A Phase 1b/2 Study of MEDI4736 in Combination With Tremelimumab, MEDI4736 Monotherapy, and Tremelimumab Monotherapy in Subjects With Metastatic or Recurrent Gastric or Gastroesophageal Junction Adenocarcinoma
Phase: PHASE1
Conditions: Gastric or Gastroesophageal Junction Adenocarcinoma
Sponsor: MedImmune LLC

MedImmune
Protocol D4190C00021
MEDI4736
24Jan2017; Amendment 6 Final
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A Phase 1b/2 Study of MEDI4736 in Combination with Tremelimumab, MEDI4736 
Monotherapy, and Tremelimumab Monotherapy in Subjects with Metastatic or Recurrent 
Gastric or Gastroesophageal Junction Adenocarcinoma
Sponsor Protocol Number: D4190C00021
Investigational Products:
MEDI4736, Tremelimumab
Sponsor:
MedImmune, LLC, a wholly owned subsidiary of 
AstraZeneca PLC
Protocol History, Date:
Original Protocol, 07Nov2014
Amendment 1, 12Dec2014
Amendment 2, 22Jan2015
Amendment 3, 03Apr2015
Amendment 4, 10Apr2015
Amendment 5, 11Jan2016
Amendment 6, 24Jan2017

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PROTOCOL SYNOPSIS
TITLE
A Phase 1b/2 Study of MEDI4736 in Combination with Tremelimumab, MEDI4736 Monotherapy, and 
Tremelimumab Monotherapy in Subjects with Metastatic or Recurrent Gastric or Gastroesophageal Junction 
Adenocarcinoma
HYPOTHESIS
MEDI4736 in combination with tremelimumab, MEDI4736 monotherapy, and tremelimumab monotherapy 
will be safe and demonstrate clinical activity in subjects with metastatic or recurrent gastric or 
gastroesophageal junction (GEJ) adenocarcinoma.
OBJECTIVES
Primary Objectives
1. For Phase 1b: To assess the safety and tolerability, describe any dose-limiting toxicity (DLT), and 
determine the maximum tolerated dose (MTD) or the highest protocol-defined doses (in the absence of 
exceeding the MTD) for MEDI4736 in combination with tremelimumab in subjects with metastatic or 
recurrent gastric or GEJ adenocarcinoma.
2. For Phase 2: To determine objective response rate (ORR) and progression-free survival (PFS) at 6 months 
(PFS-6) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as primary measures of 
clinical activity of MEDI4736 in combination with tremelimumab in second- and third-line subjects whose 
tumors have a positive interferon-gamma (IFN-γ) gene expression signature and in unselected second- and 
third-line subjects, MEDI4736 monotherapy, and tremelimumab monotherapy in subjects with metastatic 
or recurrent gastric or GEJ adenocarcinoma.
Secondary Objectives
1. For Phase 1b: To assess disease control rate (DCR; defined as complete response [CR], partial response 
[PR], or stable disease [SD]), ORR, and PFS-6 based on RECIST v1.1 as measures of clinical activity of 
MEDI4736 in combination with tremelimumab in subjects with metastatic or recurrent gastric or GEJ 
adenocarcinoma.
2. For Phase 2: To further describe the safety and tolerability of MEDI4736 in combination with 
tremelimumab, MEDI4736 monotherapy, and tremelimumab monotherapy in subjects with metastatic or 
recurrent gastric or GEJ adenocarcinoma.
3. For Phase 2: To assess DCR and duration of response (DoR) based on RECIST v1.1 and overall survival 
(OS) as additional measures of clinical activity of MEDI4736 in combination with tremelimumab in 
second- and third-line subjects whose tumors have a positive IFN-γ gene expression signature and in 
unselected second- and third-line subjects, MEDI4736 monotherapy, and tremelimumab monotherapy in 
subjects with metastatic or recurrent gastric or GEJ adenocarcinoma.
4. For Phase 2: To define the components of programmed cell death ligand 1 (PD-L1) expression (ie, tumoral 
vs stromal) that correlate with clinical activity of MEDI4736 in combination with tremelimumab, 
MEDI4736 monotherapy, and tremelimumab monotherapy in subjects with metastatic or recurrent gastric 
or GEJ adenocarcinoma.
 
 
 
 
 
 
 

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STUDY ENDPOINTS
Primary Endpoints
1. For Phase 1b: Safety of MEDI4736 in combination with tremelimumab as assessed by the presence of 
adverse events (AEs), serious adverse events (SAEs), DLTs, laboratory parameters, vital signs, physical 
examination, and electrocardiogram (ECG) results.
2. For Phase 2: ORR and PFS-6 of MEDI4736 in combination with tremelimumab in second- and third-line 
subjects whose tumors have a positive IFN-γ gene expression signature and in unselected second- and 
third-line subjects, MEDI4736 monotherapy, and tremelimumab monotherapy based on RECIST v1.1. 
Response-based endpoints would be based on blinded independent central review (BICR) if performed, or 
on investigator assessments. 
Secondary Endpoints
1. For Phase 1b: Clinical activity of MEDI4736 in combination with tremelimumab as determined by ORR, 
DCR at 16 weeks (DCR-16w), DCR at 24 weeks (DCR-24w), and PFS-6.
2. For Phase 2: Safety of MEDI4736 in combination with tremelimumab, MEDI4736 monotherapy, and 
tremelimumab monotherapy as assessed by the presence of AEs, SAEs, laboratory parameters, vital signs, 
physical examination, and ECG results.
3. For Phase 2: Clinical activity of MEDI4736 in combination with tremelimumab, MEDI4736 monotherapy, 
and tremelimumab monotherapy as determined by DCR-16w, DCR-24w, DoR, PFS, and PFS at 9 months 
(PFS-9) based on RECIST v1.1, and OS and 1-year survival.
4. For Phase 2: IFN-γ gene expression signature and how it correlates with clinical activity of MEDI4736 in 
combination with tremelimumab.
5. For Phase 2: PD-L1 expression and localization (by immunohistochemistry [IHC] or immunofluorescence
[IF]) within the tumor microenvironment and how it correlates with clinical activity for MEDI4736 in 
combination with tremelimumab, MEDI4736 monotherapy, and tremelimumab monotherapy.
 
 
 
 
 
 
 
 

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STUDY DESIGN
This is a randomized, multicenter, open-label, Phase 1b/2 study to evaluate the safety, tolerability, and clinical 
activity of MEDI4736 in combination with tremelimumab, MEDI4736 monotherapy, and tremelimumab 
monotherapy in subjects with metastatic or recurrent gastric or GEJ adenocarcinoma who meet the following
criteria:  
Second-line (Phase 1b):
•
Must have received and have progressed, or are refractory to one systemic platinum- or fluoropyrimidine-
based chemotherapy regimen for metastatic or recurrent disease, or
Second-line (Phase 2 Arms A, B, and C):
•
Must have received and have progressed, or are refractory to one systemic platinum- or fluoropyrimidine-
based chemotherapy regimen for metastatic or recurrent disease, or
•
Must have received and have progressed, or are refractory to one systemic platinum- or fluoropyrimidine-
based therapy as part of neoadjuvant or adjuvant regimen with relapse within 6 months of therapy, or
Third-line (Phase 2 Arm D):
•
Must have received and have progressed, or are refractory to two systemic regimens (one standard 
platinum- or fluoropyrimidine-based chemotherapy regimen and one approved regimen for metastatic or 
recurrent disease)
•
Subjects who have received and have progressed, or are refractory to one systemic platinum or 
fluoropyrimidine-based therapy as part of neoadjuvant or adjuvant regimen with relapse within 6 months 
will count as a line of therapy in the metastatic/recurrent setting. 
Second- and Third-line (Phase 2 Arm E; as of Amendment 6):
•
 
•
Must have received and have progressed, or are refractory to one systemic platinum- or fluoropyrimidine-
based chemotherapy regimen for metastatic or recurrent disease, or
•
Must have received and have progressed, or are refractory to one systemic platinum- or fluoropyrimidine-
based therapy as part of neoadjuvant or adjuvant regimen with relapse within 6 months of therapy, or
•
Must have received and have progressed, or are refractory to two systemic regimens (one standard 
platinum- or fluoropyrimidine-based chemotherapy regimen and one approved regimen for metastatic or 
recurrent disease), and
•
Third-line subjects who have received and have progressed, or are refractory to one systemic platinum- or 
fluoropyrimidine-based therapy as part of neoadjuvant or adjuvant regimen with relapse within 6 months 
will count as a line of therapy in the metastatic/recurrent setting.
Up to approximately 135 subjects for Phase 1b/2 will be enrolled at approximately 40 study centers globally.
Phase 1b
The dose and schedule of MEDI4736 in combination with tremelimumab for Phase 1b of the current study is
based on emerging safety, clinical, and PK/pharmacodynamic data from the ongoing Study D4190C00006, 
which is evaluating the combination of MEDI4736 and tremelimumab in subjects with non-small-cell lung 
cancer (NSCLC). It is anticipated that a dose determined as safe in NSCLC will also be safe in subjects with 
metastatic or recurrent gastric or GEJ adenocarcinoma.
 
 
 
 
 
 
 
 
 
 

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. Subjects will be monitored for 
DLT prior to initiation of enrollment in Phase 2. If unacceptable toxicity is encountered or ≥3 out of 9 of 
subjects experience a DLT during this safety run-in, a lower dose level may be evaluated prior to initiation of 
Phase 2. 
A total of 6 subjects were enrolled in Phase 1b and treated with the dose and schedule described above; there 
were no DLTs in these 6 subjects. The Phase 1b portion of the study is now complete.
Phase 2
Once the MTD or highest protocol-defined dose (in the absence of exceeding the MTD) has been defined in 
Phase 1b, enrollment in Phase 2 will begin. In Phase 2, subjects will be enrolled in 1 of 5 treatment arms, as 
listed below. Second-line subjects with metastatic or recurrent gastric or GEJ adenocarcinoma will be 
randomized in a 2:2:1 ratio to Arms A, B, or C. In parallel, third-line subjects with metastatic or recurrent 
gastric or GEJ adenocarcinoma will be enrolled in Arm D. Upon closure of Arms A, B, and C and completion 
of Arm D, second- and third-line subjects with metastatic or recurrent gastric or GEJ adenocarcinoma and a 
positive IFN-γ gene expression signature will be enrolled in Arm E.
•
Arm A: MEDI4736 in combination with tremelimumab in second-line subjects with metastatic or 
recurrent gastric or GEJ adenocarcinoma 
•
Arm B: MEDI4736 monotherapy in second-line subjects with metastatic or recurrent gastric or GEJ 
adenocarcinoma 
•
Arm C: Tremelimumab monotherapy in second-line subjects with metastatic or recurrent gastric or GEJ 
adenocarcinoma
•
Arm D: MEDI4736 in combination with tremelimumab in third-line subjects with metastatic or recurrent 
gastric or GEJ adenocarcinoma 
•
Arm E (as of Amendment 6): MEDI4736 in combination with tremelimumab in second- and third-line 
subjects with metastatic or recurrent gastric or GEJ adenocarcinoma and a positive IFN-γ gene expression 
signature 
During Phase 2, subjects will be monitored continuously for safety according to the same criteria employed 
during Phase 1b. If during the treatment period, ≥33% of subjects experience safety events meeting DLT 
criteria, even if outside of the DLT evaluation period, enrollment may be paused and study data will be 
reviewed to determine whether additional monitoring or alternate dose levels or treatment schedules should be 
evaluated prior to further enrollment. In addition, after the first 20 subjects have been dosed with MEDI4736 
in combination with tremelimumab for a minimum of 6 weeks (in both second- and third-line settings), safety 
data will be reviewed by the sponsor.
All subjects will be evaluated for clinical activity, on a regular basis as specified in the protocol, and their 
disease status primarily analyzed according to RECIST v1.1. Clinical decision making in subjects undergoing 
treatment will be based on RECIST v1.1 with modifications. Enrollment into any arm in Phase 2 may be 
discontinued at the discretion of the sponsor should emerging clinical or nonclinical data suggest that 
continued treatment may not be beneficial to a given arm.
 
Pre-specified interim analyses performed on Arms A and B showed that the 
criteria for expansion were met; however, enrollment into Arms A, B, and C was stopped at the sponsor’s 
discretion. Based on evolving science suggesting that the IFN-γ gene expression signature will better predict
responders of immunotherapy (Ulloa-Montoya et al, 2013; Peng et al, 2015) as well as data from the initial 
portion of the study, it was decided to proceed with MEDI4736 in combination with tremelimumab in both
second- and third-line subjects with metastatic or recurrent gastric or GEJ adenocarcinoma who had a positive 
IFN-γ gene expression signature. The discontinuation of Arms A, B, and C was not due to safety concerns.
Arm D has completed.
Dose-Expansion in a Biomarker Selected Population
As of Amendment 6, a new arm (Arm E) of MEDI4736 in combination with tremelimumab has been added to 
evaluate efficacy and safety in subjects with second- and third-line gastric or GEJ adenocarcinoma with a 
positive tumor IFN-γ gene expression signature. Numerous clinical trials have demonstrated the predictive 
nature of a Type 1 helper T-cell (Th1) gene signature and the subsequent response to immunotherapy for solid 

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tumors.
 
 
 
 
All 
subjects will be followed for survival until the end of study (5 years after the last subject is enrolled or the date 
the study is closed by the sponsor, whichever occurs first). Evaluation of a possible correlation between 
clinical activity of MEDI4736 and tremelimumab in combination and IFN-γ gene expression as well as other 
potential biomarkers (eg, tumoral and stromal PD-L1 expression) will be ongoing throughout the study.
TARGET SUBJECT POPULATION
Adult male or female subjects, ≥ 18 years of age at screening, with histologically- or cytologically-confirmed 
metastatic or recurrent gastric or GEJ adenocarcinomas AND the following:
Second-line (Phase 1b):
•
Must have received and have progressed, or are refractory to one systemic platinum- or fluoropyrimidine-
based chemotherapy regimen for metastatic or recurrent disease, or
Second-line (Phase 2 Arms A, B, and C):
•
Must have received and have progressed, or are refractory to one systemic platinum- or fluoropyrimidine-
based chemotherapy regimen for metastatic or recurrent disease, or
•
Must have received and have progressed, or are refractory to one systemic platinum- or fluoropyrimidine-
based therapy as part of neoadjuvant or adjuvant regimen with relapse within 6 months of therapy, or
Third-line (Phase 2 Arm D):
•
Must have received and have progressed, or are refractory to two systemic regimens (one standard 
platinum- or fluoropyrimidine-based chemotherapy regimen and one approved regimen for metastatic or 
recurrent disease)
•
Subjects who have received and have progressed, or are refractory to one systemic platinum or 
fluoropyrimidine-based therapy as part of neoadjuvant or adjuvant regimen with relapse within 6 months 
will count as a line of therapy in the metastatic/recurrent setting.
Second- and Third-line (Phase 2 Arm E; as of Amendment 6):
•
Must have a positive IFN-γ gene expression signature 
.
•
Must have received and have progressed, or are refractory to one systemic platinum- or fluoropyrimidine-
based chemotherapy regimen for metastatic or recurrent disease, or
•
Must have received and have progressed, or are refractory to one systemic platinum- or fluoropyrimidine-
based therapy as part of neoadjuvant or adjuvant regimen with relapse within 6 months of therapy, or
•
Must have received and have progressed, or are refractory to two systemic regimens (one standard 
platinum- or fluoropyrimidine-based chemotherapy regimen and one approved regimen for metastatic or 
recurrent disease), and
•
Third-line subjects who have received and have progressed, or are refractory to one systemic platinum- or 
fluoropyrimidine-based therapy as part of neoadjuvant or adjuvant regimen with relapse within 6 months 
will count as a line of therapy in the metastatic/recurrent setting.
Subjects who will be enrolled in Arm E must have measurable disease at baseline. Key exclusion criteria are 
human epidermal growth factor receptor (HER)2-overexpressing metastatic or recurrent GEJ adenocarcinomas 
and prior exposure to immunotherapy. 

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TREATMENT AND REGIMENS
Subjects will be treated in either Phase 1b or Phase 2 of the study. 
 
 
 
 
 
 
 
 
 
 
Subjects who are treated with MEDI4736 monotherapy (Arm B) or tremelimumab monotherapy (Arm C) may 
crossover to be treated with MEDI4736 in combination with tremelimumab upon  confirmed progressive 
disease (PD) under restricted circumstances (as outlined in the protocol). Subjects who are treated with the 
combination of MEDI4736 and tremelimumab may continue their study treatment or have reinduction of the 
study treatment upon a confirmed PD under restricted circumstances (as outlined in the protocol). Subjects in 
both Phase 1b and Phase 2 who derived clinical benefit from study treatment during the initial 12-month 
treatment period and who subsequently developed PD during the 12-month follow-up period, will be treated 
for up to 12 months with the same regimen that the subject was given upon initial study entry. Dose delays and 
discontinuations to manage clinically significant treatment-related toxicity will be allowed.
STATISTICAL METHODS
Sample Size and Power Calculations
Up to approximately 135 subjects for Phase 1b/2 will be enrolled in this study.
Phase 1b
The sample size for Phase 1b is not based on formal statistical power considerations. The number of subjects 
in this phase of the study is based on a safety run-in schema investigating the safety and tolerability of a dose 
and schedule selected for dose expansion in Study D4190C00006. 
Phase 2
 
 
 
 
 
 
 
 
 
 
 
 

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Efficacy
Efficacy analysis will be based on the As-treated Population, which includes all subjects who receive any 
investigational product. Response-related endpoints and corresponding time-to-event endpoints for primary 
and secondary efficacy endpoints programmatically-derived from the investigator’s assessments or BICR, as 
well as OS will be analyzed. More details will be provided in the statistical analysis plan.
OR is defined as best overall response of confirmed CR or confirmed PR according to RECIST v1.1. 
DoR is defined as the duration from the first documentation of OR to the first documented disease progression 
according to RECIST v1.1 or death due to any cause, whichever occurs first. 
DC is defined as confirmed CR, confirmed PR, or SD based on RECIST v1.1. DC at 16 and 24 weeks is 
defined as a best overall response of confirmed CR, confirmed PR or having SD with duration of SD lasting 
16 and 24 weeks, respectively.
PFS will be measured from the date of randomization or start of treatment until the documentation of disease 
progression according to RECIST v1.1 or death due to any cause, whichever occurs first. For subjects who are 
alive and progression-free at the time of data cut-off (DCO) for analysis, PFS will be censored at the last 
tumor assessment date. The PFS-6 
 are the proportion of subjects with PFS at 6 months
 
OS will be measured as the time from date of randomization or the start of treatment until death due to any 
cause. For subjects who are alive at the time of DCO, OS will be censored on the last date when subjects are 
known to be alive.
The 2 co-primary efficacy endpoints for Phase 2 are OR and PFS-6 using RECIST v1.1. The ORR is defined 
as the proportion of subjects with OR. The 2-sided 90% and 95% confidence intervals (CIs) for ORR will be 
estimated using the exact binomial distribution. Kaplan-Meier curves will be generated for PFS and used to 

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estimate the PFS-6 along with its 2-sided 90% and 95% CIs. 
Secondary efficacy endpoints include DC, DoR, PFS, 
, OS, and 1-year survival for Phase 2, and OR, DC
and PFS-6 for Phase 1b. The DCR is defined as the proportion of subjects with DC. The 2-sided 90% and 95% 
CIs of DCR will be provided using an exact probability method. DCR at 16 and at 24 weeks will be estimated 
along with their 2-sided 90% and 95% CIs. Kaplan-Meier method will be used to estimate the median 
DoR/PFS/OS and landmark PFS/OS rate along with their CIs.
Only subjects whose archival tumor tissue sample showed a positive IFN-γ gene expression signature will be 
eligible for enrollment to Arm E. This will allow identification of a unique population of gastric or GEJ 
adenocarcinoma subjects who may benefit from treatment with immune checkpoint inhibitors and will allow 
correlations between IFN-γ gene expression and clinical activity of MEDI4736 in combination with 
tremelimumab to be explored.
During the course of the study, subjects’ tumor samples (archival and/or from fresh biopsies) will be analyzed 
for PD-L1 expression (ie, tumoral vs stromal) that may predict increased frequency of response or longer 
disease stabilization. The analyses will be performed to see whether there is association between PD-L1 
expression levels at baseline and clinical activity. If such association exists, secondary analyses for primary 
and secondary efficacy endpoints will be conducted in “biomarker positive” and “biomarker negative” 
subpopulations determined by the cut-off point of PD-L1 expression. The impact of baseline prognostic 
factors will be explored as appropriate when treatment arms in the subpopulations are compared.
Safety
The safety analysis will be based on the As-treated Population, and will include AEs, SAEs, laboratory 
evaluations, vital signs, ECGs, and physical examinations from both Phase 1b and Phase 2. 
In Phase 1b, the number of DLTs that are identified in the DLT Evaluable Population (defined as subjects 
enrolled in Phase 1b who receive the protocol-assigned treatment and complete safety follow-up through the 
DLT evaluation period or experience a DLT during the DLT evaluation period) will be summarized or listed. 
For both Phase 1b and Phase 2, the number and percentage of subjects reporting treatment-emergent AEs will 
be summarized overall and by the worst National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE) v4.03 grade, system organ class, and preferred term, with a breakdown by treatment 
arm/dose cohort. Similarly, the number and percentage of subjects reporting treatment-emergent AEs 
considered related to investigational product will be summarized. Laboratory abnormalities will be graded 
according to the NCI CTCAE v4.03, if applicable. Frequencies of worst observed grade will be presented for 
each laboratory parameter as well as the rates of subjects with Grade 3-4 toxicities. A shift table, presenting 
the 2-way frequency tabulation for baseline and the worst post-baseline grade, will be provided for clinical 
laboratory tests.
 
 
 
 
 
 
 

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TABLE OF CONTENTS
PROTOCOL SYNOPSIS ..........................................................................................................2
LIST OF ABBREVIATIONS..................................................................................................16
1
INTRODUCTION.........................................................................................................19
1.1
Disease Background ...........................................................................................19
1.1.1Cancer and Immune Function.....................................................................19
1.1.2Immune-checkpoint Inhibition ...................................................................19
1.2
MEDI4736 and Tremelimumab Background .....................................................20
1.2.1MEDI4736 Background..............................................................................20
1.2.2Tremelimumab Background .......................................................................20
1.5
Rationale for Conducting the Study ...................................................................30
1.6
Research Hypothesis...........................................................................................33
2
OBJECTIVES AND ENDPOINTS...............................................................................34
2.1
Objectives ...........................................................................................................34
2.1.1Primary Objectives .....................................................................................34
2.1.2Secondary Objectives .................................................................................34
2.2
Study Endpoints..................................................................................................35
2.2.1Primary Endpoints ......................................................................................35
2.2.2Secondary Endpoints ..................................................................................35
3
STUDY DESIGN..........................................................................................................36
3.1
Description of the Study .....................................................................................36
3.1.1Overview……….........................................................................................36
3.1.2Treatment Regimen.....................................................................................41
3.1.2.4
Criteria for Treatment Beyond Progression, Crossover, and 
Retreatment in the Follow-up Period .........................44

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3.1.3Phase 1b………..........................................................................................45
3.1.3.2
Dose-limiting Toxicity..............................................................47
3.1.3.3
Maximum Tolerated Dose ........................................................48
3.1.4Phase 2………............................................................................................49
3.1.5Management of Study Medication Related Toxicities ...............................49
3.2
Study Design and Dose Rationale ......................................................................50
3.2.1Dose Rationale............................................................................................50
3.2.2Rationale for Study Population...................................................................52
3.2.3Rationale for Endpoints ..............................................................................54
4
MATERIALS AND METHODS..................................................................................59
4.1
Subjects...............................................................................................................59
4.1.1Number of Subjects ....................................................................................59
4.1.2Inclusion Criteria ........................................................................................59
4.1.3Exclusion Criteria .......................................................................................63
4.1.4Subject Enrollment and Randomization .....................................................64
4.1.5Withdrawal from the Study.........................................................................65
4.1.6Discontinuation of Investigational Product ................................................65
4.1.7Replacement of Subjects.............................................................................66
4.1.8Withdrawal of Informed Consent for Data and Biological Samples..........66
4.2
Schedule of Study Procedures ............................................................................67
4.2.1Enrollment/Screening Period......................................................................67
4.2.2Randomized Treatment Period ...................................................................69
4.2.3Follow-up Period ........................................................................................77
4.3
Description of Study Procedures ........................................................................80
4.3.1Efficacy………...........................................................................................80
4.3.1.1
Evaluation of Response by Response Evaluation Criteria in 
Solid Tumors..............................................................82
4.3.2Tumor Biopsies...........................................................................................84
4.3.2.1
Fresh Tumor Biopsies (Phase 2 Only)......................................84
4.3.2.2
Archival Tumor Samples (Phase 1b and Phase 2)....................85
4.3.4Medical History, Physical Examination, Electrocardiogram, and Vital 
Signs..........................................................................................86

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4.3.4.1
Medical History and Physical Examination..............................86
4.3.4.2
Electrocardiograms ...................................................................87
4.3.4.3
Vital Signs.................................................................................87
4.3.5Clinical Laboratory Tests............................................................................87
4.3.8Biomarker Evaluation and Methods ...........................................................90
4.3.8.1
IFN- γ Gene expression Testing ...............................................91
4.3.9Estimate of Volume of Blood to be Collected............................................91
4.4
Study Suspension or Termination.......................................................................92
4.5
Investigational Products......................................................................................93
4.5.1Identity of Investigational Product(s) .........................................................93
4.5.1.3
Investigational Product Inspection............................................96
4.5.1.5
Monitoring of Dose Administration .........................................97
4.5.1.6
Reporting Product Complaints..................................................98
4.5.2Additional Study Medications ....................................................................99
4.5.3Labeling………. .........................................................................................99
4.5.5Treatment Compliance................................................................................99
4.5.6Accountability.............................................................................................99
4.6
Treatment Assignment and Blinding................................................................100
4.6.1Methods for Assigning Treatment Groups ...............................................100
4.6.2Methods for Ensuring Blinding ................................................................100
4.7
Restrictions During the Study and Concomitant Treatment(s).........................100
4.7.1Permitted Concomitant Medications ........................................................100
4.7.2Prohibited Concomitant Medications .......................................................101
4.8
Statistical Evaluation ........................................................................................101
4.8.1General Considerations.............................................................................101
4.8.2Sample Size and Power Calculations........................................................102
4.8.2.1
Phase 1b……… ......................................................................102
4.8.3Efficacy……….........................................................................................104
4.8.3.1
Primary Efficacy Analysis......................................................105
4.8.3.2
Secondary Efficacy Analyses .................................................106

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4.8.3.4
Sensitivity Analyses................................................................107
4.8.4Safety………. ...........................................................................................107
4.8.4.1
Analysis of Adverse Events....................................................108
4.8.4.2
Analysis of Clinical Laboratory Parameters...........................108
4.8.4.3
Analysis of Vital Signs ...........................................................108
4.8.4.4
Analysis of Electrocardiograms..............................................108
5
ASSESSMENT OF SAFETY .....................................................................................111
5.1
Definition of Adverse Events ...........................................................................111
5.2
Definition of Serious Adverse Events ..............................................................112
5.3
Definition of Adverse Events of Special Interest .............................................113
5.4
Recording of Adverse Events ...........................................................................114
5.4.1Time Period for Collection of Adverse Events.........................................115
5.4.2Follow-up of Unresolved Adverse Events................................................115
5.4.3Deaths………. ..........................................................................................115
5.5
Reporting of Serious Adverse Events...............................................................116
5.6
Other Events Requiring Immediate Reporting .................................................117
5.6.1Overdose……….......................................................................................117
5.6.2Hepatic Function Abnormality .................................................................117
5.6.3Pregnancy………......................................................................................118
6
STUDY AND DATA MANAGEMENT....................................................................119
6.1
Training of Study Site Personnel......................................................................119
6.2
Monitoring of the Study....................................................................................119
6.2.1Source Data...............................................................................................119
6.2.2Study Agreements.....................................................................................120
6.2.3Archiving of Study Documents ................................................................120
6.3
Study Timetable and End of Study...................................................................120
6.4
Data Management.............................................................................................120
6.5
Medical Monitor Coverage...............................................................................120
7
ETHICAL AND REGULATORY REQUIREMENTS ..............................................121
7.1
Ethical Conduct of the Study............................................................................121
7.2
Subject Data Protection ....................................................................................121
7.3
Ethics and Regulatory Review..........................................................................121

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7.4
Informed Consent .............................................................................................122
7.5
Changes to the Protocol and Informed Consent Form......................................123
7.6
Audits and Inspections......................................................................................123
8
REFERENCES............................................................................................................124
9
SUMMARY OF PROTOCOL AMENDMENT AND ADMINISTRATIVE 
CHANGES TO THE PROTOCOL .....................................................................131
9.1
Protocol Amendment 1, 12Dec2014.................................................................131
9.2
Protocol Amendment 2, 22Jan2015..................................................................132
9.3
Protocol Amendment 3, 03Apr2015.................................................................132
9.4
Protocol Amendment 4, 10Apr2015.................................................................134
9.5
Protocol Amendment 5 21Dec2015..................................................................135
9.6
Protocol Amendment 6 24Jan2017...................................................................136
APPENDICES .......................................................................................................................140
LIST OF IN-TEXT TABLES
Table 4.1.2-1
Highly Effectivea Methods of Contraception (< 1% failure rate)........62
Table 4.2.1-1
Schedule of Screening/Baseline Procedures (as of Amendment 6).....67
Table 4.2.2-1
Schedule of Treatment Period (Initial, Retreatment, Reinduction, and 
Crossover) Study Procedures Weeks 1 to 25 (as of Amendment 6)....70
Table 4.2.2-2
Schedule of Treatment Period (Initial, Retreatment, Reinduction, and 
Crossover) Study Procedures Weeks 27 to End of Treatment (as of 
Amendment 6) .....................................................................................73
Table 4.2.3-1
Schedule of Follow-up Procedures (as of Amendment 6)...................78
Table 4.3.1.1-1
Evaluation of Overall Response at a Single Timepoint by RECIST 
V1.1......................................................................................................83
Table 4.5.1-1
Identification of Investigational Products............................................93
Table 4.8.2.2-1
Observed ORR and PFS-6 with 90 Percent CI (Arms A and B) .......103
Table 4.8.2.2-2
Observed ORR and PFS-6 with 90 Percent CI (Arm E)....................104
 
 
 
 
 
 
 
 
 

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LIST OF IN-TEXT FIGURES
Figure 3.1.1-1
Study Flow Diagram............................................................................38
LIST OF APPENDICES
Appendix 6
Diarrhea Management Flowchart ......................................................175
Appendix 7
Additional Safety Guidance...............................................................177
Appendix 8
National Institute of Allergy and Infectious Diseases and Food Allergy 
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis .....180

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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
5-FU
5-fluorouracil
ADA
antidrug antibody
ADCC
antibody-dependent cell-mediated cytotoxicity
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APC
antigen-presenting cell
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BICR
blinded independent central review
BP
blood pressure
BSC
best supportive care
CD
cluster of differentiation
CI
confidence interval
CNS
central nervous system
CR
complete response
CT
computed tomography
CTLA-4
cytotoxic T-lymphocyte-associated antigen 4
DC
disease control
DCO
Data cut-off
DCR
disease control rate
DCR-12w
disease control rate at 12 weeks
DCR-16w
disease control rate at 16 weeks
DCR-24w
disease control rate at 24 weeks
DEHP
bis (2-ethylhexyl) phthalate
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DoR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EU
European Union
FAAN
Food Allergy and Anaphylaxis Network
Fc
fragment crystallizable 
FDA
Food and Drug Administration

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Abbreviation or 
Specialized Term
Definition
GCP
Good Clinical Practice
GEJ
gastroesophageal junction
GI
gastrointestinal
GLP
Good Laboratory Practice
HER
human epidermal growth factor receptor
HIV
human immunodeficiency virus
HR
hazard ratio
ICF
informed consent form
ICH
International Council for Harmonisation
ICOS
inducible T-cell costimulator
IEC
Independent Ethics Committee
IF
immunofluorescence
IFN
interferon 
IFN-γ
interferon-gamma
IGF
insulin-like growth factor
IgG
immunoglobulin G
IgM
immunoglobulin M
IHC
immunohistochemistry
IL
interleukin
ILD 
interstitial lung disease
irAE
immune-related adverse event
IRB
Institutional Review Board
IV
intravenous(ly)
IXRS
interactive response system
mAb
monoclonal antibody
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
M(x)/T(y)
MEDI4736 (x) mg/kg and tremelimumab (y) mg/kg
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIAID
National Institute of Allergy and Infectious Diseases
NK
natural killer
NOAEL
no-observed-adverse-effect level
NSCLC
non-small-cell lung cancer
OR
objective response

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Abbreviation or 
Specialized Term
Definition
ORR
objective response rate
OS
overall survival
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L1+
programmed cell death ligand 1 positive
PD-L2
programmed cell death ligand 2
PEF
peak expiratory flow
PFS
progression-free survival
PFS-6
PFS at 6 months
PK
pharmacokinetic(s)
PR
partial response
PVC
polyvinyl chloride
Q2W
every 2 weeks
Q4W
every 4 weeks
Q12W
every 12 weeks
Q90D
every 90 days
QTcF
QT corrected using Fridericia’s formula
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
SAE
serious adverse event
SCCHN
squamous cell carcinoma of the head and neck
SD
stable disease
SID
subject identification
SMC
safety monitoring committee
sPD-L1
soluble programmed cell death ligand 1
TCGA
The Cancer Genome Atlas Research Network
TCR
T-cell receptor
Th1
Type 1 helper T-cell
TIL
tumor-infiltrating lymphocyte
TNF-α
tumor necrosis factor alpha
ULN
upper limit of normal
US
United States
w/v
weight per volume

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1
INTRODUCTION
1.1
Disease Background
1.1.1
Cancer and Immune Function
The importance of the immune system in cancer development and progression has been 
recognized during the past decade (Hanahan and Weinberg, 2000). Failure of immune 
surveillance of pre-neoplastic lesions and micro-metastases is a key step in cancer 
development. Chronically immunosuppressed individuals show higher rates of cancer. This 
observation led to the hypothesis that sporadic cancers among immune-competent individuals 
are likely to be minimally immunogenic, allowing for passive escape from immune 
surveillance. Recent data suggests that this may be an oversimplification. Some sporadic 
tumors are highly immunogenic, but actively suppress the local immune environment 
through production of immunosuppressive cytokines (Shields et al, 2010). As such, the local 
tumor environment is likely a highly dynamic environment where most tumors grow and 
metastasize through adaptive responses that modulate antitumor immunity.
The complexity and redundancy of the immune system offers multiple targets that may be 
manipulated to maximize the body’s inherent immune response to a tumor. Immune response 
may be augmented by directly stimulating effector cells, indirectly stimulating effectors by 
augmenting antigen presentation activity or costimulation, or by suppressing 
immunosuppressive factors, cells, or messages (Monti et al, 2005).
1.1.2
Immune-checkpoint Inhibition
Tumor-infiltrating lymphocytes (TILs) have the capacity to control the growth of many types 
of cancers (Gooden et al, 2011). Most tumors show infiltration by TILs, but tumors modulate 
the local microenvironment through expression of inhibitory molecules. Engagement of TIL 
cell-surface receptors with these inhibitory ligands leads to a dysfunctional immune response, 
causes T-cell exhaustion, and facilitates tumor progression (Baitsch et al, 2012; 
Crespo et al 2013). Novel monoclonal antibodies (mAbs) that block these inhibitory 
receptors have shown significant clinical activity across a number of tumor types 
(Wolchok et al, 2009; Hodi et al, 2010; Robert et al, 2011; Brahmer et al, 2010; 
Topalian et al, 2012). Specifically, blockade of immune-checkpoint inhibitors such as 
cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1), 
and programmed cell death ligand 1 (PD-L1) have shown clinical activity not only in 
conventionally immune-responsive tumors such as melanoma and renal cell carcinoma but 
also in non-small-cell lung cancer (NSCLC; Brahmer et al, 2010; Brahmer et al, 2012; 
Topalian et al, 2012; Gordon et al, 2013), prostate cancer (Harzstark and Small, 2010; 

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Slovin et al, 2013), pancreatic cancer (Royal et al, 2010), mesothelioma (Calabrò et al, 2013),
and other solid tumors (Brahmer et al, 2010; Brahmer et al, 2012; Gordon et al, 2013).
1.2
MEDI4736 and Tremelimumab Background
MEDI4736 and tremelimumab are briefly described below. Refer to the current 
Investigator’s Brochures for details.
1.2.1
MEDI4736 Background
MEDI4736 is a human immunoglobulin G (IgG)-1 kappa monoclonal antibody (mAb)
directed against human PD-L1. MEDI4736 is expressed in Chinese hamster ovary cells and 
has an overall molecular weight of approximately 149 kDa. MEDI4736 selectively binds 
human PD-L1 with high affinity and blocks its ability to bind to PD-1 and cluster of 
differentiation (CD)80. The fragment crystallizable (Fc) domain of MEDI4736 contains a 
triple mutation in the constant domain of the IgG1 heavy chain that reduces binding to the 
complement component C1q and the Fc gamma receptors responsible for mediating 
antibody-dependent cell-mediated cytotoxicity (ADCC; Oganesyan et al, 2008).
1.2.2
Tremelimumab Background
Tremelimumab (formerly CP-675,206) is a human IgG2 mAb being investigated as a cancer 
immunotherapeutic agent. Tremelimumab is expressed in NS0 (murine myeloma) cells and 
has an overall molecular weight of approximately 149 kDa. Tremelimumab is specific for 
human CTLA-4, with no cross-reactivity to related human proteins. Tremelimumab blocks 
the inhibitory effect of CTLA-4, and therefore enhances T-cell activation. Tremelimumab 
shows minimal specific binding to Fc receptors, does not induce natural killer (NK) ADCC 
activity, and does not deliver inhibitory signals following plate-bound aggregation.
 
 
 
 
 
 

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1.5
Rationale for Conducting the Study
Unmet Need in Advanced Gastric Cancer
Despite recent advances, the prognosis of patients with advanced gastric cancer remains poor 
(Kang et al, 2012). At present, regimens that combine a platinum and fluorouracil agent 
either alone or in combination with a third drug such as epirubicin or taxane constitute the 
most effective treatment option in the first-line metastatic setting, resulting in a median OS of 
approximately 10 months (Cunningham et al, 2008). In the second-line setting, ramucirumab 
(a vascular endothelial growth factor receptor 2 antagonist) was recently approved by the 
United States (US) Food and Drug Administration (FDA), and has demonstrated modest 
activity in patients with advanced gastric or GEJ adenocarcinoma who progressed after first-
line platinum- or fluoropyrimidine-containing chemotherapy (Fuchs et al, 2014). Median OS 
was 5.2 months in the ramucirumab group versus 3.8 months in the placebo group. 
Additionally, ramucirumab in combination with paclitaxel was evaluated in the second-line 
setting in the RAINBOW study, in which more than 600 subjects with metastatic gastric or 
GEJ adenocarcinoma that progressed on or within 4 months after first-line platinum- and 
fluoropyrimidine-based combination therapy were randomized to paclitaxel plus 
ramucirumab or paclitaxel alone (Wilke et al, 2014). Median OS was 9.63 months and 
7.36 months, respectively. AEs that occurred in ≥20% of subjects (n = 327) treated with 
ramucirumab plus paclitaxel were fatigue (56.9%), neutropenia (54.4%), neuropathy 
(45.9%), anorexia (40.1%), abdominal pain (36.1%), leukopenia (33.9%), diarrhea (32.4%), 

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epistaxis (30.6%), vomiting (26.9%), hypertension (25.1%), and peripheral edema (25.1%; 
Wilke et al, 2014).
An unmet medical need remains for new second- and third-line treatment options that are 
safe and effective in subjects with advanced gastric cancer. Immunotherapies hold much 
promise in treating this patient population by providing a more favorable safety profile and 
early signs of clinical activity. 
 
 
 
 
 
 
 
 
 
 
 
Rationale for MEDI4736 and Tremelimumab Combination Therapy
The rationale for evaluating MEDI4736 in combination with tremelimumab in advanced 
gastric cancer is supported by both nonclinical and clinical data in several other solid tumors.
Mouse models of transplantable solid tumors show superior antitumor activity of 
combination therapy as compared to monotherapy. Furthermore, the CTLA-4 and 
PD-1/PD-L1 pathways are non-redundant, suggesting that targeting both may have additive 
or synergistic activity. The combination of CTLA-4 and PD-1 blockade in melanoma has 
been shown to result in higher ORRs and 1-year survival than either agent alone 
(Wolchok et al, 2013).

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Profile of Adverse Events with Immunotherapy
MEDI4736 monotherapy, tremelimumab monotherapy, and MEDI4736 in combination with 
tremelimumab are currently being evaluated in other studies (see Section 1.4). Overall, the
AE profile is manageable and supports continued clinical development. 
Immune-related adverse events (irAEs) such as diarrhea and colitis have been reported with 
immunotherapies. With the approval of 2 immune checkpoint inhibitors for melanoma 
(ipilimumab [Hodi et al, 2010] and pembrolizumab [Hamid et al, 2013]), there is greater 
recognition of irAEs and management algorithms, including early, aggressive use of steroids, 
and continued improvement in outcome.
Preliminary Efficacy of Immunotherapy in Advanced Gastric Cancer
Immune checkpoint inhibitors such as MEDI4736 and tremelimumab have provided early 
evidence of clinical activity in advanced gastric cancer. Study CD-ON-MEDI4736-1108 
includes a cohort that is evaluating MEDI4736 monotherapy in subjects with 
gastroesophageal cancer (Segal et al, 2014). As of 07May2015, out of 40 evaluable subjects 
with gastroesophageal cancer, there are 2 responses (1 CR and 1 PR). The DCR-24w was
15%. A Phase 2 study of tremelimumab monotherapy in second-line gastroesophageal 
subjects
 demonstrated clinical activity (4 SD, 1 PR; Ralph et al, 2010).
Rationale for Patient Selection Based on Tumoral IFN-γ Gene Expression
Signature
Another key objective of the current study is the understanding of potential biomarkers that 
are determinants of response and non-response to MEDI4736 and tremelimumab. Clinical 
trials and preclinical studies have demonstrated the predictive nature of an elevated Type 1 
helper T-cell (Th1) gene signature within the tumor and the subsequent response to 
immunotherapy for solid tumors (Ulloa-Montoya et al, 2013; Peng et al, 2015). IFN-γ is one 
of the hallmark cytokines, both initiating and propagating the Th1 response. Its expression is 
closely tied to other proteins and cytokines within the tumor microenvironment. Based on 
internal investigations, an IFN-γ gene expression panel was identified consisting of 4 genes 
that will be utilized to try and identify a unique population of gastric or GEJ adenocarcinoma
subjects who may benefit from treatment with immune checkpoint inhibitors and spare those 
who may experience toxicity.

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Benefit-risk Evaluation
The emerging data described above demonstrate encouraging clinical activity with 
MEDI4736 and tremelimumab in gastric or GEJ adenocarcinoma. These data combined with 
nonclinical data suggesting improved anticancer activity with the MEDI4736 and 
tremelimumab combination, as compared to either agent alone, make a compelling case for 
evaluation of this combination in gastric or GEJ adenocarcinoma. 
Possible risks are associated with agents such as MEDI4736 and tremelimumab that activate 
the immune system. The occurrence of irAEs, which is either overlapping or greater for each 
of these drugs when used as monotherapy, is possible. Potential irAEs may be similar to 
those seen with the use of ipilimumab, nivolumab, or the combination thereof, and may 
include immune-mediated enterocolitis, dermatitis, pneumonitis, hepatitis (hepatotoxicity), 
neurotoxicity, and endocrinopathies (Hodi et al, 2010; Brahmer et al, 2012; 
Topalian et al, 2012; Wolchok et al, 2013). Several strategies have been incorporated in the 
study protocol to mitigate these risks (Section 3.1.5).
Summary and Conclusion
The preliminary clinical activity of immune checkpoint inhibitors as monotherapy or 
combination therapy may provide alternative options for subjects with metastatic gastric 
cancer. Many of the AEs associated with immune checkpoint inhibitors are potentially 
reversible and can be managed (eg, IV steroids for diarrhea [Weber et al, 2012]). 
 
 
In conclusion, immune checkpoint inhibitors may offer patients with advanced gastric cancer 
in the second-line and third-line setting potential clinical benefit. In addition, further PD-L1 
expression (tumoral vs stromal) may identify a subset of patients who could benefit. Early 
evaluation of MEDI4736 and tremelimumab combination therapy appears to offer a balance 
between safety and clinical activity.
1.6
Research Hypothesis
MEDI4736 in combination with tremelimumab, MEDI4736 monotherapy, and 
tremelimumab monotherapy will be safe and demonstrate clinical activity in subjects with 
metastatic or recurrent gastric or GEJ adenocarcinoma.

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2
OBJECTIVES AND ENDPOINTS
2.1
Objectives
2.1.1
Primary Objectives
1. For Phase 1b: To assess the safety and tolerability, describe any DLTs, and determine the 
MTD or the highest protocol-defined doses (in the absence of exceeding the MTD) for 
MEDI4736 in combination with tremelimumab in subjects with metastatic or recurrent 
gastric or GEJ adenocarcinoma.
2. For Phase 2: To determine ORR and PFS at 6 months (PFS-6) based on RECIST v1.1
(Eisenhauer et al, 2009) as primary measures of clinical activity of MEDI4736 in 
combination with tremelimumab in second- and third-line subjects whose tumors have a 
positive IFN-γ gene expression signature and in unselected second- and third-line 
subjects, MEDI4736 monotherapy, and tremelimumab monotherapy in subjects with 
metastatic or recurrent gastric or GEJ adenocarcinoma.
2.1.2
Secondary Objectives
1. For Phase 1b: To assess DCR (defined as CR, PR, or SD), ORR, and PFS-6 based on 
RECIST v1.1 as measures of clinical activity of MEDI4736 in combination with 
tremelimumab in subjects with metastatic or recurrent gastric or GEJ adenocarcinoma.
2. For Phase 2: To further describe the safety and tolerability of MEDI4736 in combination 
with tremelimumab, MEDI4736 monotherapy, and tremelimumab monotherapy in 
subjects with metastatic or recurrent gastric or GEJ adenocarcinoma.
3. For Phase 2: To assess DCR and DoR based on RECIST v1.1, and OS as additional 
measures of clinical activity of MEDI4736 in combination with tremelimumab in second-
and third-line subjects whose tumors have a positive IFN-γ gene expression signature and 
in unselected second- and third-line subjects, MEDI4736 monotherapy, and
tremelimumab monotherapy in subjects with metastatic or recurrent gastric or GEJ 
adenocarcinoma.
4. For Phase 2: To define the components of PD-L1 expression (ie, tumoral vs stromal) that 
correlate with clinical activity of MEDI4736 in combination with tremelimumab, 
MEDI4736 monotherapy, and tremelimumab monotherapy in subjects with metastatic or 
recurrent gastric or GEJ adenocarcinoma.
 
 
 

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2.2
Study Endpoints
2.2.1
Primary Endpoints
1. For Phase 1b: Safety of MEDI4736 in combination with tremelimumab as assessed by 
the presence of AEs, SAEs, DLTs, laboratory parameters, vital signs, physical 
examination, and electrocardiogram (ECG) results.
2. For Phase 2: ORR and PFS-6 of MEDI4736 in combination with tremelimumab in 
second- and third-line subjects whose tumors have a positive IFN-γ gene expression 
signature and in unselected second- and third- line subjects, MEDI4736 monotherapy, 
and tremelimumab monotherapy based on RECIST v1.1. Response-based endpoints 
would be based on BICR if performed, or on investigator assessments.
2.2.2
Secondary Endpoints
1. For Phase 1b: Clinical activity of MEDI4736 in combination with tremelimumab as 
determined by ORR, DCR at 16 weeks (DCR-16w), DCR-24w, and PFS-6.
2. For Phase 2: Safety of MEDI4736 in combination with tremelimumab, MEDI4736 
monotherapy, and tremelimumab monotherapy as assessed by the presence of AEs, 
SAEs, laboratory parameters, vital signs, physical examination, and ECG results. 
3. For Phase 2: Clinical activity of MEDI4736 in combination with tremelimumab, 
MEDI4736 monotherapy, and tremelimumab monotherapy as determined by DCR-16w, 
DCR-24w, DoR, PFS,
based on RECIST v1.1, and OS and 
1-year survival. 

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4. For Phase 2: IFN-γ gene expression signature and how it correlates with clinical activity 
of MEDI4736 in combination with tremelimumab.
5. For Phase 2: PD-L1 expression and localization (by immunohistochemistry [IHC] or 
immunofluorescence [IF]) within the tumor microenvironment and how it correlates with 
clinical activity of MEDI4736 in combination with tremelimumab, MEDI4736 
monotherapy, and tremelimumab monotherapy.
 
 
 
 
 
 
 
 
 
 
3
STUDY DESIGN
3.1
Description of the Study
3.1.1
Overview……….
This is a randomized, multicenter, open-label, Phase 1b/2 study to evaluate the safety, 
tolerability, and clinical activity of MEDI4736 in combination with tremelimumab, 
MEDI4736 monotherapy, and tremelimumab monotherapy in subjects with metastatic or 
recurrent gastric or GEJ adenocarcinoma who meet the following criteria:

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Second-line (Phase 1b):
•
Must have received and have progressed, or are refractory to one systemic platinum- or 
fluoropyrimidine-based chemotherapy regimen for metastatic or recurrent disease, or
Second-line (Phase 2 Arms A, B, and C):
•
Must have received and have progressed, or are refractory to one systemic platinum- or 
fluoropyrimidine-based chemotherapy regimen for metastatic or recurrent disease, or
•
Must have received and have progressed, or are refractory to one systemic platinum- or 
fluoropyrimidine-based therapy as part of neoadjuvant or adjuvant regimen with relapse 
within 6 months of therapy, or
Third-line (Phase 2 Arm D)
•
Must have received and have progressed, or are refractory to two systemic regimens (one 
standard platinum- or fluoropyrimidine-based chemotherapy regimen and one approved 
regimen for metastatic or recurrent disease)
•
Subjects who have received and have progressed, or are refractory to one systemic 
platinum- or fluoropyrimidine-based therapy as part of neoadjuvant or adjuvant regimen
with relapse within 6 months will count as a line of therapy in the metastatic/recurrent 
setting.
Second- and Third-line (Phase 2 Arm E; as of Amendment 6):
•
Must have a positive IFN-γ gene expression signature
 
•
Must have received and have progressed, or are refractory to one systemic platinum- or 
fluoropyrimidine-based chemotherapy regimen for metastatic or recurrent disease, or
•
Must have received and have progressed, or are refractory to one systemic platinum- or 
fluoropyrimidine-based therapy as part of neoadjuvant or adjuvant regimen with relapse 
within 6 months of therapy, or
•
Must have received and have progressed, or are refractory to two systemic regimens (one
standard platinum- or fluoropyrimidine-based chemotherapy regimen and one approved 
regimen for metastatic or recurrent disease), and
•
Third-line subjects who have received and have progressed, or are refractory to one 
systemic platinum- or fluoropyrimidine-based therapy as part of neoadjuvant or adjuvant 
regimen with relapse within 6 months will count as a line of therapy in the 
metastatic/recurrent setting.
Up to approximately 135 subjects for Phase 1b/2 will be enrolled at approximately 40 study 
centers globally (Figure 3.1.1-1).

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Figure 3.1.1-1
Study Flow Diagram
GEJ = gastroesophageal junction;
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A safety run-in of up to 9 subjects will be conducted
 Subjects will 
be monitored for DLT prior to initiation of enrollment in Phase 2. If unacceptable toxicity is 
encountered or ≥3 out of 9 of subjects experience a DLT during this safety run-in, a lower 
dose level may be evaluated prior to initiation of Phase 2. 
Intermediate dose levels may be explored at the discretion of the sponsor based on emerging 
data. If unacceptable toxicity is encountered at the starting dose level, dose de-escalation will 
be permitted. 
 
 
 
.
A total of 6 subjects were enrolled in Phase 1b and treated 
 
The Phase 1b portion of the study is 
now complete.
Phase 2
Once the MTD or highest protocol-defined dose (in the absence of exceeding the MTD) has 
been defined in Phase 1b, enrollment in Phase 2 will begin. In Phase 2, subjects will be 
enrolled in 1 of 5 treatment arms, as listed below. Second-line subjects with metastatic or 
recurrent gastric or GEJ adenocarcinoma will be randomized in a 2:2:1 ratio to Arms A, B, or 
C. In parallel, third-line subjects with metastatic or recurrent gastric or GEJ adenocarcinoma 
will be enrolled in Arm D. Upon closure of Arms A, B, and C and completion of Arm D, 
second- and third-line subjects with metastatic or recurrent gastric or GEJ adenocarcinoma 
and a positive IFN-γ gene expression signature will be enrolled in Arm E.
•
Arm A: MEDI4736 in combination with tremelimumab in second-line subjects with 
metastatic or recurrent gastric or GEJ adenocarcinoma 
•
Arm B: MEDI4736 monotherapy in second-line subjects with metastatic or recurrent 
gastric or GEJ adenocarcinoma 
•
Arm C: Tremelimumab monotherapy in second-line subjects with metastatic or recurrent 
gastric or GEJ adenocarcinoma 
•
Arm D: MEDI4736 in combination with tremelimumab in third-line subjects with 
metastatic or recurrent gastric or GEJ adenocarcinoma 
•
Arm E (as of Amendment 6): MEDI4736 in combination with tremelimumab in second-
and third-line subjects with metastatic or recurrent gastric or GEJ adenocarcinoma and a 
positive IFN-γ gene expression signature 

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In Phase 2 of the study, PD-L1 expression will be monitored throughout the study so as to 
potentially balance enrollment based on PD-L1 status (as specified in the Laboratory Manual; 
see Section 4.8.2.2).
Subjects who are treated with MEDI4736 monotherapy (Arm B) or tremelimumab 
monotherapy (Arm C) may crossover to be treated with MEDI4736 in combination with 
tremelimumab upon a confirmed progressive disease (PD) under restricted circumstances 
(see Section 3.1.2.4). 
Subjects in both Phase 1b and Phase 2 who derived clinical benefit from study treatment 
during the initial 12-month treatment period and who subsequently developed PD during the 
12 month follow-up period, will be treated for up to 12 months with the same regimen that 
the subject was given upon initial study entry (see Section 3.1.2.4). Dose delays and 
discontinuations to manage clinically significant treatment-related toxicity will be allowed.
All subjects will be evaluated for clinical activity, on a regular basis as specified in the 
protocol (Section 4.2), and their disease status primarily analyzed according to RECIST v1.1. 
Clinical decision making in subjects undergoing treatment will be based on RECIST v1.1 
with modifications. Enrollment into any arm of Phase 2 may be discontinued at the discretion 
of the sponsor should emerging clinical or nonclinical data suggest that continued treatment 
may not be beneficial to a given arm.
At the time of this amendment, a total of 89 subjects have been enrolled in Phase 2 in 
Arms A
 B 
 C (
 and D 
. Pre-specified interim analyses 
performed on Arms A and B showed that the criteria for expansion were met; however,
enrollment into Arms A, B, and C was stopped at the sponsor’s discretion. Based on evolving 
science suggesting that the IFN-γ gene expression signature will better predict responders of 
immunotherapy (Ulloa-Montoya et al, 2013; Peng et al, 2015) as well as data from the initial 
portion of the study, it was decided to proceed with MEDI4736 in combination with 
tremelimumab in both second- and third-line subjects with metastatic or recurrent gastric or 
GEJ adenocarcinoma who had a positive IFN-γ gene expression signature. The 
discontinuation of Arms A, B, and C was not due to safety concerns. Arm D has completed.
Dose-Expansion in a Biomarker Selected Population
As of Amendment 6, a new arm (Arm E) of MEDI4736 in combination with tremelimumab 
has been added to evaluate efficacy and safety in subjects with second- and third-line gastric 
or GEJ adenocarcinoma with a positive tumor IFN-γ gene expression signature. Numerous 
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subsequent response to immunotherapy for solid tumors
All subjects will be followed for survival until the end of 
study (5 years after the last subject is enrolled or the date the study is closed by the sponsor, 
whichever occurs first). Evaluation of a possible correlation between clinical activity of 
MEDI4736 and tremelimumab in combination and IFN-γ gene expression as well as other 
potential biomarkers (eg, tumoral and stromal PD-L1 expression) will be ongoing throughout 
the study.
The endpoints to be measured in this study are described in Section 2.2.
 
 
 
 
 
 
 
 
 
 
 
 

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3.1.2.4
Criteria for Treatment Beyond Progression, Crossover, and Retreatment in 
the Follow-up Period
Treatment Beyond Progression
For subjects in all arms and treatment periods, if PD (based on RECIST v1.1) occurs before 
completion of the treatment period, the subject may continue to be treated with the regimen 
they initially received after study enrollment (unless they have crossed over to the 
combination regimen at which time the subject would continue the combination regimen) 
until one of the following criteria is met:
1. Confirmed PD: The assessment of PD by RECIST v1.1 (baseline PD assessment) will be 
confirmed by a repeat evaluation at the next tumor assessment time point, but no sooner 
than 4 weeks later. If any subsequent tumor assessment time point shows ≥ 20% increase 
in the overall tumor burden (the sum of diameters of target lesions and new lesions), 
when compared to the baseline PD assessment (the sum of diameters of target lesions and 
new lesions), the subject would be deemed as having confirmed PD. 
a.
Note: Subjects in Arm B (MEDI4736 monotherapy) and Arm C (tremelimumab 
monotherapy) of Phase 2 who experience a confirmed PD (as defined above) will 
have the option (on a case-by-case basis) to crossover to treatment with MEDI4736 in 
combination with tremelimumab (using the Phase 2 schedule) for 12 months or until a 
second confirmed PD. Crossover will be permitted as long as the treatment beyond 
progression criteria are met and any of the investigational product discontinuation 
criteria (with the exception of criterion number 10 in Section 4.1.6) are not met. If 
crossover is not chosen by the investigator, then the study treatment must be 
discontinued.
b. Note: Subjects with confirmed PD during 12 months of treatment with MEDI4736 in 
combination with tremelimumab (Phase 1b, and Arms A and D, and E of Phase 2) 
may not crossover to either MEDI4736 monotherapy or tremelimumab monotherapy 
at any time. Subjects enrolled in Phase 1b, and Arms A, D, and E of Phase 2 who 
exhibit confirmed PD after completing the planned 4 doses of combination treatment, 
but prior to completing the 12-month dosing period (ie, while receiving MEDI4736 
monotherapy) may be eligible for reinduction (on a case-by-case basis) with 
combination therapy and continued treatment for an additional 12 months (or until the 
subject meets any of the discontinuation criteria listed below). The subject would be 
readministered investigational products according to the same treatment guidelines 
followed during their initial treatment. Subjects who are enrolled in Phase 1b and 
Arms A, D, and E of Phase 2 and who exhibit disease progression prior to completing 
the planned 4 doses of combination treatment may be eligible for continued treatment 
through the end of the planned 12-month treatment period (or until the subject meets 
any of the discontinuation criteria listed below), but will not be eligible for 
reinduction.
2. Meets any of the investigational product discontinuation criteria (Section 4.1.6).
3. Clinical symptoms or signs indicating clinically significant PD such as the benefit-risk 
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4. Decline in Eastern Cooperative Oncology Group (ECOG) performance status compared 
to baseline.
5. Rapid PD or threat to vital organs/critical anatomical sites (eg, spinal cord compression) 
requiring urgent alternative medical intervention, and/or continuation of study therapy 
would prevent institution of such intervention.
Retreatment for Subjects Who Enter Follow-up
Subjects enrolled in both Phase 1b and Phase 2 who achieve and maintain DC (ie, CR, PR, or 
SD) through the end of the initial 12-month treatment period will enter a follow-up period. 
Only those subjects who progress during the initial 12 months of the follow-up period will be 
eligible for retreatment for up to 12 months with the same regimen that the subject was given 
upon initial study entry. As there is preliminary data from other immunotherapy studies that 
subjects who initially derive clinical benefit from immunotherapy can derive benefit again 
once the subject has PD while off therapy (Wolchok et al, 2013; Hamid et al, 2013), the 
protocol will allow retreatment during the follow-up period with the same regimen that the 
subjects received when initially enrolled in the study if all the following criteria are met:
1. Has not received other anticancer treatments for their disease.
2. Does not meet any of the investigational product discontinuation criteria (Section 4.1.6).
3. Absence of clinical symptoms or signs indicating clinically significant disease 
progression.
4. No decline in ECOG performance status compared to baseline.
5. Absence of rapid PD or threat to vital organs/critical anatomical sites (eg, spinal cord 
compression) requiring urgent alternative medical intervention.
6. All AEs while receiving initial therapy must have resolved to ≤ Grade 1 or baseline. Must 
not have experienced a ≥ Grade 3 AE or neurologic or ocular AE of any grade while 
receiving initial therapy. Note: Subjects with an endocrine AE of any grade are permitted 
to be retreated if they are stably maintained on appropriate replacement therapy and are 
asymptomatic.
7. Must not have used additional immunosuppression other than corticosteroids for the 
management of an AE, must not have experienced recurrence of an AE if re-challenged, 
and not currently require maintenance doses > 10 mg prednisone or equivalent per day.
Subjects will be made aware of the potential benefits and risks of continuing the study 
regimens in the setting of PD by providing separate written informed consent.
3.1.3
Phase 1b……….
The Phase 1b portion of the study has been described in Section 3.1.1.
A total of 6 subjects were enrolled in Phase 1b; this portion of the study is now complete.
f 6 

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3.1.3.1
Dose-exploration Criteria for Phase 1b
Safety Run-in Rules 
1. A minimum of 6 subjects will be enrolled in the safety run-in.
a.
If 2 DLTs occur in the first 6 subjects, an additional 3 subjects will be enrolled. 
b. If ≥ 3 of 9 subjects experience DLTs, lower dose levels will be evaluated.
2. Dose-limiting toxicity will be evaluated during the DLT evaluation period (as defined in 
Section 3.1.3.2).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3.1.3.2
Dose-limiting Toxicity
Dose-limiting toxicity will be evaluated during the DLT evaluation period in Phase 1b. 
 
 
 
 
 
Subjects who do not remain on the study up to this time for reasons other than DLT will be 
replaced with another subject at the same dose level. Dose-limiting toxicity will be graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) v4.03.
A DLT will be defined as any Grade 3 or higher toxicity that occurs during the DLT 
evaluation period. Toxicity that is clearly and directly related to the primary disease or to 
another etiology is excluded from this definition. The following will be DLTs:
•
Any Grade 4 irAE
•
Any ≥ Grade 3 colitis
•
Any Grade 3 or 4 noninfectious pneumonitis irrespective of duration
•
Any Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the 
initiation of maximal supportive care
•
Any Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to Grade 2 
within 3 days after onset of the event despite optimal medical management including 
systemic corticosteroids or does not downgrade to ≤ Grade 1 or baseline within 14 days
•
Liver transaminase elevation > 8 × ULN or total bilirubin > 5 × ULN
•
Any ≥ Grade 3 non-irAE, except for the exclusions listed below
The definition excludes the following conditions: 
•
Grade 3 fatigue lasting ≤ 7 days
•
Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replacement 
therapy and the subject is asymptomatic
•
Grade 3 inflammatory reaction attributed to a local antitumor response (eg, inflammatory 
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•
Concurrent vitiligo or alopecia of any AE grade
•
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management
•
Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that 
improves by at least 1 grade within 3 days. Grade 3 or Grade 4 febrile neutropenia will be 
a DLT regardless of duration or reversibility
•
Grade 3 or 4 lymphopenia
•
Grade 3 thrombocytopenia that is not associated with clinically significant bleeding that 
requires medical intervention, and improves by at least 1 grade within 3 days
•
Isolated Grade 3 elevations in amylase and/or lipase that are not associated with clinical 
signs or symptoms or radiographic features suggestive of pancreatitis 
•
Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention within 3 days
Immune-related AEs are defined as AEs of an immune nature (ie, inflammatory) in the 
absence of a clear alternative etiology. In the absence of a clinically significant abnormality, 
repeat laboratory testing will be conducted to confirm significant laboratory findings prior to 
designation as a DLT.
While the rules for adjudicating DLTs in the context of dose escalation specified above, an 
AE not listed above may be defined as a DLT after a consultation with the sponsor and 
investigators, based on the emerging safety profile.
3.1.3.3
Maximum Tolerated Dose
The MTD is defined as the highest dose within a cohort where no more than 1 of 6 subjects
(or less than one-third of subjects if the cohort is larger than 6 subjects) experiences a DLT. 
This will be determined during Phase 1b based on the assessment of DLT during the DLT 
evaluation period, as defined in Section 3.1.3.2.

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3.1.4
Phase 2……….
At the time of this amendment, a total of 
 subjects have been enrolled in Phase 2 in 
Arms A 
 B 
 C
 and D 
 Pre-specified interim analyses 
performed on Arms A and B showed that the criteria for expansion were met; however,
enrollment to Arms A, B, and C was stopped at the sponsor’s discretion. It was decided to 
proceed with MEDI4736 in combination with tremelimumab only in second- and third-line 
subjects with metastatic or recurrent gastric or GEJ adenocarcinoma who had a positive 
IFN-γ gene expression signature. The discontinuation of Arms A, B, and C was not due to 
safety concerns. Arm D has completed.
As described in Section 3.1.1, Phase 2 will include the following 5 treatment arms:
•
Arm A: MEDI4736 in combination with tremelimumab in second-line subjects with 
metastatic or recurrent gastric or GEJ adenocarcinoma
•
Arm B: MEDI4736 monotherapy in second-line subjects with metastatic or recurrent 
gastric or GEJ adenocarcinoma 
•
Arm C: Tremelimumab monotherapy in second-line subjects with metastatic or recurrent 
gastric or GEJ adenocarcinoma
)
•
Arm D: MEDI4736 in combination with tremelimumab in third-line subjects with 
metastatic or recurrent gastric or GEJ adenocarcinoma
•
Arm E (as of Amendment 6): MEDI4736 in combination with tremelimumab in second-
and third-line subjects with metastatic or recurrent gastric or GEJ adenocarcinoma and a 
positive IFN-γ gene expression signature 
During Phase 2, subjects will be monitored continuously for safety according to the same 
criteria employed during Phase 1b. If during the treatment period, ≥ 33% of subjects 
experience safety events meeting DLT criteria, even if outside of the DLT evaluation period 
(see Section 3.1.3.2), enrollment may be paused and study data will be reviewed to determine 
whether additional monitoring or alternate dose levels or treatment schedules should be 
evaluated prior to further enrollment. In addition, after the first 20 subjects have been dosed 
with MEDI4736 in combination with tremelimumab for a minimum of 6 weeks (in both 
second- and third-line settings), safety data will be reviewed by the sponsor.
3.1.5
Management of Study Medication Related Toxicities
Based on the mechanism of action of MEDI4736 and tremelimumab leading to T-cell 
activation and proliferation, there is the possibility of observing irAEs during the conduct of 
this study. Potential irAEs may be similar to those seen with the use of ipilimumab, 
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hepatitis, and endocrinopathies (Hodi et al, 2010; Brahmer et al, 2012; Topalian et al 2012; 
Wolchok et al, 2013). Subjects should be monitored for signs and symptoms of irAEs. In the 
absence of an alternate etiology (eg, infection or PD), an immune-related etiology should be 
considered for signs or symptoms of enterocolitis, dermatitis, hepatitis, and endocrinopathy. 
In addition to the dose modifications shown in Appendix 5, it is recommended that 
management of irAEs follow the guidelines outlined for ipilimumab (Weber J et al, 2012). 
If the investigator has any question in regards to an AE being an irAE, the investigator 
should immediately contact the medical monitor. Dose modifications may be required for 
AEs that are clearly not attributed to MEDI4736 or tremelimumab (such as an accident) or 
for laboratory abnormalities that are deemed asymptomatic, require no intervention, and are 
documented in the medical records. Laboratory abnormalities that are felt to meet these 
criteria must be discussed and agreed on by the medical monitor before treatment can be 
continued. Dose reductions of MEDI4736 and tremelimumab are not permitted.
Dose interruptions of MEDI4736 and tremelimumab may be required in the event of 
treatment-related toxicity. General guidelines regarding dose modifications are provided in
Appendix 5. In addition, management guidelines for AESIs are detailed in Section 5.3. All 
toxicities will be graded according to NCI CTCAE v4.03. In case of doubt the investigator 
should consult with the medical monitor.
 
 
 
 
 
 
 
 
 
 
 

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3.2.2
Rationale for Study Population
The proposed study population, comprising adult subjects with metastatic or recurrent gastric 
or GEJ adenocarcinoma that have progressed during or after 1 or 2 prior standard regimens
for recurrent or metastatic disease, represents a high unmet medical need. This tumor 
indication, described below, presents an opportunity for novel treatment approaches that may 
lead to improved clinical outcomes.
In 2014, it is estimated that 22,220 and 18,170 people will be newly diagnosed with gastric 
cancer and esophageal cancer, respectively, whereas 26,440 individuals will die due to upper 
GI tumors (Siegel et al, 2014). Gastroesophageal cancer remains endemic in many parts of 
the world, with an estimated new cancer incidence of 1,471,000 people or 11.6% of the 
global cancer burden and an annual death rate of 1,144,000 people or 15.1% of 
cancer-related deaths worldwide (Ferlay et al, 2010). Globally, gastric cancer is the second 
leading cause of cancer-related mortality (Luis et al, 2013). 
Current therapeutic strategies for advanced gastric or GEJ adenocarcinoma are limited, and 
survival rarely exceeds 1 year despite aggressive treatment with chemotherapy. A number of 
different drugs (eg, alkylating agents, platinum compounds, 5-fluorouracil [5-FU], and 
taxanes) are available for the treatment of gastroesophageal cancer, but no means of selecting 
therapy based on the tumor biology is currently available. At present, the combination of a 

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platinum and fluorouracil agent either alone or in combination with a third drug such as 
epirubicin or taxane constitutes the most effective treatment option in the first-line metastatic 
setting (Cunningham et al, 2008). Standard first-line options include docetaxel, cisplatin, and 
5-FU; epirubicin, cisplatin, and capecitabine/epirubicin, oxaliplatin, and capecitabine; or 
folinic acid, 5-FU, and oxaliplatin. 
The vascular endothelial growth factor receptor 2 antagonist, ramucirumab, as evaluated in 
the REGARD study and recently approved by the US FDA, has demonstrated modest activity 
in subjects with advanced gastric or GEJ adenocarcinoma who progressed after first-line 
platinum- or fluoropyrimidine-containing chemotherapy (Fuchs et al, 2014). Median OS was 
5.2 months in the ramucirumab group versus 3.8 months in the placebo group (HR 0.776, 
95% confidence interval [CI], 0.603-0.998; p = 0.047). In the RAINBOW study, more than 
600 subjects with metastatic gastric or GEJ adenocarcinoma who had disease progression on 
or within 4 months after first-line platinum- and fluoropyrimidine-based combination therapy 
were randomized to paclitaxel plus ramucirumab or paclitaxel alone (Wilke et al, 2014).
Median OS was 9.63 months and 7.36 months, respectively (HR 0.807; 95% CI, 0.678-0.962; 
p = 0.017), and median PFS was 4.40 and 2.86 months, respectively (HR 0.635; 95% CI, 
0.536-0.752; p < 0.0001). Median time to progression was 5.5 months with ramucirumab 
plus paclitaxel versus 3.0 months with paclitaxel alone (p < 0.0001), and ORR was 28% 
versus 16%, respectively (p = 0.0001). Based on these results, the combination of 
ramucirumab plus paclitaxel is expected to become the standard of care in the second-line 
setting for metastatic upper GI tumors.
Additional FDA-approved second-line agents include docetaxel and irinotecan. In the 
COUGAR-02 study, median OS was 5.2 months with docetaxel compared with 3.6 months 
with best supportive care (BSC; HR 0.67; 95% CI, 0.49–0.92; p = 0.01; Ford et al, 2014). 
Kang and colleagues evaluated chemotherapy (docetaxel 60 mg/m2 every 3 weeks or 
irinotecan 150 mg/m2 Q2W) plus BSC versus BSC alone in subjects with advanced gastric 
cancer who received 1 or 2 prior fluoropyrimidine- and platinum-based chemotherapy 
regimens (Kang et al, 2012). The median OS was 5.3 months with chemotherapy plus BSC 
(n = 133) versus 3.8 months with BSC alone (n = 69; HR 0.657; 95% CI, 0.485-0.891; 
p = 0.007). There was no median OS difference between docetaxel and irinotecan (5.2 versus
6.5 months, respectively; p = 0.116). Despite these advances, the toxicity profile of 
second-line agents is poor and survival is still between 6 to 9 months. Consequently, 
immunotherapies hold potential promise in this setting.
To date, a number of Asian studies have investigated PD-L1 expression in gastric cancer. 
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They reported significant upregulation of PD-L1 in advanced gastric cancer patients 
compared with healthy people (p = 0.006; Zheng et al, 2014). The expression of PD-L1 was 
significantly correlated with differentiation (p = 0.026) and lymph node metastasis 
(p = 0.041). Wu and colleagues examined PD-L1 expression in cases of human gastric 
carcinoma (n = 102), adenoma (n = 10), and normal tissues (n = 10; Wu et al, 2006). 
Programmed cell death ligand 1 was not detected in normal gastric tissues, and very weak 
immunodetection in gastric adenomas, but PD-L1 was detected in 42.2% of gastric 
carcinoma tissues. There was no correlation between PD-L1 immunolocalization and patient 
age, sex, tumor location, or the degree of tumor differentiation in gastric carcinomas. 
However, PD-L1 immunodetection was significantly correlated with tumor size, invasion, 
lymph node metastasis, and survival time. Multivariate analysis demonstrated that PD-L1 
immunodetection could be used as an independent factor to evaluate the prognosis of gastric 
carcinoma. 
3.2.3
Rationale for Endpoints
Safety
Standard safety parameters (AEs, SAEs, laboratory evaluations, vital signs, ECGs, and 
physical examinations) will be employed to assess the safety profile of MEDI4736 in 
combination with tremelimumab, MEDI4736 monotherapy, and tremelimumab monotherapy.
Primary and Secondary Efficacy Assessments
OR and DC as assessed by RECIST v1.1 (Eisenhauer et al, 2009) per blinded central review, 
are standard measures of clinical activity. OS is considered the “gold standard” for 
quantifying clinical benefit, with PFS being an acceptable surrogate. In the Phase 2 portion of 
the study, blinded central review will be performed to confirm response data. 
Tumoral IFN-γ Gene Expression Signature
Clinical trials and preclinical studies have demonstrated the predictive nature of an elevated 
Th1 gene signature within the tumor and the subsequent response to immunotherapy for solid 
tumors (Ulloa-Montoya et al, 2013; Peng et al, 2015). IFN-γ is one of the hallmark cytokines, 
both initiating and propagating the Th1 response. Its expression is closely tied to other 
proteins and cytokines within the tumor microenvironment. Based on internal investigations, 
an IFN-γ gene expression panel was identified consisting of 4 genes that will be utilized to 
try and identify a unique population of gastric or GEJ adenocarcinoma subjects who may 
benefit from treatment with immune checkpoint inhibitors and to identify correlations 
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tremelimumab. IFN-γ gene expression testing will be performed for all Phase 2 treatment 
cohorts; retrospective testing will be performed as necessary.
PD-L1 Expression
In Study CD-ON-MEDI4736-1108, as of 21Aug2014, the DCR at 12 weeks (DCR-12w) was 
33% (115/352 subjects) and ORR was 10% (36/352 subjects) in subjects (across 8 tumor 
types) treated with MEDI4736 10 mg/kg Q2W (Segal et al, 2014). Greater DCR-12w (47% 
vs 28%) and ORR (22% vs 5%) were observed in PD-L1-positive versus PD-L1-negative 
subjects, based on a proprietary IHC assay which detects PD-L1 staining on tumor cells.
Of the 41 subjects with gastroesophageal cancer who have been dosed in 
Study CD-ON-MEDI4736-1108, 28 were evaluable for efficacy analysis (Segal et al, 2014). 
In these subjects, DCR-12w was 25% (7/28 subjects). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Collection of Subject Selection Biomarker Data
Candidate biomarkers for subject selection will be assessed to determine whether these 
markers predict which subjects are most likely to respond to treatment with MEDI4736 in 
combination with tremelimumab, MEDI4736 monotherapy, or tremelimumab monotherapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4
MATERIALS AND METHODS
4.1
Subjects
4.1.1
Number of Subjects
Up to approximately 135 subjects in Phase 1b/2 will be enrolled at up to approximately 
40 study centers globally. Additional subjects may be enrolled if dose de-escalation is 
required or intermediate dose levels are explored.
4.1.2
Inclusion Criteria
Subjects must meet all of the following criteria:
1. Male or female subjects; age ≥ 18 years at the time of screening or age of consent 
according to local law.
2. Written informed consent and any locally required authorization, Health Insurance and 
Portability and Accountability Act in the US, European Union (EU) Data Privacy 
Directive in the EU obtained from the subject/legal representative prior to performing any 
protocol-related procedures, including screening evaluations.
3. ECOG performance status of 0 or 1. 
4. Histologically or cytologically confirmed metastatic or recurrent gastric or GEJ 
adenocarcinomas. Note: GEJ adenocarcinomas are defined as tumors that have their 
center within 5 cm proximal and distal of the anatomical cardia, as described in the 
Siewert classification system (Siewert et al, 2000).
5. Prior lines of therapy:
a.
For Phase 1b: Must have received and have progressed, or are refractory to one
systemic platinum- or fluoropyrimidine-based chemotherapy regimen for metastatic 
or recurrent disease.
b. For Arms A, B, and C of Phase 2: Must have received and have progressed, or are 
refractory to one systemic platinum- or fluoropyrimidine-based chemotherapy 
regimen for metastatic or recurrent disease, or 
Must have received and have progressed, or are refractory to one systemic platinum 
or fluoropyrimidine-based therapy as part of neoadjuvant or adjuvant regimen with 
relapse within 6 months of therapy.
c.
For Arm D of Phase 2: Must have received and have progressed, or are refractory to 
two systemic regimens (one standard platinum- or fluoropyrimidine-based 
chemotherapy regimen and one approved regimen) for metastatic or recurrent disease.

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d. For Arm E of Phase 2: Subjects with a positive IFN-γ gene expression signature (as
defined in Section 4.3.8.1) must have received and have progressed, or are refractory 
to one systemic platinum- or fluoropyrimidine-based chemotherapy regimen for
metastatic or recurrent disease, or 
Must have received and have progressed, or are refractory to one systemic platinum-
or fluoropyrimidine-based therapy as part of neoadjuvant or adjuvant regimen with 
relapse within 6 months of therapy, or
Must have received and have progressed, or are refractory to two systemic regimens 
(one standard platinum- or fluoropyrimidine-based chemotherapy regimen and one 
approved regimen for metastatic or recurrent disease).
e.
Subjects who have received and have progressed, or are refractory to one systemic 
platinum- or fluoropyrimidine-based therapy as part of neoadjuvant or adjuvant 
regimen with relapse within 6 months will count as a line of therapy in the 
metastatic/recurrent setting.
6. Screening for IFN-γ expression prior to Arm E enrollment:
a.
Subjects who are being considered for enrollment on Arm E may undergo 
pre-screening for IFN-γ gene expression either at the time of disease progression or 
after having completed a minimum of 60 days of the prior line of systemic therapy. In 
addition, they should meet all other eligibility criteria for enrollment, with the 
exception of prior lines of therapy if they are being screened during first-or 
second-line treatment.
b. Subjects enrolling to Arm E must consent to provide archival tumor tissue for IFN-γ
testing. Only subjects with a positive IFN-γ gene expression signature (as defined in 
Section 4.3.8.1) will be eligible for enrollment to Arm E. IFN-γ testing must be 
completed to determine enrollment eligibility prior to initiation of therapy. If eligible, 
subjects must consent to initial and subsequent tumor biopsy samples, if possible.
7. Subjects must have at least one measurable lesion according to RECIST v1.1. 
a.
A previously irradiated lesion can be considered a target lesion if the lesion is well 
defined, measurable and there is objective evidence of interval increase in size.
8. Subjects must have at least one lesion amenable to biopsy and must consent to and 
provide both pre-treatment and on-treatment tumor biopsies for Phase 2 (optional for 
Phase 1b). Fresh tumor biopsies should be preferentially obtained from tumor tissues that 
are safely accessible as determined by the investigator and achieved via non-significant 
risk procedures (refer to Section 4.3.2.1). Tumor lesions used for biopsy should not be 
lesions used as RECIST target lesions. Sites are encouraged to confirm adequacy of 
tumor biopsy material at the time of the procedure. 
9. Subjects must consent to provide archival tumor tissue (initial and subsequent tumor 
biopsy samples, if possible) for correlative biomarker studies (for both Phase 1b and 2), if 
available. Availability of tissue for transfer to sponsor should be confirmed prior to 
initiation of study therapy.
10. Adequate organ and marrow function, as defined below. Criteria “a,” “b,” and “c” cannot 
be met with ongoing or recent blood transfusions (within 14 days of starting first dose) or 
require growth factor support (within 28 days of starting the first dose)
a.
Hemoglobin ≥ 8 g/dL 

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b. Absolute neutrophil count ≥ 1,500/μL
c.
Platelet count ≥ 100,000/μL
d. Total bilirubin ≤ 1.5 × ULN except subjects with documented Gilbert’s syndrome 
(> 3 × ULN)
e.
ALT and AST ≤ 3 × ULN
f.
Calculated creatinine clearance ≥50 mL/minute as determined by Cockcroft-Gault 
(using actual body weight) or 24-hour urine creatinine clearance
11. Female patients of child-bearing potential: Female subjects of childbearing potential who 
are sexually active with a non-sterilized male partner must use at least one highly
effective method of contraception (Table 4.1.2-1) from the time of screening, and must 
agree to continue using such precautions for 180 days after the last dose of MEDI4736 + 
tremelimumab combination therapy or 90 days after the last dose of MEDI4736
monotherapy. Non-sterilised male partners of a female subject must use male condom 
plus spermicide throughout this period. Cessation of birth control after this point should 
be discussed with a responsible physician. Not engaging in sexual activity for the total 
duration of the drug treatment and the drug washout period is an acceptable practice; 
however, periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. Female subjects should refrain from breastfeeding 
throughout this period.
a.
Females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
post-menopausal
Women will be considered post-menopausal if they have been amenorrheic for 
12 months without an alternative medical cause. The following age-specific 
requirements apply:
i.
Women < 50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy). 
ii. Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses > 1 year 
ago, had chemotherapy-induced menopause with last menses > 1 year ago, or 
underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy).
b. Highly effective methods of contraception, defined as one that results in a low failure 
rate (ie, less than 1% per year) when used consistently and correctly are described in 
Table 4.1.2-1. Note that some contraception methods are not considered highly 
effective (eg, male or female condom with or without spermicide; female cap, 
diaphragm, or sponge with or without spermicide; non-copper containing intrauterine 
device; progestogen-only oral hormonal contraceptive pills where inhibition of 
ovulation is not the primary mode of action [excluding Cerazette/desogestrel which is 
considered highly effective]; and triphasic combined oral contraceptive pills). 

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12. Male patients with a female partner of childbearing potential
a.
Non-sterilized male subjects who are sexually active with a female partner of 
childbearing potential must use male condom plus spermicide from screening through 
180 days after receipt of the final dose of MEDI4736 + tremelimumab combination 
therapy or 90 days after receipt of the final dose of MEDI4736 monotherapy. Not 
engaging in sexual activity is an acceptable practice; however, occasional abstinence, 
the rhythm method, and the withdrawal method are not acceptable methods of 
contraception. Male subjects should refrain from sperm donation throughout this 
period. 
b. Female partners (of childbearing potential) of a male subject must use a highly 
effective method of contraception throughout this period (Table 4.1.2-1).
Table 4.1.2-1
Highly Effectivea Methods of Contraception (< 1% failure 
rate)
Barrier Methods
Hormonal Methods
•
Copper T intrauterine device
•
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®) a
•
Implants: Etonogestrel implants: eg, Implanon® or 
Norplan®
•
Intravaginal device: eg ethinylestradiol / 
etonogestrel-releasing intravaginal devices: eg,
NuvaRing®  
•
Injection: Medroxyprogesterone injection: eg,
Depo-Provera®
•
Combined Pill: Normal and low dose combined 
oral contraceptive pill
•
Patch: Norelgestromin/ethinylestradiol-releasing
transdermal system: eg, Ortho Evra®
•
Minipill: Progesterone based oral contraceptive pill 
using desogestrel: Cerazette® is currently the only 
highly effective progesterone based pill
a
This is also considered a hormonal method.
13. All patients: Patients should not donate blood or blood components while participating in 
this study and through 180 days after receipt of the final dose of MEDI4736 + 
tremelimumab combination therapy or 90 days after receipt of the final dose of 
MEDI4736 or tremelimumab.

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4.1.3
Exclusion Criteria
Any of the following would exclude the subject from participation in the study:
1. Subjects with HER2-overexpressing metastatic or recurrent gastric or GEJ 
adenocarcinomas. Note: Subjects whose tumor HER2-expression status is not known 
must submit tumor samples for HER2 testing, which can be done locally prior to 
screening and consent.
2. Subjects with ascites that require active ongoing paracentesis (within 4 weeks prior to the 
first scheduled dose) to control their disease. 
3. Prior exposure to immunotherapy, including, but not limited to, other anti-CTLA-4, 
anti-PD-1, or anti-PD-L1 mAbs.
4. Known allergy or hypersensitivity to study drug formulations.
5. Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis, Crohn’s disease], diverticulitis with the 
exception of a prior episode that has resolved or diverticulosis, celiac disease, irritable 
bowel disease, or other serious GI chronic conditions associated with diarrhea; systemic 
lupus erythematosus; Wegener syndrome [granulomatosis with polyangiitis]; myasthenia 
gravis; Graves’ disease; rheumatoid arthritis, hypophysitis, uveitis, etc) within the past 
3 years prior to the start of treatment. The following are exceptions to this criterion: 
a.
Subjects with vitiligo or alopecia. 
b. Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement or psoriasis not requiring systemic treatment.
6. Untreated central nervous system (CNS) metastatic disease, leptomeningeal disease, or 
cord compression. Note: Subjects previously treated for CNS metastases that are 
radiographically and neurologically stable for at least 4 weeks and do not require 
corticosteroids (of any dose) for symptomatic management for at least 14 days prior to 
the first dose of MEDI4736 or tremelimumab are not excluded.
7. Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study or the follow-up period of an interventional study.
8. Receipt of any conventional or investigational anticancer therapy not otherwise specified 
above within 28 days prior to the first dose of MEDI4736 or tremelimumab.
9. Any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for 
cancer treatment. Concurrent use of hormones for noncancer-related conditions 
(eg, insulin for diabetes and hormone replacement therapy) is acceptable. In addition, 
local treatment (eg, by local surgery or radiotherapy) of isolated lesions for palliative 
intent is acceptable beyond the DLT evaluation period with prior consultation and in 
agreement with the medical monitor.
10. Any toxicity from prior therapy that has not been completely resolved to baseline at the 
time of consent. Subjects with NCI CTCAE v4.03 Grade 1 or 2 toxicities that are deemed 
stable or irreversible can be enrolled on a case-by-case basis with prior consultation and 
agreement with the medical monitor.

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11. Current or prior use of immunosuppressive medication within 14 days prior to the first 
dose of MEDI4736 or tremelimumab. The following are exceptions to this criterion:
a.
Intranasal, topical, inhaled corticosteroids or local steroid injections (eg, intra-
articular injection).
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or equivalent.
c.
Steroids as premedication for hypersensitivity reactions (eg, computed tomography 
[CT] scan premedication).
12. History of primary immunodeficiency, solid organ transplantation.
13. Known positive for human immunodeficiency virus (HIV), chronic or active hepatitis B 
or C or active hepatitis A.
14. Receipt of live, attenuated vaccine within 28 days prior to the first dose of investigational 
products (Note: Subjects, if enrolled, should not receive live vaccine during the study and 
180 days after the last dose of investigational product[s]). Vaccination with a killed 
vaccine is permitted at any time with consultation with the medical monitor.
15. Females who are pregnant, lactating, or intend to become pregnant during their
participation in the study.
16. Major surgery (as defined by the investigator) within 28 days prior to first dose of 
MEDI4736 or tremelimumab or still recovering from prior surgery. Local procedures 
(eg, placement of a systemic port, core needle biopsy, and prostate biopsy) are allowed if 
completed at least 24 hours prior to the administration of the first dose of study treatment. 
17. Other invasive malignancy within 2 years except for noninvasive malignancies such as 
cervical carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma of the 
skin, ductal carcinoma in situ of the breast that has been surgically cured.
18. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina 
pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, or psychiatric 
illness/social situations that would limit compliance with study requirement, substantially 
increase risk of incurring AEs from MEDI4736 or tremelimumab, or compromise the 
ability of the subject to give written informed consent.
19. Any condition that, in the opinion of the investigator or sponsor, would interfere with 
evaluation of the investigational products or interpretation of subject safety or study 
results.
20. Subjects who are involuntarily incarcerated or are unable to willingly provide consent or 
are unable to comply with the protocol procedures.
4.1.4
Subject Enrollment and Randomization
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained. Once informed consent is obtained, a subject identification (SID) number will be 
assigned by a central system (eg, an interactive response system [IXRS]), and the 
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(inclusion/exclusion) criteria. The SID number will be used to identify the subject during the 
pre-screening/screening process and throughout study participation. 
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria), 
including the reason(s) for screening failure.
Subjects who fail to meet the inclusion/exclusion criteria (ie, screening failures) should not 
receive investigational products. There can be no exceptions to this rule. Subjects who are 
screening failures should be withdrawn from the study.
4.1.5
Withdrawal from the Study
Subjects are free to withdraw their consent to participate in the study (investigational product 
and assessments) at any time without prejudice to further treatment. Subjects who withdraw 
consent will be asked about the reason(s) and the presence of any AEs. If the subject is
willing, the subject will be seen and assessed by the investigator. AEs will be followed up. If 
a subject withdraws from further participation in the study, then no further study visits or 
data collection should take place.
4.1.6
Discontinuation of Investigational Product
An individual subject will not receive any further investigational product(s) if any of the 
following occur in the subject in question:
1. Withdrawal of consent from further participation in the study
2. Lost to follow-up
3. An AE that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing
4. Subject experienced an AE that meets the criteria for a DLT during the DLT evaluation 
period (for Phase 1b and Phase 2; see Section 3.1.3.2 for definition of DLT)
5. Subject experienced an AE that meets the criteria for a DLT, except its occurrence is 
outside the DLT evaluation period (for Phase 1b and Phase 2; see Section 3.1.3.2 for 
definition of DLT)
6. Any AE that meets criteria for discontinuation as defined in Section 3.1.5
7. Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational product(s) might constitute a 
safety risk
8. Pregnancy or intent to become pregnant
9. Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (eg, refusal to adhere to scheduled visits)

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10. Initiation of alternative anticancer therapy including another investigational agent
11. Confirmed PD and all retreatment criteria in the setting of PD are not met (Section 3.1.2)
Subjects who are permanently discontinued from receiving investigational product(s) 
regardless of the reason (withdrawal of consent from further treatment, due to an AE, other), 
will be identified as having permanently discontinued treatment and will be followed for 
protocol-specified assessments including follow-up of any AEs unless consent is withdrawn 
specifically from further study participation; the subject is lost to follow-up; the subject starts 
alternative anticancer treatment; or the subject is enrolled in another clinical study. All 
subjects will be followed for survival until the end of the study. Subjects who decline to 
return to the site for evaluations should be contacted by phone every 3 months to assess for 
survival unless consent is withdrawn.
4.1.7
Replacement of Subjects
Phase 1b subjects who are not evaluable for DLT assessment will be replaced. Subjects in 
Phase 2 will not be replaced.
4.1.8
Withdrawal of Informed Consent for Data and Biological Samples
Biological Samples Obtained for the Main Study
Study data are protected by the use of an SID number, which is a number specific to the 
subject. The investigator is in control of the information that is needed to connect a study 
sample to a subject. A subject’s consent to the use of data does not have a specific expiration 
date, but the subject may withdraw consent at any time by notifying the investigator. If 
consent is withdrawn, any samples collected prior to that time may still be given to and used 
by the sponsor but no new data or samples will be collected unless specifically required to 
monitor safety of the subject.
Samples Obtained for Genetic Research or Future Research
Samples obtained for genetic research or future research will be labeled with a sample 
identification number linked to the SID number but will not be labeled with personal 
identifiers such as the subject’s name. If the subject withdraws consent for participating in 
the genetic research or future research, the sponsor will locate the subject’s sample and 
destroy it. The coding of samples and results is to ensure that these research results are kept 
confidential by keeping the subject’s identity and these results separate. 

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If the subject consents to have his/her sample(s) used for genetic research or future research, 
this additional research may not start immediately and may start at any time during the 
storage period. The subject’s sample(s) including any specimens of extracted DNA will be 
stored by the sponsor with similar samples from other subjects at a secure central laboratory. 
The subject’s samples will not be kept for more than 25 years after the end of the study in 
which they were collected. If the subject chooses not to allow his/her study samples to be 
used for genetic research or future research, the samples will be destroyed by the sponsor 
once they are no longer required for the main study.
If consent is withdrawn after a sample has been taken but before the subject’s sample is sent 
to the sponsor for genetic research or future research, the investigator will arrange to have it 
destroyed. If consent is withdrawn after the subject’s sample(s) have been sent to the sponsor 
for genetic research or future research, the sponsor and the investigator will ensure that these 
sample(s) are destroyed unless the sample identification number has been removed and the 
subject can no longer be linked to any sample(s). However, if the subject’s samples have 
already been used for research, the sponsor is not required to destroy results of this research. 
In this case only the remaining sample(s) will be destroyed.
4.2
Schedule of Study Procedures
4.2.1
Enrollment/Screening Period
Table 4.2.1-1 shows all procedures to be conducted at the screening visit. Screening 
procedures are required for subjects at initial enrollment and prior to re-treatment; repeated 
screening is not required for subjects who crossover from monotherapy to combination 
therapy or for subjects who enter reinduction. 
Table 4.2.1-1
Schedule of Screening/Baseline Procedures (as of 
Amendment 6)
Procedure
Screening/Baseline
Days -28 to -1
Written informed consent/assignment of SID number
X
Verify eligibility criteria
X
Tumor and disease assessments
History of prior cancer treatment
X
Disease assessment by RECIST v1.1 (CT or MRI)a
X
Brain imaging
X
Study procedures and examinations
Demographics (including age, sex, race, ethnicity)
X

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Table 4.2.1-1
Schedule of Screening/Baseline Procedures (as of 
Amendment 6)
Procedure
Screening/Baseline
Days -28 to -1
Medical history
X
Physical examination, including height, weight
X
ECOG performance status
X
12-lead ECG b
X
Vital signs (temperature, BP, respiratory rate, pulse oximetry)
X
Assessment of AEs/SAEs
X
Concomitant medications
X
Laboratory tests
Serum chemistry
X
Hematology
X
Thyroid function tests (TSH, free T3, and free T4)
X
Urinalysis
X
Serum pregnancy test
X
Hepatitis B and C c; HIV
X
Other laboratory tests and assays
Archival tumor sample (if available) d
X
Fresh tumor biopsy e
X
 
AE = adverse event; BP = blood pressure; CT = computed tomography; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; HIV = human immunodeficiency virus; Ig = immunoglobulin; 
MRI = magnetic resonance imaging; 
 
RECIST = Response Evaluation Criteria in Solid Tumors; 
; SAE = serious adverse 
event; SID = subject identification; TSH = thyroid-stimulating hormone.
a
Disease assessment does not need to be repeated if done within 28 days of first dose on the retreatment 
schedule.
b
At screening, a single ECG will be obtained.
c
Includes hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, IgM hepatitis 
B core antibody, and hepatitis C antibody.  If hepatitis B core (total) antibody testing is unavailable then the 
hepatitis B core IgG and IgM should both be obtained instead.  
d
In Phase 2 for Arm E, only archival tumor (no older than 36 months) tissue will be accepted for biomarker 
pre-screening.
e
Fresh tumor biopsies are optional for subjects in Phase 1b. For Arm E, if archival specimens were obtained 
within 3 months of screening, with no intervening anti-cancer therapy, then these may be submitted in 
place of a repeat fresh biopsy.

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4.2.2
Randomized Treatment Period
Procedures to be conducted during the treatment period are presented in Table 4.2.2-1 for 
Weeks 1 to 25 and in Table 4.2.2-2 for Week 27 to end of treatment. This schedule of 
assessments will be followed for the initial Week 1 to 25 treatment period, if subjects enter 
reinduction, if subjects enter retreatment, or if subjects are allowed to crossover. At study 
visits when subjects do not receive investigational product, all of the pre-treatment 
assessments will be performed.
The timing of ECGs and vital sign assessments should be such that it allows the blood draw 
to occur at the exact nominal time. All samples are collected pre-dose 
unless otherwise indicated.

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Table 4.2.2-1
Schedule of Treatment Period (Initial, Retreatment, Reinduction, and Crossover) Study 
Procedures Weeks 1 to 25 (as of Amendment 6)
Study Period
Treatment Period: Weeks 1 to 25
Week/Day
W1
D1
W1
D2
W2
D1
± 1D
W3
D1
± 3D
W5
D1
± 3D
W7
D1
± 3D
W9
D1
± 3D
W11
D1
± 3D
W13
D1
± 3D
W15
D1
± 3D
W17
D1
± 3D
W19
D1
± 3D
W21
D1
± 3D
W23
D1
± 3D
W25
D1
± 3D
Procedure/Study Day
1
2
8
15
29
43
57
71
85
99
113
127
141
155
169
Randomization/enrollment
X
Tumor and disease assessments
Disease assessment by RECIST v1.1
(CT or MRI) a
X
X
X
Brain imaging (if metastasis found 
at baseline) a
X
X
X
Fresh tumor biopsy i
X 
Study procedures and examinations
Physical examination, including 
weight
X b
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
X
Vital signs (Q2W dosing) c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (Q4W dosing) c
X
X
X
X
X
X
X
X
12-lead ECG d
X
X
Assessment of AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory tests b
Serum chemistry, including LFTs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Table 4.2.2-1
Schedule of Treatment Period (Initial, Retreatment, Reinduction, and Crossover) Study 
Procedures Weeks 1 to 25 (as of Amendment 6)
Study Period
Treatment Period: Weeks 1 to 25
Week/Day
W1
D1
W1
D2
W2
D1
± 1D
W3
D1
± 3D
W5
D1
± 3D
W7
D1
± 3D
W9
D1
± 3D
W11
D1
± 3D
W13
D1
± 3D
W15
D1
± 3D
W17
D1
± 3D
W19
D1
± 3D
W21
D1
± 3D
W23
D1
± 3D
W25
D1
± 3D
Procedure/Study Day
1
2
8
15
29
43
57
71
85
99
113
127
141
155
169
Hematology
X
X
X
X
X
X
X
Thyroid function tests (TSH, free 
T3, free T4)
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Urine or serum pregnancy test
X
X
X
X
X
X
X
 
 
 
 
 
 
 
 
 
 
 
 

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Table 4.2.2-1
Schedule of Treatment Period (Initial, Retreatment, Reinduction, and Crossover) Study 
Procedures Weeks 1 to 25 (as of Amendment 6)
Study Period
Treatment Period: Weeks 1 to 25
Week/Day
W1
D1
W1
D2
W2
D1
± 1D
W3
D1
± 3D
W5
D1
± 3D
W7
D1
± 3D
W9
D1
± 3D
W11
D1
± 3D
W13
D1
± 3D
W15
D1
± 3D
W17
D1
± 3D
W19
D1
± 3D
W21
D1
± 3D
W23
D1
± 3D
W25
D1
± 3D
Procedure/Study Day
1
2
8
15
29
43
57
71
85
99
113
127
141
155
169
 
 
 
AE = adverse event; BP = blood pressure; CT = computed tomography; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI 
= end of infusion; 
 LFT = liver function test; 
 MRI = 
magnetic resonance imaging; 
tic; Q2W = every 2 weeks; Q4W = every 4 weeks; Q12W = every 12 
weeks; 
; RECIST = Response 
Evaluation Criteria in Solid Tumors; 
 SAE = serious adverse event;TSH = thyroid-stimulating hormone; W = week.
Note: On treatment days, evaluations and sample collections should be conducted prior to administration of MEDI4736/tremelimumab unless otherwise 
indicated. On nontreatment days, all of the pre-treatment assessments will be performed. 
a
Disease assessments should occur within 7 days prior to dosing.
b
If physical examination or safety laboratory tests are performed within 3 days prior to Dose 1, they do not need to be repeated.
c
For all treatment arms: Vital signs (temperature, BP, pulse rate, and respiratory rate) will be measured on MEDI4736 and/or tremelimumab treatment days. 
Vital signs will be measured within 30 minutes prior to the start of tremelimumab and/or MEDI4736 infusion, every 15 minutes (± 5 minutes) during 
tremelimumab and/or MEDI4736 infusion, at EOI of tremelimumab and/or MEDI4736 infusion (± 5 minutes), and at 30 and 60 minutes (± 5 minutes) post 
EOI of tremelimumab and/or MEDI4736 infusion. To clarify for subjects receiving combination therapy, vital signs will be measured within 30 minutes 
prior to start of tremelimumab and MEDI4736 infusion, every 15 minutes (± 5 minutes) during tremelimumab and MEDI4736 infusion, at EOI of 
tremelimumab and MEDI4736 infusion (+ 5 minutes), and at 30 and 60 minutes (± 5 minutes) post EOI of MEDI4736 infusion. For the first day of 
administration of investigational product, an additional 2-hour (± 15 minutes) post EOI period of observation will be required following the 60 minutes (± 5 
minutes) post EOI assessment of vital signs. For subsequent doses, the additional 2-hour observation period will not be required unless clinically indicated 
(eg subject experiences an infusion reaction).
d
For all treatment arms: On Day 1 of Week 1, a single ECG will be obtained within 30 minutes prior to start of infusion, within 30 minutes post EOI, and 
between 2 and 6 hours post EOI of tremelimumab and/or MEDI4736 infusion. To clarify for subjects receiving combination therapy: On Day 1 of Week 1, a 

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Table 4.2.2-1
Schedule of Treatment Period (Initial, Retreatment, Reinduction, and Crossover) Study 
Procedures Weeks 1 to 25 (as of Amendment 6)
Study Period
Treatment Period: Weeks 1 to 25
Week/Day
W1
D1
W1
D2
W2
D1
± 1D
W3
D1
± 3D
W5
D1
± 3D
W7
D1
± 3D
W9
D1
± 3D
W11
D1
± 3D
W13
D1
± 3D
W15
D1
± 3D
W17
D1
± 3D
W19
D1
± 3D
W21
D1
± 3D
W23
D1
± 3D
W25
D1
± 3D
Procedure/Study Day
1
2
8
15
29
43
57
71
85
99
113
127
141
155
169
single ECG will be obtained within 30 minutes prior to start of tremelimumab infusion, within 30 minutes post EOI of MEDI4736, and between 2 and 6 
hours post EOI of MEDI4736 infusion. At all other timepoints, a single ECG will be obtained prior to investigational product(s) administration and as 
clinically indicated.
  
 
 
 
 
h
As previously specified in Section 4.3.2, fresh tumor biopsies will be obtained on Week 5 Day 1 (± 7 days).
Table 4.2.2-2
Schedule of Treatment Period (Initial, Retreatment, Reinduction, and Crossover) Study 
Procedures Weeks 27 to End of Treatment (as of Amendment 6)
Study Period
Treatment Period: Week 27 to End of Treatment
Week/Day
W27
D1 ± 1D
W29
D1 ± 3D
W31
D1 ± 3D
W33
D1 ± 3D
W35
D1 ± 3D
W37
D1 ± 3D
W39
D1 ± 3D
W41
D1 ± 3D
W43
D1 ± 3D
W45
D1 ± 3D
W47
D1 ± 3D
W49
D1 ± 3D
W51
D1 ± 3D
Procedure / Study Day
183
197
211
225
239
253
267
281
295
309
323
337
351
 

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Table 4.2.2-2
Schedule of Treatment Period (Initial, Retreatment, Reinduction, and Crossover) Study 
Procedures Weeks 27 to End of Treatment (as of Amendment 6)
Study Period
Treatment Period: Week 27 to End of Treatment
Week/Day
W27
D1 ± 1D
W29
D1 ± 3D
W31
D1 ± 3D
W33
D1 ± 3D
W35
D1 ± 3D
W37
D1 ± 3D
W39
D1 ± 3D
W41
D1 ± 3D
W43
D1 ± 3D
W45
D1 ± 3D
W47
D1 ± 3D
W49
D1 ± 3D
W51
D1 ± 3D
Procedure / Study Day
183
197
211
225
239
253
267
281
295
309
323
337
351
Tumor and disease assessments
Disease assessment by RECIST v1.1
(CT or MRI) a
X
X
X
Brain imaging (if metastasis found at 
baseline) a
X
X
X
Study procedures and examinations
Physical examination, including 
weight
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs 
 
X
X
X
X
X
X
Assessment of AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory tests
Serum chemistry, including LFTs 
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Thyroid function tests (TSH, free T3, 
free T4)
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
Urine or serum pregnancy test
X
X
X
X
X
X

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Table 4.2.2-2
Schedule of Treatment Period (Initial, Retreatment, Reinduction, and Crossover) Study 
Procedures Weeks 27 to End of Treatment (as of Amendment 6)
Study Period
Treatment Period: Week 27 to End of Treatment
Week/Day
W27
D1 ± 1D
W29
D1 ± 3D
W31
D1 ± 3D
W33
D1 ± 3D
W35
D1 ± 3D
W37
D1 ± 3D
W39
D1 ± 3D
W41
D1 ± 3D
W43
D1 ± 3D
W45
D1 ± 3D
W47
D1 ± 3D
W49
D1 ± 3D
W51
D1 ± 3D
Procedure / Study Day
183
197
211
225
239
253
267
281
295
309
323
337
351
 
 
 
 
 
 
 

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Table 4.2.2-2
Schedule of Treatment Period (Initial, Retreatment, Reinduction, and Crossover) Study 
Procedures Weeks 27 to End of Treatment (as of Amendment 6)
Study Period
Treatment Period: Week 27 to End of Treatment
Week/Day
W27
D1 ± 1D
W29
D1 ± 3D
W31
D1 ± 3D
W33
D1 ± 3D
W35
D1 ± 3D
W37
D1 ± 3D
W39
D1 ± 3D
W41
D1 ± 3D
W43
D1 ± 3D
W45
D1 ± 3D
W47
D1 ± 3D
W49
D1 ± 3D
W51
D1 ± 3D
Procedure / Study Day
183
197
211
225
239
253
267
281
295
309
323
337
351
AE = adverse event; BP = blood pressure; CT = computed tomography; D = day; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; 
 
; LFT = liver function test; MRI = magnetic resonance imaging; PK = pharmacokinetic; Q2W = 
every 2 weeks; 
 
RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; TSH = thyroid-stimulating hormone; W = 
week.
Note: On treatment days, evaluations and sample collections should be conducted prior to administration of MEDI4736/tremelimumab unless otherwise 
indicated. 
a
Disease assessments should occur within 7 days prior to dosing.
 
 
 
 
 
 
 
 

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4.2.3
Follow-up Period
Table 4.2.3-1 shows all procedures to be conducted during the end of treatment visit and 
follow-up period. For subjects who complete all 12 months of treatment, the last dosing visit 
within the 12-month period is considered to be the end of treatment visit. Subjects who 
discontinue before 12 months will complete the end of treatment visit at the time the decision 
is made to discontinue treatment.
All subjects are to complete the end of treatment visit, all follow-up visits and be contacted 
for survival status in accordance with the Schedule of Study Procedures. However, if a 
subject discontinues from treatment and moves onto alternative anticancer treatment, the 
follow-up visits will no longer be required; however, survival follow-up assessments would 
be required as indicated in the Schedule of Study Procedures unless the subject withdraws 
consent for further survival follow-up. Survival follow-up will continue until the end of study 
as defined in Section 6.3.
After 90 days, only subjects with investigational product-related SAEs will continue to be 
followed for safety.

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Table 4.2.3-1
Schedule of Follow-up Procedures (as of Amendment 6)
Study Period
Follow-up Period
Procedure / Study Day or Month
EOT a
Day 30 
post-EOT 
± 3 Days
Day 60
post-EOT 
± 3 Days
Day 90
post-EOT
± 7 Days
Q3M After Day 90
post-EOT up to 
Month 12 post-
EOT ± 7 Days
Q6M After 
Month 12 post-
EOT ± 14 Days
Disease assessments
Disease assessment by RECIST v1.1 (CT or MRI) b
X
X
X
X
Fresh tumor biopsy
X c
Subsequent anticancer therapy
X
X
X
X
X
Survival status
X
X
X
X
X
Study procedures and examinations
Physical examination
X
X
X
X
ECOG performance status
X
X
X
Vital signs
X
X
X
X
12-lead ECG d
X
Assessment of AEs/SAEs
X
X
X
X
Concomitant medications
X
X
X
X
Laboratory tests
Serum chemistry 
X
X
X
X
Hematology
X
X
X
X
Thyroid function tests (TSH, free T3, free T4)
X
X
X
X
Urinalysis
X
X
X
X
Urine or serum pregnancy test
X

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Table 4.2.3-1
Schedule of Follow-up Procedures (as of Amendment 6)
Study Period
Follow-up Period
Procedure / Study Day or Month
EOT a
Day 30 
post-EOT 
± 3 Days
Day 60
post-EOT 
± 3 Days
Day 90
post-EOT
± 7 Days
Q3M After Day 90
post-EOT up to 
Month 12 post-
EOT ± 7 Days
Q6M After 
Month 12 post-
EOT ± 14 Days
 
AE = adverse event; CT = computed tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; 
 
EOT = end of treatment; 
; MRI = magnetic resonance imaging; 
 
PD = progressive disease; 
 
 
RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse 
event; TSH = thyroid-stimulating hormone.
a
For subjects who complete the 12-month treatment period, the last dosing visit within that period is considered to be the EOT visit. Subjects who discontinue 
before 12 months will complete the EOT visit at the time the decision is made to discontinue treatment. 
b
If a subject discontinues treatment due to confirmed PD, only the EOT disease assessment is required if it has been > 28 days since the last disease 
assessment.
c
Tumor biopsy collected once upon confirmed PD.
d
A single ECG will be obtained.
 
.

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4.3
Description of Study Procedures
4.3.1
Efficacy……….
Tumor assessments will be based on RECIST v1.1 (Eisenhauer et al, 2009) and will be 
performed according to the schedule presented in Section 4.2. All subjects will be followed 
for survival according to the schedule in Table 4.2.3-1 through the end of the study (defined 
as 5 years after the final subject is enrolled or the sponsor stops the study, whichever occurs 
first). 
Sites will be required to store electronic copies of all scans, and the sponsor will arrange for 
centralized storage of all imaging data. All imaging assessments, including unscheduled visit 
scans, will be collected on an ongoing basis and sent to the sponsor or designee for storage. 
The centralized storage of imaging data will occur for independent centralized third-party 
blinded review of disease assessments. At the discretion of the sponsor, an independent 
central review of all scans used in the assessment of tumors by RECIST v1.1 for the Phase 2 
portion of the study will be conducted. Guidelines for imaging collection and storage will be 
provided in a separate document. The management of subjects will be based solely upon the 
results of assessment conducted by the investigator based on RECIST v1.1 per protocol.
Tumor assessments should include the following evaluations: physical examination and CT 
or magnetic resonance imaging (MRI) scan of the chest, abdomen, and pelvis (pelvic scan is 
optional unless known pelvic disease is present at baseline). CT or MRI scans of the head 
and neck will be performed on all subjects at screening; follow-up head and neck scans are 
optional unless disease is found on the screening examination or clinically indicated. MRI
scan of the brain will be performed on all subjects at screening. If the subject has CNS 
metastases, a brain MRI is also required at each post baseline assessment. If a subject 
becomes neurologically symptomatic during treatment outside of the setting where the 
subject has known CNS metastases, a brain MRI is required.
The preferred method of disease assessment is CT with contrast. If CT with contrast is 
contraindicated, CT without contrast is preferred over MRI. The same method is preferred 
for all subsequent tumor assessments.

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Tumor Evaluations
Physical examination
•
Lesions detected by physical examination will only be considered measurable if 
superficial, eg, skin nodules and palpable lymph nodes. Documentation by color 
photography including ruler is recommended for estimating the size of skin lesions.
CT scan with contrast of the head and neck, chest, abdomen, and pelvis
•
CT scans should be performed with contiguous cuts in slice thickness of 5 mm or less. 
Spiral CT should be performed using a 5-mm contiguous reconstruction algorithm.
•
Pelvis scan is optional unless known pelvic disease is preset at baseline.
MRI scans
•
MRI of the head and neck, abdomen and pelvis (pelvic scan is optional unless known 
pelvic disease is present at baseline) is acceptable for measurement of lesions provided 
that the same anatomical plane is used for serial assessments. If possible, the same 
imaging device should be used for serial evaluations. In case of MRI, measurements will 
be preferably performed in the axial (transverse) plane on contrast-enhanced T1-weighted 
images. However, there are no specific sequence recommendations.
Measurability of Tumor Lesions 
Tumor lesions will be categorized as follows:
•
Measurable 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 (irrespective of scanner type) and MRI (no less than double the 
slice thickness and a minimum of 10 mm)
◦
10 mm caliper measurement by clinical exam (when superficial)
◦
Malignant lymph nodes are considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm)
•
Nonmeasurable Lesions - Nonmeasurable lesions are defined as all other lesions 
(or sites of disease), including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm in short axis). Lesions considered truly 
nonmeasurable include the following: leptomeningeal disease, ascites, pleural/pericardial 
effusion, and 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.

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•
Target Lesions - All lesions up to a maximum of 5 lesions total (and a maximum of 
2 lesions per organ) representative of all involved organs should be identified as target 
lesions. It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.
•
Non-target Lesions - It is possible to record multiple non-target lesions involving the 
same organ as a single item on the electronic case report form (electronic case report 
form [eCRF]; eg, “multiple enlarged pelvic lymph nodes” or “multiple liver metastases”).
4.3.1.1
Evaluation of Response by Response Evaluation Criteria in Solid Tumors 
Tumor response will be assessed by RECIST v1.1.
Evaluation of Target Lesions
•
CR - Disappearance of all target lesions. Any pathological lymph nodes (whether target 
or non-target) must have reduction in short axis to < 10 mm (the sum may not be “0” if 
there are target nodes). 
•
PR - At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters.
•
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 demonstrate an absolute 
increase of at least 5 mm. (Note: The appearance of one or more new lesions may be 
considered progression.)
•
SD - Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum of diameters while on study.
Evaluation of Non-target Lesions
•
CR - Disappearance of all non-target lesions and normalization of tumor marker level. 
All lymph nodes must be non-pathological in size (< 10 mm in short axis). 
•
Non-CR/Non-PD - Persistence of 1 or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits.
•
PD - Unequivocal progression of existing non-target lesions will be defined as the overall 
level of substantial worsening in non-target disease such that, even in presence of SD or 
PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. In the absence of measurable disease, change in 
nonmeasurable disease comparable in magnitude to the increase that would be required to 
declare PD for measurable disease. Examples include an increase in a pleural effusion 
from “trace” to “large,” an increase in lymphangitic disease from localized to widespread.

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Appearance of New Lesions
The appearance of new lesions is considered PD according to RECIST v1.1. Considering the 
unique response kinetics that have been observed with immunotherapy, new lesions may not 
represent true disease progression. In the absence of rapid clinical deterioration, subjects may 
continue to receive study treatment until confirmed PD (see Section 3.1.2.4).
Evaluation of Overall Response
Confirmation of CR, PR, as well as PD is required by a repeat, consecutive assessment no 
less than 4 weeks from the date of first documentation. If the next protocol scheduled scan is 
due within 2 weeks after the confirmatory scan was obtained, the protocol-scheduled scan 
does not need to be done. Treatment of subjects in Phase 1b and Phase 2 will continue 
between the initial assessment of PD and confirmation for PD (which is not required by 
RECIST v1.1; see Section 3.1.2.4). These subjects may continue to receive MEDI4736 in 
combination with tremelimumab beyond confirmed PD in accordance with Section 3.1.2 and 
if investigators consider that subjects continue to receive benefit from treatment. In the 
absence of clinical deterioration, such modifications to the RECIST criteria may discourage 
the early discontinuation of MEDI4736 in combination with tremelimumab and provide a 
more complete evaluation of MEDI4736 in combination with tremelimumab antitumor 
activity than would be seen with conventional response criteria.
Table 4.3.1.1-1 provides overall responses for all possible combinations of tumor responses 
in target and non-target lesions with or without the appearance of new lesions.
Table 4.3.1.1-1
Evaluation of Overall Response at a Single Timepoint by 
RECIST V1.1
Target Lesions
Non-target Lesions
New Lesions
Overall Response
Complete response
Complete response
No
Complete response
No target lesion a
Complete response
No
Complete response
Complete response
Not evaluable b
No
Partial response
Complete response
Non-complete response/
non-progressive disease
No
Partial response
Partial response
Non-progressive disease and
not evaluable b
No
Partial response
Stable disease
Non-progressive disease and
not evaluable b
No
Stable disease
Not all evaluated
Non-progressive disease
No
Not evaluable
No target lesion a
Not all evaluated
No
Not evaluable

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Table 4.3.1.1-1
Evaluation of Overall Response at a Single Timepoint by 
RECIST V1.1
Target Lesions
Non-target Lesions
New Lesions
Overall Response
No target lesion a
Non-complete response /
non-progressive disease
No
Non-complete response /
non-progressive disease
Progressive disease
Any
Yes or No
Progressive disease
Any
Progressive disease
Yes or No
Progressive disease
Any
Any
Yes
Progressive disease
No target lesion a
Unequivocal progressive disease
Yes or No
Progressive disease
No target lesion a
Any
Yes
Progressive disease
RECIST = Response Evaluation Criteria in Solid Tumors.
a
Defined as no target lesions at baseline.
b
Not evaluable is defined as either when no or only a subset of lesion measurements are made at an 
assessment.
 
4.3.2
Tumor Biopsies
4.3.2.1
Fresh Tumor Biopsies (Phase 2 Only)
Fresh tumor biopsies should be preferentially obtained from tumor tissues that are safely 
accessible as determined by the investigator and are not obtained from sites that require 
significant risk procedures, which include, but are not limited to, biopsies of the brain, lung, 
mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, stomach 
or bowel wall [refer to the definition of a significant risk device under §812.3(m) in the 
Investigational Device Exemptions regulation (21 CFR 812)]. 
At baseline, fresh tumor biopsies will be obtained prior to administration of the first dose of 
investigational product(s) for all subjects. 
In addition, fresh tumor biopsies will be obtained on Week 5 Day 1 (± 7 days) and upon 
confirmed PD if clinically feasible (ie, repeat biopsy does not pose unacceptable medical risk 
to a subject as determined by the investigator). Additional biopsies may also be performed if 
clinically indicated (eg, for mixed responses). For subjects requiring serial image-guided core 
needle tumor biopsy, those biopsies will be performed according to institutional practice.

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For fresh biopsies, the tumor lesion should not be used as a RECIST target lesion. Additional 
tumor biopsies are permitted as clinically indicated (eg, for mixed responses or upon 
confirmed PD). If clinically practical, at each fresh biopsy time point, subjects will undergo 
4 core biopsies, but a minimum of at least 3 core biopsies are required.
 
 
 
 
 
 
 
 
Tumor biopsies will be stored at MedImmune or an appropriate vendor selected by 
MedImmune. 
 
 
Additional details for sample collection, processing, storage, and shipment will be provided 
in the Laboratory Manual.
4.3.2.2
Archival Tumor Samples (Phase 1b and Phase 2)
Initial and subsequent archival tumor tissue should be provided. In Phase 2 Arm E, only 
archival tumor tissue will be accepted for biomarker pre-screening. Archival tumor samples 
must be 
 in paraffin blocks for IHC and additional correlative 
markers 
For Phase 1b 
and Arms A, B, C, and D in Phase 2, when an archival tumor block cannot be provided, only 
freshly cut sections should be provided as described in the Laboratory Manual.
 
 
 
 
 
 
 
 

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4.3.4
Medical History, Physical Examination, Electrocardiogram, and Vital 
Signs
4.3.4.1
Medical History and Physical Examination
Physical examinations will be performed according to institutional guidelines on study days 
noted in Section 4.2, and will include assessments of the head, eyes, ears, nose, and throat, 
respiratory, cardiovascular, GI, urogenital, musculoskeletal, neurological, psychiatric, 
dermatological, hematologic/lymphatic, and endocrine systems; weight; and height (at 
screening only).

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Findings from medical history (obtained at screening) and physical examination shall be 
given a baseline grade according to the procedure for AEs. Increases in severity of 
pre-existing conditions during the study will be considered AEs, with resolution occurring 
when the grade returns to the prestudy grade or below.
4.3.4.2
Electrocardiograms
ECGs (12-lead) will be recorded on study days as noted in Section 4.2. At Week 1 Day 1, 
single ECGs will be obtained within 30 minutes prior to the start of infusion, within 
30 minutes post-, and between 2 and 6 hours post-end of infusion of tremelimumab and/or 
MEDI4736. All other ECGs will be performed once per visit, (prior to investigational 
product(s) administration if during the treatment period) and as clinically indicated. In case 
of clinically significant ECG abnormalities, including an ECG that demonstrates a QT 
corrected using Fridericia’s formula (QTcF) value > 500 milliseconds, 2 additional 12-lead 
ECGs should be obtained over a brief period (eg, 30 minutes) to confirm prolongation.
The same recorder will be used for each subject at each time point, if possible. Date and time 
settings should be checked at the start of each study day and aligned with an official 
timekeeper for all machines used in the study.
Skin preparations should be thorough and electrode positions should be according to standard 
12-lead ECG placement.
In this study lead V2 will be analyzed and reported as primary. Lead V5 will be analyzed, for 
all visits, as backup for the individual where analysis in lead V2 is not deemed possible for 
pre-dose or significant parts of whole visits or whole visits.
The following variables will be reported: heart rate, PR, RR, QRS and QT intervals from the 
primary lead of the digital 12-lead ECG.
4.3.4.3
Vital Signs
Vital signs (temperature, blood pressure [BP], pulse rate [or pulse oximetry at screening], and 
respiratory rate) will be measured on study days noted in Section 4.2.
4.3.5
Clinical Laboratory Tests
A Laboratory Manual will be provided to the sites that specifies the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information, specific to this clinical research study. If the subject has completed any safety 
laboratory tests within 72 hours before Week 1 Day 1, they will not need to be repeated.

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Clinical laboratory safety tests including serum pregnancy tests will be performed in a 
licensed clinical laboratory. Urine pregnancy tests may be performed at the site using a 
licensed test (dipstick). Abnormal laboratory results should be repeated as soon as possible 
(preferably within 24 to 48 hours).
The following clinical laboratory tests will be performed according to the schedules of 
procedures in Section 4.2:
Serum Chemistry
•
Calcium
•
Lipase
•
Chloride
•
Gamma glutamyl transferase 
•
Magnesium
•
Lactic dehydrogenase
•
Potassium
•
Uric acid
•
Sodium
•
Creatinine
•
Bicarbonate
•
Blood urea nitrogen
•
AST
•
Glucose
•
ALT
•
Albumin
•
ALP
•
Total protein
•
Total bilirubin
•
Triglycerides
•
Direct bilirubin
•
Cholesterol
•
Indirect bilirubin
•
Amylase
•
Thyroid stimulating hormone, free T4, free T3
Note for serum chemistries: Tests for AST, ALT, ALP, direct bilirubin, indirect bilirubin, and total bilirubin 
must be conducted concurrently and assessed concurrently. If serum chemistry is unavailable then plasma 
chemistry may be obtained instead.
Hematology
•
White blood cell count with differential
•
Red blood cell count
•
Platelet count
•
Hemoglobin
•
Hematocrit
•
Mean corpuscular volume
•
Prothrombin time/ International Normalized Ratio
•
Mean corpuscular hemoglobin concentration
•
Activated partial thromboplastin time
•
Fibrinogen

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Urinalysis
•
Color
•
Glucose
•
Appearance
•
Ketones
•
Specific gravity
•
Blood
•
pH
•
Bilirubin
•
Protein
Pregnancy Test (females of childbearing potential only)
•
Urine human chorionic gonadotropin
•
Serum beta-human chorionic gonadotropin)
Other Safety Tests
•
Hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, IgM hepatitis B core 
antibody, hepatitis C antibody
•
HIV antibodies
 
 
 
 
 
 
 
 

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4.3.8
Biomarker Evaluation and Methods
Blood samples will be collected and analyzed to evaluate 
 
biomarkers that relate to MEDI4736 treatment according to the schedule presented in 
Section 4.2.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Other biomarkers may be evaluated as determined by additional data. Details for sample 
collection, processing, storage, and shipment will be provided in the Laboratory Manual.
4.3.8.1
IFN- γ Gene expression Testing
The Thermo Fisher Interferon Gamma Signature Assay - Gastric Test will be used to identify 
subjects with a positive IFN-γ gene expression signature for enrollment into Arm E of the 
Phase 2 portion of the study.
 
 
 
 
 
 
Utilizing a ratio of the genes of interest compared to the housekeeping 
genes, a numeric value will be generated for each subject and evaluated against a 
pre-determined threshold. The result reported will then be reported as either positive (above 
the pre-determined cut-off) or negative (below the pre-determined cut-off).
4.3.9
Estimate of Volume of Blood to be Collected
A total of approximately 26 mL of blood in total will be collected during the screening period 
for all screening tests, which may be collected during the 28-day screening period. No more 

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than approximately 29 mL of blood will be drawn for any one protocol visit during treatment. 
During the follow-up period, no more than approximately 29 mL of blood will be collected at 
any one follow-up visit. The total volume to be collected will depend on the length of a 
subject’s participation in the study as well as to which phase of the study they are enrolled 
(eg, Phase 1b vs Phase 2).
4.4
Study Suspension or Termination
The sponsor reserves the right to temporarily suspend or terminate this study at any time. The 
reasons for temporarily suspending or terminating the study may include but are not limited 
to the following: 
1. The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects
2. Subject enrollment is unsatisfactory
3. Noncompliance that might significantly jeopardize the validity or integrity of the study
4. Enrollment into Phase 2 may be discontinued at the discretion of the sponsor should 
emerging clinical or nonclinical data suggest that continued treatment may not be 
beneficial to a given treatment
If MedImmune determines that temporary suspension or termination of the study is required, 
MedImmune will discuss the reasons for taking such action with all participating 
investigators (or head of the medical institution, where applicable). When feasible, 
MedImmune will provide advance notice to all participating investigators (or head of the 
medical institution, where applicable) of the impending action.
If the study is suspended or terminated for safety reasons, MedImmune will promptly inform 
all investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study. MedImmune will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the investigator or head of the medical institution must 
inform the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) promptly 
and provide the reason(s) for the suspension/termination. If the study is suspended for safety 
reasons and it is deemed appropriate by the sponsor to resume the study, approval from the 
relevant regulatory authorities (and IRBs/IECs when applicable) will be obtained prior to 
resuming the study.

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4.5
Investigational Products
4.5.1
Identity of Investigational Product(s)
MedImmune will provide the investigator(s) with investigational product (Table 4.5.1-1)
using designated distribution centers.
Table 4.5.1-1
Identification of Investigational Products 
Investigational Product
Manufacturer
MEDI4736
MedImmune
 
 
Tremelimumab
MedImmune
 
 
The investigator’s or site’s designated investigational product manager is required to 
maintain accurate investigational product accountability records. Commercially available 
0.9% (weight per volume [w/v]) saline will be supplied by each site. Upon completion of the 
study, copies of investigational product accountability records will be returned to 
MedImmune.
 
 
 
 
 

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.
The corresponding volume of tremelimumab should be rounded to the nearest tenth mL 
(0.1 mL). If no institutional standard on dose calculations exists, then dose adjustments for 
each cycle are only needed for a greater than 10% change in weight.
 
 
 
 
 
 
 

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4.5.1.3
Investigational Product Inspection
Investigational products will be supplied to the site in vials in coded kits. Each kit has a 
unique number that is printed on all labels within the kit (ie, the outer carton label and the 
label of each vial within the carton). Each vial selected for dose preparation should be 
inspected. If there are any defects noted with the investigational product(s), the investigator 
and site monitor should be notified immediately. Refer to the Product Complaint section 
(Section 4.5.1.6) for further instructions.
 
 
 
 
If there are any defects noted with the investigational product, the investigator and site 
monitor should be notified immediately. Refer to the Product Complaint section 
(Section 4.5.1.6) for further instructions.
 
 
 
 
 
 

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4.5.1.5
Monitoring of Dose Administration
Subjects will be monitored prior to, during, and after infusion of MEDI4736 and 
tremelimumab. Vital signs (temperature, BP, pulse rate, and respiratory rate) will be 
measured on MEDI4736/tremelimumab treatment days within 30 minutes prior to the start of 
MEDI4736 and/or tremelimumab administration, every 15 minutes (± 5 minutes) during 
MEDI4736 and/or tremelimumab administration, at the end of MEDI4736 and/or
tremelimumab infusion (± 5 minutes), and at 30 and 60 minutes (± 5 minutes) post end of 
infusion of MEDI4736. For subjects receiving combination therapy, vital signs will be 
measured within 30 minutes prior to start of tremelimumab and MEDI4736 infusion, every 
15 minutes (± 5 minutes) during tremelimumab and MEDI4736 infusion, at EOI of 
tremelimumab and MEDI4736 (± 5 minutes), and at 30 and 60 minutes (± 5 minutes) post 
EOI of MEDI4736 infusion. Pulse oximetry is a required vital sign at screening for baseline 
comparison. Pulse oximetry is optional on future visits, and should be obtained per clinical 
investigator if there is clinical concern for respiratory evaluation, including but not limited to 
immune-related pneumonitis or interstitial lung disease (ILD), as detailed in Appendix 5. For 
Dose 1, an additional 2-hour (± 15 minutes) observation period will be required after the 60 

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minutes (± 5 minutes) post end of infusion of MEDI4736 vital sign assessment. The 
additional 2-hour observation period will not be required for subsequent doses unless
clinically indicated (eg, the subject experiences an infusion reaction).
In the event of ≤ Grade 2 infusion-related reaction, the infusion rate of MEDI4736 and 
tremelimumab may be decreased by 50% or temporarily interrupted until resolution of the 
event (up to 4 hours) and re-initiated at 50% of the initial rate until completion of the 
infusion. In subjects experiencing ≤ Grade 2 infusion-related reaction, subsequent infusions 
may be administered at 50% of the initial rate.
Primary prophylaxis against infusion-related reactions is not permitted during this study in 
order to avoid obscuring a potential safety signal and to enable a future assessment regarding 
whether premedications should be required for all subjects in future studies. However, at the 
discretion of the investigator, secondary prophylaxis (ie, prevention of infusion-related 
reaction following initial episode) is appropriate and will be permitted. Acetaminophen 
and/or an antihistamine (eg, diphenhydramine) or equivalent medications per institutional 
standard may be administered per institutional standard at the discretion of the investigator. If 
the infusion-related reaction is Grade 3 or higher in severity, treatment with MEDI4736 and 
tremelimumab will be discontinued.
As with any mAb, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis.
All dosing visits are scheduled based on the date of Week 1 Day 1 dosing. Future dosing 
visits should not be recalibrated based on actual dosing dates unless approved by the sponsor.
 
 
 
 
 the subject experiences a related toxicity, the management guidelines 
provided in Section 3.1.5 should be followed.
4.5.1.6
Reporting Product Complaints
Any defects with the investigational product must be reported immediately to the 
MedImmune Product Complaint Department by the site with further notification to the site 
monitor. All defects will be communicated to MedImmune and investigated further with the 

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Product Complaint Department. During the investigation of the product complaint, all 
investigational product must be stored at labeled conditions unless otherwise instructed.
MedImmune contact information for reporting product complaints:
4.5.2
Additional Study Medications
No other study medications are specified for use in this clinical protocol.
4.5.3
Labeling……….
Labels for the investigational product will be prepared in accordance with Good 
Manufacturing Practice and local regulatory guidelines. Label text will be translated into 
local languages, as required.
4.5.5
Treatment Compliance
Investigational product is administered by study site personnel, who will monitor 
compliance.
4.5.6
Accountability
The investigator’s or site’s designated investigational product manager is required to 
maintain accurate investigational product accountability records. Upon completion of the 
study, copies of investigational product accountability records will be returned to 
MedImmune. All unused investigational product will be returned to a 
MedImmune-authorized depot or disposed of upon authorization by MedImmune.

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4.6
Treatment Assignment and Blinding
4.6.1
Methods for Assigning Treatment Groups
In Phase 2, subjects will be enrolled in 1 of 5 treatment arms. Second-line subjects with 
metastatic or recurrent gastric or GEJ adenocarcinoma will be randomized in a 2:2:1 ratio to 
Arm A (MEDI4736 in combination with tremelimumab), Arm B (MEDI4736 monotherapy), 
or Arm C (tremelimumab monotherapy). In parallel, third-line subjects with metastatic or 
recurrent gastric or GEJ adenocarcinoma will be enrolled in Arm D (MEDI4736 in 
combination with tremelimumab). Upon closure of Arms A, B, and C and completion of 
Arm D, second- and third-line subjects with metastatic or recurrent gastric or GEJ 
adenocarcinoma and a positive IFN-γ gene expression signature will be enrolled in Arm E
(MEDI4736 in combination with tremelimumab).
 
 
The randomization code will be produced by an independent statistician, who is not part of 
the study team. Randomization/enrollment to treatment groups will be performed using 
IXRS. 
The time between randomization/enrollment and the initiation of treatment should be as short 
as possible and no more than 1 business day. If there is a delay in the administration of 
investigational product such that it will not be administered within the specified timeframe, 
the study monitor must be notified immediately.
4.6.2
Methods for Ensuring Blinding
This is an open-label study.
4.7
Restrictions During the Study and Concomitant Treatment(s)
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the clinical phase of the study (final study visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the eCRF.
4.7.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments (eg, acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care 
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supportive care (including antibiotics, nutritional support, correction of metabolic disorders, 
optimal symptom control and pain management [including palliative radiotherapy, etc]) 
should be used when necessary for all subjects. 
4.7.2
Prohibited Concomitant Medications
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator.
The following medications are considered exclusionary during the study. The sponsor must 
be notified if a subject receives any of these during the study.
1. Any investigational anticancer therapy
2. Monoclonal antibodies against CTLA-4, PD-1, or PD-L1 through 90 days post last dose 
of the study
3. Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy), 
immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of 
hormones for noncancer-related conditions (eg, insulin for diabetes and hormone 
replacement therapy) is acceptable
4. Immunosuppressive medications including, but not limited to systemic corticosteroids at 
doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and 
TNF-α blockers. Use of immunosuppressive medications for the management of 
investigational product-related AEs or in subjects with contrast allergies is acceptable. In 
addition, use of inhaled, topical, intranasal corticosteroids or local steroid injections 
(eg, intra-articular injection) is permitted. Temporary uses of corticosteroids for 
concurrent illnesses (eg, food allergies, CT scan contrast hypersensitivity, etc) are 
acceptable upon discussion with the medical monitor 
5. Live attenuated vaccines during the study through 180 days after the last dose of 
investigational product
6. Herbal and natural remedies should be avoided
4.8
Statistical Evaluation
4.8.1
General Considerations
For the purpose of generating the clinical study report, the primary analysis for this study 
may occur after all subjects in corresponding arms have either discontinued from the study or 
been on the study for at least 7 months (Arms, A, B, C, and E) or 5 months (Arm D). Final 
analyses for this study including selected efficacy/safety endpoints (if primary analysis 
occurred) will occur after study closure. The study populations are defined as follows:

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•
DLT Evaluable Population is defined as subjects enrolled in Phase 1b who receive the 
protocol-assigned treatment and complete safety follow-up through the DLT evaluation 
period (Section 3.1.3.2) or experience a DLT during the DLT evaluation period. 
•
As-treated Population is defined as subjects who receive any dose of either 
investigational product(s). 
•
Response Evaluable Population is defined as all subjects from the As-treated Population 
who have a baseline disease assessment with measurable disease and one of the 
following: (1) at least one post-baseline disease assessment, and/or (2) withdrawn from 
study treatment prior to post-baseline disease assessment due to clinical progression or 
death.
•
Crossover Population is defined as all subjects who crossover to receive combination 
therapy (MEDI4736 in combination with tremelimumab) after confirmed progression on 
the initial treatment assignment of MEDI4736 or tremelimumab monotherapy.
•
Re-treated Population is defined as all subjects who have been re-treated with 
combination therapy (MEDI4736 in combination with tremelimumab) during the first 
12 months of follow-up.
Tabular summaries will be presented by treatment group. Categorical data will be 
summarized by the number and percentage of subjects in each category. Continuous 
variables will be summarized by descriptive statistics. Analyses may be performed for the 
crossover and the re-treated populations (if warranted by data). Additional details of 
statistical analyses will be described in the statistical analysis plan.
4.8.2
Sample Size and Power Calculations
The planned sample size includes up to approximately 135 subjects in Phase 1b/2. 
4.8.2.1
Phase 1b………
A safety run-in of up to 9 subjects will be required to investigate the safety and tolerability of 
a dose and schedule selected for dose expansion 
The sample size for Phase 1b of the study is not based on formal statistical power 
considerations. 
4.8.2.2
Phase 2……….
Arms A, B and C (Prior to Amendment 6)
Approximately 125 subjects will be randomly assigned in a 2:2:1 ratio to Arms A, B, or C. 
 
 
 

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Arm D (Prior to Amendment 6)
It is planned to enroll 
 subjects in Arm D.

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Arm E
Approximately 
 additional subjects who are biomarker positive will be assigned to Arm E. 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
4.8.3
Efficacy……….
The efficacy analysis will be based on the As-treated Population. Sensitivity analyses for 
response-related endpoints (OR, DoR, and DC) will be performed based on the Response 
Evaluable Population. 
The following response-related endpoints and corresponding time-to-event endpoints for
primary and secondary efficacy endpoints programmatically-derived from the investigator’s 
assessments or BICR, as well as OS, will be analyzed. More details will be provided in the 
statistical analysis plan.

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•
OR is defined as best overall response of confirmed CR or confirmed PR according to 
RECIST v1.1. The best overall response is defined as the best response (in the order of 
CR, PR, SD, PD, and not evaluable) among all overall responses recorded from the start 
of treatment/until progression, or the last evaluable disease assessment in the absence of 
PD prior to the initiation of subsequent anticancer therapy or discontinuation from the 
study, whichever occurs first. The best overall response of CR or PR must be confirmed, 
which means a response of CR/PR is recorded at 1 visit and confirmed by repeat imaging 
not less than 28 days (4 weeks) after the visit when the response was first observed with 
no evidence of progression between the initial and CR/PR confirmation visit.
•
DoR is defined as the duration from the first documentation of OR to the first 
documented disease progression according to RECIST v1.1 or death due to any cause, 
whichever occurs first. For subjects who are alive and progression-free at the time of 
DCO for analysis, DoR will be censored at the last tumor assessment date. The DoR will 
be evaluated only for the subjects with an OR.
•
DC is defined as confirmed CR, confirmed PR, or SD based on RECIST v1.1. DC at 
16 and 24 weeks is defined as a best overall response of confirmed CR, confirmed PR or 
having SD with duration of SD lasting 16 and 24 weeks, respectively.
•
PFS will be measured from the date of randomization or start of treatment until the 
documentation of disease progression according to RECIST v1.1 or death due to any 
cause, whichever occurs first. For subjects who are alive and progression-free at the time 
of DCO for analysis, PFS will be censored at the last tumor assessment date. PFS-6 and 
 are the proportion of subjects with PFS at 6 months 
, respectively.
•
OS will be measured as the time from date of randomization or the start of treatment until 
death due to any cause. For subjects who are alive at the time of DCO, OS will be 
censored on the last date when subjects are known to be alive.
4.8.3.1
Primary Efficacy Analysis
Phase 2 
•
The 2 co-primary efficacy endpoints for Phase 2 are OR and PFS-6 based on RECIST 
v1.1. The primary analysis of primary efficacy endpoints will be performed as follows.
•
The ORR is defined as the proportion of subjects with OR. The 2 sided 90 and 95% CIs 
for ORR will be estimated using the exact binomial distribution. In addition, to help make 
a comparison to historical data, the unconfirmed ORR which is defined as the proportion 
of subjects who achieved a best overall response of confirmed/unconfirmed CR or 
confirmed/unconfirmed PR will be presented along with its CIs.
•
The PFS-6 is the proportion of subjects with PFS at 6 months. Kaplan-Meier curves will 
be generated for PFS and used to estimate the PFS-6 along with its 2-sided 90% and 95% 
CIs. The CIs for PFS-6 will be calculated by applying asymptotic normality to the log-log 
transformation of PFS-6.

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4.8.3.2
Secondary Efficacy Analyses
Phase 1b
Secondary efficacy endpoints for Phase 1b include OR and DC according to RECIST v1.1.
The analysis of each efficacy endpoint is described below.
•
The ORR is defined as the proportion of subjects with OR. The 2-sided 90% and 95% 
CIs of ORR will be provided based on an exact probability method.
•
The DCR is defined as the proportion of subjects with DC. The 2-sided 90% and 95% 
CIs of DCR will be provided using an exact probability method. DCR-16w and 
DCR-24w (defined as the proportion of subjects with DC at 16 and 24 weeks, 
respectively) will be estimated along with their 2-sided 90% and 95% CIs. 
Phase 2 
Secondary efficacy endpoints for Phase 2 include DoR, DC, PFS, and OS. The analyses of all 
secondary endpoints will be performed as follows:
•
The DoR according to RECIST v1.1 will be analyzed using the Kaplan-Meier method for 
those subjects with OR in the corresponding analysis populations. The median of DoR 
with 90% and 95% CIs will be estimated based on the Kaplan-Meier curves. 
•
The DCR according to RECIST v1.1 is defined as the proportion of subjects with DC.
The 2-sided 90% and 95% CIs of DCR will be provided using an exact probability 
method. DCR at 16 and at 24 weeks (defined as the proportion of subjects with DC at 16 
and 24 weeks, respectively) will be estimated along with their 2-sided 90% and 95% CIs. 
•
The PFS according to RECIST v1.1 will be analyzed using the Kaplan-Meier method. 
The median PFS with 90% and 95% CIs will be estimated based on the Kaplan-Meier 
curves. The landmark 9-months PFS rate will be estimated based on the Kaplan-Meier 
curves along with their 2-sided 90% and 95% CIs.
•
The OS will be analyzed using the Kaplan-Meier method. The median OS with 90% and 
95% CIs will be estimated based on the Kaplan-Meier curves. The 1-year OS rate will be 
estimated based on the Kaplan-Meier curves along with their 2-sided 90% and 95% CIs.
Only subjects whose archival tumor tissue sample showed a positive IFN-γ gene expression 
signature will be eligible for enrollment to Arm E. This will allow identification of a unique 
population of gastric or GEJ adenocarcinoma subjects who may benefit from treatment with 
immune checkpoint inhibitors and will allow correlations between IFN-γ gene expression 
and clinical activity of MEDI4736 in combination with tremelimumab to be explored.   

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4.8.4
Safety……….
The safety analysis will be based on the As-treated Population, and will include AEs, SAEs, 
laboratory evaluations, vital signs, ECGs, and physical examinations from both Phase 1b and 
Phase 2.

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4.8.4.1
Analysis of Adverse Events
In Phase 1b, the number of DLTs that are identified in the DLT Evaluable Population during 
the DLT evaluation period will be summarized or listed. For both Phase 1b and Phase 2, the 
number and percentage of subjects reporting treatment-emergent AEs will be summarized 
overall and by the worst NCI CTCAE v4.03 grade, system organ class, and preferred term, 
with a breakdown by treatment arm. Similarly, the number and percentage of subjects 
reporting treatment-emergent AEs considered related to investigational product will be 
summarized. At each level of subject summarization, a subject will be counted once using the 
highest grade and level of causality if one or more occurrences of the same system organ 
class/preferred term is reported. AEs will be graded according to the NCI CTCAE v4.03 and 
coded using the Medical Dictionary for Regulatory Activities. 
4.8.4.2
Analysis of Clinical Laboratory Parameters
Descriptive statistics will be provided for the clinical laboratory results and changes from 
baseline by scheduled time of evaluation and by treatment arm including end of treatment 
visit as well as for the maximum and minimum post-baseline values. Laboratory 
abnormalities will be graded according to the NCI CTCAE v4.03, if applicable. Frequencies 
of worst observed grade will be presented for each laboratory parameter as well as the rates 
of subjects with Grade 3-4 toxicities. A shift table, presenting the 2-way frequency tabulation 
for baseline and the worst post-baseline grade, will be provided for clinical laboratory tests.
4.8.4.3
Analysis of Vital Signs
Descriptive statistics will be provided for the vital signs measurements and changes from 
baseline by scheduled time of evaluation and by treatment arm including end of treatment 
visit as well as for the maximum and minimum post-baseline values.
4.8.4.4
Analysis of Electrocardiograms
ECG parameters (PR, RR, QRS, QT, QTcF) will be summarized using descriptive statistics 
for actual values and for changes from baseline by treatment arm by scheduled time of 
evaluation including end of treatment visit as well as for the maximum post-baseline values. 
The QTcF will be considered as the primary correction method to assess subject cardiac 
safety.
The notable ECG interval values in maximum absolute QTcF intervals 
(new ! 450 milliseconds, new > 480 milliseconds, new > 500 milliseconds) and the 
maximum absolute uncorrected QT intervals (new ! 500 milliseconds) over all post-baseline 
evaluations, as well as in QTcF maximum changes from baseline (! 30 and 

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! 60 milliseconds) over all post-baseline evaluations will be summarized by treatment. 
“New” means the category of the QTc abnormality was not present at baseline and became 
present at least one post-baseline ECG assessment.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5
ASSESSMENT OF SAFETY
5.1
Definition of Adverse Events
The International Council for Harmonisation (ICH) Guideline for Good Clinical Practice 
(GCP) E6(R1) defines an AE as:
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE includes but is not limited to any clinically significant worsening of a subject’s 
pre-existing condition. The term disease progression should not be reported as an AE or 
SAE, however, individual events and/or laboratory abnormalities associated with disease 
progression (see definition of disease progression below) that fulfill the AE or SAE 
definition should be reported. An abnormal laboratory finding (including ECG finding) that 
requires medical intervention by the investigator, or a finding judged by the investigator as 
medically significant should be reported as an AE. If clinical sequelae are associated with a 
laboratory abnormality, the diagnosis or medical condition should be reported (eg, renal 
failure, hematuria) not the laboratory abnormality (eg, elevated creatinine, urine red blood 
cell increased). 
AEs may be treatment emergent (ie, occurring after initial receipt of investigational product) 
or nontreatment emergent. A nontreatment-emergent AE is any new sign or symptom, 

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disease, or other untoward medical event that begins after written informed consent has been 
obtained but before the subject has received investigational product. 
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE.
Adverse Events Associated with Disease Progression
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which the investigational product is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The 
development of a new metastasis or progression of existing metastasis related to the primary 
cancer under study should not be considered an AE. 
New Cancers
The development of a new cancer should be regarded as an SAE. New cancers are those that 
are not the primary reason for the administration of the investigational product and have been 
identified after the subject’s inclusion in the study.
5.2
Definition of Serious Adverse Events
An SAE is any AE that:
•
Results in death
•
Is immediately life-threatening
•
Requires inpatient hospitalization or prolongation of existing hospitalization 
•
Results in persistent or significant disability/incapacity 
•
Is a congenital anomaly/birth defect in offspring of the subject
•
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above
Medical or scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in this situation. Examples of medically important events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 

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convulsions that do not result in hospitalizations; or development of drug dependency or drug 
abuse.
5.3
Definition of Adverse Events of Special Interest
An AESI is one of scientific and medical interest specific to understanding of the 
investigational product and may require close monitoring and rapid communication by the 
investigator to the sponsor. An AESI may be serious or non-serious. The rapid reporting of 
AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of this investigational product.
AESIs for MEDI4736 include but are not limited to events with a potential inflammatory or 
immune-mediated mechanism and which may require more frequent monitoring and/or 
interventions such as steroids, immunosuppressants and/or hormone replacement therapy.
These AESIs are being closely monitored in clinical studies with MEDI4736 monotherapy 
and combination therapy. An irAE is defined as anAE that is associated with drug exposure 
and is consistent with an immune-mediated mechanism of action and where there is no clear 
alternate etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate,
should be used to support an irAE diagnosis. Appropriate efforts should be made to rule out
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the irAE. If the 
investigator has any questions in regards to an AE being an irAE, the Investigator should 
promptly contact the Study Physician.
AESIs observed with MEDI4736 include:
∀
Diarrhea / colitis
•
Pneumonitis / ILD
•
ALT / AST increases / hepatitis / hepatotoxicity
•
Neuropathy / neuromuscular toxicity (eg, Guillain-Barré, and myasthenia gravis) 
•
Endocrinopathies (ie, events of hypophysitis, hypopituitarism adrenal insufficiency, 
diabetes insipidus, hyper- and hypothyroidism and Type I diabetes mellitus)
•
Rash / dermatitis
•
Nephritis / blood creatinine increases
•
Pancreatitis (or labs suggestive of pancreatitis - increased serum lipase , increased serum 
amylase) 
•
Other inflammatory responses that are rare with a potential immune-mediated aetiology 
include, but are not limited to, myocarditis, pericarditis, and uveitis 

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•
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological aetiology are also considered AESIs. 
Further information on these risks (eg, presenting symptoms) can be found in the current 
version of the MEDI4736 Investigator’s Brochure. More specific guidelines for their 
evaluation and treatment are described in detail in guidelines for their evaluation and 
treatment are described in detail in the Dosing Modification and Toxicity Management 
Guidelines (see Appendix 5). These guidelines have been prepared by the Sponsor to assist 
the Investigator in the exercise of his/her clinical judgment in treating these types of 
toxicities. These guidelines apply to AEs considered causally related to the study drug/study 
regimen by the reporting investigator.
Hypersensitivity Reactions
Hypersensitivity reactions as well as infusion-related reactions have been reported with 
anti-PD-L1 and anti-PD-1 therapy (Brahmer et al, 2012). As with the administration of any 
foreign protein and/or other biologic agents, reactions following the infusion of mAbs can be 
caused by various mechanisms, including acute anaphylactic (IgE-mediated) and 
anaphylactoid reactions against the mAb, and serum sickness. Acute allergic reactions may 
occur, may be severe, and may result in death. Acute allergic reactions may include 
hypotension, dyspnea, cyanosis, respiratory failure, urticaria, pruritus, angioedema, 
hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, 
hypertension, myalgia, vomiting, and unresponsiveness.
5.4
Recording of Adverse Events
AEs will be recorded on the eCRF using a recognized medical term or diagnosis that 
accurately reflects the event. AEs will be assessed by the investigator for severity, 
relationship to the investigational product, possible etiologies, and whether the event meets 
criteria of an SAE and therefore requires immediate notification to MedImmune Patient 
Safety. See Section 5.2 for the definition of SAEs and Appendix 7 for guidelines for 
assessment of severity and relationship. If an AE evolves into a condition that meets the 
regulatory definition of “serious,” it will be reported on the SAE Report Form.
Infusion of biological products is commonly associated with infusion-related reactions. 
Anaphylaxis and infusion-related reactions have some common manifestations and may be 
difficult to distinguish from each other. Infusion-related reactions are commonly observed 
during or shortly after the first time exposure to therapeutic mAbs delivered through IV 
infusion. These reactions are less common following subsequent exposures. Unlike infusion-

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related reactions, anaphylaxis is a rare event, usually occurring after subsequent exposure to 
an antigen, and it is most commonly accompanied by severe systemic skin and/or mucosal 
reactions. The investigator is advised to carefully examine symptoms of adverse reactions 
observed during or shortly after exposure to MEDI4736 and tremelimumab, and consider the 
above mentioned facts prior to making a final diagnosis. Reactions occurring at the time of or 
shortly after subsequent infusions of investigational product are to be judged by the 
investigator at his/her own discretion. For the investigator’s convenience and in order to 
facilitate consistency in judgments a copy of the National Institute of Allergy and Infectious 
Diseases (NIAID) and Food Allergy and Anaphylaxis Network (FAAN) guidance for 
anaphylaxis diagnosis is provided in Appendix 8.
5.4.1
Time Period for Collection of Adverse Events
AEs will be collected from time of signature of informed consent, enrollment, randomization, 
throughout the treatment period and including the follow-up period of 90 days after the last 
dose of MEDI4736 and tremelimumab.
SAEs will be recorded from the time of informed consent signature through 90 days after the 
last dose of MEDI4736 and tremelimumab.
5.4.2
Follow-up of Unresolved Adverse Events
Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the investigator for as long as medically 
indicated, but without further recording in the eCRF. MedImmune retains the right to request 
additional information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary. After 90 days, only subjects with investigational product-related SAEs will 
continue to be followed for safety.
5.4.3
Deaths……….
All deaths that occur during the study, including the protocol-defined follow-up period must 
be reported as follows:
•
Death clearly the result of disease progression should be reported at the next visit 
and documented in the eCRF but should not be reported as an SAE.

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•
Where death is not due (or not clearly due) to disease progression, the AE causing the 
death must be reported as an SAE within 24 hours. The report should contain a comment 
regarding the co-involvement of disease progression, if appropriate, and should assign 
main and contributory causes of death.
•
Deaths with an unknown cause should always be reported as an SAE. A post-mortem 
may be helpful in the assessment of the cause of death, and if performed a copy of the 
post-mortem results should be forwarded to MedImmune Patient Safety or designee 
within the usual timeframes.
5.5
Reporting of Serious Adverse Events
Within 24 hours of identifying an SAE, regardless of the presumed relationship to the 
investigational product, the investigator or qualified designee must complete the SAE 
Report Form and fax it to MedImmune Patient Safety.
MedImmune contact information: 
 
The sponsor is responsible for reporting certain SAEs as expedited safety reports to 
applicable regulatory authorities, ethics committees, and participating investigators, in 
accordance with ICH guidelines and/or local regulatory requirements. The sponsor may be 
required to report certain SAEs to regulatory authorities within 7 calendar days of being 
notified about the event; therefore, it is important that investigators submit additional 
information requested by the sponsor as soon as it becomes available.
Investigators should provide all available information at the time of SAE Report Form 
completion. Investigators should not wait to collect additional information to fully document 
the event before notifying MedImmune Patient Safety of an SAE. When additional 
information becomes available, investigators should submit a follow-up SAE Report Form 
(separate from the initial report form) with the new information. Any follow-up information 
to an SAE also needs to be provided to MedImmune Patient Safety within 24 hours of 
learning of the new information. 

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5.6
Other Events Requiring Immediate Reporting
5.6.1
Overdose……….
An overdose is defined as a subject receiving a dose of investigational product in excess of 
that specified in the Investigator’s Brochures, unless otherwise specified in this protocol.
Any overdose of a study subject with the investigational product, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to 
MedImmune Patient Safety using the Safety Fax Notification Form (see Section 5.5 for 
contact information). If the overdose results in an AE, the AE must also be recorded on the 
AE eCRF (see Section 5.4). Overdose does not automatically make an AE serious, but if the 
consequences of the overdose are serious, for example death or hospitalization, the event is 
serious and must be reported as an SAE (see Section 5.4 and Section 5.5). MedImmune does 
not recommend specific treatment for an overdose. The investigator will use clinical
judgment to treat any overdose.
5.6.2
Hepatic Function Abnormality
Hepatic function abnormality meeting the definition of Hy’s law (ie, any increase in ALT or 
AST to greater than 3 × ULN and concurrent increase in total bilirubin to be greater than 
2 × ULN) is considered an AESI. Concurrent findings are those that derive from a single 
blood draw or from separate blood draws taken within 8 days of each other. Follow-up 
investigations and inquiries will be initiated promptly by the investigational site to determine 
whether the findings are reproducible and/or whether there is objective evidence that clearly 
supports causation by a disease (eg, cholelithiasis and bile duct obstruction with distended 
gallbladder) or an agent other than the investigational product. Guidelines for management of 
subjects with hepatic function abnormality are outlined in Section 3.1.5.
Hepatic function abnormality in a study subject, with or without associated clinical 
manifestations, is required to be reported as “hepatic function abnormal” within 24 hours of 
knowledge of the event to MedImmune Patient Safety using the Safety Fax Notification Form 
(see Section 5.5 for contact information), unless a definitive underlying diagnosis for the 
abnormality (eg, cholelithiasis or bile duct obstruction) that is unrelated to investigational 
product has been confirmed.
If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study subject will 
be based on the clinical judgment of the investigator.

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If no definitive underlying diagnosis for the abnormality is established, dosing of the study 
subject must be interrupted immediately. Follow-up investigations and inquiries must be 
initiated by the investigational site without delay.
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor. If the etiology of the event remains unconfirmed and/or is 
considered related to investigational product (see Appendix 7), a prompt cumulative review 
of safety data and the circumstances of the event in question will be conducted and assessed 
by the MedImmune Safety Monitoring Committee (SMC; or equivalent) to determine 
whether continued dosing of current study subjects and/or study entry should be interrupted, 
whether the protocol will be modified, or whether the study will be discontinued 
permanently. Review and approval by the SMC (or equivalent) is required for resumption of 
subject dosing or study entry in the event that the study is interrupted. Where applicable, 
regulatory authorities IRBs/IECs will be notified of any actions taken with the study.
5.6.3
Pregnancy……….
Pregnancy in a female subject who has received investigational product is required to be 
reported within 24 hours of knowledge of the event to MedImmune Patient Safety using the 
Safety Fax Notification Form (see Section 5.5 for contact information).
Subjects who become pregnant during the study period must not receive additional doses of 
investigational product but will not be withdrawn from the study. The pregnancy will be 
followed for outcome of the mother and child (including any premature terminations) and 
should be reported to MedImmune Patient Safety after outcome.
Should the investigator become aware of a pregnancy in the partner of a male study subject 
who has received investigational product this should be reported within 24 hours of 
knowledge of the event to MedImmune Patient Safety using the Safety Fax Notification 
Form (see Section 5.5 for contact information). The sponsor will endeavor to collect follow-
up information on such pregnancies provided the partner of the study subject provides 
consent.

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6
STUDY AND DATA MANAGEMENT
6.1
Training of Study Site Personnel
Before the first subject is entered into the study, a MedImmune representative will review 
and discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study-specific procedures and system(s) 
utilized.
The principal investigator will ensure that appropriate training relevant to the study is given 
to all of these staff, and that any new information relevant to the performance of this study is
forwarded to the staff involved.
The principal investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
6.2
Monitoring of the Study
During the study, a MedImmune representative will have regular contacts with the study site, 
including visits to:
•
Provide information and support to the investigator(s).
•
Confirm that facilities remain acceptable.
•
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed.
•
Perform source data verification (a comparison of the data in the eCRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating subjects. This will 
require direct access to all original records for each subject (eg, clinic charts).
•
Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject.
The MedImmune representative will be available between visits if the investigator(s) or other 
staff at the center needs information and advice about the study conduct.
6.2.1
Source Data
Refer to the Clinical Study Agreement for location of source data.

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6.2.2
Study Agreements
The principal investigator at each/the center should comply with all the terms, conditions, 
and obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of 
any inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, 
the terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and 
the treatment of subjects and in all other respects, not relating to study conduct or treatment 
of subjects, the terms of the Clinical Study Agreement shall prevail.
Agreements between MedImmune and the principal investigator must be in place before any 
study-related procedures can take place, or subjects are enrolled.
6.2.3
Archiving of Study Documents
The investigator follows the principles outlined in the Clinical Study Agreement.
6.3
Study Timetable and End of Study
An individual subject will be considered to have completed the study if the subject was 
followed through the end of the study (defined below), regardless of the number of doses of 
investigational product that was received. 
The end of the study (“study completion”) is 5 years after the final subject is enrolled or the 
date the study is closed by the sponsor, whichever occurs first.
6.4
Data Management
Data management will be performed according to the Data Management Plan.
A Web Based Data Capture system will be used for data collection and query handling. The 
investigator will ensure that data are recorded on the eCRFs as specified in the study protocol 
and in accordance with the instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.
6.5
Medical Monitor Coverage
Each subject will be provided with contact information for the principal investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 

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physician access to a medical monitor 24 hours a day, 7 days a week in the event of an 
emergent situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or health care provider 
requires access to a physician who has knowledge of the investigational product and the 
clinical study protocol and the principal investigator is not available, the treating physician or 
health care provider can contact a medical monitor through this system, which is managed by 
a third party vendor.
7
ETHICAL AND REGULATORY REQUIREMENTS
7.1
Ethical Conduct of the Study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, and applicable regulatory 
requirements.
7.2
Subject Data Protection
The informed consent form (ICF) will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
MedImmune will not provide individual genotype results to subjects, any insurance 
company, any employer, their family members, general physician or any other third party, 
unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked 
to the identity of the subject. In exceptional circumstances, however, certain individuals 
might see both the genetic data and the personal identifiers of a subject. For example, in the 
case of a medical emergency, a MedImmune medical monitor or an investigator might know 
a subject’s identity and also have access to his or her genetic data. Also regulatory authorities 
may require access to the relevant files, though the subject’s medical information and the 
genetic files would remain physically separate.
7.3
Ethics and Regulatory Review
An IRB/IEC should approve the final study protocol, including the final version of the ICF
and any other written information and/or materials to be provided to the subjects. The 
investigator will ensure the distribution of these documents to the applicable IRB/IEC, and to 
the study site staff.

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The opinion of the IRB/IEC should be given in writing. The investigator should submit the 
written approval to MedImmune before enrollment of any subject into the study. 
The IRB/IEC should approve all advertising used to recruit subjects for the study.
MedImmune should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the protocol should be re-approved by the IRB/IEC annually.
Before enrollment of any subject into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.
MedImmune will handle the distribution of any of these documents to the national regulatory 
authorities.
MedImmune will provide regulatory authorities, IRB/IEC, and principal investigators with 
safety updates/reports according to local requirements, including suspected unexpected 
serious adverse reactions, where relevant.
Each principal investigator is responsible for providing the IRB/IEC with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the 
investigational product. MedImmune will provide this information to the principal 
investigator so that he/she can meet these reporting requirements.
7.4
Informed Consent
The principal investigator(s) at each center will:
•
Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study
•
Ensure each subject is notified that they are free to discontinue from the study at any time
•
Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided
•
Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study
•
Ensure the original, signed ICF(s) is/are stored in the investigator’s Study File
•
Ensure a copy of the signed ICF is given to the subject

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•
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the ICF that is approved by an IRB/IEC
7.5
Changes to the Protocol and Informed Consent Form
Study procedures will not be changed without the mutual agreement of the coordinating 
investigator and MedImmune.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol.
The amendment is to be approved by the relevant IRB/IEC and if applicable, also the 
national regulatory authority approval, before implementation. Local requirements are to be 
followed for revised protocols.
MedImmune will distribute any subsequent amendments and new versions of the protocol to 
each principal investigator(s). For distribution to IRB/IEC, see Section 7.3.
If a protocol amendment requires a change to a site’s ICF, MedImmune and the site’s 
IRB/IEC are to approve the revised ICF before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each IRB/IEC.
7.6
Audits and Inspections
Authorized representatives of MedImmune, a regulatory authority, or an IRB/IEC may 
perform audits or inspections at the center, including source data verification. The purpose of 
an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data 
were recorded, analyzed, and accurately reported according to the protocol, GCP, guidelines 
of the ICH, and any applicable regulatory requirements. The investigator will contact 
MedImmune immediately if contacted by a regulatory agency about an inspection at the site.

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8
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Nurieva R, Thomas S, Nguyen T, Martin-Orozco N, Wang Y, Kaja MK, et al. T-cell 
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9
SUMMARY OF PROTOCOL AMENDMENT AND 
ADMINISTRATIVE CHANGES TO THE PROTOCOL
9.1
Protocol Amendment 1, 12Dec2014
The purpose of this amendment was to address comments by the FDA. Key changes were as 
follows: 1) clarified that MedImmune does not plan to dose escalate beyond the starting 
doses stated in the protocol; 2) revised the stopping rules for severe late immune-related 
toxicities; and 3) removed the statement that laboratory abnormalities not deemed to be 
clinically significant will not be considered DLT. Text revisions resulting from this 
amendment are incorporated in the body of Protocol Amendment 1. Major changes to the 
protocol are summarized below.
1. Protocol Synopsis: The synopsis was updated to align with the body of the protocol.
2. Section 3.1.1 (Overview): Added text to clarify that dose levels higher than the starting 
dose levels stated in the protocol will not be explored.
3. Section 3.1.3.1 (Dose-exploration Criteria for Phase 1b): Removed any reference to dose 
escalation from this section.
4. Section 3.1.3.2 (Dose-limiting Toxicity): Removed the statement, “Laboratory 
abnormalities that are no deemed to be clinically significant will not be considered a 
DLT.”
5. Section 3.1.4 (Phase 2): The following changes were made:
◦
Replaced “dose expansion” with “Phase 2”, and replaced “dose exploration with 
“Phase 1b.”
◦
Added the following statement: “In addition, after the first 20 subjects have been 
dosed with MEDI4736 in combination with tremelimumab for a minimum of 6 weeks 
(in both second- and third-line settings), safety data will be reviewed by the sponsor.”
6. Section 4.1.3 (Exclusion Criteria): Revised criterion 10 to indicate “Any prior therapy 
that has NOT been…”
7. Section 4.1.6 (Discontinuation of Investigational Product): The following changes were 
made:
◦
Revised criterion 4 as follows (changes underlined): “Subject experienced an AE that 
meets the criteria for a DLT during the DLT evaluation period (for Phase 1b and 
Phase 2; see Section 3.1.3.2 for definition of DLT).
◦
Added criterion 5: “Subject experienced an AE that meets the criteria for a DLT, 
except its occurrence is outside the DLT evaluation period (for Phase 1b and Phase 2; 
see Section 3.1.3.2 for definition of DLT).”
8. Section 4.2.2 (Randomized Treatment Period): Added “Procedures/Study Day” to header 
of Table 4.2.2-1 (Schedule of Treatment Period Study Procedures Weeks 1 to 25).

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9.2
Protocol Amendment 2, 22Jan2015
The purpose of this amendment was to address comments by the FDA. The key change was 
to state that fresh tumor biopsies should be preferentially obtained from tumor tissues that are 
safely accessible.
1. Section 4.1.2 (Inclusion Criterion 7): Language was added to indicate that fresh tumor 
biopsies should be preferentially obtained from tumor tissues that are safely accessible.
2. Table 4.2.1-1 (Schedule of Screening/Baseline Procedures): Electrocardiograms in 
triplicate were removed from the screening period. A single ECG is required at this time 
point.
3. Table 4.2.2-1 (Schedule of Treatment Period Study Procedures Weeks 1 to 25): 
Electrocardiogram on Week 17 Day 1 was changed to Week 9 Day 1 1 to allow recording 
of ECGs of subjects who progress prior to Week 17.
4. Section 4.3.2.1 (Fresh Tumor Biopsies [Phase 2 Only]): Text was added to indicate that 
fresh tumor biopsies should be preferentially obtained from tumor tissues that are safely 
accessible as determined by the investigator and achieved via non-significant risk 
procedures.
5. Section 4.3.4.2 (Electrocardiograms): Electrocardiograms in triplicate were removed 
from the screening period. A single ECG is required at this time point. The formula for 
analysis of ECGs was changed to Fridericia’s formula for consistency across other 
studies.
6. Section 4.8.4.4: The formula for analysis of ECGs was changed from Bazett’s to 
Fridericia’s formula for consistency across other studies.
9.3
Protocol Amendment 3, 03Apr2015
The purpose of this amendment was to delete Scenarios 1 and 2; Scenario 2 will be utilized 
under Amendment 3. Language was modified to indicate the selected dose of
 
 to be utilized in Phase 1b. Major changes are listed 
below:
1. The Synopsis was updated to align with changes made to the protocol body.
2. Section 1.4.1 (MEDI4736 Clinical Experience): Clinical experience with combination 
therapy was moved to section 1.4.3.
3. Section 1.4.2 (Tremelimumab Clinical Experience): Tremelimumab clinical data were 
updated based on the most recent Investigator’s Brochure (12Nov2014 data cut-off date).
4. Section 1.4.3 (Clinical Experience with MEDI4736 and Tremelimumab Combination): 
This section was added to describe clinical experience with MEDI4736 + tremelimumab 
combination therapy.
5. Section 1.5 (Rationale for Conducting the Study): A subsection for benefit-risk 
evaluation was added.

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6. Section 3.1.1 (Overview): Text for Scenario 1, which was to be followed if a dose and 
schedule were not identified in Study D4190C00006, was deleted. Text was added to 
describe the MEDI4736 + tremelimumab combination dose and schedule that were 
identified in Study D4190C00006. Language was added to indicate that any Phase 1b 
cohort not exceeding the MTD may be expanded up to a maximum of 
subjects for 
further evaluation of exposure versus safety, 
and efficacy. The 
study flow diagram was updated to reflect the study conduct under Amendment 3.
 
 
 
 
 
9. Section 3.1.2.4 (Criteria for Treatment Beyond Progression, Crossover, and Retreatment 
in the Follow-up Period): Text describing retreatment was added.
10. Section 3.1.3.2 (Dose-limiting Toxicity): Text describing DLT evaluation for
 
dosing was deleted.
11. Section 3.1.5 (Management of Study Medication Related Toxicities): Table 3.1.5-1 was 
deleted and new toxicity management guidelines were inserted in Appendix 5. 
12. Section 3.2.1 (Dose Rationale): The dose rationale for combination therapy was updated 
based on latest available data.
13. Section 4.1.2 (Inclusion Criteria): Inclusion criterion 8 was modified. The following 
statement was deleted: “For subjects enrolling in Phase 1b, if an archival specimen is not 
considered suitable for biomarker studies, the subject must provide consent and undergo 
a fresh tumor biopsy during screening.”
14. Section 4.1.3 (Exclusion Criteria): Exclusion criterion 13 was modified to exclude 
subjects with true positive test results for HIV, hepatitis B, or hepatitis C. Hepatitis A was 
deleted from the exclusion criterion.
15. Section 4.1.8 (Withdrawal of Informed Consent for Data and Biological Samples): Under 
the subsection Samples Obtained for Genetic Research or Future Research, the following 
sentence was deleted: “A file linking this sample identification number with the SID 
number will be kept in a secure place at the sponsor with restricted access.” 
Modifications were made to describe that the sample identification number is linked to 
the SID number.
16. Section 4.2.1 (Enrollment/Screening Period): Screening procedures are required for 
subjects at initial enrollment and prior to re-treatment; screening does not need to be 
repeated for subjects who crossover from monotherapy to combination therapy. Disease 
assessment does not need to be repeated if done within 28 days of first dose on the 
retreatment schedule.
17. Section 4.2.2 (Randomized Treatment Period): Table 4.2.2-1 will be followed for the 
initial Week 1 to 25 treatment period, if subjects enter reinduction, if subjects enter re-

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treatment, or if subjects are allowed to crossover. Evaluation of ECOG performance 
status was added at Weeks 5, 13, and 21, and at Weeks 29, 37, and 45 in Table 4.2.2-2. 
 
 
 
 
 
19. Section 4.3.5 (Clinical Laboratory Tests): Red blood cell count and hematocrit were 
added to hematology tests.
20. Section 4.3.9 (Estimate of Volume of Blood to be Collected): Blood volume during 
screening was decreased to approximately 43 mL. No more than 63 mL blood will be 
drawn for any one protocol visit during treatment. Blood volume during follow-up was 
decreased to approximately 33 mL.
21. Section 4.8.2.1 (Phase 1b): Text was modified to indicate that the number of subjects is
based on a safety run-in schema and may be expanded to a maximum of
 subjects for 
any cohort if the MTD is not exceeded.
22. Appendix 5 (MEDI4736 and Tremelimumab Dose Modifications for Toxicity 
Management): Toxicity management information was modified to align with current 
practice and moved to the appendix from Section 3.1.5.
9.4
Protocol Amendment 4, 10Apr2015
The purpose of this amendment is to correct Table 4.2.2-2 (Schedule of Treatment Period 
[Initial, Retreatment, Reinduction, and Crossover] Study Procedures Weeks 27 to End of 
Treatment). In Protocol Amendment 3, there was a formatting error in the sequence of the 
Section 4.2.2 table heading numbering; consequently the Table 4.2.2-2 was truncated. Also 
the serology exclusion criterion was updated and minor edits were added.
1. Table 4.2.2-2 (Schedule of Treatment Period [Initial, Retreatment, Reinduction, and 
Crossover] Study Procedures Weeks 27 to End of Treatment) has been restored in full.
2. Section 4.1.3 (Exclusion Criteria): Exclusion Criterion 13 was changed from “True 
positive test results for HIV, hepatitis B, or hepatitis C” to “Known positive for HIV, 
chronic or active hepatitis B or C or active hepatitis A.”
3. Synopsis; Section 4.8.8: Futility analysis for Arm A and Arm B in Phase 2 was added.

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9.5
Protocol Amendment 5 21Dec2015
The purpose of this amendment was to update the study design and to update the description 
of study procedures. Additionally, the potential expansion plan for third-line gastric or GEJ 
adenocarcinoma, Arm D, was updated. Clarifications of eligible prior therapies, study 
schedules, collection of vitals and ECGs were also made.
1. The EudraCT number was added and the information for the Medical Monitor was 
updated.
2. The Protocol synopsis text was modified to include updated eligibility and study design.  
Planned analyses in the summary section were updated. 
3. Section 1.4 Summary of Clinical Experience and subheadings were updated based on 
current information from clinical studies.
4. Section 2.1.1 Primary Objectives the abbreviation for RECIST was used in replacement 
of the full term. 
 
6. Section 3.1.1 was updated with new criteria to provide clarification regarding subject 
eligibility
7. Figure 3.1.1-1 The study flow diagram was updated to reflect changes in study design. 
8. Section 3.1.2 Treatment Regimen was updated to provide clarification for the duration of 
infusion.
9. Section 3.1.4 was updated to provide additional details for the Arm D expansion cohort.
10. Section 3.1.5 Management of Study Medication Related Toxicities was updated based on 
02Oct2015 Dosing and Toxicity Management Guidelines.
11. Section 3.2.3 Rationale for Endpoints was updated to include information on how data 
would be reviewed.
12. Section 4.1.2 Inclusion criteria updated to include clarifications of eligible prior therapy, 
hepatitis history, hemoglobin, transfusion time prior to study enrollment, and number of 
weeks from last paracentesis prior to study enrollment.
 
13. Table 4.2.2-1 was updated to reflect new highly effective methods of contraception.
14. Section 4.2.1 was updated to specify that subjects who enter reinduction do not need to 
undergo repeated screening. 
15. Table 4.2.1-1 Schedule of Screening/Baseline Procedures was updated to clarify labs for 
reinduction. 
16. Table 4.2.2-1 Schedule of Treatment period was updated to clarify collection of vital 
signs and ECGs across the treatment arms. 
17. Table 4.2.3-1 Schedule of Follow-up Procedures was clarified to allow urine or serum 
pregnancy tests. 
18. Section 4.3.1 Efficacy was updated to clarify written statements.

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19. Section 4.5.1.4 Treatment Administration was update to clarify the duration of 
MEDI4736 infusion.
20. Section 4.5.1.5 Monitoring Dose Administration was updated to clarify collection of vital 
signs across the treatment arms. 
21. Section 4.7.1 was clarified to remove the sentence regarding use of opioids.
22. Section 4.8 was updated with the planned number of subjects, sample size and power 
calculations for Phase 2.
23. Section 4.8.8 Interim analysis was updated commensurate with the amended study 
design. Added text to clarify futility cut-off in the initial group of patients prior to 
proceeding with a potential expansion of Arm D.
24. Section 4.8.2.2 Sample size and power calculations updated to describe a futility cut-off 
in the initial group of patients prior to proceeding with a potential expansion of Arm D. 
25. Section 5.2 Definition of Serious Adverse Events was revised with updated MedImmune 
patient safety guidelines.
26. Section 5.3 Definition of Adverse Events of Special Interest was revised with updated 
MedImmune patient safety guidelines.
27. Section 5.6.2 Hepatic Function Abnormality was updated.
28. Appendix 5 MEDI4736 and Tremelimumab Dose Modifications for Toxicity 
Management was updated according to MedImmune patient safety guidelines.
9.6
Protocol Amendment 6 24Jan2017
The purpose of this amendment was to add a new arm (Arm E) to the Phase 2 portion of the 
study to evaluate the efficacy and safety of MEDI4736 in combination with tremelimumab in 
subjects with second- and third-line gastric or GEJ adenocarcinoma with a positive tumor 
IFN-γ gene expression signature. Major changes to the protocol are summarized below.
1. The EudraCT number was deleted as the study will no longer be opened in the EU.
2. Information for the Medical Monitors was updated.
3. Protocol Synopsis: The synopsis was updated to align with the body of the protocol.
4. Section 1.3.1 (MEDI4736 Nonclinical Experience): The summary of toxicology studies 
was updated.
5. Section 1.4.1 (MEDI4736 Clinical Experience): The section was revised to include 
updated data.
6. Section 1.4.2 (Tremelimumab Clinical Experience): The section was revised to include 
updated data.
 
 
8. Section 1.5 (Rationale for Conducting the Study): Rationale was added for patient 
selection based on tumoral IFN-γ gene expression signature in Arm E.

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9. Section 2.1.1 (Primary Objectives): The primary objective for Phase 2 was amended to 
specify the inclusion of subjects with second and third-line metastatic or recurrent gastric 
or GEJ adenocarcinoma whose tumors have a positive IFN-γ gene expression signature.
10. Section 2.1.2 (Secondary Objectives, Number 3): Amended to specify the inclusion of 
subjects with second- and third-line metastatic or recurrent gastric or GEJ 
adenocarcinoma whose tumors have a positive IFN-γ gene expression signature.
 
12. Section 2.2.1 (Primary Endpoints): The primary endpoint for Phase 2 was amended to 
specify the inclusion of subjects with second and third-line metastatic or recurrent gastric 
or GEJ adenocarcinoma whose tumors have a positive IFN-γ gene expression signature.
13. Section 2.2.2 (Secondary Endpoints): A new secondary endpoint "IFN- gene expression 
signature and how it correlates with clinical activity of MEDI4736 in combination with 
tremelimumab." was added.
 
15. Section 3 (Study Design): The study design section was updated to add a new study flow 
diagram, add the criteria the subjects must be meet to be enrolled in Arm E, update the 
approximate number of subjects to be enrolled, add the current status of Phase 1b, 
describe the addition of Arm E to Phase 2 of the study, and state the subject numbers in 
Arms A, B, C, and D at the time of the interim analyses. References to the expansion of 
Arm D up to 
 were removed.
16. Section 3.1.2.4 (Criteria for Treatment Beyond Progression, Crossover, and Retreatment 
in the Follow-up Period): The criteria governing treatment beyond progression and 
retreatment for subjects who enter follow-up were clarified and details for treatment 
beyond progression in Arm E were added.
17. Section 3.1.3 (Phase 1b): A status update for Phase 1b was added.
18. Section 3.1.4 (Phase 2): A status update for Phase 2 was added, including the addition of 
Arm E and the removal of the expansion of Arm D by up to 
 additional subjects. 
19. Section 3.2.3 (Rationale for Endpoints): The rationale for the new secondary endpoint 
"IFN- gene expression signature and how it correlates with clinical activity of MEDI4736 
in combination with tremelimumab." was added.
 
20. Section 4.1.1 (Number of Subjects): The approximate number of subjects to be enrolled 
in Phase 1b/2 was updated 
.
21. Section 4.1.2 (Inclusion Criteria),the following changes were made:
◦
Inclusion criterion 5 was updated to specify prior lines of therapy for subjects in 
Arm E. 
◦
Inclusion criterion 6 was added to describe pre-screening for IFN-α expression for 
enrollment into Arm E of Phase 2 and to specify the requirement for subjects 
enrolling to Arm E to provide archival tumor tissue for IFN-γ testing. 

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◦
Inclusion criterion 7 (was inclusion criterion 6) revised to remove requirement for 
measurable disease at baseline confirmed by 
 for the planned expansion in 
Arm D, which has now been removed from the protocol.
◦
Inclusion criteria 11 and 12 (were criteria 10 and 11, respectively) revised to update 
text regarding contraception.
◦
Inclusion criterion 13 was added to specify requirements regarding blood donation for 
subjects participating in this study.
22. Section 4.1.4 (Subject Enrollment and Randomization): The text was revised to include 
pre-screening evaluations where appropriate.
23. Section 4.2.1 (Enrollment/Screening Period), Table 4.2.1-1: The table title was amended 
to clarify that
 
 
; a footnote was 
added to provide a list of hepatitis B and C tests, to accommodate global practices; a 
footnote was added to specify that in Arm E only archival tumor tissue (no older than 
36 months) will be accepted for biomarker pre-screening.
24. Section 4.2.2 (Randomized Treatment Period), Table 4.2.2-1: The table title was 
amended to clarify that
Text was added to specify that the physical examination 
includes measurement of weight.
 
Footnote “d” was modified to remove the requirement to obtain ECGs on Day 1 of 
Week 1 in triplicate; footnote “f” was modified to clarify details of 
 
 Table 4.2.2-2: The table title was 
amended to clarify that schedule is applicable as of Amendment 6, text was added to 
specify that the physical examination includes measurement of weight,
25. Section 4.2.3 (Follow-up Period), Table 4.2.3-1: The table title was amended to clarify 
that
 
 
 
 
26. Section 4.3.1 (Efficacy): Text was added to specify that CT or MRI scans of the head and 
neck will be performed at screening but that follow-up scans will be optional unless 
disease is found on the screening examination or clinically indicated.
27. Section 4.3.2.1 (Fresh Tumor Biopsies [Phase 2 Only]):
 
28. Section 4.3.2.2 (Archival Tumor Samples [Phase 1b and Phase 2]): Text was added to 
state that in Phase 2 Arm E 
 will be accepted for biomarker 
pre-screening; in all other Phase 2 arms and in Phase 1b, when an archival tumor 
 
cannot be provided then only freshly cut sections should be provided.

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29. Section 4.3.4.2 (Electrocardiograms): Text was modified to remove the requirement to 
obtain ECGs on Day 1 of Week 1 in triplicate.
30. Section 4.3.8 (Biomarker Evaluation and Methods)
 
 
 
31. Section 4.3.9 (Estimate of Volume of Blood to be Collected): Blood volumes updated to 
account 
 
.
32. Section 4.6.1 (Methods for Assigning Treatment Groups): Text revised in line with the 
addition of Arm E to Phase 2. Text regarding ensuring balance between treatment groups 
with respect to PD-L1 expression level was deleted.
33. Section 4.8.1 (General Considerations): Arm E was added to the list of arms in which the 
primary analysis may occur after all subjects in the arm have either discontinued from the 
study or been on the study for at least 7 months.
34. Section 4.8.2 (Sample Size and Power Calculations): The approximate number of 
subjects to be enrolled in Phase 2 was updated, the sample size considerations for
expansion of Arm D 
 was deleted, the sample size 
calculations for Arm E were added.
35. Section4.8.3 (Efficacy): The text detailing the expansion of Arm D 
 
 was deleted.
36. Section 4.8.3.2 (Secondary Efficacy Analyses): Text was added that detailed the
enrollment of subjects whose archival tumor tissue sample showed a positive IFN-γ gene 
expression signature to Arm E.
 The text was amended to
clarify that the 
38. Section 4.8.8: Text describing the interim analysis for Arm D was deleted. It was 
originally planned to perform an interim analysis for Arm D when
 subjects had been 
enrolled and followed for at least 8 weeks; enrollment could be stopped if ≤ 2 out of the 
subjects experienced a CR/PR or at the Sponsor’s discretion. Text describing the 
interim analysis that will be performed for Arm E was added.
39. Section 5.3: The list of AESIs observed with MEDI4736 was updated. A new subsection 
on hypersensitivity reactions was added. Text on the the Dosing Modification and 
Toxicity Management Guidelines (which are presented in Appendix 5) was added.
40. Section8: New references were added and references that are no longer cited were 
removed.
41. Appendix 5: The guidelines for MEDI4736 and tremelimumab toxicity management were 
updated according to the 31Aug2016 version.

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Appendix 1
Signatures

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Sponsor Signature(s)
A Phase 1b/2 Study of MEDI4736 in Combination with Tremelimumab, MEDI4736 
Monotherapy, and Tremelimumab Monotherapy in Subjects with Metastatic or Recurrent 
Gastric or Gastroesophageal Junction Adenocarcinoma
I agree to the terms of this protocol.
Signature and date: electronic signature is appended
 

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Signature of Principal Investigator
A Phase 1b/2 Study of MEDI4736 in Combination with Tremelimumab, MEDI4736 
Monotherapy, and Tremelimumab Monotherapy in Subjects with Metastatic or Recurrent 
Gastric or Gastroesophageal Junction Adenocarcinoma
I, the undersigned, have reviewed this protocol, and I agree to conduct this protocol in 
accordance with ethical principles that have their origin in the Declaration of Helsinki and 
are consistent with the International Council for Harmonisation (ICH) guidelines on Good 
Clinical Practice (GCP), any applicable laws and requirements, and any conditions required 
by a regulatory authority and/or Institutional Review Board/Independent Ethics Committee 
(IRB/IEC). 
I understand that the protocol may not be modified without written approval of the sponsor. 
All changes to the protocol must be submitted to the applicable regulatory authority and 
IRB/IEC, and must be approved by the IRB/IEC prior to implementation except when 
necessary to eliminate immediate hazards to the subjects or when the change(s), as deemed 
by the sponsor, involves only logistical or administrative changes. Documentation of 
IRB/IEC approval must be sent to the sponsor immediately upon receipt.
Signature and date: 
Name and title:
Address including postal code: 
Telephone number: 
Site/Center Number (if available):
This document contains confidential information, which should not be copied, referred to, released, or published 
without written approval from MedImmune or AstraZeneca. Investigators are cautioned that the information in 
this protocol may be subject to change and revision.

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Appendix 5
MEDI4736 and Tremelimumab Dose Modifications for 
Toxicity Management

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Appendix 6
Diarrhea Management Flowchart

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AE = adverse event; GI = gastrointestinal; IV = intravenous; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; 
PI = principal investigator; Sx = symptom; Tx = treatment; w/ = with.