 
of 0.025 using a log-rank test, given 1 efficacy interim at 66.7% information. With an accrual 
period of 18 months, minimum follow-up of 18 months, and a 10% annual dropout rate, a total 
sample size of 430 subjects (215 subjects per treatment group) is needed to observe the required 
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As the targeted number of deaths is large (~286), if the null hypothesis of the primary end point 
of OS is rejected, it will convincingly demonstrate clinical treatment effect and would provide a 
narrow confidence interval. Based on the number of deaths and the assumed treatment effect on 
OS in the protocol, the expected 95% confidence interval on HR of OS between the 2 treatment 
groups is approximately (0.627, 0.996). At the time of final analysis and assuming OS is 
significant, PFS will be tested at one-sided type I error of 0.016. Assuming that the hazard ratio 
for PFS is 0.7, which is expected to be on par or better than the treatment effect in OS, and that 
median PFS for the control is 9 months, a sample size of 430 subjects (322 PFS events) will 
provide 85% power under the planned study enrollment (18 months), follow-up duration (18 month),
and drop-out rate (annually 10%).
8.12.
Data Monitoring Committee
An independent DMC will review the data for safety and efficacy. Safety review by the DMC 
will be performed when the first 60 subjects have completed 4 treatment cycles. Thereafter, 
review of safety data will be performed at regular intervals as described in the DMC charter. In 
addition, the DMC will meet after approximately 33.3% and approximately 66.7% of the 
expected number of events have occurred to review the results from the futility and efficacy 
interim analysis, respectively.
The DMC’s specific activities will be defined by a mutually agreed charter, which will define the 
DMC’s membership, conduct and meeting schedule.
While the DMC will be asked to advise Gilead regarding future conduct of the study, including 
possible early study termination, Gilead retains final decision-making authority on all aspects of 
the study.

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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), International Conference on Harmonisation (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject. These standards are consistent with the European Union 
Clinical Trials Directive 2001/20/EC and Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of Good Clinical Practice, as 
outlined in 21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, part 50, 1998, and 21 CFR, part 56, 1998.
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/IEC. The investigator will not begin any study subject activities 
until approval from the IRB/IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from
the IRB/IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial IRB/IECapproval, 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. 

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The investigator must use the most current IRB/IEC approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by IRB/IEC 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/IEC, or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions. 
NOTE: The investigator must keep a screening log showing codes, names, and addresses for all 
subjects screened and for all subjects enrolled in the trial. Subject data will be processed in 
accordance with all applicable regulations.
The investigator agrees that all information received from Gilead, including but not limited to the 
investigator brochure, this protocol, eCRF, the 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 2 categories: (1) investigator’s study file, and (2) subject 
clinical source documents.
The investigator’s study file will contain the protocol/amendments, IRB/IEC and governmental 
approval with correspondence, informed consent, drug records, staff curriculum vitae and 
authorization forms, and other appropriate documents and correspondence.
The required source data 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 randomized

Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of IMP, including dates of dispensing and return;

Record of all adverse events 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, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, eCRFs will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRFs should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data. Subsequent to data entry, a study monitor will perform source data verification 
within the electronic data capture (EDC) system. Original entries as well as any changes to data 

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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.
9.1.7.
Investigational Medicinal Product & mFOLFOX6 Accountability and 
Return
Used and unused study drug supplies and mFOLFOX6, should be destroyed on site if the site has 
an appropriate standard operating procedure (SOP) for drug destruction as determined by Gilead. 
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.
The study monitor will evaluate each study center’s study drug disposal procedures and provide 
appropriate instruction for destruction of unused study drug supplies on site. The investigator 
must maintain accurate records for all study drug destroyed at the site. Records must show the 
identification and quantity of each unit destroyed, the method of destruction, and the person who 
disposed of the study drug. Upon study completion, copies of the study drug accountability 
records must be filed at the site. Another copy will be returned to Gilead.
If destruction of study drug on site is not possible, arrangements will be made between the site 
and Gilead Sciences (or Gilead Sciences’ representative) for return of unused study drug 
supplies. The monitor will provide further instructions for the return.
The study monitor will review study drug supplies and associated records at study monitoring 
visits.
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 IRB/IEC, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.

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9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC in 
accordance with local requirements and receive documented IRB/IECapproval before 
modifications can be implemented.
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency (ies) Gilead 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases. 
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

The results of the study in their entirety have been publicly disclosed by or with the consent 
of Gilead in an abstract, manuscript, or presentation form or the study has been completed at 
all study sites for at least 2 years

The investigator will submit to Gilead any proposed publication or presentation along with 
the respective scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation

No such communication, presentation, or publication will include Gilead’s confidential
information (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.

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9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
eCRF.
The monitor is responsible for routine review of the eCRF at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the eCRF. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.

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Gilead Sciences, Inc.
Amendment 6
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10.
REFERENCES
Agrawal S, Anderson P, Durbeej M, van Rooijen N, Ivars F, Opdenakker G, et al. Dystroglycan 
is selectively cleaved at the parenchymal basement membrane at sites of 
leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp 
Med 2006;203 (4):1007-19.
Castaneda FE, Walia B, Vijay-Kumar M, Patel NR, Roser S, Kolachala VL, et al. Targeted 
deletion of metalloproteinase 9 attenuates experimental colitis in mice: central 
role of epithelial-derived MMP. Gastroenterology 2005;129 (6):1991-2008.
Chen EI, Kridel SJ, Howard EW, Li W, Godzik A, Smith JW. A unique substrate recognition 
profile for matrix metalloproteinase-2. J Biol Chem 2002;277 (6):4485-91.
Dubois B, Masure S, Hurtenbach U, Paemen L, Heremans H, van den Oord J, et al. Resistance of 
young gelatinase B-deficient mice to experimental autoimmune encephalomyelitis 
and necrotizing tail lesions. J Clin Invest 1999;104 (11):1507-15.
Farina AR, Mackay AR. Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression. Cancers 
2014;6 (1):240-96.
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 
v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. 
Available at http://globocan.iarc.fr. Accessed 09 July 2014. International Agency 
for Research on Cancer 2013.
Ford HE, Marshall A, Bridgewater JA, Janowitz T, Coxon FY, Wadsley J, et al. Docetaxel 
versus active symptom control for refractory oesophagogastric adenocarcinoma 
(COUGAR-02): an open-label, phase 3 randomised controlled trial. Lancet Oncol 
2014;15 (1):78-86.
Garg P, Vijay-Kumar M, Wang L, Gewirtz AT, Merlin D, Sitaraman SV. Matrix 
metalloproteinase-9-mediated tissue injury overrides the protective effect of 
matrix metalloproteinase-2 during colitis. American journal of physiology. 
Gastrointestinal and liver physiology 2009;296 (2):G175-84.
Hijova E. Matrix metalloproteinases: their biological functions and clinical implications. 
Bratislavske lekarske listy 2005;106 (3):127-32.
Hu J, Van den Steen PE, Sang QX, Opdenakker G. Matrix metalloproteinase inhibitors as 
therapy for inflammatory and vascular diseases. Nat Rev Drug Discov 2007;6 
(6):480-98.
Hung HM, Wang SJ, O'Neill R. Statistical considerations for testing multiple endpoints in group 
sequential or adaptive clinical trials. J Biopharm Stat 2007;17 (6):1201-10.

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Final
Gilead Sciences, Inc.
Amendment 6
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Imai K, Yokohama Y, Nakanishi I, Ohuchi E, Fujii Y, Nakai N, et al. Matrix metalloproteinase 7 
(matrilysin) from human rectal carcinoma cells. Activation of the precursor, 
interaction with other matrix metalloproteinases and enzymic properties. J Biol 
Chem 1995;270 (12):6691-7.
Itoh T, Matsuda H, Tanioka M, Kuwabara K, Itohara S, Suzuki R. The role of matrix 
metalloproteinase-2 and matrix metalloproteinase-9 in antibody-induced arthritis. 
J Immunol 2002;169 (5):2643-7.
Itoh T, Tanioka M, Matsuda H, Nishimoto H, Yoshioka T, Suzuki R, et al. Experimental 
metastasis is suppressed in MMP-9-deficient mice. Clinical & experimental 
metastasis 1999;17 (2):177-81.
Kang JH, Lee SI, Lim do H, Park KW, Oh SY, Kwon HC, et al. Salvage chemotherapy for
pretreated gastric cancer: a randomized phase III trial comparing chemotherapy 
plus best supportive care with best supportive care alone. J Clin Oncol 2012;30 
(13):1513-8.
Kridel SJ, Chen E, Kotra LP, Howard EW, Mobashery S, Smith JW. Substrate hydrolysis by 
matrix metalloproteinase-9. J Biol Chem 2001;276 (23):20572-8.
Lan KKG, Hu P, Proschan M. A Conditional Power Approach to the Evaluation of Predictive 
Power. Statistics in biopharmaceutical research 2012;1 (2):131-6.
Lausch E, Keppler R, Hilbert K, Cormier-Daire V, Nikkel S, Nishimura G, et al. Mutations in 
MMP9 and MMP13 determine the mode of inheritance and the clinical spectrum 
of metaphyseal anadysplasia. American journal of human genetics 2009;85 
(2):168-78.
Li H, Mittal A, Makonchuk DY, Bhatnagar S, Kumar A. Matrix metalloproteinase-9 inhibition 
ameliorates pathogenesis and improves skeletal muscle regeneration in muscular 
dystrophy. Human molecular genetics 2009;18 (14):2584-98.
Miyazaki D, Nakamura A, Fukushima K, Yoshida K, Takeda S, Ikeda S. Matrix 
metalloproteinase-2 ablation in dystrophin-deficient mdx muscles reduces 
angiogenesis resulting in impaired growth of regenerated muscle fibers. Human 
molecular genetics 2011;20 (9):1787-99.
Mott JD, Werb Z. Regulation of matrix biology by matrix metalloproteinases. Current opinion in 
cell biology 2004;16 (5):558-64.
Naito Y, Yoshikawa T. Role of matrix metalloproteinases in inflammatory bowel disease. 
Molecular aspects of medicine 2005;26 (4-5):379-90.

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Gilead Sciences, Inc.
Amendment 6
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Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982;5 (6):649-55.
Olson MW, Gervasi DC, Mobashery S, Fridman R. Kinetic analysis of the binding of human 
matrix metalloproteinase-2 and -9 to tissue inhibitor of metalloproteinase (TIMP)-
1 and TIMP-2. J Biol Chem 1997;272 (47):29975-83.
Opdenakker G, Nelissen I, Van Damme J. Functional roles and therapeutic targeting of 
gelatinase B and chemokines in multiple sclerosis. Lancet neurology 2003;2 
(12):747-56.
Santana A, Medina C, Paz-Cabrera MC, Diaz-Gonzalez F, Farre E, Salas A, et al. Attenuation of 
dextran sodium sulphate induced colitis in matrix metalloproteinase-9 deficient 
mice. World J Gastroenterol 2006;12 (40):6464-72.
Tamhane AC, Mehta CR, Liu L. Testing a primary and a secondary endpoint in a group 
sequential design. Biometrics 2010;66 (4):1174-84.
Thuss-Patience PC, Kretzschmar A, Bichev D, Deist T, Hinke A, Breithaupt K, et al. Survival 
advantage for irinotecan versus best supportive care as second-line chemotherapy 
in gastric cancer--a randomised phase III study of the Arbeitsgemeinschaft 
Internistische Onkologie (AIO). Eur J Cancer 2011;47 (15):2306-14.
Van Wart HE, Birkedal-Hansen H. The cysteine switch: a principle of regulation of 
metalloproteinase activity with potential applicability to the entire matrix 
metalloproteinase gene family. Proc Natl Acad Sci U S A 1990;87 (14):5578-82.
Vempati P, Karagiannis ED, Popel AS. A biochemical model of matrix metalloproteinase 9 
activation and inhibition. J Biol Chem 2007;282 (52):37585-96.
Vu TH, Shipley JM, Bergers G, Berger JE, Helms JA, Hanahan D, et al. MMP-9/gelatinase B is 
a key regulator of growth plate angiogenesis and apoptosis of hypertrophic 
chondrocytes. Cell 1998;93 (3):411-22.
Waddell T, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D. Gastric cancer: 
ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and 
follow-up. Ann Oncol 2013;24 Suppl 6:vi57-63.

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Amendment 6
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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 4.
ECOG Performance Status
Appendix 5.
Dose Modification Tables for mFOLFOX6
Appendix 6.
Details for Testing Efficacy Endpoints
Appendix 7.
Revised RECIST Guideline (version 1.1)

PPD
PPD
GS-5745 
Protocol GS-US-296-1080 
Final 
Gilead Sciences, Inc. 
Amendment 6 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
STUDY ACKNOWLEDGEMENT 
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and 
Safety of GS-5745 Combined with mFOLFOX6 as First Line Treatment in Patients with 
Advanced Gastric or Gastroesophageal Junction Adenocarcinoma 
GS-US-296-1080, Amendment 6, 06 March 2017 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
this approval. 
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. 
Principal Investigator Name (Printed) 
Signature 
Date 
Site Number 
CONFIDENTIAL 
Page 77 
06 March 2017 

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Amendment 6
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Appendix 2.
Study Procedures Table
Study Phase
Screening
Randomization
Cycle 1
Cycle 1
Each Cycle
(28 days )
Cycle 2
(PK/Antibody/ 
Biomarker)
Cycle 3
(PK/Antibody/ 
Biomarker)
Cycle 4 &
every 2 cycles
(PK/Antibody/
Biomarker )
Cycle 5, 7 & 
Every 3 Cycles
(PK/Antibody/
Biomarker)
EOT r
Every
8 weeks
Disease 
Progression
EOSs
30-day Safety 
Follow-upt
55-day Safety 
Follow-Upu
5-year
Long Term 
Follow-Up
Cycle Day
1a
15
1
15
1h, i, j, k, 
2i, 8i, 
15i
1
1
1
N/A
N/A
N/A
N/A
N/A
N/A
Window (day)
-28
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
±7
N/A
Informed Consent
X
Medical and Medication 
History 
X
Physical Examinationb
X
X
X
X
X
X
Vital Signs & Weight
X
X
X
X
X
X
X
X
ECOG Performance Statusc
X
Xc
X
X
X
X
12-lead ECGv
X
X
X
X
X
X
X
Adverse events/
Concomitant medicationsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IXRS Registration
X
X
X
X
X
X
X
Study Drug/Chemotherapy 
Administratione
X
X
X
X
QLQ-C30 & STO22
X
X
X
X
X
EQ-5D-3L
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X

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Gilead Sciences, Inc.
Amendment 6
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Study Phase
Screening
Randomization
Cycle 1
Cycle 1
Each Cycle
(28 days )
Cycle 2
(PK/Antibody/ 
Biomarker)
Cycle 3
(PK/Antibody/ 
Biomarker)
Cycle 4 &
every 2 cycles
(PK/Antibody/
Biomarker )
Cycle 5, 7 & 
Every 3 Cycles
(PK/Antibody/
Biomarker)
EOT r
Every
8 weeks
Disease 
Progression
EOSs
30-day Safety 
Follow-upt
55-day Safety 
Follow-Upu
5-year
Long Term 
Follow-Up
Cycle Day
1a
15
1
15
1h, i, j, k, 
2i, 8i, 
15i
1
1
1
N/A
N/A
N/A
N/A
N/A
N/A
Window (day)
-28
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
±7
N/A
Coagulation
X
X
X
Urinalysis 
X
X
X
X
X
X
Pregnancy Testf
X
X
X
X
X
X
HER2 Testingg
X
GS-5745 PKh
X
X
X
X
X
X
Anti-GS-5745 Antibodyj
X
X
X
X
X
X
X
Blood biomarkersk
X
X
X
X
Pharmacodynamic
biomarker and immune 
monitoringl
X
X
Biomarker sample for 
circulating tumor DNAm
X
X
X
Collect archival tumor 
tissue for biomarker 
testingo
X
CCI
CCI

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Amendment 6
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Study Phase
Screening
Randomization
Cycle 1
Cycle 1
Each Cycle
(28 days )
Cycle 2
(PK/Antibody/ 
Biomarker)
Cycle 3
(PK/Antibody/ 
Biomarker)
Cycle 4 &
every 2 cycles
(PK/Antibody/
Biomarker )
Cycle 5, 7 & 
Every 3 Cycles
(PK/Antibody/
Biomarker)
EOT r
Every
8 weeks
Disease 
Progression
EOSs
30-day Safety 
Follow-upt
55-day Safety 
Follow-Upu
5-year
Long Term 
Follow-Up
Cycle Day
1a
15
1
15
1h, i, j, k, 
2i, 8i, 
15i
1
1
1
N/A
N/A
N/A
N/A
N/A
N/A
Window (day)
-28
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
±7
N/A
CT or MRI & Treatment 
Response Assesmentp
X
X
X
Core Biopsyq
X
Overall Survival and Other 
Antitumor Therapy
X (Every
3 months)
a
Cycle 1 Day 1 (C1D1) must occur within 3 days following randomization.
b
Complete physical examination (PE) to be performed at Screening, EOT and EOS. A modified PE capturing changes from prior exams will be performed at subsequent visits. 
Height is required at Screening only.
c
ECOG performance status on Cycle 1 Day 1 may be waived if has been conducted during screening within 4 days of Cycle 1 Day 1. 
d
Adverse events will be assessed at each clinic visit from Screening up to and including the 55-day Safety Follow-up visit. Concomitant medications will be recorded at each 
clinic visit from Screening up to and including the 55-day Safety Follow-up visit or EOS visit whichever is later. 
e
Study drug (GS-5745/placebo) will be dosed on Days 1 and 15 of each cycle over 30  (± 5) min.  Chemotherapy (mFOLFOX6) will be administered after study drug and will 
consist of l-LV 200mg/m2 or dl-LV 400mg/m2 and oxaliplatin 85 mg/m2 followed by bolus 5-FU 400mg/m2 and a 46 hour infusion of 5-FU 2400 mg/m2. After 6 cycles of 
mFOLFOX6, the oxaliplatin component will be discontinued. Leucovorin and 5-FU will be continued as maintenance therapy, in combination with GS-5745/placebo, in the 
absence of disease progression or toxicity warranting discontinuation of therapy.
f
If applicable (females of child bearing potential). Serum pregnancy testing will be conducted at Screening. Urine pregnancy testing will be conducted pre-dose on Day 1 of 
each cycle, at EOT, and EOS.
g
Tumor tissue will be tested for HER2 status, if unknown, with an approved IHC and ISH kit.
h
Plasma samples will be collected for GS-5745 PK at 30(± 15) min after the end of infusion on Day 1 of Cycle 1, prior to dosing and 30(± 15) min after the end of infusion on 
Day 1 of cycles 2, 3, 5, 7, and every 3 cycles thereafter, at the EOT and EOS visits. 
i
 
CCI

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Amendment 6
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j
Serum samples for anti-GS-5745 antibody will be collected prior to dosing on Day 1 of cycles 1, 2, 3, 5, 7, and every 3 cycles thereafter, EOT, EOS, and 30-day Safety 
Follow Up visits.
k
Blood biomarkers will be collected prior to dosing on Cycle 1 Day 1, Cycle 1 Day 15, and Day 1 of Cycles 2 and 4 and every 2 cycles thereafter
l
Samples for pharmacodynamic biomarkers and immune-monitoring will be collected prior to dosing on Day 1 of cycles 1and 3 only
m
Biomarker Sample for circulating tumor DNA will be collected predose on Day 1 of cycles 1 and 3 and at disease progression.
n
 
o
Archival tumor tissue block will be collected and shipped to central laboratory for sectioning after Day 1 of Cycle 1. If an archival block was submitted for HER2 testing, and 
the subject is randomized, the block will be stored for biomarker analysis. However, if slides were submitted for HER2 testing, additional slides will be required after Day 1 
of Cycle 1 for biomarker analysis.
p
Tumor evaluation by CT or MRI will be performed during screening and approximately every 8 weeks (starting from Cycle 1 Day 1) regardless of cycle number or dose 
interruption. Scan at EOS visit is not necessary if restaging scan is performed within the prior 8 weeks. Treatment response assessment will be per RECIST v1.1.
q
For subjects who stop study treatment in the absence of disease progression (eg. experienced unexpected toxicity) and remain on study for follow up for progression-free 
survival, tumor evaluation by CT or MRI should continue approximately every 8 weeks until disease progression or initiation of non-study specific anti-neoplastic therapy in 
the absence of progression, whichever occurs earlier.
r
A core biopsy will be performed after disease progression, if medically feasible. The sample should be collected by the last clinic visit on study ie EOS or 30 Day Safety 
Follow up visit.
s
End of treatment (EOT) assessments will be completed only by subjects who discontinue all treatment prior to disease progression.  These assessments should be completed 
as soon as possible after the decision is made. Every attempt should be made to keep the subject in the study and continue to perform tumor evaluation by CT or MRI every 
8 weeks until disease progression.
t
End of study (EOS) assessments will be completed when the subject meets at least 1 of the criteria for study discontinuation (Section 3.6).
u
The 30-day safety follow up visit will be performed following the last dose of GS-5745/placebo, or all components mFOLFOX6, whichever is discontinued later.  
v
The 55-day safety follow up phone visit will be performed following the last dose of GS-5745/placebo, or all components mFOLFOX6, whichever is discontinued later.  
w
A single 12-lead electrocardiogram (ECG) will be collected at Screening, Day 1 of each cycle, and at the EOT and EOS visits, per standard practice. Additional ECGs 
following administration of oxaliplatin will be collected at visits when oxaliplatin is administered after the infusion is completed (i.e., Days 1 and 15 of each cycle, up to a 
maximum of six 28-day cycles) as required per country label guidance regarding cardiac monitoring.
CCI

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Final
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Amendment 6
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Appendix 3.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Requirements
1) Pregnancy and Contraception Requirements for Males and Females of Childbearing 
Potential
The risks of treatment with GS-5745 during pregnancy have not been evaluated in humans. The 
potential for genotoxicity and embryofetal toxicity is considered to be low based on nonclinical 
toxicological studies. In both the rat and rabbit definitive embryofetal developmental toxicity 
studies, there were no GS-5745 related effects on embryofetal survival and growth and no fetal 
anomalies. In a fertility study in male and female rats, no test article-related effects on 
reproductive performance and intrauterine survival were observed at any dosage level. Please 
refer to the latest version of the investigator’s brochure for additional information on the study 
drug of GS-5745. Please refer to the regional prescribing information for information on the 
potential risks of treatment with mFOLFOX6. 
2) Definition of Female of Childbearing Potential
For the purposes of this study, a female subject of childbearing potential is a woman who has not 
had a hysterectomy, bilateral oophorectomy, or medically documented ovarian failure. This 
definition includes pubertal females regardless of whether or not she has had a menses 
(premenarchal, Tanner Stage 3) and perimenopausal women who have had a spontaneous 
menses in the last 12 months. A woman who has had a tubal sterilization is considered to be of 
childbearing potential.

Women ≤ 54 years of age with amenorrhea of any duration will be considered to be of 
childbearing potential unless they have had a hysterectomy, bilateral oophorectomy, or 
medically documented ovarian failure.

Women > 54 years of age with cessation (for ≥12 months) of previously occurring menses 
due to ovarian failure will not be considered to be of childbearing potential.
3) Contraceptive Requirements for Females
Female subjects of childbearing potential must agree to use protocol specified method(s) of 
contraception from the screening/randomization visit throughout the study period, 90 days 
following the last dose of study drug (GS-5745/placebo) and for 4 months after the last dose of 
oxaliplatin or 6 months after the last dose of 5-FU whichever occurs later, unless the subject 
chooses continuous heterosexual abstinence as a lifestyle choice. The investigator should counsel 
subjects on the protocol specified method(s) for avoiding pregnancy during the study. These 
methods are recommended due to the low failure rate (ie, less than 1% per year). See the 
protocol specified contraceptive methods listed below. 
Female study subjects who are not heterosexually active must have periodic confirmation of 
continued abstinence from heterosexual intercourse and regular pregnancy testing while taking 
study drug. The investigator should counsel subjects on the protocol specified method(s) for 
avoiding pregnancy in case the subject chooses to engage in heterosexual intercourse.

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Amendment 6
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06 March 2017
Female subjects of childbearing potential must have a negative serum pregnancy test at screening 
and a negative urine pregnancy test at Day 1 of each cycle prior to receiving the dose of study 
drug. Lactating females must discontinue nursing before study drug administration.
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). 
This is not yet approved in Japan.

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 90 days following the last dose of GS-5745 and for 4 months after the last dose 
of oxaliplatin or 6 months following the last dose of 5-FU whichever occurs later.
4) Contraceptive Requirements for Males
Male subjects must agree to use condoms and avoid sperm donation from the 
screening/randomization visit throughout the study period, 90 days after administration of the 
last dose of study drug (GS-5745/placebo) and for 6 months after the last dose of oxaliplatin or 
6 months following the last dose of 5-FU whichever occurs later.
5) Contraception Requirements for Oxaliplatin
Female subjects of childbearing potential must use a protocol recommended method of 
contraception from the screening visit throughout the study treatment period and for 4 months 
after the last dose of oxaliplatin unless the subject chooses continuous heterosexual abstinence as 
a lifestyle-choice. Male subjects of reproductive potential, must use a protocol-recommended 
method of contraception and to refrain from sperm donation from the start of study drug, 
throughout the study treatment period, for 6 months following the last dose of oxaliplatin.
6) Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhea method (LAM). Female condom and male condom should not 
be used together.
7) Procedures to be Followed in the Event of Pregnancy
Subjects should be instructed to notify the investigator if they become pregnant at any time 
during the study, and if they become pregnant within 90 days following the last dose the study 
drug (GS-5745/placebo) and within 4 months (or 6 months for the partner of male subjects) of 

GS-5745
Protocol GS-US-296-1080
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 84
06 March 2017
the last dose of oxaliplatin, or 6 months after the last dose of 5-FU whichever occurs later.
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. The 
investigator should report all pregnancies to the CRO Safety Department using the pregnancy 
report form within 24 hours of becoming aware of the pregnancy. The investigator should 
counsel the subject regarding the possible effects of prior study drug exposure on the fetus and 
the need to inform the study site of the outcome of the pregnancy. Subjects whose partner has 
become pregnant or suspects she is pregnant during the study must report the information to the 
investigator. Instructions for reporting partner pregnancy, pregnancy and pregnancy outcome are 
outlined in Section 7.7.2.1.

GS-5745
Protocol GS-US-296-1080
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 85
06 March 2017
Appendix 4.
ECOG Performance Status
Grade
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
Reference for ECOG {Oken 1982}

GS-5745
Protocol GS-US-296-1080
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 86
06 March 2017
Appendix 5.
Dose Modification Tables for mFOLFOX6
Appendix Table 1.
Recommended Dose Modifications for 
Oxaliplatin+5-Fluorouracil/Leucovorina
NCI CTCAE v. 4.03
System Organ Classb
Adverse Event
Dose Level for 
Subsequent Cycles
Based on Interval 
Adverse Events
At Time of 
Retreatment
All Adverse Events < 1
Maintain dose level
Maintain dose level
Blood and lymphatic 
system disorders:
Hemolytic uremic syndrome 
(HUS)c
> Grade 3
Discontinue oxaliplatin
Discontinue 
oxaliplatin
Investigations:
Neutrophil count decreased
If ANC < 1500 at 
start of cycle, hold 
and check weekly 
then treat based on 
interval adverse 
event. If ANC < 1500 
after 4 weeks, 
discontinue therapy.
Grade 1
(ANC < LLN - 1500/mm3)
Maintain dose level
Grade 2
(ANC < 1500 - 1000/mm3)
Maintain dose level
Grade 3
(ANC < 1000 - 500/mm3)
Omit bolus 5-
FU and decrease 1 
oxaliplatin dose level
Grade 4
(ANC < 500/mm3)
Omit bolus 5-FU and
decrease both infusion 5-FU 
and oxaliplatin 1 dose level
Platelet count decreased
If PLT < 75,000 at 
start of cycle, hold 
and check weekly 
then treat based on 
interval adverse 
event. If PLT 
< 75,000 after 
4 weeks, discontinue 
therapy.
Grade 1
(PLT < LLN - 75,000/mm3)
Maintain dose level
Grade 2
(PLT < 75,000 - 50,000/mm3)
Maintain dose level
Grade 3
(PLT < 50,000 - 25,000/mm3)
Omit bolus 5-FU and 
decrease 1 oxaliplatin dose 
level
Grade 4
(PLT < 25,000/mm3)
Omit bolus 5-FU and 
decrease 2 oxaliplatin dose 
levels

GS-5745
Protocol GS-US-296-1080
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 87
06 March 2017
NCI CTCAE v. 4.03
System Organ Classb
Adverse Event
Dose Level for 
Subsequent Cycles
Based on Interval 
Adverse Events
At Time of 
Retreatment
Gastrointestinal 
disorders:
Diarrhea
If Grade 2 at start 
of cycle, hold and 
check weekly then 
treat based on 
interval adverse 
event. If Grade 2 
after 4 weeks, 
discontinue therapy.
Grade 1, 2
Maintain dose level
Grade 3
Decrease one 5-FU dose 
level
Grade 4
Decrease both 5-FU and 
oxaliplatin 1 dose level
Mucositis oral
Grade 1, 2
Maintain dose level
Grade 3
Decrease one 5-FU dose 
level
Grade 4
Decrease one 5-FU dose 
level
Vomiting
Grades 1, 2
Maintain dose level
Grade 3
Decrease1 oxaliplatin dose 
level
Grade 4
Decrease both 5-FU and 
oxaliplatin 1 dose level
Metabolism and 
nutrition disorders:
Hypomagnesemia
Note: Dose reduction is not required for 
hypomagnesemia unless symptoms are present. 
If Grade 2 after 4 weeks, discontinue therapy.
Neurology:
Do not use CTCAE.
See Appendix Table 2 for adverse event scale and 
oxaliplatin dose modifications.
Respiratory, thoracic, 
and mediastinal 
disorders:
Cough Grade 3
Dyspnea Grade 3
Hypoxia Grade 3
Pneumonitis Grade 3
Hold oxaliplatin until interstitial lung disease is ruled 
out. If interstitial lung disease, oxaliplatin should be 
permanently discontinued.
Other 
non-hematologic 
adverse eventsd, e:
Grades 1, 2
Maintain dose level
Grades 3, 4
Decrease offending agent 1 dose level
a
The dose of leucovorin will not be adjusted due to adverse event.  It should remain at 400 mg/m2 dl-leucovorin or 
200 mg/m2 of l-leucovorin for all courses. Leucovorin will be given immediately prior to each 5-FU dose; thus, if 5-FU is 
delayed, leucovorin will be delayed. Leucovorin doses may be adjusted per institutional guidelines in the event of a supply 
shortage.
b
For NCI CTCAE v. 4.03 Grade 2 toxicity not described, maintain dose level of agent.
c
Recommended evaluation of suspected HUS: Evaluation should include CBC differential, platelets, PT, PTT, fibrinogen, 
FDP, Anti thrombin III, Von Willebrand factor, anti-nuclear antibody, rheumatoid factor, Compliment Cascade C3, C4, and 
CH50, anti-platelet antibodies, platelet-associated IgG, and circulating immune complexes.  Renal evaluation should include 
creatinine, BUN, and urinalysis with microscopic examination.  Other laboratory and hematologic evaluations as appropriate 
should also be obtained, including peripheral blood smear and free hemoglobin.
d
Exceptions: fatigue, anorexia, nausea/vomiting if can be controlled by antiemetics, and viral infections.
e
Dose modifications for other non-hematologic adverse events at the start of subsequent courses of therapy, and at time of 
retreatment are also based on NCI CTCAE v. 4.03 criteria.

GS-5745
Protocol GS-US-296-1080
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 88
06 March 2017
Appendix Table 2.
Oxaliplatina Dose Modifications for Non-CTCAE Neurologic 
Adverse Events
Adverse Events
Duration of Adverse Event
Persistentb 
Between Cycles
1 - 7 Days
> 7 Days
Paresthesias/Dysesthesias
Paresthesias/dysesthesiasc of 
short duration that resolve and do 
not interfere with function 
(Grade 1)
No change
No change
No change
Paresthesias/dysesthesiasc
interfering with function, but not 
activities of daily living (ADL)
(Grade 2)
No change
No change
Decrease 
1 oxaliplatin 
dose level
Paresthesias/dysesthesiasc with 
pain or with functional 
impairment that also interfere 
with ADL
(Grade 3)
1st time:
Decrease 1 oxaliplatin 
dose level
2nd time:
Decrease 1 oxaliplatin 
dose level
1st time:
Decrease 1 oxaliplatin 
dose level
2nd time:
Decrease 1 oxaliplatin 
dose level
Discontinue
Persistent 
paresthesias/dysesthesias that are 
disabling or life-threatening
(Grade 4)
Discontinue
Discontinue
Discontinue
Laryngeal Dysesthesias (investigator discretion used for grading):
Grade 0 = none; Grade 1 = mild
No change
Increase duration of 
infusion to 6 hours
Increase duration of 
infusion to 6 hours
Grade 2 = moderate 
(Also recommended is 
administration of benzodiazepine 
and patient education. 
Management of patient if 
Grade 2 laryngeal dysesthesias 
occurs while treatment is 
being administered.)
Stop oxaliplatin infusion.
Administer benzodiazepine and give patient reassurance.
At the discretion of the investigator, the infusion can be restarted at 
1/3 the original rate of infusion.
Grade 3 = severe
a
If oxaliplatin is discontinued, continue other study agents unless adverse events preclude their continuation.
b
Not resolved by the beginning of the next cycle.
c
May be cold-induced.
I 

GS-5745
Protocol GS-US-296-1080
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 89
06 March 2017
Appendix 6.
Details for Testing Efficacy Endpoints
This appendix provides details for testing multiple efficacy endpoints at interim and final 
analyses.
The final analysis will occur when 286 overall survival (OS) events have been observed. 
Two formal interim analyses are planned: the futility interim analysis and the efficacy interim 
analysis will be performed when approximately 33.3% and 66.7% of OS events have occurred, 
respectively.
Futility Interim Analysis
The end point of the futility interim analysis is OS. The futility analysis will occur approximately 
after 95 OS events (33.3% of the information relative to the final analysis) have been observed in 
the ITT population. The analysis will perform a stratified log-rank test for OS in the ITT 
population. A non-binding futility rule will be implemented. Based on the analysis results, the 
DMC may recommend terminating the study for lack of efficacy if the predictive power (PP) on 
OS in ITT population is < 14%. Otherwise, the study will be continued. 
Predictive power is defined as a weighted average of the conditional power; the weighting 
function is determined by the sampling distribution of the observed hazard ratio based on the 
data at the interim analysis {Lan 2012}. When exactly 95 OS events are observed at the interim, 
this futility rule of PP <14% corresponds to observing an OS hazard ratio (HR) > 0.95 in the ITT 
population. 
Appendix Figure 1 presents the operating characteristics of futility rule at the interim of 95 OS 
events with futility boundary of 0.95. When the true hazard ratio is 0.7, the probability of 
terminating the study early is 7%. On the other hand, when the true hazard ratio is 1, indicating 
lack of efficacy, the probability of terminating the study early is 60%. 

GS-5745
Protocol GS-US-296-1080
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 90
06 March 2017
Appendix Figure 1. Probability of Early Stop due to Futility 
Efficacy Interim and Final Analysis 
In the efficacy interim and final analysis, the primary and secondary endpoints will be tested 
sequentially in the following gatekeeping order: the primary OS endpoint, then the secondary 
PFS endpoint, and finally the secondary ORR endpoint. Specifically:

At the efficacy interim analysis, the OS event point will be tested at one-sided alpha level of 
0.006. If the OS endpoint is not rejected, the study will continue to final analysis. If the OS 
endpoint is rejected, the DMC would recommend early stop for efficacy. Furthermore, the 
PFS endpoint will be tested at one-sided alpha level of 0.016. Only if the PFS endpoint is 
rejected, the ORR endpoint will be tested at one-sided alpha level of 0.016.

At the final analysis, the OS event point will be tested at one-sided alpha level of 0.023. If 
the OS endpoint is rejected, the PFS endpoint will be tested at one-sided alpha level of 0.016. 
If the PFS endpoint is also rejected, the ORR endpoint will be tested at one-sided alpha level 
of 0.016.
This gatekeeping testing strategy is summarized in the table below. Overall, this testing strategy 
employs O’Brian-Fleming boundary for the primary OS endpoint and the Pocock type boundary 
for the secondary PFS/ORR endpoints. The testing strategy controls the overall one-sided 
family-wise type I error to be at 0.025, equivalent to two sided 0.05 by appropriately adjusting 
for multiplicity in the efficacy interim and final analyses.
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GS-5745
Protocol GS-US-296-1080
Final
Gilead Sciences, Inc.
Amendment 6
CONFIDENTIAL
Page 94
06 March 2017
Appendix 7.
Revised RECIST Guideline (version 1.1)

PPD
PPD
PPD
EUROPEAN J O URN A L O F CANCER 45 (2009) 228 247 
a v a il a ble at www.sciencedirect.c o m 
__ ,, 
·.;, ScienceDirect 
-----
--,--
journal homep a ge: www.ejconline .com 
New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1) 
E.A. Eisenhauer1•·, P. Therasseb, ]. BogaertsC, L.H. Schwartzd, D. Sargente, R. Ford!, 
]. Dancey9, S. Arbuckh, S. Gwyther\ M. Mooney9, L. Rubinstein9, L. Shankar9, L. Dodd9, 
R. Kaplani, D. LacombeC, ]. Verwei/ 
3National Cancer Institute of Canada 
Clinical Trials Group, 10 Stuart Street, Queen's University, Kingston, ON, Canada 
bGlaxoSmithKline Biologicals, Rixensart, Belgium 
cEuropean Organisatioo for Research and Treatment of Cancer, Data Centre, Brussels, Belgium 
dMemorial Sloan Kettering Cancer Center, New York, NY, USA 
eMayo Clinic, Rochester, MN, USA 
rRadPharm, Princeton, NJ, USA 
gDivision of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA 
hSchering 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 RECIST was 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 RECIST 1.1: Major changes include: Number of lesions 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 10 to 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 ;;,,.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. Confirma 
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 progression 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 au~
: 
. 
E mail address:---- (EA 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.
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229

1.3.
Process of RECIST 1.1 development
The RECIST Working Group, consisting of clinicians with
expertise in early drug development from academic research
organisations, government and industry, together with imag
ing specialists and statisticians, has met regularly to set the
agenda for an update to RECIST, determine the evidence
needed to justify the various changes made, and to review
emerging evidence. A critical aspect of the revision process
was to create a database of prospectively documented solid
tumour measurement data obtained from industry and aca
demic group trials. This database, assembled at the EORTC
Data Centre under the leadership of Jan Bogaerts and Patrick
Therasse (co authors of this guideline), consists of >6500 pa
tients with >18,000 target lesions and was utilised to investi
gate the impact of a variety of questions (e.g. number of
target lesions required, the need for response conﬁrmation,
and lymph node measurement rules) on response and pro
gression free survival outcomes. The results of this work,
which after evaluation by the RECIST Working Group led to
most of the changes in this revised guideline, are reported
in detail in a separate paper in this special issue.10 Larry Sch
wartz and Robert Ford (also co authors of this guideline) also
provided key databases from which inferences have been
made that inform these revisions.11
The publication of this revised guideline is believed to be
timely since it incorporates changes to simplify, optimise
and standardise the assessment of tumour burden in clinical
trials. A summary of key changes is found in Appendix I. Be
cause the fundamental approach to assessment remains
grounded in the anatomical, rather than functional, assess
ment of disease, we have elected to name this version RECIST
1.1, rather than 2.0.
1.4.
What about volumetric or functional assessment?
This raises the question, frequently posed, about whether it is
‘time’ to move from anatomic unidimensional assessment of
tumour burden to either volumetric anatomical assessment
or to functional assessment (e.g. dynamic contrast enhanced
MRI or CT or (18)F ﬂuorodeoxyglucose positron emission
tomographic (FDG PET) techniques assessing tumour metab
olism). As can be seen, the Working Group and particularly
those involved in imaging research, did not believe that there
is at present sufﬁcient standardisation and widespread avail
ability to recommend adoption of these alternative assess
ment methods. The only exception to this is in the use of
FDG PET imaging as an adjunct to determination of progres
sion, as described later in this guideline. As detailed in paper
in this special issue12, we believe that the use of these prom
ising newer approaches (which could either add to or substitute
for anatomical assessment as described in RECIST) requires
appropriate and rigorous clinical validation studies. This pa
per by Sargent et al. illustrates the type of data that will be
needed to be able to deﬁne ‘endpoints’ for these modalities
and how to determine where and when such criteria/modal
ities can be used to improve the reliability with which truly
active new agents are identiﬁed and truly inactive new agents
are discarded in comparison to RECIST criteria in phase II
screening trials. The RECIST Working Group looks forward
to such data emerging in the next few years to allow the
appropriate changes to the next iteration of the RECIST
criteria.
2.
Purpose of this guideline
This guideline describes a standard approach to solid tumour
measurement and deﬁnitions for objective assessment of
change in tumour size for use in adult and paediatric cancer
clinical trials. It is expected these criteria will be useful in all
trials where objective response is the primary study endpoint,
as well as in trials where assessment of stable disease, tu
mour progression or time to progression analyses are under
taken, since all of these outcome measures are based on an
assessment of anatomical tumour burden and its change on
study. There are no assumptions in this paper about the pro
portion of patients meeting the criteria for any of these end
points which will signal that an agent or treatment regimen is
active: those deﬁnitions are dependent on type of cancer in
which a trial is being undertaken and the speciﬁc agent(s) un
der study. Protocols must include appropriate statistical sec
tions which deﬁne the efﬁcacy parameters upon which the
trial sample size and decision criteria are based. In addition
to providing deﬁnitions and criteria for assessment of tumour
response,
this
guideline
also
makes
recommendations
regarding standard reporting of the results of trials that utilise
tumour response as an endpoint.
While these guidelines may be applied in malignant brain
tumour studies, there are also separate criteria published for
response assessment in that setting.13 This guideline is not in
tended for use for studies of malignant lymphoma since
international guidelines for response assessment in lym
phoma are published separately.14
Finally, many oncologists in their daily clinical practice fol
low their patients’ malignant disease by means of repeated
imaging studies and make decisions about continued therapy
on the basis of both objective and symptomatic criteria. It is
not intended that these RECIST guidelines play a role in that
decision making, except if determined appropriate by the
treating oncologist.
3.
Measurability of tumour at baseline
3.1.
Deﬁnitions
At baseline, tumour lesions/lymph nodes will be categorised
measurable or non measurable as follows:
3.1.1.
Measurable
Tumour lesions: Must be accurately measured in at least one
dimension (longest diameter in the plane of measurement is
to be recorded) with a minimum size of:
• 10 mm by CT scan (CT scan slice thickness no greater than
5 mm; see Appendix II on imaging guidance).
• 10 mm caliper measurement by clinical exam (lesions
which cannot be accurately measured with calipers should
be recorded as non measurable).
• 20 mm by chest X ray.
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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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231

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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233

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.
234
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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 
response, 
PD = progressive 
NE = inevaluable. 
Overall response 
CR 
Non CR/non PDa 
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 Table 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 PRa 
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 If 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 PETand biopsy res
olution/sensitivity.
For equivocal ﬁndings of progression (e.g. very small and
uncertain new lesions; cystic changes or necrosis in existing
lesions), treatment may continue until the next scheduled
assessment. If at the next scheduled assessment, progression
is conﬁrmed, the date of progression should be the earlier
date when progression was suspected.
4.5.
Frequency of tumour re-evaluation
Frequency
of
tumour
re evaluation
while
on
treatment
should be protocol speciﬁc and adapted to the type and sche
dule of treatment. However, in the context of phase II studies
where the beneﬁcial effect of therapy is not known, follow up
every 6 8 weeks (timed to coincide with the end of a cycle) is
reasonable. Smaller or greater time intervals than these could
be justiﬁed in speciﬁc regimens or circumstances. The proto
col should specify which organ sites are to be evaluated at
baseline (usually those most likely to be involved with meta
static disease for the tumour type under study) and how often
evaluations are repeated. Normally, all target and non target
sites are evaluated at each assessment. In selected circum
stances certain non target organs may be evaluated less fre
quently. For example, bone scans may need to be repeated
only when complete response is identiﬁed in target disease
or when progression in bone is suspected.
After the end of the treatment, the need for repetitive tu
mour evaluations depends on whether the trial has as a goal
the response rate or the time to an event (progression/death).
If ‘time to an event’ (e.g. time to progression, disease free
survival, progression free survival) is the main endpoint of
the study, then routine scheduled re evaluation of protocol
speciﬁed sites of disease is warranted. In randomised com
parative trials in particular, the scheduled assessments
should be performed as identiﬁed on a calendar schedule
(for example: every 6 8 weeks on treatment or every 3 4
months after treatment) and should not be affected by delays
in therapy, drug holidays or any other events that might lead
to imbalance in a treatment arm in the timing of disease
assessment.
4.6.
Conﬁrmatory measurement/duration of response
4.6.1.
Conﬁrmation
In non randomised trials where response is the primary end
point, conﬁrmation of PR and CR is required to ensure re
sponses identiﬁed are not the result of measurement error.
This will also permit appropriate interpretation of results in
the context of historical data where response has traditionally
required conﬁrmation in such trials (see the paper by Bogaerts
et al. in this Special Issue10). However, in all other circum
stances, i.e. in randomised trials (phase II or III) or studies
where stable disease or progression are the primary endpoints,
conﬁrmation ofresponseis notrequiredsince itwillnotaddva
lue to theinterpretationoftrial results.However, eliminationof
the requirement for response conﬁrmation may increase the
importance of central review to protect against bias, in partic
ular in studies which are not blinded.
In the case of SD, measurements must have met the SD
criteria at least once after study entry at a minimum interval
(in general not less than 6 8 weeks) that is deﬁned in the
study protocol.
4.6.2.
Duration of overall response
The duration of overall response is measured from the time
measurement criteria are ﬁrst met for CR/PR (whichever is ﬁrst
recorded) until the ﬁrst date that recurrent or progressive dis
ease is objectively documented (taking as reference for progres
sive disease the smallest measurements recorded on study).
The duration of overall complete response is measured
from the time measurement criteria are ﬁrst met for CR until
the ﬁrst date that recurrent disease is objectively documented.
4.6.3.
Duration of stable disease
Stable disease is measured from the start of the treatment (in
randomised trials, from date of randomisation) until the crite
ria for progression are met, taking as reference the smallest
sum on study (if the baseline sum is the smallest, this is the
reference for calculation of PD).
The clinical relevance of the duration of stable disease var
ies in different studies and diseases. If the proportion of pa
tients achieving stable disease for a minimum period of time
is an endpoint of importance in a particular trial, the protocol
should specify the minimal time interval required between
two measurements for determination of stable disease.
Note: The duration of response and stable disease as well as
theprogression free survivalareinﬂuenced by thefrequencyof
follow up after baseline evaluation. It is not in the scope of this
guideline to deﬁne a standard follow up frequency. The fre
quency should take into account many parameters including
disease types and stages, treatment periodicity and standard
practice. However, these limitations of the precision of the
measured endpoint should be taken into account if compari
sons between trials are to be made.
4.7.
Progression-free survival/proportion progression-free
4.7.1.
Phase II trials
This guideline is focused primarily on the use of objective re
sponse endpoints for phase II trials. In some circumstances, ‘re
sponse rate’ may not be the optimal method to assess the
potential anticancer activity of new agents/regimens. In such
cases ‘progression free survival’ (PFS) or the ‘proportion pro
gression free’ at landmark time points, might be considered
appropriate alternatives to provide an initial signal of biologic
effect of new agents. It is clear, however, that in an uncontrolled
trial, these measures are subject to criticism since an appar
ently promising observation may be related to biological factors
such as patient selectionand not theimpactof theintervention.
Thus, phase II screening trials utilising these endpoints are best
designed with a randomised control. Exceptions may exist
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.
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2 4 7
237

Appendix I. Summary of major changes RECIST 1.0 to RECIST 1.1 
Minimum size measurable 
lesions 
Special considerations on 
lesion measurability 
Overall tumour burden 
Response criteria target 
disease 
Response criteria non target 
disease 
New lesions 
Overall response 
RECIST 1.0 
CT: 10 mm spiral 
20 mm non spiral 
Clinical: 20 mm 
Lymph node: not mentioned 
10 lesions (5 per organ) 
CR lymph node not mentioned 
PD 20'/4 increase over smallest sum on 
study or new lesions 
'unequivocal progression' considered as PD 
Table integrated target and non target 
lesions 
RECIST 1.1 
CT 10 mm; delete reference to 
spiral scan 
Clinical: 10 mm (must be 
measurable with calipers) 
CT: 
;;,,, 15 mm short axis for target 
;;,,,10 <15 mm 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 
More detailed description of 
'unequivocal progression' to 
indicate that it should not 
normally trump target disease 
status. It must be 
re pre sen tative of overall 
disease status change, not a 
single lesion increase 
New section on New lesions 
1wo tables: one integrating 
target 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 if it is greater than 5 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 yields 
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 ve.ry small and 20'/4 
increase is within measurement error 
Confusion with R£CIST 1.0 where some were 
considering PD if '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 RF.GIST 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 
Dancey et al.21 
"' 
w 
(X) 
.., 
C 
)'l 
0 ... .., 
> z -
0 
C 
)'l z 
> ... 
0 .., 
<"l 
> z 
<"l 
"' 
)'l 
-1>-
v, 
..., 
0 
0 
\0 
..., 
..., 
00 
I ..., 
-I>-
'-' 

Confirmatory measure 
Progression free survival 
Reporting of response 
results 
Response in phase m 
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 II 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 II endpoint 
Greater detail on PFS 
assessment in phase III trials 
Divided into phase II and phase 
m 
9 categories collapsed into 5 
In phase III, guidance given 
about reporting response 
This section removed and 
referenced in section 
above: no need to have 
different criteria for phase II 
and!Il 
Appendix ll: updated with 
detailed guidance on 
use of MRI, PET/CT 
Other practical guidance 
included 
Appendix I: comparison of 
RECisr 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 III trials 
requires guidance on assessment of PD in 
patients with non measurable disease 
Simplifies reporting and clarifies how to 
report phase II and III data consistently 
Simplification of response assessment by 
reducing number oflesions 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 10 
Dancey et al.21 
"' 
C 
"' 
0 .,, 
"' > z 
0 
C 
"' z 
> ... 
0 .., 
r, 
> z 
r, 
"' "' 
.,,. 
V1 
"' 
0 
0 
"' 
"' "' 
00 
I 
"' 
.,,. 
...... 
ID 

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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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 begiven 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. IV 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. Typically, 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 IV 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. This 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 IV contrast due to
allergy
or
renal
insufﬁciency,
the
decision
as
to
whether a non contrast CT or MRI (with or without IV
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 interval: 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
parameters, a minimum 10 mm lesion is considered
measurable at baseline. Occasionally, institutions may
perform medically acceptable scans at slice thicknesses
greater than 5 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 (left) 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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241

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 contrast 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.
FDG PET has gained acceptance as a valuable tool for
detecting, staging and restaging 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,
FDG 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 FDG 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 of a combined PET CT are of limited 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 RECIST mea
surements. 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 IV 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 10 mm 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 T1
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
Fig. 2 – CT versus MRI of same lesions showing apparent ‘progression’ due only to differing method of measurement.
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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 performed, 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 or in 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 identiﬁed
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 P15 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 of reappearance. 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 CT with 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).
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243

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 boundary 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 distin
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 overall
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 Figs. 5 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).
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
<10 mm.
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Appendix III. Frequently asked questions
Question
Answer
What should be done if several unique lesions at
baseline become conﬂuent at a follow up
evaluation?
Measure the longest diameter of the conﬂuent mass and record to add into the sum of
the longest diameters
How large does a new lesion have to be to count
as progression? Does any small subcentimetre
lesion qualify, or should the lesion be at least
measurable?
New lesions do not need to meet ‘measurability criteria’ to be considered valid. If it is
clear on previous images (with the same technique) that a lesion was absent then its
deﬁnitive appearance implies progression. If there is any doubt (because of the
techniques or conditions) then it is suggested that treatment continue until next
scheduled assessment when, generally, all should be clear. Either it gets bigger and the
date of progression is the date of the ﬁrst suspicion, or it disappears and one may then
consider it an artefact with the support of the radiologists
How should one lesion be measured if on
subsequent exams it is split into two?
Measure the longest diameter of each lesion and add this into the sum
Does the deﬁnition of progression depend on
the status of all target lesions or only one?
As per the RECIST 1.1 guideline, progression requires a 20% increase in the sum of
diameters of all target lesions AND a minimum absolute increase of 5 mm in the sum
Are RECIST criteria accepted by regulatory
agencies?
Many cooperative groups and members of pharma were involved in preparing RECIST
1.0 and have adopted them. The FDA was consulted in their development and supports
their use, though they don’t require it. The European and Canadian regulatory
authorities also participated and the RECIST criteria are now integrated in the European
note for guidance for the development of anticancer agents. Many pharmaceutical
companies are also using them. RECIST 1.1 was similarly widely distributed before
publication
What is the criterion for a measurable lesion if
the CT slice thickness is >5 mm?
RECIST 1.1 recommends that CT scans have a maximum slice thickness of 5 mm and the
minimum size for a measurable lesion is twice that: 10 mm (even if slice thickness is
<5 mm). If scanners with slice thickness >5 mm are used, the minimum lesion size must
have a longest diameter twice the actual slice thickness
What should we record when target lesions
become so small they are below the 10 mm
‘measurable’ size?
Target lesion measurability is deﬁned at baseline. Thereafter, actual measurements,
even if <10 mm, should be recorded. If lesions become very small, some radiologists
indicate they are ‘too small to measure’. This guideline advises that when this occurs, if
the lesion is actually still present, a default measurement of 5 mm should be applied. If
in fact the radiologist believes the lesion has gone, a default measurement of 0 mm
should be recorded
If a patient has several lesions which have
decreased in size to meet PR criteria and one
has actually disappeared, does that patient have
PD if the ‘disappeared’ lesion reappears?
Unless the sum meets the PD criteria, the reappearance of a lesion in the setting of PR (or
SD) is not PD. The lesion should simply be added into the sum.
If the patients had had a CR, clearly reappearance of an absent lesion would qualify for
PD
When measuring the longest diameter of target
lesions in response to treatment, is the same
axis that was used initially used subsequently,
even if there is a shape change to the lesion that
may have produced a new longest diameter?
The longest diameter of the lesion should always be measured even if the actual axis is
different from the one used to measure the lesion initially (or at different time point
during follow up)
The only exception to this is lymph nodes: as per RECIST 1.1 the short axis should
always be followed and as in the case of target lesions, the vector of the short axis may
change on follow up
Target lesions have been selected at baseline
and followed but then one of these target
lesions then becomes non evaluable (i.e.
different technique used)
What may be done in such cases is one of the following:
What is the effect this has on the other target
lesions and the overall response?
(a) If the patient is still being treated, call the centre to be sure that future evaluations are
done with the baseline technique so at least SOME courses are fully evaluable
(b) If that is not possible, check if there IS a baseline exam by the same technique which
was used to follow patients...in which case if you retrieve the baseline measures from
that technique you retrieve the lesion evaluability
(c) If neither (a) nor (b) is possible then it is a judgement call about whether you delete
the lesion from all forms or consider the impact of the lesion overall is so important that
its being non evaluable makes the overall response interpretation inevaluable without
it. Such a decision should be discussed in a review panel
It is NOT recommended that the lesion be included in baseline sums and then excluded
from follow up sums since this biases in favour of a response
(continued on next page)
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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
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