Clinical trial NCT02625623
Conditions: Unresectable, Recurrent, Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma Gastric Cancer Third Line
Keywords: Avelumab Gastric cancer Gastroesophageal junction adenocarcinoma
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2015-12-28; Completion date: 2019-11-13
Enrollment: 371 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to demonstrate superiority of treatment with avelumab plus best supportive care (BSC) versus physician's choice (chosen from a pre-specified list of therapeutic options) plus BSC.

Detailed description:

Arms: arm 1: Participants received BSC plus physician's choice chemotherapy. Chemotherapy comprises of one of the following: paclitaxel at a dose of 80 milligram per meter square (mg/m\^2) on Days 1, 8, and 15 of a 4-week treatment cycle until confirmed progressive disease or unacceptable toxicity OR irinotecan at a dose of 150 mg/m\^2 on Days 1 and 15 of a 4-week treatment cycle until confirmed progressive disease or unacceptable toxicity. Participants who are not deemed eligible to receive paclitaxel or irinotecan at the dose and schedule specified above receive BSC alone once every 3 weeks. BSC is defined as treatment administered with the intent to maximize quality of life without a specific antineoplastic regimen and is based on investigator's discretion. arm 2: Participants received avelumab as a 1-hour intravenous (IV) infusion at 10 milligram per kilogram (mg/kg) once every 2-week treatment cycle until confirmed progressive disease or unacceptable toxicity along with BSC. BSC is defined as treatment administered with the intent to maximize quality of life without a specific antineoplastic regimen and is based on investigator's discretion.
Interventions: intervention 1: Avelumab intervention 2: Irinotecan intervention 3: Paclitaxel intervention 4: Best Supportive Care (BSC)
Intervention descriptions: intervention 1: Avelumab was administered as a 1-hour intravenous (IV) infusion at 10 milligram per kilogram (mg/kg) once every 2-week treatment cycle until confirmed progressive disease or unacceptable toxicity along with best supportive care (BSC). intervention 2: Irinotecan was administered at a dose of 150 mg/m \^2 on Day 1 and 15 of a 4-week treatment cycle until disease progression or unacceptable toxicities along with BSC. intervention 3: Paclitaxel was administered at a dose of 80 mg/m\^2 on Day 1, 8, and 15 of a 4-week treatment cycle until disease progression or unacceptable toxicities along with BSC. intervention 4: BSC is defined as treatment administered with the intent to maximize Quality of life without a specific antineoplastic regimen and is based on investigator's discretion. BSC was administered once every 3 weeks.

Protocol documents:
Prot_002.pdf: 


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Protocol Table of Contents
Protocol Table of Contents ..................................................................................................2
Table of In-Text Tables .......................................................................................................7
Table of In-Text Figures......................................................................................................7
List of Abbreviations ...........................................................................................................8
1
Synopsis..............................................................................................11
2
Sponsor, Investigators and Trial Administrative Structure ................34
2.1
Investigational Sites............................................................................34
2.2
Trial Coordination/Monitoring...........................................................34
2.3
Review Committees............................................................................35
2.3.1
Independent Data Monitoring Committee..........................................35
2.3.2
Independent Review Committee.........................................................35
3
Background Information.....................................................................36
3.1
Gastric Cancer ....................................................................................36
3.2
Programmed Death Receptor and Ligands.........................................36
3.3
Avelumab............................................................................................37
3.3.1
Safety..................................................................................................37
3.3.2
Pharmacokinetic Results.....................................................................38
3.3.3
Clinical Pharmacodynamics ...............................................................39
3.4
Rationale for the Current Clinical Trial..............................................40
3.4.1
Data from Anti-PD-1/PD-L1 Therapies in Gastric Cancer ................40
3.4.2
Efficacy Data Generated During the Development of Avelumab......41
3.5
Summary of the Overall Benefit and Risk..........................................41
4
Trial Objectives ..................................................................................42
4.1
Primary Objectives .............................................................................42
4.2
Secondary Objectives .........................................................................42
4.3
Exploratory Objectives .......................................................................43
5
Investigational Plan ............................................................................43
5.1
Overall Trial Design and Plan ............................................................43
5.1.1
Overall Design....................................................................................44
5.1.2
Trial Treatment Administration and Schedule ...................................46
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5.1.3
Dose Modification and Adverse Drug Reactions Requiring 
Treatment Discontinuation .................................................................47
5.2
Discussion of Trial Design .................................................................48
5.2.1
Rationale Supporting the Selection of Eligible First-Line 
Therapies.............................................................................................49
5.2.2
Rationale Supporting the Selection of Eligible Second-Line 
Therapies.............................................................................................49
5.2.3
Rationale for Physician’s Choice Chemotherapy in the Third-Line 
Setting.................................................................................................51
5.2.4
Rationale for the Primary Endpoint....................................................52
5.2.5
Rationale for the Expected Treatment Effect .....................................52
5.2.6
Rationale for Stratification by Region................................................52
5.2.7
Inclusion of Special Populations ........................................................52
5.3
Selection of Trial Population..............................................................53
5.3.1
Inclusion Criteria ................................................................................53
5.3.2
Exclusion Criteria...............................................................................55
5.4
Criteria for Initiation of Trial Treatment ............................................57
5.5
Criteria for Subject Withdrawal..........................................................57
5.5.1
Withdrawal from Trial Therapy..........................................................57
5.5.2
Withdrawal from the Trial..................................................................58
5.6
Premature Termination of the Trial ....................................................59
5.7
Definition of End of Trial...................................................................59
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................60
6.1
Description of the Investigational Medicinal Product........................60
6.1.1
Avelumab............................................................................................60
6.1.2
Physician’s Choice Chemotherapy.....................................................60
6.2
Dosage and Administration ................................................................60
6.2.1
Avelumab Dosage and Administration...............................................60
6.2.2
Physician’s Choice Chemotherapy - Dosage and Administration......62
6.3
Assignment to Treatment Groups.......................................................63
6.4
Non-investigational Medicinal Products to be Used ..........................63
6.4.1
Best Supportive Care ..........................................................................63
6.4.2
Other Non-investigational Medicinal Products to be Used ................63
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6.5
Concomitant Medications, Therapies, and Procedures.......................64
6.5.1
Permitted Medicines...........................................................................64
6.5.2
Prohibited Medicines..........................................................................65
6.5.3
Other Interventions.............................................................................66
6.5.4
Special Precautions.............................................................................66
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................76
6.6
Packaging and Labeling of the Investigational Medicinal Product....76
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................76
6.8
Investigational Medicinal Product Accountability.............................77
6.9
Assessment of Investigational Medicinal Product Compliance .........78
6.10
Blinding ..............................................................................................78
6.11
Emergency Unblinding.......................................................................78
6.12
Treatment of Overdose .......................................................................79
6.13
Medical Care of Subjects after End of Trial.......................................79
7
Trial Procedures and Assessments......................................................79
7.1
Schedule of Assessments....................................................................79
7.1.1
Screening and Baseline Procedures and Assessments........................79
7.1.2
Treatment Period ................................................................................81
7.1.3
End of Treatment Visit .......................................................................82
7.1.4
Safety Follow-up ................................................................................82
7.1.5
Long-term Follow-up..........................................................................82
7.2
Demographic and Other Baseline Characteristics ..............................82
7.2.1
Demographic Data..............................................................................82
7.2.2
Diagnosis of Gastric Cancer ...............................................................83
7.2.3
Medical History ..................................................................................83
7.2.4
Computed Tomography or Magnetic Resonance Imaging Scans 
for Tumor Assessment at Baseline .....................................................83
7.2.5
Other Baseline Assessments...............................................................84
7.3
Efficacy Assessments .........................................................................84
7.4
Assessment of Safety..........................................................................85
7.4.1
Adverse Events ...................................................................................85
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7.4.2
Pregnancy and In Utero Drug Exposure.............................................90
7.4.3
Clinical Laboratory Assessments .......................................................90
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............93
7.7
Other Assessments..............................................................................96
7.7.1
Subject-reported Outcomes/Quality of Life .......................................96
8
Statistics..............................................................................................96
8.1
Sample Size ........................................................................................96
8.2
Randomization....................................................................................97
8.3
Endpoints............................................................................................97
8.3.1
Primary Endpoint................................................................................97
8.3.2
Secondary Endpoints ..........................................................................97
8.3.3
Safety Endpoints.................................................................................98
8.3.4
Exploratory Endpoints........................................................................98
8.4
Analysis Sets.......................................................................................99
8.5
Description of Statistical Analyses.....................................................99
8.5.1
General Considerations.......................................................................99
8.5.2
Analysis of Primary Endpoints.........................................................100
8.5.3
Analysis of Secondary Endpoints.....................................................101
8.5.4
Analysis of Exploratory Endpoints...................................................103
8.5.5
Analysis of Safety Endpoints............................................................105
8.5.6
Reporting of Other Clinical Data of Interest ....................................106
8.6
Interim Analysis................................................................................107
9
Ethical and Regulatory Aspects........................................................108
9.1
Responsibilities of the Investigator ..................................................108
9.2
Subject Information and Informed Consent .....................................108
9.3
Subject Identification and Privacy....................................................109
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9.4
Emergency Medical Support and Subject Card................................109
9.5
Clinical Trial Insurance and Compensation to Subjects...................110
9.6
Independent Ethics Committee or Institutional Review Board........110
9.7
Health Authorities.............................................................................110
10
Trial Management.............................................................................110
10.1
Case Report Form Handling.............................................................110
10.2
Source Data and Subject Files..........................................................111
10.3
Investigator Site File and Archiving.................................................111
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ........................................................................................112
10.5
Changes to the Clinical Trial Protocol..............................................112
10.6
Clinical Trial Report and Publication Policy....................................112
10.6.1
Clinical Trial Report.........................................................................112
10.6.2
Publication........................................................................................113
11
References Cited in the Text.............................................................113
12
Appendices .......................................................................................118
Appendix I
Signature Pages and Responsible Persons for the Trial....................119
Signature Page – Protocol Lead.......................................................................................120
Signature Page – Coordinating Investigator ....................................................................121
Signature Page – Principal Investigator...........................................................................122
Sponsor Responsible Persons not Named on the Cover Page .........................................123
Appendix II
Guidance on contraception ...............................................................124
Appendix III:
Protocol Amendments and List of Changes .....................................125
Amendment 7 / Clinical Trial Protocol Version 8.0 (23 March 2018, Global)...............127
Rationale for Changes......................................................................................................127
List of Changes
..........................................................................................................127
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Table of In-Text Tables
Table 1
Schedules of Assessments ..................................................................18
Table 2
Schedule of Assessments for Pharmacokinetic, Anti-drug 
Antibody, and Biomarker Samples for Subjects in the Avelumab 
Arm.....................................................................................................32
Table 3
Overall Survival and Progression-free Survival for Subjects 
Receiving Second-line Chemotherapy ...............................................50
Table 4
Physician’s Choice Chemotherapies...................................................63
Table 5
Treatment Modification for Symptoms of Infusion-related 
Reactions Associated With Avelumab ...............................................67
Table 6
Management of Immune-related Adverse Events ..............................70
Table 7
Clinical Laboratory Assessments .......................................................92
Table of In-Text Figures
Figure 1
Schematic of the Trial Design ............................................................46
Figure 2
Assessment and Initial Management of Tumor Lysis Syndrome.......69
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List of Abbreviations
ADA
Anti-drug Antibody
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
AUCtau
Area Under the Concentration-time Curve
β-hCG
β-human Chorionic Gonadotropin
BOR
Best Overall Response
BSC
Best Supportive Care
CI
Confidence Interval
Cmax
Maximum Concentration Observed
Cmin
Minimum Trough Concentration
CR
Complete Response
CRA
Clinical Research Associate
CRO
Contract Research Organization
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Disease Control Rate
ECG
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
Electronic Case Report Form
EORTC
European Organization for Research and Treatment of Cancer
EQ-5D-5L
European Quality of Life 5-dimensions and 5-levels Questionnaire
EuroQOL
European Quality of Life
FFPE
Formalin-fixed Paraffin-embedded
FOLFIRI
Triplet Therapy Consisting of Fluorouracil, Leucovorin, and Irinotecan
FSH
Follicle-stimulating Hormone
GCP
Good Clinical Practice
HBV
Hepatitis B Virus
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HCV
Hepatitis C Virus
HER2
Human epidermal growth factor receptor 2
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IMP
Investigational Medicinal Product
IPMP
Integrated Project Management Plan
irAE
Immune-related Adverse Event
IRB
Institutional Review Board
IRC
Independent Review Committee
ITT
Intention-to-Treat
IV
Intravenous(ly)
IWRS
Interactive Web Response System
MRI
Magnetic Resonance Imaging
NCI
National Cancer Institute
ORR
Objective Response Rate
OS
Overall Survival
PD
Progressive Disease
PD-1
Programmed Death 1 (receptor)
PD-L (1 and 2)
Programmed Death Ligand (1 and 2)
PFS
Progression-free Survival
PK
Pharmacokinetics
PP
Per-Protocol
PR
Partial Response
QoL
Quality of Life
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious Adverse Event
SAF
Safety (Analysis Set)
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SAP
Statistical Analysis Plan
SD
Standard Deviation
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reactions
t1/2
Terminal Half-life
T4
Free Thyroxine
TEAE
Treatment-emergent Adverse Event
TLS
Tumor Lysis Syndrome
TSH
Thyroid-stimulating Hormone
ULN
Upper Limit of Normal
USA
United States of America
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Subjects receiving avelumab plus BSC who have experienced a complete response (CR) should 
continue to receive avelumab for at least 12 months after confirmation of response and/or until 
disease progression or unacceptable toxicity. In case a subject with a confirmed CR relapses 
after stopping treatment, but prior to the end of the trial, 1 re-initiation of treatment is allowed 
at the discretion of the Investigator and agreement of the Medical Monitor. To be eligible for 
re-treatment, the subject must not have experienced any toxicity that led to treatment 
discontinuation of the initial avelumab therapy. Subjects who re-initiate treatment will stay on 
trial and will be treated and monitored according to the protocol and the “until progression” 
schedule in the Schedules of Assessments (see Table 1).
Subjects receiving physician’s choice chemotherapy plus BSC or BSC alone will receive trial 
treatment until progressive disease (PD) per RECIST v1.1, significant clinical deterioration 
(clinical progression), unacceptable toxicity, or if any criterion for withdrawal from the trial or 
trial treatment is fulfilled. Subjects receiving physician’s choice plus BSC will not be offered
to cross over to avelumab plus BSC.
Investigators must specify which of the physician’s choice treatment regimens will be selected 
prior to randomization.
Assessments will be made by the Investigators for the purpose of subject management, but the 
disease response determinations, including PD assessments associated with the trial endpoints, 
will be supported by tumor assessments performed by an IRC.
Subjects will attend clinic visits at regular intervals to receive trial treatment and for efficacy 
and safety assessments.
The primary endpoint of the trial is OS, defined as the time (in months) from randomization to 
the date of death, regardless of the actual cause of the subject’s death.
Safety endpoints include adverse events (AEs) assessed throughout the trial and evaluated 
using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03, physical examination findings, clinical laboratory assessments, vital signs, 
and electrocardiograms (ECGs).
Planned number of subjects: Approximately 330 subjects are planned to be enrolled.
Primary endpoints: The primary endpoint of the trial is OS, defined as the time (in months) 
from randomization to the date of death, regardless of the actual cause of the subject’s death.
Secondary endpoints: The secondary endpoints include PFS according to RECIST v1.1 and 
as adjudicated by the IRC, BOR as adjudicated by the IRC, subject-reported outcomes/QoL
(assessed by the EQ-5D-5L, EORTC QLQ-C30, and EORTC module QLQ-STO22 
questionnaires) and safety endpoints (including AEs, physical examination findings, clinical
laboratory assessments, vital signs, ECG parameters, and ECOG PS).
Exploratory endpoints: Exploratory endpoints include the following:
! Duration of response 
! Time to response 
! Tumor shrinkage in target lesions at each time point from Baseline
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! Irinotecan (as a single agent or in combination)
Trastuzumab in combination with first-line therapy or second-line therapy listed above for 
human epidermal growth factor receptor 2 (HER2) – neu overexpressing adenocarcinoma is 
acceptable.
Key exclusion criteria
Prior therapy with any antibody or drug targeting T-cell coregulatory proteins, concurrent 
anticancer treatment, or immunosuppressive agents. Other exclusion criteria include severe 
hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTCAE v4.03), brain 
metastases (except those treated locally, have not been progressing at least 2 months after 
completion of therapy, those with no steroid maintenance therapy required, and no ongoing 
neurological symptoms related to brain localization of the disease), any history of anaphylaxis, 
or uncontrolled asthma (that is, 3 or more features of partially controlled asthma) and persisting 
toxicity related to prior therapy of Grade ≥2 NCI-CTCAE v4.03 (except neuropathy and 
alopecia).
Investigational Medicinal Product: dose/mode of administration/dosing schedule: 
Avelumab will be administered as a 1-hour IV infusion at 10 mg/kg once every 2-week 
treatment cycle until PD or unacceptable toxicity. To mitigate infusion-related reactions, 
premedication with an antihistamine and with paracetamol (acetaminophen) approximately 
30 to 60 minutes prior to the first 4 doses of avelumab is mandatory (for example, 25 to 50 mg 
diphenhydramine and 500 to 650 mg paracetamol [acetaminophen] IV or oral equivalent). 
Premedication should be administered for subsequent avelumab doses based upon clinical 
judgment and presence/severity of prior infusion reactions. This regimen may be modified 
based on local treatment standards and guidelines as appropriate provided it does not include 
systemic corticosteroids.
Reference therapy: dose/mode of administration/dosing schedule: Subjects will receive 
BSC plus physician’s choice chemotherapy selected from one of the following options:
! Paclitaxel as monotherapy (80 mg/m2 on Days 1, 8, and 15 of a 4-week treatment cycle). 
Subjects should be premedicated with 20 mg dexamethasone orally approximately 12 and 
6 hours prior to injection, 50 mg diphenhydramine (or equivalent) IV 30 to 60 minutes prior 
to injection, and 300 mg cimetidine or 50 mg ranitidine IV 30 to 60 minutes prior to 
injection. The premedication regimen may be modified based on local treatment standards 
and guidelines as appropriate.
! Irinotecan as monotherapy (150 mg/m2 on Days 1 and 15 of a 4-week treatment cycle). 
Subjects should be premedicated with anti-emetics, such as 10 mg prochloroperazine orally, 
30 minutes prior to beginning therapy. If subjects have cholinergic symptoms, premedicate 
with 0.2 to 0.3 mg atropine subcutaneously. The premedication regimen may be modified 
based on local treatment standards and guidelines as appropriate.
! Subjects who are not deemed eligible to receive paclitaxel or irinotecan at the dose and 
schedule specified above will receive BSC once every 3 weeks.
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The Investigator will determine what systemic therapy will be administered to the subjects.
In the absence of unequivocal data on the doses and schedules of drugs that should be used as 
a third-line treatment of gastric cancer, the doses and schedules will be determined by the 
Investigator according to institutional guidelines.
Treatment will be administered until disease progression or unacceptable toxicity.
Physician’s choice plus BSC will be stopped after the first on-treatment radiological evaluation 
of disease progression.
Planned trial and treatment duration per subject: Treatment with avelumab plus BSC will 
continue until disease progression or unacceptable toxicity. For subjects receiving avelumab 
plus BSC, treatment may continue past the initial determination of disease progression 
according to RECIST v1.1 if the subject’s ECOG PS has remained stable, and if in the opinion 
of the Investigator, the subject will benefit from continued treatment (see criteria above). 
Additionally, subjects receiving avelumab plus BSC who have experienced a CR should 
continue to receive avelumab for a minimum of 12 months after confirmation of response 
and/or until disease progression or unacceptable toxicity. Physician’s choice plus BSC will be 
administered until disease progression or unacceptable toxicity.
Statistical methods: The sample size of this trial is driven by the primary endpoint (OS); 
therefore, the trial is event driven and the primary analysis will take place after 256 deaths and 
a minimum of 6 months follow-up since the last subject randomized have occurred to ensure 
sufficient follow-up for all subjects for the primary analysis of OS. With 256 OS events, the 
trial provides 90% power to demonstrate an improvement of 2 months median OS time (i.e., 
median OS time of 6 months in the avelumab plus BSC arm versus 4 months in the control 
arm, which is equivalent to a reduction of 33% in hazard rate, i.e., hazard ratio of avelumab 
versus control = 0.67, at the 1-sided 2.5% overall significance level). Assuming a 
randomization ratio of 1:1 (avelumab plus BSC versus physician’s choice plus BSC), an 
exponential distribution of OS time, a uniform distribution of subject accrual period over 
15 months, an additional 6 months’ minimum follow-up period for all subjects, and an expected 
5% 
overall 
drop-out 
rate, 
the 
trial 
should
enroll 
approximately 
330 subjects 
(n=165 subjects/arm) to achieve 256 OS events in total.
The primary endpoint is OS and will be analyzed using a stratified 1-sided log-rank test. The 
primary analysis set will be the Intention-to-Treat (ITT) Analysis Set. The type I error rate for 
the primary endpoint (OS) and 2 key secondary endpoints (PFS and BOR) will be controlled 
at 2.5% (1-sided) level using a gatekeeping procedure. The primary hypothesis (OS) will serve 
as a gate keeper and be tested at an overall 1-sided type I error of 2.5%. Only if it is significant, 
the 2 key secondary endpoints (PFS and BOR) will be tested, and the Hochberg procedure will 
be used to control the type I error rate at 2.5% (1-sided) for PFS and BOR. The stratification 
factor used for the stratified statistical analysis in the analysis of the primary and key secondary 
endpoints will be region (Asia versus non-Asia).
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Table 1
Schedules of Assessments
Avelumab Plus Best Supportive Care Arm
Measure
Screening/
Baseline 
Assessments
Treatment Phasea
End of 
Treatment Visit
Safety Follow-up
Long-term 
Follow-upb
Day -28 to 
Randomization
V1
V2
V3
V4
V5
V6
V7
Until 
Progression
Within 7 Days of 
Decision to 
Discontinue 
Treatmentc
Visit 30 
Days after 
Last 
Treatment 
(± 5 days)d
Phone Call 
90 Days 
after Last 
Treatment 
(± 1 week)
Every 
12 Weeks 
after Last 
Treatment 
(± 2 weeks)
W1
W3
W5
W7
W9
W11
W13
D1
D15
D29
D43
D57
D71
D85
Written informed consent
X
Tumor tissue availability 
(biopsy/surgery)e
X
Inclusion/exclusion criteria
X
Medical history, including 
disease and treatment historyf
X
Demographic data
X
HBV and HCV testing
X
Subject-reported 
outcomes/quality of life 
assessmentsg
X
Xg
X
X
X
6 weeks
X
X
Physical examination
X
X
X
X
X
X
X
X
6 weeks
X
X
Vital signs, including height at 
Screening
X
X
X
X
X
X
X
X
2 weeks
X
X
Weight
X
X
X
X
X
X
X
X
2 weeks
X
X
ECOG PS
X
Xh
X
X
X
X
X
X
2 weeks
X
X
Enrollment (if eligible)i
X
12-lead ECGj
X
X
Hematology and 
hemostaseology
X
X
X
X
X
X
X
X
2 weeks
X
X
Core serum chemistryk
X
X
X
X
X
X
X
2 weeks
Full serum chemistryl
X
X
X
Urinalysism
X
X
X
X
12 weeks
X
X
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Measure
Screening/
Baseline 
Assessments
Treatment Phasea
End of 
Treatment Visit
Safety Follow-up
Long-term 
Follow-upb
Day -28 to 
Randomization
V1
V2
V3
V4
V5
V6
V7
Until 
Progression
Within 7 Days of 
Decision to 
Discontinue 
Treatmentc
Visit 30 
Days after 
Last 
Treatment 
(± 5 days)d
Phone Call 
90 Days 
after Last 
Treatment 
(± 1 week)
Every 
12 Weeks 
after Last 
Treatment 
(± 2 weeks)
W1
W3
W5
W7
W9
W11
W13
D1
D15
D29
D43
D57
D71
D85
β-hCG pregnancy testn
X
X
X
X
X
4 weeks
X
X
Tumor evaluation/staging (CT 
scan/MRI/other established 
methods)o
X
X
X
6 weeks for 
the first 
12 months, 
and every 
12 weeks 
thereaftero
Xp
Concomitant medications and 
proceduresq
X
X
X
X
X
X
X
X
X
X
X
AE collection
X
X
X
X
X
X
X
X
X
X
Xb
Xb
SAE collection
X
X
X
X
X
X
X
X
X
X
Xb
Xb
Xb
T4 and TSHr
X
X
X
6 weeks
X
X
Pretreatment and trial treatment 
administrations
X
X
X
X
X
X
X
2 weeks
ADA=anti-drug antibody, AE=adverse events, β-hCG=β-human chorionic gonadotropin, CR=complete response, CT=computed tomography, D=day, 
ECG=electrocardiogram, ECOG PS=Eastern Cooperative Oncology Group Performance Status, EORTC=European Organization for Research and Treatment of 
Cancer, EQ-5D-5L=European Quality of Life 5-dimensions and 5-levels Questionnaire, HBV=hepatitis B virus, HCV=hepatitis C virus, ICF=informed consent form, 
IMP=investigational medicinal product, IRC=Independent Review Committee, IV=intravenous, MRI=magnetic resonance imaging, PD=progressive disease, 
, 
, PR=partial response, RECIST=Response Evaluation Criteria in Solid Tumors version 1.1, SAE=serious adverse 
event, T4=free thyroxine, TSH=thyroid-stimulating hormone, V=visit, W=week.
a.
A time window of up to 3 days before or 1 day after the scheduled visit day (-3/+1 days) will be permitted for all trial procedures. The calculation of the dose of 
avelumab will be based on the weight of the subject determined within 72 hours prior to the day of drug administration. The dose of avelumab used for the 
previous administration can be repeated if the change in the subject’s weight is 10% or less than the weight used for the last dose calculation. Subjects should
start treatment administration within 28 days after signing the ICF. Treatment administration will start within 4 days after the randomization call.
b.
All subjects will have an End of Treatment visit within 7 days after the decision to discontinue trial treatment. All AEs will be documented until the 30-day 
Safety Follow-Up visit. Subjects with an ongoing SAE at the 30-day Safety Follow-up visit must be monitored and followed up until stabilization or until the 
outcome is known. After this visit, all SAEs and all treatment related non-serious AEs need to be documented until the 90-day Safety Follow-up Phone Call. 
Subjects with an ongoing SAE at the 90-day Safety Follow-up Phone Call must be monitored and followed by the Investigator until stabilization or until the 
outcome is known, unless the subject is documented as “lost to follow-up”. At 90 days following the last treatment, subjects will be contacted by telephone to 
collect information on new or ongoing SAEs and treatment related non-serious AEs. Any SAE assessed as related to IMP must be reported whenever it 
Document No. 
Object No. 
CCI
CCI
CCI
CCI


Avelumab
Avelumab in Third-line Gastric Cancer
EMR 100070-008
20/133
occurs, irrespective of the time elapsed since the last administration of IMP. For subjects without PD at End of Treatment visit, follow-up for disease 
progression and survival will end on the date of treatment discontinuation (see Section 7.1.5 for details).
c.
Tumor evaluation at the End of Treatment visit should only be performed if no disease progression has been documented previously.
d.
If another antineoplastic therapy is administered before the end of the 30-day period, the 30-day Safety Follow-Up visit should be conducted, if possible, prior 
to the start of this new therapy.
e.
A biopsy should be collected unless tissue from an archival specimen (biopsy or surgery) is available (biopsies are only to be obtained from safely accessible 
tumor tissue/sites). Samples can be provided as block or slides (see Section 7.6 for details).
f.
Medical history should include history of gastric cancer, previous and ongoing medications, previous surgeries and radiotherapies, and Baseline medical 
condition.
g.
The subject-reported outcomes/quality of life questionnaires (EQ-5D-5L, EORTC QLQ-C30, and module QLQ-STO22) should be completed by all subjects 
prior to any of the other trial-related assessments being performed, that is, physical examinations, blood draws, trial treatment administration, etc. The 
questionnaires should be conducted at Screening; in the event that this does not occur, it can be done at Visit 1 (Day 1) prior to first treatment.
h.
If the Screening ECOG PS was performed within 3 days prior to Day 1, it does not have to be repeated at Visit 1.
i.
Enrollment will be done after the confirmation of fulfilling all screening inclusion criteria (Section 5.3.1) without matching any exclusion criterion (Section 5.3.2). 
j.
12-lead ECG should be assessed during screening and at the End of Treatment visit.
k.
Core serum chemistry and other laboratory assessments are detailed in Table 7. 
l.
Full chemistry panel, which includes core serum chemistry, and other laboratory assessments are detailed in Table 7. Follicle-stimulating hormone at 
Screening, if applicable (Section 7.1.1).
m.
Full urinalysis (dipstick plus microscopic evaluation) at the Screening and End of Treatment visits.
n.
β-hCG should be determined from serum at Screening and from a urine or serum sample thereafter. Results of the most recent pregnancy test should be 
available prior to the next administration of trial treatment.
o.
In general, the tumor visit time window is 5 days prior to dosing. In case a tumor response according to RECIST v1.1 is documented during the course of the 
trial, confirmation of the response should be performed according to RECIST v1.1, preferably at the regularly scheduled 6-week assessment interval (after 
12 months of treatment, 12-week assessment interval will be used), but no sooner than 5 weeks after the initial documentation of CR or PR. Confirmation of 
PR can be confirmed at an assessment later than the next assessment after the initial documentation of PR. A CT scan or MRI should always be used (if MRI 
is used, CT of chest is mandatory). The tumor evaluation (see Section 7.3) has a tumor assessment visiting time window of 5 days prior to dosing (-5 days) 
and ± 5 days after the End of Treatment visit. Disease response determinations, including PD assessments associated with the trial endpoints, will be 
supported by tumor assessments performed by an IRC.
p.
For subjects without PD at End of Treatment visit, follow-up for disease progression and survival will end on the date of treatment discontinuation (see 
Section 7.1.5 for details).
q.
Concomitant medications and procedures will be documented at each trial visit until the 30-day Safety Follow-Up visit.
r.
Blood samples for T4 and TSH will be collected at the times indicated from all subjects.
 
s.
Premedication with an antihistamine and with paracetamol (acetaminophen) approximately 30 to 60 minutes prior to the first 4 doses of avelumab is 
mandatory (for example, 25 to 50 mg diphenhydramine and 500 to 650 mg paracetamol [acetaminophen] IV or oral equivalent). Premedication should be 
administered for subsequent avelumab doses based upon clinical judgment and presence/severity of prior infusion reactions. This regimen may be modified 
based on local treatment standards and guidelines as appropriate provided it does not include systemic corticosteroids. 
Document No. 
Object No. 
CCI
CCI
C


Avelumab
Avelumab in Third-line Gastric Cancer
EMR 100070-008
21/133
Physician’s Choice: Best Supportive Care Plus Irinotecan
Measure
Screening/
Baseline 
Assessments
Treatment Phasea
End of 
Treatment Visit
Safety Follow-up
Long-term 
Follow-upb
Day -28 to 
Randomization
V1
V2
V3
V4
V5
V6
V7
Until 
Progression
Within 7 Days 
of Decision to 
Discontinue 
Treatmentc
Visit 30 
Days after 
Last 
Treatment 
(± 5 days)d
Phone Call 
90 Days 
after Last 
Treatment 
(± 1 week)
Every 
12 Weeks 
after Last 
Treatment 
(± 2 weeks)
W1
W3
W5
W7
W9
W11
W13
D1
D15
D29
D43
D57
D71
D85
Written informed consent
X
Tumor tissue availability 
(biopsy/surgery)e
X
Inclusion/exclusion criteria
X
Medical history, including 
disease and treatment historyf
X
Demographic data
X
HBV and HCV testing
X
Subject-reported 
outcomes/quality of life 
assessmentsg
X
Xg
X
X
X
6 weeks
X
X
Physical examination
X
X
X
X
X
X
X
X
6 weeks
X
X
Vital signs, including height at 
Screening
X
X
X
X
X
X
X
X
2 weeks
X
X
Weight and BSA calculation
X
X
X
X
X
X
X
X
2 weeks
X
X
ECOG PS
X
Xh
X
X
X
X
X
X
2 weeks
X
X
Enrollment (if eligible)i
X
12-lead ECGj
X
X
Hematology and 
hemostaseology
X
X
X
X
X
X
X
X
2 weeks
X
X
Core serum chemistryk
X
X
X
X
X
X
X
2 weeks
Full serum chemistryl
X
X
X
Urinalysism
X
X
X
X
12 weeks
X
X
Document No. 
Object No. 
CCI


Avelumab
Avelumab in Third-line Gastric Cancer
EMR 100070-008
22/133
Measure
Screening/
Baseline 
Assessments
Treatment Phasea
End of 
Treatment Visit
Safety Follow-up
Long-term 
Follow-upb
Day -28 to 
Randomization
V1
V2
V3
V4
V5
V6
V7
Until 
Progression
Within 7 Days 
of Decision to 
Discontinue 
Treatmentc
Visit 30 
Days after 
Last 
Treatment 
(± 5 days)d
Phone Call 
90 Days 
after Last 
Treatment 
(± 1 week)
Every 
12 Weeks 
after Last 
Treatment 
(± 2 weeks)
W1
W3
W5
W7
W9
W11
W13
D1
D15
D29
D43
D57
D71
D85
β-hCG pregnancy testn
X
X
X
X
X
4 weeks
X
X
Tumor evaluation/staging (CT 
scan/MRI/other established 
methods)o
X
X
X
6 weeks for 
the first 
12 months, 
and every 
12 weeks 
thereaftero
Xp
Concomitant medications and 
proceduresq
X
X
X
X
X
X
X
X
X
X
X
AE collection
X
X
X
X
X
X
X
X
X
X
Xb
Xb
SAE collection
X
X
X
X
X
X
X
X
X
X
Xb
Xb
Xb
T4 and TSHr
X
X
X
6 weeks
X
X
Pretreatment and trial treatment 
administrations
X
X
X
X
X
X
X
2 weeks
AE=adverse events, β-hCG=β-human chorionic gonadotropin, BSA=body surface area, CR= complete response, CT=computed tomography, D=day, 
ECG=electrocardiogram, ECOG PS=Eastern Cooperative Oncology Group Performance Status, EORTC=European Organization for Research and Treatment of 
Cancer, EQ-5D-5L=European Quality of Life 5-dimensions and 5-levels Questionnaire, HBV=hepatitis B virus, HCV=hepatitis C virus, ICF=informed consent form, 
IMP=investigational medicinal product, IRC=Independent Review Committee, IV=intravenous, MRI=magnetic resonance imaging, PD=progressive disease,
, PR=partial response, RECIST=Response Evaluation Criteria in Solid Tumors version 1.1, SAE=serious adverse event, T4=free thyroxine, 
TSH=thyroid-stimulating hormone, V=visit, W=week.
a.
A time window of up to 3 days before or 1 day after the scheduled visit day (-3/+1 days) will be permitted for all trial procedures. The calculation of the dose of 
irinotecan will be calculated based on the BSA determined within 72 hours prior to the day of drug administration. The dose of irinotecan used for the previous 
administration can be repeated if the change in the subject’s weight is 10% or less than the weight used for the last dose calculation as allowed by local 
standards. Subjects should start treatment administration within 28 days after signing the ICF. Treatment administration will start within 4 days after the 
randomization call.
Document No. 
Object No. 
CCI
CCI
CCI


Avelumab
Avelumab in Third-line Gastric Cancer
EMR 100070-008
23/133
b.
All subjects will have an End of Treatment visit within 7 days after the decision to discontinue trial treatment. All AEs will be documented until the 30-day 
Safety Follow-Up visit. Subjects with an ongoing SAE at the 30-day Safety Follow-up visit must be monitored and followed up until stabilization or until the 
outcome is known. After this visit, all SAEs and all treatment related non-serious AEs need to be documented until the 90-day Safety Follow-up Phone Call. 
Subjects with an ongoing SAE at the 90-day Safety Follow-up Phone Call must be monitored and followed by the Investigator until stabilization or until the 
outcome is known, unless the subject is documented as “lost to follow-up”. At 90 days following the last treatment, subjects will be contacted by telephone to 
collect information on new or ongoing SAEs and treatment related non-serious AEs. Any SAE assessed as related to IMP must be reported whenever it 
occurs, irrespective of the time elapsed since the last administration of IMP. For subjects without PD at End of Treatment visit, follow-up for disease 
progression and survival will end on the date of treatment discontinuation (see Section 7.1.5 for details).
c.
Tumor evaluation at the End of Treatment visit should only be performed if no disease progression has been documented previously.
d.
If another antineoplastic therapy is administered before the end of the 30-day period, the 30-day Safety Follow-Up visit should be conducted, if possible, prior 
to the start of this new therapy.
e.
A biopsy should be collected unless tissue from an archival specimen (biopsy or surgery) is available (biopsies are only to be obtained from safely accessible 
tumor tissue/sites). Samples can be provided as block or slides (see Section 7.6 for details).
f.
Medical history should include history of gastric cancer, previous and ongoing medications, previous surgeries and radiotherapies, and Baseline medical 
condition.
g.
The subject-reported outcomes/quality of life questionnaires (EQ-5D-5L, EORTC QLQ-C30, and module QLQ-STO22) should be completed by all subjects 
prior to any of the other trial-related assessments being performed, that is, physical examinations, blood draws, trial treatment administration, etc. The 
questionnaires should be conducted at Screening; in the event that this does not occur, it can be done at Visit 1 (Day 1) prior to first treatment.
h.
If the Screening ECOG PS was performed within 3 days prior to Day 1, it does not have to be repeated at Visit 1.
i.
Enrollment will be done after the confirmation of fulfilling all screening inclusion criteria (Section 5.3.1) without matching any exclusion criterion (Section 5.3.2). 
j.
12-lead ECG should be assessed during Screening and at the End of Treatment visit.
k.
Core serum chemistry and other laboratory assessments are detailed in Table 7.
l.
Full chemistry panel, which includes core serum chemistry, and other laboratory assessments are detailed in Table 7. Follicle-stimulating hormone at 
Screening, if applicable (Section 7.1.1).
m.
Full urinalysis (dipstick plus microscopic evaluation) at the Screening and End of Treatment visits.
n.
β-hCG should be determined from serum at Screening and from a urine or serum sample thereafter. Results of the most recent pregnancy test should be 
available prior to the next administration of trial treatment.
o.
In general, the tumor visit time window is 5 days prior to dosing. In case a tumor response according to RECIST v1.1 is documented during the course of the 
trial, confirmation of the response should be performed according to RECIST v1.1, preferably at the regularly scheduled 6-week assessment interval (after 
12 months of treatment, 12-week assessment interval will be used), but no sooner than 5 weeks after the initial documentation of CR or PR. Confirmation of 
PR can be confirmed at an assessment later than the next assessment after the initial documentation of PR. A CT scan or MRI should always be used (if MRI 
is used, CT of chest is mandatory). The tumor evaluation (see Section 7.3) has a tumor assessment visiting time window of 5 days prior to dosing (-5 days) 
and ± 5 days after the End of Treatment visit. Disease response determinations, including PD assessments associated with the trial endpoints, will be 
supported by tumor assessments performed by an IRC.
p.
For subjects without PD at End of Treatment visit, follow-up for disease progression and survival will end on the date of treatment discontinuation (see 
Section 7.1.5 for details). 
q.
Concomitant medications and procedures will be documented at each trial visit until the 30-day Safety Follow-Up visit.
r.
Blood samples for T4 and TSH will be collected at the times indicated from all subjects.
s.
Irinotecan will be administered on Days 1 and 15 of a 4-week treatment cycle. Subjects receiving irinotecan should be premedicated with anti-emetics, such 
as 10 mg prochloroperazine orally, 30 minutes prior to beginning therapy. If subjects have cholinergic symptoms, premedicate with 0.2 to 0.3 mg atropine 
subcutaneously. The premedication regimen may be modified based on local treatment standards and guidelines as appropriate.
Document No. 
Object No. 
CCI




Avelumab
Avelumab in Third-line Gastric Cancer
EMR 100070-008
25/133
Physician’s Choice: Best Supportive Care Plus Paclitaxel
Measure
Screening/
Baseline 
Assessments
Treatment Phasea
End of 
Treatment 
Visit
Safety Follow-up 
Visit
Long-term 
Follow-upb
Day -28 to 
Randomization
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
Until 
Progression
Within 
7 Days of 
Decision to 
Discontinue 
Treatmentc
Visit 
30 Days 
after Last 
Treatment 
(± 5 days)d
Phone 
Call 
90 Days 
after Last 
Treatment 
(± 1 week)
Every 
12 Weeks 
after Last 
Treatment 
(± 2 weeks)
W1
W2
W3
W5
W6
W7
W9
W10
W11
W13
D1
D8
D15
D29
D36
D43
D57
D64
D71
D85
Written informed consent
X
Tumor tissue availability 
(biopsy/surgery)e
X
Inclusion/exclusion criteria
X
Medical history, including disease 
and treatment historyf
X
Demographic data
X
HBV and HCV testing
X
Subject-reported outcomes/quality
of life assessmentsg
X
Xg
X
X
X
6 weeks
X
X
Physical examination
X
X
X
X
X
X
X
X
X
X
X
6 weeks
X
X
Vital signs, including height at 
Screening
X
X
X
X
X
X
X
X
X
X
X
Every week 
for the first 
3 weeks of 
each 4-week 
cycle
X
X
Weight and BSA calculationh
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
Xi
X
X
X
X
X
X
X
X
X
X
X
Enrollment (if eligible)j
X
12-lead ECGk
X
X
Hematology and hemostaseology
X
X
X
X
X
X
X
X
X
X
X
Every week 
for the first 
3 weeks of 
each 4-week 
cycle
X
X
Core serum chemistryl
X
X
X
X
X
X
X
X
X
X
Full serum chemistrym
X
X
X
Urinalysisn
X
X
X
X
12 weeks
X
X
Document No. 
Object No. 
CCI


Avelumab
Avelumab in Third-line Gastric Cancer
EMR 100070-008
26/133
Measure
Screening/
Baseline 
Assessments
Treatment Phasea
End of 
Treatment 
Visit
Safety Follow-up 
Visit
Long-term 
Follow-upb
Day -28 to 
Randomization
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
Until 
Progression
Within 
7 Days of 
Decision to 
Discontinue 
Treatmentc
Visit 
30 Days 
after Last 
Treatment 
(± 5 days)d
Phone 
Call 
90 Days 
after Last 
Treatment 
(± 1 week)
Every 
12 Weeks 
after Last 
Treatment 
(± 2 weeks)
W1
W2
W3
W5
W6
W7
W9
W10
W11
W13
D1
D8
D15
D29
D36
D43
D57
D64
D71
D85
β-hCG pregnancy testo
X
X
X
X
X
4 weeks
X
X
Tumor evaluation/staging (CT 
scan/MRI/other established 
methods)p
X
X
X
6 weeks for 
the first 12 
months, and 
every 
12 weeks 
thereafterp
Xq
Concomitant medications and 
proceduresr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE collection
X
X
X
X
X
X
X
X
X
X
X
X
X
Xb
Xb
SAE collection
X
X
X
X
X
X
X
X
X
X
X
X
X
Xb
Xb
Xb
T4 and TSHs
X
X
X
6 weeks
X
X
Pretreatment and trial treatment 
administrationt
X
X
X
X
X
X
X
X
X
X
Every week 
for the first 
3 weeks of 
each 4-week 
cycle
AE=adverse events, β-hCG=β-human chorionic gonadotropin, BSA=body surface area, CR= complete response, CT=computed tomography, D=day, 
ECG=electrocardiogram, ECOG PS=Eastern Cooperative Oncology Group Performance Status, EORTC=European Organization for Research and Treatment of 
Cancer, EQ-5D-5L=European Quality of Life 5-dimensions and 5-levels Questionnaire, HBV=hepatitis B virus, HCV=hepatitis C virus, ICF=informed consent form, 
IMP=investigational medicinal product, IRC=Independent Review Committee, IV=intravenous, MRI=magnetic resonance imaging, PD=progressive disease, 
, PR=partial response, RECIST=Response Evaluation Criteria in Solid Tumors version 1.1, SAE=serious adverse event, T4=free thyroxine, 
TSH=thyroid-stimulating hormone, V=visit, W=week.
Document No. 
Object No. 
CCI
CCI
CCI


Avelumab
Avelumab in Third-line Gastric Cancer
EMR 100070-008
27/133
a.
A time window of up to 3 days before or 1 day after the scheduled visit day (-3/+1 days) will be permitted for all trial procedures. The calculation of the dose of
paclitaxel will be based on the BSA of the subject determined within 72 hours prior to the day of drug administration. The dose of paclitaxel used for the 
previous administration can be repeated if the change in the subject’s weight is 10% or less than the weight used for the last dose calculation as allowed by 
local standards. Subjects should start treatment administration within 28 days after signing the ICF. Treatment administration will start within 4 days after the 
randomization call.
b.
All subjects will have an End of Treatment visit within 7 days after the decision to discontinue trial treatment. All AEs will be documented until the 30-day 
Safety Follow-Up visit. Subjects with an ongoing SAE at the 30-day Safety Follow-up visit must be monitored and followed up until stabilization or until the 
outcome is known. After this visit, all SAEs and all treatment related non-serious AEs need to be documented until the 90-day Safety Follow-up Phone Call. 
Subjects with an ongoing SAE at the 90-day Safety Follow-up Phone Call must be monitored and followed by the Investigator until stabilization or until the 
outcome is known, unless the subject is documented as “lost to follow-up”. At 90 days following the last treatment, subjects will be contacted by telephone to 
collect information on new or ongoing SAEs and treatment related non-serious AEs. Any SAE assessed as related to IMP must be reported whenever it 
occurs, irrespective of the time elapsed since the last administration of IMP. For subjects without PD at End of Treatment visit, follow-up for disease 
progression and survival will end on the date of treatment discontinuation (see Section 7.1.5 for details).
c.
Tumor evaluation at the End of Treatment visit should only be performed if no disease progression has been documented previously.
d.
If another antineoplastic therapy is administered before the end of the 30-day period, the 30-day Safety Follow-Up visit should be conducted, if possible, prior 
to the start of this new therapy.
e.
A biopsy should be collected unless tissue from an archival specimen (biopsy or surgery) is available (biopsies are only to be obtained from safely accessible 
tumor tissue/sites). Samples can be provided as block or slides (see Section 7.6 for details).
f.
Medical history should include history of gastric cancer, previous and ongoing medications, previous surgeries and radiotherapies, and Baseline medical 
condition.
g.
The subject-reported outcomes/quality of life questionnaires (EQ-5D-5L, EORTC QLQ-C30, and module QLQ-STO22) should be completed by all subjects 
prior to any of the other trial-related assessments being performed, that is, physical examinations, blood draws, trial treatment administration, etc. The 
questionnaires should be conducted at Screening; in the event that this does not occur, it can be done at Visit 1 (Day 1) prior to first treatment.
h.
The BSA will be calculated for subjects receiving paclitaxel.
i.
If the Screening ECOG PS was performed within 3 days prior to Day 1, it does not have to be repeated at Visit 1.
j.
Enrollment will be done after the confirmation of fulfilling all screening inclusion criteria (Section 5.3.1) without matching any exclusion criterion (Section 5.3.2). 
k.
12-lead ECG should be assessed during Screening and at the End of Treatment visit.
l.
Core serum chemistry and other laboratory assessments are detailed in Table 7.
m.
Full chemistry panel, which includes core serum chemistry, and other laboratory assessments are detailed in Table 7. Follicle-stimulating hormone at 
Screening, if applicable (Section 7.1.1).
n.
Full urinalysis (dipstick plus microscopic evaluation) at the Screening and End of Treatment visits.
o.
β-hCG should be determined from serum at Screening and from a urine or serum sample thereafter. Results of the most recent pregnancy test should be 
available prior to the next administration of trial treatment.
p.
In general, the tumor visit time window is 5 days prior to dosing. In case a tumor response according to RECIST v1.1 is documented during the course of the 
trial, confirmation of the response should be performed according to RECIST v1.1, preferably at the regularly scheduled 6-week assessment interval (after 
12 months of treatment, 12-week assessment interval will be used), but no sooner than 5 weeks after the initial documentation of CR or PR. Confirmation of 
PR can be confirmed at an assessment later than the next assessment after the initial documentation of PR. A CT scan or MRI should always be used (if MRI 
is used, CT of chest is mandatory). The tumor evaluation (see Section 7.3) has a tumor assessment visiting time window of 5 days prior to dosing (-5 days) 
and ± 5 days after the End of Treatment visit. Disease response determinations, including PD assessments associated with the trial endpoints, will be 
supported by tumor assessments performed by an IRC.
q.
For subjects without PD at End of Treatment visit, follow-up for disease progression and survival will end on the date of treatment discontinuation (see 
Section 7.1.5 for details).
Document No. 
Object No. 
CCI




Avelumab
Avelumab in Third-line Gastric Cancer
EMR 100070-008
29/133
Physician’s Choice: Best Supportive Care Only
Measure
Screening/
Baseline 
Assessments
Treatment Phasea
End of Treatment 
Visit
Safety Follow-up
Long-term 
Follow-upb
Day -28 to 
Randomization
V1
V2
V3
V4
V5
Until 
Progression
Within 7 Days of 
Decision to 
Discontinue 
Treatmentc
Visit 
30 Days 
after Last 
Treatment 
(± 5 days)d
Phone Call 
90 Days 
after Last 
Treatment 
(± 1 week)
Every 
12 Weeks 
after Last 
Treatment 
(± 2 weeks)
W1
W4
W7
W10
W13
D1
D22
D43
D64
D85
Written informed consent
X
Tumor tissue availability 
(biopsy/surgery)e
X
Inclusion/exclusion criteria
X
Medical history, including 
disease and treatment history f
X
Demographic data
X
HBV and HCV testing
X
Subject-reported 
outcomes/quality of life 
assessmentsg
X
Xg
X
X
X
6 weeks
X
X
Physical examination
X
X
X
X
X
X
6 weeks
X
X
Vital signs, including height at 
Screening
X
X
X
X
X
X
3 weeks
X
X
Weight and BSA calculation
X
X
X
X
X
X
3 weeks 
X
X
ECOG PS
X
Xh
X
X
X
X
3 weeks
X
X
Enrollment (if eligible)i
X
12-lead ECG
X
Hematology and 
hemostaseology
X
X
X
X
X
X
3 weeks
X
X
Core serum chemistryj
X
X
X
X
X
3 weeks
Full serum chemistryk
X
X
X
Urinalysisl
X
X
X
X
12 weeks
X
β-hCG pregnancy testm
X
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Measure
Screening/
Baseline 
Assessments
Treatment Phasea
End of Treatment 
Visit
Safety Follow-up
Long-term 
Follow-upb
Day -28 to 
Randomization
V1
V2
V3
V4
V5
Until 
Progression
Within 7 Days of 
Decision to 
Discontinue 
Treatmentc
Visit 
30 Days 
after Last 
Treatment 
(± 5 days)d
Phone Call 
90 Days 
after Last 
Treatment 
(± 1 week)
Every 
12 Weeks 
after Last 
Treatment 
(± 2 weeks)
W1
W4
W7
W10
W13
D1
D22
D43
D64
D85
Tumor evaluation/staging (CT 
Scan/MRI/other established 
methods)n
X
X
X
6 weeks for 
the first 
12 months, 
and every 12 
weeks 
thereaftern
Xo
Concomitant medications and 
proceduresp
X
X
X
X
X
X
X
X
X
AE collection
X
X
X
X
X
X
X
X
Xb
Xb
SAE collection
X
X
X
X
X
X
X
X
Xb
Xb
Xb
T4 and TSHq
X
X
X
6 weeks
X
X
AE=adverse events, β-hCG=β-human chorionic gonadotropin, BSA=body surface area, BSC=best supportive care, CR=complete response, CT=computed 
tomography, D=Day, ECG=electrocardiogram, ECOG PS=Eastern Cooperative Oncology Group Performance Status, EORTC=European Organization for 
Research and Treatment of Cancer, EQ-5D-5L=European Quality of Life 5-dimensions and 5-levels Questionnaire, HBV=hepatitis B virus, HCV=hepatitis C virus, 
ICF=informed consent form, IMP=investigational medicinal product, IRC=Independent Review Committee, IV=intravenous, MRI=magnetic resonance imaging, 
PD=progressive disease, 
, PR=partial response, RECIST=Response Evaluation Criteria in Solid Tumors version 1.1, SAE=serious adverse 
event, T4=free thyroxine, TSH=thyroid-stimulating hormone, V=visit, W=Week.
a.
A time window of up to 3 days before or 1 day after the scheduled visit day (-3/+1 days) will be permitted for all trial procedures. Subjects should start 
treatment administration within 28 days after signing the ICF. Treatment administration will start within 4 days after the randomization call. Subjects will 
receive BSC once every 3 weeks.
b.
All subjects will have an End of Treatment visit within 7 days after the decision to discontinue trial treatment. All AEs will be documented until the 30-day 
Safety Follow-Up visit. Subjects with an ongoing SAE at the 30-day Safety Follow-up visit must be monitored and followed up until stabilization or until the 
outcome is known. After this visit, all SAEs need to be documented until the 90-day Safety Follow-up Phone Call. Subjects with an ongoing SAE at the 90-day 
Safety Follow-up Phone Call must be monitored and followed by the Investigator until stabilization or until the outcome is known, unless the subject is 
documented as “lost to follow-up”. At 90 days following the last treatment, subjects will be contacted by telephone to collect information on new or ongoing 
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2
Sponsor, Investigators and Trial Administrative Structure
The Sponsor of this clinical trial with avelumab is EMD Serono Research & Development 
Institute, Inc. (EMD Serono R&D), Billerica, MA, in the United States of America (USA) and 
Merck KGaA, Darmstadt, Germany, in rest of world.
A contract research organization (CRO), 
, will undertake the 
operational aspects of this trial. Details of such structures and associated procedures will be defined 
in a separate Integrated Project Management Plan (IPMP). The IPMP will be prepared by the 
 in cooperation with other 
.
2.1
Investigational Sites
The trial will be conducted at approximately 170 sites globally in North America, South America, 
Asia, Australia, and Europe, with approximately 28 sites in the USA.
2.2
Trial Coordination/Monitoring
The Sponsor will coordinate the trial and will enlist the support of CROs for some activities of the 
trial. The Sponsor will perform oversight of the activities performed by the CROs.
The Clinical Trial Supplies department of the Sponsor will supply or reimburse the trial treatment
of avelumab and physician’s choice chemotherapy. Packaging and distribution of clinical supplies 
will be performed by the Clinical Trial Supplies department of the Sponsor.
The Coordinating Investigator (
) represents all Investigators for decisions and 
discussions regarding this trial, consistent with the International Council for Harmonisation (ICH) 
Topic E6 Good Clinical Practice (GCP; hereafter referred to as ICH GCP). The Coordinating 
Investigator will provide expert medical input and advice relating to trial design and execution and 
is responsible for the review and signoff of the clinical trial report. Signature pages for the protocol 
lead and the Coordinating Investigator as well as a list of Sponsor responsible persons are in 
Appendix I.
The trial will appear in the following clinical trial registry: ClinicalTrials.gov (NCT02625623).
Subject enrollment and randomization will be managed by an interactive web response system 
(IWRS).
Safety laboratory assessments will be performed centrally. Local laboratories may be used at the 
discretion of the Investigator as clinically needed for safety management of the subject, and results 
from the local laboratories will be entered in the electronic case report forms (eCRFs) per the eCRF 
Completion Guidelines; however, central laboratory results must also be collected. Urinalysis and 
urine pregnancy testing will be done locally only.
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A β-human chorionic gonadotropin (β-hCG) should be determined from serum at Screening and 
from a urine or serum sample thereafter. Results of the most recent pregnancy test should be 
available prior to next administration of trial treatment.
 
assessments will be performed under the responsibility and/or supervision of the Sponsor.
The Global Drug Safety Department, Merck KGaA, Darmstadt, Germany, or their designated 
representatives will supervise drug safety and the timely reporting of adverse events (AEs) and 
serious adverse events (SAEs).
Quality assurance of the trial conduct will be performed by the Development Quality Assurance 
Department, Merck KGaA, Darmstadt, Germany.
The department of Global Biostatistics, Merck KGaA, Darmstadt, Germany, will supervise the 
statistical analyses, which will be outsourced to a CRO.
2.3
Review Committees
2.3.1
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will be composed of a minimum of 
3 members who do not have any conflict of interests with the trial Sponsor, including 2 clinicians 
and a biostatistician. The IDMC will periodically review safety data. The full membership, 
mandate, and processes of the IDMC will be detailed in the IDMC charter.
2.3.2
Independent Review Committee
A central facility will read and interpret all radiographic scans for this trial. The data for all images 
will be transferred from each trial site to the central reading center for evaluation. All scans will 
be evaluated at the central facility in accordance with Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST v1.1) (1). The response evaluation data will be transferred to the 
Sponsor or designee at regular intervals throughout the trial. A manual from the vendor will be 
provided to each trial site. 
The Independent Review Committee (IRC) will perform a blinded determination as to whether the 
criteria for tumor response or progression according to RECIST v1.1 have been met. The IRC will 
be composed of a minimum of 3 members, including 1 oncologist. The role of the IRC will be to 
review radiographic image findings and physical findings for the determination of the time point 
overall response and date of disease progression according to RECIST v1.1 for each subject. 
The IRC determines disease response, including progressive disease (PD) assessments associated 
with the trial endpoints, which will be supported by tumor assessments performed during the trial.
The full membership, mandate, and processes of the IRC will be detailed in the IRC charter.
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3
Background Information
3.1
Gastric Cancer
Globally, gastric cancer is the fifth most common cancer and the third leading cause of cancer 
death. In 2012, there were approximately 950,000 new cases and 723,000 deaths worldwide (2). 
Of these cancers, approximately 90% to 95% were adenocarcinomas with the remaining 5% to 
10% comprising neuroendocrine tumors, lymphomas, squamous cell cancer, and sarcomas.
The incidence of gastric cancer varies widely by country, with no true global standard treatment 
established. Higher incidence rates are observed in Asia, Costa Rica, Peru, and Eastern Europe, 
while Western Europe and the USA have lower incidence rates (3).
The use of chemotherapy to treat gastric cancer has no firmly established standard of care. Some 
drugs used in gastric cancer treatment include the following, sometimes using drugs in various 
combinations: fluorouracil and other fluoropyrimidines (capecitabine, S1), doxorubicin, cisplatin, 
oxaliplatin, taxanes, irinotecan, and others. Currently, combinations of fluoropyrimidine and 
platinum with or without doxorubicin or docetaxel are the most commonly used as first-line 
treatment. For patients with human epidermal growth factor receptor 2 (HER2)-positive gastric 
cancer, trastuzumab plus chemotherapy is the standard of care (4). Recently, the benefit of 
second-line chemotherapy has been demonstrated by several clinical trials; however, there is no 
standard treatment for patients after they have progressed on second-line therapy (5-24). 
Improvement in overall survival (OS) has been demonstrated for 4 drugs (paclitaxel, ramucirumab
with or without paclitaxel, docetaxel, and irinotecan) in the context of a randomized controlled 
trial in subjects with metastatic gastric cancer who have progressed after 1 line of a platinum-based 
doublet.
Despite these results, advanced, unresectable, and/or metastatic gastric cancer remains a 
significant unmet medical need. In addition, there is currently no recommended therapeutic 
approach for patients who progress after 2 lines of therapy for the treatment of recurrent, locally 
advanced, or metastatic gastric cancer.
3.2
Programmed Death Receptor and Ligands
The programmed death 1 (PD-1) receptor and PD-1 ligands 1 and 2 (PD-L1, PD-L2) play integral 
roles in immune regulation. Expressed on activated T cells, PD-1 is activated by PD-L1 and PD-L2 
expressed by stromal cells, tumor cells, or both, initiating T-cell death and localized immune 
suppression (25-28), potentially providing an immune-tolerant environment for tumor 
development and growth. Conversely, inhibition of this interaction can enhance local T-cell 
responses and mediate antitumor activity in nonclinical animal models (26, 29).
In the clinical setting, treatment with antibodies that block the PD-1 – anti-PD-L1 interaction have 
been reported to produce objective response rates (ORRs) of 7% to 38% in subjects with advanced 
or metastatic solid tumors, with tolerable safety profiles (30-32). Notably, responses appeared 
prolonged, with durations of 1 year or more for the majority of subjects. Recent trials have 
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documented the activity of anti-PD-L1 antibodies in subjects with advanced gastric cancer (33, 
34).
3.3
Avelumab
The investigational medicinal product (IMP) for the present trial is avelumab (anti-PD-L1 
monoclonal antibody MSB0010718C). Avelumab is a fully human monoclonal antibody of the 
immunoglobulin (Ig) G1 isotype. 
Avelumab selectively binds to PD-L1 and blocks the interaction between PD-L1 and its receptors 
PD-1 and B7.1. Compared with anti-PD-1 antibodies that target T-cells, avelumab targets tumor 
cells and is therefore expected to have fewer side effects, including a lower risk of 
autoimmune-related safety issues, as blockade of PD-L1 leaves the PD-L2/PD-1 pathway intact to 
promote peripheral self-tolerance (35). For complete details of the in vitro and nonclinical trials, 
please refer to the current Investigator’s Brochure (IB).
In light of the recent data demonstrating the clinical efficacy of an anti-PD-L1 antibody in 
advanced gastric cancer, and given the clinical importance of PD-L1 expression in gastric cancer 
tumor cells (36) and the mode of action of avelumab, avelumab is being developed as a potential 
therapy for patients with various advanced solid tumors, including gastric cancer. This anti-PD-L1 
therapeutic antibody concept is intended to be developed in oncological settings by Merck KGaA, 
Darmstadt, Germany, and by its subsidiary, EMD Serono R&D.
The ongoing clinical trials for avelumab are described in the IB. Of the Phase I studies, 2 of these 
studies have cohorts of subjects with advanced gastric cancer:
! Trial EMR 100070-001 is “a Phase I, open-label, multiple-ascending dose trial to investigate 
the safety, tolerability, PK, biological, and clinical activity of avelumab in subjects with 
metastatic or locally advanced solid tumors.”
! Trial EMR 100070-002 is “a Phase I trial to investigate the tolerability, safety, PK, biological, 
and clinical activity of avelumab in Japanese subjects with metastatic or locally advanced solid 
tumors, with expansion part in Asian subjects with gastric cancer.”
In addition to the trial described in this protocol, EMR 100070-008, another Phase III study in 
subjects with advanced gastric cancer (EMR 100070-007) is ongoing for 1L switch maintenance 
treatment.
3.3.1
Safety
Available safety and efficacy data for the avelumab program are discussed in the IB and establish 
a positive benefit risk for conducting Phase III studies with 10 mg/kg (the dosing used in this trial). 
The safety profile of avelumab has been evaluated based on data of more than 1750 subjects, 
including all subjects treated with 10 mg/kg from studies EMR100070-001 (1650 subjects) and 
EMR100070-003 Part A (88 subjects) as pooled safety dataset with a data cutoff of 09 June 2016, 
and subjects in the ongoing local Japanese Phase I Trial EMR100070-002. These safety data from 
subjects with different tumor types treated with avelumab suggests an acceptable safety profile of 
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the compound. Most of the observed events were either in line with those expected in subjects with 
advanced solid tumors or with similar class effects of monoclonal antibody blocking the 
PD-1/PD-L1 axis. Infusion-related reactions including drug hypersensitivity reactions and 
immune-mediated adverse reactions (immune-related pneumonitis, immune-related colitis, 
immune-related hepatitis, immune-related endocrinopathies [thyroid disorders, adrenal 
insufficiency, new onset type I diabetes mellitus, pituitary disorders], immune-related nephritis 
and renal dysfunction and other immune-related AEs [myositis, myocarditis, Guillain-Barré 
syndrome, uveitis]) have been identified as important risks for avelumab (please see the current
IB for details). Detailed guidelines for the management of immune-related adverse events and 
infusion-related reactions have been implemented in the study protocols, including this one (please 
see Sections 3.5, 5.1.2, 5.1.3, 6.2.1, 6.4.2, 6.5.4, 6.5.5 and 6.12).
3.3.2
Pharmacokinetic Results
Draft PK assessments have been performed in ongoing Trials EMR 100070-001 and 
EMR 100070-002. The preliminary results based on the data available as of 19 December 2014 
are presented under the individual trial headings.
3.3.2.1
Trial EMR 100070-001
Pharmacokinetics following the first 1-hour infusion and dose proportionality of avelumab have 
been characterized in 57 Caucasian subjects treated in the dose-escalation and expansion cohort of 
the Phase I Trial EMR 100070-001 by standard non-compartmental analysis based on rich serum 
concentration-time data obtained over a complete dosing interval of 2 weeks (= tau). The analysis 
of these data revealed that the exposure parameters maximum concentration observed postdose 
(Cmax) and area under the concentration-time curve (AUCtau) increased with the doses in a linear 
fashion.
The mean (standard deviation [SD]) apparent terminal half-life (t1/2) was 69 ± 21 hours for 
1 mg/kg, 84 ± 22 hours for the 3 mg/kg, 106 ± 29 hours for 10 mg/kg, and 134 ± 74 hours for the 
20 mg/kg dose. Taking into account the variability, the t1/2 of the 10 and 20 mg/kg doses can be 
regarded as similar, indicating that target mediated elimination does not increase at these doses. 
This implies that target occupancy is likely to be high at these 2 doses throughout the dosing 
interval. 
Minimum trough concentrations (Cmin) were obtained for the majority of subjects enrolled in the 
trial. The median Cmin at the end of the first cycle after administration of the 10 mg/kg dose was 
20 μg/mL (n=256). This median Cmin increased during the subsequent cycles to 24 μg/mL (second 
cycle; n=233), 26 μg/mL (third cycle; n=167), and remained between 24 and 37 μg/mL during the 
subsequent cycles (n=22 to 114) indicative for no significant accumulation with the biweekly 
dosing scheme. Median Cmin after the 3 mg/kg dose were 3.7 μg/mL after the first dose, 3.9 μg/mL 
after the second dose and 8.3 μg/mL after the third dose (n=7 to 12), though some trough values 
below 1 μg/mL were observed, as well as antidrug antibodies in at least 1 subject in this dose group 
on Day 85 of the treatment period, accompanied by loss of quantifiable exposure. Median trough 
concentrations after the 20 mg/kg dose were 44, 70, and 77 μg/mL after the first, second, and third 
dose, respectively (n=14 to 19).
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For the 10 mg/kg dose, the mean (SD) volume of distribution was 55 ± 12 mL/kg and total systemic 
clearance was low (0.38 ± 0.11 mL/h/kg).
3.3.2.2
Trial EMR 100070-002
A preliminary analysis of the PK data was performed based on the serum concentration of 
avelumab obtained from 5 Japanese subjects treated with 3 mg/kg, 6 Japanese subjects treated with 
10 mg/kg, and 6 Japanese subjects treated with 20 mg/kg as a 1-hour intravenously (IV) infusion 
once every 2 weeks. 
Non-compartmental PK parameter calculation was performed based on non-quality-assured 
concentrations obtained during the first infusion using scheduled sample collection times and 
infusion duration of 1 hour.
Following the first infusion, serum Cmax (geometric mean) of 64 μg/mL (range: 50 to 78 μg/mL) 
for the 3 mg/kg, 179 μg/mL (range: 148 to 228 μg/mL) for the 10 mg/kg, and 459 μg/mL (range: 
374 to 533 μg/mL) for the 20 mg/kg were observed at a median time to reach maximum 
concentration of 1.5, 1.3, and 1.8 hours after infusion start (ranging between 1 and 5 hours). The 
average AUCtau (geometric mean) over the first dosing interval was 5437 μg/mL∙h (range: between 
3826 and 7246 μg/mL∙h) for the 3 mg/kg dose, 20126 μg/mL∙h (range: 12185 to 34390 μg/mL∙h) 
for the 10 mg/kg dose, and 47259 μg/mL∙h (range: 37238 to 67591 μg/mL∙h) for the 20 mg/kg. 
Variability in exposure parameters (Cmax and AUCtau) was in general low as indicated by geometric 
coefficients of variation of 22% and 27% for the 3 mg/kg dose, 20% and 40% for the 10 mg/kg 
dose, and 14% and 22% for the 20 mg/kg dose. In regards to Cmax and Cmin, inter-individual 
variability was generally higher than intra-individual variability. The apparent t1/2 was 89 hours 
(range: 52 to 118 hours) for 3 mg/kg, 122 hours (range: 68 to 152 hours) for 10 mg/kg, and 
114 hours (range: 92 to 133 hours) for 20 mg/kg. The mean estimated volume of distribution was 
in the range of 61 to 73 mL/kg, the mean total systemic clearance ranged between 0.37 and 
0.51 mL/h/kg.
Mean Cmin obtained immediately before next infusion and mean Cmax obtained immediately after 
infusion end (at Days 15, 29, 43, and 85) remained at fairly constant levels, indicating no 
accumulation following multiple infusions. This is in line with the calculated apparent t1/2 and the 
applied dosing scheme (once every 2 weeks). 
Exposure values Cmax and AUC increased almost proportional with dose.
Although a formal analysis has not been conducted, it is apparent that the preliminary 
concentrations obtained over time and the clearance during the first dosing interval were similar 
in Japanese and Caucasian subjects.
3.3.3
Clinical Pharmacodynamics
Receptor occupancy was measured in vitro by flow cytometry on peripheral blood CD3+ T cells 
after spiking of human whole blood samples from 8 healthy volunteers with avelumab over a 
concentration range of 0.003 to 10 μg/mL. In this assay, free receptors were measured in samples 
spiked over this range and compared with the amount of free receptors in the unspiked sample. A 
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50% receptor occupancy was observed at a drug concentration (SD) of 0.122 μg/mL ± 
0.042 μg/mL, and a plateau indicating at least 95% receptor occupancy was reached in all donor 
blood samples at 1 μg/mL.
These in vitro data combined with PK data were confirmed in ex vivo samples taken at Cmin after 
the first dose (Day 15) in a small number of subjects during the initial dose-escalation part of the 
Phase Ib Trial EMR 100070-001 (n=9). For doses of 10 mg/kg, target occupancy was greater than 
90% for these 4 subjects, at Cmin levels ranging between 12.69 to 26.87 μg/mL. Also, for doses of 
3 mg/kg, available target occupancy data for 2 subjects with trough levels ranging from 4.56 to 
6.99 μg/mL, showed greater than 90% target occupancy at trough exposure levels. At dose level 
1 mg/kg, 2 out of 3 subjects displayed less than 90% target occupancy at trough serum 
concentrations. Avelumab serum concentrations were below the quantification limit of 0.2 μg/mL 
in these 2 subjects.
Based on the observed avelumab serum concentrations in the EMR 100070-001 Phase I clinical 
trial and the in vitro receptor occupancy data, trough concentrations were sufficient to achieve full 
target occupancy throughout the entire dosing interval in all of the subjects receiving the 10 mg/kg 
dose. After the 3 mg/kg dose, Cmin was insufficient in 3 of the 13 subjects to assure full target 
occupancy; therefore, in order to achieve target saturation during the whole treatment period in all 
subjects, the dose of 10 mg/kg every 2 weeks was selected as the dose for further investigation in 
the Phase Ib expansion cohorts and for the subsequent clinical trials.
3.4
Rationale for the Current Clinical Trial
The safety and clinical efficacy of avelumab have been determined in multiple tumor types 
(non-small cell lung cancer, ovarian cancer, mesothelioma, melanoma, thymoma, and 
adrenocorticocarcinoma) (37, 38). The rationale to enroll subjects with unresectable, recurrent, 
locally advanced or metastatic adenocarcinoma of the stomach or gastro-esophageal junction is 
supported by data reported from other PD-1/PD-L1 agents and from 2 expansion cohorts in 
2 avelumab Phase I studies.
3.4.1
Data from Anti-PD-1/PD-L1 Therapies in Gastric Cancer
Data from other anti PD-1/PD-L1 therapies in gastric cancer are as follows:
! Data presented at the American Society for Clinical Oncology Annual Meeting 2014 from a 
Phase I expansion cohort of 16 subjects with gastroesophageal cancer treated with MEDI4736 
(anti-PD-L1), which reported 4 out of 16 responders (33).
! Data presented at the European Society for Medical Oncology Annual Meeting 2014 from a 
Phase I cohort of 39 PD-L1+ subjects with advanced gastric cancer treated with anti-PD-1 
(Keynote012), which reported 12 out of 39 responders (34).
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3.4.2
Efficacy Data Generated During the Development of 
Avelumab
Subjects with advanced gastric cancer have been enrolled in 2 clinical trials: Trial 
EMR 100070-001 (see Section 3.3.2.1) and Trial EMR 100070-002 (see Section 3.3.2.2).
Efficacy results observed in these trials are below:
!
Trial EMR 100070-001: As of the data cutoff of 23 October 2015, in the primary cohort of 
151 subjects with unresectable, locally advanced, or metastatic gastric or gastroesophageal 
junction adenocarcinoma, the ORR in second-line subjects was 9.7% (6/62 subjects; 95% 
confidence interval [CI], 3.6 to 19.9; all 6 subjects had partial response [PR], and 3 were
ongoing at cutoff). In switch-maintenance subjects, ORR was 9.0% (8/89 subjects; 95% 
CI, 4.0 to 16.9; 2 subjects had complete response [CR], and 6 had PR; 4 subjects were 
ongoing at cutoff). Stable disease was observed in 12 additional second-line subjects 
(19.4%) and 43 additional switch-maintenance
subjects (48.3%). The median 
progression-free survival (PFS) was 6.0 weeks and PFS rate at 24 weeks was 8.8% in 
second-line subjects. In the switch-maintenance subjects, the median PFS was 12.0 weeks 
and PFS rate at 24 weeks was 25.7%.
!
Trial EMR 100070-002: As of the data cutoff of 11 March 2015, Japanese subjects with 
recurrent or refractory gastric or gastroesophageal junction adenocarcinoma had ORR 15% 
(3/20 subjects, 95% CI, 3.2 to 37.9), with 3 subjects having a PR. Ten subjects (50%) had 
stable disease, median PFS was 11.9 weeks, and PFS rate at 12 weeks was 43.3%.
Overall, the data generated in subjects with gastric cancer suggest that the administration of 
avelumab is well tolerated and clinically active.
The response rate and the duration of response observed compare favorably with those reported 
with chemotherapy in the second-line gastric cancer setting.
3.5
Summary of the Overall Benefit and Risk
Based on the nonclinical and Phase I data available to date, the conduct of the trial is considered 
justifiable using the dose and dose regimen of the avelumab as specified in this clinical trial 
protocol. For details regarding the dose selection rationale, refer to the IB. An IDMC (see 
Section 2.3.1) will assess the risk-benefit ratio on an ongoing basis. The trial will be discontinued 
in the event of any new findings that indicate a relevant deterioration of the risk benefit relationship 
that would render continuation of the trial unjustifiable.
The primary known identified risks of exposure to avelumab include: 
! Infusion-related reactions 
! Immune-related adverse events (irAEs).
As of 05 November 2014, 2 Grade 4 infusion reactions have been reported in 480 subjects (0.4%) 
treated with avelumab (see Section 3.3.2.1); therefore, already implemented risk mitigation 
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measures for infusion-related reactions/hypersensitivity have been extended. Premedication with 
an antihistamine and with paracetamol (acetaminophen) approximately 30 to 60 minutes prior to 
the first 4 doses of avelumab is mandatory (for example, 25 to 50 mg diphenhydramine and 500 to 
650 mg paracetamol [acetaminophen] IV or oral equivalent). Premedication should be 
administered for subsequent avelumab doses based upon clinical judgment and presence/severity 
of prior infusion reactions. This regimen may be modified based on local treatment standards and 
guidelines as appropriate provided it does not include systemic corticosteroids. 
In addition, since avelumab can induce antibody-dependent cell-mediated cytotoxicity, there is a 
potential risk of tumor lysis syndrome (TLS, see Section 6.5.4.3). 
As noted in Section 3.2, trials with antibodies that block the PD-1 – PD-L1 interaction have been 
reported to produce ORRs of 7% to 38% in subjects with advanced or metastatic solid tumors 
(30-32), with response durations of 1 year or more for the majority of subjects. More specifically, 
avelumab has a reported ORR in the range of 10% to 15% for second-line 
(Trial EMR 100070-001) 
and 
third-
or 
fourth-line 
gastric 
cancer 
subjects 
(Trial EMR 100070-001). While that response rate is similar to that reported by Lee et al (39), it 
is expected that the responses with avelumab will be long lasting. In addition, the ORR does not 
recapitulate the clinical benefit provided by checkpoint inhibitors, as previously demonstrated for 
ipilimumab and nivolumab, for which dramatic improvement of OS and PFS was observed, with 
ORR usually less than 20%. In the absence of any established therapy for third-line gastric cancer, 
which has a very poor prognosis (median OS less than 5 months), the administration of avelumab 
represents an option that carries a favorable risk/benefit.
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP, and 
the applicable national regulatory requirements.
4
Trial Objectives
4.1
Primary Objectives
The primary objective is to demonstrate superiority with regard to OS of avelumab plus best 
supportive care (BSC) versus physician’s choice (chosen from a pre-specified list of therapeutic 
options) plus BSC.
4.2
Secondary Objectives
Secondary objectives are as follows:
! To compare avelumab plus BSC versus physician’s choice plus BSC in regard to the following:
! Progression-free survival based on an IRC assessment
! ORR based on IRC assessment
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are authorized and marketed. Investigators must specify which of the physician’s choice treatment 
regimens will be selected prior to randomization. Before making a decision and starting 
administration of chemotherapy, the Investigator is required to refer to what is stated in the 
respective current product information (local label, Summary of Product Characteristics [SmPC]), 
particularly in regard to contraindications, warnings and precautions for use, dosage adjustments 
in the event of toxicity, subject monitoring provisions, the duration of the need for contraception, 
and medicinal products that are prohibited or that must be used with caution. In case of a potential 
contradiction between the specifications outlined in this clinical trial protocol and the information 
contained in the product information (local label, SmPC) of irinotecan or paclitaxel, respectively, 
the local label always prevails. Investigators should check updated labeling information via 
relevant websites before randomization and before chemotherapy administration.
5.1.1
Overall Design
Approximately 330 subjects will be randomized, stratified by region, in a 1:1 ratio to receive BSC 
with either avelumab at a dose of 10 mg/kg as a 1-hour IV infusion once every 2 weeks or 
physician’s choice chemotherapy from the following (Table 4): 
! Paclitaxel as monotherapy (80 mg/m2 on Days 1, 8 and 15 of a 4-week treatment cycle). 
Subjects should be premedicated with 20 mg dexamethasone orally approximately 12 and 
6 hours prior to injection, 50 mg diphenhydramine (or equivalent) IV 30 to 60 minutes prior to 
injection, and 300 mg cimetidine or 50 mg ranitidine IV 30 to 60 minutes prior to injection. The 
premedication regimen may be modified based on local treatment standards and guidelines as 
appropriate.
! Irinotecan as monotherapy (150 mg/m2 on Days 1 and 15 of a 4-week treatment cycle). Subjects 
should be premedicated with anti-emetics, such as 10 mg prochloroperazine orally, 30 minutes 
prior to beginning therapy. If subjects have cholinergic symptoms, premedicate with 0.2 to 
0.3 mg atropine subcutaneously. The premedication regimen may be modified based on local 
treatment standards and guidelines as appropriate.
! Subjects who are not deemed eligible to receive paclitaxel or irinotecan at the dose and schedule 
specified above will receive BSC once every 3 weeks.
Subjects will return to the clinic at regular intervals for assessments. Tumor measurements by 
computed tomography (CT) scan or magnetic resonance imaging (MRI) will be performed every 
6 weeks for the first 12 months and every 12 weeks thereafter to determine response to treatment. 
A central imaging laboratory will be used to read and interpret all CT/MRI data. Response will be 
evaluated using RECIST v1.1 and as adjudicated by a blinded IRC. Treatment will continue until:
! Disease progression (see Section 5.5.1)
! Significant clinical deterioration (clinical progression, see Section 5.5.1)
! Unacceptable toxicity, or
! Any criterion for withdrawal from the trial or trial treatment is fulfilled (see Section 5.5).
For subjects receiving avelumab plus BSC, treatment may continue past the initial determination 
of disease progression per RECIST v1.1 as long the following criteria are met:
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! No new symptoms or worsening of previous symptoms
! Tolerance of trial treatment
! Stable Eastern Cooperative Oncology Group performance status (ECOG PS)
! Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (for example, central nervous system metastases).
Subjects receiving avelumab plus BSC who have experienced a CR should continue to receive 
avelumab for a minimum of 12 months after confirmation of response and/or until disease 
progression or unacceptable toxicity. In case a subject with a confirmed CR relapses after stopping 
treatment, but prior to the end of the trial, 1 re-initiation of treatment is allowed at the discretion 
of the Investigator and agreement of the Medical Monitor. To be eligible for re-treatment, the 
subject must not have experienced any toxicity that led to treatment discontinuation of the initial 
avelumab therapy. Subjects who re-initiate treatment will stay on trial and will be treated and 
monitored according to the protocol and the “until progression” schedule in the Schedules of 
Assessments (see Table 1). Subjects who re-initiate treatment will not have to undergo a second 
Screening visit.
Investigators must specify which of the physician’s choice treatment regimens will be selected 
prior to randomization.
Subjects receiving physician’s choice plus BSC will receive trial treatment until PD per RECIST 
v1.1, significant clinical deterioration (clinical progression), unacceptable toxicity, withdrawal of 
consent, or if any criterion for withdrawal from the trial or trial treatment is fulfilled. Subjects 
receiving physician’s choice plus BSC will not be offered to cross over to avelumab plus BSC.
Assessments will be made by the Investigator for the purpose of subject management, but the 
disease response endpoint determinations, including PD assessments associated with the trial 
endpoints, will be supported by tumor assessments performed by an IRC (see Sections 2.3.2 and 
7.3).
Subjects will attend clinic visits at regular intervals to receive trial treatment and for efficacy and 
safety assessments (see Section 7.1.2).
The primary endpoint of the trial is OS, defined as the time (in months) from randomization to the 
date of death, regardless of the actual cause of the subject’s death.
Safety endpoints include AEs assessed throughout the trial and evaluated using the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03, 
physical examination findings, clinical laboratory assessments, vital signs, and electrocardiograms
(ECGs).
The trial design schematic is presented in Figure 1.
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Figure 1
Schematic of the Trial Design
BSC=best supportive care, ORR=overall response rate, OS=overall survival, PD=progressive disease, 
PFS=progression-free survival, QoL=quality of life, R=randomization.
5.1.2
Trial Treatment Administration and Schedule
The trial Schedules of Assessments are presented in Table 1.
5.1.2.1
Avelumab
Subjects randomized to the avelumab plus BSC arm will receive IV infusion of avelumab 
(10 mg/kg over 1 hour) once every 2 weeks. To mitigate infusion-related reactions, premedication 
with an antihistamine and with paracetamol (acetaminophen) approximately 30 to 60 minutes prior 
to the first 4 doses of avelumab is mandatory (for example, 25 to 50 mg diphenhydramine and 
500 to 650 mg paracetamol [acetaminophen] IV or oral equivalent). Premedication should be 
administered for subsequent avelumab doses based upon clinical judgment and presence/severity 
of prior infusion reactions. This regimen may be modified based on local treatment standards and 
guidelines as appropriate provided it does not include systemic corticosteroids.
The formulation and packaging information of avelumab is provided in Sections 6.1.1 and 6.6, 
respectively.
5.1.2.2
Physician’s Choice Chemotherapy
Subjects randomized to the physician’s choice arm will receive BSC plus physician’s choice
chemotherapy (paclitaxel or irinotecan monotherapy) until disease progression, unacceptable 
toxicity, or any of the criteria for withdrawal from trial treatment is fulfilled (Section 5.5). Dosing 
and regimen of the physician’s choice chemotherapy (paclitaxel or irinotecan monotherapy) is 
summarized in Section 6.2.2.
Additionally, in order to reduce the incidence and severity of fluid retention as well as the severity 
of hypersensitivity reactions, subjects will be administered pre-treatment prior to each therapy
infusion per local institutional practice.
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5.1.2.3
Best Supportive Care
All subjects in both arms will receive BSC as background therapy. Subjects who are not deemed 
eligible to receive paclitaxel or irinotecan will receive BSC alone with no active therapy once 
every 3 weeks.
There is no universal definition of BSC that can be applied across institutions, countries, or regions 
(40). Best supportive care is defined as “treatment administered with the intent to maximize QoL 
without a specific antineoplastic regimen, which include antibiotics, analgesics, antiemetics, 
thoracentesis, paracentesis, blood transfusions, nutritional support (including jejunostomy), and 
focal external-beam radiation for control of pain, cough, dyspnea, or bleeding” (41). Best 
supportive care will be administered per institutional guidelines. Best supportive care can be 
administered without any additional therapy.
5.1.3
Dose Modification and Adverse Drug Reactions Requiring 
Treatment Discontinuation
5.1.3.1
Dose Modification for Avelumab
The dose of avelumab will be calculated based on the weight of the subject determined within 
72 hours prior to the day of drug administration. The dose of avelumab used for the previous 
administration can be repeated if the change in the subject’s weight is 10% or less than the weight 
used for the last dose calculation.
Each subject will stay on the avelumab assigned dose of 10 mg/kg unless treatment needs to be 
stopped. Dosing modifications (changes in infusion rate) and dose delays are described in 
Sections 5.1.3.2 and 6.5.4.1. There will be no dose reductions.
5.1.3.2
Adverse 
Drug 
Reactions 
Requiring 
Avelumab 
Discontinuation or Modifications
The following adverse drug reactions (ADRs, see Section 7.4.1.1) require permanent treatment 
discontinuation of avelumab:
! Any Grade 4 ADRs require treatment discontinuation with avelumab except for single 
laboratory values out of normal range that are unlikely related to trial treatment as assessed by 
the Investigator, do not have any clinical correlate, and resolve within 7 days with adequate 
medical management
! Any Grade 3 ADRs require treatment discontinuation with avelumab except for any of the 
following: 
! Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which are controlled with medical 
management
! Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, or emesis that 
resolve to Grade ≤ 1 
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! Single laboratory values out of normal range (excluding Grade ≥ 3 liver function test 
increase) that are unlikely related to trial treatment according to the Investigator, do not have 
any clinical correlate, and resolve to Grade ≤ 1 within 7 days with adequate medical 
management
! Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known 
or suspected tumor
! Change in ECOG PS to ≥ 3 that resolves to ≤ 2 within 14 days (infusions should not be given 
on the following cycle, if the ECOG PS is ≥ 3 on the day of trial treatment administration)
! Asymptomatic Grade ≥3 drug-related amylase or lipase abnormality that is not associated 
with symptoms or clinical manifestations of pancreatitis does not require dose delay or 
discontinuation. The study Medical Monitor should be consulted for such abnormalities.
! Infusion should not be given in case of ongoing Grade 2 ADR on the day of trial treatment 
administration.
Treatment can be resumed according to the original schedule once the ADR has resolved to 
Grade ≤1. Up to 2 subsequent trial treatment doses may be omitted to allow for recovery to 
Grade ≤1. If more than 2 doses are skipped, treatment may be resumed after consultation with 
the trial Medical Monitor.
Infusion-related reactions, hypersensitivity reactions and flu-like symptoms (Grades 1 to 4), TLS, 
and irAEs should be handled according to guidelines in Sections 6.5.4.1, 6.5.4.2, 6.5.4.3, and 
6.5.4.4, respectively.
5.1.3.3
Dose Modification for Physician’s Choice Chemotherapy
The starting dose of physician’s choice chemotherapy will be determined per local institutional 
guidelines in the absence of established doses and schedules for these agents when administered 
in the context of the management of third-line gastric cancer. Suggested dosing is summarized in 
Section 6.2.2.
Dose modification (dose delays and dose changes) for physician’s choice chemotherapy should be 
performed according to local institutional guidelines.
5.2
Discussion of Trial Design
This is a Phase III, 2-arm, randomized, open-label trial to determine the efficacy and safety of 
avelumab plus BSC compared with physician’s choice of third-line therapy as monotherapy
(paclitaxel or irinotecan) plus BSC, or BSC alone in subjects with unresectable, recurrent, locally 
advanced or metastatic adenocarcinoma of the stomach or of the gastroesophageal junction who 
have failed or relapsed from 2 prior chemotherapeutic regimens.
First-line therapy may consist of any of the following:
! Fluoropyrimidine-platinum-based doublet
! Fluoropyrimidine components can consist of S1, 5-fluorouracil, or capecitabine
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! Platinum component can consist of either oxaliplatin or cisplatin
! Fluoropyrimidine-platinum-based triplets consisting of the addition of docetaxel or epirubicin
to a fluoropyrimidine-platinum-based doublet
! FOLFIRI, which consists of the administration of fluorouracil, leucovorin, and irinotecan 
! Adjuvant or neo-adjuvant fluoropyrimidine-platinum-containing doublets will be considered as
a first-line if relapse occurs within 6 months after the last administration of the platinum salt.
Second-line therapy is defined as any of the following:
! Another line of a platinum-based treatment or FOLFIRI if the disease has progressed more than 
6 months after completion of the first-line platinum-based treatment or FOLFIRI
! Ramucirumab (as a single agent or in combination)
! Docetaxel (as a single agent or in combination)
! Paclitaxel (as a single agent or in combination) (nab-paclitaxel is acceptable)
! Irinotecan (as a single agent or in combination).
Trastuzumab in combination with first-line therapy or second-line therapy listed above for 
HER2 – neu overexpressing adenocarcinoma is acceptable.
5.2.1
Rationale Supporting the Selection of Eligible First-Line 
Therapies
Acceptable regimens as first-line treatment of unresectable, recurrent, locally advanced or 
metastatic gastric cancer are described in Section 5.2.
All of these regimens are considered to be acceptable first-line regimens for the management of 
unresectable, recurrent, locally advanced or metastatic gastric cancer, as per the National 
Comprehensive Cancer Network guidelines, the European Society for Medical Oncology, and the 
Japanese guidelines.
The 
rationale 
to 
consider 
the 
administration 
of 
an 
adjuvant 
or 
neo-adjuvant 
platinum-fluoropyrimidine-containing doublet as a first-line therapy if a relapse occurs within 
6 months after the last administration of the platinum salt is based on the concept that the 
subsequent administration of that same chemotherapy would not be adequate.
5.2.2
Rationale Supporting the Selection of Eligible Second-Line 
Therapies
In addition to the first-line regimens, acceptable regimens as second-line treatment of unresectable, 
recurrent, locally advanced or metastatic gastric cancer are described in Section 5.2.
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The selection of these regimens is based on data (Table 3) demonstrating a statistically significant 
improvement in OS for irinotecan, docetaxel, paclitaxel, and ramucirumab in second-line 
advanced gastric cancer subjects compared to BSC.
Table 3
Overall Survival and Progression-free Survival for Subjects Receiving 
Second-line Chemotherapy
German AIO 
N=40
Korean Trial
N=202
Cougar 02
N=168
Regard
N=355
WJOG 4007
N= 223
Rainbow
N=665
Previous 
treatment 
(first-line)
Fluoropyrimidine and/or platinum
Treatment
Irinotecan vs. 
BSC
Irinotecan or 
docetaxel 
(n=133) vs. 
BSC (n=69)
Docetaxel 
(n=84) vs. 
active 
symptom 
management
Ramucirumab 
vs placebo
Paclitaxel 
(n=108) vs. 
irinotecan 
(n=111)
Ramucirumab 
+ weekly 
paclitaxel 
(n=330) vs. 
weekly 
paclitaxel 
(n=335)
Second-line 
subjects
40
148
168
355
219
665
Third-line 
subjects
NA
54
NA
NA
NA
NA
Median PFS
Irinotecan 
arm only: 2.6 
months
4.4 months 
(95% CI, 4.2 
to 5.3 
months) vs. 
2.9 months 
(95% CI, 2·8 
to 3·0)
HR=0.635
95% CI, 
0.536 to 
0.752
p<0.0001
Median OS
4.0 months 
vs. 2.4 
months
HR=0.48
95% CI, 0.25 
to 0.9
p=0.012
5.3 months 
vs. 3.8 
months 
HR=0.657
95% CI, 0.48 
to 0.89
p=0. 007
5·2 months 
vs. 3.6 
months
HR=0·67, 
95% CI, 0·49 
to 0·92
p=0·01
5·2 months 
vs. 3·8 
months
HR=0·776, 
95% CI, 
0·603 to 
0·998
p=0·047
9.5 months 
vs. 8.3 
months
HR=1.13; 
95% CI, 0.86 
to 1.49
p=0.38
9.6 months 
vs. 7.4 
months
HR=0.807
95% CI, 
0.678 to 
0.962
p=0.017
Source: Thuss-Patience et al. (42), Kang et al. (43), Ford et al. (44), Fuchs et al. (45), Hironaka et al. (46), Wilke et 
al. (47).
BSC=best supportive care, CI=confidence interval, HR=hazard ratio, NA=not applicable, OS=overall survival, 
PFS=progression-free survival.
In addition, the use of another combination therapy in the second-line setting that is not 
cross-resistant with previously administered first-line therapy is another common therapeutic 
approach in advanced gastric cancer subjects who have progressed after a first-line of combination 
therapy (48, 49).
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5.2.3
Rationale for Physician’s Choice Chemotherapy in the 
Third-Line Setting
There is no standard of care for the treatment of patients with advanced gastric cancer who have 
progressed after 2 prior chemotherapies. 
Based on this, a study versus BSC may have been considered appropriate; however, there is 
literature supporting the use of chemotherapy in a third-line advanced gastric cancer trial (39). In 
particular, data from a cohort of Korean subjects with advanced gastric cancer who were treated 
with single-agent docetaxel after progression on m-FOLFOX-4 and m-FOLFIRI suggest that 
chemotherapy in the third line setting is feasible. Therefore, administration of chemotherapy is 
considered a reasonable option for these patients.
The data from this study are summarized below:
Lee et al. analyzed 33 subjects who had been histologically diagnosed with adenocarcinoma of the 
stomach and who had progressed after m-FOLFOX-4 and m-FOLFIRI regimens (39). Subjects 
were treated with docetaxel (75 mg/m2) on Day 1 every 3 weeks. All subjects were evaluated in 
terms of tumor response: 5 (15%), 9 (27%), and 19 (58%) subjects experienced PR, stable disease, 
and PD, respectively. The median time to progression was 2.1 months (95% CI, 1.63 to 2.58 
months), and OS was 4.7 months (95% CI, 3.20 to 6.20 months) from the start of the docetaxel 
regimen. Assessing the subjects’ toxicity profiles, the median number of cycles was 2.0 (range, 
1.0 to 12.0 cycles). The major hematologic toxicities included Grade 3 or 4 neutropenia (19/33, 
58%), Grade 3 or 4 thrombocytopenia (2/33, 6%), and Grade 3 or 4 anemia (5/33, 15%). 
Neutropenic fever developed in 3 subjects (9%). The nonhematological toxicities were nausea and 
vomiting (10/33, 30%), abdominal pain (4/33, 12%), skin rash (1/33, 3%), and fluid retention 
(3/33, 9%). Overall, the conclusion was that docetaxel is a feasible third-line therapy regimen for 
subjects with advanced gastric cancer after m-FOLFIRI and m-FOLFOX-4 regimens.
Despite these limited data suggesting chemotherapy may be feasible in the third-line setting, BSC 
may still be considered standard of care for many advanced gastric patients who have progressed 
after 2 lines of chemotherapy agents. In clinical practice, many patients with gastric cancer develop 
peritoneal carcinomatosis during the course of their disease, which usually leads to a rapid 
symptomatic deterioration and chemotherapy intolerance (44). Although data from COUGAR-02 
and other trials have shown activity of select therapies after first-line treatment for advanced gastric 
disease, only a small subset of patients may have an adequate PS after first-line treatment failure 
that would allow them to be able to tolerate second-line chemotherapy and, therefore, also third 
line treatment as well. 
For patients who are not candidates for chemotherapy, BSC may still be considered a reasonable 
alternative for patients considered to be unfit for palliative chemotherapy in the second-line setting. 
Subsequently, BSC should also be considered a reasonable treatment option for third-line patients. 
Based on this, BSC alone or BSC plus physician’s choice of active chemotherapy is considered an 
appropriate comparator for the proposed target population.
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Subjects randomized to the physician’s choice plus BSC will receive physician’s choice treatment 
selected from one of the following options:
! Paclitaxel as monotherapy (80 mg/m2 on Days 1, 8, and 15 of a 4-week treatment cycle)
! Irinotecan as monotherapy (150 mg/m2 on Days 1 and 15 of a 4-week treatment cycle)
! Subjects who are not deemed eligible to receive paclitaxel or irinotecan at the dose and schedule 
specified above will receive BSC once every 3 weeks.
Dose and regimen of both paclitaxel and irinotecan monotherapy are consistent with recommended 
regiments in the National Comprehensive Cancer Network guidelines for gastric cancer and based 
on published Phase III data from the WJOG 4007 trial in advanced gastric cancer (46).
5.2.4
Rationale for the Primary Endpoint
Overall survival was chosen as the primary endpoint because this is an unequivocal measurement 
of clinical benefit that will not be confounded by the open-label nature of the study.
5.2.5
Rationale for the Expected Treatment Effect
The study sample size has been determined on the hypothesis of a hazard ratio of 0.67.
The expected treatment effect for avelumab plus BSC when compared with physician’s choice
plus BSC is based on the following considerations:
! The response rate of approximately 15% reported to date in the second-line population of the 
2 avelumab Phase I studies is similar with that of chemotherapy in the third-line setting
! Rapid onset of responses has been reported with avelumab, as well as with the other anti-PD-1 
and anti-PD-L1 therapies, suggesting that treatment with avelumab will be effective despite the 
rapid progression of these advanced subjects.
5.2.6
Rationale for Stratification by Region
Region (Asia versus non Asia) has been retained as a stratification factor because it is well 
established that gastric cancer physiopathology and clinical management differ significantly in 
Asian countries compared to non-Asian countries (50).
Differences in clinical outcomes between Asian and non-Asian subjects have been reported in the 
Phase III studies performed with ramucirumab, trastuzumab, and bevacizumab (47, 51, 52).
5.2.7
Inclusion of Special Populations
Not applicable.
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5.3
Selection of Trial Population
Subject enrollment will be randomized and managed by an IWRS (see Section 6.3). Only persons
meeting all inclusion criteria and no exclusion criteria may be enrolled into the trial as subjects.
Prior to performing any trial assessments not part of the subject’s routine medical care, the 
Investigator will ensure that the subject or the subject’s legal representative has provided written 
informed consent following the procedure described in Section 9.2.
5.3.1
Inclusion Criteria
For inclusion in the trial, all of the following inclusion criteria must be fulfilled:
1. Signed written informed consent before any trial-related procedure is undertaken that is not 
part of the standard patient management
2. Male or female subjects aged ≥ 18 years
3. Availability of a formalin-fixed, paraffin-embedded (FFPE) block containing tumor tissue 
or a minimum of 7 slides (preferably 10) unstained tumor slides suitable for PD-L1 
expression assessment. PD-L1 expression determination is not a requirement for 
enrollment and will be done retrospectively
4. Subjects with histologically confirmed unresectable, recurrent, locally advanced or 
metastatic adenocarcinoma of the stomach or the gastroesophageal junction
5. Documented objective radiographic or clinical disease progression (e.g., any new or 
worsening malignant effusion documented by ultrasound examination) that may be 
confirmed by pathologic criteria (histology and/or cytology)
6. Subjects must have received 2 prior courses of systemic treatment for unresectable, 
recurrent, locally advanced or metastatic gastric cancer, and must have progressed after the 
second line
a.
Acceptable regimens as first-line treatment of unresectable, recurrent, locally 
advanced or metastatic gastric cancer may include the following:
i. Fluoropyrimidine-platinum-based doublet
1. Fluoropyrimidine components can consist of S1, 5-fluorouracil, or 
capecitabine
2. Platinum component can consist of either oxaliplatin or cisplatin
ii. Fluoropyrimidine-platinum-based triplets consisting of the addition of 
docetaxel or epirubicin to a fluoropyrimidine-platinum-based doublet
iii. FOLFIRI 
iv. Any prior adjuvant or neo-adjuvant treatment is allowed. Treatment with 
adjuvant or neo-adjuvant fluoropyrimidine-platinum-containing doublets 
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will be considered as a first-line if relapse occurs within 6 months after the 
last administration of the platinum salt.
b. Second-line therapy is defined as any of the following:
i. Another line of a platinum-based treatment or FOLFIRI if the disease has 
progressed more than 6 months after completion of the first-line 
platinum-based treatment or FOLFIRI
ii. Ramucirumab (as a single agent or in combination)
iii. Docetaxel (as a single agent or in combination)
iv. Paclitaxel (as a single agent or in combination) (nab-paclitaxel is 
acceptable)
v. Irinotecan (as a single agent or in combination)
Trastuzumab in combination with first-line therapy or second-line therapy 
listed above for HER2 – neu overexpressing adenocarcinoma is acceptable.
7. ECOG PS of 0 to 1 at trial entry 
8. Adequate hematological function defined by white blood cell count ≥ 2.0 × 109/L with 
absolute neutrophil count ≥ 1.0 × 109/L, lymphocyte count ≥ 0.5 × 109/L, platelet count 
≥100 × 109/L, and hemoglobin ≥ 9 g/dL (may have been transfused)
9. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of 
normal (ULN) and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
levels ≤ 2.5 × ULN for all subjects
10. Adequate renal function defined by an estimated creatinine clearance ≥30 mL/min 
according to the Cockcroft-Gault formula (or local institutional standard method)
11. Negative blood pregnancy test at Screening for women of childbearing potential. For the 
purposes of this trial, women of childbearing potential are defined as: “All female subjects 
after puberty unless they are post-menopausal (age-related amenorrhea ≥ 12 consecutive 
months and increased follicle-stimulating hormone [FSH] > 40 mIU/mL), are surgically 
sterile, or are sexually inactive”
12. Highly effective contraception (i.e., methods with a failure rate of less than 1% per year) 
for both male and female subjects if the risk of conception exists (Note: The effects of the 
trial treatment on the developing human fetus are unknown; thus, women of childbearing 
potential and men must agree to use highly effective contraception, defined in Appendix II
or as stipulated in national or local guidelines. Highly effective contraception must be used 
15 days prior to first trial treatment administration and for the duration of trial treatment
for all subjects. Highly effective contraception must be used at least for 60 days after 
stopping avelumab treatment and as indicated in the respective label [SmPC] for irinotecan 
or paclitaxel for subjects receiving chemotherapy or as per label of any other therapy used 
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as BSC. Should a woman become pregnant or suspect she is pregnant while she or her 
partner is participating in this trial, the treating physician should be informed immediately).
5.3.2
Exclusion Criteria
Subjects are not eligible for this trial if they fulfill any of the following exclusion criteria:
1. Prior therapy with any antibody or drug targeting T-cell coregulatory proteins (immune
checkpoints), such as PD-1, PD-L1, or cytotoxic T-lymphocyte antigen-4. Adjuvant 
therapy is acceptable as described in Section 5.3.1. Maintenance treatment with oral 
fluoropyrimidine is acceptable
2. Concurrent anticancer treatment (for example, cytoreductive therapy, radiotherapy [with 
the exception of palliative bone-directed radiotherapy], immune therapy, or cytokine 
therapy, except for erythropoietin)
3. Major surgery for any reason, except diagnostic biopsy, within 4 weeks of the trial 
treatment and/or if the subject has not fully recovered from the surgery within 4 weeks of
the trial treatment
4. Subjects receiving immunosuppressive agents (such as steroids) for any reason should be 
tapered off these drugs before initiation of the trial treatment (with the exception of subjects 
with adrenal insufficiency, who may continue corticosteroids at physiologic replacement 
dose, equivalent to < 10 mg prednisone daily). Note: 
a.
Subjects receiving bisphosphonate or denosumab are eligible provided treatment 
was initiated at least 14 days before first dose of trial treatment 
b. Previous or ongoing administration of systemic steroids for the management of an 
acute allergic phenomenon is acceptable as long as it is anticipated that the 
administration of steroids will be completed in 14 days, or that the daily dose after 
14 days will be ≤ 10 mg per day of equivalent prednisone
5. All subjects with brain metastases, except those meeting the following criteria:
a.
Brain metastases have been treated locally, have not been progressing at least 
2 months after completion of therapy, and no steroid maintenance therapy is 
required, and
b. No ongoing neurological symptoms that are related to the brain localization of the 
disease (sequelae that are a consequence of the treatment of the brain metastases 
are acceptable)
6. Previous malignant disease (other than gastric cancer) within the last 5 years with the 
exception of basal or squamous cell carcinoma of the skin or carcinoma in situ (bladder, 
cervical, colorectal, breast)
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7. Prior organ transplantation, including allogeneic stem cell transplantation 
8. Significant acute or chronic infections, including, among others:
a.
Known history of testing positive for human immunodeficiency virus or known 
acquired immunodeficiency syndrome
b. Positive test for hepatitis B virus (HBV) surface antigen and/or confirmatory 
hepatitis C virus (HCV) ribonucleic acid (if anti-HCV antibody tested positive)
c.
Active tuberculosis (history of exposure or history of positive tuberculosis test; plus 
presence of clinical symptoms, physical or radiographic findings)
9. Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent:
a.
Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not 
requiring immunosuppressive treatment are eligible
b. Subjects requiring hormone replacement with corticosteroids are eligible if the 
steroids are administered only for the purpose of hormonal replacement and at 
doses ≤ 10 mg or 10 mg equivalent prednisone per day
c.
Administration of steroids through a route known to result in a minimal systemic 
exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
10. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 
NCI-CTCAE v4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more 
features of partially controlled asthma)
11. Persisting toxicity related to prior therapy of Grade ≥2 NCI-CTCAE v4.03 (except 
neuropathy [see exclusion criterion #12] and alopecia)
12. Neuropathy ≥ Grade 3
13. Pregnancy or lactation
14. Known alcohol or drug abuse
15. History of uncontrolled intercurrent illness including but not limited to:
a.
Hypertension uncontrolled by standard therapies (not stabilized to 150/90 mmHg 
or lower)
b. or, uncontrolled active infection, 
c.
or, uncontrolled diabetes (e.g., hemoglobin A1c ≥ 8%) 
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16. Clinically significant (that is, active) cardiovascular disease: cerebral vascular 
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior 
to enrollment), unstable angina pectoris, congestive heart failure (New York Heart 
Association Classification Class ≥ II), or serious cardiac arrhythmia requiring medication 
(including corrected QT interval prolongation of > 470 msec calculated according to 
Fridericia and/or pacemaker or prior diagnosis of congenital long QT syndrome)
17. All other significant diseases (for example, inflammatory bowel disease), which, in the 
opinion of the Investigator, might impair the subject’s tolerance of trial treatment
18. Any psychiatric condition that would prohibit the understanding or rendering of informed 
consent and that would limit compliance with trial requirements
19. Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited
except for administration of inactivated vaccines (for example, inactivated influenza 
vaccines)
20. Legal incapacity or limited legal capacity
21. Subjects will be excluded from the treatment with irinotecan or paclitaxel monotherapy if 
administration of their chemotherapy would be inconsistent with the current local labeling 
(e.g., in regard to contraindications, warnings/precautions, or special provisions) for that 
chemotherapy. Investigators should check updated labeling via relevant websites before 
randomization.
5.4
Criteria for Initiation of Trial Treatment
The inclusion and exclusion criteria will be checked at the Screening visit. Eligible subjects will 
be randomized before treatment start after verification of fulfilling all inclusion criteria without 
matching any exclusion criteria. Subjects should start treatment administration within 28 days after
signing the informed consent form (ICF). Treatment administration will start within 4 days after
the randomization call.
5.5
Criteria for Subject Withdrawal
5.5.1
Withdrawal from Trial Therapy 
Subjects will be withdrawn from trial treatment for any of the following reasons:
! Subjects meeting the definition of PD while on treatment based on RECIST v1.1 (subjects in 
the avelumab plus BSC arm who experience disease progression may continue treatment with 
avelumab if the Investigator believes the subject will experience clinical benefit from the 
treatment and there is no unacceptable toxicity resulting from the treatment [see Section 6.2.1]. 
Such subjects will be withdrawn from treatment if there is a subsequent scan/assessment of PD 
based on RECIST v1.1.)
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! Significant clinical deterioration (clinical progression), defined as new symptoms that are 
deemed by the Investigator to be clinically significant or significant worsening of existing 
symptoms
! Unacceptable toxicity 
! Withdrawal of consent
! Occurrence of an exclusion criterion, which is clinically relevant and affects the subject’s 
safety, if discontinuation is considered necessary by the Investigator and/or Sponsor
! Therapeutic failure requiring urgent additional drug (if applicable)
! Occurrence of any Grade ≥ 3 ADRs or repetitive Grade 2 ADRs as defined in Section 5.1.3.2
! Occurrence of AEs resulting in the discontinuation of the trial treatment being desired or 
considered necessary by the Investigator and/or the subject 
! Occurrence of pregnancy 
! Use of a prohibited concomitant drug, as defined in Section 6.5.2, where the predefined 
consequence is withdrawal from the trial treatment
! Noncompliance (see Section 6.9)
! After primary analysis is completed, the subjects may be offered to enroll into a roll-over trial 
or receive commercial supply.
For subjects receiving avelumab plus BSC, if discontinuation occurs due to progression and a 
definitive diagnosis/radiographic confirmation is not made at the time of discontinuation, a second 
imaging scan may be allowed for confirmation of progression. If progression at the second imaging 
scan is not confirmed and the subject wishes to continue, the subject will be allowed to continue 
receiving avelumab as long as they meet the criteria for continuation of treatment beyond 
progression (see Section 6.2.1).
Subjects who withdraw from trial therapy will no longer be followed for survival after the date to 
discontinue treatment.
5.5.2
Withdrawal from the Trial
Subjects may withdraw from the trial at any time without giving a reason. Withdrawal of consent 
will be considered withdrawal from the trial. In case of withdrawal from the trial, the assessments 
scheduled for the last visit (End of Treatment visit) should be performed (see Section 7.1.3), if 
possible, with focus on the most relevant assessments. In any case, the appropriate End of Safety 
Follow-up eCRF page must be completed. In case of withdrawal, subjects will be asked to continue 
safety follow-up. Subjects who withdraw from trial therapy will no longer be followed for survival 
after the date to discontinue treatment.
A subject must be withdrawn if any of the following occur during the trial:
! Withdrawal of the subject’s consent
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! Participation in any other therapeutic trial during the treatment duration of this trial; however, 
subjects will continue to be followed for survival
If a subject fails to attend scheduled trial assessments, the Investigator must determine the reasons 
and the circumstances as completely and accurately as possible.
If a subject is withdrawn prior to progression for any reason, the subject will not be replaced.
5.6
Premature Termination of the Trial
The whole trial may be discontinued prematurely in the event of any of the following:
! New information leading to unfavorable risk-benefit judgment of the trial treatment, for 
example, due to: 
! Evidence of inefficacy of the trial treatment
! Occurrence of significant previously unknown adverse reactions or unexpectedly high 
intensity or incidence of known adverse reactions
! Other unfavorable safety findings.
(Note: Evidence of inefficacy may arise from this trial or from other trials; unfavorable safety 
findings may arise from clinical or nonclinical examinations, for example, toxicology.)
! Sponsor’s decision that continuation of the trial is unjustifiable for medical or ethical reasons
! Poor enrollment of subjects making completion of the trial within an acceptable time frame 
unlikely
! Discontinuation of development of the Sponsor’s trial treatment
! After primary analysis is completed, the subjects may be offered to enroll into a roll-over trial.
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs)
will be informed about the discontinuation of the trial in accordance with applicable regulations.
The whole trial may be terminated or suspended upon request of Health Authorities.
5.7
Definition of End of Trial
If the trial is not terminated for a reason given in Section 5.6, the trial is complete after the last 
subject comes off treatment and completes the safety follow-up. The sponsor may terminate the 
study at any time once access to study intervention for participants still benefitting is provisioned 
via a rollover study, expanded access, marketed product or another mechanism of access as 
appropriate.
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6
Investigational Medicinal Product and Other Drugs Used in 
the Trial
The term IMP refers to the investigational drug undergoing a clinical trial, as well as to any 
comparator drug or placebo (as applicable). In this trial, the IMPs are avelumab and physician’s 
choice chemotherapy (comparator).
6.1
Description of the Investigational Medicinal Product
6.1.1
Avelumab
Avelumab is a sterile, clear, and colorless solution intended for IV administration. It is presented 
at a concentration of 20 mg/mL in single-use glass vials closed with a rubber stopper and sealed 
with an aluminum polypropylene flip-off seal.
6.1.2
Physician’s Choice Chemotherapy
Subjects will receive physician’s choice chemotherapy selected from one of the following options
as monotherapy in addition to BSC:
! Paclitaxel is a clear, colorless to slightly yellow viscous solution intended for IV administration. 
It is a white to off-white crystalline powder with a molecular weight of 853.9 kDa
! Irinotecan is a sterile, pale yellow, clear, aqueous solution. 
Subjects can also receive BSC alone as described in Section 6.4.1.
6.2
Dosage and Administration
6.2.1
Avelumab Dosage and Administration
Subjects randomized to the avelumab plus BSC arm will receive an IV infusion of avelumab at a 
dose of 10 mg/kg (over the duration of 1 hour) following pretreatment as described in 
Section 5.1.2.1 (refer to Table 1). Modifications of the infusion rate due to infusion-related 
reactions are described in Section 6.5.4.1. The dose of avelumab will be calculated based on the 
weight of the subject determined within 72 hours prior to the day of drug administration. The dose 
of avelumab used for the previous administration can be repeated if the change in the subject’s 
weight is 10% or less than the weight used for the last dose calculation. Subjects will receive 
avelumab once every 2 weeks until the criteria in Sections 5.5 through 5.7 are met.
For subjects receiving avelumab plus BSC, treatment may continue past the initial determination 
of disease progression per RECIST v1.1 as long as the following criteria are met:
! No new symptoms or worsening of previous symptoms
! Tolerance of avelumab
! Stable ECOG PS
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! Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (for example, central nervous system metastases).
The decision to continue treatment should be discussed with the Medical Monitor and documented 
in the trial records.
A radiographic assessment should be performed within 6 weeks of original PD to determine 
whether there has been a decrease in the tumor size, or continued PD. The assessment of clinical 
benefit should be balanced by clinical judgment as to whether the subject is clinically deteriorating 
and unlikely to receive any benefit from continued treatment with avelumab.
For subjects receiving avelumab plus BSC, if discontinuation occurs due to progression and a 
definitive diagnosis/radiographic confirmation is not made at the time of discontinuation, a second 
imaging scan may be allowed for confirmation of progression. If progression at the second imaging 
scan is not confirmed and the subject wishes to continue, the subject will be allowed to continue 
receiving avelumab as long as they meet the criteria for continuation of treatment beyond 
progression.
If the Investigator feels that the subject continues to achieve clinical benefit by continuing 
treatment, the subject should remain on the trial and continue to receive monitoring according to 
the Schedule of Assessments (Table 1).
Any additional continuation of avelumab plus BSC beyond further progression must be discussed 
and agreed upon with the medical monitor. Further disease progression is defined as an additional 
10% increase in tumor burden volume from time of initial PD. This includes an increase in the 
sum of all target lesions and/or the development of new measurable lesions.
New lesions are considered measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 
15 mm). Any new lesion considered nonmeasurable at the time of initial progression may become 
measurable and therefore included in the tumor burden volume if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 
15 mm).
Additionally, subjects receiving avelumab plus BSC who have experienced a CR should continue 
to receive avelumab for a minimum of 12 months after confirmation of response and/or until 
disease progression or unacceptable toxicity. In case a subject with a confirmed CR relapses after 
stopping treatment, but prior to the end of the trial, 1 re initiation of treatment is allowed at the 
discretion of the Investigator and agreement of the Medical Monitor. To be eligible for 
re-treatment, the subject must not have experienced any toxicity that led to treatment 
discontinuation of the initial avelumab plus BSC therapy. Subjects who re initiate treatment will 
stay on trial and will be treated and monitored according to the protocol and the “until progression” 
schedule in the Schedules of Assessments (see Table 1).
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6.2.2
Physician’s 
Choice 
Chemotherapy 
-
Dosage 
and 
Administration
Subjects randomized to the physician’s choice plus BSC will receive one physician’s choice
treatment selected from the following options:
! Paclitaxel as monotherapy (80 mg/m2 on Days 1, 8, and 15 of a 4-week treatment cycle)
! Irinotecan as monotherapy (150 mg/m2 on Days 1 and 15 of a 4-week treatment cycle)
! Subjects who are not deemed eligible to receive paclitaxel or irinotecan at the dose and schedule 
specified above will receive BSC once every 3 weeks.
The Investigator will determine what systemic therapy will be administered to the subjects. The 
Investigator can also decide to administer BSC alone without any additional systemic therapy.
In the absence of unequivocal data on the doses and schedules of drugs that should be used as a 
third-line treatment of gastric cancer, the doses and schedules will be determined by the 
Investigator according to institutional guidelines.
Therapy will be administered until disease progression or unacceptable toxicity.
Physician’s choice plus BSC will be stopped after the first on-treatment radiological evaluation of 
disease progression.
Monotherapy dosing is summarized below and in Table 4.
! Paclitaxel; 80 mg/m2 on Days 1, 8, and 15 of a 4-week treatment cycle. Subjects should be 
premedicated with 20 mg dexamethasone orally approximately 12 and 6 hours prior to 
injection, 50 mg diphenhydramine (or equivalent) IV 30 to 60 minutes prior to injection, and 
300 mg cimetidine or 50 mg ranitidine IV 30 to 60 minutes prior to injection. The premedication 
regimen may be modified based on local treatment standards and guidelines as appropriate.
! Irinotecan; 150 mg/m2 on Days 1 and 15 of a 4-week treatment cycle. Subjects should be 
premedicated with anti-emetics, such as 10 mg prochloroperazine orally, 30 minutes prior to 
beginning therapy. If subjects have cholinergic symptoms, premedicate with 0.2 to 0.3 mg 
atropine subcutaneously. The premedication regimen may be modified based on local treatment 
standards and guidelines as appropriate.
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Table 4
Physician’s Choice Chemotherapies
Product 
Description
Dosage Form
Dose
Dosing Frequency
Paclitaxel
Intravenous
80 mg/m2
Days 1, 8, and 15 of a 4-week treatment 
cycle
Irinotecan
Intravenous
150 mg/m2
Days 1 and 15 of a 4-week treatment cycle
Subjects will receive trial treatment until disease progression per RECIST v1.1, significant clinical 
deterioration (clinical progression), unacceptable toxicity, withdrawal of consent, or if any 
criterion for withdrawal from the trial or trial treatment is fulfilled.
6.3
Assignment to Treatment Groups
Once the subject has provided a signed ICF and meets inclusion and exclusion criteria, the 
Investigator or delegate will request the trial treatment assignment using the IWRS. Qualified 
subjects will be randomized in a 1:1 ratio to receive either avelumab plus BSC or physician’s 
choice plus BSC. The trial is fully controlled by the IWRS, which assigns treatment individual 
(unique) vial numbers for each subject. The vial number is linked via the Good Manufacturing 
Practice qualified system to the corresponding treatment as well as to the subject.
Allocation of subjects will be stratified according to region (Asia versus non-Asia). This stratified 
randomization will be centrally allocated across all trial sites via the IWRS.
Subject identifiers will comprise 17 digits, the first 10 digits representing the trial number, the 
following 3 digits representing the site number, and the last 4 digits representing the subject 
number, which is allocated sequentially starting with 0001.
6.4
Non-investigational Medicinal Products to be Used
6.4.1
Best Supportive Care
All subjects in both arms will receive BSC as background therapy. There is no universal definition 
of BSC that can be applied across institutions, countries, or regions (40). Best supportive care is 
defined as “treatment administered with the intent to maximize QoL without a specific 
antineoplastic regimen, which include antibiotics, analgesics, antiemetics, thoracentesis, 
paracentesis, blood transfusions, nutritional support (including jejunostomy), and focal 
external-beam radiation for control of pain, cough, dyspnea, or bleeding” (41). Best supportive 
care will be administered per institutional guidelines. Best supportive care can be administered 
without any additional therapy.
6.4.2
Other Non-investigational Medicinal Products to be Used
Subjects randomized to receive avelumab plus BSC will receive pretreatment as described in 
Section 5.1.2.1.
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Subjects randomized to receive physician’s choice chemotherapy plus BSC will receive 
pretreatment prior to each infusion per local institutional practice.
Immediate access to an intensive care unit or equivalent environment and appropriate medical 
therapy (including epinephrine, corticosteroids, IV antihistamines, bronchodilators, and oxygen)
must be available for use in the treatment of infusion-related reactions. Infusion of avelumab will 
be stopped in case of Grade ≥ 2 infusion-related, allergic, or anaphylactoid reactions. Following 
avelumab infusions, subjects must be observed for 2 hours post infusion for potential 
infusion-related reactions. 
As with all monoclonal antibody therapies, there is a risk of allergic reaction. Avelumab 
should be administered in a setting that allows for immediate access and administration of 
therapy for severe allergic/hypersensitivity reactions, such as the ability to implement 
immediate resuscitation measures. Steroids (dexamethasone 10 mg), epinephrine (1:1000 
dilution), allergy medications (antihistamines), or equivalents should be available for 
immediate access.
If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice. Guidelines for management of infusion-related reactions and severe 
hypersensitivity and flu-like symptoms according to the NCI are found in Sections 6.5.4.1 and 
6.5.4.2, respectively. A complete guideline for the emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (United Kingdom) can be found at 
https://www.resus.org.uk/pages/reaction.pdf (53). Subjects should be instructed to report any 
delayed reactions to the Investigator immediately.
6.5
Concomitant Medications, Therapies, and Procedures
6.5.1
Permitted Medicines
Any medications, therapies, or procedures (other than those excluded by the clinical trial protocol) 
that are considered necessary to protect subject welfare and will not interfere with the trial 
treatment may be given at the Investigator’s discretion.
Other drugs to be used for prophylaxis, treatment of hypersensitivity reactions, and treatment of 
fever or flu-like symptoms are described in Section 6.5.4.2.
The Investigator will record all concomitant medications, therapies, and procedures taken by the 
subject during the trial, from the date of signature of informed consent, in the appropriate section 
of the eCRF.
Any additional concomitant therapy or procedures that become necessary during the trial and any 
change to concomitant drugs or procedures must be recorded in the corresponding section of the 
eCRF, noting the name, dose, duration, and indication of each drug as well as the name of the 
procedure, its start and end date, and reason.
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Palliative bone-directed radiotherapy may be administered during the trial. The assessment of PD 
will be made according to RECIST v1.1 (1) and not based on the necessity for palliative 
bone-directed radiotherapy.
Rescue medications may be administered to address ineffective treatment, anticipated adverse 
reactions, or anticipated emergency situations.
6.5.2
Prohibited Medicines
As stated for the exclusion criteria in Section 5.3.2, subjects must not have had prior therapy with 
any antibody or drug targeting T-cell coregulatory proteins (immune checkpoints) such as 
anti-PD-1, anti-PD-L1, or anti-cytotoxic T-lymphocyte antigen-4 antibody or concurrent 
anticancer treatment (for example, cytoreductive therapy, radiotherapy [with the exception of 
palliative bone-directed radiotherapy*, or radiotherapy administered on superficial lesions], 
immune therapy, or cytokine therapy except for erythropoietin), major surgery (excluding prior 
diagnostic biopsy), or concurrent systemic therapy with steroids or other immunosuppressive 
agents or use of any investigational drug. 
* Palliative bone-directed radiotherapy should be within a limited field of radiation and for palliation only. It should 
be a short course, according to local institutional recommendation, and should be completed at least 7 days prior to 
the first administration of avelumab.
In addition, the following treatments must not be administered during the trial:
! Immunotherapy, immunosuppressive drugs (that is, chemotherapy or systemic corticosteroids 
except for short-term treatment of allergic reactions or for the treatment of irAEs), or other 
experimental pharmaceutical products. Short-term administration of systemic steroid (that is, 
for allergic reactions or the management of irAEs is allowed)
! Growth factors for subjects randomized to receive avelumab plus BSC (granulocyte 
colony-stimulating factor or granulocyte macrophage colony-stimulating factor). Exception: 
Erythropoietin and darbepoetin alpha may be prescribed at the Investigator’s discretion
! Bisphosphonate or denosumab treatment is not allowed unless it has been initiated more than 
14 days prior to receiving the first administration of avelumab or physician’s choice
If the administration of a nonpermitted concomitant drug becomes necessary during the trial, the 
subject will be withdrawn from trial treatment (the Medical Monitor may be contacted to discuss 
whether the trial treatment must be discontinued). The subject should complete the End of 
Treatment visit (Section 7.1.3).
For subjects randomized to physician’s choice plus BSC, use of concomitant strong cytochrome 
P450 3A4 inhibitors and/or inducers should be avoided (for example, ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin,
voriconazole, rifampin, and carbamazepine). For more information on cytochrome P450 3A4 
inhibitors 
and 
inducers, 
Investigators 
are 
directed 
to 
the 
following 
URL: 
http://medicine.iupui.edu/clinpharm/ddis/clinical-table (54).
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Medications other than those specifically excluded in this trial may be administered for the 
management of symptoms associated with the administration of avelumab plus BSC or physician’s 
choice plus BSC as required. These might include analgesics, antinausea medications, 
antihistamines, diuretics, anti-anxiety medications, and medication for pain management, 
including narcotic agents.
Any additional concomitant therapy that becomes necessary during the trial and any change to 
concomitant drugs must be recorded in the corresponding section of the eCRF, noting the name, 
dose, duration, and indication of each drug.
6.5.3
Other Interventions
The following nondrug therapies must not be administered during the trial (or within 28 days 
before randomization):
! Major surgery (excluding prior diagnostic biopsy)
! Herbal remedies with immunostimulating properties (for example, mistletoe extract) or known 
to potentially interfere with major organ function (for example, hypericin)
! Subjects should not abuse alcohol or other drugs during the trial.
6.5.4
Special Precautions
As a routine precaution, subjects randomized to the avelumab plus BSC arm must be observed for 
2 hours post infusion, in an area with resuscitation equipment and emergency agents. At all times 
during avelumab plus BSC or physician’s choice chemotherapy plus BSC treatment, immediate 
emergency treatment of an infusion-related reaction or a severe hypersensitivity reaction according 
to institutional standards must be assured. In order to treat possible hypersensitivity reactions, for 
instance, dexamethasone 10 mg and epinephrine in a 1:1000 dilution or equivalents should always 
be available along with equipment for assisted ventilation. 
Infusion of avelumab will be stopped in case of Grade ≥ 2 hypersensitivity, inflammatory response, 
or infusion-related reaction. The treatment recommendations for infusion-related reactions, severe 
hypersensitivity reactions, and TLS according to the NCI are as outlined in Sections 6.5.4.1, 
6.5.4.2, and 6.5.4.3, respectively.
Investigators should also monitor subjects closely for potential irAEs, which may first manifest 
after weeks of treatment. Such events may consist of persistent rash, diarrhea and colitis, 
autoimmune hepatitis, arthritis, glomerulonephritis, cardiomyopathy, or uveitis and other 
inflammatory eye conditions. See Section 6.5.4.4 for details on the management of irAEs.
6.5.4.1
Infusion-related Reactions
Symptoms of infusion-related reactions are fever, chills, rigors, diaphoresis, and headache. These 
symptoms can be managed according to Table 5.
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Table 5
Treatment Modification for Symptoms of Infusion-related Reactions 
Associated With Avelumab
NCI-CTCAE Grade 
Treatment Modification for Avelumab
Grade 1 – mild
!
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.
!
Decrease the avelumab infusion rate by 50% 
and monitor closely for any worsening.
!
The total infusion time for avelumab should not 
exceed 120 minutes.
Grade 2 – moderate
!
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(for example, antihistamines, NSAIDs, 
narcotics, IV fluids); prophylactic medications 
indicated for ∀24 hours.
!
Stop avelumab infusion.
!
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or 
decreased to at least Grade 1 in severity, and 
monitor closely for any worsening.
Grade 3 or Grade 4 – severe or life-threatening
!
Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae.
!
Grade 4: Life-threatening consequences; 
urgent intervention indicated.
!
Stop the avelumab infusion immediately and 
disconnect infusion tubing from the subject.
!
Subjects have to be withdrawn immediately 
from avelumab treatment and must not receive 
any further avelumab treatment.
IV=intravenous, NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Event (version 
4.03), NSAIDs=nonsteroidal anti-inflammatory drugs.
Once the avelumab infusion rate has been decreased by 50% or interrupted due to an 
infusion-related reaction, it must remain decreased for all subsequent infusions. If the subject has 
a second infusion-related reaction Grade ≥ 2 on the slower infusion rate, the infusion should be 
stopped and the subject should discontinue avelumab treatment. If a subject experiences a Grade 
3 or 4 infusion-related reaction at any time, the subject must discontinue avelumab. If an infusion 
reaction occurs, all details about drug preparation and infusion must be recorded.
6.5.4.2
Severe Hypersensitivity Reactions and Flu-like Symptoms
If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice. A complete guideline for the emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (United Kingdom) can be found at 
https://www.resus.org.uk/pages/reaction.pdf (53). Subjects should be instructed to report any 
delayed reactions to the Investigator immediately.
Symptoms include impaired airway, decreased oxygen saturation (< 92%), confusion, lethargy, 
hypotension, pale or clammy skin, and cyanosis. These symptoms can be managed with 
epinephrine injection and dexamethasone. Subjects should be placed on monitor immediately, and 
the intensive care unit should be alerted for possible transfer if required.
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For prophylaxis of flu-like symptoms, 25 mg indomethacin or comparable nonsteroidal 
anti-inflammatory drug dose (e.g., 600 mg ibuprofen, 500 mg naproxen sodium) may be 
administered 2 hours before and 8 hours after the start of each dose of avelumab IV infusion. 
Alternative treatments for fever (for example, acetaminophen) may be given to subjects at the 
discretion of the Investigator.
6.5.4.3
Tumor Lysis Syndrome
In addition, because avelumab can induce antibody-dependent cell-mediated cytotoxicity, there is 
a potential risk of TLS. Should this occur, subjects should be treated per the local guidelines and 
the management algorithm (Figure 2) published by Howard et al (55).
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Figure 2
Assessment and Initial Management of Tumor Lysis Syndrome
TLS=tumor lysis syndrome.
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ACTH=adrenocorticotropic hormone, ADL=activities of daily living, AHA=American Heart Association, ALT=alanine 
aminotransferase, AST=aspartate aminotransferase, BNP=B-type natriuretic peptide, CK-MB=creatine kinase MB, 
CT=computed tomography, ESC=European Society of Cardiology, FSH=follicle-stimulating hormone, FT4=free 
thyroxine, GH=growth hormone, IGF-1=insulin-like growth factor 1, irAE=immune-related adverse event, 
IV=intravenous, LH=luteinizing hormone, LLN=lower limit of normal, MRI=magnetic resonance imaging, 
NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Event, PRL=prolactin, 
TSH=thyroid-stimulating hormone, ULN=upper limit of normal.
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions
The management of irAEs is described in Section 6.5.4.4.
6.6
Packaging and Labeling of the Investigational Medicinal 
Product
Avelumab is formulated as a 20.0 mg/mL solution and is supplied by the Sponsor in single-use 
glass vials, stoppered with a rubber septum and sealed with an aluminum polypropylene flip-off 
seal.
Paclitaxel and irinotecan will be supplied or reimbursed by the Sponsor.
All IMPs will be packaged and labeled in accordance with all applicable regulatory requirements 
and Good Manufacturing Practice Guidelines. Each box of IMP will contain 1 vial. The 
information on the label will be in accordance with approved submission documents. 
All IMPs will be shipped in suitable transport containers according to each IMP’s storage and 
shipping conditions. Shipments are monitored with temperature control devices.
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product
The contents of the avelumab vials are sterile and nonpyrogenic, and do not contain bacteriostatic 
preservatives. Any spills that occur should be cleaned up using the facility’s standard cleanup 
procedures for biologic products.
Avelumab must be stored at 2°C to 8°C until use, with a temperature log maintained daily. All 
medication boxes supplied to each trial site must be stored carefully, safely, and separately from 
other drugs.
Avelumab stored at room temperature (23°C to 27°C) or at elevated temperatures (38°C to 42°C) 
for extended periods is subject to degradation. Avelumab must not be frozen. Rough shaking of 
avelumab must be avoided.
For application in this trial, avelumab must be diluted with 0.9% saline solution (sodium chloride 
injection). Detailed information on infusion bags and medical devices to be used for the 
preparation of the dilutions and subsequent administration will be provided in the Pharmacy 
Manual.
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Avelumab must not be used for any purpose other than the trial. The administration of avelumab
to subjects who have not been enrolled into the trial is not covered by the trial insurance.
For handling, preparation, and storage of the physician’s choice chemotherapy, please refer to local 
institutional guidelines.
Any unused portion of the solution should be discarded in biohazard waste disposal with final 
disposal by accepted local and national standards of incineration.
Storage, handling, preparation, and disposal of IMP should be according to local institutional 
guidelines.
6.8
Investigational Medicinal Product Accountability
The Investigator is responsible for ensuring accountability for avelumab and physician’s choice
chemotherapy, including reconciliation of drugs and maintenance of drug records.
! Upon receipt of trial treatment, the Investigator (or designee) will check for accurate delivery 
and acknowledge receipt by signing (or initialing) and dating the documentation provided by 
the Sponsor and returning it to the Sponsor or designee. A copy will be retained for the 
Investigator Site File.
! The dispensing of the trial treatment will be carefully recorded on the appropriate drug 
accountability forms provided by the Sponsor and an accurate accounting will be available for 
verification by the clinical research associate (CRA) at each monitoring visit.
! Trial treatment accountability records will include:
1. Confirmation of trial treatment delivery to the trial site
2. The inventory at the site of trial treatment provided by the Sponsor and prepared at
the site
3. The use of each dose by each subject
4. The disposition of unused trial treatment
5. Dates, quantities, batch numbers, expiry dates and (for trial treatment prepared at the 
site) formulation, as well as the subjects’ trial numbers.
! The Investigator should maintain records that adequately document
1. That the subjects were provided the doses specified by the clinical trial 
protocol/amendment(s)
2. That all trial treatment provided by the Sponsor was fully reconciled.
Unused trial treatment must not be discarded or used for any purpose other than the present trial. 
Any trial treatment that has been dispensed to a subject must not be re-dispensed to a different 
subject.
The CRA will periodically collect the trial treatment accountability forms and will check all returns 
(both unused and used containers) before authorizing their destruction by the trial site.
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At the conclusion or termination of this trial, trial site personnel and the CRA will conduct a final 
product supply inventory on the investigational drug accountability forms and all unused 
containers will be destroyed. Instructions for destruction of product will be provided to the site. 
The Clinical Trial Monitor will be supplied with a copy for filing of the investigational drug 
accountability forms. This documentation must contain a record of clinical supplies used, unused, 
and destroyed and shall include information on:
! All administered units
! All unused units
! All destroyed units (during the trial)
! All destroyed units at the end of the trial
! Date of destruction(s)
! Name and signature of the Investigator/pharmacist.
It must be ensured at each trial site that the trial treatment is not used:
! After the expiry date
! After the retest date unless the trial treatment is reanalyzed and its retest date extended.
This is to be closely monitored by the Clinical Trial Monitor.
6.9
Assessment of Investigational Medicinal Product Compliance
In this trial, subjects will receive trial treatment at the investigational site. Well-trained medical 
staff will monitor and perform the trial treatment administration. The information of each trial 
treatment administration including the date, time, and dose of trial treatment will be recorded on 
the eCRF. The Investigator will make sure that the information entered into the eCRF regarding 
drug administration is accurate for each subject. Any reason for noncompliance should be 
documented.
Noncompliance is defined as a subject missing > 1 administration of avelumab, paclitaxel, or 
irinotecan for nonmedical reasons (see Section 5.5.1). If 1 administration is missed and the interval 
between the subsequent administration and the last administered treatment is longer than 4 weeks 
for nonmedical reasons, the criteria of insufficient compliance are met as well.
6.10
Blinding
This is an open-label trial; thus, trial treatment is not blinded.
6.11
Emergency Unblinding
Not applicable.
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6.12
Treatment of Overdose
An overdose is defined as any dose ≥ 5% over the calculated dose for that particular administration 
as described in this clinical trial protocol. Any overdose must be recorded in the trial treatment
section of the eCRF.
For monitoring purposes, any case of overdose, whether or not associated with an AE (serious or 
nonserious), must be reported to the Sponsor’s Global Drug Safety department in an expedited 
manner using the appropriate reporting form (see Section 7.4.1.4).
There are no known symptoms of avelumab overdose to date. The Investigator should use his or 
her clinical judgment when treating an overdose of the trial treatment.
In the case of an overdose of paclitaxel, subjects should receive therapeutic granulocyte 
colony-stimulating factor according to local institutional guidelines as soon as possible. For all 
physician’s choice chemotherapy, Investigators must follow local institutional guidelines for 
overdose treatment.
6.13
Medical Care of Subjects after End of Trial
After a subject has stopped trial treatment, usual treatment will be administered, if required, in 
accordance with the trial site’s standard of care and generally accepted medical practice and 
depending on the subject’s individual medical needs.
Upon withdrawal from trial treatment, subjects may receive whatever care they and their 
physicians agree upon. Subjects will be followed for AEs as specified in Section 7.1.4.
7
Trial Procedures and Assessments
7.1
Schedule of Assessments
Complete Schedules of Assessments are provided in Table 1.
Prior to performing any trial assessments not part of the subject’s routine medical care, the 
Investigator will ensure that the subject or the subject’s legal representative has provided written 
informed consent according to the procedure described in Section 9.2.
7.1.1
Screening and Baseline Procedures and Assessments
The Screening procedures and Baseline assessments will be completed within 28 days before trial 
treatment starts.
During the Screening period and before any trial-related investigations and assessments are started, 
subjects will be asked to sign the ICF. The Screening procedures and Baseline assessments will be 
completed within 28 days of signing the ICF and before randomization. Subjects should also start 
treatment administration within 28 days after signing the ICF. Treatment administration will start 
within 4 days after the randomization call. Failure to establish eligibility within 28 days would 
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Assessments will be made by the Investigators for the purpose of subject management, but the 
disease response determinations, including PD assessments associated with the trial endpoints, will 
be supported by tumor assessments performed by an IRC.
7.1.2
Treatment Period
In this trial, the treatment will be given until disease progression, significant clinical deterioration 
(clinical progression), unacceptable toxicity, or any criterion for withdrawal from the trial or trial 
treatment is fulfilled (see Section 5.5.1). For subjects receiving avelumab plus BSC, treatment may 
continue past the initial determination of disease progression according to RECIST v1.1 if the 
subject’s ECOG PS has remained stable, and if in the opinion of the Investigator, the subject will 
benefit from continued treatment (see Section 6.2.1). Additionally, subjects receiving avelumab
plus BSC who have experienced a CR should continue to receive avelumab for a minimum of 
12 months after confirmation of response and/or until disease progression or unacceptable toxicity.
In case a subject with a confirmed CR relapses after stopping treatment, but prior to the end of the 
trial, 1 re-initiation of treatment is allowed at the discretion of the Investigator and agreement of 
the Medical Monitor. In order to be eligible for re-treatment, the subject must not have experienced 
any toxicity that led to treatment discontinuation of the initial avelumab therapy. Subjects who re-
initiate treatment will stay on trial and will be treated and monitored according to the protocol and 
the “until progression” schedule in the Schedules of Assessments (see Table 1).
Subjects should start treatment administration within 28 days after signing the ICF. Treatment 
administration will start within 4 days after the randomization call. While on trial treatment, 
subjects will be asked to visit the trial site at the following schedules according to the Schedule of
Assessments: 
! Once every 2 weeks until disease progression for subjects randomized to receive avelumab plus 
BSC
! Once every week for the first 3 weeks of each 4-week cycle until disease progression for 
subjects randomized to receive paclitaxel plus BSC
! Once every 2 weeks until disease progression for subjects randomized to receive irinotecan plus 
BSC
! Once every 3 weeks until disease progression for subjects randomized to receive BSC alone
with no active therapy.
For avelumab plus BSC, a time window of up to 3 days before or 1 day after the scheduled visit 
day (-3/ +1 days) will be permitted for all trial procedures; however, the bi-weekly 14-day schedule 
should be strictly adhered to, and subjects should return to the target date even if the previous visit 
was off schedule.
For physician’s choice plus BSC, a time window of up to 3 days before or 1 day after the scheduled 
visit day (-3/ +1 days) will be permitted for all trial procedures.
The tumor evaluation (see Section 7.3) will be performed every 6 weeks for the first 12 months 
and every 12 weeks thereafter with a time window of -5 days for both arms.
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Subjects will receive either:
! Avelumab by IV infusion following pretreatment (see Section 5.1.2.1), once every 2 weeks (see 
Section 6.2.1) plus BSC, or
! Physician’s choice chemotherapy by IV infusion following pretreatment as applicable prior to 
each infusion (see Section 6.2.2) plus BSC or BSC alone.
Assessments to be performed during the treatment period are presented in Table 1 and Table 2.
7.1.3
End of Treatment Visit
Subjects must undergo an End of Treatment visit after discontinuation of treatment. This visit 
should be performed within 7 days of the decision to discontinue treatment but before any new 
antineoplastic therapy is started (if possible), whichever occurs earlier. Please refer to Table 1 and 
Table 2 for the specific assessments to be performed.
7.1.4
Safety Follow-up
All subjects will have a subsequent Safety Follow-up visit scheduled 30 days (± 5 days) after the 
last administration of trial treatment. The visit will include an assessment of safety parameters as 
described in Table 1 and 
 Subjects will also 
be contacted by telephone 90 days after the last administration of trial treatment to collect 
information on new or ongoing SAEs and treatment related non-serious AEs.
All AEs will be documented until the 30-day Safety Follow-Up visit. Subjects with an ongoing 
SAE at the 30-day Safety Follow-up visit must be monitored and followed up until stabilization or 
until the outcome is known. After this visit, all SAEs and all treatment-related non-serious AEs 
need to be documented until the 90-day Safety Follow-up Phone Call.
If another antineoplastic therapy is administered before the end of the 30-day period, the 30-day 
Safety Follow-up visit should be conducted, if possible, prior to the start of this new therapy.
7.1.5
Long-term Follow-up
All SAEs ongoing at the 90-day Safety Follow-up Phone Call must be monitored and followed up 
by the Investigator until stabilization or until the outcome is known, unless the subject is 
documented as “lost to follow-up”.
For subjects without PD according to RECIST v1.1 at the End of Treatment visit, follow-up for 
disease progression and survival will end on the date of treatment discontinuation . 
7.2
Demographic and Other Baseline Characteristics
7.2.1
Demographic Data
At screening, the following demographic data will be collected: date of birth, sex, and race.
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7.2.2
Diagnosis of Gastric Cancer
The tumor disease information that will be documented and verified at the Screening visit for each 
subject includes:
! Detailed history of the tumor, including histopathological diagnosis, grading, and staging in 
accordance with the International Union Against Cancer Tumor Node Metastasis Classification 
of Malignant Tumors at diagnosis
! All therapy used for prior treatment of the tumor (including surgery, radiotherapy and 
chemotherapy, immunotherapy)
! Any other conditions that were treated with chemotherapy, radiation therapy, or immunotherapy
! Current cancer signs and symptoms and side effects from current and previous anticancer 
treatments
! Current cancer disease status.
7.2.3
Medical History
In order to determine the subject’s eligibility to the trial, a complete medical history of each subject 
will be collected and documented during Screening, which will include, but may not be limited to, 
the following:
! Past and concomitant nonmalignant diseases and treatments
! All medications (including herbal medications) taken and procedures carried out within 28 days 
prior to Screening.
For the trial entry, all of the subjects must fulfill all inclusion criteria described in Section 5.3.1, 
and none of the subjects should have any exclusion criterion from the list described in 
Section 5.3.2.
7.2.4
Computed Tomography or Magnetic Resonance Imaging
Scans for Tumor Assessment at Baseline
Baseline imaging will be performed within 28 days prior to randomization in order to establish 
Baseline disease status of target and nontarget lesions according to RECIST v1.1. Acceptable 
modalities include CT scans (chest, abdomen, and pelvis), CT chest with contrast together with 
MRI of the abdomen and pelvis, or positron emission tomography/CT scans. The use of IV contrast 
is preferred unless there is a history of allergy or other risk in the opinion of the Investigator (chest 
X-ray is not acceptable and other imaging modalities may be performed at the discretion of the 
Investigator and as clinically indicated). Baseline tumor burden should be determined as outlined 
in Section 7.3. In general, lesions detected at Screening/Baseline need to be followed using the 
same imaging methodology and preferably the same imaging equipment at subsequent tumor 
evaluation visits.
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7.2.5
Other Baseline Assessments
All other Baseline measurements, such as vital signs, a complete physical examination, ECOG PS, 
clinical laboratory parameters, and 12-lead ECG, will be assessed.
7.3
Efficacy Assessments
Radiographic images and physical findings (physical assessments) used for the local determination 
of disease progression will be read centrally and reviewed by a blinded IRC. The IRC will make a 
determination as to whether the criteria for tumor response or progression according to 
RECIST v1.1 have been met. 
For each subject, tumor response assessment will be performed by CT scan or MRI (if MRI is 
used, chest CT is mandatory) imaging of the chest/abdomen/pelvis (plus other regions as 
specifically required) and other established assessments of tumor burden if CT/MRI imaging is 
insufficient for the individual subject. All the scans performed at Baseline and other imaging 
performed as clinically required (other supportive imaging) need to be repeated at subsequent 
visits. In general, lesions detected at Baseline need to be followed using the same imaging 
methodology and preferably the same imaging equipment at subsequent tumor evaluation visits.
For each subject, the Investigator will designate 1 or more of the following measures of tumor 
status to follow for determining response: CT or MRI images of primary and/or metastatic tumor 
masses, physical examination findings, and the results of other assessments. All available images 
collected during the trial period will be considered. The most appropriate measures to evaluate the 
tumor status of a subject should be used. The measure(s) to be chosen for sequential evaluation 
during the trial must correspond to the measures used to document the progressive tumor status 
that qualifies the subject for enrollment. The tumor response assessment will be assessed and listed 
according to the Schedules of Assessments (refer to Table 1).
Treatment decisions will be made by the Investigator based on the Investigator’s assessment of 
tumor status.
For efficacy determination, tumor responses to treatment will be assigned by the IRC based on the 
evaluation of the response of target, nontarget, and new lesions according to RECIST v1.1 (all 
measurements should be recorded in metric notation, as described in RECIST v1.1 (1)).
To assess objective response, the tumor burden at Baseline will be estimated and used for 
comparison with subsequent measurements. At Baseline, tumor lesions will be categorized in 
target and nontarget lesions as described in RECIST v1.1 (1).
Results for these evaluations will be recorded with as much specificity as possible so that pre- and 
post-treatment results will provide the best opportunity for evaluating tumor response. 
Any CR or PR should be confirmed, preferably at the scheduled 6-week interval (after 12 months 
of treatment, 12-week assessment interval will be used), but no sooner than 5 weeks after the initial 
documentation of CR or PR. Confirmation of PR can be confirmed at an assessment later than the 
next assessment after the initial documentation of PR.
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The Investigator may perform scans in addition to a scheduled trial scan for medical reasons or if 
the Investigator suspects PD. Subjects who withdraw from the trial for clinical or symptomatic 
deterioration before objective documentation of PD will be requested to undergo appropriate 
imaging to confirm PD. Every effort should be made to confirm a clinical diagnosis of PD by 
imaging. For subjects receiving avelumab plus BSC, if discontinuation occurs due to progression 
and a definitive diagnosis/radiographic confirmation is not made at the time of discontinuation, a 
second imaging scan may be allowed for confirmation of progression. If progression at the second 
imaging scan is not confirmed and the subject wishes to continue, the subject will be allowed to 
continue receiving avelumab as long as they meet the criteria for continuation of treatment beyond 
progression.
7.4
Assessment of Safety
The safety profile of the trial treatments will be assessed through the recording, reporting, and 
analyzing of Baseline medical conditions, AEs, physical examination findings, including vital 
signs, and laboratory tests.
Comprehensive assessment of any apparent toxicity experienced by the subject will be performed 
throughout the course of the trial, from the time of the subject’s signature of informed consent. 
Trial site personnel will report any AE, whether observed by the Investigator or reported by the 
subject (see Section 7.4.1.2). Given the intended mechanism of action of avelumab, particular 
attention will be given to AEs that may follow the enhanced T cell activation, such as dermatitis, 
colitis, hepatitis, uveitis, or other immune-related reactions. Ophthalmologic examinations should 
be considered, when clinically indicated, for signs or symptoms of uveitis.
The reporting period for AEs is described in Section 7.4.1.3.
The safety assessments will be performed according to the Schedules of Assessments (refer to 
Table 1).
7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
AE
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, regardless of 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. 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity or toxicity of each AE.
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Investigators will reference the NCI-CTCAE v4.03 (publication date: 14 June 2010), a descriptive 
terminology that can be used for AE reporting.
A general grading (severity/intensity; hereafter referred to as severity) scale is provided at the 
beginning of the above referenced document, and specific event grades are also provided.
If a particular AE’s severity is not specifically graded by the guidance document, the Investigator
is to use the general NCI-CTCAE definitions of Grade 1 through Grade 5 following his or her best 
medical judgment.
The 5 general grades are:
! Grade 1 or Mild
! Grade 2 or Moderate
! Grade 3 or Severe 
! Grade 4 or Life-threatening
! Grade 5 or Death 
According to Sponsor convention, any clinical AE with severity of Grade 4 or 5 must also be 
reported as an SAE. However, a laboratory abnormality of Grade 4, such as anemia or neutropenia,
is considered serious only if the condition meets one of the serious criteria described below.
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this specific event and death will 
not be recorded as separate event. Only, if no cause of death can be reported (for example, sudden 
death, unexplained death), the death per se might then be reported as an SAE.
Investigators must also systematically assess the causal relationship of AEs to trial treatment using 
the following definitions. Decisive factors for the assessment of causal relationship of an AE to 
the trial treatment include, but may not be limited to, temporal relationship between the AE and 
the trial treatment, known side effects of trial treatment, medical history, concomitant medication, 
course of the underlying disease, trial procedures.
Unrelated:
Not 
reasonably 
related 
to 
the 
IMP. 
The 
AE 
could 
not 
medically 
(pharmacologically/clinically) be attributed to the trial treatment under study in this 
clinical trial protocol. A reasonable alternative explanation must be available.
Related:
Reasonably 
related 
to 
the 
IMP. 
The 
AE 
could 
medically 
(pharmacologically/clinically) be attributed to the trial treatment under study in this 
clinical trial protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (for example, on an 
ECG trace) should not be reported as AEs unless they are associated with clinical signs and 
symptoms, lead to treatment discontinuation or are considered otherwise medically important by 
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the Investigator. If a laboratory abnormality fulfills these criteria, the identified medical condition 
(for example, anemia, increased ALT) must be reported as the AE rather than the abnormal value 
itself.
SAEs
An SAE is any untoward medical occurrence that at any dose:
! Results in death
! Is life-threatening. (Note: The term “life-threatening” refers to an event in which the subject is 
at risk of death at the time of the event, not an event that hypothetically might have caused death 
if it was more severe.)
! Requires inpatient hospitalization or prolongs an existing hospitalization
! Results in persistent or significant disability or incapacity
! Is a congenital anomaly or birth defect
! Is otherwise considered to be medically important.
Note: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered as SAEs when, based upon appropriate medical judgment, they 
may jeopardize the subject or may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.
For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is also 
considered an SAE, as described in Section 7.4.1.4.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (for 
example, an overnight stay to facilitate therapy and related hydration therapy application) are not 
considered SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (for example, undesirable effects of any administered 
treatment) must be documented and reported as SAEs.
Events Not to Be Considered as AEs/SAEs
Medical conditions present at the initial trial visit that do not worsen in severity or frequency during 
the trial are defined as Baseline medical conditions, and are not to be considered AEs.
AE/SAEs Observed in Association with Disease Progression
Disease progression recorded in the course of efficacy assessments only, but without any adverse 
signs or symptoms should not be reported as AEs.
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However, if adverse signs or symptoms occur in association with disease progression then these 
should be recorded as AEs or reported as SAEs, if they meet criteria for seriousness.
AESIs
Any AE that is suspected to be a potential irAE will be considered an adverse event of special 
interest (AESI). 
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each trial visit, the subject will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the subject’s condition will be recorded as AEs, 
whether reported by the subject or observed by the Investigator. 
Complete, accurate, and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the eCRF. 
All SAEs must be additionally documented and reported using the appropriate report form as 
described in Section 7.4.1.4.
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates [and times when it is important to assess the time of AE onset relative to the 
recorded treatment administration time]), its severity, its causal relationship with the trial 
treatment, any other potential causal factors, any treatment given or other action taken, including 
dose modification or discontinuation of the trial treatment, and its outcome. In addition, serious 
cases should be identified and the appropriate seriousness criteria documented. 
Specific guidance can be found in the eCRF Completion and Monitoring Conventions.
7.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is initially included in the 
trial (date of first signature of informed consent) and continues for all SAEs and treatment related 
non-serious AEs through the trial’s Safety Follow-up Phone Call, defined at 90 days (± 1 week) 
after the last trial treatment administration.
Any SAE assessed as related to IMP must be reported whenever it occurs, irrespective of the time 
elapsed since the last administration of IMP. 
7.4.1.4
Procedure for Reporting Serious Adverse Events and Adverse 
Events of Special Interest
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 hours after becoming aware of the event) inform the 
Sponsor or its designee using the SAE Report Form following specific completion instructions.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, an SAE Report From must be provided immediately thereafter.
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Relevant pages from the eCRF may be provided in parallel (for example, medical history, 
concomitant drugs). Additional documents may be provided by the Investigator, if available (for 
example, laboratory results, hospital report, autopsy report). In all cases, the information provided 
on the SAE Report Form must be consistent with the data about the event recorded in the eCRF.
The Investigator must respond to any request for follow-up information (for example, additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee and 
(as applicable) to allow the Sponsor to meet strict regulatory timelines associated with expedited 
safety reporting obligations.
Requests for follow-up will usually be made via the responsible monitor, although in exceptional 
circumstances the Global Drug Safety department of the Sponsor may contact the Investigator
directly to obtain clarification or to obtain further information or to discuss the event.
7.4.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards and Investigators
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving trial subjects to the IEC/IRB that approved the 
trial.
In accordance with ICH GCP, the Sponsor/designee will inform the Investigator of “findings that 
could adversely affect the safety of subjects, impact the conduct of the trial or alter the IEC’s/IRB’s 
approval/favorable opinion to continue the trial.” In particular and in line with respective 
regulations, the Sponsor/designee will inform the Investigator of AEs that are both serious and 
unexpected and are considered to be related to the administered product (suspected unexpected 
serious adverse reactions [SUSARs]). The Investigator should place copies of Safety Reports in 
the Investigator Site File. National regulations with regard to Safety Report notifications to 
Investigators will be taken into account.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records of 
these notifications. When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IEC/IRB of 
any Safety Reports provided by the Sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File.
For trials covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities regarding 
the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with that Directive 
and with the related Detailed Guidance documents.
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7.4.1.6
Monitoring of Subjects with Adverse Events
Adverse events are recorded and assessed continuously throughout the trial (see Section 7.4.1.3) 
and are assessed for final outcome at the 30-day Safety Follow-up Visit. SAEs and 
treatment-related non-serious AEs are recorded and assessed continuously until the 90-day Safety 
Follow-up Phone Call.
All SAEs ongoing at the 90-day Safety Follow-up Phone Call must be monitored and followed up 
by the Investigator until stabilization or until the outcome is known, unless the subject is 
documented as “lost to follow-up”. Reasonable attempts to obtain this information must be made 
and documented. It is also the responsibility of the Investigator to ensure that any necessary 
additional therapeutic measures and follow-up procedures are performed.
7.4.2
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator to be related to trial treatment (for example,
resulting from a drug interaction with a contraceptive medication) are considered to be AEs. 
However, all pregnancies with an estimated conception date during the period defined in 
Section 7.4.1.3 must be recorded by convention in the AE page/section of the eCRF. The same 
rule applies to pregnancies in female subjects and to pregnancies in female partners of male 
subjects. The Investigator must notify the Sponsor/designee in an expedited manner of any 
pregnancy using the Pregnancy Report Form, which must be transmitted according to the same 
process as described for SAE reporting in Section 7.4.1.4. 
Investigators must actively follow up, document, and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the trial.
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form will be used if the subject sustains 
an event and the Parent-Child/Fetus AE Report Form if the child/fetus sustains an event.
Any abnormal outcome must be reported in an expedited manner as described in Section 7.4.1.4, 
while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from trial treatment immediately. The Sponsor/designee must be notified without 
delay and the subject must be followed as mentioned above.
7.4.3
Clinical Laboratory Assessments
All laboratory samples, as detailed in the Schedules of Assessments (see Table 1), must be 
collected and sent to the central laboratory for analysis, except for some samples that may be 
analyzed locally (Screening pregnancy testing, HBV, and HCV testing). Urinalysis and urine 
pregnancy testing will be done locally only.
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Results from the central laboratory for complete blood count and core chemistry must be available 
and reviewed prior to randomization. Results of all central laboratory testing will be transferred to 
the clinical database.
Local laboratory samples may be drawn and if collected are required to be recorded in the eCRFs.
In case of liver function test elevations (AST, ALT, and/or total bilirubin) requiring additional 
laboratory draws (according to guidelines set forth in Table 6), an unscheduled laboratory draw 
should be sent to the central laboratory for analysis.
Blood samples will be drawn, processed, and stored in accordance with directions provided in the 
Study Manual and as per timing shown in the Schedules of Assessments (Table 1).
The report of the results must be retained as a part of the subject’s medical record or source 
documents. Blood samples for the full safety tests listed in Table 7 will be taken from nonfasted 
subjects as detailed in the Schedules of Assessments (Table 1). The T4, TSH, and urinalysis will 
only be assessed at the time points defined in Table 7 and Table 1. If confirmation of a subject’s 
postmenopausal status is necessary, an FSH level will also be performed at Screening, see 
Section 7.1.1.
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Table 7
Clinical Laboratory Assessments
Full Chemistry
Core Chemistrya
Hematology
Albumin
Alkaline phosphatase
Absolute lymphocyte count
Alkaline phosphatase
ALT
Absolute neutrophil count
ALT
Amylase
Hematocrit
Amylase
AST
Hemoglobin
AST
BUN/total urea
Platelet count
GGT
Calcium
RBC count
BUN/total urea
Chloride
White blood cell count and differential count
Calcium
Creatine kinase
RBC morphology
Chloride
Creatinine 
Reticulocytes
Cholesterol
Glucose
MCH
Creatine kinase
LDH
Mean corpuscular volume
Creatinine
Lipase
MCHC
CRP
Phosphorus/Phosphates
Glucose
Magnesium
Hemostaseology
LDH
Potassium
aPTT
Lipase
Sodium
Prothrombin time/INR
Phosphorus/Phosphates
Total bilirubin
Magnesium
Basic Urinalysis (dipstick, including macroscopic 
appearance, bilirubin, blood, color, glucose, 
ketones, leukocyte esterase, nitrite, pH, protein, 
specific gravity, urobilinogen)
Full urinalysis (dipstick plus microscopic evaluation) 
to be performed only at the Screening and End of 
Treatment visit.
Potassium
Sodium
Total bilirubin
Total protein
Uric acid
Totality of binding ADAs
Triglycerides
TSH and T4
Hormone
FSH (yes/no if applicable)
ADA=anti-drug antibody, ALT=alanine aminotransferase, aPTT=activated partial thromboplastin time, 
AST=aspartate aminotransferase, BUN=blood urea nitrogen, CRP=C-reactive protein, FSH=follicle-stimulating 
hormone, GGT=gamma-glutamyltransferase, INR=international normalized ratio, LDH=lactate dehydrogenase, 
MCH=mean corpuscular hemoglobin, MCHC=mean corpuscular hemoglobin concentration, RBC=red blood cell, 
TSH=thyroid-stimulating hormone, T4=free thyroxine.
a.
Core serum chemistries.
If a subject has a clinically significant abnormal laboratory test value that is not present at Baseline, 
the test will be repeated weekly and the subject will be followed until the test value has returned 
to the normal range or the Investigator has determined that the abnormality is chronic or stable.
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expected 5% overall drop-out rate, the trial should enroll approximately 330 subjects 
(n=165 subjects/arm) to achieve 256 OS events in total.
8.2
Randomization
The trial is a randomized, active-controlled (based on physician’s choice), and open-label trial. 
Eligible subjects will be randomized into either the avelumab plus BSC arm or control plus BSC 
arm (physician’s choice) in a 1:1 ratio, stratified by region (Asia versus non-Asia). The purpose of 
the stratification is to ensure balance of the treatment arms within region. Randomization will 
occur using the IWRS as described in Section 6.3 upon completion of the Screening/Baseline
procedures and determination of subject eligibility.
8.3
Endpoints
8.3.1
Primary Endpoint
The primary endpoint of the trial is OS, defined as the time (in months) from randomization to the 
date of death, regardless of the actual cause of the subject’s death.  
For subjects who are still alive at the time of data analysis or who are lost to follow-up, OS time 
will be censored at the last recorded date that the subject is known to be alive (date of last contact, 
last visit date, date of last trial treatment administration, or date of last scan, whichever is the latest) 
as of the data cut-off date for the analysis.
With the completion of the primary analysis, subjects will no longer be followed for survival.
8.3.2
Secondary Endpoints
8.3.2.1
Progression-free Survival
Progression-free survival is a key secondary endpoint and will be determined according to RECIST 
v1.1 as adjudicated by an IRC (see Section 2.3.2). It is defined as the time (in months) from date 
of randomization until date of the first documentation of PD or death by any cause (whichever 
occurs first).
For the primary analysis, PFS data will be censored on the date of the last adequate tumor 
assessment for subjects who do not have an event (PD or death), for subjects who start new 
anti-cancer treatment prior to an event, or for subjects with an event after 2 or more missing tumor 
assessments. Subjects who do not have a Baseline tumor assessment or who do not have any post-
baseline tumor assessments will be censored on the date of randomization unless death occurred 
on or before the time of the second planned tumor assessment, in which case the death will be 
considered an event.
As a sensitivity analysis, the following 3 sensitivity analyses of PFS will also be performed:
1. Considering events after start for new anticancer treatment.
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2. Clinical progression will be considered as an event
3. PFS based on Investigator assessment
Additional sensitivity analyses may be provided, and details will be documented in the SAP.
8.3.2.2
Best Overall Response
The confirmed BOR will be determined according to RECIST v1.1 and as adjudicated by an IRC. 
It is defined as the best response obtained among all tumor assessment visits after the date of 
randomization until documented disease progression, excluding assessments after start of 
subsequent anticancer therapy, taking requirements for confirmation into account as detailed 
below. Clinical deterioration will not be considered as documented disease progression. Details of 
determination of tumor response date at each time point will be provided in the IRC charter. 
For a BOR of PR or CR, confirmation of the response according to RECIST v1.1 will be required, 
preferably at the regularly scheduled 6-week assessment interval (after 12 months of treatment, 
12-week assessment interval will be used), but no sooner than 5 weeks after the initial 
documentation of CR or PR. Confirmation of PR can be confirmed at an assessment later than the 
next assessment after the initial documentation of PR. A BOR of stable disease requires that an
overall response of stable disease has been determined at a time point at least 6 weeks after 
randomization.
The ORR is defined as the proportion of all randomized subjects with a confirmed BOR of PR or 
CR according to RECIST v1.1 and as adjudicated by the IRC.
The confirmed BOR according to Investigator assessment will be derived in the same way as the 
confirmed BOR according to the IRC.
8.3.2.3
Subject-reported Outcomes/Quality of Life
The following subject-reported outcomes are further secondary endpoints:
! The EQ-5D-5L
! The EORTC QLQ-C30
! The EORTC Module QLQ-STO22
8.3.3
Safety Endpoints
Safety endpoints include AEs, physical examination findings, laboratory assessments, vital signs, 
ECG parameters, and ECOG PS as described in Section 7.4.
8.3.4
Exploratory Endpoints
Exploratory endpoints include the following:
! Duration of response 
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In order to provide overall estimates of treatment effects, data will be pooled across trial centers. 
The “center” factor will not be considered in statistical models or for subgroup analyses due to the 
high number of participating centers in contrast to the anticipated small number of subjects 
randomized at each center. Region will be considered as a stratification factor for stratified 
statistical analysis as appropriate.
In general, continuous variables will be summarized using number (n), mean, median, SD, 
minimum, and maximum. Categorical variables will be summarized using frequency counts and 
percentages.
The calculation of proportions will be based on the number of subjects in the analysis set of 
interest, unless otherwise specified in the trial SAP.
Baseline
Baseline is defined as the last measurement taken prior to the first dose of trial treatment for safety 
endpoints and the last measurement taken prior to randomization for efficacy endpoints.
On-Treatment
The on-treatment period is defined as the time from the first trial treatment administration to the 
last trial treatment administration date + 30 days or the earliest date of subsequent anticancer drug 
therapy minus 1 day, whichever occurs first, unless otherwise stated.
Multiplicity Adjustment Strategy
The type I error rate for the primary endpoint (OS) and 2 key secondary endpoints (PFS and BOR) 
will be controlled at 2.5% (1-sided) level using a gatekeeping procedure. The primary hypothesis 
(OS) will serve as a gate keeper and be tested at an overall 1-sided type I error of 2.5%. Only if it 
is significant, the 2 key secondary endpoints (PFS and BOR) will be tested, and the Hochberg 
procedure will be used to control the type I error rate at 2.5% (1-sided) for PFS and BOR (56). 
Statistical analyses will be performed using SAS® version 9.2 or higher.
8.5.2
Analysis of Primary Endpoints
Primary Analysis
The primary endpoint is OS and will be considered as confirmatory evidence of efficacy. Analysis 
of the primary endpoint will occur after 256 events (deaths) have been observed and a minimum 
of 6 months follow-up since the last subject randomized. The primary analysis set will be the ITT 
Analysis Set. The OS difference between the 2 treatment arms will be compared using a stratified, 
1-sided, log-rank test at an overall 1-sided type I error rate of 2.5%. The stratification factor will 
be region (Asia vs. non-Asia). The following null hypothesis will be tested:
H0: λA(t) = θλB(t), θ ≥ 1, versus H1: λA(t)= θλB(t), θ < 1,
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where λ (t) represents the hazard rate at time t and θ the unknown constant of proportionality of 
hazards in treatment arms A (avelumab plus BSC) and B (physician’s choice plus BSC).
Kaplan-Meier estimates (production-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median OS time with 2-sided 95% CIs. In 
particular, the survival rate at 3, 6, 9 and 12 months will be estimated with corresponding 2-sided 
95% CIs. The CIs for the median will be calculated according to Brookmeyer and Crowley (57)
and the CIs for the survival function estimates at the time points defined above will be derived 
using the log-log transformation according to Kalbfleisch and Prentice (58). The estimate of the 
standard error will be computed using Greenwood’s formula.
Note that the statistical conclusion will be drawn from the stratified, 1-sided log-rank test.
A stratified Cox proportional hazards model will be used to assess the magnitude of treatment 
difference between the 2 treatment arms and to explore the robustness of the primary endpoint 
confirmatory analysis. The natural parameter of this model is the log hazard ratio. Ties will be 
handled by replacing the proportional hazards model by the discrete logistic model. The hazard 
ratio of avelumab versus physician’s choice (with physician’s choice chemotherapy as reference) 
together with the corresponding Wald 2-sided 95% CI will be presented.
The validity of the proportional hazards assumption will be assessed visually by plotting 
log(-log[survival]) versus log(time) by treatment.
Sensitivity Analysis
The primary endpoint analysis described above will be repeated based on the PP Analysis Set as a 
means of sensitivity analysis if this analysis set includes less than 90% of subjects in the ITT 
Analysis Set.
8.5.3
Analysis of Secondary Endpoints
8.5.3.1
Key Secondary Endpoints – Progression-free Survival and 
Best Overall Response
Secondary efficacy analyses will be performed on the ITT Analysis Set.
Based on the gatekeeping testing strategy described in Section 8.5.1, if the 1-sided p-value from 
the stratified log-rank test of the primary endpoint OS is less than 0.0250, the key secondary 
endpoints (i.e., PFS and BOR) will be tested per the Hochberg procedure used to control the type I 
error rate at 2.5% (1-sided).
8.5.3.1.1
Progression-free Survival
For the key secondary endpoint PFS, the primary statistical analysis will be the same as described 
for the analysis of OS.
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A sensitivity analysis will be performed based on the PP Analysis Set if the PP Analysis Set 
includes less than 90% of subjects in the ITT Analysis Set. The PFS according to Investigator
assessment will be analyzed in the same manner as another means of sensitivity analysis. Other 
sensitivity analyses based on different censoring rules will be conducted. Details will be provided 
in the trial SAP.
8.5.3.1.2
Best Overall Response
For the key secondary endpoint analysis of BOR according to RECIST v1.1 and as adjudicated by 
the IRC, the ORR in terms of having a confirmed BOR of CR or PR will be calculated along with 
corresponding 2-sided exact Clopper-Pearson 95% CIs for the 2 treatment arms. The Cochran-
Mantel-Haenszel test will be performed with the stratum of region to compare the ORR between 
the 2 treatment arms.
The ORR according to Investigator assessment will be analyzed in the same manner as a means of 
sensitivity analysis.
8.5.3.2
Other 
Secondary 
Endpoints
–
Subject-reported 
Outcomes/QoL
8.5.3.2.1
European Quality of Life 5-dimensions and 5-levels 
Questionnaire
Observed and change from Baseline values for the EQ-5D-5L index score will be summarized 
descriptively at planned visits during the treatment phase and End of Treatment visit by treatment 
arm. In addition, change from Baseline values will be compared between the 2 treatment arms 
using analysis of covariance (ANCOVA) with region and Baseline value as covariates. The 
EQ-5D-5L Visual Analog Scale scores will be presented by data listing only.
8.5.3.2.2
European Organization for Research and Treatment of 
Cancer QLQ-C30
Observed and change from Baseline values for the Global health status/QoL scale and each of the 
5 QLQ-C30 functional scales (i.e., Physical, Role, Emotional, Cognitive, and Social) will be 
summarized descriptively at planned visits during the treatment phase and End of Treatment visit 
by treatment arm. In addition, the best (largest positive change), worst (largest negative change), 
and last observed on-treatment change from Baseline values will be summarized. Each measure 
will be compared between the 2 treatment arms using ANCOVA with region and Baseline value 
as covariates.
8.5.3.2.3
European Organization for Research and Treatment of 
Cancer QLQ-STO22
Observed and change from Baseline values for each of the 5 QLQ-STO22 gastric cancer module 
symptom scales (i.e., Dysphagia, Pain, Reflux, Eating, and Anxiety) will be summarized 
descriptively at planned visits during the treatment phase and End of Treatment visit by treatment 
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Results for laboratory tests that are not part of NCI-CTCAE will be presented categorically (e.g., 
below, within, or above normal limits). Only subjects with post-Baseline laboratory values will be 
included in these analyses. Urinalysis results will be listed only. Further details of analyses for the 
laboratory parameters will be provided in the trial SAP.
Eastern Cooperative Oncology Group Performance Status
Shifts from Baseline in ECOG PS score will be presented at planned visits during the treatment 
phase and End of Treatment visit by number and percentage for each treatment arm. Shifts from 
Baseline to highest on-treatment ECOG PS score will be summarized in a similar fashion.
Physical Examinations
Clinically significant, abnormal findings from physical examinations before ICF signature are to 
be reported as pre-existing medical conditions and will be included in summaries of medical 
history. On the other hand, clinically significant, abnormal findings from physical examinations 
after ICF signature are to be reported as AEs and will be included in summaries of AEs. 
Vital Signs
Maximum on-treatment increase and maximum on-treatment decrease from Baseline values will 
be summarized by parameter (e.g., body temperature, respiratory rate, heart rate, and blood 
pressure) using descriptive statistics by treatment arm. 
12-Lead Electrocardiograms
Observed and change from Baseline values based on 12-lead ECGs will be summarized at the End 
of Treatment visit by parameter (e.g., heart rate, PR interval, QRS interval, RR interval, QT 
interval, and Fridericia-corrected QT interval) and treatment arm for the SAF Analysis Set. In 
addition, shifts from Baseline in ECG results (e.g., normal, abnormal) will be presented at the End 
of Treatment visit by parameter and treatment arm.
Further details of safety analyses will be provided in the trial SAP.
8.5.6
Reporting of Other Clinical Data of Interest
Subject Characteristics
Subject characteristics will be obtained prior to randomization and will be summarized by 
treatment arm and overall for the ITT Analysis Set. Subject characteristics may include, but are 
not limited to, age, sex, race/ethnicity, height, weight, body mass index, region corresponding to 
the site at which the subject is enrolled, and ECOG PS.
Disease Characteristics
Information on Baseline disease characteristics collected on the eCRF will be summarized by 
treatment arm and overall for the ITT Analysis Set. Disease characteristics may include, but are 
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not limited to, site of primary tumor (i.e., stomach, gastro-esophageal junction), and PD-L1 assay 
status (i.e., positive, negative).
Enrollment and Disposition
The number and percentage of subjects screened (number only), discontinued prior to 
randomization (number only), randomized, randomized but not treated, treated, and prematurely 
discontinued will be summarized by treatment arm and overall. All premature terminations will be 
summarized by primary reason for treatment discontinuation/withdrawal. The number and 
percentage of subjects in the ITT Analysis Set with major protocol deviations leading to exclusion 
from the PP Analysis Set will be presented by treatment arm and reason for exclusion. All major 
protocol deviations will be listed.
Medical History
Pre-existing medical conditions reported at the time of the Screening/Baseline procedures will be 
summarized using frequency tables by treatment arm and overall for the SAF Analysis Set.
Treatment Exposure and Compliance
The extent of exposure to trial treatment (avelumab or physician’s choice) will be characterized 
by duration (weeks), number of administrations (avelumab plus BSC arm only), cumulative dose 
(e.g., mg/kg or mg/m2), dose intensity (e.g., mg/kg/week or mg/m2/week), relative dose intensity 
(actual dose given/planned dose), number of dose delays, number of infusion rate reductions 
(avelumab plus BSC arm only), and number of dose reductions (physician’s choice chemotherapy 
plus BSC arm only) for the SAF Analysis Set. The number and percentage of non-compliant 
subjects (see Section 6.9) with regard to trial treatment will be presented by treatment arm based 
on the SAF Analysis Set.
Anticancer Therapies and Procedures
Prior anticancer therapies (i.e., anticancer medications other than trial treatment taken at any time 
pre-treatment) will be summarized using frequencies and percentages by drug class and preferred 
name within treatment arm and overall for the SAF Analysis Set. Prior anticancer procedures (i.e., 
procedures undertaken at any time pre-treatment) will be listed only.
Post anticancer therapies (i.e., anticancer medications other than trial treatment taken at any time 
post-treatment) will be summarized using frequencies and percentages by type of therapy collected 
on the eCRF. 
8.6
Interim Analysis
No interim analysis for efficacy is planned for this trial. There will be periodic safety review by 
the IDMC. Details will be provided in the IDMC charter and the IDMC SAP.
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9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the trial at the site and will ensure that the trial 
is performed in accordance with this protocol, the ethical principles outlined in the Declaration of 
Helsinki, ICH GCP, the Japanese ministerial ordinance on GCP, and any other applicable 
regulations. The Investigator must ensure that only subjects who have given informed consent are 
included in the trial.
According to United States Code of Federal Regulations Part 54.2 (e), for trials conducted in any 
country that could result in a product submission to the United States Food and Drug 
Administration for marketing approval and could contribute significantly to the demonstration of 
efficacy and safety of an IMP (which are considered “covered clinical trials” by the United States 
Food and Drug Administration), the Investigator and all sub-Investigators are obliged to disclose 
any financial interest which they, their spouses or their dependent children may have in the Sponsor
or the Sponsor’s product under study. This information is required during the trial and for 
12 months following completion of the trial.
9.2
Subject Information and Informed Consent
An unconditional prerequisite for each subject prior to participation in the trial is written informed 
consent, which must be given before any trial-related activities are carried out. Adequate 
information must therefore be given to the subject by the Investigator or an appropriate designee 
(if local regulations permit) before informed consent is obtained. A separate specific PGt ICF will 
be provided to subjects who are willing to participate in this optional procedure, which refers to 
the extraction and analysis of germline DNA from blood in order to better understand how gene(s) 
may affect the efficacy of avelumab.
A subject information sheet must be prepared in the local language in accordance with ICH GCP
and will be provided by the Sponsor for the purpose of obtaining informed consent. In addition to 
providing this written information to a potential subject, the Investigator or a designate will inform 
the subject verbally of all pertinent aspects of the trial, using language chosen so that the 
information can be fully and readily understood by laypersons. The subject will be given sufficient 
time to read the information and the opportunity to ask questions and to request additional 
information and clarification.
If permitted by national regulations, a person other than the Investigator may inform the subject 
about the trial and sign the ICF, as above.
After the information is provided by the Investigator, the ICF must be signed and dated by the 
subject and the Investigator. 
The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived so that the forms can be retrieved at any time for monitoring, auditing, and 
inspection purposes. A copy of the signed and dated information and ICF should be provided to 
the subject prior to participation.
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number at a call center, whereby the health care providers will be given access to the appropriate 
Sponsor physician to assist with the medical emergency.
9.5
Clinical Trial Insurance and Compensation to Subjects
Insurance coverage will be provided for each country participating to the trial. Insurance conditions 
shall meet good local standards, as applicable.
9.6
Independent Ethics Committee or Institutional Review Board
Prior to commencement of the trial at a given site, this clinical trial protocol will be submitted 
together with its associated documents (such as the ICF) to the responsible IEC or IRB for its 
favorable opinion or approval, which will be filed in the Investigator Site File. A copy will be filed 
in the Sponsor Trial Master File and a copy will be filed with the CRO.
The IEC or IRB will be asked to document the date of the meeting at which the favorable opinion
or approval was given and the members and voting members present. Written evidence of 
favorable opinion or approval that clearly identifies the trial, the clinical trial protocol version and 
the Subject Information and ICF version reviewed should be provided. Where possible, copies of 
the meeting minutes should be obtained.
Amendments to this clinical trial protocol will also be submitted to the concerned IEC or IRB, 
before implementation of substantial changes (see Section 10.5). Relevant safety information will 
be submitted to the IEC or IRB during the course of the trial in accordance with national 
regulations and requirements.
9.7
Health Authorities
The clinical trial protocol and any applicable documentation (for example, IMP Dossier, Subject 
Information and ICF) will be submitted or notified to the Health Authorities in accordance with 
all local and national regulations for each site.
10
Trial Management
10.1
Case Report Form Handling
Refer to the IPMP for eCRF handling guidelines.
The main purpose of the eCRF is to obtain data required by the clinical trial protocol in a complete, 
accurate, legible, and timely manner. The data in the eCRF should be consistent with the relevant 
source documents.
The Investigator or designee is responsible for ensuring that the data collected in the course of this 
trial is accurate and documented appropriately on all applicable forms. They will then be 
processed, evaluated, and stored in anonymous form in accordance with applicable data protection 
regulations. The Investigator must ensure that the eCRFs and any other associated documents 
forwarded to Sponsor or its designated organization contain no mention of any subject names.
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For subject-reported outcome data such as QoL and pain assessments, electronic subject-reported 
outcome will be used.
The data will be entered into a validated database. The CRO will follow the standards of the 
Sponsor in the database design and data structure. The Sponsor or its designee will be responsible 
for data processing, in accordance with the Sponsor’s or designee’s data management procedures. 
Database lock will occur once quality control and quality assurance procedures have been 
completed. PDF files of the eCRFs will be provided to the Investigators at the completion of the 
trial.
10.2
Source Data and Subject Files
The Investigator must keep a file (medical file, original medical records) on paper or electronically 
for every subject in the trial. It must be possible to identify each subject by using this subject file. 
This file will contain the demographic and medical information for the subject listed below and 
should be as complete as possible. 
! Subject’s full name, date of birth, sex, height, weight
! Medical history and concomitant diseases
! Prior and concomitant therapies (including changes during the trial)
! Trial identification, that is, the Sponsor trial number for this clinical trial, and subject number
! Dates for entry into the trial (informed consent) and visits to the site
! Any medical examinations and clinical findings predefined in this clinical trial protocol
! All AEs
! Date that the subject left the trial including any reason for early withdrawal from the trial or 
IMP (if applicable).
All documents containing source data must be filed, including, but not limited to CT or MRI scan 
images, ECG recordings, and laboratory results. Such documents must bear the subject number 
and the date of the procedure. If possible, this information should be printed by the instrument 
used to perform the assessment or measurement. As necessary, medical evaluation of such records 
should be performed; all evaluations should be documented, signed, and dated by the Investigator.
Electronic subject files will be printed whenever the Monitor performs source data verification. 
Printouts must be signed and dated by the Investigator, countersigned by the monitor and kept in 
a safe place at the site.
10.3
Investigator Site File and Archiving
Upon initiation of the trial, the Investigator will be provided with an Investigator Site File 
containing all necessary trial documents, which will be completed throughout the trial and updated 
as necessary. The file must be available for review by the monitor, during Sponsor audits and for 
inspection by Health Authorities during and after the trial, and must be safely archived for at least 
15 years (or longer, per local requirements or as otherwise notified by the Sponsor) after the end 
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of the trial. The documents to be archived include the Subject Identification List and the signed 
subject ICFs. If archiving of the Investigator Site File is no longer possible at the site, the 
Investigator must notify the Sponsor/designee.
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per ICH 
GCP guidelines, whichever is longer. In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor.
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH GCP, and any other applicable regulations. 
The site monitor will perform visits to the trial site at regular intervals.
The clinical trial protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent Quality Assurance activities. 
Audits may be conducted at any time during or after the trial to ensure the validity and integrity of 
the trial data. Representatives of the Quality Assurance unit from the Sponsor or a designated 
organization, as well as Health Authorities, must be permitted to access all trial documents and 
other materials at the site, including the Investigator Site File, the completed CRFs, all IMP and
IMP accountability records, and the original medical records or files for each subject.
10.5
Changes to the Clinical Trial Protocol
Changes to the clinical trial protocol will be documented in writing. Substantive amendments will 
usually require submission to the Health Authorities and to the relevant IEC/IRB for approval or 
favorable opinion. In such cases, the amendment will be implemented only after approval or 
favorable opinion has been obtained.
Minor (nonsubstantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant IEC/IRB or to Health Authorities 
only where requested by pertinent regulations. Any amendment that could affect the subject’s 
agreement to participate in the trial requires additional informed consent prior to implementation 
following the process as described in Section 9.2.
10.6
Clinical Trial Report and Publication Policy
10.6.1
Clinical Trial Report
After completion of the trial, a clinical trial report will be written by the Sponsor in consultation 
with the Coordinating Investigator following the guidance in ICH Topic E3.
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10.6.2
Publication
The first publication will include the results of the analysis of the primary endpoints and will 
include data from all trial sites. The Investigator will inform the Sponsor in advance about any 
plans to publish or present data from the trial. Any publications and presentations of the results 
(abstracts in journals or newspapers, oral presentations, etc.), either in whole or in part, by 
Investigators or their representatives will require review by the Sponsor before submission. The 
Sponsor will not suppress publication, but maintains the right to delay publication in order to 
protect intellectual property rights.
Posting of data on Clintrials.gov is planned and will occur 12 months after the last clinic visit of 
the final trial subject or another appropriate date to meet applicable requirements.
11
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22. Seo HY, Kim DS, Choi YS, et al. Treatment outcomes of oxaliplatin, 5-FU, and leucovorin 
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27. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor 
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activate anti-tumor immunity. Curr Opin Immunol. 2012;24(2):207-12.
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host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci 
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30. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-
PD-1) in melanoma. N Engl J Med. 2013;369(2):134-44.
31. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in 
patients with advanced cancer. N Engl J Med. 2012;366(26):2455-65.
32. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-
PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-54.
33. Lutzky J, Antonia SJ, Blake-Haskins A, et al. A phase 1 study of MEDI4736, an anti–PD-
L1 antibody, in patients with advanced solid tumors [ASCO abstract 3001^]. Journal of 
Clinical Oncology. 2014;32(5s):abstr 3001^.
34. Muro K, Bang Y, Shankaran V, et al. A Phase 1B Study of pembrolizumab (pembro; MK-
3475) in patients with advanced gastric cancer. Annals of Oncology. 2014;25(suppl 4).
35. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits 
T cell activation. Nat Immunol. 2001;2(3):261-8.
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36. Oki E, Okano S, Ando K, et al. HER2 and programmed death-1 ligand-1 (PD-L1) 
expression in gastric carcinoma. . Journal of Clinical Oncology. 2014;32(No 15_suppl 
(May 20 Supplement)):e15041.
37. Disis ML, Patel MR, Pant S, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, 
in patients with previously treated, recurrent or refractory ovarian cancer: A phase Ib, open-
label expansion trial [ASCO abstract 5509]. Journal of Clinical Oncology. 
2015;33(suppl):abstr 5509.
38. Gulley JL, Spigel DR, Kelly K, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, 
in advanced NSCLC patients: A phase 1b, open-label expansion trial in patients 
progressing after platinum-based chemotherapy [ASCO abstract 8034]. Journal of Clinical 
Oncology. 2015;33(suppl):abstr 8034.
39. Lee JH, Kim SH, Oh SY, et al. Third-line docetaxel chemotherapy for recurrent and 
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40. Zafar SY, Currow D, Abernethy AP. Defining best supportive care. J Clin Oncol. 
2008;26(31):5139-40.
41. Jassem J, Ramlau R, Santoro A, et al. Phase III trial of pemetrexed plus best supportive 
care compared with best supportive care in previously treated patients with advanced 
malignant pleural mesothelioma. J Clin Oncol. 2008;26(10):1698-704.
42. Thuss-Patience PC, Kretzschmar A, Bichev D, et al. Survival advantage for irinotecan 
versus best supportive care as second-line chemotherapy in gastric cancer--a randomised 
phase III study of the Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer. 
2011;47(15):2306-14.
43. Kang JH, Lee SI, Lim do H, et al. Salvage chemotherapy for pretreated gastric cancer: a 
randomized phase III trial comparing chemotherapy plus best supportive care with best 
supportive care alone. J Clin Oncol. 2012;30(13):1513-8.
44. Ford HE, Marshall A, Bridgewater JA, et al. Docetaxel versus active symptom control for 
refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 
randomised controlled trial. Lancet Oncol. 2014;15(1):78-86.
45. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated 
advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an 
international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 
2014;383(9911):31-9.
46. Hironaka S, Ueda S, Yasui H, et al. Randomized, open-label, phase III study comparing 
irinotecan with paclitaxel in patients with advanced gastric cancer without severe 
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47. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus 
paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal 
junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet 
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48. Pistelli M, Scartozzi M, Bittoni A, et al. Second-line chemotherapy with irinotecan, 5-
fluorouracil and leucovorin (FOLFIRI) in relapsed or metastatic gastric cancer: lessons 
from clinical practice. Tumori. 2011;97(3):275-9.
49. Baek SK, Kim SY, Jeong JH, et al. Second-line chemotherapy for advanced gastric cancer 
in Korea. Gastric Cancer. 2012;15(4):345-54.
50. Shah MA. Gastric cancer: an update. Curr Oncol Rep. 2006;8(3):183-91.
51. Sawaki A, Ohashi Y, Omuro Y, et al. Efficacy of trastuzumab in Japanese patients with 
HER2-positive advanced gastric or gastroesophageal junction cancer: a subgroup analysis 
of the Trastuzumab for Gastric Cancer (ToGA) study. Gastric Cancer. 2012;15(3):313-22.
52. Ohtsu A, Shah MA, Van Cutsem E, et al. Bevacizumab in combination with chemotherapy 
as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-
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53. (UK) WGotRC. Emergency Treatment of Anaphylactic Reactions: Guidelines for 
Healthcare Providers: The Resuscitation Council (UK); 2008 [24 April 2015]. Available 
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54. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University 
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of 
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2007 
[24 
April 
2015]. 
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from: 
http://medicine.iupui.edu/clinpharm/ddis/clinical-table.
55. Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 
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56. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 
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John Wiley & Sons; 1980.
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12
Appendices
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Appendix I
Signature Pages and Responsible Persons for the Trial
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Signature Page – Principal Investigator
Trial Title
A Phase III open-label, multicenter trial of avelumab 
(MSB0010718C) as a third-line treatment of 
unresectable, recurrent, or metastatic gastric or 
gastroesophageal junction adenocarcinoma
IND Number
EudraCT Number
2015-003301-42
Clinical 
Trial 
Protocol 
Date/Version
27 March 2018/Version 8.0
Center Number
Principal Investigator
I, the undersigned, am responsible for the conduct of the trial at this site and affirm that I 
understand and will conduct the trial according to the clinical trial protocol, any approved protocol 
amendments, International Council for Harmonisation Good Clinical Practice (Topic E6) and all 
applicable Health Authority requirements and national laws.
I also affirm that I understand that Health Authorities may require the Sponsors of clinical trials to 
obtain and supply details about ownership interests in the Sponsor or Investigational Medicinal 
Product and any other financial ties with the Sponsor. The Sponsor will use any such information 
solely for the purpose of complying with the regulatory requirements. I therefore agree to supply 
the Sponsor with any necessary information regarding ownership interest and financial ties 
including those of my spouse and dependent children, and to provide updates as necessary to meet 
Health Authority requirements.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function/Title:
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
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Sponsor Responsible Persons not Named on the Cover Page
Name, academic degree:
Function/Title:
Institution:
EMD Serono Research & Development Institute, Inc.
Address:
45B Middlesex Turnpike, Billerica, MA 01821, USA
Telephone number:
E-mail address:
Name, academic degree:
Function/Title:
Institution:
EMD Serono Research & Development Institute, Inc.
Address:
45A Middlesex Turnpike, Billerica, MA 01821, USA
Telephone number:
E-mail address:
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Appendix II
Guidance on contraception
Birth control methods considered as highly effective
According to the Clinical Trials Facilitation Group (CTFG) “Recommendations related to 
contraception and pregnancy testing in clinical trials” methods that can achieve a failure rate of 
less than 1% per year when used consistently and correctly are considered as highly effective birth 
control methods, such as:
- combined (estrogen and progesterone containing) hormonal contraception associated with 
inhibition of ovulation1 (oral, intravaginal, transdermal)
-
progesterone-only hormonal contraception associated with inhibition of ovulation1 (oral, 
injectable, implantable2)
- intrauterine device (IUD)2
- intrauterine hormone-releasing system (IUS)2
- bilateral tubal occlusion2
- vasectomized partner2,3
- sexual abstinence4
1 Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method
2Contraception methods in the context of this guidance are considered to have low user dependency
3Vasectomised partner is a highly effective birth control method provided that the partner is the sole sexual partner of 
the woman of childbearing potential trial participant and that the vasectomized partner has received medical 
assessment of the surgical success
4In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject.
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Appendix III:Protocol Amendments and List of Changes
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Previous Protocol Amendments
!
Version 1.0 was an initial version. After agency review, the protocol was revised and 
Version 2.0 (23 September 2015) was considered the original final version.
!
Version 3.0, 22 October 2015 (Global), Amendment no. 2 (Substantial)
!
Version 3.1, 05 November 2015 (Local, Japan only), initial version for Japan
!
Version 3.1, 18 March 2016 (Local, France only), Amendment 3.1 (Substantial)
!
Version 4.0, 06 January 2016 (Global), Amendment no. 3 (Substantial) 
!
Version 5.0, 29 April 2016 (Global), Amendment no. 4 (Substantial)
!
Version 5.1, 15 July 2016 (Local, Japan only), Amendments no. 3 and 4 (Substantial)
!
Version 5.2, 01 July 2016 (Local, VHP only), Amendment no. 4 (Minor)
!
Version 6.0, 28 December 2016 (Global), Amendment no. 5 (Nonsubstantial)
!
Version 6.1, 16 January 2017 (Local, Japan only), Amendment no. 5 (Nonsubstantial)
!
Version 6.2, 27 January 2017 (Local, VHP and Korea only), Amendment no. 5 
(Nonsubstantial)
!
Version 7.0, 30 May 2017 (Global), Amendment 6 (substantial)
!
Version 7.1, 21 June 2017 (Local, Japan only), Amendment 6 (substantial)
!
Version 7.2, 21 June 2017 (Local, VHP and Korea only), Amendment 6 (substantial)
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Amendment 7 / Clinical Trial Protocol Version 8.0 (27 March 2018, Global)
The purpose of this protocol amendment is to:
! To change the follow-up time such that subjects who discontinue treatment will no longer be 
followed for disease progression of survival.
The changes to be made to the clinical trial protocol and the rationale for the changes are described 
below.
Rationale for Changes
Due to the completion of the primary analysis, follow-up survival information is no longer 
required.
List of Changes
Changes to the clinical trial protocol text are presented in the table below. Additions and amended 
text are shown in bold. If the original clinical trial protocol text was already bold, changes are 
shown in bold and underlined, and deletions are marked using strike through. Any changes to the 
use of abbreviations or numbering of references within the clinical trial protocol are not included 
in the list of changes.
Based on the CT-1 guideline Section 119(e), this amendment is considered substantial in nature.
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Comparison with Clinical Trial Protocol Version 7.0 (Amendment 6), 30 May 2017
Change
Section
Pages
Previous Wording
New Wording
Rationale
Changed language to 
delete 5-year survival 
follow-up
Table 1 Schedules 
of Assessments -
Avelumab Plus Best 
Supportive Care 
Arm – footnote “b”
Physician’s Choice:  
Best Supportive 
Care Plus Irinotecan
– footnote “b”
Physician’s Choice:  
Best Supportive 
Care Plus paclitaxel
– footnote “b”
Physician’s Choice:  
Best Supportive 
Care Only –
footnote “b”
19-20
22
27
30-31
All subjects will have an End of 
Treatment visit within 7 days after the 
decision to discontinue trial treatment. 
All AEs will be documented until the 
30-day Safety Follow-Up visit. Subjects 
with an ongoing SAE at the 30-day 
Safety Follow-up visit must be monitored 
and followed up until stabilization or 
until the outcome is known. After this 
visit, all SAEs and all treatment related 
non-serious AEs need to be documented 
until the 90-day Safety Follow-up Phone 
Call. Subjects with an ongoing SAE at the 
90-day Safety Follow-up Phone Call 
must be monitored and followed by the 
Investigator until stabilization or until the 
outcome is known, unless the subject is 
documented as “lost to follow-up”. At 
90 days following the last treatment, 
subjects will be contacted by telephone to 
collect information on new or ongoing 
SAEs and treatment related non-serious 
AEs. Any SAE assessed as related to IMP 
must be reported whenever it occurs, 
irrespective of the time elapsed since the 
last administration of IMP. Subjects For 
subjects without PD at End of Treatment 
visit 
will, 
follow-up 
for 
disease 
progression and survival will end on 
the date of treatment discontinuation 
(see Section 7.1.5
for details)
be 
followed up for disease progression 
(CT/MRI scans every 6 weeks, and after 
12 months every 12 weeks) until PD. In 
addition, subjects will be followed every 
All subjects will have an End of 
Treatment visit within 7 days after the
decision to discontinue trial treatment. 
All AEs will be documented until the 
30-day Safety Follow-Up visit. Subjects 
with an ongoing SAE at the 30-day 
Safety Follow-up visit must be monitored 
and followed up until stabilization or 
until the outcome is known. After this 
visit, all SAEs and all treatment related 
non-serious AEs need to be documented 
until the 90-day Safety Follow-up Phone 
Call. Subjects with an ongoing SAE at the 
90-day Safety Follow-up Phone Call 
must be monitored and followed by the 
Investigator until stabilization or until the 
outcome is known, unless the subject is 
documented as “lost to follow-up”. At 90 
days following the last treatment, 
subjects will be contacted by telephone to 
collect information on new or ongoing 
SAEs and treatment related non-serious 
AEs. Any SAE assessed as related to IMP 
must be reported whenever it occurs, 
irrespective of the time elapsed since the 
last administration of IMP. For subjects 
without PD at End of Treatment visit, 
follow-up for disease progression and 
survival will end on the date of treatment 
discontinuation (see Section 7.1.5 for 
details).
Following the 
completion of the 
primary analysis, 
survival follow-
up information is 
no longer needed.
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Change
Section
Pages
Previous Wording
New Wording
Rationale
12 
weeks 
for 
survival 
(including 
assessment of any further tumor therapy). 
The survival follow up will continue until 
5 years after the last subject receives the 
last dose of trial drug or the last subject 
dies, whichever comes first (see Section 
7.1.5 for details).
Changed language to 
delete 5-year survival 
follow-up
Table 1 Schedules 
of Assessments -
Avelumab Plus Best 
Supportive Care 
Arm – footnote “p”
Physician’s Choice:  
Best Supportive 
Care Plus Irinotecan
– footnote “p” 
Physician’s Choice:  
Best Supportive 
Care Plus Paclitaxel
– footnote “q”  
Physician’s Choice:  
Best Supportive 
Care Only –
footnote “o”
20
23
27
31
p. Subjects without PD at End of 
Treatment visit will be followed up for 
disease progression (CT/MRI scans 
every 6 weeks, and after 12 months every 
12 weeks) until PD. In addition, subjects 
will be followed every 12 weeks for 
survival (including assessment of any 
further tumor therapy). The survival 
follow up will continue until 5 years after 
the last subject receives the last dose of 
trial drug or the last subject dies, 
whichever comes first (see Section 7.1.5 
for details). For subjects without PD at 
End of Treatment visit, follow-up for 
disease progression and survival will 
end 
on 
the 
date 
of 
treatment 
discontinuation (see Section 5.1.5 for 
details).
p. For subjects without PD at End of 
Treatment visit, follow-up for disease 
progression and survival will end on the 
date of treatment discontinuation (see 
Section 5.1.5 for details).
Following the 
completion of the 
primary analysis, 
survival 
follow-up 
information is no 
longer needed.
Added bullet 
regarding primary 
analysis and changed 
language to delete 
5-year survival 
follow-up
5.5.1  Withdrawal 
from Trial Therapy
58
•  Use of a prohibited concomitant drug, 
as defined in Section 6.5.2, where the 
predefined consequence is withdrawal 
from the trial treatment
•  Noncompliance (see Section 6.9) 
•  After primary analysis is completed, 
the subjects may be offered to enroll 
into a roll-over trial or receive 
commercial supply.
For subjects receiving avelumab plus 
BSC, if discontinuation occurs due to 
•  Use of a prohibited concomitant drug, 
as defined in Section 6.5.2, where the 
predefined consequence is withdrawal 
from the trial treatment
•  Noncompliance (see Section 6.9) 
•  After primary analysis is completed, 
the subjects may be offered to enroll into 
a roll-over trial or receive commercial 
supply.
For subjects receiving avelumab plus 
BSC, if discontinuation occurs due to 
Following the 
completion of the 
primary analysis, 
survival 
follow-up 
information is no 
longer needed.
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progression 
and 
a 
definitive 
diagnosis/radiographic confirmation is 
not made at the time of discontinuation, a 
second imaging scan may be allowed for 
confirmation 
of 
progression. 
If
progression at the second imaging scan is 
not confirmed and the subject wishes to 
continue, the subject will be allowed to 
continue receiving avelumab as long as 
they meet the criteria for continuation of 
treatment 
beyond 
progression 
(see 
Section 6.2.1).
Subjects who withdraw from trial therapy 
will no longer be followed for survival 
after the date to discontinue treatment
continue to be followed for survival. The 
survival follow up will continue until 5 
years after the last subject receives the 
last dose of trial treatment or the last 
subject dies, whichever comes first. 
Under some circumstances, the subjects 
may not be followed for 5 years for 
survival in this trial, e.g., the subjects 
may be offered to enroll into a roll over 
trial, or the sponsor may terminate the 
trial early.
progression 
and 
a 
definitive 
diagnosis/radiographic confirmation is 
not made at the time of discontinuation, a 
second imaging scan may be allowed for 
confirmation 
of 
progression. 
If 
progression at the second imaging scan is 
not confirmed and the subject wishes to 
continue, the subject will be allowed to 
continue receiving avelumab as long as 
they meet the criteria for continuation of 
treatment 
beyond 
progression 
(see 
Section 6.2.1).
Subjects who withdraw from trial therapy 
will no longer be followed for survival 
after the date to discontinue treatment.
Changed language to 
delete 5-year survival 
follow-up
5.5.2  Withdrawal 
from the Trial
58
Subjects may withdraw from the trial at 
any time without giving a reason. 
Withdrawal of consent will be considered 
withdrawal from the trial. In case of 
withdrawal 
from 
the 
trial, 
the 
assessments scheduled for the last visit 
(End of Treatment visit) should be 
performed (see Section 7.1.3), if possible, 
with focus on the most relevant 
assessments. In any case, the appropriate 
End of Safety Follow-up eCRF page 
Subjects may withdraw from the trial at 
any time without giving a reason. 
Withdrawal of consent will be considered
withdrawal from the trial. In case of 
withdrawal 
from 
the 
trial, 
the 
assessments scheduled for the last visit 
(End of Treatment visit) should be 
performed (see Section 7.1.3), if possible, 
with focus on the most relevant 
assessments. In any case, the appropriate 
End of Safety Follow-up eCRF page 
Following the 
completion of the 
primary analysis, 
survival follow 
up information is 
no longer needed.
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must 
be 
completed. 
In 
case 
of 
withdrawal, subjects will be asked to 
continue safety and survival follow-up,
which includes the collection of data on 
survival, subject reported outcomes/QoL 
questionnaires, 
and 
subsequent 
anticancer 
therapy. 
Subjects 
who 
withdraw from trial therapy will no 
longer be followed for survival after 
the date to discontinue treatment.
must 
be 
completed. 
In 
case 
of 
withdrawal, subjects will be asked to 
continue safety follow-up. Subjects who 
withdraw from trial therapy will no 
longer be followed for survival after the 
date to discontinue treatment.
Added new bullet 
regarding possible 
enrollment in 
rollover study
5.6  Premature 
Termination of the 
Trial
59
•  Discontinuation of development of the 
Sponsor’s trial treatment 
•  After primary analysis is completed, 
the subjects may be offered to enroll 
into a roll-over trial.
Health Authorities and Independent 
Ethics Committees (IECs)/Institutional 
Review Boards (IRBs) will be informed 
about the discontinuation of the trial in 
accordance with applicable regulations.
•  Discontinuation of development of the 
Sponsor’s trial treatment 
•  After primary analysis is completed, 
the subjects may be offered to enroll into 
a roll-over trial.
Health Authorities and Independent 
Ethics Committees (IECs)/Institutional 
Review Boards (IRBs) will be informed 
about the discontinuation of the trial in 
accordance with applicable regulations.
To provide 
subjects 
additional 
treatment 
options.
Modified the end of 
trial language
5.7  Definition of 
End of Trial
59
If the trial is not terminated for a reason 
given in Section 5.6, the trial is complete 
after the last subject comes off 
treatment and completes the safety 
follow-up
survival 
follow up 
will 
continue until up to 5 years after the last 
subject receives the last dose of avelumab 
or the last subject dies, whichever comes 
first. Under some circumstances, the 
subjects may not be followed for 5 years 
for survival in this trial, e.g., the subjects 
may be offered to enroll into a roll over 
trial, or the Sponsor may terminate the 
trial early. The sponsor may terminate 
the study at any time once access to 
study intervention for participants still 
If the trial is not terminated for a reason 
given in Section 5.6, the trial is complete 
after the last subject comes off treatment 
and completes the safety follow-up. 
Survival follow-up will end on the date to 
discontinue treatment. The sponsor may 
terminate the study at any time once 
access 
to 
study 
intervention 
for 
participants 
still 
benefitting 
is 
provisioned 
via 
a 
rollover 
study, 
expanded access, marketed product or 
another 
mechanism 
of 
access 
as 
appropriate.
To account for 
the completion of 
the primary 
analysis and 
termination of the 
trial.
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benefitting is provisioned via a rollover 
study, expanded access, marketed 
product or another mechanism of 
access as appropriate.
Deleted survival 
follow-up language
6.5.2  Prohibited 
Medicines
65
If the administration of a nonpermitted 
concomitant drug becomes necessary 
during the trial, the subject will be 
withdrawn from trial treatment (the 
Medical Monitor may be contacted to 
discuss whether the trial treatment must 
be discontinued). The subject should 
complete the End of Treatment visit 
(Section 7.1.3) and be followed for 
survival according to Section 7.1.5.
If the administration of a nonpermitted 
concomitant drug becomes necessary 
during the trial, the subject will be 
withdrawn from trial treatment (the 
Medical Monitor may be contacted to 
discuss whether the trial treatment must 
be discontinued). The subject should 
complete the End of Treatment visit 
(Section 7.1.3).
Following the 
completion of the 
primary analysis, 
survival follow 
up information is 
no longer needed.
Deleted survival 
follow-up language
6.13  Medical Care 
of Subjects after 
End of Trial
79
Upon withdrawal from trial treatment, 
subjects may receive whatever care they 
and their physicians agree upon. Subjects 
will be followed for survival and AEs as 
specified in Section 7.1.4.
Upon withdrawal from trial treatment, 
subjects may receive whatever care they 
and their physicians agree upon. Subjects 
will be followed for AEs as specified in 
Section 7.1.4.
Following the 
completion of the 
primary analysis, 
survival follow 
up information is 
no longer needed.
Changed language to 
delete 5-year survival 
follow-up
7.1.5  Long-term 
Follow-up
82
Subjects
For subjects
without PD 
according to RECIST v1.1 at the End of 
Treatment visit will, follow-up for 
disease progression and survival will 
end 
on 
the 
date 
of 
treatment 
discontinuation be followed up for 
disease progression (CT/MRI scans 
every 6 weeks, and after 12 months every 
12 weeks using the same procedures and 
review as while on treatment) until PD. 
Subjects will be followed every 12 weeks 
(± 2 weeks) after the last administration 
of trial treatment for survival (including 
assessment of any further tumor therapy). 
The survival follow up will continue 
until 5 years after the last subject receives 
For subjects without PD according to 
RECIST v1.1 at the End of Treatment 
visit, follow-up for disease progression 
and survival will end on the date of 
treatment discontinuation. 
Following the 
completion of the 
primary analysis, 
survival follow
up information is 
no longer needed.
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the last dose of trial treatment or the last 
subject dies, whichever comes first. 
Under some circumstances, the subjects 
may not be followed for 5 years for 
survival in this trial, e.g., the subjects 
may be offered to enroll into a roll over 
trial, or the sponsor may terminate the 
trial early.
Modified survival 
follow-up language
8.3.1  Primary 
Endpoint
97
The primary endpoint of the trial is OS, 
defined as the time (in months) from 
randomization to the date of death, 
regardless of the actual cause of the 
subject’s death.  
The survival follow up will continue until 
5 years after the last subject receives the 
last dose of trial treatment. Under some 
circumstances, the subjects may not be 
followed for 5 years for survival in this 
trial, e.g., the subjects may be offered to 
enroll into a roll over trial, or the sponsor 
may terminate the trial early. For subjects 
who are still alive at the time of data 
analysis or who are lost to follow-up, OS 
time will be censored at the last recorded 
date that the subject is known to be alive 
(date of last contact, last visit date, date 
of last trial treatment administration, or 
date of last scan, whichever is the latest) 
as of the data cut-off date for the analysis.
With the completion of the primary 
analysis, subjects will no longer be 
followed for survival.
The primary endpoint of the trial is OS, 
defined as the time (in months) from 
randomization to the date of death, 
regardless of the actual cause of the 
subject’s death.  
For subjects who are still alive at the time 
of data analysis or who are lost to 
follow-up, OS time will be censored at 
the last recorded date that the subject is 
known to be alive (date of last contact, 
last visit date, date of last trial treatment 
administration, or date of last scan, 
whichever is the latest) as of the data cut-
off date for the analysis.
With the completion of the primary 
analysis, subjects will no longer be 
followed for survival.
Following the 
completion of the 
primary analysis, 
survival follow 
up information is 
no longer needed.
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2
Table of Contents 
1 
Signature Page ......................................................................................2 
2 
Table of Contents ..................................................................................3 
3 
List of Abbreviations and Definition of Terms ....................................6 
4 
Modification History ............................................................................9 
5 
Purpose of the Statistical Analysis Plan ...............................................9 
5.1 
Changes to Previous Version ................................................................9 
6 
Summary of Clinical Trial Features ...................................................14 
7 
Sample Size/Randomization ...............................................................18 
8 
Overview of Planned Analyses ...........................................................18 
8.1 
Sequence of Analysis ..........................................................................19 
8.2 
Interim Analysis ..................................................................................19 
8.3 
Primary Analysis ................................................................................19 
9 
Changes to the Planned Analyses in the Clinical Trial Protocol ........20 
10 
Analysis Sets .......................................................................................20 
11 
General Specifications for Statistical Analyses ..................................23 
12 
Trial Subjects ......................................................................................30 
12.1 
Disposition of Subjects and Discontinuations ....................................30 
12.2 
Protocol Deviations ............................................................................31 
13 
Demographics and Other Baseline Characteristics .............................32 
13.1 
Demographics .....................................................................................32 
13.2 
Medical History ..................................................................................33 
13.3 
Other Baseline Characteristics ............................................................33 
13.3.1 
Disease Characteristics .......................................................................33 
13.3.2 
Prior Anti-Cancer Therapies ...............................................................34 
13.3.3 
PD-L1 Expression Status at Baseline .................................................35 
14 
Previous or Concomitant Medications/Procedures .............................35 
14.1 
Prior and Concomitant Medications/Procedures ................................35 
14.2 
Subsequent Anti-Cancer Therapies/Procedures .................................36 
15 
Treatment Compliance and Exposure .................................................37 
16 
Endpoint Evaluation ...........................................................................39 
16.1 
Primary Endpoint Analyses ................................................................39 


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16.1.1 
Primary Efficacy Analysis of Overall Survival ..................................39 
16.1.2 
Sensitivity Analyses of Primary Endpoint ..........................................41 
16.1.3 
Subgroup Analysis of Primary Endpoint ............................................43 
16.1.4 
Time of Follow-up for OS ..................................................................43 
16.2 
Secondary Endpoint Analyses ............................................................44 
16.2.1 
Progression-Free Survival (PFS) ........................................................44 
16.2.2 
Best Overall Response (BOR) ............................................................46 
16.2.3 
Time of Follow-up for PFS .................................................................50 
16.2.4 
Subgroup Analysis of Secondary Efficacy Endpoints ........................50 
16.2.5 
Health-Related Quality of Life ...........................................................51 
16.3 
Other Endpoint Analyses ....................................................................54 
16.3.1 
Duration of Response (DR) ................................................................54 
16.3.2 
Time to Response ...............................................................................55 
16.3.3 
Tumor Shrinkage ................................................................................55 
16.3.4 
Disease Control Rate (DCR) ..............................................................56 
17 
Safety Evaluation ................................................................................57 
17.1 
Adverse Events ...................................................................................58 
17.1.1 
All Adverse Events .............................................................................59 
17.1.2 
Adverse Events Leading to Treatment Discontinuation .....................60 
17.2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...................................................................................60 
17.2.1 
Deaths .................................................................................................60 
17.2.2 
Serious Adverse Events ......................................................................61 
17.2.3 
Other Significant Adverse Events ......................................................61 
17.3 
Clinical Laboratory Evaluation ...........................................................63 
17.3.1 
Hematology and Chemistry Parameters .............................................63 
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17.3.2 
Other Laboratory Parameters ..............................................................66 
17.4 
Vital Signs ..........................................................................................67 
17.5 
Other Safety or Tolerability Evaluations ............................................68 
17.5.1 
ECG ....................................................................................................68 
17.5.2 
ECOG Performance Status .................................................................69 
18 
References ...........................................................................................72 
19 
Appendices .........................................................................................73 
Appendix I 
Important and Clinically Important Protocol Deviations by 
Programming Check and Medical Review .........................................73 
Appendix II 
EORTC QLQ-C30 Version 3.0 ..........................................................75 
Appendix III 
EORTC QLQ-C30-STO22: Gastric Cancer Module ..........................76 
Appendix IV 
Description of the Case Review for Assessment of Immune-
Related AEs and IRR ..........................................................................77 
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3 
List of Abbreviations and Definition of Terms 
ADA 
Anti-drug Antibody 
AE 
Adverse Event 
ALK 
Anaplastic Lymphoma kinase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BSA 
Body Surface Area 
BSC 
Best Supportive Care 
CI 
Confidence Interval 
CIPD 
Clinically Important Protocol Deviations 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computed Tomogrophy 
CTP 
Clinical Trial Protocol 
DCR 
Disease Control Rate 
DR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic Case Report Form 
eDISH 
Evaluation of Drug-Induced Serious Hepatotoxicity 
EORTC 
European Organization for Research and Treatment of Cancer 
EQ-5D-5L 
European Quality of Life (EuroQoL) - 5 Dimensions - 5 Levels 
EU 
European Union 
FAS 
Full Analysis Set 
HR 
Hazard Ratio 
HRQoL 
Health-related Quality of Life 


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IC 
Immune Cell 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IP 
Investigational Product 
IPD 
Important Protocol Deviation 
IRC 
Independent Review Committee 
irAE 
Immune-related Adverse Event 
IRR 
Infusion-related Reaction 
ITT  
Intention-to-Treat 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
nAb 
Neutralizing Antibody 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse 
Events 
nd 
Not Done 
NE 
Non-evaluable 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PCSA 
Potentially Clinically Significant Abnormalities 
PD 
Progressive Disease 
PT 
Preferred Term 
Pd 
Pharmacodynamics 
PFS 
Progression-Free Survival 
PGt 
Pharmacogenetics 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PR 
Partial Response 
Q1 
First Quartile 
Q3 
Third Quartile 


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QoL 
Quality of Life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
StDev 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class 
TC 
Tumor Cell 
TEAE 
Treatment Emergent Adverse Event 
VAS 
Visual Analogue Scale 


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4
Modification History 
Unique 
Identifier for 
SAP Version
Date of SAP 
Version
Author
Changes from the Previous Version
1.0
20 November 2015
NA. The first version.
2.0
27 May 2016
Details of changes are specified in Section 
5.1 “Changes to Previous Version”
3.0
31 July 2017
Details of changes are specified in Section 
5.1 “Changes to Previous Version”
4.0
12 October 2017
Details of changes are specified in Section 
5.1 “Changes to Previous Version”
5
Purpose of the Statistical Analysis Plan 
The purpose of this statistical analysis plan (SAP) is to document technical and detailed 
specifications for the final analysis of data collected for Clinical Trial Protocol (CTP) EMR 
100070-008. Results of the analyses described in this SAP will be included in the Clinical Study 
Report (CSR). Additionally, the planned analyses identified in this SAP may be included in any 
regulatory submissions and/or manuscripts. Any post-hoc, or unplanned analyses performed to 
provide results for inclusion in the CSR but not identified in this prospective SAP will be clearly 
identified in the CSR.
The SAP is based upon Section 8 (Statistics) of the CTP and is prepared in compliance with ICH 
E9. The first version (version 1.0) was created based on the protocol version 3.0 dated 22 October 
2015. Version 2.0 was created based on the protocol version 5.0 dated 29 April 2016. Additional 
updates in version 2.0 and version 3.0 are specified in Section 5.1, Changes to Previous Version.
5.1
Changes to Previous Version 
Version 4.0 
The following changes are made in version 4.0 of the SAP: 
1. Section 9 Changes to the Planned Analyses in the Clinical Trial Protocol: Details were 
updated to specify the changes that are deviated from what are in the CTP; 
2. Section 10 Analysis Sets: Added rationale of including subject who received BSC only in 
the safety analysis set; the definition of HRQoL Analysis Set was updated to clarify post-
baseline HRQoL assessment; 
3. Section 11 General Specification for Statistical Analyses: On-treatment period was updated 
by adding definition for subjects who received BSC only; 
4. Section 17.3.1 Hematology and Chemistry Parameters: Added boxplot for changes from 
baseline. 
PPD
PPD
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Version 3.0 
The following changes are made in version 3.0 of the SAP: 
1. Section 7 Sample Size/Randomization was updated to include the condition of a minimum 
of 6 months follow-up since the last subject randomized for the primary analysis per 
protocol version 7;  
2. Section 8 Sequence of Analysis was updated to include the condition of a minimum of 6 
months follow-up since the last subject randomized for the primary analysis per protocol 
version 7. Data cut-off date for the primary analysis was updated; 
3. Section 10 Analysis Set was updated to include HRQoL analysis set, 
 additional subgroup analysis set was added; 
4. Section 11 General Specification for Statistical Analyses was updated for definition of 
baseline and on-treatment period; imputation rule for partial missing subsequent anti-
cancer therapy date was added;
5. Section 12.1 Disposition of Subjects and Discontinuations was updated for region and 
disposition category; 
6. Section 12.2 Protocol Deviations was updated with more details on how to summarize 
important protocol deviations and clinically important protocol deviations; 
7. Section 13.1 Demographics was updated for geographic region category; 
8. Section 13.3.2 Prior Anti-Cancer Therapies was updated to add summary of number of 
prior therapies;  
10. Section 14.1 Prior and Concomitant Medications/Procedures was updated to include 
summary table for pre-medications and concomitant procedures; 
11. Section 14.2 Subsequent Anti-Cancer Therapies/Procedures was updated to include more 
details on the summary analysis; 
12. Section 15 Treatment Compliance and Exposure was updated to add clarification for the 
definition of relative dose intensity; 
13. Section 16.1.2 Sensitivity Analyses of Primary Endpoint was updated to add additional 
sensitivity analysis of OS. Details of RMST analysis was added; 
14. Section 16.1.4 Time of Follow-up for OS was updated to specify time point of follow-up 
rate estimates;
15. Section 16.2.1 Progression-free Survival Table 3 was updated for the censoring rules. 
Multivariate Cox regression analysis on PFS was added; 
16. Section 16.2.2. Best Overall Response was updated to include additional details for 
confirmation of response and summary of BOR = NE; multivariable logistic regression 
analysis was added as a sensitivity analysis; 
17. Section 16.2.3 Time of Follow-up for PFS was added; 
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18. Section 16.2.4 Subgroup Analysis of Secondary Efficacy Endpoints was added; 
19. Section 16.2.5 Health-Related Quality of Life was updated to include completion and 
compliance summary, mixed-effects model repeated measures analysis and more details 
on summary of change from baseline; 
20. Section 16.3.1 Duration of Response was updated to include DR analysis according to 
investigator assessment; 
24. Section 17.1 Adverse Events definition of irAE and IRR was updated; added details of 
pooling the same AE with different toxicity grade, outcome or seriousness recorded as 
different entries on the eCRF; 
25. Section 17.2.3 Other Significant Adverse Events was updated to replace SOC by Cluster; 
27. Section 17.3.1 Hematology and Chemistry Parameters was updated to specify the 
denominator for worst-grade during the on-treatment period analysis;  
28. Section 17.5.1. ECG was updated to specify the denominator of ECG PCSA summary 
table; 
30. Appendix I Programmed Clinically Important Protocol Deviations was updated per the 
updated protocol deviation category per Medical team input; 
31. Appendix II was added to include the screenshot of EORTC QLQ-C30 version 3.0 scoring 
system; 
32. Appendix III was added to include the screenshot of EORTC QLQ-C30-STO22 Gastric 
Cancer Module scoring system; 
33. Appendix IV was added to include “Description of the Case Review for Assessment of 
Immune-Related AEs and IRR”.
Version 2.0 
The following changes are made in version 2.0 of the SAP: 
1. The term “Intention-to-Treat (ITT) analysis set” was updated as “Full analysis set (FAS)” 
throughout this document (the definition remains the same); 
2. Section 10 Analysis Set was updated for the per-protocol analysis set; additional subgroup 
analysis sets were added; 
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3. Section 11 General Specifications for Statistical Analyses was updated; 
4. Section 12.1 Disposition of Subjects and Discontinuations was updated; 
5. Section 13.1 Demographics was updated;
6. Section 13.3.1 Disease Characteristics was updated to delete PD-L1 assay status it is not 
collected on the “Disease History” eCRF page; 
7. Section 13.3.2 Prior Anti-Cancer Therapies was updated on the sorting order of summary 
output; 
8. Section 13.3.3 PD-L1 Expression Status at Baseline was added;  
9. Section 14.1 Prior and Concomitant Medications/Procedures, definition of prior 
medications was updated and sorting order of the summary output was updated; 
10. Section 16.1.1 Primary Efficacy Analysis of Overall Survival was updated to add 
additional time points in estimating survival probability; 
11. Section 16.1.2 Sensitivity Analyses was updated to include Restricted Mean Survival Time 
(RMST) as a method for evaluating the validity of Cox proportional hazard model 
assumptions; 
12. Section 16.1.3 was added for exploratory analyses of primary endpoint; 
13. Section 16.2.1 Progression-Free Survival was updated to include Table 2 for censoring 
rule; 
14. Section 16.2.2 Best Overall Response was updated to include summary of subjects with 
BOR; the derivation rule for the BOR was updated to include subjects who only have non-
target lesions at baseline; 
15. Section 16.2.3 Subject-reported Outcomes/Quality of Life was updated to include the 
graphical summary of QoL data; symptom scales of QLQ-C30 was added; 
16. Section 16.3.1 Duration of Response was updated for the definition of duration of response; 
17. Section 16.3.2 Time to Response was updated; 
18. Section 16.3.3 Tumor Shrinkage was updated; 
19. Section 16.3.4 Disease Control Rate was updated to included Non-CR/Non-PD in the 
numerator of disease control rate calculation for subjects who have only non-target lesions 
at baseline; 
21. Section 17.1 Adverse Events, definition of infusion-related reactions was updated;
22. Section 17.1.1 All Adverse Events, additional categories were added to the overall AE 
summary; 
23. Section 17.2.4 Immunogenicity Subgroup Analysis of Adverse Events was added; 
24. Section 17.3.1 Hematology and Chemistry Parameters was updated; 
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25. Appendix I Required Full Laboratory Safety Tests was deleted from the SAP as these tests 
have been clearly identified in the CTP; 
26. Programmed Clinically Important Protocol Deviations were added as Appendix I per 
sponsor SOP. 
 
 


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6
Summary of Clinical Trial Features 
Trial objectives
Primary objective
The primary objective is to demonstrate superiority with regard to 
overall survival (OS) of avelumab plus best supportive care (BSC) 
versus physician’s choice (chosen from a pre-specified list of 
therapeutic options) plus BSC.
Secondary objectives
Secondary objectives are as follows:
x To compare avelumab plus BSC versus physician’s choice plus 
BSC in regard to the following:
x Progression-free survival (PFS) based on an Independent
Review Committee (IRC) assessment 
x Objective response rate (ORR) based on IRC assessment
x Subject-reported outcomes/quality of life (QoL) using the 
European Quality of Life (EuroQOL) 5-dimensions and 5-
levels 
questionnaire 
(EQ-5D-5L), 
and 
the 
European 
Organization for Research and Treatment of Cancer (EORTC) 
QLQ-C30 and module QLQ-STO22.
x To determine the safety and tolerability of avelumab.
Exploratory objectives
Exploratory objectives are as follows:
x To determine duration of response of avelumab plus BSC versus 
physician’s choice plus BSC based on IRC assessment
x To determine time to response of avelumab plus BSC versus 
physician’s choice plus BSC based on IRC assessment
x To evaluate tumor shrinkage in target lesions at each time point 
from Baseline based on IRC assessment
x To evaluate the disease control rate (DCR)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Trial design and plan
This is a multicenter, international, randomized, open-label Phase III 
trial in subjects with unresectable, recurrent, locally advanced or 
metastatic adenocarcinoma of the stomach or of the gastroesophageal 
junction who have failed or relapsed from 2 prior chemotherapeutic 
regimens administered for the treatment of unresectable, recurrent, 
locally advanced or metastatic disease.
All subjects in both arms will receive BSC as background therapy. 
Subjects will receive BSC with either avelumab or physician’s choice 
chemotherapy from among a prespecified list of therapeutic options 
or BSC alone with no active therapy.
Approximately 330 subjects will be randomized, stratified by region 
(Asia versus non-Asia), in a 1:1 ratio to receive BSC with either 
avelumab at a dose of 10 mg/kg as a 1-hour intravenous (IV) infusion 
once every 2 weeks or physician’s choice chemotherapy from the 
following options: 
x Paclitaxel as monotherapy (80 mg/m2 on Days 1, 8, and 15 of a 4-
week treatment cycle)
x Irinotecan as monotherapy (150 mg/m2 on Days 1 and 15 of a 4-
week treatment cycle)
x Subjects who are not deemed eligible to receive paclitaxel or 
irinotecan at the dose and schedule specified above will receive 
BSC once every 3 weeks.
Subjects will return to the clinic at regular intervals for assessments. 
Tumor measurements by computed tomography (CT) scan or 
magnetic resonance imaging (MRI) will be performed every 6 weeks 
for the first 12 months and every 12 weeks thereafter to determine 
response to treatment. A central imaging laboratory will be used to 
read and interpret all CT/MRI data. Response will be evaluated using 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 
v1.1) and as adjudicated by a blinded IRC. Treatment will continue 
until:
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x Disease progression  
x Significant clinical deterioration (clinical progression) 
x Unacceptable toxicity, or 
x Any criterion for withdrawal from the trial or study treatment is 
fulfilled. 
For subjects receiving avelumab plus BSC, treatment may continue 
past the initial determination of disease progression per RECIST v1.1 
as long the following criteria are met: 
x No new symptoms or worsening of previous symptoms 
x Tolerance of study treatment 
x Stable Eastern Cooperative Oncology Group performance status 
(ECOG PS) 
x Treatment beyond progression will not delay an imminent 
intervention to prevent serious complications of disease 
progression (for example, central nervous system metastases). 
Subjects receiving avelumab plus BSC who have experienced a 
complete response (CR) should continue to receive avelumab for at 
least 12 months after confirmation of response and/or until disease 
progression or unacceptable toxicity. In case a subject with a 
confirmed CR relapses after stopping treatment, but prior to the end 
of the trial, 1 re-initiation of treatment is allowed at the discretion of 
the Investigator and agreement of the Medical Monitor. To be eligible 
for re-treatment, the subject must not have experienced any toxicity 
that led to treatment discontinuation of the initial avelumab therapy. 
Subjects who re-initiate treatment will stay on trial and will be treated 
and monitored according to the protocol and the “until progression” 
schedule in the Schedules of Assessments (see Table 1 in the clinical 
protocol). 
Subjects receiving physician’s choice chemotherapy plus BSC or 
BSC alone will receive study treatment until progressive disease (PD) 
per RECIST v1.1, significant clinical deterioration (clinical 
progression), unacceptable toxicity, or if any criterion for withdrawal 
from the trial or study treatment is fulfilled. Subjects receiving 
physician’s choice plus BSC will not be offered to cross over to 
avelumab plus BSC. 
Investigators must specify which of the physician’s choice treatment 
regimens will be selected prior to randomization. 
Assessments will be made by the Investigators for the purpose of 
subject management, but the disease response determinations, 


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including PD assessments associated with the trial endpoints, will be 
supported by tumor assessments performed by an IRC.
Subjects will attend clinic visits at regular intervals to receive study 
treatment and for efficacy and safety assessments.
The primary endpoint of the trial is OS, defined as the time (in 
months) from randomization to the date of death, regardless of the 
actual cause of the subject’s death.
Safety endpoints include adverse events (AEs) assessed throughout 
the trial and evaluated using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) v4.03, 
physical examination findings, clinical laboratory assessments, vital 
signs, and electrocardiograms (ECGs).
Planned number of 
subjects
Approximately 330 subjects are planned to be enrolled.
Primary endpoint
The primary endpoint for the trial is OS, defined as the time (in 
months) from randomization to the date of death, regardless of the 
actual cause of the subject’s death.
Secondary/Exploratory 
endpoints
Secondary endpoints include:
x
PFS according to RECIST 1.1 and as adjudicated by the IRC
x
BOR according to RECIST 1.1 and as adjudicated by the IRC
x
Subject-reported outcomes / quality of life (QoL) as assessed 
by the EQ-5D-5L, the EORTC QLQ-C30, and the EORTC 
Gastric Cancer Module QLQ-STO22
x
Safety endpoints (including AEs, physical examination
findings, clinical laboratory assessments, vital signs, ECG
parameters, and ECOG PS)
Exploratory endpoints include:
x
Duration of response 
x
Time to response 
x
Tumor shrinkage in target lesions at each time point from 
baseline
x
Disease Control Rate
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7
Sample Size/Randomization 
The sample size of this study is driven by the primary endpoint – OS, therefore the study is event-
driven and the primary analysis will take place after 256 deaths have occurred and after a minimum 
of 6 months follow-up since the last subject was randomized (whichever is later) to ensure 
sufficient follow-up for all subjects for the primary analysis of OS. With 256 OS events, the study 
provides 90% power to demonstrate an improvement of 2 months median OS time (i.e., median 
OS time of 6 months in the avelumab + BSC arm versus 4 months in the control arm, which is 
equivalent to a reduction of 33% in hazard rate, i.e., hazard ratio (HR) of avelumab + BSC versus 
control = 0.67, at the one-sided 2.5% overall significance level. Assuming a randomization ratio 
of 1:1 (avelumab + BSC versus control), an exponential distribution of OS time, a uniform 
distribution of subject accrual period over 15 months, an additional 6 months minimum follow-up
period for all subjects and an expected 5% overall drop-out rate, the study should enroll 
approximately 330 subjects (n=165 subjects/arm) to achieve 256 OS events in total. 
The study is a randomized, active-controlled (based on physician’s choice, including paclitaxel or 
irinotecan + BSC), and open- label study. Eligible subjects will be randomized into either the 
avelumab + BSC arm or control arm (physician’s choice, including paclitaxel or irinotecan + BSC)
in a 1:1 ratio using a stratified, fixed block design. The randomization will be stratified by region 
(Asia vs. non-Asia). The purpose of the stratification is to ensure a balance of the treatment arms 
within each region. Randomization will occur using the interactive web response system (IWRS) 
as described in CTP Section 6.3 upon completion of the Screening/Baseline procedures and 
determination of subject eligibility.  
8
Overview of Planned Analyses 
This SAP covers the analyses for efficacy and safety based on the data cut-off date for the primary 
analysis. Statistical analyses will be performed using cleaned eCRF data as well as data collected 
by the external vendor, including 
 patient quality of life data and tumor assessment 
results adjudicated by the IRC. All data will be included up to a clinical cut-off date which is 
determined by the requested number of events. The cut-off date is determined once a data extract 
(before data base lock) is available which indicates that the required number of events have 
occurred.  
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Due to data cleaning activities the final number of events might deviate from the planned number. 
The data cutoff date will not be adjusted retrospectively in this case. 
A separate SAP will cover the analyses for periodic safety reviews conducted by the IDMC. 
Separate or supplemental analysis plans might be written to cover:
8.1
Sequence of Analysis 
The following analyses will be performed during this trial: 
x
A primary analysis will be performed after approximately 256 events (deaths) have 
occurred and after a minimum of 6 months follow-up since the last subject was randomized, 
whichever is later. The actual data cut-off date for the primary analysis will be 
prospectively determined based on the event projection and the requirement of minimum 
of 6-month follow-up since the last subject randomized. The actual number of events may 
be slightly different from 256 at the data cut-off date for the primary analysis.  
x
There will be ongoing periodic safety reviews by the IDMC. Details will be provided in 
the IDMC charter and the IDMC SAP (see Section 8.2 as well).  
8.2
 Interim Analysis 
No interim analysis for efficacy is planned for this study. An IDMC will be formed and will be 
responsible for periodic safety evaluations of the trial. The IDMC will be presented with patient 
disposition, patient background, baseline disease and demographic information, along with safety 
information as described in the IDMC SAP. An independent statistical provider will perform such 
partially blinded analyses to support the IDMC. Results from these periodic safety analyses will 
be transmitted from this independent statistical provider to the IDMC only. Details of the IDMC 
mission, composition, and operations and of maintaining the blinding of the study are provided in 
the IDMC charter. 
8.3
 Primary Analysis 
The primary analysis will take place after the planned number of OS events (deaths) has occurred 
and after a minimum of 6 months follow-up since the last subject was randomized, whichever is 
later.  
All planned analyses outlined in this SAP will be performed for the primary analysis. A partial 
database lock will be performed for the primary analysis.  
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A data review meeting will be held prior to partial database lock at the time of the primary analysis. 
In addition, no database can be locked until this SAP has been approved. 
9 
Changes to the Planned Analyses in the Clinical Trial 
Protocol 
The statistical methods as described in the protocol version 7.0 dated 30 May 2017 were adopted.  
The definition of Safety Analysis Set is updated to include subjects who received BSC only.  
The definition of on-treatment period was updated to include subjects who received BSC only.  
10 
Analysis Sets 
Screening Analysis Set 
The Screening analysis set includes all subjects who signed the Informed Consent Form (ICF).  
Full Analysis Set / Intention-to-Treat (ITT)  
The Full Analysis Set (FAS) / Intention-to-Treat (ITT) analysis set will include all subjects who 
were randomized to study treatment. Analyses performed on the FAS will take into account 
subjects’ allocation to treatment arms as randomized. The FAS will be the primary analysis set for 
all primary and secondary efficacy endpoints. 
Per-Protocol Analysis Set 
The Per-Protocol (PP) analysis set is a subset of the FAS and will include subjects who do not 
meet any of the following criteria that could impact the key objectives of the study. Subjects who 
meet any of the following criteria will be excluded from the PP analysis set: 
x Subjects randomized to one treatment, but received the incorrect treatment.  
x Subjects without histologically confirmed unresectable, recurrent, locally advanced or 
metastatic, adenocarcinoma of the stomach or the gastroesophageal junction, as per 
inclusion criterion #4. 
x Subjects did not receive 2 prior courses of systemic treatment for unresectable recurrent, 
locally advanced or metastatic gastric cancer, and/or did not progress after the second 
line, as per inclusion criterion #6. 
x Subjects received “prior therapy with any antibody or drug targeting T-cell coregulatory 
proteins (immune checkpoints), such as PD-1, PD L1, or cytotoxic T-lymphocyte 
antigen-4”, as per exclusion criterion #1. 
x Subjects received concurrent anticancer treatment, as per exclusion criterion 2. 
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Safety Analysis Set   
Safety analysis set will include all subjects who were administered at least one dose of study 
treatment or those who were randomized in the control arm but only received BSC. Subjects will 
be classified according to the treatment assigned at randomization unless the incorrect treatment 
was received throughout the dosing period in which case subjects will be classified according to 
the first study treatment received.  
The rationale that subjects only received BSC are included in the safety analysis set is because 
they were randomized and they received the intended medication.  
HRQoL Analysis Set 
The HRQoL analysis set is a subset of the FAS and includes all FAS subjects who meet all of the 
following criteria: 
x
Have one baseline HRQoL assessment 
x
Have at least one post-baseline HRQoL questionnaire completed 
Baseline HRQoL assessment is defined in Section 11, “Definition of baseline”. Post-baseline 
assessment is defined as HRQoL questionnaires completed after the first dose of study treatment 
for subjects who received avelumab or physician’s choice chemotherapy treatment, and 
questionnaires completed after date of randomization for subjects on BSC only.  
  
  
Table 1 summarizes how each of the analysis sets will be used.
Table 1 
Statistical Analyses by Analysis Set 
Analysis
Analysis Set
FAS
PP
Analysis
Set
Safety 
Analysis
Set
HRQoL
Analysis 
Set
Demographic and Baseline 
Characteristics
9
9
Prior and Concomitant 
Therapies/Procedures
9
Compliance and Exposure
9
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x Male (Reference) 
x Female 
x Race 
x Caucasian / White (Reference) 
x Asian 
x Black/ African American 
x Other 
x Pooled Geographical Region:  
x Asia 
x Non-Asia (Reference) 
x Country 
x Japan 
x ECOG PS at baseline 
x ECOG PS 0 (Reference) 
x ECOG PS 1 
x Site of primary tumor 
x Stomach  
x Gastro-esophageal Junction (GEJ) (Reference) 
x Type of prior anti-cancer treatment  
x Platinum-based regimen (reference)  
x Ramucirumab-based regimen  
x HER-2 directed regimen  
x Other regimens 
Detailed grouping of type of prior anti-cancer treatments will be determined before database lock 
after a comprehensive medical review on all such therapy in the database.  
11 
General Specifications for Statistical Analyses 
Unless otherwise stated all table summaries will be presented by treatment arm. All statistical 
analyses will be performed using SAS® Version 9.2 or higher. 
Data handling after cut-off date: 
Data after cut-off does not undergo the cleaning process.  


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Data obtained after a cut-off will not be displayed in any listings or used for summary statistics, 
statistical analyses or imputations.  
Pooling of centers: 
In order to provide overall estimates of treatment effects, data will be pooled across trial centers. 
The “center” factor will not be considered in statistical models or for subgroup analyses due to the 
high number of participating centers in contrast to the anticipated small number of subjects 
randomized at each center. 
Significance level: 
The overall significance level is 2.5% one-sided. The confirmatory statistical tests for the primary 
and key secondary efficacy endpoint analyses are described in Sections 16.1 and 16.2 along with 
procedures for controlling the overall type I error rate. The statistical tests performed on the 
primary and key secondary efficacy endpoints in comparing treatment arms will be one-sided with 
a significance level of 2.5%. The statistical tests to compare treatment arms on other secondary, 
exploratory, and safety analyses will be two-sided with a significance level of 5%.  
Presentation of continuous and qualitative variables: 
Continuous variables will be summarized using descriptive statistics i.e., number of non-missing 
values, mean, median, standard deviation (StDev), minimum, maximum, first quartile (Q1), and 
third quartile (Q3). For reporting conventions, mean, median, Q1, and Q2 will generally be 
displayed with one more decimal place than the raw data and StDev will be displayed to two more 
decimal places than the raw data. Percentages will be reported to one decimal place. The rounding 
will be performed to closest integer/first decimal using the common mid-point between the two 
consecutive values. E.g. 5.1 to 5.4 will be rounded to an integer of 5, and 5.5 to 5.9 will be rounded 
to an integer of 6. 
Qualitative variables will be summarized by counts and percentages based on the number of 
subjects in the analysis set of interest, unless otherwise specified. In general, percentages will be 
reported to 1 decimal place unless greater precision is deemed appropriate. 
In case the analysis refers only to certain visits, percentages will be based on the number of subjects 
still present in the study at that visit, unless otherwise specified. 
Definition of baseline: 
For the safety analysis, baseline is defined as the last measurement before the first dose of study 
treatment. Baseline for heart rate and QTc assessments will be derived from the visit where both 
heart rate and QT are not missing. 
For the efficacy analysis, baseline is defined as the last measurement prior to randomization. If 
such a value is missing, the last measurement prior to the first study drug administration will be 
used as the baseline measurement for the efficacy analysis except for analyses of tumor assessment 
data where the baseline assessment would be considered missing.   


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If an assessment is planned to be performed prior to the randomization/first dose of study treatment 
in the protocol and the assessment is performed on the same day as the randomization/first dose 
of study treatment, it will be assumed that it was performed prior to randomization/study treatment 
administration, if assessment time point is not collected or is missing. If assessment time points 
are collected, the observed time point will be used to determine pre- randomization/pre-dose on 
study day 1 for baseline calculation. Unscheduled assessments will be used in the determination 
of baseline. However, if time is missing, an unscheduled assessment on study day 1 will be 
considered to have been obtained after study treatment administration. 
Subjects who start treatment and discontinue from the study on the same day may have two 
different sets of data collected on study day 1 (one during study and one in the End of Treatment 
(EOT) visit. Data reported at the EOT visit are not eligible for baseline selection.  
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement.  
Definition of duration: 
Duration will be calculated by the difference of start and stop date + 1, if not otherwise specified. 
For example, survival time (days) = date of death – date of randomization + 1. 
The time since an event (e.g. time since first diagnosis) will be calculated as reference date minus 
date of event. 
Definition of study day/treatment day: 
Study day / Treatment day are defined relative to the date of randomization / start of treatment. 
Study day 1 corresponds to the day of randomization and Study day -1 corresponds to the day 
before randomization (i.e., no Study day 0 is defined). Treatment day will be defined similarly 
with Study day 1 corresponding to the date of first administration of study treatment. 
Definition of on-treatment period: 
For subjects who received avelumab or physician’s choice chemotherapy treatment, the on-
treatment period is defined as the time from the first dose of study treatment through minimum (30 
days + last dose of study treatment, start day of new anti-cancer drug therapy – 1 day).  
For subjects in the control arm who only received BSC, the on-treatment period is defined as the 
time from the date of randomization through minimum (30 days + end date of BSC treatment 
period, start day of new anti-cancer drug therapy – 1 day), while end date of BSC treatment period 
is defined as the date collected on the “End of Assessments Visit” eCRF page. 
The date of new anti-cancer drug therapy is derived as outlined in Section 14.2. 
Standard derivations and reporting conventions: 
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1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days. 
Demographics and physical measurements:  
x Age [years]:  
- (date of given informed consent - date of birth + 1) / 365.25  
- In case of missing day, day only:  
Age [years]: (year/month of given informed consent – year/month of birth)  
- In case only year of birth is given:  
Age [years]: (year of given informed consent - year of birth)  
The integer part of the calculated age will be used for reporting purposes.  
x BMI (kg/m2) = weight (kg)/[height (m)]2.  
x BSA (m²) = ([height (cm) × weight (kg)] / 3600)0.5  
Unscheduled visits: 
Data collected at unscheduled visits will be included and analyzed for both safety and efficacy 
analyses in the same fashion as the data collected at scheduled visits except where otherwise noted 
in the sections that follow. Descriptive statistics (mean, StDev, median, minimum, maximum and 
quartiles) by nominal visit or time point for safety endpoints such as laboratory measurements, 
ECGs and vital signs will include only data from scheduled visits.  
Summary statistics over time: 
For descriptive statistics over time by nominal visit or time point for QoL data and safety endpoints 
(laboratory, ECG and vital signs), only those scheduled visits/time points per-protocol that have 
at least 5 subjects in both treatment arms will be included in the summary tables and figures. The 
exception is Discontinuation and End-of-Treatment visit which will be included in the summary 
statistics despite the number of subjects who completed such visit. 
Missing data and imputation rules: 
Unless otherwise specified in this SAP, all data will be evaluated as reported and no imputation of 
missing values will be done. 
In all subject data listings imputed values will be presented. In all listings imputed information 
will be flagged. 
Missing statistics (i.e. when they cannot be calculated) will be presented as “nd” (i.e. not done).  
For example, if n=1, the measure of variability cannot be computed and will be presented as “nd”. 
Partial dates will be imputed as follows: 


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Disease history 
Incomplete dates for disease history (initial diagnosis date, date of documented, locally advanced, 
inoperable or metastatic disease diagnosis, date of response or progression in prior treatment) will 
be imputed as follows: 
x If the day is missing, it will be imputed to the 15th day of the month.  
x If both day and month are missing and the year is prior to the year of the first study treatment, 
the month and day will be imputed as July 1st. 
x If both day and month are missing and the year is same as the year of the first study treatment, 
the month and day will be imputed as January 1st.  
x If the date is completely missing, no imputation will be performed. 
Adverse events 
Incomplete AE-related dates will be imputed as follows: 
x If the AE onset date is missing completely, then the onset date will be replaced by the start of 
randomized treatment. 
x If only the day part of the AE onset date is missing, but the month and year are equal to the start 
of randomized treatment, then the AE onset date will be replaced by the start of randomized 
treatment. For example, if the AE onset date is --/JAN/2015, and randomized treatment start 
date is 15/JAN/2015, then the imputed AE onset date will be 15/JAN2015. 
x If both the day and month of the AE onset date are missing but the onset year is equal to the 
start of randomized treatment, then the onset date will be replaced by the start of randomized 
treatment. For example, if AE onset date is --/---/2014, and randomized treatment start date is 
19/NOV/2014, then the imputed AE onset date will be 19/NOV/2014. 
x In all other cases the missing onset day or missing onset month will be replaced by 1. 
x Incomplete stop date will be replaced by the last day of the month (if day is missing only), if 
not resulting in a date later than the date of subject's death. In the latter case the date of death 
will be used to impute the incomplete stop date.  
x In all other cases the incomplete stop date will not be imputed.  
Prior/concomitant medication 
Incomplete prior/concomitant medication dates will be imputed as follows: 
x If the medication date is missing completely, then the medication date will be replaced by 
the start of randomized treatment. 
x If the day of medication date is missing, but the month and year are equal to the start of 
randomized treatment, then the medication date will be replaced by the start of randomized 
treatment. For example, if the medication start date is --/JAN/2015, and randomized 
treatment start date is 15/JAN/2015, then the imputed medication start date will be 
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x If both the day and month of medication start date are missing but the start year is equal to 
the start of randomized treatment, then the medication date will be replaced by the start of 
randomized treatment. For example, if the medication start date is --/---/2014, and 
randomized treatment start date is 19/NOV/2014, then the imputed medication start date 
will be 19/NOV/2014. 
x In all other cases the missing medication day or missing medication month will be replaced 
by 1. 
x Incomplete stop date will be replaced by the last day of the month (if day is missing only), 
if not resulting in a date later than the date of subject's death. In the latter case the date of 
death will be used to impute the incomplete stop date. 
x In all other cases the incomplete medication stop date will not be imputed. 
Subsequent anti-cancer therapy 
Incomplete subsequent anti-cancer therapy start dates will be imputed as follows: 
x If only day is missing, it will be imputed as the last day of the month unless the end date 
of the subsequent anti-cancer therapy is before the last day of the month. In that case, the 
incomplete anti-cancer therapy start date will be imputed as the end date of the anti-cancer 
therapy.   
x If both day and month are missing, no imputation will be performed.  
Exposure 
 
x If the study medication start date is missing, it is assumed that the first dose of study 
medication is given at the randomization date. The randomization date will replace 
incomplete dates of the first dose of study medications.  
x In case the last date of study drug is incomplete the date of last administration of study 
drug will be taken from the treatment termination eCRF pages.  
Date of last dose of study drug if unknown or partially unknown will be imputed as follows: 
x If the last date of study drug is completely missing and there is no End of Treatment eCRF 
page and no death date the subject should be considered to be ongoing and use the last 
dosing date on or prior to the cut-off date for the analysis as the last dosing date  
x If the last date of study drug is completely or partially missing and there is either an End 
of Treatment eCRF page or a death date available (within the cut-off date) then imputed 
last dose date:  
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death    
date)  
= Last day of the month, if both Year and Month are available and Year = Year of    
min (EOT date, death date) and Month < the month of min (EOT date, death date)  
= min (EOT date, death date), for all other cases 


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Date of last contact 
The last contact date will be the latest complete date among the following: 
x All subject assessment dates (blood draws (laboratory, PK), vital signs, performance status, 
ECG, tumor assessments) 
x Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation 
x AE start and end dates 
x Date last known to be alive collected on the eCRF form “Subject Status / Survival Follow-
up” (only used if status is ‘alive’) 
x Study drug start and end dates 
x Randomization date 
x Date of discontinuation from the “Study Termination” eCRF page (do not use if reason for 
discontinuation is lost to follow-up) 
Death date 
Missing or partial death dates will be imputed based on the last contact date: 
x If the date is missing it will be imputed as day after date of last contact from the CRF 
survival page 
x If the day or month is missing, death will be imputed to the maximum of the full (non-
imputed) date of last contact (excluding the date of death) and the following: 
- Missing day: 
 
1st day of the month and year of death 
- Missing day and month: January 1st of the year of death 
If the day is missing from the date of last contact it will be imputed to 1st day of the month and 
year of last contact only if derived from the survival page. 
Tumor assessments 
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.  
If there are multiple scan dates associated with an evaluation, i.e., radiological assessments occur 
over a series of days rather the same day, the choice of date of assessment could impact the date 
of progression and/or date of response. If there are multiple scan dates associated with an 
evaluation, the earliest of the scan dates associated with the evaluation will be used as the date of 
assessment.  
If one or more investigation dates for an evaluation are incomplete but other investigation dates 
are available, the incomplete date(s) are not considered for calculation of the assessment date and 
assessment date is calculated as the earliest of all investigation dates (e.g. X-ray, CT-scan).  


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If all measurement dates for an evaluation have no day recorded, the 1st of the month is used.  
If the month is not completed, for any of the investigations for an evaluation, the respective 
assessment will be considered to be at the date which is exactly between the previous and the 
following assessment. If both a previous and following assessments are not available, this 
assessment will not be used for any calculations. 
12
Trial Subjects 
The subsections in this section include specifications for reporting subject disposition and 
treatment/study discontinuations. Additionally, procedures for reporting protocol deviations are 
provided. 
12.1
Disposition of Subjects and Discontinuations 
The following will be summarized overall and by treatment arm (as randomized) for all 
randomized subjects: 
x
Number of subjects screened (overall only) 
x
Number of subjects who failed screening overall and grouped by the main reason  
x
Number and percentage of subjects randomized in the following analysis sets 
•
FAS 
•
PP analysis set
•
Safety analysis set 
•
HRQoL analysis set
x
Number and percentage of subjects randomized but not treated by study treatment by 
reason 
-
Subject with only BSC after randomization 
-
Other reasons collected on “Study Termination” eCRF page
x
Number of randomized subjects still on treatment 
x
Number of randomized subjects off-treatment overall and by the main reason of 
discontinuation 
x
Number of randomized subjects who discontinued treatment but are still in follow-up
x
Number of subjects who discontinued the study and primary reasons for study 
discontinuation 
x
Number and percentage of subjects who re-initiated avelumab treatment  
C
C
I


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- Number of subjects discontinued the treatment after re-initiation 
Number and percentage of subjects who received new anti-cancer therapy after study treatment 
discontinuation. In addition, the following will be summarized: 
x Number and percentage of randomized subjects overall, by region (Europe, European 
Economic Area (EEA) (required by EudraCT), North America, Latin America, Western 
Europe, Eastern Europe, Asia, Australasia, Africa and Middle East, by country within region 
x Number and percentage of randomized subjects by center.  
x Cross tabulation: subjects randomized (avelumab + BSC or physician’s choice + BSC) 
versus subjects treated (avelumab + BSC or physician’s choice + BSC),  
- Reasons if randomized ≠ treated 
12.2 
Protocol Deviations 
Analysis sets: FAS 
All important protocol deviations (IPDs) that impact the safety of the subjects and/or the conduct 
of the study and/or its evaluation will be reported. These include: 
x Subjects that are dosed on the study despite not satisfying the inclusion criteria; 
x Subjects that develop withdrawal criteria while on the study but are not withdrawn; 
x Subjects that receive the wrong treatment or an incorrect dose; 
x Subjects that receive an excluded concomitant medication; 
x Deviation from GCP. 
IPDs will be determined for all subjects by either medical review processes or programming based 
on the inclusion/exclusion criteria or other criteria presented in the protocol.  
In addition, the IPDs that lead to the exclusion of a subject from the PP analysis set as specified in 
Section 10 are clinically important protocol deviations (CIPD), which are a subset of important 
protocol deviations will be reported. 
All IPDs will be documented in CDISC datasets whether identified through site monitoring, 
medical review or programming. Other protocol deviations will not be included in the CDISC 
datasets but will be maintained in separate clinical trial master file. The complete list of IPDs and 
CIPDs are maintained by the medical team and will be finalized prior to database lock. IPDs to be 
identified by both medical review process and programming as well as all CIPDs are specified in 
Appendix I.   
All IPDs and CIPDs identified by medical review process and/or programming will be presented 
in the summary tables by treatment arm and in data listings.   


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13 
Demographics and Other Baseline Characteristics 
13.1 
Demographics 
Analysis sets: FAS, Safety Analysis Set 
Demographic characteristics will be summarized by treatment arm and overall using the following 
information from the Screening/Baseline Visit CRF pages. 
x Demographic characteristics  
- Gender: Male, Female  
- Race: White, Black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or other Pacific Islander, Other, Unknown 
- Ethnic origin: Hispanic/Latino (Yes/No), Japanese (Yes/No) 
- Age (years): summary statistics  
- Age categories :  
 < 65 years, 
 ≥ 65 years  
x 65-<75  
x 75-<85 
x ≥ 85 
- Pooled Geographical Region:  
 North America 
 Europe 
 Asia 
 Rest of the World (Australia and/or Latin America will be included as 
additional pooled geographical regions if including > 10% of the overall 
randomized population) 
- Geographic Region: 
 North America  
 Latin America  
 Western Europe  
 Eastern Europe 
 Australasia 
 Asia  
 Africa 
 Middle East 
- EEA: Yes or No 
- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS): 0 or 1 
- Physical measurements 
 Height (cm) 
 Weight (kg) 


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 Body Mass Index (BMI) (kg/m2) 
- Body Surface Area (BSA) (m²) 
Site codes will be used for the determination of the subject’s geographic region. 
 
The listing of demographics and baseline characteristics will include the following information: 
subject identifier, treatment group, age, sex, race, ethnicity, height (cm), weight (kg), BMI (kg/m2), 
BSA (m²), and ECOG performance status. 
13.2 
Medical History 
Analysis sets: FAS, Safety Analysis Set 
Medical history reported at the time of the Screening/Baseline procedures will be coded using the 
most current available version of Medical Dictionary for Regulatory Activities (MedDRA) and 
will be summarized from the “Medical History” eCRF page. Medical history will be summarized 
as the numbers and percentages of subjects by MedDRA preferred term (PT) as event category 
and MedDRA primary system organ class (SOC) as summary category. Each subject will be 
counted only once within each PT or SOC. 
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and PT 
in alphabetical order by treatment arm based on the safety analysis set and FAS. 
13.3 
Other Baseline Characteristics 
Analysis sets: FAS, Safety Analysis Set 
13.3.1 
Disease Characteristics 
Information on disease characteristics collected on the “Disease History” eCRF page will be 
summarized by treatment arm and overall. Summary statistics will be presented for the following: 
x Primary site of tumor 
x Sub-site of tumor 
x Histopathologic / cytologic type of tumor 
x Time since first occurrence of metastatic disease (months), defined as (date of randomization 
- date of first occurrence of metastatic disease)/30.4375 
x Time since documented, locally advanced or inoperable disease diagnosis (months), defined 
as (date of randomization – date of documented locally advanced, inoperable or metastatic 
disease)/30.4375 
x TNM classification at initial diagnosis 
x TNM classification at study entry 


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Baseline characteristics with respect to ECOG PS, vital signs, physical examinations, ECGs, and 
hematology/biochemistry will be part of Section 17 (Safety Evaluation). 
13.3.2 
Prior Anti-Cancer Therapies 
The prior anti-cancer therapies are collected under the “Prior Anti-Cancer Drug Therapies 
Details”, “Prior Anti-Cancer Radiotherapy Details” and “Prior Anti-Cancer Surgeries Details” 
eCRF pages. 
The number of subjects in each of the following anti-cancer therapy (i.e., anti-cancer medications 
other than study treatment taken at any time pre-treatment) categories will be tabulated by 
treatment arm and overall based on the safety analysis set and FAS: 
x Subjects with at least one type of prior anti-cancer treatment 
x Subjects with at least one prior anti-cancer drug therapy 
x Subjects with at least one prior anti-cancer radiotherapy 
x Subjects with at least one prior anti-cancer surgery 
Prior anti-cancer drug therapy will be summarized as follows by treatment arm and overall: 
x Number of subjects with at least one prior anti-cancer drug therapy 
x Number of any prior anti-cancer therapy regimens: missing / 1 / 2 / 3 / ≥4 
x Number of prior anti-cancer therapy regimens for metastatic or locally advanced disease: 
missing / 1 / 2 / 3 / ≥4 
x Type of prior anti-cancer therapy: Cytotoxic therapy / Endocrine therapy / Monoclonal 
antibody therapy / Small molecules / Immunotherapy / Other 
x Intent of Therapy: Neo-Adjuvant / Adjuvant / Metastatic or Locally advanced 
x Type of prior anti-cancer treatment: Platinum-based regimen / Ramucirumab-based 
regimen / HER-2 directed regimen / Other regimens. Detailed grouping of type of prior 
anti-cancer regimens will be determined before database lock after a comprehensive 
medical review on all such therapy in the database.  
x Best response: Complete Response (CR) / Partial Response (PR) / Stable Disease (SD) / 
Progressive Disease (PD) / Not assessable / Unknown / Not applicable. Best response will 
be summarized by each regimen.  
The prior anti-cancer drugs will also be summarized based on the number and percentage of 
subjects by the drug class level and preferred term. Within each regimen, a subject will be counted 
only once within a given drug class and within a given preferred term, even if he/she received the 
same medication at different times in the same regimen. The summary will be sorted on decreasing 
frequency of drug class and preferred term in the given drug class. In case of equal frequency 
regarding drug class (respectively drug name), alphabetical order will be used. 


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The following listings of prior anti-cancer treatments and procedures will also be provided. These 
listings will include the subject identification number and all relevant collected data on the 
corresponding eCRF pages. 
x Listing of prior anti-cancer drug therapies  
x Listing of prior anti-cancer radiotherapy  
x Listing of prior anti-cancer surgeries 
13.3.3 
PD-L1 Expression Status at Baseline 
Three scoring methods to evaluate PD-L1 expression status will be used as follows: 
x Conventional tumor cell (TC) (cell number-based percentage) scoring method 
x Non-tumor cell elements area-based scoring method 
x Whole tumor area-based scoring method 
Additional details of these scoring algorithms are specified in the Pathology Report Form (PRF). 
PD-L1 expression status (positive vs. negative) at baseline with different cutoff values will be 
summarized in total, by treatment arm, by scoring methods, as well as by treatment arm within 
region (Asia vs. non-Asia). PD-L1 assay status of total % of PD-L1 positive tumor cells will be 
summarized as below: 
x < 1% 
x ≥ 1% to < 5% (cut-off is 1%) 
x ≥ 5% to < 25%, (cut-off is 5%) 
x ≥ 25% (cut-off is 25%) 
14 
Previous or Concomitant Medications/Procedures 
Analysis sets: FAS 
14.1 
Prior and Concomitant Medications/Procedures 
Concomitant medications are medications, other than study medications, which started prior to 
first dose date of study treatment and continued during the on-treatment period as well as those 
that started during the on-treatment period. Prior medications are medications, other than study 
medications and pre-medications for study treatment, which are started before first dose date of 
study treatment.  
Prior and concomitant medications will be summarized from the “Concomitant Medications 
Details” eCRF page. Premedications for study drug will also be summarized separately. 
In cases where date values do not allow unequivocal allocation of a medication to concomitant (as 
opposed to previous) medication, the medication will be considered as concomitant medication. 


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Summaries of prior and concomitant medications will include the number and percentage of 
subjects by Anatomical Therapeutic Chemical (ATC) classification level 2 and preferred term 
within treatment arm and overall. A subject will be counted only once within a given ATC class 
and within a given preferred term, even if he/she received the same medication at different times. 
If any prior or concomitant medication is classified into multiple ATC classes, the medication will 
be summarized separately under each of these ATC classes. The summary tables will be sorted on 
decreasing frequency of drug class and decreasing frequency of drug name in a given drug class. 
In case of equal frequency regarding drug class (respectively drug name), alphabetical order will 
be used. In case any specific medication does not have ATC classification level 2 coded term, it 
will be summarized under the “Unavailable ATC classification” category.  
A listing of concomitant medications will be created with the relevant information collected on the 
“Concomitant Medications Details” eCRF page. 
All concurrent procedures, which were undertaken any time during the on-treatment period, will 
be summarized by treatment arm and overall. Number of subjects with concurrent procedures will 
be tabulated overall and by reason for procedure as collected in the eCRF page “Concomitant 
Procedures Details”. 
All concurrent procedures recorded on the eCRF page “Concomitant Procedures Details” will also 
be presented in the listing. 
Premedications for study drug will also be presented in the listing. 
14.2 
Subsequent Anti-Cancer Therapies/Procedures 
Anti-cancer treatment after discontinuation will be provided in a data listing with data retrieved 
from 
“Anti-Cancer 
Treatment 
after 
Discontinuation 
Details”, 
“Radiotherapy 
after 
Discontinuation”, and “Surgery after Discontinuation” eCRF pages. The earliest date of start of 
new anti-cancer drug therapy will be used for the definition of the on-treatment period and the 
earliest date of start of any new anti-cancer therapy will be used for censoring for efficacy analyses. 
Number and percentage of subjects with any anti-cancer treatment after discontinuation will be 
tabulated overall and by type of therapy within treatment arm based on data collected from the 
“Anti-Cancer Treatment after Discontinuation Details” eCRF page.  
Summary statistics will be created for best response across all post study treatments based on the 
data collected from “Anti-Cancer Treatment after Discontinuation Details” eCRF page. For 
subjects who received more than one anti-cancer drug therapy after treatment discontinuation, the 
best overall response among all anti-cancer drug therapies will be summarized. 
Summary of subsequent anti-cancer treatment will include the number and percentage of subjects 
by ATC Classification level 2 and preferred term. The same approach as prior and concomitant 
medications will be applied in presenting the summary table of subsequent anti-cancer treatment. 


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15 
Treatment Compliance and Exposure 
Analysis sets: Safety Analysis Set 
All dosing calculations and summaries will be based on the administration of study medications 
from the corresponding eCRF pages. 
x Subjects randomized to the avelumab + BSC arm will receive an IV infusion of avelumab at 
a dose of 10 mg/kg (over the duration of 1 hour) once every 2 weeks (one cycle).  
x Subjects randomized to the physician’s choice arm (paclitaxel + BSC or irinotecan + BSC) 
will receive an IV infusion of one of the following therapies: 
o Paclitaxel – Days 1, 8, and 15 of a 4-week treatment cycle 
o Irinotecan – Days 1 and 15 of a 4-week treatment cycle 
Analysis of exposure is based on the calculated actual dose level. The last available weight of the 
subject on or prior to the day of dosing will be used. Height at Screening visit will be used in 
deriving BSA.  
x Avelumab:  total dose administered/weight [mg/kg]  
x Physician’s choice (paclitaxel + BSC or irinotecan + BSC treatment: total dose 
administered/BSA [mg/m2]  
Any BSC therapy will not be included in the compliance and exposure calculation.  
Duration  
The duration of avelumab treatment (in weeks) during the study is defined as:  
Treatment duration (weeks) = (date of last dose – date of first dose + 14)/7  
 
The duration of paclitaxel and irinotecan treatment (in weeks) during the study is defined as:  
Treatment duration (weeks) = {date of last dose – date of first dose + [28 – (date of last 
dose of last cycle – date of first dose of last cycle)]} /7  
 
Cumulative Dose 
The overall cumulative dose (mg/kg) of avelumab per subject across all cycles is the sum of the 
actual dose levels that the subject received (i.e. total dose administered (mg) / weight (kg)). 
The overall cumulative dose (mg/m2) of paclitaxel and irinotecan per subject across all cycles is 
the sum of the actual dose levels that the subject received (i.e. total dose administered (mg) / BSA 
(m2)). 
Dose Intensity 


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The dose intensity will be calculated for each subject across all cycles. The dose intensity of 
avelumab (mg/kg/cycle) is defined as: 
  ൌ൬
   
ሺ   ሺ ሻሻȀʹ൰ 
The dose intensity of irinotecan (mg/m2/cycle), and paclitaxel (mg/m2/cycle) is defined as 
  ൌ൬     
ሺ   ሺ ሻሻȀͶ
൰ 
Relative Dose Intensity 
The relative dose intensity is defined as the actual dose intensity divided by the planned dose as 
specified in the protocol per cycle. 
Summaries of treatment exposure and compliance will include the following information: 
x Duration of therapy (weeks) 
x Total number of infusions received  
x Cumulative dose of therapy (mg/kg or mg/m2) 
x Dose intensity (mg/kg/cycle) or (mg/m2/cycle) 
x Relative dose intensity of therapy categories: 80%-<90%, 90%-<110%, >=110% 
A listing of treatment exposure and compliance will also be created to summarize the information 
listed above for each subject. 
Dose Reduction  
A dose reduction is defined as an actual non-zero dose < 90% of the planned dose. The number of 
subjects with at least one dose reduction as well as a categorical breakdown of dose reductions (1 
/ 2 / 3 / >=4) will be summarized for the physician’s choice (paclitaxel or irinotecan) + BSC arm. 
There are no dose reductions allowed for the avelumab treatment arm in the protocol. 
Dose Delays 
The number of subjects with delayed infusions will be summarized. Delays are defined as infusions 
given ≥3 days from the planned administration date and will be derived based on study drug 
administration date and will be grouped into the following categories based on the deviation of the 
actual to the planned treatment administration day (relative to the previous treatment 
administration date 
x No delay (including 1-2 days delays) 
x 3-6 days delay 
x 7 or more days delay 


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For example, if a subject receives avelumab on Day 1, then the next avelumab administration date 
should be on Day 15; however, if the subject receives avelumab on Day 16 or 17, this is not 
considered a delay. In the event that a subject has more than one delay, the maximum delay will 
be used.  
Number and percentage of subjects with delayed study drug administration and maximum length 
of delay, i.e. the worst case of delay if subjects have multiple dose delays will be summarized by 
treatment group. 
Infusion Rate Reductions 
Infusion rate reductions will be calculated for avelumab + BSC arm only. It will be derived based 
on the infusion rate recorded by visit on the eCRF. Number of subjects with at least one infusion 
rate reduction as well as a breakdown of the number of infusion rate reductions (1 / 2 / ≥3) will be 
summarized. 
A listing of study drug administration will be created with the information collected on the 
applicable treatment administration details eCRF pages. 
Subjects with dose reductions, dose delays or infusion rate reductions and the corresponding 
reasons will be summarized in the listing. 
16
Endpoint Evaluation 
The primary endpoint of the study is Overall Survival (OS). The key secondary efficacy endpoints 
include Progression-free Survival (PFS) and Best Overall Response (BOR) according to RECIST 
1.1 criteria and as adjudicated by the IRC.  
The type I error rate for the primary endpoint (OS) and two key secondary endpoints of PFS and 
BOR will be controlled at 2.5% (one-sided) significance level using a gatekeeping procedure. The 
primary hypothesis (overall survival) will serve as a gate keeper and be tested at an overall one-
sided type I error of 2.5%. Only if the primary endpoint is statistically significant, the two key 
secondary endpoints of PFS and BOR will be tested, and the Hochberg step-up procedure will be 
used to control the type I error rate at 2.5% (one-sided) for PFS and BOR.
No formal adjustment for multiplicity will be undertaken for sensitivity or subgroup analyses 
involving the primary endpoint, analyses of non-key secondary endpoints, or analyses involving 
exploratory endpoints. 
16.1
Primary Endpoint Analyses 
16.1.1
Primary Efficacy Analysis of Overall Survival 
Analysis sets: FAS, PP Analysis Set, CCI


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The primary efficacy analysis of Overall Survival (OS) will be performed on the FAS. All data 
required for the calculation of time to event will be taken from the eCRF. 
OS is defined as the time from randomization to the date of death, regardless of the actual cause 
of the subject’s death. For subjects who are still alive at the time of data analysis or who are lost 
to follow up, OS time will be censored at the last recorded date that the subject is known to be 
alive as specified in Section 11 as of the data cut-off date for the analysis.  
OS (in months) = (Date of death – Date of randomization +1) / 30.4375 
The primary efficacy analysis will compare the OS time between the treatment arms, and will be 
performed using a one-sided stratified log-rank test at the alpha level of 0.025.  The stratification 
factor is region (Asia vs. non-Asia).  
The following null hypothesis will be tested: 
H0: OA(t) = TOB(t), T ≥ 1, versus H1: OA(t)=TOB(t), T < 1, 
where O(t) represents the hazard at time t and T the unknown constant of proportionality of hazards 
in treatment groups A (avelumab + BSC) and B (physician’s choice + BSC).  
The treatment effect will be estimated using a Cox’s Proportional Hazard model stratified by the 
randomization strata to calculate the hazard ratio. Each stratum will define a separate baseline 
hazard function (using the 'STRATA' statement in SAS PROC PHREG), i.e., for the i-th stratum 
the hazard function is expressed as: h(i;t) = h(i,0;t) exp(xE), where h(i,0;t) defines the baseline 
hazard function for the i-th stratum and x defines the treatment arm (0=physician’s choice + BSC, 
1= avelumab + BSC) and E is the unknown regression parameter.  
Ties will be handled by replacing the proportional hazards model by the discrete logistic model 
(i.e., ties=discrete option in SAS PHREG procedure). 
Kaplan-Meier (i.e. product-limit) estimates of median OS time will be presented by treatment arm 
together with two-sided 95% confidence intervals (CIs) calculated according to Brookmeyer and 
Crowley (1). Finally, the number of subjects at risk vs. failed along with Kaplan-Meier estimates 
of survival probability at 3, 6, 9 and 12 months will be estimated with corresponding two-sided 
95% CIs derived using the log-log transformation according to Kalbfleisch and Prentice (2) (i.e., 
conftype=loglog default option in SAS LIFETEST procedure). The estimate of the standard error 
will be computed using Greenwood’s formula.   
Frequency (number and percentage) of subjects with an event (death) and censoring reasons will 
be presented by treatment arm. Censoring reasons are as follows: 
x Alive 
x Withdrawal of consent 
x Lost to follow-up  
Lost to follow-up will include the following subjects: 


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x Lost to follow-up status is collected on the eCRF page prior to the analysis cut-off; 
x Subjects with the last contact date > 13 weeks prior to the analysis cut-off date (duration 
of 13 weeks is based on the assessment schedule of every 12 week for survival follow-up 
interval + 1 week window). 
The OS time or censoring time and the reasons for censoring will also be presented in a subject 
listing. 
16.1.2 
Sensitivity Analyses of Primary Endpoint 
Analysis sets: FAS 
The following sensitivity analyses will be performed to assess the robustness of the primary 
analysis results. These analyses are regarded as purely exploratory.  
x The primary analyses described above will be repeated based on the PP analysis set if the 
PP analysis set includes less than 90% of subjects in the FAS. 
x An unstratified analysis will be performed to compare the OS time between the treatment 
arms. 
x If the actual number of events is 10% more than the planned number at the primary 
analysis, i.e. if there are > 282 events based on the prospectively determined cut-off date 
at the primary analysis, the primary analysis will be repeated by using the first cut-off date 
at which exactly 256 events that were observed in the study for the primary analysis. 
x The primary analysis will be repeated by censoring those subjects in FAS who received 
subsequent anti-cancer therapy after discontinuing the study treatment with the date of the 
first dose of subsequent anti-cancer therapy minus 1 day. The final list of subsequent anti-
cancer therapy will be provided upon medical review of all subsequent anti-cancer 
therapies. 
Methods for Evaluating the Validity of Model Assumptions 
In order to assess the usefulness of the treatment difference estimate from the Cox proportional 
hazards model, the validity of the proportional hazards assumption will be assessed visually by 
plotting log(-log(survival)) versus log(time) by treatment. 
Schoenfeld residuals including a LOESS curve will be plotted to graphically investigate violations 
of the proportional hazards assumption. Schoenfeld residuals will be computed in SAS using the 
PHREG procedure via the OUTPUT statement (keyword=RESSCH). With proportional hazards 
the LOESS curve should be parallel to the x-axis. 
If these show large departures from proportional hazards then OS will also be analyzed based on 
restricted mean survival time (RMST) differences (Zhang, 2013) (6).   
Restricted Mean Survival Time (RMST) 


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The RMST methodology is applicable independently of the proportional hazards (PH) assumption 
and can be used, at a minimum, as a sensitivity analysis to explore the robustness of the primary 
analysis results.  In particular, as it pertains to the cut-off point (τ) to evaluate the RMST, it is 
noted that the cut-off point should not exceed the minimum of the largest observed time for both 
treatment arms so that the RMST of both treatment arms being evaluated can be adequately 
estimated and comparison between treatments is feasible; τ should be clinically meaningful and 
closer to the end of the study follow-up so that the majority of survival outcomes will be covered 
by the time interval.  The RMST up to time τ can then be interpreted as the expected survival time 
restricted to the common follow-up time τ among all patients.  The selection of τ should ensure 
that the RMST evaluation will not go beyond the maximum time point where the evaluation can 
be performed while also taking into account a large period of time that is expected to provide a 
meaningful assessment of treatment effect.   To avoid arbitrary selection of the common cut-off τ 
for both treatment arms, the following analyses will be performed: 
x τ1 = minimum of (largest observed survival time for avelumab + BSC arm, largest observed 
survival time for physician’s choice + BSC arm).   
x τ2 = minimum of (largest survival event time for avelumab + BSC arm, largest survival event 
time for physician’s choice + BSC arm). 
In this section, ‘survival’ is meant to denote OS. 
The treatment effect between the two treatment arms will be assessed based on the difference in 
RMST. The associated 95% CI for the difference in means and 1-sided p-value will be generated.  
RMST as a function of τ and the associated treatment effect between the two treatment arms will 
be plotted against time τ 
Exploratory Analyses to Investigate the Impact of Potential Prognostic Factors 
Multivariable Cox regression analysis will be carried out to assess and adjust the treatment effect 
for relevant baseline factors of potential prognostic impact.   
To include baseline variables into Cox's proportional hazards model, the subgroup levels defined 
in Section 10 “Subgroup Analysis Sets” are to be used. For variables with more than two 
categories, an indicator variable will be defined for each category except for the first category, 
which defines the reference always. The final parameterization will be updated and fixed at the 
Data Review Meeting at the latest and documented in an amendment to this SAP if different from 
the following definition.  
A stepwise selection procedure will serve to identify explanatory variables of potential prognostic 
values additional to the randomization strata which will be included in all models during the 
selection procedure. The Cox's Proportional Hazard model is defined as: h(t) = h(0;t) exp(Xb), 
where h(0;t) defines the baseline hazard function and X defines the vector of explanatory variables 
and b the unknown vector of regression parameters. Variables are entered into and removed from 
the model in such a way that each forward selection step can be followed by one or more backward 
elimination steps. The stepwise selection process terminates if no further variable can be added to 
the model or if the variable just entered into the model is the only variable removed in the 


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subsequent backward elimination. The level of significance for an explanatory variable to enter 
the model is set to 0.15 (p-value of Score test) and the significance level for removing it is set to 
0.40 (p-value of Wald test). This analysis will be performed using the stepwise selection method 
in SAS (Proc PHREG). Once this procedure stops, the factor 'treatment group' will be added to the 
last selected model in order to evaluate the effect of treatment on OS time when adjusted for the 
selected explanatory variables. The hazard ratios of all selected explanatory variables and of 
treatment effects will be reported including 2-sided 95% confidence intervals. No interactions will 
be considered. Post-baseline factors will not be considered for the model. 
16.1.3 
Subgroup Analysis of Primary Endpoint 
Analysis sets: FAS 
Subgroup analyses will be performed on the primary endpoint using all subgroup levels defined in 
Section 10 “Subgroup Analysis Sets”. All subgroup analyses are exploratory and will be performed 
as unstratified. No adjustment for multiplicity will be performed. In the case of a low number of 
subjects within a category (< 5% of the randomized population), the categories may be pooled.  
The OS time between the two treatment arms will be compared using a two-sided unstratified log 
rank test per subgroup level; the unstratified HR and its corresponding 95% CI will be computed 
per subgroup level. 
 
To assess the heterogeneity of treatment effects across the subgroup levels, the Cox regression 
model will be fitted with the OS time as the dependent variable; subgroup, treatment, and with and 
without the treatment-by-subgroup interaction as explanatory variables.  
 
x Model 1: treatment + subgroup  
x Model 2: treatment + subgroup + treatment * subgroup-variable  
 
A p-value for the interaction test (Likelihood Ratio test) will be provided together with the HR and 
corresponding 95% CI of the interaction model parameter.  
The HR and its corresponding 95% CI of all subgroups will also be presented in a forest plot. 
16.1.4 
Time of Follow-up for OS 
Analysis sets: FAS 
A Kaplan-Meier plot for OS follow-up duration will also be generated to assess the follow-up time 
in the treatment arms reversing the OS censoring and event indicators.  
Kaplan-Meier estimates will be presented by treatment group together with the median time of 
follow-up for OS. In particular, the follow-up rate at 3, 6, 9 and 12 months will be estimated with 
corresponding two-sided 95% CIs. 


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Table 2 
Censoring Rules for Duration of Overall Survival Follow-up
Date of event / censoring
Censoring
Subjects alive or lost to follow-up
Time from randomization to last date known to be alive
No
Subjects who died
Time from randomization to date of death
Yes
16.2
Secondary Endpoint Analyses 
Based on the gatekeeping testing strategy described at the beginning of Section 16, if the one-sided 
p-value from the stratified log-rank test of the primary endpoint OS is less than 0.025, the key 
secondary endpoints (i.e., PFS and BOR) will be tested per the Hochberg step-up procedure used 
to control the type I error rate at 2.5% (one-sided). Per this procedure according to Westfall, et al. 
(3), the one-sided p-value from the stratified log-rank test of PFS and the Cochran-Mantel-
Haenszel test (CMH) of ORR will be calculated. If the least significant p-value (the larger p-value 
is less than 0.025 then both null hypotheses corresponding to the key secondary endpoints of PFS
and BOR will be rejected. Otherwise, if the least significant p-value (the larger p-value) of the two 
secondary endpoints is greater than 0.025, then the null hypothesis of this secondary endpoint will 
not be rejected at the one-sided alpha level of 0.025, and the other secondary endpoint will be 
tested at the one-sided p-value of 0.0125.  
A separate Imaging Data Management Plan and Data Transfer Plan will be created to summarize 
the details of the data structure and data delivery schedule of IRC assessment results. 
16.2.1
Progression-Free Survival (PFS) 
Analysis sets: FAS, PP Analysis Set,
PFS is defined as the time from date of randomization until date of the first documentation of PD 
or death by any cause (whichever occurs first). The tumor response will be determined according 
to RECIST 1.1 and adjudicated by an IRC. Details on determination of the first disease progression 
date are specified in the IRC charter. 
PFS time (in months) = (Date of PD or death - Date of randomization + 1)/ 30.4375  
PFS data will be censored on the date of the last adequate tumor assessment for subjects who do 
not have an event (PD or death), for subjects who start new anti-cancer treatment prior to an event, 
or for subjects with an event after two or more consecutive missing tumor assessments. Subjects 
who do not have a baseline tumor assessment or who do not have any post-baseline tumor 
assessments will be censored on the date of randomization unless death occurred on or before the 
time of the second planned tumor assessment in which case the death will be considered an event. 
If a tumor assessment was performed on the same day as start of new anti-cancer therapy, it will 
be assumed that the tumor assessment was performed prior to the start of the new anti-cancer 
therapy, therefore the tumor assessment will be included in the derivation of the PFS time.
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Last adequate tumor assessment is defined as the last tumor assessment result that is not “NE” or 
“NA”. 
The censoring and event date options to be considered for the PFS and Duration of Response (DR) 
analysis are presented in Table 3. 
Table 3 
Outcome and Event Dates for PFS and DR Analyses 
Scenario 
Date of event / censoring 
Outcome 
No baseline assessment 
Date of randomization 
Censored a 
PD or death  
- After at most one missing or inadequate 
post-baseline tumor assessment, OR 
≤ 12 weeks after date of randomization 
Date of progression or death 
Event 
PD or death after 2 or more missing or 
inadequate post-baseline tumor 
assessments 
 Date of last adequate tumor assessmentb 
documenting no PD before new anti-
cancer therapy is given or missed tumor 
assessments 
Censored 
No progression and no death 
 Date of last adequate tumor assessmentb 
documenting no PD before new anti-
cancer therapy is given or missed tumor 
assessments 
 
Censored 
Treatment discontinuation due to 
“Disease progression” without  
documented progression 
Not applicable 
Information collected on 
treatment discontinuation 
page is ignored since 
outcome should be derived 
based on documented 
progression only. General 
censoring rule is applied. 
New anti-cancer therapy given 
Date of last adequate tumor assessment 
before anti-cancer therapy is given 
Censored 
a However if the subject dies ≤ 12 weeks after treatment start date the death is an event with date on death date.     
b If there are no adequate post-baseline assessments prior to the PD or death, then the time without adequate   
      assessment should be measured from the date of randomization; if the criteria were met the censoring will be on   
      the date of randomization.  
 
The analysis of PFS will be analogous to that for OS time as described in section 16.1.1.  
Frequency (number and percentage) of subjects with each event type (PD or death) and censoring 
reasons will be presented by treatment arm. Censoring reasons are as follows: 
x Ongoing in the study without an event 
x No baseline assessment 
x No adequate post-baseline assessment 
x Start of new anti-cancer therapy prior to PD 


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x
Event after 2 or more missing or inadequate post-baseline assessments 
x
Withdrawal of consent 
x
Lost to follow-up
Lost to follow-up will include the following subjects: 
x
Lost to follow-up status is collected on the eCRF page prior to the analysis cut-off; 
x
Subjects with the last contact date > 13 weeks prior to the analysis cut-off date (duration 
of 13 weeks is based on the assessment schedule of every 12 week for survival follow-up
interval + 1 week window). 
The PFS time or censoring time and the reasons for censoring will also be presented in a subject 
listing. 
Sensitivity Analysis 
The following sensitivity analyses of PFS will also be performed.  
1. The primary analyses will be repeated on the PP analysis set if the PP analysis set includes 
less than 90% of subjects in the FAS;
2. An unstratified analysis will be performed to compare PFS time between the treatment 
arms; 
3. PFS based on IRC assessment and counting all PD and deaths as events without 
considering the censoring rule for PD or death as described in Table 3; 
4. PFS based on IRC assessment and initiation of subsequent anticancer therapies will not be 
used as a censoring reason for PFS. 
5. PFS based on investigator assessment will be analyzed using the same censoring rules 
described in Table 3. For this sensitivity analysis, the date of tumor assessment will be 
derived from the eCRF. The earliest tumor assessment date corresponding to the respective 
visit that is collected on this page will be used for date of disease progression; 
6. A summary of concordance of disease progression status between IRC and investigator 
assessment will be provided including status of “No Event”, “Progressive disease” and 
“Death as event”.
16.2.2
Best Overall Response (BOR) 
Analysis sets: FAS, PP Analysis Set,
The confirmed BOR is defined as the best confirmed response obtained among all tumor 
assessment visits after the date of randomization until documented disease progression, taking 
requirements for confirmation into account as detailed below. The tumor response at each 
assessment visit will be determined according to RECIST 1.1 and as adjudicated by an IRC. Details 
of determination of tumor response date are provided in the Imaging Review Charter. 
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Only tumor assessments performed before the start of any further anti-cancer treatment will be 
considered in the assessment of BOR. Clinical deterioration will not be considered as documented 
disease progression. If a tumor assessment was performed on the same day as start of new anti-
cancer therapy, it will be assumed that the tumor assessment was performed prior to the start of 
the new anti-cancer therapy, therefore the tumor assessment will be included in the assessment of 
BOR. 
The following requirements must be met for confirmation of response: 
x PR or CR needs to be confirmed at a subsequent tumor assessment, preferably at the 
regularly scheduled 6-week assessment interval (after 12 months of treatment, 12-week 
assessment interval will be used), but no sooner than 5 weeks after the initial 
documentation of CR or PR. 
x PR or CR can be confirmed at an assessment later than the next assessment after the initial 
documentation of PR or CR, respectively.  
x The minimum duration for a BOR of stable disease (SD) is defined as at least 6 weeks after 
randomization.  
x PD = progression ≤ 12 weeks after date of randomization (and not qualifying for CR, PR 
or SD), i.e. tumor assessment of PD that is >12 weeks after date of randomization and there 
is no tumor assessment in between will have a BOR of NE. 
Table 4 summarizes the derivation rules described by Eisenhauer, et al. for the BOR when 
confirmation from subsequent assessment is needed (4). For subjects who have non-target lesions 
only at baseline, the time-point tumor assessment of “Non-CR/non-PD” will be evaluated with the 
same criteria as SD (minimum criteria for SD duration) in deriving the overall BOR.  
Table 4 
Best Overall Response When Confirmation of CR/PR Is Required 
Overall response 
1st time point 
Overall response  
subsequent time 
point  
Best overall response (BOR) 
CR 
CR 
CR  
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD duration met; otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met; otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR  
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, otherwise NE 
NE 
NE 
NE 


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Overall response 
1st time point 
Overall response  
subsequent time 
point  
Best overall response (BOR) 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease,  
NE = in-evaluable. 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed when 
subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the first time 
point. Under these circumstances, the original CR should be changed to PR and the best response is PR.   
The confirmed objective response rate (ORR) is defined as the proportion of subjects having 
reached a confirmed BOR of CR or PR according to RECIST v1.1 and as adjudicated by the IRC. 
Subjects with BOR of non-CR/non- PD are not considered as having achieved objective response. 
Therefore, these subjects will only be counted in the denominator of the rate, but not in the 
numerator. 
The confirmed ORR by treatment group will be calculated along with the two-sided 95% CI using 
the Clopper-Pearson method (exact CI for a binomial proportion as computed by default by the 
FREQ procedure using the EXACT option).  
The association of treatment effect and objective response (OR) will be tested by the General 
Association Statistic of the Cochran-Mantel-Haenszel test (CMH) according to Cochran (5) with 
the stratification factor of region (Asia vs. non-Asia). The null hypothesis of no association in any 
of the strata is tested against the alternative, which specifies that there is an association between 
treatment effect and ORR in at least one stratum. The one-sided CMH test will be performed with 
the alpha level of 0.025.  
In case the assumptions of the CMH test are violated due to a small number of subjects in some 
strata (i.e., number of subjects ≤ 10 in at least one of the stratum), a Fisher’s exact test will be used. 
The stratified (i.e. adjusted) odds ratio in terms of ORR will also be estimated with a Mantel-
Haenszel estimator along with its 95% CI to compare the treatment effect. The odds ratio is defined 
as the odds of OR with avelumab + BSC divided by the odds of OR with physician’s choice + 
BSC. The Breslow-Day test will be used to test the null hypothesis that odds ratios in all regions 
are equal against the alternative hypothesis that the odds ratio in at least one region is different. 
In case the null hypothesis of homogeneity of odds ratios across regions is not rejected at the two-
sided alpha level of 5%, the common odds ratio will be determined as the Mantel-Haenszel 
estimate (by the SAS FREQ procedure using the CMH option); if the null hypothesis of 
homogeneity of odds ratios across all regions is rejected, the odds ratio per region will be 
calculated with the corresponding exact CI. 
In addition, the frequency (number and percentage) of subjects with BOR of CR, PR, SD, PD, 
non-CR/non-PD (applicable only to subjects with non-measurable disease at baseline), and NE 
will be tabulated. Subjects with BOR of NE will be summarized by reason for having NE status. 
The following reasons will be used:  


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x No baseline assessment (independent review committee identifies neither any target  nor 
any non-target lesions) 
x No post-baseline assessments due to death within 6 weeks after randomization 
x No post-baseline assessments due to other reasons 
x All post-baseline assessments have overall response NE 
x New anticancer therapy started before first post-baseline assessment  
x SD of insufficient duration (<6 weeks after date of randomization without further evaluable 
tumor assessment) 
x PD too late (i.e. tumor assessment of PD was >12 weeks after date of randomization and 
there was no tumor assessment in between)  
Special and rare cases where BOR is NE due to both early SD and late PD will be classified as 
‘SD too early’. 
Sensitivity Analysis 
The following sensitivity analyses of ORR will be performed: 
x The analysis of ORR will be repeated on the PP analysis set if this analysis set includes 
less than 90% of subjects in the FAS; 
x ORR according to investigator assessment will be analyzed in the same manner as ORR 
according to IRC assessment. The confirmed BOR according to Investigator assessment 
will be derived in the same way as the confirmed BOR according to the IRC. 
x A summary of concordance of BOR between IRC and investigator assessment will also be 
provided. The confirmed BOR according to investigator assessment will be derived in the 
same way as the confirmed BOR according to the IRC. 
x A multivariable logistic regression analysis will be performed to assess and adjust the 
treatment effect for relevant baseline factors of potential prognostic impact. The subgroup 
variables defined in Section 10 “Subgroup Analysis Sets” will be included in the model. A 
stepwise selection procedure will serve to identify explanatory variables of potential 
prognostic values additional to the randomization strata which will be included in all 
models during the selection procedure. The level of significance for an explanatory variable 
to enter the model is set to 0.15 (p-value of Score test) and the significance level for 
removing it is set to 0.40 (p-value of Wald test). Once this procedure stops, the factor 
'treatment group' will be added to the last selected model in order to evaluate the effect of 
treatment on BOR when adjusted for the selected explanatory variables. The odd ratios of 
all selected explanatory variables and of treatment effects will be reported including 2-
sided 95% confidence intervals. No interactions will be considered. Post-baseline factors 
will not be considered for the model. 


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16.2.3 
Time of Follow-up for PFS 
Analysis sets: FAS 
A Kaplan-Meier plot for PFS follow-up duration will also be generated to assess the follow-up 
time in the treatment arms reversing the PFS censoring and event indicators. 
Table 5 
Reverse Censoring Rules for Duration of PFS Follow-up  
 
Date of event / censoring 
Censoring 
Subjects alive or lost to follow-up 
Time from randomization to last date known to be alive 
No  
Subjects who died or had PD 
Time from randomization to date of first PD or death 
Yes 
Kaplan-Meier estimates will be presented by treatment group together with the median time of 
follow-up for PFS. In particular, the follow-up rate at 3, 6, 9 and 12 months will be estimated with 
corresponding two-sided 95% CIs. 
16.2.4 
Subgroup Analysis of Secondary Efficacy Endpoints 
Analysis sets: FAS  
Analysis on subgroups as defined in Section 10 will be performed for the secondary efficacy 
endpoints, PFS and BOR.  
All the subgroup analyses will be exploratory; no adjustment for multiplicity will be performed.  
In the case of a low number of subjects within a category (< 19 subjects, which is about 5% of the 
randomized population), the categories may be pooled when meaningful.  
All the subgroup analyses will be performed as unstratified. The unadjusted 95% CI will be 
calculated for all subgroup analyses. 
The subgroup analysis of PFS will be analogous to that of subgroup analysis of OS time as 
described in section 16.1.3. 
For the subgroup analysis of BOR, the association of treatment effect and BOR will be tested using 
the two-sided CMH test per subgroup level. The ORR along with the two-sided exact Clopper-
Pearson 95% CIs will be calculated for each subgroup.  
In addition, to assess the heterogeneity of treatment effect across the subgroup levels for the 
secondary endpoint of BOR, a logistic regression model will be fitted with BOR as the dependent 
variable (=1 for subjects with a confirmed BOR of PR or CR; =0 otherwise); subgroup, treatment, 
and with and without the treatment-by-subgroup interaction as explanatory variables. A p-value 
for the interaction term (Wald Chi-Square test) will be provided together with the odds ratio and 
corresponding 95% CI of the interaction model parameter.  


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16.2.5 
Health-Related Quality of Life  
Analysis sets:  HRQoL Analysis Set 
Health-related quality of life (HRQoL) will be assessed by the EuroQOL 5-dimensions 
questionnaire (EQ-5D), the European Organization for Research and Treatment of Cancer 
(EORTC) QLQ-C30 supplemented by the gastric cancer module QLQ-STO22 questionnaire. The 
analyses specified below will be performed for HRQoL analysis set. Further exploratory and 
sensitivity analyses on HRQoL assessment will be detailed in an addendum to this analysis plan.  
The EQ-5D questionnaire is a generic measure of health status that provides a descriptive profile 
and a simple index value. It includes 5 items assessing mobility, self-care, usual activities, pain / 
discomfort, anxiety / depression on a 5-level response scale (EQ-5D-5L).  It also includes a visual 
analogue scale (VAS) ranging from 0 to 100 for self-rated health status.  A higher score indicates 
better health status.  Utilities can be derived from the EQ-5D, ranging from 0.0 (worst health state) 
to 1.0 (best health state).   
 
The EQ-5D-5L scoring system will also be converted into a single index value. The index value is 
country specific and is a major feature of the EQ-5D instrument, facilitating the calculation of 
quality-adjusted life years (QALYs) that are used to inform economic evaluations of health care 
interventions.  The Japan country specific value set will be used in deriving the index value for 
Asian countries which ranges from -0.111 (worst health state) to 1.000 (best health state); the UK 
country specific value set will be used in deriving the index value for non-Asian countries which 
ranges from -0.594 (worst health state) to 1.000 (best health state).  
The QLQ-C30 self-assessment questionnaire incorporates five functional scales (Physical, Role, 
Cognitive, Emotional, and Social), a global health status / QoL scale, and a number of single items 
assessing additional symptoms commonly reported by cancer subjects (e.g. dyspnea, loss of 
appetite, insomnia, constipation, and diarrhea), and financial impact of the disease.  
All of the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. Therefore, a high score for a functional scale represents a 
high/healthy level of functioning, a high score for the global health status / QoL represents a high 
QoL, but a high score for a symptom scale/item represents a high level of 
symptomatology/problems. The scoring procedure for each of the scales is the same and consists 
of computing the raw score (RS) and then computing the actual scale score (S) by making a linear 
transformation to standardize the score to values from 0 to 100 as shown below. 
                                             Raw Score = RS = (I1+I2+…+In) / n 
For Functional scales: 
Score = 100 x [1 – (RS – 1) / Range] 
For Symptom scales / items and Global health status / QoL: 
Score = 100 x [(RS – 1) / Range)] 




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Hair Loss 
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The analysis will be performed on the following scores: 
1. Each of the EQ-5D scores 
2. QLQ-C30 Global health status/QoL scale, each of the five QLQ-C30 functional scales, 
and each of the nine QLQ-C30 symptoms/items 
3. Each of the nine QLQ-STO22 gastric cancer module symptom scales 
 
The following analyses will be performed for each of these score/scale systems: 
x HRQoL questionnaires compliance and full completion rate: 
HRQoL compliance rate across all instruments will be summarized by considering the EQ-5D-
5L, the QLQ-C30, and the QLQ-STO22 for each scheduled visit using the following definition: 
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The compliance and full completion rate for each questionnaire will be displayed using a line 
plot with time on the x-axis and completion rate on the y-axis. Separate lines will be presented 
for each treatment arm. 
x HRQoL questionnaires descriptive statistics 
Observed and change from baseline values will be summarized descriptively at planned visits 
during the treatment phase, the Discontinuation visit, End of Treatment visit and 30-day Safety 
Follow-up visit by treatment arm. The percent of subjects at the worst possible score (i.e., 5 on 
each of the EQ-5D scores, 0 on VAS, 0 on index score, 100 on symptom scales and 0 on QLQ-
C30 functional scales and quality of life) and at the best possible score (i.e., 0 on each of the 
EQ-53 scores, 100 on VAS, 1 on index score, 0 on symptom scales and 100 on QLQ-C30 
functional and quality of life) will be reported. In addition, the best (largest positive change), 
worst (largest negative change), and last observed post-baseline change from baseline values 
will be summarized. 
Change from baseline will also be displayed using a line plot with time point (scheduled visit) 
on the x-axis, mean change score on the y-axis, standard errors around each mean score, and 
separate lines for each treatment arm. 
If there are multiple complete assessments for any scheduled visit during the treatment phase, 
the assessment that is closest to the planned visit per protocol will be used in the analysis. If 
there are multiple complete assessments at Discontinuation visit and End of Treatment visit, 
the first assessment will be used in the analysis. 


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x Longitudinal analysis of change from baseline 
A mixed-effects model repeated measures (MMRM) analysis will evaluate longitudinal change 
from baseline on the QLQ-C30 physical function scale and the QLQ-STO22 scales. Covariates 
will include the baseline score for the domain score being evaluated and randomization 
stratification factors, and the questionnaire entry time point including both scheduled and 
unscheduled visits will be analyzed as a continuous variable. The overall significance of the 
difference between the MMRM trajectories for the treatment arms will be tested at a 
significance level of 0.05 (two-sided). An unstructured covariance structure will be used, if 
possible, though a simpler covariance structure will be used if the model does not converge. 
x Subject level change from baseline 
For the HRQoL domain scores analyzed using MMRM, an empirical cumulative distribution 
function (eCDF) curves, separated by treatment arm, will display the proportion of subjects 
who experienced specific changes from baseline to end of treatment. For each eCDF, the range 
of change scores will be displayed on the x-axis, and the cumulative percentage of patients 
achieving that change score or better will be displayed on the y-axis. The eCDF may be 
interpreted by choosing a change score magnitude that may be considered clinically 
meaningful on the x-axis and comparing the rate of subjects who achieved at least that amount 
of change in the treatment arms on the y-axis. 
Missing Values and Imputation Rules 
If 50% or more of the items for a given scale are non-missing, then the Raw Score should be 
computed as the average of the non-missing items; if more than 50% of the items for a given scale 
are missing the scale score will be set to missing. 
Missing data will be retained as observed, and no imputation of HRQoL scores will be conducted. 
16.3 
Other Endpoint Analyses 
Analysis sets: FAS 
16.3.1 
Duration of Response (DR) 
DR is defined, for subjects with an OR, as the time from first documentation of OR (CR or PR 
according to RECIST 1.1 and adjudicated by an IRC) to the date of first documentation of objective 
progression of disease or death due to any cause.  For subjects with an OR but neither documented 
disease progression nor death as of the cut-off date for the analysis, duration of response will be 
censored at the date of the last adequate tumor assessment. The censoring rules for DR are the 
same as described for PFS in Section 16.1.2. 
  
DR (months) = (date of PD or death – date of 1st OR + 1)/30.4375  


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DR will be displayed graphically and analyzed using Kaplan-Meier methodology analogous to that 
used for OS as described in Section 16.1.1. In particular, the DR rate at 3, 6 and 12 months will be 
estimated with corresponding two-sided 95% CIs.  
In addition, DR according to investigator assessment will be analyzed in the same manner as DR 
according to IRC assessment. 
If the number of subjects with OR is small, the Kaplan-Meier method may not provide reliable 
estimates. In this case, only descriptive statistics or listings will be provided. 
16.3.2 
Time to Response 
Time to response (TTR) is defined, for subjects with an OR according to RECIST v1.1, as the time 
from randomization to the first documentation of OR which is subsequently confirmed. 
TTR (weeks) = (First date of CR or PR – date of randomization + 1)/7 
TTR will be summarized using simple descriptive statistics (mean, StDev. median, min, max. 
Q1, Q3). 
16.3.3 
Tumor Shrinkage 
Tumor shrinkage will be summarized as the percent change from baseline in target lesions (sum 
of longest diameter for non-nodal lesions and short axis for nodal lesions) per time point. See 
Section 11 for the definition of baseline. Tumor response will be based on the IRC assessment. It 
will be derived as: 
[(Sum of target lesions at week XX – sum of target lesions at baseline)/sum of target lesions at 
baseline] x 100 
The maximum reduction in target lesions from baseline will be derived across all the post-baseline 
assessments until documented disease progression, excluding assessments after start of subsequent 
anticancer therapy, as: 
Minimum of [(sum of target lesions at week XX – sum of target lesions at baseline)/sum of target 
lesions at baseline] x 100 
The percent change from baseline in target lesions as well as the first occurrence of a new lesion 
and subject off treatment will be displayed against time point (weeks) in a line plot. A waterfall 
plot of maximum percent reduction in the sum of longest diameter for non-nodal lesions and short 
axis for nodal lesions from baseline will also be created by treatment group. These plots will 
display the best percentage change from baseline in the sum of the diameter of all target lesions 
for each subject with measurable disease at baseline and at least one valid post-baseline 
assessment. 


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16.3.4
Disease Control Rate (DCR) 
Disease Control Rate (DCR) is the proportion of subjects with confirmed BOR of CR, PR, SD and 
Non-CR/Non-PD (applicable only to subjects with non-measurable disease at baseline) according 
to RECIST v1.1 and adjudicated by the IRC obtained among all tumor assessment visits after the 
date of randomization until documented disease progression in the analysis set of interest.  
DCR by treatment group will be calculated along with the two-sided 95% CI using the Clopper-
Person method (exact CI for a binomial proportion as computed by default by the FREQ procedure 
using the EXACT option). 
  
  
  
  
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17
Safety Evaluation 
Analysis sets: Safety Analysis Set 
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical trials such as adverse events, laboratory tests and vital signs. All safety 
related summary tables will be based on the analysis sets as indicated above. The safety endpoints 
will be tabulated using descriptive statistics. 
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17.1 
Adverse Events 
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring during 
the on-treatment period or if the worsening of an event is during the on-treatment period. 
All analyses described in Section 17.1 will be based on TEAEs unless otherwise specified. The 
adverse event (AE) listings will include all AEs (whether treatment-emergent or not). A separate 
listing for AEs that started after the on-treatment period will also be provided. 
x Related Adverse Events: adverse events with relationship to study treatment (as recorded 
on the AE eCRF page, Relationship with study treatment = Related) reported by the 
investigator and those of unknown relationship (i.e. no answer to the question “Relationship 
with study treatment”). 
x Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF page, 
Serious Adverse Event = Yes). 
x Adverse Events Leading to Treatment Discontinuation: adverse events leading to 
permanent discontinuation of study treatment (as recorded on the AE eCRF page, Action 
taken with study treatment = Drug withdrawn). 
x Adverse Events Leading to Death: adverse event leading to death (as recorded on the AE 
eCRF page, Outcome = Fatal, as well as AEs of Grade 5). 
x Immune Related Adverse Events (irAE):  immune related adverse events according to 
case definition classified by medical review. Details are included in Table 14 in Appendix 
IV). 
x Infusion Related Reactions (IRR):  IRRs are identified based on a list of MedDRA PTs. 
The detailed criteria of the timing relationship to infusion are specified in Table 15 in 
Appendix IV. 
Unless otherwise stated adverse events will be displayed in terms of frequency tables: PT and 
primary SOC by decreasing frequency based on the avelumab + BSC treatment arm. 
Each subject will be counted only once within each PT or SOC. If a subject experiences more than 
one AE within a SOC or PT for the same summary period, only the AE with the strongest 
relationship or the worst severity, as appropriate, will be included in the summaries of relationship 
and severity. 
Changes in toxicity grade, seriousness or outcome of AEs are recorded as separate entries in the 
eCRF with associated end and start dates (start date equals end date of previous entry). Such entries 
reporting the same event in such immediately consecutive periods will be considered as one event 
in the analysis in case of an improvement in toxicity grade. These events will be kept as separate 
records in the database in order to maintain the full detailed history of the events. The start date of 
the initial record in the sequence is taken as start date of the entire event. Duration of the AE and 
the TEAE flag will be adjusted accordingly in the analysis. 


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17.1.1 
All Adverse Events 
Adverse events will be summarized by worst grade per the latest National Cancer Institute – 
Common Terminology Criteria for Adverse Events (NCI-CTCAE version 4.03) per subject, using 
the latest version of MedDRA PT as event category and MedDRA primary SOC as body system 
category. 
In case a subject has events with missing and non-missing grades, the maximum of the non-missing 
grades will be displayed. No imputation of missing grades will be performed.  
The following tables will be created:  
x The overall summary of AEs table will include the following categories: 
- TEAEs 
- TEAEs, grade ≥ 3 
- Related TEAEs 
- Related TEAEs, grade ≥ 3 
- TEAEs leading to permanent treatment discontinuation  
- Related TEAEs leading to permanent treatment discontinuation  
- Serious TEAEs 
- Related serious TEAEs 
- TEAEs leading to death 
- Related TEAEs leading to death 
- Treatment emergent irAEs 
- Related treatment emergent irAEs 
- Treatment emergent IRRs 
- Related treatment emergent IRRs 
x TEAEs by SOC and PT and worst grade 
x Related TEAEs by SOC and PT and worst grade  
x TEAEs leading to death by SOC and PT 
x Related TEAEs leading to death by SOC and PT 
x TEAEs by SOC and PT: displaying in separate columns the All TEAEs / Related TEAEs / 
Grade ≥3 TEAEs / Related Grade ≥3 TEAEs  
x TEAEs Excluding SAEs, with Frequency ≥ 5% in any treatment arm by SOC and PT  
In addition, a listing of AEs with onset or worsening date after the on-treatment period will also 
be provided.  


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17.1.2 
Adverse Events Leading to Treatment Discontinuation 
The following overall frequency tables will be prepared for the adverse event actions that lead to 
treatment discontinuation: 
x TEAEs leading to treatment discontinuation by SOC and PT 
x Related TEAEs leading to treatment discontinuation by SOC and PT  
A data listing of TEAEs leading to treatment discontinuation will also be provided with the 
relevant information. 
17.2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events 
17.2.1 
Deaths 
All deaths, deaths within 30 days after last dose of study treatment, deaths within 60 days after the 
date of first dose of study treatment, and primary reason for death will be tabulated based on 
information from the “Report of Subject Death” and “Survival Follow-Up” CRFs.  
x All Deaths  
x Deaths within 30 days after last dose of study treatment 
x Deaths within 60 days after first dose of study treatment 
x Primary Reason for Death  
- Disease progression 
- Adverse event related to study treatment  
- Adverse event not related to study treatment  
- Other 
- Unknown 
In addition, date and primary reason for death will be provided in a data listing together with 
selected dosing information (study treatment received, date of first / last dose administration, dose 
and number of infusions received of study treatment) and will include the following information: 
x AEs with fatal outcome (list preferred terms of AEs with outcome=Fatal, as well as AEs of 
Grade 5) 
x Flag for death within 30 days of last dose of study treatment 
x Flag for death within 60 days of first dose study treatment 


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17.2.2 
Serious Adverse Events 
The following overall frequency tables will be prepared for treatment-emergent SAEs: 
x SAEs by SOC and PT 
x Related SAEs by SOC and PT 
A data listing of SAEs will also be provided with the relevant information with a flag for treatment-
emergent SAEs. 
17.2.3 
Other Significant Adverse Events 
The following overall frequency tables will be prepared for treatment emergent irAEs, by 
treatment group. The cluster is a compilation of PTs that are categorized by immune-related event 
of special interest as specified in Appendix IV. 
x The overall summary of irAEs table will include the following categories: 
- All irAEs 
- Related irAEs  
- Serious irAEs 
- Related serious irAEs 
- irAEs, Grade ≥ 3 
- Related irAEs, Grade ≥ 3  
- irAEs leading to permanent treatment discontinuation 
- Related irAEs leading to permanent treatment discontinuation 
- irAEs leading to death  
- Related irAEs leading to death 
x irAEs leading to death, by Cluster and PT 
x Related irAEs leading to death, by Cluster and PT 
x irAEs by Cluster and PT 
x irAEs, grade ≥ 3, by Cluster and PT 
x Related irAEs by Cluster and PT 
x Related irAEs, grade ≥ 3, by Cluster and PT 
x irAEs leading to permanent treatment discontinuation by Cluster and PT 
x Related irAEs leading to permanent treatment discontinuation by Cluster and PT 
x irAEs by Cluster and PT and worst grade 
x Related irAEs by Cluster and PT and worst grade 


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The listing of all irAEs will also be provided with the relevant information with a flag for irAEs 
with onset outside of the on-treatment period.  A separate listing of irAEs with onset after the on-
treatment period will also be provided.  
The following overall frequency tables will be prepared for treatment emergent IRRs, by treatment 
group: 
x The overall summary of IRR table will include the following categories: 
- All IRRs 
- Related IRRs  
- Serious IRRs 
- Related serious IRRs 
- IRRs, Grade ≥ 3 
- Related IRRs, Grade ≥ 3  
- IRRs leading to permanent treatment discontinuation 
- Related IRRs leading to permanent treatment discontinuation 
- IRRs leading to death  
- Related IRRs leading to death 
x IRRs, by PT  
x IRRs, Grade ≥ 3, by PT  
x Related IRRs, by PT  
x Related IRRs, Grade ≥ 3, by PT  
x IRRs leading to permanent treatment discontinuation, by PT  
x Related IRRs leading to permanent treatment discontinuation, by PT  
x Serious IRRs, by PT  
x Related serious IRRs, by PT  
x IRRs leading to death, by PT  
x Related IRRs leading to death, by PT  
x Time related to first onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or later)  
 
The listing of all IRRs will also be provided with the relevant information with a flag for IRRs 
with onset outside of the on-treatment period. 


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17.3
Clinical Laboratory Evaluation 
17.3.1
Hematology and Chemistry Parameters 
Hematology and chemistry laboratory results will be classified according to the NCI-CTCAE 
criteria version 4.03. Non-numerical qualifiers (with the exception of fasting flags) will not be 
taken into consideration in the derivation of CTCAE criteria (e.g., hypokalemia Grade 1 and Grade 
2 are only distinguished by a non-numerical qualifier and therefore Grade 2 will not be derived). 
Additional laboratory results that are not part of NCI-CTCAE will be presented according to the 
categories: below normal limit, within normal limits and above normal limit (according to the 
laboratory normal ranges). 
The worst grade during the on-treatment period will be summarized per treatment group 
considering only subjects with post baseline laboratory samples: Laboratory tests by NCI-CTC 
grade (0, 1, 2, 3, 4).
Quantitative data will be summarized using descriptive statistics (mean, StDev, median, Q1, Q3, 
minimum, and maximum) of actual values and changes from baseline for each nominal visit over 
time (unscheduled measurements would therefore not be included in these summaries as described 
in Section 11). Changes from baseline at each nominal visit over time will also be presented in 
boxplots. End of Treatment visit will be summarized separately. Qualitative data based on 
reference ranges will be described according to the categories (i.e. Low, Normal, High). 
If both central and local labs are collected for a subject, these summary statistics by visit will be 
based only on the central lab collected data, while summaries of worst on-treatment abnormalities 
will be based on both local and central lab data. 
Abnormalities classified according to NCI-CTCAE toxicity grading version 4.03 will be described 
using the worst grade. For those parameters which are graded with two toxicities such as potassium 
(hypokalemia/hyperkalemia), the toxicities will be summarized separately. Low direction toxicity 
(e.g., hypokalemia) grades at baseline and post baseline will be set to 0 when the variables are 
derived for summarizing high direction toxicity (e.g., hyperkalemia), and vice versa.
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For WBC differential counts (total neutrophil [including bands], lymphocyte, monocyte, 
eosinophil, and basophil counts), the absolute value will be used when reported. When only 
percentages are available (this is mainly important for neutrophils and lymphocytes, because the 
CTCAE grading is based on the absolute counts), the absolute value is derived as follows:  
 
Derived differential absolute count = (WBC count) * (Differential %value / 100)  
 
If the range for the differential absolute count is not available (only range for value in % is 
available) then Grade 1 will be attributed to as follows:  
 
x Lymphocyte count decreased:  
o derived absolute count does not meet Grade 2-4 criteria, and  
o % value < % LLN value, and  
o derived absolute count ≥ 800/mm3  
x Neutrophil count decreased  
o derived absolute count does not meet Grade 2-4 criteria, and  
o % value < % LLN value, and  
o derived absolute count ≥ 1500/mm3  
For calcium, CTCAE grading is based on Corrected Calcium. Corrected Calcium is calculated 
from Albumin and Calcium as follows  
Corrected Calcium (mg/dL) = measured total Calcium (mmol/L) + 0.02 (40 - serum 
albumin [g/L]) 
 
Liver function tests: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and 
total bilirubin are used to assess possible drug induced liver toxicity. The ratios of test result over 
upper limit of normal (ULN) will be calculated and classified for these three parameters during the 
on-treatment period.  
Summary of liver function tests will include the following categories. The number and percentage 
of subjects with each of the following during the on-treatment period will be summarized by 
treatment group: 
x ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN  
x AST ≥ 3×ULN, AST ≥ 5xULN, AST ≥ 10×ULN, AST ≥ 20×ULN  
x (ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 10×ULN, (ALT or 
AST) ≥ 20×ULN  
x TBILI ≥ 2×ULN  
x Concurrent ALT ≥ 3×ULN and TBILI ≥ 2×ULN  
x Concurrent AST ≥ 3×ULN and TBILI ≥ 2×ULN  
x Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN  


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x Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and ALP > 2×ULN  
x Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and ALP ≤ 2×ULN or missing  
 
Concurrent measurements are those occurring on the same date.  
 
Categories will be cumulative, i.e., a subject with an elevation of AST ≥10×ULN will also appear 
in the categories ≥5×ULN and ≥3×ULN. Liver function elevation and possible Hy’s Law cases 
will be summarized using frequency and percentage.  
 
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, with 
different symbols for different treatment groups, by graphically displaying  
x peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at ALT 
=3×ULN and total bilirubin =2×ULN.  
x peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at AST 
=3×ULN and total bilirubin =2×ULN.  
In addition, a listing of all TBILI, ALT, AST and ALP values for subjects with a post-baseline 
TBILI ≥ 2×ULN, ALT≥ 3×ULN or AST ≥ 3×ULN will be provided. 
Parameters with NCI-CTC grades available: 
 
The laboratory toxicities will be tabulated using descriptive statistics (number of subjects and 
percentages) during the on-treatment period.  
x The summary of laboratory parameters by CTCAE grade table will include number and 
percentage of subjects with Grade 1, 2, 3, 4, 3/4, and any grade, laboratory abnormalities 
during the on-treatment period.  
x The shift table will summarize baseline CTCAE grade versus the worst on-treatment 
CTCAE grade. The highest CTCAE grade during the on-treatment period is considered as 
the worst grade for the summary.  
The above analyses apply to hematology and chemistry evaluations which can be graded per 
CTCAE, i.e.: 
x Hematology:  
Hemoglobin (HB), Leukocytes (white blood cell decreased), Lymphocytes (lymphocyte 
count increased/decreased), Neutrophils / Absolute Neutrophils Count (ANC) (neutrophil 
count decreased), Platelet Count (PLT) (platelet count decreased). 
x  Serum Chemistry: 
Albumin (hypoalbuminemia), Alkaline Phosphatase (ALP) (alkaline phosphatase 
increased), Alanine Aminotransferase (ALT) (ALT increased), Amylase (serum amylase 
increased), Aspartate Aminotransferase (AST) (AST increased), Total Bilirubin (blood 
bilirubin increased, Cholesterol (cholesterol high), Creatinine (creatinine increased), 
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(hyponatremia/ 
hypernatremia), 
Magnesium 
(hypomagnesemia/hypermagnesemia), 
Calcium (hypocalcemia/ hypercalcemia), Glucose (hypoglycemia/hyperglycemia), Gamma 
Glutamyl Transferase (GGT) (GGT increased), Lipase (lipase increased), Phosphates 
(hypophosphatemia), Triglycerides (hypertriglyceridemia). 
Parameters with NCI-CTC grades not available: 
Hematology and chemistry tests which cannot be graded per CTCAE criteria will be summarized 
as frequency (number and percentage) of subjects with:  
x shifts from baseline normal to at least one result above normal during on-treatment period  
x shifts from baseline normal to at least one result below normal during on-treatment period 
In this study, these apply to the following laboratory tests: 
x Hematology:  
Basophils (absolute and percent), Eosinophils (absolute and percent), Monocytes (absolute 
and percent), Neutrophils (absolute and percent), Hematocrit, Red Blood Cell (RBC), 
Reticulocytes, Mean Corpuscular Hemoglobin (MCH), Mean Corpuscular Volume (MCV), 
Mean Corpuscular Hemoglobin Concentration (MCHC). 
x Serum Chemistry:  
Chloride, C-Reactive Protein, Lactate Dehydrogenase (LDH), Total Protein, Total Urea, 
Uric Acid.  
17.3.2 
Other Laboratory Parameters 
All other parameters collected on the eCRF will be listed in dedicated listings presenting all 
corresponding collected information on the eCRF.  
x Hemostaseology: activated partial thromboplastin time (aPTT), prothrombin time (PT), and 
International Normalized Ratio (INR).  
x Urinalysis: all urinalysis parameters 
x Other parameters: hormone and immunology parameters 
x Pregnancy test 
Listings of laboratory results will be provided for all laboratory parameters. These listings will be 
sorted by parameters and assessment dates or visits for each subject; laboratory values that are 
outside the normal range will be flagged along and corresponding normal ranges will be provided 
in addition to NCI-CTCAE grade.  
In addition, listings of abnormal values will be provided for chemistry, hematology, 
hemostaseology, and urinalysis parameters. If there is at least one abnormal result for any 
parameter, all the data for that parameter will be included in the listing.  


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For all tests not mentioned above but present in the clinical data, a listing of subjects with at least 
one result for the relevant test will be provided. 
17.4 
Vital Signs 
Vital sign summaries will include all vital sign assessments from the on-treatment period. All vital 
sign assessments will be listed, and those collected outside the on-treatment period will be flagged 
in the listing.  
All vital sign parameters will be summarized using descriptive statistics (mean, StDev, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each planned 
visit over time. Discontinuation/End of Treatment visit will be summarized separately. The 
changes computed will be the differences from baseline. 
The maximum on-treatment change from baseline will be calculated and categorized by vital sign 
measurement (see Table 8). Missing values will define a separate category. A summary of 
maximum shift from baseline by category will be provided by treatment arm.  
Table 8 
Categories of Change from Baseline for Vital Sign Parameters  
Parameters 
Categories of Change from Baseline 
Body temperature increase 
< 1qC , 1-<2qC , 2-<3qC, t 3 qC 
Weight increase 
<10%, t 10% 
Weight decrease 
<10%, t 10% 
Heart rate increase from baseline  
<100 bpm ; ≥ 100 bpm 
d20 bpm, >20 – 40 bpm, >40 bpm 
Heart rate decrease from baseline  
<100 bpm ; ≥ 100 bpm 
d20 bpm, >20 – 40 bpm, >40 bpm 
SBP increase from baseline  
<140 mmHg; ≥ 140 mmHg  
d20 mmHg, >20 – 40 mmHg, >40 mmHg 
SBP decrease from baseline  
<140 mmHg; ≥ 140 mmHg, 
d20 mmHg, >20 – 40 mmHg, >40 mmHg 
DBP increase from baseline  
<90 mmHg; ≥ 90 mmHg  
d20 mmHg, >20 – 40 mmHg, >40 mmHg 
DBP decrease from baseline  
<90 mmHg; ≥ 90 mmHg, 
d20 mmHg, >20 – 40 mmHg, >40 mmHg 
Respiration rate increase from baseline <20 
breaths/min; ≥ 20 breaths/min 
d5 breaths/min, >5 – 10 breaths/min, >10 breaths/min 
Respiration rate decrease from baseline <20 
breaths/min; ≥ 20 breaths/min 
d5 breaths/min, >5 – 10 breaths/min, >10 breaths/min 
   bpm = beats per minute; DBP=diastolic blood pressure; SBP=systolic blood pressure. 


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17.5 
Other Safety or Tolerability Evaluations 
17.5.1 
ECG 
 
The 12-lead Electrocardiogram (ECG) assessment will be performed during screening (baseline) 
and at the Discontinuation / End-of-Treatment visit. For each of the ECG parameters, descriptive 
statistics at baseline and at the Discontinuation / End-of-Treatment visit and changes from baseline 
will be summarized by treatment group. 
The incidence and percentage of subjects with the worst potentially clinically significant 
abnormalities (PCSA) for ECG parameters will be summarized during the on-treatment period. 
Each subject will be counted only once within each category. As ECG assessments are only 
performed during screening and at the Discontinuation/End-of-Treatment visit, the denominator 
to calculate percentages for each PCSA category is the number of subjects with 
Discontinuation/End of Treatment visit. The PCSA criteria are provided in Table 9. 
 
Table 9 
Potentially Clinically Significant Abnormalities criteria for ECG 
Test 
Potentially Clinically Significant Abnormalities (PCSA) Criteria 
Heart Rate 
≤ 50 bpm and decrease from baseline ≥ 20 bpm 
≥ 120 bpm and increase from baseline ≥ 20 bpm 
PR Interval 
≥ 220 ms and increase from baseline ≥ 20 ms 
QRS 
 ≥ 120 ms 
QTcF and QTcB absolute 
>450 ms 
>480 ms 
>500 ms 
QTcF and QTcB change from 
baseline 
Increase from baseline > 30 ms 
Increase from baseline > 60 ms 
QTc will be corrected based on Fridericia’s formula for QTcF and Bazett's formula for QTcB 
(QTcF= QT/ ξܴܴ
య
 and QTcB= QT/ ξܴܴ
మ
) where RR=60/heart rate. Baseline QTcF and QTcB will 
be derived from the visit that other ECG parameters are flagged as baseline.  
A listing of abnormal 12-lead ECGs will be provided with all relevant information and derived 
variables. 
Unscheduled ECG measurements will not be used in computing the descriptive statistics for 
change from baseline at each post-baseline time point. However, they will be used in the analysis 
of notable ECG changes. 


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17.5.2
ECOG Performance Status 
The ECOG shift from baseline to highest score during the on-treatment period will be summarized. 
ECOG performance status with shift from ECOG=0 or 1 to ECOG=2 or higher will also be 
presented in a data listing with subject identifier and other relevant information. 
  
 
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18 
References 
1. Brookmeyer R, Crowley J. A Confidence Interval for the Median Survival Time. 
Biometrics 1982;38:29-41. 
2. Kalbﬂeisch JD, Prentice RL. The Statistical Analysis of Failure Time Data, New York: 
John Wiley & Sons 1980. 
3. Westfall P, Tobias R, Rom D, et al. Multiple Comparisons and Multiple Tests Using 
SAS, Cary, NC: SAS Institute Inc. 1999: 32-33. 
4. Eisenhauer, E.A, Therasse, P., Bogaerts. J. et. al. (2009): New response evaluation 
criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of 
Cancer 45, 228-247. 
5. Cochran WG. Some Methods for Strengthening the Common Chi-square Tests. 
Biometrics 1954;10:417-51. 
6. Zhang X. Comparison of restricted mean survival times between treatments based on a 
stratified Cox model. DOI 10.1515/bams-2013-0101 Bio-Algorithms and Med-Systems 
2013; 9(4): 183–9. 
7. Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. DOI 10.1200/jco.1998.16.1.139 J Clin Oncol. 1998 
Jan;16(1):139-44. 
8. AS Pickard, MP Neary, D Cella : Estimation of minimally important differences in EQ-
5D utility and VAS scores in cancer Health Qual Life Outcomes 5: 70,2007 
9. Maringwa JT, Quinten C, King M, Ringash J, Osoba D, Coens C, et al. Minimal 
important differences for interpreting health-related quality of life scores from the 
EORTC QLQ-C30 in lung cancer patients participating in randomized controlled 
trials.Support Care Cancer2011;19:1753-60 
 
 
 






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Appendix II 
EORTC QLQ-C30 Version 3.0 
 
 


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Appendix III 
EORTC QLQ-C30-STO22: Gastric Cancer Module 
 
 
 


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Appendix IV 
Description of the Case Review for Assessment of Immune-
Related AEs and IRR  
In order to thoroughly and consistently analyze potential immune-mediated adverse events (AEs), 
a two-level approach is proposed including: 
1. A MedDRA Preferred Term (PT) query is proposed for each event category (i.e., immune-
mediated rash, colitis, pneumonitis, hepatitis, nephritis and renal dysfunction, 
endocrinopathies and other immune-mediated adverse reactions). 
2. AEs identified by the MedDRA PT queries will then be medically reviewed using pre-
defined case definitions for immune-mediated adverse reactions.  
Level 1: 
To identify potentially immune-mediated AEs, the MedDRA PT queries will be used to search for 
AEs of interest in the clinical database. The proposed event categories such as: 
Immune-mediated rash, Immune-mediated colitis, Immune-mediated pneumonitis, Immune-
mediated hepatitis, Immune-mediated nephritis and renal dysfunction, Immune-mediated 
endocrinopathies (Thyroid disorders: Hypothyroidism, Hyperthyroidism, and Thyroiditis), 
Immune-mediated endocrinopathies (Adrenal insufficiency, Immune-mediated endocrinopathies 
(Type 1 Diabetes Mellitus), Immune-mediated endocrinopathies (Pituitary dysfunction), Immune-
mediated endocrinopathies (Hypogonadism), Other immune-mediated adverse events. Further 
details e.g. MedDRA PT queries are regularly updated based on the current MedDRA version.  
In order to standardize the MedDRA PT queries as much as possible, High Level Terms (HLT) and 
Standardized MedDRA Queries (SMQ) were used whenever a choice, that was considered 
reflective of the events of interest, was available. 
Level 2: 
In a second level (medical review), the potential immune-mediated AEs identified from the search 
performed at Level 1, will be reviewed by qualified medical personnel to determine whether the 
AE meets the criteria (case definition) for an immune-mediated adverse reaction based on the 
following algorithm: 
Table 14 
Algorithm for immune-related adverse reactions 
Criteria 
Description 
Onset 
AE onset after 1st avelumab administration until up to 90 days after last dose  
Duration 
AE does not spontaneously resolve (i.e., without corticosteroids/ immunosuppressant 
treatment) within 7 days after onset 
Immunosuppressive 
therapy 
AE treated with corticosteroid or other immunosuppressant therapy. 
For endocrinopathies only:  AE required hormone replacement* and /or 
(corticosteroid or other immunosuppressive therapy) 


Avelumab 
Avelumab in Third-line Gastric Cancer 
EMR 100070-008 
 
 
 
 
78/78 
 
Etiology 
No other clear etiology or  
Histopathology/biopsy consistent with immune-mediated event  
All criteria listed in the left column need to be fulfilled for an event to meet the case definition of immune-
mediated reaction. 
*Hormone replacement will be evaluated for specific endocrinopathy disorders only as follows:  
x 
Thyroid disorders (HLT): Thyroid therapy (ATC codes (H03A, H03B)) 
x 
Diabetes mellitus (including hyperglycaemia): Insulin (ATC code A10A)   
Infusion related reactions are identified based on a list of MedDRA PTs and criteria on the timely 
relationship according to Table 17. 
Table 15 
Criteria for infusion related reactions 
 
Infusion related reactions 
Reactions - Considered when onset is on the day of avelumab 
infusion (during or after the infusion) or the day after the 
avelumab infusion (irrespective of resolution date): 
x 
Infusion related reaction 
x 
Drug hypersensitivity 
x 
Anaphylactic reaction 
x 
Hypersensitivity 
x 
Type 1 hypersensitivity  
 
Signs and Symptoms - occurring on the day of avelumab infusion 
(during or after the infusion) and resolved with end date within 2 
days after onset 
x 
Pyrexia 
x 
Chills 
x 
Flushing  
x 
Hypotension 
x 
Dyspnoea 
x 
Wheezing 
x 
Back pain 
x 
Abdominal pain 
x 
Urticaria