A Phase 3, Global, Multi-Center, Double-Blind, Randomized, Efficacy Study of Zolbetuximab (IMAB362) Plus mFOLFOX6 Compared With Placebo Plus mFOLFOX6 as First-line Treatment of Subjects With Claudin (CLDN)18.2-Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
Phase: PHASE3
Conditions: Locally Advanced Unresectable Gastroesophageal Junction (GEJ) Adenocarcinoma or Cancer, Locally Advanced Unresectable Gastric Adenocarcinoma or Cancer, Metastatic Gastric Adenocarcinoma or Cancer, Metastatic Gastroesophageal Junction (GEJ) Adenocarcinoma
Sponsor: Astellas Pharma Global Development, Inc.

Sponsor: APGD 
ISN/Protocol 8951-CL-0301 
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A Phase 3, Global, Multi-Center, Double-Blind, Randomized, 
Efficacy Study of Zolbetuximab (IMAB362) Plus mFOLFOX6 
Compared with Placebo Plus mFOLFOX6 as First-line 
Treatment of Subjects with Claudin (CLDN)18.2-Positive, 
HER2-Negative, Locally Advanced Unresectable or Metastatic 
Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma 
ISN/Protocol 8951-CL-0301 
Spotlight 
 
Version 8.0 
Incorporating Substantial Amendment 7  
14 Nov 2024 
 
IND 129598 
EU CT 2024-511365-11 
EudraCT 2017-002567-17 
Sponsor: 
Astellas Pharma Global Development, Inc. (APGD) 
Northbrook, IL 60062 
 
Protocol History: 
Version 1.0 [31 Jan 2018] 
Version 2.0 [06 Jul 2018] Incorporating Substantial Amendment 1 
Version 3.0 [06 Aug 2019] Incorporating Substantial Amendment 2 
Version 3.1 [06 Jan 2021] Incorporating Nonsubstantial Amendment 1 
Version 4.0 [29 Aug 2019] Incorporating Country-specific Substantial Amendment 3 for China 
Version 4.1 [11 Jan 2021] Incorporating Country-specific Nonsubstantial Amendment 2 for China 
Version 5.0 [18 Oct 2021] Incorporating Substantial Amendment 4 
Version 6.0 [18 Oct 2021] Incorporating Country-specific Substantial Amendment 5 for China 
Version 6.1 [04 Oct 2023] Incorporating Country-specific Nonsubstantial Amendment 3 for Japan 
Version 7.0 [17 Nov 2023] Incorporating Substantial Amendment 6 
Version 7.1 [20 Dec 2023] Incorporating Nonsubstantial Amendment 4 
-------------------------------------------------------------------------------------------------------------------------------------- 
The information contained in this document is supplied as a background for clinical investigations. This document contains 
confidential information which is the intellectual property of Astellas. By accepting or reviewing this document, you agree 
to hold this information in confidence and not copy or disclose it to others or use it for unauthorized purposes except (1) as 
otherwise agreed to in writing; (2) where required by applicable law; (3) where disclosure is directly related to the care and 
safety of the research participant; and (4) where disclosure of such information is made to a member of the investigator’s 
team who agrees to hold this information in confidence.  

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Table of Contents  
I 
SIGNATURES ······················································································ 8 
II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL ···························· 11 
III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ·················· 12 
IV. 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ······························ 16 
V. 
SYNOPSIS ·························································································· 19 
VI. 
FLOW CHART, STUDY SCHEMATICS, AND SCHEDULE OF 
ASSESSMENTS ··················································································· 36 
1 
INTRODUCTION ················································································· 49 
1.1 
Background ···················································································· 50 
1.2 
Nonclinical and Clinical Data ······························································· 51 
1.2.1 
Nonclinical Data ········································································· 51 
1.2.2 
Clinical Data ············································································· 52 
1.3 
Summary of Key Safety Information for Study Drugs ··································· 53 
1.4 
Efficacy ························································································· 54 
1.4.1 
Efficacy of Zolbetuximab ······························································ 54 
1.4.2 
Efficacy of mFOLFOX6 ································································ 55 
1.5 
Risk Benefit Assessment ····································································· 55 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ·································· 56 
2.1 
Study Objective(s) ············································································ 56 
2.1.1 
Primary Objectives ······································································ 56 
2.1.2 
Secondary Objectives ··································································· 56 
2.1.3 
Exploratory Objectives ································································· 57 
2.2 
Study Design and Dose Rationale ··························································· 57 
2.2.1 
Study Design ············································································· 57 
2.2.2 
Dose Rationale ··········································································· 61 
2.3 
Endpoints ······················································································· 61 
2.3.1 
Primary Endpoints ······································································· 61 
2.3.2 
Secondary Endpoints ···································································· 62 
2.3.3 
Exploratory Endpoints ·································································· 62 
3 
STUDY POPULATION ·········································································· 62 
3.1 
Selection of Study Population ······························································· 62 
3.2 
Inclusion Criteria ·············································································· 63 

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3.3 
Exclusion Criteria ············································································· 64 
4 
IDENTIFICATION OF STUDY TREATMENT(S) ········································ 66 
4.1 
Zolbetuximab (IMAB362) (Investigational Product) ····································· 66 
4.2 
0.9% Sodium Chloride Injection ···························································· 67 
4.3 
Comparative Drug (Placebo) ································································ 67 
4.4 
mFOLFOX6 (Backbone Treatment) ························································ 67 
4.5 
Other Drug(s) ·················································································· 68 
4.5.1 
Antiemetic Premedication ······························································ 68 
4.6 
Study Drug Handling ········································································· 68 
4.7 
Blinding ························································································ 69 
4.7.1 
Blinding Method ········································································· 69 
4.7.2 
Confirmation of the Indistinguishability of the Study Drugs ······················ 69 
4.7.3 
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ·················································································· 69 
4.7.4 
Breaking the Treatment Code for Emergency ······································· 69 
4.7.5 
Breaking the Treatment Code by the Sponsor ······································· 70 
4.8 
Assignment and Allocation ·································································· 70 
5 
TREATMENTS AND EVALUATION ························································ 71 
5.1 
Dosing and Administration of Study Drug(s) and Other Medication(s) ················ 71 
5.1.1 
Dose/Dose Regimen and Administration Period ···································· 71 
5.1.2 
Study Treatment Dose Modifications, Delays And Interruptions ················· 73 
5.1.3 
Treatment Compliance ·································································· 84 
5.1.4 
Criteria for Continuation of Treatment ··············································· 84 
5.1.5 
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy ··················································································· 85 
5.2 
Demographics and Baseline Characteristics ··············································· 87 
5.2.1 
Demographics ············································································ 87 
5.2.2 
Medical History ·········································································· 87 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease ·············· 87 
5.3 
Efficacy Assessments ········································································· 87 
5.4 
Safety Assessment ············································································ 88 
5.4.1 
Vital Signs ················································································ 88 
5.4.2 
Observation Period Following Zolbetuximab/Placebo Infusion ··················· 88 
5.4.3 
Laboratory Assessments ································································ 89 

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5.4.4 
Physical Examination ··································································· 91 
5.4.5 
Electrocardiogram ······································································· 91 
5.4.6 
Performance Status ······································································ 92 
5.5 
Adverse Events and Other Safety Aspects ················································· 92 
5.5.1 
Definition of Adverse Events ·························································· 92 
5.5.2 
Definition of Serious Adverse Events················································· 93 
5.5.3 
Criteria for Causal Relationship to Study Treatment ································ 94 
5.5.4 
Criteria for Defining the Severity of an Adverse Event ···························· 95 
5.5.5 
Reporting of Serious Adverse Events ················································· 96 
5.5.6 
Follow-up of Adverse Events ·························································· 98 
5.5.7 
Monitoring of Common Serious Adverse Events ··································· 98 
5.5.8 
Adverse Events of Special Interest ···················································· 98 
5.5.9 
Special Situations ········································································ 99 
5.5.10 
Supply of New Information Affecting the Conduct of the Study ················ 101 
5.5.11 
Urgent Safety Measures ······························································ 101 
5.5.12 
Reporting Urgent Safety Measures ·················································· 102 
5.6 
Test Drug Concentration ··································································· 102 
5.7 
Other Measurements, Assessments or Methods ········································· 102 
5.7.1 
Biomarkers ············································································· 102 
5.7.2 
Blood, Serum and Plasma Samples ················································· 103 
5.7.3 
Tumor Tissue Samples ································································ 103 
5.7.4 
Immunogenicity Assessment (ADA)················································ 104 
5.7.5 
Optional Samples for Future Pharmacogenomic Analysis ······················· 104 
5.7.6 
Electronic Clinical Outcome Assessments (HRQoL and HRU) ················· 105 
5.8 
Total Amount of Blood ····································································· 106 
6 
DISCONTINUATION ·········································································· 106 
6.1 
Discontinuation of Individual Subject(s) From Study Treatment ····················· 106 
6.2 
Discontinuation of the Site ································································· 108 
6.3 
Discontinuation of the Study······························································· 108 
7 
STATISTICAL METHODOLOGY ························································· 108 
7.1 
Sample Size ·················································································· 109 
7.2 
Analysis Sets ················································································· 109 
7.2.1 
Full Analysis Set ······································································ 109 
7.2.2 
Safety Analysis Set ···································································· 109 

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7.2.3 
Pharmacokinetic Analysis Set ······················································· 109 
7.3 
Demographics and Baseline Characteristics ············································· 110 
7.3.1 
Subject Disposition ···································································· 110 
7.3.2 
Previous and Concomitant Medications ············································ 110 
7.3.3 
Medical History ········································································ 110 
7.4 
Analysis of Efficacy ········································································ 110 
7.4.1 
Analysis of Primary Endpoint ······················································· 110 
7.4.2 
Analysis of Secondary Endpoints ··················································· 111 
7.4.3 
Analysis of Exploratory Endpoints ·················································· 113 
7.5 
Analysis of Safety ··········································································· 114 
7.5.1 
Adverse Events ········································································ 114 
7.5.2 
Laboratory Assessments ······························································ 114 
7.5.3 
Vital Signs ·············································································· 115 
7.5.4 
Routine 12-lead Electrocardiograms ················································ 115 
7.5.5 
Eastern Cooperative Oncology Group Performance Status ······················ 115 
7.6 
Analysis of Pharmacokinetics ····························································· 115 
7.6.1 
Serum Concentrations································································· 115 
7.6.2 
Immunogenicity ······································································· 115 
7.7 
Major Protocol Deviations and Other Analyses ········································· 115 
7.8 
Interim Analysis (and Early Discontinuation of the Clinical Study) ·················· 115 
7.9 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ······· 116 
8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ·················· 116 
8.1 
Procedure for Clinical Study Quality Control ··········································· 116 
8.1.1 
Data Collection ········································································ 116 
8.2 
Major Protocol Deviations ································································· 118 
9 
END OF TRIAL IN ALL PARTICIPATING COUNTRIES ··························· 118 
10 
STUDY ORGANIZATION ···································································· 119 
10.1 
Independent Data Monitoring Committee ················································ 119 
10.2 
Other Study Organization ·································································· 119 
11 
REFERENCES ·················································································· 120 
12 
APPENDICES ··················································································· 123 
12.1 
Ethical, Regulatory, and Study Oversight Considerations ····························· 123 
12.1.1 
Ethical Conduct of the Study ························································· 123 

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12.1.2 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Competent Authorities (CA) ················································· 123 
12.1.3 
Protocol Amendment and/or Revision ·············································· 123 
12.1.4 
Informed Consent of Subjects ······················································· 124 
12.1.5 
Source Documents ···································································· 125 
12.1.6 
Record Retention ······································································ 125 
12.1.7 
Subject Confidentiality and Privacy ················································· 125 
12.1.8 
Arrangement for Use of Information and Publication of the Clinical Study ··· 126 
12.1.9 
Insurance of Subjects and Others (UNIQUE TO JAPAN 
REGION/STUDIES ENROLLING SUBJECTS IN EU) ························· 126 
12.1.10 
Signatory Investigator for Clinical Study Report ·································· 127 
12.2 
Procedures for Clinical Study Quality Control ·········································· 128 
12.2.1 
Clinical Study Monitoring ···························································· 128 
12.2.2 
Direct Access to Source Data/Documents ·········································· 128 
12.2.3 
Data Management ····································································· 128 
12.2.4 
Quality Assurance ····································································· 128 
12.3 
Contraception Requirements ······························································· 129 
12.4 
Concomitant Medication Restrictions or Requirements ································ 131 
12.5 
Liver Safety Monitoring and Assessment ················································ 133 
12.6 
Common Serious Adverse Events ························································· 136 
12.7 
Pharmacogenomic Analysis with Banked Samples (Optional) ························ 137 
12.8 
Eastern Cooperative Oncology Group Performance Status Scale ····················· 139 
12.9 
Clinical Study Continuity ·································································· 140 
12.10 
Unblinding Procedures Following Final Overall Survival Database Lock ··········· 157 
13 
PROTOCOL VERSION 7.0 (SUBSTANTIAL AMENDMENT 6) AND 
LATER: FLOW CHART, STUDY SCHEMATICS, AND SCHEDULE OF 
ASSESSMENTS ················································································· 158 
14 
COORDINATING INVESTIGATOR’S SIGNATURE ·································· 170 
15 
SPONSOR’S SIGNATURES ·································································· 171 
 

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List of In-text Tables 
Table 1 
Up Through Protocol 6.1 (Original Protocol Version 1 Through 6.1): Schedule 
of Assessments ················································································ 41 
Table 2 
Guidelines for Zolbetuximab/Placebo Treatment Modification Due to Non-
Hematologic Toxicity ········································································· 74 
Table 3 
Guidelines for Zolbetuximab/Placebo Treatment Modification Due to 
Hematologic Toxicity ········································································· 75 
Table 4 
Infusion-Related Reactions ·································································· 77 
Table 5 
Recommended Dose Adjustment Levels for Oxaliplatin and 5-FU ····················· 78 
Table 6 
mFOLFOX6 Dose Modification Due to Hematologic Toxicity ························· 79 
Table 7 
mFOLFOX6 Dose Modification Due to Non-hematologic Toxicity ··················· 81 
Table 8 
Oxaliplatin Dose Modification for Associated Neurotoxicity ··························· 82 
Table 9 
Comparison of the Symptoms and Treatment of Laryngopharyngeal and 
Platinum Hypersensitivity Reactions ······················································· 83 
Table 10 
Up Through Protocol Version 6.1 or Earlier (Original Protocol Version 1 
through 6.1): Alternate Schedule of Assessments in Response to a Crisis ··········· 142 
Table 11 
Protocol Version 7.0 (Substantial Amendment 6) and Later: Schedule of 
Assessments ················································································· 159 
Table 12 
Protocol Version 7.0 (Substantial Amendment 6) and Later: Alternate Schedule 
of Assessments in Response to a Crisis ·················································· 164 
 

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I 
SIGNATURES 
1.  SPONSOR’S SIGNATURES 
Required signatures (e.g., Protocol authors and contributors, etc.) are located in [Section 15 
Sponsor’s Signatures].   
 

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2. COORDINATING INVESTIGATOR’S SIGNATURE 
The Coordinating Investigator’s signature, where applicable, can be found in [Section 14 
Coordinating Investigator’s Signature]; located at the end of this document. 

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3. INVESTIGATOR’S SIGNATURE 
A Phase 3, Global, Multi-Center, Double-Blind, Randomized, Efficacy Study of 
Zolbetuximab (IMAB362) Plus mFOLFOX6 Compared with Placebo Plus 
mFOLFOX6 as First-line Treatment of Subjects with Claudin (CLDN)18.2-
Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric 
or Gastroesophageal Junction (GEJ) Adenocarcinoma 
ISN/Protocol 8951-CL-0301  
Version 8.0 Incorporating Substantial Amendment 7 
14 Nov 2024 
I have read all pages of this clinical study protocol for which Astellas is the sponsor. I agree to 
conduct the study as outlined in the protocol and to comply with all the terms and conditions set 
out therein. I confirm that I will conduct the study in accordance with International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and applicable local regulations. I 
will also ensure that sub-investigator(s) and other relevant members of my staff have access to 
copies of this protocol and the ICH GCP guidelines to enable them to work in accordance with the 
provisions of these documents. 
Principal Investigator: 
 
Signature:   --------------------------------------------------------------------------------------------------------- 
                                                                                                                       Date (DD Mmm YYYY) 
 
Printed Name:    --------------------------------------------------------------------------------------------------- 
 <Insert name and qualification of the Investigator> 
 
Address:    ---------------------------------------------------------------------------------------------------------- 
 
                  ---------------------------------------------------------------------------------------------------------- 
 
 

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III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
5-FU 
fluorouracil  
ADA 
anti-drug antibody 
ADCC 
antibody-dependent cellular cytotoxicity 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (GPT) 
ANC 
absolute neutrophil count 
APEBV 
Astellas Pharma Europe B.V. 
AST 
aspartate aminotransferase (GOT) 
βhCG 
beta human chorionic gonadotropin (hCG) 
C1D1 
Cycle 1 Day 1 
CA 
Competent Authorities 
CDC 
complement-dependent cytotoxicity 
CI 
confidence interval 
CLDN 
claudin 
Cmax 
maximum concentration 
CMH 
Cochran-Mantel-Haenszel 
CR 
complete response 
CRO 
contract research organization 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria For Adverse Events 
DCR 
disease control rate 
DOR 
duration of response 
DPD 
dihydropyrimidine dehydrogenase deficiency 
ECG 
electrocardiogram 
ECL 
electrochemiluminescense 
eCOA 
Electronic Clinical Outcomes Assessment  
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EEA 
European Economic Area 
EORTC 
European Organization for Research and Treatment of Cancer 
EOX 
epirubicin, oxaliplatin and capecitabine 
EQ-5D 
EuroQOL Five Dimensions Questionnaire 
EQ5D-5L  
EuroQOL Five Dimensions Questionnaire 5L  
EU 
European Union 
FAS 
full analysis set 
FIM 
first-in-human 
FFPE 
formalin-fixed paraffin embedded 
GCP 
Good Clinical Practices 

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Abbreviations 
Description of abbreviations 
GE 
gastroesophageal 
GEJ 
gastroesophageal junction 
GHS/QoL 
Global Health Status/Quality of Life 
GMP 
Good Manufacturing Practices 
GP 
Global Pain 
Hgb 
hemoglobin 
HEOR 
health economics and outcomes research 
HER2 
human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
HRU 
Health Resource Utilization 
HSR 
hypersensitivity reactions 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH  
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IDMC 
independent data monitoring committee 
IEC 
independent ethics committee 
IHC 
immunohistochemistry 
IMAB 
ideal monoclonal antibody 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
institutional review board 
IRC 
independent review committee 
IRR 
infusion-related reaction 
IRT 
interactive response technology 
ISN 
international study number 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
Intravenous, intravenously 
LA-CRF 
liver abnormality case report form 
LFT 
liver function tests 
mAbs 
monoclonal antibodies 
MCH 
mean corpuscular hemoglobin 
mFOLFOX6 
5-fluorouracil, folinic acid and oxaliplatin 
MRI 
magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NSAID 
nonsteroidal anti-inflammatory drugs 
OG25-Pain 
oesophago-gastric questionnaire (OG25) on abdominal pain and discomfort 
ORR 
objective response rate 

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Abbreviations 
Description of abbreviations 
OS 
overall survival 
PD 
progressive disease 
PF 
physical function 
PFS 
progression free survival 
PFS2 
progression free survival following second-line anticancer treatment  
PGx 
pharmacogenomics 
PKAS 
pharmacokinetic analysis set 
PR 
partial response 
PRES 
posterior reversible encephalopathy syndrome 
PT 
prothrombin time 
PTL 
platelet count 
QLQ-C30 
Quality of Life Questionnaire – Core Questionnaire (EORTC QLQ-C30) 
QLQ-OG25 
Quality of Life Questionnaire – Oesophago-Gastric Module 25 (OG-25) 
QTc 
QT corrected 
QTcF 
Fridericia-corrected QT interval 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RSI 
Reference Safety Information 
(S)AE 
serious adverse event and/or adverse event 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SD 
stable disease 
SOP 
standard operating procedure 
SPC 
summary of product characteristics 
SUSAR 
suspected unexpected serious adverse reactions 
T4 
thyroxine 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid stimulating hormone 
TTCD 
time to confirmed deterioration 
TTP 
time to progression 
ULN 
upper limit of normal 
USM 
urgent safety measure 
VEGF 
vascular endothelial growth factor 
WBC 
white blood cell 
WOCBP 
woman of childbearing potential 
 
 

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Definition of Key Study Terms 
Terms 
Definition of terms 
Baseline  
Assessments of subjects as they enter a trial before they receive any 
treatment.  
Endpoint  
Variable that pertains to the efficacy or safety evaluations of a trial. 
Enroll 
To register or enter a subject into a clinical trial. NOTE: Once a subject has 
received the study drug or placebo, the clinical trial protocol applies to the 
subject.  
Intervention 
The drug, device, therapy or process under investigation in a clinical study 
that is believed to have an effect on outcomes of interest in a study (e.g., 
health-related quality of life, efficacy, safety, pharmacoeconomics).  
Investigational 
period 
Period of time where major interests of protocol objectives are observed, 
and where the test drug or comparative drug (sometimes without 
randomization) is usually given to a subject, and continues until the last 
assessment after completing administration of the test drug or comparative 
drug. 
Post investigational 
period 
Period of time after the last assessment of the protocol. Follow-up 
observations for sustained adverse events and/or survival are done in this 
period. 
Randomization 
The process of assigning trial subjects to treatment or control groups using 
an element of chance to determine assignments in order to reduce bias. 
Screening 
A process of active consideration of potential subjects for enrollment in a 
trial. 
Screen failure 
Potential subject who did not meet 1 or more criteria required for 
participation in a trial. 
Screening period 
Period of time before entering the investigational period, usually from the 
time when a subject signs the consent until just before the test drug or 
comparative drug (sometimes without randomization) is given to a subject.  
Study period 
Period of time from the first site initiation date to the last site completing the 
study. 
Study treatment  
Includes zolbetuximab/placebo and all components of mFOLFOX6 
Variable 
Any entity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values. 
 
 

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IV. 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Global 
Country Specific 
Initial Protocol 
Version 1.0 
N/A 
First Global Substantial Amendment 
Version 2.0 
N/A 
Second Global Substantial Amendment 
Version 3.0 
N/A 
First Global Nonsubstantial Amendment 
Version 3.1 
N/A 
First China Country-specific Substantial Amendment 
N/A 
4.0 [CN] 
Second China Country-specific Nonsubstantial Amendment 
N/A 
4.1 [CN] 
Third Global Substantial Amendment 
Version 5.0 
N/A 
Third China Country-specific Substantial Amendment 
N/A 
6.0 [CN] 
First Japan Country-specific Nonsubstantial Amendment 
N/A 
6.1 [JP] 
Fourth Global Substantial Amendment 
Version 7.0 
N/A 
Second Global Nonsubstantial Amendment 
Version 7.1 
N/A 
Amendment 7 [Substantial] 14 Nov 2024 
This amendment is considered to be substantial based on the criteria set forth in Regulation (EU) No 536/2014 of the European Parliament. The changes 
in this amendment do not include any change in study conduct that would affect participant outcomes. 
Overall Rationale for the Amendment: 
The amendment updates the following: 
• Description of the investigational product vial to match the drug label update.  
• Clarifications are made to existing study procedures and guidance is provided on transitioning participants to commercially marketed and locally 
accessible product supply.  

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Summary of Changes 
 
Substantial Changes 
Section Number 
Description of Change 
Brief Rationale 
V, 2.2.1, 5.1.1.1, 6.3 
Added study discontinuation criterion to conclude study once 
participants have transitioned to commercially marketed and 
locally accessible product supply. 
Zolbetuximab is available outside of clinical trials in 
some regions. 
 
Nonsubstantial Changes 
Section Number 
Description of Change 
Brief Rationale 
II, 15 
Update affiliation of Medical Monitor. 
Change in name of affiliated department. 
II 
Remove contact information for Sponsor’s individual clinical 
research personnel (while retaining Medical Monitor). 
Prevents additional future protocol amendments due to 
future personnel changes.  
V, 2.2.1, 5.1.1.1, 5.1.4, 
6.1 
Add a guidance to transition participants to commercially 
marketed and locally accessible product supply. 
Zolbetuximab is available outside of clinical trials in 
some regions. 
V, 4.1 
Add description of amount of zolbetuximab extractable from the 
investigational product vial. 
Update vial description in protocol to match drug label 
update. 
1.1, 1.2.1 
Clarify and update nonclinical background information. 
Additional relevant information for nonclinical 
background. 
2.2.1 
Clarify that the 90-day Safety Follow-up Visit will be conducted 
by phone. 
Clarify and make consistent between sections. 
5.5, 5.5.5, 5.5.6, 13 
Specify requirements for safety reporting for participants 
continuing treatment on commercially marketed and locally 
accessible product supply. 
Define safety reporting requirements once a participant 
transitions to commercially marketed and locally 
accessible product supply and is no longer 
participating in the clinical trial. 
11 
Updated list of references to include all cited in protocol body. 
Update for completeness of reference list. 
13 
Specify that the section and schedules of assessments (Tables 11 
and 12) apply for Protocol Versions 7.0 and later. 
Clarify the continued applicability of the section. 
13 
Add footnote to schedules of assessments (Tables 11 and 12) to 
clarify that participants assigned to Arm B (mFOLFOX6 
Clarify that participants assigned to Arm B are not 
required to be dosed with placebo and not required to 

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Section Number 
Description of Change 
Brief Rationale 
chemotherapy in combination with placebo) who continue in the 
study are not required to receive placebo (and may receive the 
chemotherapy components without placebo), and are not required 
to attend Day 22 visits.  
attend Day 22 visits. If they choose to stay in the study, 
they may receive chemotherapy without placebo. 
Throughout 
Minor administrative-type changes were made, e.g., typos, 
formatting, section and footnote numbering and other continuity 
throughout the protocol.  
To provide clarification and consistency. 
 
 

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V. 
SYNOPSIS 
Date and Version No of Protocol Synopsis: 
14 Nov 2024, Version 8.0 
Sponsor:   
Astellas Pharma Global Development, Inc. (APGD) 
Protocol Number:  
8951-CL-0301 
Name of Study Drug:  
zolbetuximab (IMAB362) 
Phase of Development:   
Phase 3 
Title of Study:   
A Phase 3, Global, Multi-Center, Double-Blind, Randomized, Efficacy Study of Zolbetuximab 
(IMAB362) Plus mFOLFOX6 Compared with Placebo Plus mFOLFOX6 as First-line Treatment of 
Subjects with Claudin (CLDN)18.2-Positive, HER2-Negative, Locally Advanced Unresectable or 
Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma 
Planned Study Period:  
From 2Q2018 to 2Q2025 
Study Objective(s):  
Primary 
• 
To evaluate the efficacy of zolbetuximab plus mFOLFOX6 compared with placebo plus 
mFOLFOX6 (as first-line treatment) as measured by Progression Free Survival (PFS) in 
subjects with Claudin (CLDN)18.2 positive, human epidermal growth factor receptor 2 
(HER2)–negative locally advanced unresectable or metastatic gastric and gastroesophageal 
junction (GEJ) adenocarcinoma 
Secondary 
• 
To evaluate efficacy as measured by Overall Survival (OS) as a key secondary objective  
• 
To evaluate the physical function (PF), OG25-Pain and GHS/QoL scores as measured by 
European Organization for Research and Treatment of Cancer (EORTC) as a key secondary 
objective 
• 
To evaluate efficacy as measured by Objective Response Rate (ORR) 
• 
To evaluate efficacy as measured by Duration of Response (DOR) 
• 
To evaluate safety and tolerability of zolbetuximab 
• 
To further evaluate other health related quality of life (HRQoL) using additional parameters 
as measured by EORTC QLQ-C30, QLQ-OG25, Global Pain (GP) and the EuroQOL Five 
Dimensions Questionnaire 5L (EQ5D-5L) questionnaires 
• 
To evaluate the pharmacokinetics of zolbetuximab 
• 
To evaluate the immunogenicity profile of zolbetuximab 
Exploratory 
• 
To evaluate efficacy as measured by Time to Progression (TTP)  
• 
To evaluate PFS following subsequent anticancer treatment (PFS2)  
• 
To evaluate Disease Control Rate (DCR)  
• 
To evaluate potential genomic and/or other biomarkers that may correlate with treatment 
outcome to zolbetuximab and mFOLFOX6. (NOTE: Genomic and exploratory biomarker 
testing will not be performed on samples from subjects in China.) 
• 
To evaluate Health Resource Utilization (HRU) 
Planned Total Number of Study Centers and Location(s):   
Approximately 240 centers globally 

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Study Population:   
Subjects with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma whose 
tumors are CLDN18.2 positive, HER2-negative and who have not been previously treated for 
metastatic disease with chemotherapy (1st line). 
For the purpose of this study, CLDN18.2-positive is defined as CLDN18.2 expression in ≥ 75% of 
tumor cells demonstrating moderate to strong membranous staining as determined by central 
immunohistochemistry (IHC) testing.   
Number of Subjects to be Enrolled/Randomized:   
Approximately 550 subjects 
Study Design Overview:   
This global, multi-center, double-blind, 1:1 randomized, phase 3 study will evaluate efficacy of 
zolbetuximab plus mFOLFOX6 versus placebo plus mFOLFOX6 as first-line treatment in subjects 
with CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric and 
GEJ adenocarcinoma. 
PFS is the primary outcome. Secondary outcomes include OS, ORR, DOR, safety and tolerability, 
HRQoL, pharmacokinetics and the immunogenicity profile of zolbetuximab. Exploratory outcomes 
include TTP, PFS2, DCR biomarkers, and HRU.  
Approximately 550 subjects will be 1:1 randomized into 1 of 2 treatment arms:  
• 
Arm A (mFOLFOX6 chemotherapy in combination with zolbetuximab)  
• 
Arm B (mFOLFOX6 chemotherapy in combination with placebo) 
Randomization of subjects will be stratified by the following factors:  
• 
Region (Asia vs Non-Asia) 
• 
Number of organs with metastatic sites (0 to 2 vs ≥ 3) 
• 
Prior gastrectomy (Yes or No) 
Screening: 
The Screening period is 45 days from full main informed consent form (ICF) signature. Retesting 
of lab values is allowed within the 45-day Screening period. Re-screening outside the 45-day 
window under a new subject number may be allowed once and upon discussion with the Medical 
Monitor. Computerized tomography (CT) scans and magnetic resonance imaging (MRI) conducted 
as part of a subject’s routine clinical management (i.e., standard of care) obtained before signing 
the ICF may be utilized for screening or baseline purposes, provided the procedures met the 
protocol-specified criteria and were performed within the Screening period.  
Formalin fixed paraffin embedded (FFPE) tumor tissue will be collected for central testing to 
determine CLDN18.2 and HER2 status. 
An optional partial screening ICF may be available to allow central testing of tissue for CLDN18.2 
and HER2 only. (Unique to China: An optional partial screening ICF may be available to allow 
central testing of tissue for CLDN18.2.)   
• Archival tumor tissue is preferred.  
o A minimum of 1 FFPE tumor tissue block (preferred) OR a minimum* of 15 FFPE 
unstained slides are required, as allowed per local policy. If slides are submitted, the 
slides should be freshly cut from the FFPE block within the time frame described in the 
laboratory manual.  
o If local HER2 results are already available from local testing, a minimum* of 12 FFPE 
unstained slides are required to be submitted to the central laboratory, as allowed per 
local policy.  
*If the required minimum number of slides is not able to be submitted, sponsor 
notification and approval is required. 

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o (Unique to China: Five FFPE unstained slides are required, as allowed per local policy. 
The slides should be freshly cut from the FFPE block within the time frame described in 
the laboratory manual.)  
• If the specimen is insufficient or unavailable, a biopsy may be performed to obtain tumor 
sample.  
o Sponsor pre-approval is required when the sole purpose of the biopsy procedure is to 
assess eligibility for this study.  
o If the required number of slides cannot be provided, the sponsor or designee should be 
contacted for further guidance.  
Treatment Period: 
Subjects will be treated with either zolbetuximab (Arm A) or placebo (Arm B) on Days 1 and 22 
starting at C1D1 until the subject meets study treatment discontinuation criteria or zolbetuximab is 
commercially marketed and locally accessible. 
Once the product is commercially marketed and locally accessible, participants should complete 
the study, transition to commercial supply and follow the local label for treatment. 
Astellas is planning to close the clinical study when zolbetuximab (Vyloy) is commercially 
marketed in all countries with active participants and all participants have successfully transitioned 
to an alternative means of drug supply. 
During treatment on study protocol, subjects will receive up to 12 treatments of mFOLFOX6 (or 
components of mFOLFOX6 if some components are discontinued due to toxicity) over 4 or more 
cycles (each cycle is approximately 42 days) in which mFOLFOX6 is administered on Days 1, 15 
and 29 of each cycle. After 12 mFOLFOX6 treatments, subjects may continue to receive 
fluorouracil (5-FU) and folinic acid on Days 1, 15 and 29 of each cycle at the investigator’s 
discretion until the subject meets study treatment discontinuation criteria. (NOTE: An ECG is 
required to be performed and assessed locally prior to every oxaliplatin infusion [before any 
antiemetic treatment] and following completion of every oxaliplatin infusion. ECG should be 
performed up to 48 hours prior to and up to 6 hours following every oxaliplatin infusion. 
Oxaliplatin administration and electrolyte levels should be managed according to the investigator’s 
judgement for subjects with grade 1 or 2 hypokalemia, hypomagnesemia and/or hypocalcemia.) 
Participants who discontinue zolbetuximab and continue to receive mFOLFOX6 or components of 
mFOLFOX6 should complete procedures on the study and transition to commercially marketed 
and locally accessible product(s) (mFOLFOX6 or its applicable components). 
If a subject discontinues mFOLFOX6 (or components of mFOLFOX6) due to any reason other 
than disease progression as confirmed locally or by independent review committee (IRC), they 
may continue on zolbetuximab/placebo at the discretion of the investigator provided that all of the 
following have been met: 
• the subject completed at least 1 cycle (42 days) of mFOLFOX6 treatment; 
• the subject will not receive another systemic chemotherapy, immunotherapy, radiotherapy or 
other treatment intended for antitumor activity; and 
• in the investigator’s opinion the subject continues to derive clinical benefit with acceptable 
toxicity. 
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), radiological 
disease progression will be determined locally and subjects should continue to follow the Study 
Treatment Period Schedule of Assessments [Table 11]. Under Protocol Version 6.1 or earlier (e.g., 
Original Protocol Version 1 through 6.1), radiological disease progression was determined by IRC 
and subjects followed the Study Treatment Period Schedule of Assessments [Table 1]. 
Safety Assessments 
Safety will be evaluated based on adverse events (AEs), vital signs, electrocardiograms (ECGs), 
physical exams, Eastern Cooperative Oncology Group (ECOG) performance status and laboratory 

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Version 8.0 Incorporating Substantial Amendment 7 
assessments. Severity of AEs and laboratory abnormalities will be assessed based on Common 
Terminology Criteria For Adverse Events (CTCAE) v4.03.  
Radiologic Imaging and Independent Review Committee: 
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), radiologic 
imaging will be evaluated locally [Table 11]. Under Protocol Version 6.1 or earlier (e.g., Original 
Protocol Version 1 through 6.1), radiographic imaging was evaluated centrally by IRC.  
Radiologic imaging will be evaluated at Screening (within 28 days prior to randomization) and 
every 9 weeks (± 7 days) counting from C1D1 for the first 54 weeks and then every 12 weeks 
(± 7 days) thereafter until subject develops radiological disease progression per Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 by local confirmation or IRC confirmation or 
starts other systemic anticancer treatment, whichever comes earlier.  
All radiologically evaluable disease (measurable and/or non-measurable), per local assessment, 
must be documented at Screening and re-assessed at each subsequent radiologic evaluation. 
Imaging will include CT scans with contrast of the thorax, abdomen, and pelvis. If CT scan with 
contrast is medically not feasible, magnetic resonance imaging may be used for imaging. Bone 
scans (or focal X-ray) or brain imaging should be performed if metastatic disease in bone or brain 
is suspected, respectively. The same mode of imaging should be utilized throughout the study 
unless medical necessity requires a change. For randomized subjects, screening imaging should be  
sent to the central imaging vendor no later than at the time of submission of the first on-treatment 
imaging. All imaging acquired post randomization will be sent to the local or central imaging 
vendor within 7 days of scanning for the blinded independent central assessment of radiological 
tumor response based on RECIST 1.1 [Eisenhauer et al, 2009]. The investigator should make every 
effort to immediately submit radiologic assessments for local or IRC review when progressive 
disease (PD) is suspected. 
Study Treatment Discontinuation and Safety Follow-up Visits 
Following discontinuation from zolbetuximab/placebo, subjects will have a zolbetuximab/placebo 
Study Treatment Discontinuation Visit, and 30-day and 90-day Safety Follow-up Visits following 
their last dose of zolbetuximab/placebo.   
Additionally, if mFOLFOX6 (all components) is discontinued on a different day than 
zolbetuximab/placebo, subjects will also have a Study Treatment Discontinuation Visit, and 30-day 
and 90-day Safety Follow-up Visits following the last dose of mFOLFOX6 (all components). The 
mFOLFOX6 30-day and 90-day Safety Follow-up Visits may be conducted by telephone if the 
subject is unable to visit the study site and will require only contact for AE/SAE collection. 
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), the 90-day 
Safety Follow-up Visit will be conducted by phone; see the Schedule of Assessments [Table 11] in 
[Section 13].  
Post-Treatment Follow-up Period (for PFS): 
Note: Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), the 
Post-Treatment Follow-up Period (for PFS) is discontinued; see the Schedule of Assessments 
[Table 11] in [Section 13].  
Subjects that completed the 90-Day Safety Follow up Visit(s) treatment period under Protocol 
Version 6.1 or earlier (e.g., Original Protocol Version 1 through 6.1) were eligible for the 
Post-Treatment Follow-up Period (for PFS) and were followed as outlined in Protocol Version 6.1 
with radiological disease progression determined by IRC as outlined in [Table 1]. If a subject 
discontinues all study treatments (zolbetuximab/placebo and all components of mFOLFOX6) prior 
to IRC-confirmed radiological disease progression, the subject will enter the Post-Treatment 
Follow-up Period and continue to undergo scheduled imaging assessments every 9 weeks (or every 

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12 weeks if subjects has been on study over 54 weeks) until radiologic disease progression (i.e., 
PFS event) or the subject starts any other anticancer treatment, whichever occurs earlier.  
If study treatment (zolbetuximab/placebo and all components of mFOLFOX6) is discontinued due 
to disease progression (PFS event), the subject will enter the Long Term and Survival Follow-up 
Period.  
Long Term Follow-up Period (for PFS2) and Survival Follow-up (for OS) Period: 
Note: Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), the Long 
Term Follow-up Period (for PFS2) and Survival Follow-up (for OS) Period is discontinued; see the 
Schedule of Assessments [Table 11] in [Section 13].  
Subjects that completed the Post-Treatment Follow-up Period (for PFS)  under Protocol Version 
6.1 or earlier (e.g., Original Protocol Version 1 through 6.1) were eligible for the Long Term 
Follow-up Period (for PFS2) and Survival Follow-up (for OS) Period and were followed as 
outlined in Protocol Version 6.1 as outlined in [Table 1]. Following disease progression on first-
line treatment or start of any other anticancer treatment, subjects will be followed in the Long-
Term and Survival Follow-up Period per institutional guidelines, but not less frequently than every 
12 weeks to confirm survival status (i.e. OS) and collect subsequent anticancer treatment details 
and progression status until PD following subsequent anticancer therapy (PFS2) is documented or 
the subject starts another systemic anticancer treatment , whichever occurs earlier. Radiologic 
imaging for PFS2 will be done per standard of care and read locally. Survival Follow-up Period 
will continue until death (from any cause). 
All post-progression details, including subsequent anticancer treatment and date and site of 
progression, will be recorded on the electronic case report form (eCRF). Subject contact by phone 
or other remote methods is sufficient during Long Team and Survival Follow-up. Additional 
follow-up contacts may be required per sponsor request for analysis purposes. 
Biomarkers and Other Sampling 
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), samples for 
pharmacokinetics, immunogenicity and biomarkers, as well as FFPE tumor tissue specimens will 
be collected as outlined in [Table 11]. Under Protocol Version 6.1 or earlier (e.g., Original Protocol 
Version 1 through 6.1), samples for pharmacokinetics, immunogenicity and biomarkers, as well as 
FFPE tumor tissue specimens (for eligibility) will be collected as outlined in [Table 1]; optional 
pharmacogenomics and post-progression tumor samples may be collected for those subjects who 
sign a separate ICF. 
Electronic Clinical Outcomes Assessments (HRQoL and HRU) 
HRQoL and HRU should be assessed during the visit (or up to 48 hours) before any antiemetic or 
drug treatment(s) administration and before the disease status is discussed with the subject. 
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), assessments 
are discontinued [Table 11]. Under Protocol Version 6.1 or earlier (e.g., Original Protocol Version 1 
through 6.1), HRQoL and HRU were assessed at Screening (except HRU), every 3 weeks, at study 
treatment discontinuation and 30 and 90 days post zolbetuximab/placebo treatment [Table 1]. 
HRQoL will be measured by EORTC QLQ-C30, QLQ-OG25, GP and the EQ5D-5L. 
Independent Data Monitoring Committee and Independent Data Analysis Center 
An Independent Data Monitoring Committee (IDMC) will be established and will monitor the 
benefit-risk of study treatment in an unblinded fashion per pre-defined IDMC charter. The first 
IDMC meeting will be approximately 6 weeks after the 40th subject enrolled has completed or 

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discontinued Cycle 1 (6 weeks) and meetings will be conducted regularly thereafter, as determined 
by the IDMC.  
An Independent Data Analysis Center will conduct an interim analysis of OS at the same time as 
the final PFS analysis, which will occur when approximately 300 PFS events have occurred. This 
analysis will be utilized by the IDMC to recommend whether the study should be stopped earlier 
than planned if zolbetuximab in combination with mFOLFOX6 has a favorable outcome compared 
with mFOLFOX6 in combination with placebo. If the OS interim analysis demonstrates a highly 
more favorable outcome for zolbetuximab in combination with mFOLFOX6, the study may be 
stopped for success. However, any subject continuing to derive clinical benefit from 
zolbetuximab/placebo in combination with mFOLFOX6 as assessed by the investigator will be 
allowed to continue treatment. The full procedures for IDMC review will be described in a separate 
IDMC charter. 
(UNIQUE to JP): In case that zolbetuximab is approved for marketing authorization in Japan, the 
study will continue as a “phase 4 post-marketing study” in accordance with Good Post-marketing 
Study Practice on and after the day of marketing authorization. In this case, “Study” in the 
protocol is read as “Post-marketing study.” 
Inclusion/Exclusion Criteria: 
Inclusion Criteria:   
Waivers to the inclusion criteria will NOT be allowed. 
General Criteria: 
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
informed consent and privacy language as per national regulations (e.g., Health Insurance 
Portability and Accountability Act [HIPAA] Authorization for US sites) must be obtained from 
the subject or legally authorized representative (if applicable) prior to any study-related 
procedures. 
2. Subject is considered an adult (e.g., ≥ 18 years of age in the US) according to local regulation 
at the time of signing the informed consent. 
3. Subject agrees not to participate in another interventional study while on study treatment. 
4. A female subject is eligible to participate if she is not pregnant (negative serum pregnancy test 
at Screening; female subjects with elevated serum beta human chorionic gonadotropin (βhCG) 
and a demonstrated non-pregnant status through additional testing are eligible) and at least 1 of 
the following conditions applies: 
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 12.3 
Contraception Requirements 
OR 
b. WOCBP who agrees to follow the contraceptive guidance as defined in Appendix 12.3 
Contraception Requirements throughout the treatment period and for 9 months after 
the final administration of oxaliplatin and 6 months after the final administration of all 
other study drugs. 
5. Female subject must agree not to breastfeed starting at Screening and throughout the study 
period, and for 6 months after the final study treatment administration. 
6. Female subject must not donate ova starting at Screening and throughout the study period, and 
for 9 months after the final administration of oxaliplatin and 6 months after the final 
administration of all other study drugs. 
7. A sexually active male subject with female partner(s) who are of childbearing potential must 
agree to use contraception as detailed in Appendix 12.3 Contraception Requirements during 
the treatment period and for at least 6 months after the final study drug administration.  
8. Male subject must not donate sperm starting at Screening and throughout the study period and 
for 6 months after the final study drug administration.  

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9. Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent 
or use a condom for the duration of the pregnancy or for the time partner is 
breastfeeding throughout the study period and for 6 months after the final study drug 
administration.  
Disease Specific Criteria: 
10. Subject has histologically confirmed diagnosis of Gastric or GEJ adenocarcinoma.  
11. Subject has radiologically confirmed locally advanced unresectable or metastatic disease within 
28 days prior to randomization.  
12. Subject has radiologically evaluable disease (measurable and/or non-measurable disease 
according to RECIST 1.1), per local assessment, ≤ 28 days prior to randomization. For subjects 
with only 1 evaluable lesion and prior radiotherapy ≤ 3 months before randomization, the lesion 
must either be outside the field of prior radiotherapy or have documented progression following 
radiation therapy. 
13. Subject’s tumor expresses CLDN18.2 in ≥ 75% of tumor cells demonstrating moderate to strong 
membranous staining as determined by central IHC testing. 
14. Subject has a HER2-negative tumor as determined by local or central testing on a gastric or 
GEJ tumor specimen. (Unique to China: Subject has a known HER2-negative gastric or GEJ 
tumor). 
Physical or Laboratory Findings 
15. Subject has ECOG performance status 0 to 1. 
16. Subject has predicted life expectancy  12 weeks in the opinion of the investigator. 
17. Subject must meet all of the following criteria based on the centrally or locally analyzed 
laboratory tests collected within 14 days prior to randomization. In the case of multiple sample 
collections within this period, the most recent sample collection with available results should 
be used to determine eligibility.  
a. Hemoglobin (Hgb) ≥ 9 g/dL. Subjects requiring transfusions are eligible if they have a 
post-transfusion Hgb ≥ 9 g/dL. 
b. Absolute neutrophil count ≥ 1.5 x 109/L 
c. Platelets ≥ 100 x 109/L 
d. Albumin ≥ 2.5 g/dL 
e. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) without liver metastases (or < 3.0 
x ULN if liver metastases are present) 
f. Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN without liver 
metastases (or ≤ 5 x ULN if liver metastases are present)  
g. Estimated creatinine clearance ≥ 30 mL/min  
h. Prothrombin time/international normalized ratio and partial thromboplastin time 
≤ 1.5 x ULN (except for subjects receiving anticoagulation therapy) 

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Exclusion Criteria: 
Waivers to the exclusion criteria will NOT be allowed.   
Subject who meets any of the following exclusion criteria prior to enrollment is not eligible for 
enrollment:  
Prohibited Treatment or Therapies 
1. Subject has received prior systemic chemotherapy for locally advanced unresectable or 
metastatic gastric or GEJ adenocarcinoma. However, subject may have received either neo-
adjuvant or adjuvant chemotherapy, immunotherapy or other systemic anticancer therapies as 
long as it was completed at least 6 months prior to randomization. Subject may have received 
treatment with herbal medications that have known antitumor activity > 28 days prior to 
randomization. 
2. Subject has received radiotherapy for locally advanced unresectable or metastatic gastric or 
GEJ adenocarcinoma ≤ 14 days prior to randomization and has not recovered from any related 
toxicity.  
3. Subject has received systemic immunosuppressive therapy, including systemic corticosteroids 
within 14 days prior to randomization. Subjects using a physiologic replacement dose of 
hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 
mg per day of prednisone), receiving a single dose of systemic corticosteroids or receiving 
systemic corticosteroids as premedication for radiologic imaging contrast use are allowed. 
4. Subject has received other investigational agents or devices within 28 days prior to 
randomization. 
Medical History or Concurrent Disease 
5. Subject has prior severe allergic reaction or intolerance to known ingredients of zolbetuximab 
or other monoclonal antibodies, including humanized or chimeric antibodies. 
6. Subject has known immediate or delayed hypersensitivity, intolerance or contraindication to 
any component of study treatment. 
7. Subject has prior severe allergic reaction or intolerance to any component of mFOLFOX6. 
8. Subject has known dihydropyrimidine dehydrogenase deficiency (DPD). (NOTE: Screening 
for DPD deficiency should be conducted per local requirements.) 
9. Subject has a complete gastric outlet syndrome or a partial gastric outlet syndrome with 
persistent/recurrent vomiting. 
10. Per investigator judgement, subject has significant gastric bleeding and/or untreated gastric 
ulcers that exclude the subject from participation. 
11. Subject has a known history of a positive test for human immunodeficiency virus (HIV) 
infection or known active hepatitis B (positive HBs Ag) or C infection. NOTE: Screening for 
these infections should be conducted per local requirements.  
a. For subjects who are negative for HBs Ag, but HBc Ab positive, an HB DNA test will 
be performed and if positive, the subject will be excluded. 
b. Subjects with positive hepatitis C virus (HCV) serology, but negative HCV RNA test 
are eligible. 
c. Subjects treated with HCV with undetectable viral load results are eligible. 
12. Subject has an active autoimmune disease that has required systemic treatment within the past 
3 months prior to randomization.  
13. Subject has active infection requiring systemic therapy that has not completely resolved within 
7 days prior to randomization. 

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Cautionary Concomitant Treatment  
Considerations should be given to avoid or minimize the use of the following concomitant 
medications, if possible, during zolbetuximab/placebo treatment: 
• 
Systemic corticosteroids, because of their impact on the potential efficacy of zolbetuximab is 
not known. 
o Systemic corticosteroids should be avoided or minimized while subject is on study 
treatment unless required for management of an emergent medical condition (e.g., 
severe nausea/vomiting or hypersensitivity reaction).  
o For a Subject’s first dose of zolbetuximab/placebo, it is recommended that the 
prophylactic use of corticosteroids be avoided. 
o Inhaled, intranasal, ophthalmic, otic and topically applied steroids are allowed. 
o Subjects are allowed to use a physiologic replacement dose of hydrocortisone or its 
equivalent (defined as up to 30 mg/day of hydrocortisone or up to 10 mg/day of 
prednisone), receive a single dose of systemic corticosteroids or receive systemic 
corticosteroids as premedication for radiologic imaging contrast use.  
• 
Administer 5-HT3 blockers with caution in subjects who have or may develop QTc 
prolongation. 
• 
Nonsteroidal anti-inflammatory drugs (NSAIDs) because of the potential to cause gastric 
ulcers and covert bleeding.  
o In such cases where NSAID use is necessary, the use of NSAIDs with lower gastric 
ulcerogenic potential is preferred and concomitant gastric protection with proton pump 
inhibitors is recommended.  
The following should be avoided or used with caution during 5-FU treatment and appropriate 
monitoring should be conducted:  
• 
CYP2C9 substrates  
• 
Metronidazole and cimetidine  
• 
Anti-epileptic medications (e.g., phenobarbital, phenytoin and primidone) 
The following should be avoided or used with caution during oxaliplatin treatment and appropriate 
monitoring should be conducted:  
• 
Medications known to prolong the QT or QTc interval (refer to https://www.crediblemeds.org 
for a list of these medications) 
Duration of Treatment:   
Subjects will receive zolbetuximab/placebo until locally or IRC confirmed disease progression, 
toxicity requiring study treatment cessation, start of another anticancer treatment or other treatment 
discontinuation criteria are met.  
Subjects will also receive up to 12 treatments (4 or more cycles) of mFOLFOX6 (or some of its 
components) followed by continued use of folinic acid and 5-FU (based on investigator’s 
judgement) beyond 12 treatments until study treatment discontinuation criteria are met.  

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Study Treatment Discontinuation Criteria  
A subject who enrolled in the study and for whom study treatment (zolbetuximab/placebo and all 
components mFOLFOX6) is permanently discontinued for any reason will be assessed as having 
met study treatment discontinuation criteria.  
As survival is the secondary end-point of the study, all subjects will be followed for survival after 
meeting study treatment discontinuation criteria unless the subject withdraws consent or is 
considered lost to follow-up after repeated attempts to contact or if the sponsor discontinues the 
study.  
A subject is free to withdraw from the study treatment and/or study for any reason and at any time 
without giving reason for doing so and without penalty or prejudice. The investigator is also free to 
terminate a subject's involvement in the study at any time if the subject's clinical condition 
warrants it. 
A subject will be discontinued from study treatment (zolbetuximab/placebo and all components 
mFOLFOX6) if any of the following occur: 
• 
Investigator determines it is in the subject’s best interest to discontinue study treatment  
• 
Subject develops radiological disease progression per RECIST 1.1 criteria based on assessment 
locally or by IRC. 
o If the investigator believes that the subject is continuing to derive clinical benefit 
(asymptomatic and/or without worsening of performance status or overall health) from 
study treatment, and an increase in tumor burden is not likely to affect vital organ 
function, the subject may remain on study treatment until an additional radiologic 
assessment is completed (≤ 9 weeks from previous radiologic assessment). 
▪ 
If the additional radiologic assessment locally or by IRC indicates PD per 
RECIST 1.1 then the subject must be discontinued from study treatment. 
▪ 
If the additional radiologic assessment locally or by IRC does not confirm the 
initial assessment of PD, the subject may continue study treatment. 
• 
Subject develops clinical progression per investigator assessment and radiologic assessment is 
not medically feasible to confirm radiologic progression due to the subject’s condition.  
• 
Subject starts another systemic chemotherapy, immunotherapy, radiotherapy or other treatment 
intended for antitumor activity. 
• 
Subject starts another investigational agent or device.  
• 
Subject develops unacceptable toxicity. 
• 
Subject has a delay of study treatment (zolbetuximab/placebo and all components 
mFOLFOX6) for > 28 days from when the next study treatment was scheduled to be 
administered (> 49 days from when the last dose of zolbetuximab/placebo and > 42 days from 
when the last dose of mFOLFOX6 began). 
• 
Subject develops inter-current illness that the investigator determines may jeopardize the 
subject’s safety if the subject continues to receive study treatment. 
• 
Female subject becomes pregnant. 
• 
Significant deviation from the protocol or eligibility criteria as determined by the sponsor. 
• 
Subject declines further treatment. 
• 
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the subject. 
• 
Subject is noncompliant with the protocol based on investigator or Medical Monitor 
assessment. 
Note: If a subject discontinues mFOLFOX6 and/or zolbetuximab/placebo due to any reason other 
than locally confirmed or IRC confirmed disease progression (and is not receiving any other 
anticancer therapy), the subject must be followed according to the protocol-specified radiologic 

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assessment schedule until radiological disease progression per RECIST 1.1 criteria is confirmed 
locally or by IRC assessment. 
Study Discontinuation Criteria 
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6) [Flow Chart] all 
subjects should remain in the study through the 90-Day Safety Follow-up and the Post Treatment 
Follow-up Period (for PFS) is no longer applicable; see the Schedule of Assessments [Table 11] in 
[Section 13].  
Participation in the study will end when subjects transition to commercially marketed and locally 
accessible product(s) (both zolbetuximab and mFOLFOX6). Astellas is planning to close the study 
when zolbetuximab (Vyloy) is commercially marketed in all countries with active participants. 
Subjects that completed the 90-Day Safety Follow up Visit(s) treatment period under Protocol 
Version 6.1 or earlier (e.g., Original Protocol Version 1 through 6.1) were eligible for the 
Post-Treatment Follow up Period (for PFS) and were to remain in the study through Survival 
Follow-up Period (OS is a key secondary study endpoint) [Flow Chart] and followed as outlined in 
Protocol Version 6.1 [Table 1]. A subject will be discontinued from the Post-Treatment, Long 
Term and Survival Follow-up Periods if any of the following occur: 
• 
Subject declines further study participation (i.e., withdraws consent)  
• 
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the subject 
• 
Death (from any cause) 
• 
Study termination by the sponsor 
Endpoints for Evaluation:   
Primary: 
• 
PFS, defined as the time from the date of randomization until the date of radiological PD (per 
RECIST 1.1 by IRC) or death from any cause, whichever is earliest 
Secondary: 
• 
OS, defined as the time from the date of randomization until the date of death from any cause 
• 
Time to confirmed deterioration (TTCD) using the PF, OG25-Pain and GHS/QoL scores as 
measured by EORTC QLQ-C30 and QLQ-OG25. TTCD is defined as time to first confirmed 
deterioration, i.e., time from randomization to first clinically meaningful deterioration that is 
confirmed at the next scheduled visit.  
• 
ORR, defined as the proportion of subjects who have a best overall response (BOR) of CR or 
PR as assessed by IRC per RECIST 1.1 
• 
DOR, defined as the time from the date of the first response (CR/PR) until the date of PD as 
assessed by IRC per RECIST 1.1 or date of death from any cause, whichever is earliest 
• 
Safety and tolerability, as measured by AEs, laboratory test results, vital signs, ECGs, and 
ECOG performance status  
• 
HRQoL using the additional parameters as measured by EORTC QLQ-C30, QLQ-OG25 plus 
GP and EQ5D-5L questionnaires  
• 
Pharmacokinetics of zolbetuximab, Ctrough 
• 
Immunogenicity of zolbetuximab as measured by the frequency of anti-drug antibody (ADA) 
positive subjects.  

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Exploratory: 
• 
TTP, defined as the time from the date of randomization until the date of PD as assessed by 
IRC per RECIST 1.1. 
• 
Progression Free Survival 2 (PFS2), defined as the time from the date of randomization until 
the date of PD (per investigator) following subsequent anticancer therapy, death from any 
cause or start of any other anticancer therapy, whichever is earliest.  
• 
DCR, defined as the proportion of subjects who have a BOR of stable disease (SD), CR or PR 
as assessed by IRC per RECIST 1.1. 
• 
Potential genomic and/or other exploratory biomarkers that may be related to treatment 
outcome of zolbetuximab. (NOTE: Genomic and exploratory biomarker testing will not be 
performed on samples from subjects in China.) 
• 
HRU 
Statistical Methods: 
Sample Size Justification:  
One interim analysis and 1 final analysis are planned for OS, while only 1 analysis is planned for 
PFS as final. The OS interim analysis will occur at the same time of final PFS analysis (after pre-
specified number of PFS events) and final OS analysis will be performed after the pre-specified 
number of OS events are observed. The O’Brien-Fleming boundaries as implemented by Lan-
DeMets (1983) alpha spending method (East®) will be used for the OS interim and OS final 
analyses. All statistical tests of treatment effects will be conducted at the 1-sided 0.025 level of 
significance unless otherwise specified. 
Approximately 550 subjects will be randomized in a 1:1 ratio to receive zolbetuximab in 
combination with mFOLFOX6 chemotherapy (Arm A) or placebo in combination with 
mFOLFOX6 chemotherapy (Arm B).  
The planned 300 PFS events during the study will provide 93.4% power to detect a difference in 
PFS between Arm A (zolbetuximab + mFOLFOX6) with the assumption of 9 months median PFS 
time and Arm B (placebo + mFOLFOX6) with the assumption of 6 months median PFS time 
(hazard ratio = 0.67) at the overall 1-sided 0.025 significance level. Similarly, the planned 396 OS 
events during the study will provide 81% power to detect a difference in OS between Arm A 
(zolbetuximab+mFOLFOX6) with the assumption of 14.7 months median survival time and Arm B 
(placebo + mFOLFOX6) with the assumption of 11 months median survival time 
(hazard ratio = 0.75) at the overall 1-sided 0.025 significance level. 
Analysis Populations: 
The full analysis set (FAS) will include all subjects who are randomized to 1 of the treatment arms. 
Subjects will be analyzed according to the treatment arm to which they were randomized. The FAS 
will be used for description of baseline characteristics and all efficacy analyses.  
The safety analysis set (SAF) will contain all subjects who received at least 1 dose of any study 
drug (zolbetuximab/placebo/mFOLFOX6). The safety analysis set will be used for all safety 
analyses. Subjects would be analyzed according to the actual treatment they received. 
The pharmacokinetic analysis set (PKAS) will consist of the subset of the SAF for which at least 1 
zolbetuximab concentration measurement is available. Additional subjects may be excluded from 
the PKAS at the discretion of the Pharmacokineticist. The PKAS will be used for description of 
pharmacokinetic data. 
Efficacy Analysis: 
All efficacy analyses will be conducted using FAS.  

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Primary Efficacy Endpoint:   
The primary efficacy endpoint of PFS will be analyzed using the stratified Log Rank Test with 
stratification factors to be specified in the SAP. 
The hypothesis testing on the primary analysis will be performed at an overall 1-sided 
0.025 significance level to test the null hypothesis that PFS is not prolonged in Arm A compared to 
Arm B versus the alternative hypothesis that PFS is prolonged in Arm A compared to Arm B. 
Estimates of the treatment effect will be expressed as Hazard Ratio (HR) using a stratified Cox 
model, including 95% Confidence Interval (CI).  
The sensitivity analysis for the primary efficacy endpoint will also be performed.  
Secondary Endpoints: 
The key secondary efficacy endpoint of OS will be analyzed using the stratified Log Rank Test 
with the same strata used in the analysis of PFS. To maintain the overall Type I error rate at the 
0.025 significance level, the hypothesis testing on OS will be performed only if the null hypothesis 
on the primary analysis is rejected at the overall 1-sided 0.025 significance level. The key 
secondary TTCD endpoints of PF, OG25 Pain, and GHS/QoL will be analyzed using the same 
method as OS and PFS. 
The secondary efficacy endpoint of ORR will be analyzed using the Cochran-Mantel-Haenszel 
(CMH) test to control for the same strata used in the analysis of PFS and OS.  
The secondary HRQoL endpoints collected via the EORTC QLQ-C30 and QLQ-OG25, GP and 
EQ-5D-5L will be analyzed with summary of change from baseline over time through the end of 
mFOLFOX6 treatment and inferential methods. Detailed analysis of HRQoL endpoints will be 
provided in the SAP.  
Exploratory Endpoints: TTP and PFS2 will be analyzed in a similar way as PFS. However, in 
TTP analysis, deaths are not counted as events - rather, deaths are censored. DCR will be analyzed 
similarly as ORR. The HRU variables will be summarized by treatment arm.  
Safety Analyses: 
The safety evaluation will be based on AEs, clinical laboratory tests, vital signs, ECG and ECOG 
status. Descriptive statistics will be used to summarize safety data. All safety data will be 
summarized by treatment received. 
All summaries of AEs will include only treatment-emergent events unless otherwise stated. AEs 
will be categorized by SOC and preferred term using MedDRA and will be graded for severity 
according to the National Cancer Institute-Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) v4.03.  
Pharmacokinetics: 
Descriptive statistics (e.g., number of subjects, mean, standard deviation, minimum, median, 
maximum, coefficient of variation [CV], geometric mean, and geometric CV) will be provided for 
concentration of zolbetuximab. The potential relationship between zolbetuximab immunogenicity 
and zolbetuximab pharmacokinetics, efficacy, and safety profile may be assessed. Additional 
model-based analyses may be performed and reported separately. 
Biomarkers: 
Biomarkers will be summarized graphically or descriptively, and summary statistics may be 
tabulated. Associations between biomarkers and clinical (e.g., efficacy, safety or 
pharmacodynamics or pharmacokinetics) measures may be performed on subjects who have 
sufficient baseline and on-study treatment measurements to provide interpretable results for 
specific parameters. 
 

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Interim Analyses:  
To evaluate whether zolbetuximab + mFOLFOX6 (Arm A) is particularly beneficial compared to 
placebo + mFOLFOX6 (Arm B) while the study is ongoing, a formal OS interim analysis is 
planned when the final PFS analysis occurs with the pre-specified number of PFS events. A group 
sequential design using the O’Brien-Fleming type alpha-spending function [Lan & DeMets, 1983] 
for efficacy will be utilized to control the overall 1-sided 0.025 significance level (East®) for the 
OS analyses.  
The IDMC may recommend terminating the trial for favorable or unfavorable results at the formal 
efficacy interim analysis using PFS and OS. If the PFS is not significant at 0.025 1-sided alpha, the 
trial may be terminated for failure. In the case of favorable results, the 1-sided significance level 
for superiority is 0.0082, assuming about 72% of the target number of OS events is obtained, for 
the interim OS analysis and 0.0225 for the final OS analysis (Note: The OS significance boundary 
may be adjusted depending on the number of OS events at the time of interim analysis). If the 1-
sided P value of the interim OS analysis is less than the significance level (and PFS is also 
significant at 1-sided 0.025 alpha), the IDMC may recommend terminating the trial for success. If 
the study is not stopped after the interim analysis, a final OS analysis will occur after 100% of the 
planned death events have been observed. 
Details for the interim analyses, monitoring subject safety, enrollment rates and event (PFS/death) 
rates will be contained in the IDMC Charter. Recommendations regarding study conduct will be 
made by the IDMC based on their assessment of these rates. 
 
 

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5-FU: fluorouracil; CLDN: Claudin; HER2: human epidermal growth factor receptor 2; IRC: independent review committee; mFOLFOX6: 5-fluorouracil, folinic acid and oxaliplatin; 
RECIST: Response Evaluation Criteria in Solid Tumors. 
†This assessment at this timepoint has been changed with implementation of Protocol Version 7.0. Please refer to [Table 11] for the Protocol Version 7.0 and later Schedule of 
Assessments. 
 
b. Study Treatment Period Dosing Schedule (1 Cycle = approximately 42 Days) 
 
5-FU: fluorouracil 

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Dosing Schematics  
a. Combination Zolbetuximab/Placebo and mFOLFOX6 Dosing Visits (e.g., C1D1, C2D1, C3D1 and C4D1) 
 
5-FU: fluorouracil; C1D1: Cycle 1 Day 1; C2D1: Cycle 2 Day 1; C3D1: Cycle 3 Day 1; C4D1: Cycle 4 Day 1; mFOLFOX6: 5-fluorouracil, folinic acid and oxaliplatin; tx: treatment 
 

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c. Zolbetuximab/Placebo Only Dosing Visits (e.g. C1D22, C2D22, C3D22, C4D22) 
 
C1D22: Cycle 1 Day 22; C2D22: Cycle 2 Day 22; C3D22: Cycle 3 Day 22; C4D22: Cycle 4 Day 22; tx: treatment 
 

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5-FU: fluorouracil; AE: adverse event; βhCG: beta human chorionic gonadotropin; C1D1: Cycle 1 Day 1; CLDN: Claudin; CT: computerized tomography; DPD: dihydropyrimidine 
dehydrogenase; ECG: electrocardiogram; eCOA: electronic Clinical Outcomes Assessment; ECOG: Eastern Cooperative Oncology Group; eCRF: electronic case report form; FFPE: 
formalin fixed paraffin embedded; HER2: human epidermal growth factor receptor 2; HRQoL: health-related quality of life; HRU: Health Resource Utilization; ICF: informed consent 
form: INR: international normalized ratio; IRC: independent review committee; IRR: infusion-related reaction; IV: intravenous; mFOLFOX6: 5-fluorouracil, folinic acid and 
oxaliplatin; MRI: magnetic resonance imaging; OS: overall survival; PD: progressive disease; PFS: progression free survival; PFS2: progressive disease following 2nd line therapy; 
PGx: pharmacogenomics; PT: prothrombin time; PTT: partial thromboplastin time; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: serious adverse event; 
T4: thyroxine; TSH: thyroid stimulating hormone 
†Local and/or regional protocols or precautions for COVID-19 management should be followed as applicable. 
*+ 6 calendar day visit window does not apply to C1D1. 
1. Screening: The Screening period is 45 days from full main ICF signature. Re-testing of lab values is allowed within the 45-day screening period. Re-screening outside of the 45-
day window under a new subject number may be allowed once and upon discussion with the Medical Monitor. CT scans and MRIs conducted as part of a subject’s routine clinical 
management (i.e., standard of care) obtained prior to signing the ICF may be utilized for screening or baseline purposes, provided the procedures met the protocol-specified criteria 
and were performed within the Screening period.  
• Optional Partial Screening: A partial screening ICF may be available for central testing of tissue for CLDN18.2 and HER2 only. 
• Laboratory testing: 
Eligibility can be determined based on central and/or local testing, however: 
o 
The most recent laboratory tests with available results must be used to confirm the subject’s eligibility. 
o 
Central labs must be collected and submitted to the central laboratory during the Screening period. 
o 
If retesting of lab values is necessary to confirm eligibility, local labs can be used without requiring additional sample collection for central laboratory submission.  
o 
The screening labs used to determine eligibility should be collected within 14 days prior to randomization.    
• Radiologic imaging used to confirm eligibility must be conducted within 28 days prior to randomization.  
2. CLDN18.2 and HER2 Testing: FFPE tumor tissue will be collected for central testing to determine CLDN18.2 and HER2 status. (Unique to China: FFPE tumor tissue will be 
collected for central testing to determine CLDN18.2 status.) Archival tumor tissue from the primary tumor (gastric or GEJ) is preferred. If primary tumor tissue is not available, 
tumor tissue from a metastatic site (excluding bone metastasis) may be used. A minimum of 1 FFPE tumor tissue block (preferred) OR a minimum of 15 FFPE unstained slides are 
required, as allowed per local policy. If slides are submitted, the slides should be freshly cut from the FFPE block within the time frame described in the laboratory manual. If local 
HER2 results are already available from local testing, a minimum of 12 FFPE unstained slides are required to be submitted to the central lab, as allowed per local policy. If the 
specimen is insufficient or unavailable, a biopsy may be performed to obtain primary tumor tissue (preferred) or tumor tissue from metastatic site (excluding bone metastasis). 
Sponsor pre-approval is required when the sole purpose of the biopsy procedure is to assess eligibility for this study. (Unique to China: Five FFPE unstained slides are required, as 
allowed per local policy.) See [Section 5.7.3 Tumor Tissue Samples].  
If the required number of slides cannot be provided, the sponsor or designee should be contacted for further guidance.   
3. Randomization: After confirmation of eligibility, the blinded site user will perform the randomization IRT transaction. The unblinded pharmacist/designee will be notified by the 
IRT system about the randomly assigned treatment. Confirmation of Inclusion/Exclusion Criteria must be completed prior to randomization. Randomization may be performed 
prior to C1D1. If C1D1 cannot be performed within 5 calendar days from Randomization, please contact the Medical Monitor. Details of infusion preparation and storage 
requirements are defined in the Pharmacy Manual and Infusion Guidelines. 

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4. Antiemetic Pre-treatment: Antiemetic premedication (prophylactic antiemetics) should be administered prior to each study treatment. IV antiemetic premedication should be 
initiated prior to treatment, or oral antiemetic premedication should be initiated at a minimum of 30 minutes prior to treatment. Antiemetic premedication should be given 
according to institutional standard of care, published guidelines and the respective product package insert(s). For further details, see [Section 5.1.1.2 Antiemetics].  
5. Zolbetuximab/placebo will be administered as a minimum 2-hour IV infusion every 3 weeks starting on C1D1 (i.e., C1D1, C1D22, C2D1, etc.). Please refer to the Pharmacy 
Manual and Infusion Guidelines for more detailed information. If both zolbetuximab/placebo and mFOLFOX6 are to be administered during the same visit, zolbetuximab/placebo 
should be administered prior to mFOLFOX6. For further details, see [Section 5.1.1.1 Zolbetuximab/Placebo].  
6. Post-Infusion Observation Period: Following the first dose of zolbetuximab/placebo in C1, the subject must be observed for 2 hours post zolbetuximab/placebo infusion. The post-
infusion observation period can be conducted during the mFOLFOX6 administration. If any ≥ grade 2 AEs are observed during infusion or during the post-infusion observation 
period, subsequent zolbetuximab/placebo infusion times should be extended and subjects should continue to be observed for 2 hours post zolbetuximab/placebo infusion. If the 
subject does not develop any ≥ grade 2 AEs, the subject should be observed for 1 hour post-infusion for their subsequent zolbetuximab/placebo infusions. The subject should be 
instructed to notify site personnel if they develop any AEs during this observation time period. In the event of an IRR with features of anaphylaxis (regardless of grade) or grade 3 
or 4 IRR, blood samples for cytokine/chemokine panel and serum total tryptase level (levels typically peak within 3 hours after the onset of symptoms) should be collected once 
the subject has stabilized for shipment to the central laboratory. See Observation Period following zolbetuximab/placebo [Section 5.4.2] for further details.   
7. mFOLFOX6 will be administered every 2 weeks starting at C1D1 (i.e., C1D1, C1D15, C1D29, etc.) for 4 cycles (up to 12 treatments). A maximum of 12 doses of oxaliplatin can 
be administered. If both zolbetuximab/placebo and mFOLFOX6 are to be administered during the same visit, zolbetuximab/placebo should be administered prior to mFOLFOX6. 
See [Section 5.1.1.3 mFOLFOX6].  
8. 5-FU and Folinic Acid may continue to be administered at the discretion of the investigator after completion of 12 treatments of mFOLFOX6. If 5-FU is not continued after 
12 treatments of mFOLFOX6, then day 15 and day 29 visits are not required. If both zolbetuximab/placebo and 5-FU and folinic acid are to be administered during the same visit, 
zolbetuximab/placebo should be administered first. See [Section 5.1.1.1 Zolbetuximab/Placebo].  
9. Physical Exam: should include height (at Screening only), weight and ECOG performance status. A full physical exam is required at Screening. The physical exam only needs to 
be repeated on C1D1 if clinically significant changes from Screening are observed (in the opinion of the investigator). For all cycles, the physical examination, weight and ECOG 
performance status assessments can be completed up to 48 hours prior to zolbetuximab/placebo administration. Targeted (symptom driven) physical exams should be conducted 
every 3 weeks on zolbetuximab/placebo visit days. For further details, see [Section 5.4.4 Physical Examination]. 
10. Vital signs (pulse, blood pressure, temperature) should be taken during every visit at the following time points (see [Section 5.4.1 Vital Signs]): 
o Pre-dose at every visit  
o C1D1: Every 30 (± 10) minutes during zolbetuximab/placebo infusion  
o If the subject did not develop any ≥ grade 2 AEs during the C1D1 zolbetuximab/placebo infusion or the Post-Infusion Observation Period, the site may do the following for 
subsequent zolbetuximab/placebo infusions: 
▪ 
The post-infusion observation period can be 1 hour for subsequent visits after C1D1 
▪ 
The vital signs can be assessed every 60 minutes for subsequent visits after C1D1 
o Every 60 (±10) minutes post zolbetuximab/placebo infusion during the Post-Infusion Observation Period (for 1 or 2 hours. See footnote 6) 
o Unscheduled if clinically indicated 

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11. ECGs: ECGs will be locally read. When collected on the same day, ECG should be collected prior to pharmacokinetic samples. For further details, see [Section 5.4.5 
Electrocardiogram]. A single ECG will be performed at the following time points: 
o Screening 
o Up to 48 hours prior to every oxaliplatin infusion (before any antiemetic treatment) 
o Up to 6 hours following completion of every oxaliplatin infusion 
o Zolbetuximab/placebo study treatment discontinuation visit 
o Zolbetuximab/placebo 30-day safety follow-up visit 
o If clinically indicated and/or per local requirements  
12. Imaging Assessments: Radiologic imaging will be evaluated at Screening (must be conducted within 28 days prior to randomization) and every 9 weeks (± 7 days) counting from 
C1D1 for the first 54 weeks and then every 12 weeks (± 7 days) thereafter until subject develops radiological disease progression per RECIST 1.1 by IRC or starts other systemic 
anticancer treatment, whichever comes earlier. Imaging schedule should be maintained regardless of treatment delay. Imaging will include CT scans with contrast of the thorax, 
abdomen, and pelvis. If CT scan with contrast is medically not feasible, MRI may be used for imaging. Bone scans (or focal X-ray) or brain imaging should be performed if 
metastatic disease in bone or brain is suspected, respectively. The same mode of imaging should be utilized throughout the study unless medical necessity requires a change. For 
randomized subjects, screening imaging should be sent to the central imaging vendor no later than submission of the first on-treatment imaging. All imaging acquired post 
randomization will be sent to the central imaging vendor within 7 days of scanning for the blinded independent central assessment of radiological tumor response based on 
RECIST 1.1. The investigator should make every effort to immediately submit radiologic assessments for IRC review when PD is suspected. See [Section 5.3 Efficacy 
Assessments]. Refer to Imaging Acquisition Guidelines for further detail on scan modality and contrast options.  
13. Laboratory Assessments: See [Section 5.4.3 Laboratory Assessments] for list of laboratory assessments. Laboratory tests must be sent to the central laboratory for analysis unless 
otherwise approved by the sponsor. For screening/eligibility laboratory assessments, see footnote 1.   
o Laboratory test results (central or local) will be reviewed by the investigator prior to any study treatment. Clinical significance of out-of-range laboratory findings is to be 
determined and documented by the investigator/sub-investigator who is a qualified physician.  
o Local laboratory results may be used for treatment decisions; however, central laboratory samples must also be drawn per protocol and sent to the central laboratory unless 
otherwise approved by the sponsor.   
o Central and local labs may be collected up to 48 hours prior to study treatment. 
o Holidays and weekends should be taken into account when scheduling these sample collections. 
o Additional assessments may be done centrally or locally to monitor AEs or as clinically indicated. 
14. Coagulation (PT, PTT and INR): Coagulation tests should be done at Screening and during study treatment period if clinically indicated. Local or central lab results may be used to 
confirm eligibility. Ongoing evaluation should be continued for Subjects who are receiving therapeutic anticoagulation according to local standard of care. See [Section 5.4.3 
Laboratory Assessments].  
15. Serum Pregnancy Test: Serum pregnancy tests will be collected for female subjects of child bearing potential only. Serum pregnancy tests collected at Screening, during study 
treatment period and if clinically indicated or per local requirements. Serum pregnancy test can be completed up to 48 hours prior to zolbetuximab/placebo administration. (Note: 
For Screening, subjects with elevated serum βHCG and a demonstrated non-pregnant status through additional testing are eligible.) Local or central laboratory results may be used 
to confirm eligibility.  

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16. Urine Pregnancy Test: for female subjects of child bearing potential only. Local urine pregnancy tests to be performed during the treatment period every 3 weeks at 
zolbetuximab/placebo visits and at the zolbetuximab/placebo Study Treatment Discontinuation and 30-Day Safety Follow up Visits. Urine pregnancy test can be completed up to 
48 hours prior to zolbetuximab/placebo administration. Additional urine pregnancy testing for up to 9 months after the final study treatment administration may be applied based 
on local requirements. 
17. HRQoL and HRU questionnaires: eCOA questionnaires are to be completed by the subject at Screening (except HRU), on day 1 and day 22 of each cycle (or up to 48 hours) 
before any antiemetic or drug treatment and before the disease status is discussed with the subject using the electronic tablet device provided. When completion by the subject is 
not possible, the questionnaires may be administered to the subject by site personnel using the electronic tablet device. For subjects with low literacy, situations where translations 
are unavailable or other circumstances preventing the screening questionnaires to be completed, please contact the sponsor for further guidance. 
18. Study Treatment Discontinuation Visit (End of Study Treatment): The Study Treatment Discontinuation Visits will take place ≤ 7 days following the decision to discontinue all 
study treatment (zolbetuximab/placebo and mFOLFOX6 [all components]). If zolbetuximab/placebo and mFOLFOX6 (all components) are discontinued on a different day, 
subjects will have a separate Study Treatment Discontinuation Visit following each treatment’s discontinuation. Laboratory tests must be sent to the central laboratory for analysis. 
HRQoL and HRU questionnaires are not required at mFOLFOX6 treatment discontinuation visit. A combined visit can be completed if zolbetuximab/placebo are discontinued on 
the same day.  
19. 30-Day Safety Follow-up Visit: A 30-Day Safety Follow-up visit should occur 30 days after the last dose of zolbetuximab/placebo and will include the assessments as shown in 
the Schedule of Assessments above. A 30-Day Safety Follow-Up Visit should occur 30 days after the last dose of mFOLFOX6 (all components) and may be conducted by phone if 
the subject is unable to visit the site and will require only contact for AE/SAE collection. HRQoL and HRU questionnaires are not required at mFOLFOX6 30-day safety follow up 
visit. A combined visit can be completed if zolbetuximab/placebo and all components of mFOLFOX6 are discontinued on the same day and HRQoL and HRU questionnaires 
should be completed for a combined visit. 
20. 90-Day Safety Follow-up Visits: A 90-Day Safety Follow-up visit should occur 90 days after the last dose of zolbetuximab/placebo and will include the assessments as shown in 
the Schedule of Assessments above. A 90-Day Safety Follow-Up Visit should occur 90 days after the last dose of mFOLFOX6 (all components) and may be conducted by phone if 
the subject is unable to visit the site and will require only contact for AE/SAE collection. HRQoL and HRU questionnaires are not required at mFOLFOX6 90-day safety follow up 
visit. A combined visit can be completed if zolbetuximab/placebo and all components of mFOLFOX6 are discontinued on the same day and HRQoL and HRU questionnaires 
should be completed for a combined visit. 
21. Post-Treatment Follow-up: if a subject discontinues all study treatments (zolbetuximab/placebo and all components of mFOLFOX6) prior to IRC confirmed radiological disease 
progression, the subject will enter the Post-Treatment Follow-up Period and continue to undergo imaging assessments every 9 weeks (or every 12 weeks if subject has been on 
study over 54 weeks) until radiologic disease progression (i.e., PFS) or the subject starts subsequent anticancer treatment, whichever occurs earlier. If study treatment 
(zolbetuximab/placebo and all components of mFOLFOX6) is discontinued due to PD, the subject will enter the Long Term and Survival Follow-up Period.   
22. Long Term and Survival Follow-up Period: Following disease progression on 1st line treatment or start of subsequent anticancer treatment, subjects will be followed in the Long-
Term and Survival Follow-up Period per institutional guidelines, but at least every 12 weeks. Radiologic imaging will be done per standard of care and read locally. Survival 
Follow-up Period will continue until death (from any cause). All post-progression details including subsequent anticancer treatment and date and site of progression will be 
recorded on the eCRF. Subject contact by phone or other remote methods is sufficient during Long Team and Survival Follow-up.  

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23. Pharmacokinetic (Serum) for zolbetuximab/placebo samples will be taken at the below timepoints and sent to the central laboratory. The date and time of each blood sample 
collection will be recorded to the nearest minute. 
o Cycle 1 Day 1: End of zolbetuximab/placebo infusion  
o Cycle 1 Day 22: Predose  
o Cycle 2 Day 1: End of zolbetuximab/placebo infusion  
o Pre-dose on Day 1 of Cycles 3, 5, 7 and 9 
o Zolbetuximab/placebo 30-Day Safety Follow-up visit   
o Zolbetuximab/placebo 90-Day Follow-up visit  
o Unscheduled pharmacokinetic blood samples may be taken at any time during the study to evaluate drug exposure following a safety event 
Pharmacokinetic Sampling Window:  
o Predose: within 60 minutes prior to dosing 
o End of Infusion: within 10 minutes after the end of the infusion 
24. Anti-Drug Antibodies (ADA): Blood samples (Serum) for ADA will be taken at the below timepoints and sent to the central laboratory.  
o Cycle 1 Day 1: Predose  
o Cycle 1 Day 22: Predose  
o Pre-dose on Day 1 of Cycle 3, 5, 7 and 9 
o Zolbetuximab/placebo 30-Day Safety Follow-up visit  
o Zolbetuximab/placebo 90-Day Follow-up visit  
ADA Sampling Window: Predose: within 60 minutes prior to dosing 
25. Genetic Immune Polymorphism: To be collected per local policy. Whole blood sample taken at C1D1 will be sent to the central laboratory. Samples may be collected up to 
48 hours prior to study treatment. 
26. Exploratory Biomarker (Serum and Plasma): To be collected per local policy. Samples should be taken at the below timepoints and sent to the central laboratory: 
o Cycle 1 Day 1: Predose  
o Cycle 1 Day 22: Predose 
o Cycle 2 Day 1: Predose 
o Cycle 2 Day 22: Predose 
o Cycle 3 Day 1: Predose  
o Cycle 3 Day 22: Predose 
o Cycle 4 Day 22: Predose 
o Zolbetuximab/placebo Study Treatment Discontinuation Visit 
Exploratory Biomarker samples may be collected up to 48 hours prior to study treatment 
27. Optional PGx: for subjects who signed a separate ICF, an optional whole blood sample for PGx for exploratory biomarker analysis may be collected at up to 48 hours prior to first 
study drug administration at C1D1. Sample collection is optional and only collected as allowed per local policy. 

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28. Optional Post-Progression Tumor Sample: for subjects who signed a separate ICF, an optional post-progression tumor sample for exploratory biomarker analysis may be collected 
following IRC confirmation of disease progression and prior to initiation of subsequent anticancer therapy. Sample collection is optional and only collected as allowed per local 
policy.  
29. Concomitant medications: Concomitant medications will be collected from the time of full main informed consent through 90 days following the last dose of study treatment. 
30. AEs/SAEs: AEs/SAEs (regardless of causality) will be collected from the time of full main informed consent through 90 days following the last dose of study treatment. See 
[Section 5.5.5]. 
31. With implementation of Protocol Version 7.0, please refer to [Table 11] for the Protocol Version 7.0 and later Schedule of Assessments.  
 

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1 
INTRODUCTION 
Gastric and gastroesophageal junction (GEJ) cancers are among the malignancies with the 
highest unmet medical need. Gastric cancer-related mortality is the fourth leading cause of 
cancer death worldwide, even if its incidence has decreased over the last 50 years in different 
regions of the world [Cancer Fact Sheet, 2018; Amiri et al, 2011]. On the other hand, the 
incidence of subjects with GEJ adenocarcinoma has increased in recent decades, coinciding 
with a shift in histological type and primary tumor location [Waddell et al, 2013; Sahin et al, 
2008]. 
In 2017, an estimated 723,100 people died worldwide from gastric cancer [Lederman 2017].  
The overall 5-year survival rate for gastric and GEJ cancers is averaging 20% in the US and 
Europe, despite aggressive standard treatments, which are also associated with substantial 
side effects [Pennathur et al, 2013; Sahin et al, 2008].   
There is no single standard, globally accepted first-line reference chemotherapeutic regimen 
for advanced gastric cancer. In the US and Europe, the current standard of care cytotoxic 
chemotherapy regimen consists of fluoropyrimidine with platinum-based combination 
chemotherapy regimens with or without a third agent such as docetaxel or epirubicin 
[National Comprehensive Cancer Network (NCCN), 2017; Waddell et al, 2013; Pasini et al, 
2011]. Subjects in this study will receive mFOLFOX6 (a combination of fluorouracil [5-FU], 
folinic acid and oxaliplatin), which is a globally accepted standard-of-care treatment for 
subjects with locally advanced unresectable metastatic gastric or gastroesophageal (GE) 
cancer. The safety of this combination regimen is well-documented [Lee et al, 2010]. 
The lack of a major benefit from the various newer generation combination chemotherapy 
regimens for these cancers has stimulated research into the use of targeted agents such as 
monoclonal antibodies (mAbs). Two mAbs, trastuzumab and ramucirumab, have received 
approval for treatment of gastric cancer. Trastuzumab selectively binds the extracellular 
domain of human epidermal growth factor receptor 2 (HER2), which is overexpressed in 
approximately 20% to 30% of gastric tumors [Bang et al, 2009], and ramucirumab 
specifically binds vascular endothelial growth factor (VEGF) receptor 2 and blocks binding 
of VEGF receptor ligands VEGF-A, VEGF-C and VEGF-D. Trastuzumab is approved for 
treatment of HER2 overexpressing metastatic gastric or GEJ adenocarcinoma while 
ramucirumab is approved as a single agent or in combination with paclitaxel, for treatment of 
advanced gastric or GEJ adenocarcinoma, with disease progression on or after prior 
fluoropyrimidine-or platinum-containing chemotherapy [CYRAMZA Prescribing 
Information, 2017; HERCEPTIN Prescribing Information, 2016]. These agents prolonged 
median overall survival (OS) by 4 or fewer months when given alone or in combination with 
chemotherapy compared with standard of care cytotoxic chemotherapy [Fuchs et al, 2014; 
Wilke et al, 2014; Ohtsu et al, 2011; Bang et al, 2010].   
Approximately 70% to 80% of subjects with metastatic or advanced unresectable gastric and 
GEJ adenocarcinoma in the first line setting have tumors that are HER2 negative and are not 
treatable with trastuzumab. These subjects have an expected median survival of 
approximately 1 year. Therefore, a significant unmet medical need exists for the first-line 

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treatment of subjects with HER2 negative locally advanced or metastatic unresectable gastric 
and GEJ cancers. Zolbetuximab (IMAB362) is being developed with the goal of addressing 
this unmet medical need. 
1.1 
Background 
Zolbetuximab is a genetically engineered, highly purified chimeric (mouse/human IgG1) 
antibody directed against the tight junction molecule Claudin 18.2 (CLDN18.2). The target is 
a member of the claudin family of more than 20 structurally related proteins that are involved 
in the formation of tight junctions in epithelia and endothelia [Niimi et al, 2001].  Tight 
junctions, together with adherens junctions and desmosomes, form the apical junctional 
complex in epithelial and endothelial cellular sheets. Adherens junctions and desmosomes are 
responsible for the mechanical adhesion between adjacent cells, whereas tight junctions are 
essential for the tight sealing of the cellular sheets forming a luminary barrier and controlling 
the paracellular ion flux. 
CLDN18.2 is a 27.7 kDa protein with 4 membrane-spanning domains and 2 small 
extracellular loops [Gunzel & Yu, 2013; Sahin et al, 2008]. Zolbetuximab recognizes the first 
extracellular domain of CLDN18.2 with high affinity and specificity. Zolbetuximab does not 
bind to any other claudin family member including the closely related splice variant 1 of 
Claudin 18 (CLDN18.1). 
CLDN18.2 is a highly cell type specific differentiation antigen that is expressed by 
differentiated gastric mucosa cells in the pit and base regions of gastric glands. Moreover, 
CLDN18.2 is not detectable in any other normal cell type of the human body either at 
transcript level or as protein. This highly selective tissue distribution pattern results in 
CLDN18.2 expression being strictly confined to a subpopulation of gastric epithelial cells in 
normal tissue [Sahin et al, 2008].  
CLDN18.2 is expressed in a diversity of human cancers and is the dominant isoform in GE 
and pancreatic cancer [Lee et al, 2011]. The expression of CLDN18.2 is retained upon 
malignant transformation of gastric epithelia and is present in 81% of primary gastric 
adenocarcinomas. CLDN18.2 expression is frequently detected in diffuse and in intestinal 
gastric cancers. The CLDN18.2 protein is also localized in lymph node metastases of gastric 
cancer adenocarcinomas and in distant metastases into the bile duct, lung and especially into 
the ovary (so-called Krukenberg tumors). Furthermore, over 42% of esophageal 
adenocarcinomas and 50% to 70% of pancreatic cancers display significant expression of 
CLDN18.2 [Wöll et al, 2014; Lee et al, 2011; Sanada et al, 2010; Karanjawala et al, 2008; 
Sahin et al, 2008]. 
Zolbetuximab is being developed for the first-line treatment of adult subjects with locally 
advanced unresectable or metastatic CLDN18.2-positive, HER2-negative gastric or GEJ 
adenocarcinoma in combination with platinum- and fluoropyrimidine-based chemotherapy. 
For this study, a subject’s tumor must express CLDN18.2 in ≥ 75% of tumor cells 
demonstrating moderate to strong membranous staining as determined by central 
immunohistochemistry (IHC) testing.  

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1.2 
Nonclinical and Clinical Data 
1.2.1 
Nonclinical Data 
In vitro studies with CLDN18.2-positive and negative cancer cell lines showed that 
zolbetuximab binds to the extracellular domain 1 of CLDN18.2 on human gastric cancer cell 
lines with high relative affinity and selectivity. In vitro assays demonstrated that 
zolbetuximab mediated an efficient lysis of CLDN18.2-positive cells through antibody-
dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). 
All zolbetuximab-mediated effects are strictly CLDN18.2 antigen-specific. 
In bio-distribution studies in nude mice with human tumor xenografts, intravenously (IV) 
administered zolbetuximab was retained, as well as specifically and strongly enriched in 
CLDN18.2-positive human xenografts. No or little in vivo binding of zolbetuximab to any 
other mouse tissues including stomach tissue was observed. 
Administration of repeated doses of zolbetuximab to mice bearing CLDN18.2-positive 
tumors resulted in retardation of tumor growth kinetics in tumor models. 
A series of in vitro experiments were conducted with CLDN18.2-expressing cell lines 
derived from NUGC-4 and KATO-III to investigate the effects of combining these 
chemotherapy agents with zolbetuximab. Combinations of chemotherapy agents used in the 
treatment of gastric and esophageal cancers, including 5-FU, oxaliplatin and epirubicin (e.g., 
5-FU/oxaliplatin, 5-FU/oxaliplatin/epirubicin) augmented zolbetuximab activity. In vitro pre-
sensitization of human gastric cancer cells with chemotherapy resulted in an increase in the 
amount of cell surface CLDN18.2 and thus improved zolbetuximab-mediated ADCC and 
CDC. 
In immunocompetent mice, zolbetuximab in combination with chemotherapy resulted in a 
pronounced T cell infiltration into the tumors and significant long-term survival benefit over 
zolbetuximab alone. In the same animal model, the combination treatment of zolbetuximab 
with oxaliplatin and 5-FU significantly inhibited tumor growth compared with each 
monotherapy of zolbetuximab or the chemotherapeutic agents, along with an increase in 
tumor-infiltrating CD8+ T cells. These effects might be mediated by induction of adaptive 
T cell immunity, which may have led to the antitumor effect and immune surveillance. 
CLDN18.2 is highly conserved across species, and the epitope of zolbetuximab is identical 
between humans, mice and cynomolgus monkeys. In addition, the binding affinity of 
zolbetuximab to CLDN18.2 orthologs from mice, humans and cynomolgus monkeys was 
shown to be comparable, providing sufficient evidence that testing in mice and monkeys 
covers the potential on-target effects and toxicities of zolbetuximab.  
The nonclinical pharmacology studies conducted with zolbetuximab provide sufficient 
experimental evidence that zolbetuximab depletes CLDN18.2-positive cells via ADCC and 
CDC. Cytotoxic drugs were shown to increase CLDN18.2 expression on human cancer cells 
and to improve the activity of the major mechanism of action (ADCC and CDC). Hence, the 
combination of zolbetuximab with first-line chemotherapy is being investigated in the clinic. 

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Safety pharmacology and toxicity of zolbetuximab were assessed in mice and cynomolgus 
monkeys. In mice, the maximum exposure tested was 300 mg/kg weekly over 13 weeks, and 
in cynomolgus monkeys, the maximum exposure tested was 100 mg/kg weekly over 4 weeks. 
In both species, no target organs of toxicity were identified; however, in monkeys, emesis 
was observed in a non-dose-related manner. The emesis that was observed in monkeys was 
not severe and spontaneously resolved despite continued dosing. The emetic potential of 
zolbetuximab was confirmed in an investigational study in ferrets. This effect is considered to 
be related to the binding of zolbetuximab to junctional protein, CLDN18.2, in the gastric 
epithelium. A human tissue cross-reactivity study of zolbetuximab showed that the gastric 
mucosa was the only tissue with strong membrane staining. However, histological 
assessment of the gastric tissue in monkeys failed to identify any histopathological lesions. 
Besides the findings listed previously, no other zolbetuximab-related adverse effects were 
observed in any organ, neither clinically, nor macroscopically or histologically upon 
postmortem analysis. 
In summary, the nonclinical data outlined above supports the clinical development of 
zolbetuximab in combination with standard chemotherapy for the treatment of 
CLDN18.2-positive gastric or GEJ adenocarcinoma.  
1.2.2 
Clinical Data 
Zolbetuximab has been evaluated in clinical studies as a single agent and in combination with 
epirubicin, oxaliplatin and capecitabine (EOX) chemotherapy or in combination with 
immunomodulation therapy (zoledronic acid [ZA] with or without interleukin-2 [IL-2]) for 
the treatment of adult subjects with CLDN18.2-positive advanced adenocarcinoma of the 
stomach, esophagus or GEJ. 
CLDN18.2 expression was immunohistochemically determined for all subjects enrolled in 
the clinical studies. Several studies had an enrichment type of design meaning that only 
subjects above a certain threshold of CLDN18.2 positivity in their tumors were eligible for 
treatment. Eligibility for enrollment in the GM-IMAB-001-03 (EudraCT No. 2011-005285-
38) and GM-IMAB-001-04 (EudraCT No. 2011-005509-64) studies, hereafter referred to as 
FAST and PILOT, respectively, was determined using the analytically validated and 
Conformité Européene-marked diagnostic kit, CLAUDETECTTM18.2. 
To date, 4 clinical studies have been completed and include GM-IMAB-001 (EudraCT No. 
2008-004719-37, referred to as first-in-human [FIM]), PILOT, FAST and GM-IMAB-001-02 
(EudraCT No. 2009-017365-36), referred to as MONO.  
Zolbetuximab has been granted orphan drug designation for the treatment of stomach cancer 
by the EMA and FDA.  
Clinical data from the studies described above supports the clinical development of 
zolbetuximab in combination with standard chemotherapy for the treatment of 
CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric or 
GEJ adenocarcinomas. 

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1.3 
Summary of Key Safety Information for Study Drugs 
As of 06 May 2019, zolbetuximab has been administered to 306 subjects, including 
259 subjects in the following 4 completed clinical studies:  
● 
FIM study as a single monotherapy dose (up to 1000 mg/m2) in 15 subjects; 
● 
MONO study as repeated monotherapy doses up to 600 mg/m2 once every 2 weeks in 
54 subjects (maximum exposure was 72 infusions);  
● 
FAST study as repeated doses of zolbetuximab in combination with EOX chemotherapy 
(up to 1000 mg/m2 once every 3 weeks) in 162 subjects (maximum exposure greater than 
40 infusions); and 
● 
PILOT study in combination with immunomodulation therapy (up to 600 mg/m2 once 
every 3 weeks) in 28 subjects.  
And 2 ongoing open-label clinical studies: 
● 
8951-CL-0103 (ILUSTRO) as monotherapy or in combination with mFOLFOX6 in 
32 subjects, and 
● 
8951-CL-0104 as monotherapy in 15 Japanese subjects. 
Current phase 1/2 study status and enrollment are available in the zolbetuximab 
Investigator’s Brochure (IB) (see end-of-text Table 4.1 in the IB). 
Nausea and vomiting have been confirmed as important identified risks as has 
hypersensitivity reactions (HSRs), including infusion-related reactions (IRRs). Anemia and 
neutropenia are considered important potential risks. These important identified risks along 
with important potential risks, based on observations from the clinical studies, are described 
in Section 5.2 of the IB. Expected adverse drug reactions, including Reference Safety 
Information (RSI) used for expedited health authority reporting are described in Appendix 1 
of the IB. 
One patient from an ongoing phase 2 study (monotherapy arm) experienced grade 4 acute 
coronary syndrome, grade 4 cardiac arrest, grade 4 posterior reversible encephalopathy 
syndrome (PRES) and grade 3 pulmonary embolism, 22 days after the first infusion of 
zolbetuximab monotherapy. The patient had a medical history significant for uncontrolled 
hypertension, asthenia, and anemia. The patient recovered from these events that were 
deemed serious and a possible causal relationship to zolbetuximab could not be excluded. 
Refer to Section 6 of the IB for additional details. 
In clinical studies, adverse reactions with nausea and/or vomiting and HSRs up to National 
Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade 3 
were reported. Subjects receiving zolbetuximab should receive prophylactic antiemetic 
medications, but do not need to be premedicated for prevention of HSRs and IRRs; however, 
subjects should be closely monitored for IRRs to facilitate early identification and management. 
In the case of zolbetuximab-induced nausea, vomiting or hypersensitivity including IRRs, the 
infusion rate of zolbetuximab may be reduced or the infusion may be paused or discontinued 
based on investigator’s clinical judgement about severity of toxicity and local standard of care.  

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Detailed information on the toxicities associated with mFOLFOX6 can be found within 
Section 4.8 of the summary of product characteristics (SPC) for each component. Potential 
overlapping toxicities during treatment with zolbetuximab in combination with mFOLFOX6 
include nausea, vomiting, abdominal pain, anemia and neutropenia. 
1.4 
Efficacy 
1.4.1 
Efficacy of Zolbetuximab 
1.4.1.1 Efficacy Results from Study GM-IMAB-001-02 (MONO) 
In the MONO study, efficacy analyses included subjects who received zolbetuximab at least 
once (Full Analysis Set [FAS]) at doses of 300 mg/m2 (3 subjects) and 600 mg/m2 
(40 subjects). The best overall confirmed response for FAS subjects in the zolbetuximab 
600 mg/m2 dose group was partial response [PR] in 4 subjects (10.0%) that ranged in 
duration from 43 through 1037 days (GM-IMAB-001, Listing 13.2.6.4). The best overall 
confirmed response was stable disease (SD) in 6 subjects (15.0%) and progressive disease 
(PD) in 28 subjects (70.0%) in the 600 mg/m2 group (GM-IMAB-001-02, Table 12.3.7.1). 
No subject achieved complete response (CR). Median progression free survival (PFS) in the 
FAS was 10 weeks (95% confidence interval [CI]: 8.6, 10.1 weeks) in the 600 mg/m2 group 
(GM-IMAB-001-02, Table 12.3.3.1). 
1.4.1.2 Efficacy Results from Study GM-IMAB-001-03 (FAST) 
Treatment groups in the FAST study are referred to as EOX, EOX + IMAB600 (EOX plus 
zolbetuximab 600 mg/m2 once every 3 weeks, with a loading dose of 800 mg/m2 in Cycle 1) 
and EOX + IMAB1000 (EOX plus zolbetuximab 1000 mg/m2 once every 3 weeks). 
In the FAST study, efficacy analyses of all randomized subjects were included in the intent-
to-treat set and included subjects randomized to EOX only (85 subjects), EOX + IMAB600 
(79 subjects) and EOX + IMAB1000 (88 subjects). Additional analyses were completed for 
the FAS, defined as randomized subjects who received at least 1 dose of any study drug 
(E, Ox, capecitabine or zolbetuximab). The FAS differed from the intent-to-treat set (all 
randomized subjects) by 6 subjects all of whom discontinued the study early without death or 
post-baseline tumor assessment. The reasons for early discontinuation of these subjects 
included protocol violation (1 subject), physician decision (1 subject), withdrawal by subject 
(2 subjects) and AE (1 subject was anemic and another had a deep vein thrombosis)  
(GM-IMAB-001-03, Listing 13.2.1). 
PFS Based on Central Independent Review (Kaplan-Meier Model, Intent-to-Treat) 
The addition of zolbetuximab to EOX led to a statistically significant prolongation of PFS, 
both for the lower zolbetuximab dose (hazard ratio [HR] 0.45, P < 0.0005) and the higher 
zolbetuximab dose (HR 0.57, P = 0.0114). Median PFS was 7.5 months in the EOX + 
IMAB600 arm and 7.1 months in the EOX + IMAB1000 arm vs 5.3 months in the EOX arm, 
representing a median PFS prolongation by 2.2 and 1.8 months, respectively [IB, Table 17].  

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Overall Survival (Kaplan-Meier, Intent-to-Treat) 
The addition of zolbetuximab 600 mg/m2 led to a statistically significant prolongation in OS 
(HR 0.52, P < 0.0005). Median OS was 13 months in the EOX + IMAB600 arm vs 
8.3 months in the EOX arm, representing an increase in median OS by 4.7 months. In the 
EOX + IMAB1000 arm, median OS was 9.6 months and hence, numerically longer than in 
the EOX arm [IB, Table 18]. However, the difference between the groups did not reach 
statistical significance. The difference in OS between the 2 zolbetuximab doses was 
statistically significant (P = 0.0406) (GM-IMAB-001-03, Table 12.3.2.1.5.3).  
No major imbalances were seen between the treatment groups in the subsequent use of any 
anticancer therapy (EOX: 38.1%; EOX + IMAB600: 40.3%; EOX + IMAB1000: 34.1%) and 
any chemotherapy (EOX: 34.5%; EOX + IMAB600: 39.0%; EOX + IMAB1000: 29.4%) 
(GM-IMAB-001-03, Tables 12.2.1.1.5.1 and 12.2.1.5 [Safety-evaluable Set]). 
Best Objective Tumor Response by Independent Review Committee  
Based on confirmed responses, the ORR was 38.0% in the EOX + IMAB600 arm, 29.5% in 
the EOX + IMAB1000 arm and 24.7% in the EOX arm [IB, Table 21]. This included 10.1% 
of subjects with a CR in the EOX + IMAB600 arm, 4.5% in the EOX + IMAB1000 arm and 
3.5% in the EOX arm (GM-IMAB-001-03, Table 12.3.3.1.3). 
1.4.2 
Efficacy of mFOLFOX6  
Subjects in this study will receive mFOLFOX6 (a combination of fluorouracil [5-FU], folinic 
acid and oxaliplatin), which is an accepted standard-of-care treatment for subjects with 
locally advanced unresectable metastatic gastric or gastroesophageal (GE) cancer [NCCN 
2017]. 
1.5 
Risk Benefit Assessment 
Zolbetuximab is an investigational agent for the treatment of CLDN18.2-positive, 
HER2-negative locally advanced unresectable or metastatic gastric and GEJ adenocarcinoma 
in combination with standard of care oxaliplatin fluoropyrimidine-based combination 
chemotherapy as first-line treatment. 
Based on clinical efficacy and safety data from the MONO study, preliminary data from the 
FAST study and supportive preclinical pharmacological studies, there is potential of 
achieving clinically relevant benefit in combination with oxaliplatin and 
fluoropyrimidine-based chemotherapy in a first-line setting and as a single agent in the later 
line setting.  
Based on currently available clinical data, zolbetuximab was tolerated from a safety 
perspective and most observed AEs have been considered manageable. Nonclinical toxicity 
data were supportive of clinical findings. 
Important identified risks of zolbetuximab are:  
● 
Nausea 
● 
Vomiting  

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● 
HSRs (including IRRs) 
Important potential risks of zolbetuximab include:  
● 
Neutropenia  
● 
Anemia 
Management of the important identified risks associated with zolbetuximab includes 
antiemetic pretreatment reduction of the initial zolbetuximab infusion rate, and pausing or 
discontinuing the infusion based on patient tolerability and investigator’s clinical judgment 
about severity of toxicity and local standard of care. Subjects receiving zolbetuximab do not 
need to be premedicated for prevention of HSRs and IRRs; however, subjects should be 
closely monitored for IRRs to facilitate early identification and management. 
Overall, the risks, both identified and potential associated with zolbetuximab in combination 
with mFOLFOX6 are balanced by the anticipated benefits to subjects with 
CLDN18.2-positive, HER2 negative locally advanced unresectable or metastatic gastric or 
GEJ adenocarcinoma. 
As described in [Section 10.1], an Independent Data Monitoring Committee (IDMC) will be 
responsible for reviewing the unblinded data from the trial to ensure the safety of the 
subjects. 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS 
2.1 
Study Objective(s) 
2.1.1 
Primary Objectives 
The primary objective is to evaluate the efficacy of zolbetuximab plus mFOLFOX6 
compared with placebo plus mFOLFOX6 (as first-line treatment) as measured by PFS in 
subjects with Claudin (CLDN)18.2 positive, HER2–negative locally advanced unresectable 
or metastatic gastric and GEJ adenocarcinoma 
2.1.2 
Secondary Objectives 
The secondary objectives are: 
● 
To evaluate efficacy as measured by Overall Survival (OS) as a key secondary 
objective  
● 
To evaluate the physical function (PF), OG25-Pain and GHS/QoL scores as measured 
by European Organization for Research and Treatment of Cancer (EORTC) as a key 
secondary objective  
● 
To evaluate efficacy as measured by Objective Response Rate (ORR) 
● 
To evaluate efficacy as measured by Duration of Response (DOR) 
● 
To evaluate safety and tolerability of zolbetuximab  
● 
To further evaluate other health related quality of life (HRQoL) using additional 
parameters as measured by EORTC QLQ-C30, QLQ-OG25, Global Pain (GP) and the 
EuroQOL Five Dimensions Questionnaire 5L (EQ5D-5L) questionnaires  

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● 
To evaluate the pharmacokinetics of zolbetuximab 
● 
To evaluate the immunogenicity profile of zolbetuximab 
2.1.3 
Exploratory Objectives 
The exploratory objectives are: 
● 
To evaluate efficacy as measured by Time to Progression (TTP)  
● 
To evaluate PFS following second-line anticancer treatment (PFS2)  
● 
To evaluate Disease Control Rate (DCR)  
● 
To evaluate potential genomic and/or other biomarkers that may correlate with 
treatment outcome to zolbetuximab and mFOLFOX6. (NOTE: Genomic and 
exploratory biomarker testing will not be performed on samples from subjects in 
China.) 
● 
To evaluate Health Resource Utilization (HRU) 
2.2 
Study Design and Dose Rationale 
2.2.1 
Study Design 
This global, multi-center, double-blind, 1:1 randomized, phase 3 study will evaluate efficacy 
of zolbetuximab plus mFOLFOX6 versus placebo plus mFOLFOX6 as first-line treatment in 
subjects with CLDN18.2-positive, HER2-negative locally advanced unresectable or 
metastatic gastric and GEJ adenocarcinoma. 
PFS is the primary outcome. Secondary outcomes include OS, ORR, DOR, safety and 
tolerability, HRQoL, pharmacokinetic and the immunogenicity profile of zolbetuximab. 
Exploratory outcomes include TTP, PFS2, DCR biomarkers and HRU. 
Approximately 550 subjects will be 1:1 randomized into 1 of 2 treatment arms:  
● 
Arm A (mFOLFOX6 chemotherapy in combination with zolbetuximab)  
● 
Arm B (mFOLFOX6 chemotherapy in combination with placebo) 
Randomization of subjects will be stratified by the following factors:  
● 
Region (Asia vs Non-Asia) 
● 
Number of organs with metastatic sites (0 to 2 vs ≥ 3) 
● 
Prior gastrectomy (Yes or No) 
Screening 
The Screening period is 45 days from full main informed consent form (ICF) signature. 
Retesting of lab values is allowed within the 45-day Screening period. Re-screening outside 
the 45-day window under a new subject number may be allowed once and upon discussion 
with the Medical Monitor. Computerized tomography (CT) scans and magnetic resonance 
imaging (MRI) conducted as part of a subject’s routine clinical management (i.e., standard of 
care) obtained prior to signing the ICF may be utilized for screening or baseline purposes, 
provided the procedures met the protocol-specified criteria and were performed within the 
Screening period. 

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An optional partial screening ICF may be available to allow central testing of tissue for 
CLDN18.2 and HER2 only. 
Formalin fixed paraffin embedded (FFPE) tumor tissue will be collected for central testing to 
determine CLDN18.2 and HER2 status. (Unique to China: An optional partial screening ICF 
may be available to allow central testing of tissue for CLDN18.2.)  
● Archival tumor tissue is preferred.  
o 
A minimum of 1 FFPE tumor tissue block (preferred) OR a minimum* of 15 
FFPE unstained slides are required, as allowed per local policy. If slides are 
submitted, the slides should be freshly cut from the FFPE block within the time 
frame described in the laboratory manual.  
o 
If local HER2 results are already available from local testing, a minimum* of 12 
FFPE unstained slides are required to be submitted to the central laboratory, as 
allowed per local policy.  
*If the required minimum number of slides is not able to be submitted, sponsor 
notification and approval is required. 
o (Unique to China: Five FFPE unstained slides are required, as allowed per local 
policy. The slides should be freshly cut from the FFPE block within the time frame 
described in the laboratory manual.) 
● If the specimen is insufficient or unavailable, a biopsy may be performed to obtain tumor 
sample.  
o 
Sponsor pre-approval is required when the sole purpose of the biopsy procedure 
is to assess eligibility for this study.  
o 
If the required number of slides cannot be provided, the sponsor or designee 
should be contacted for further guidance.  
Re-screening 
Subjects who have failed screening are allowed to be re-screened one time after consultation 
with the Medical Monitor. Upon re-screening, a new subject number will be assigned. 
Subjects have to re-consent to the study and all screening procedures must be repeated, with 
the exception of the CLDN18.2 and HER2 testing, as well as the radiologic imaging 
procedure to confirm eligibility if the scan is within 28 days prior to randomization.  
Laboratory values re-tested within the original 45-day Screening period are not considered 
re-screening and no new subject number will be assigned.  
Treatment Period 
Subjects will be treated with either zolbetuximab (Arm A) or placebo (Arm B) on Days 1 and 
22 starting at C1D1 until the subject meets study treatment discontinuation criteria or 
zolbetuximab is commercially marketed and locally accessible. 
Once the product is commercially marketed and locally accessible, participants should 
complete the study, transition to commercial supply, and follow the local label for treatment. 

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Astellas is planning to close the clinical trial when zolbetuximab (Vyloy) is commercially 
marketed in all countries with active patients and all patients have successfully transitioned to 
an alternative means of drug supply. 
During treatment on study protocol, subjects will receive up to 12 treatments of mFOLFOX6 
(or components of mFOLFOX6 if some components are discontinued due to toxicity) over 4 
or more cycles (each cycle is approximately 42 days) in which mFOLFOX6 is administered 
on Days 1, 15 and 29 of each cycle. A maximum of 12 doses of oxaliplatin is permitted. After 
12 mFOLFOX6 treatments, subjects may continue to receive 5-FU and folinic acid on Days 
1, 15 and 29 of each cycle at the investigator’s discretion until the subject meets study 
treatment discontinuation criteria. 
(NOTE: An ECG is required to be performed and assessed locally prior to every oxaliplatin 
infusion [before any antiemetic treatment] and following completion of every oxaliplatin 
infusion. ECG should be performed up to 48 hours prior to and up to 6 hours following every 
oxaliplatin infusion. Oxaliplatin administration and electrolyte levels should be managed 
according to the investigator’s judgment for subjects with grade 1 or 2 hypokalemia, 
hypomagnesemia and/or hypocalcemia.) 
Participants who discontinue zolbetuximab and continue to receive mFOLFOX6 or 
components of mFOLFOX6 should complete procedures on the study and transition to 
commercially marketed and locally accessible product(s). 
Study Treatment Discontinuation and Safety Follow-up Visits 
Following discontinuation from zolbetuximab/placebo, subjects will have a 
zolbetuximab/placebo Study Treatment Discontinuation Visit, and 30- and 90-day Safety 
Follow-up Visits following their last dose of zolbetuximab/placebo.  
Additionally, if mFOLFOX6 (all components) is discontinued on a different day than 
zolbetuximab/placebo, subjects will also have a Study Treatment Discontinuation Visit, and 
30- and 90-day Safety Follow-up Visits following the last dose of mFOLFOX6 (all 
components). The mFOLFOX6 30- and 90-day Safety Follow-up Visits may be conducted by 
phone if the subject is unable to visit the site and will require only contact for AE/SAE 
collection. Effective with implementation of Protocol Version 7.0 (Substantial 
Amendment 6), the 90-day Safety Follow-up Visit will be conducted by phone; see the 
Schedule of Assessments [Table 11] in [Section 13]. 
Post-Treatment Follow-up Period (for PFS) 
Note: Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), the 
Post-Treatment Follow-up Period (for PFS) is discontinued; see the Schedule of Assessments 
[Table 11] in [Section 13].  
Subjects that completed the 90-Day Safety Follow up Visit(s) treatment period under 
Protocol Version 6.1 or earlier (e.g., Original Protocol Version 1 through 6.1) were eligible 
for the Post-Treatment Follow-up Period (for PFS) with radiological disease progression 
determined by IRC as outlined in [Table 1]. If a subject discontinues all study treatments 

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(zolbetuximab/placebo and all components of mFOLFOX6) prior to IRC-confirmed 
radiological disease progression, the subject will enter the Post-Treatment Follow-up Period 
and continue to undergo scheduled imaging assessments every 9 weeks (or every 12 weeks if 
subjects has been on study over 54 weeks) until radiologic disease progression (i.e., PFS 
event) or the subject starts any other anticancer treatment (2nd line), whichever occurs earlier. 
If study treatment (zolbetuximab/placebo and all components of mFOLFOX6) is 
discontinued due to disease progression (PFS event), the subject will enter the Long Term 
and Survival Follow-up Period.  
Long Term Follow-up Period (for PFS2) and Survival Follow-up (for OS) Period 
Note: Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), the 
Long Term Follow-up Period (for PFS2) and Survival Follow-up (for OS) Period is 
discontinued; see the Schedule of Assessments [Table 11] in [Section 13].  
Subjects that completed the Post-Treatment Follow-up Period (for PFS) under Protocol 
Version 6.1 or earlier (e.g., Original Protocol Version 1 through 6.1) were eligible for the 
Long Term Follow-up Period (for PFS2) and Survival Follow-up (for OS) Period. Following 
disease progression on first-line treatment or start of any other anticancer treatment, subjects 
will be followed in the Long-Term and Survival Follow-up Period per institutional 
guidelines, but not less frequently than every 12 weeks to confirm survival status (i.e., OS) 
and collect subsequent anticancer treatment details and progression status until PD following 
subsequent anticancer therapy (PFS2) is documented or the subject starts another systemic 
anticancer treatment, whichever occurs earlier. Radiologic imaging for PFS2 will be done per 
standard of care and read locally. The Survival Follow-up Period will continue until death 
(from any cause). All post-progression details, including subsequent anticancer treatment and 
date and site of progression, will be recorded on the electronic case report form (eCRF). 
Subject contact by phone or other remote methods is sufficient during Long Team and 
Survival Follow-up. Additional follow-up contacts may be required per sponsor request for 
analysis purposes. IDMC and Independent Data Analysis Center 
Independent Data Monitoring Committee and Independent Data Analysis Center 
An IDMC will be established and will monitor the benefit-risk of study treatment in an 
unblinded fashion per pre-defined IDMC charter. The first IDMC meeting will be 
approximately 6 weeks after the 40th subject enrolled has completed or discontinued Cycle 1 
(6 weeks) and meetings will be conducted regularly thereafter, as determined by the IDMC.  
An Independent Data Analysis Center will conduct an interim analysis of OS at the same 
time as the final PFS analysis, which will occur when approximately 300 PFS events have 
occurred. This analysis will be utilized by the IDMC to recommend whether the study should 
be stopped earlier than planned if zolbetuximab in combination with mFOLFOX6 has a 
favorable outcome compared with mFOLFOX6 in combination with placebo. If the OS 
interim analysis demonstrates a highly more favorable outcome for zolbetuximab in 
combination with mFOLFOX6, the study may be stopped for success. However, any subject 
continuing to derive clinical benefit from zolbetuximab/placebo in combination with 

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mFOLFOX6 as assessed by the investigator will be allowed to continue treatment. The full 
procedures for IDMC review will be described in a separate IDMC charter. 
(UNIQUE to JP): In case that zolbetuximab is approved for marketing authorization in 
Japan, the study will continue as a “phase 4 post-marketing study” in accordance with Good 
Post-marketing Study Practice on and after the day of marketing authorization. In this case, 
“Study” in the protocol is read as “Post-marketing study.” 
2.2.2 
Dose Rationale 
The dose of zolbetuximab in this study is an 800 mg/m2 loading dose (C1D1) followed by 
600 mg/m2 every 3 weeks in combination with mFOLFOX6. This dose and schedule of 
zolbetuximab (800/600 mg/m2 every 3 weeks) were chosen based on the observed data from 
the GM-IMAB-001-03 (FAST) study. In the GM-IMAB-001-03 (FAST) study, addition of 
zolbetuximab 800/600 mg/m2 every 3 weeks to EOX (Arm 2) demonstrated a statistically 
significant and clinically meaningful improvement on PFS and OS in subjects with 
CLDN18.2-positive advanced gastric/GEJ cancer compared to EOX (Arm 1). The mean 
serum trough concentration of zolbetuximab was maintained above the targeted value of 
50 μg/mL (based on half maximal effective concentration [EC50] of in vitro ADCC and CDC 
activities) following 800/600 mg/m2 every 3 weeks administration. A higher zolbetuximab 
dose (1000 mg/m2 every 3 weeks) in combination with EOX was added 18 months later (with 
the allocation ratio of 1:1:7) as Arm 3 in the FAST study to evaluate safety and efficacy at 
the higher dose. However, this arm had less treatment benefit compared to Arm 2. Although 
there were numerical differences observed in some demographics and baseline 
characteristics, the sample size was not sufficient to evaluate and confirm the impact of such 
differences; therefore, the reason for underperformance in Arm 3 remains inconclusive. 
There is no single standard, globally accepted first-line reference chemotherapeutic regimen 
for advanced gastric cancer. A fluoropyrimidine (5-FU or capecitabine) in combination with 
platinum agent (cisplatin or oxaliplatin) is an accepted standard of care cytotoxic 
chemotherapy regimen in both Western and Asian countries [NCCN, 2017; Ajani et al, 2010; 
Ohtsu et al, 2011; Ajani, 2000; Kim et al, 1993]. Both classes of agents are considered to be 
interchangeable according to NCCN and European Society for Medical Oncology treatment 
guidelines. Subjects in this study will receive mFOLFOX6 (a combination of 5-FU, folinic 
acid and oxaliplatin), which is a globally accepted standard-of-care treatment for subjects 
with locally advanced unresectable metastatic gastric or GEJ cancer. The safety of this 
combination regimen is well-documented. 
2.3 
Endpoints  
2.3.1 
Primary Endpoints 
The primary endpoint is PFS, which is defined as the time from the date of randomization 
until the date of radiological PD (per Response Evaluation Criteria in Solid Tumors 
[RECIST] 1.1 by independent review committee [IRC]) or death from any cause, whichever 
is earliest.  

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2.3.2 
Secondary Endpoints  
The secondary endpoints are: 
● 
OS, defined as the time from the date of randomization until the date of death from any 
cause 
● 
Time to confirmed deterioration (TTCD) using the PF, OG25-Pain and GHS/QoL scores 
as measured by EORTC QLQ-C30 and QLQ-OG25. TTCD is defined as time to first 
confirmed deterioration, i.e., time from randomization to first clinically meaningful 
deterioration that is confirmed at the next scheduled visit 
● 
ORR, defined as the proportion of subjects who have a best overall response (BOR) of 
CR or PR as assessed by IRC per RECIST 1.1 
● 
DOR, defined as the time from the date of the first response (CR/PR) until the date of PD 
as assessed by IRC per RECIST 1.1 or date of death from any cause, whichever is 
earliest 
● 
Safety and tolerability, as measured by AEs, laboratory test results, vital signs, ECGs and 
Eastern Cooperative Oncology Group (ECOG) performance status  
● 
HRQoL using the additional parameters as measured by EORTC QLQ-C30, 
QLQ-OG25, GP and EQ5D-5L questionnaires 
● 
Pharmacokinetics of zolbetuximab, Ctrough 
● 
Immunogenicity of zolbetuximab as measured by the frequency of anti-drug antibody 
(ADA) positive subjects.  
2.3.3 
Exploratory Endpoints 
The exploratory endpoints are: 
● 
TTP, defined as the time from the date of randomization until the date of PD as assessed 
by IRC per RECIST 1.1. 
● 
PFS2, defined as the time from the date of randomization until the date of PD (per 
investigator) following subsequent anticancer therapy, death from any cause or start of 
any other anticancer therapy, whichever is earliest.  
● 
DCR, defined as the proportion of subjects who have a BOR of SD, CR or PR as 
assessed by IRC per RECIST 1.1. 
● 
Potential genomic and/or other exploratory biomarkers that may be related to treatment 
outcome of zolbetuximab. (NOTE: Genomic and exploratory biomarker testing will not 
be performed on samples from subjects in China.) 
● 
HRU 
3 
STUDY POPULATION 
3.1 
Selection of Study Population  
Subjects with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma 
whose tumors are CLDN18.2 positive, HER2-negative and who have not been previously 
treated for metastatic disease with chemotherapy (1st line).  

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For the purpose of this study, CLDN18.2-positive is defined as CLDN18.2 expression in 
≥ 75% of tumor cells demonstrating moderate to strong membranous staining as determined 
by central IHC testing.  
3.2 
Inclusion Criteria 
Waivers to the inclusion criteria will NOT be allowed. 
General Criteria: 
1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written 
informed consent and privacy language as per national regulations (e.g., HIPAA 
Authorization for US sites) must be obtained from the subject or legally authorized 
representative (if applicable) prior to any study-related procedures. 
2. Subject is considered an adult (e.g., ≥ 18 years of age in the US) according to local 
regulation at the time of signing the informed consent. 
3. Subject agrees not to participate in another interventional study while on study treatment. 
4. A female subject is eligible to participate if she is not pregnant (negative serum 
pregnancy test at Screening; female subjects with elevated serum beta human chorionic 
gonadotropin (βhCG) and a demonstrated non-pregnant status through additional testing 
are eligible) and at least 1 of the following conditions applies: 
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 12.3 
Contraception Requirements 
OR 
b. WOCBP who agrees to follow the contraceptive guidance as defined in 
Appendix 12.3 Contraception Requirements throughout the treatment period and 
for 9 months after the final administration of oxaliplatin and 6 months after the 
final administration of all other study drugs. 
5. Female subject must agree not to breastfeed starting at Screening and throughout the 
study period, and for 6 months after the final study treatment administration. 
6. Female subject must not donate ova starting at Screening and throughout the study 
period, and for 9 months after the final administration of oxaliplatin and 6 months after 
the final administration of all other study drugs. 
7. A sexually active male subject with female partner(s) who are of childbearing potential 
must agree to use contraception as detailed in Appendix 12.3 Contraception Requirements 
during the treatment period and for at least 6 months after the final study drug 
administration.  
8. Male subject must not donate sperm starting at Screening and throughout the study period 
and for 6 months after the final study drug administration. 
9. Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or 
use a condom for the duration of the pregnancy or for the time partner is breastfeeding 
throughout the study period and for 6 months after the final study drug administration.  
Disease Specific Criteria: 
10. Subject has histologically confirmed diagnosis of Gastric or GEJ adenocarcinoma.  

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11. Subject has radiologically confirmed locally advanced unresectable or metastatic disease 
within 28 days prior to randomization.  
12. Subject has radiologically evaluable disease (measurable and/or non-measurable disease 
according to RECIST 1.1), per local assessment, ≤ 28 days prior to randomization. For 
subjects with only 1 evaluable lesion and prior radiotherapy ≤ 3 months before 
randomization, the lesion must either be outside the field of prior radiotherapy or have 
documented progression following radiation therapy. 
13. Subject’s tumor expresses CLDN18.2 in ≥ 75% of tumor cells demonstrating moderate to 
strong membranous staining as determined by central IHC testing. 
14. Subject has a known HER2-negative tumor as determined by local or central testing on a 
gastric or GEJ tumor specimen. (Unique to China: Subject has a known HER2-negative 
gastric or GEJ tumor.) 
Physical or Laboratory Findings 
15. Subject has ECOG performance status 0 to 1. 
16. Subject has predicted life expectancy  12 weeks in the opinion of the investigator. 
17. Subject must meet all of the following criteria based on the centrally or locally analyzed 
laboratory tests collected within 14 days prior to randomization. In the case of multiple 
sample collections within this period, the most recent sample collection with available 
results should be used to determine eligibility.  
a. Hemoglobin (Hgb) ≥ 9 g/dL. Subjects requiring transfusions are eligible if 
post-transfusion hemoglobin ≥ 9 g/dL. 
b. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
c. Platelets ≥ 100 x 109/L 
d. Albumin ≥ 2.5 g/dL 
e. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) without liver metastases (or 
< 3.0 x ULN if liver metastases are present) 
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x 
ULN without liver metastases (or ≤ 5 x ULN if liver metastases are present) 
g. Estimated creatinine clearance ≥ 30 mL/min  
h. Prothrombin time (PT)/international normalized ratio (INR) and PTT ≤ 1.5 x ULN 
(except for subjects receiving anticoagulation therapy) 
3.3 
Exclusion Criteria 
Waivers to the exclusion criteria will NOT be allowed.  
Subject who meets any of the following exclusion criteria prior to enrollment is not eligible 
for enrollment:  
Prohibited Treatment or Therapies 
1. Subject has received prior systemic chemotherapy for locally advanced unresectable 
or metastatic gastric or GEJ adenocarcinoma. However, subject may have received 
either neo-adjuvant or adjuvant chemotherapy, immunotherapy or other systemic 
anticancer therapies as long as it was completed at least 6 months prior to 

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randomization. Subject may have received treatment with herbal medications that 
have known antitumor activity > 28 days prior to randomization. 
2. Subject has received radiotherapy for locally advanced unresectable or metastatic 
gastric or GEJ adenocarcinoma ≤ 14 days prior to randomization and has not 
recovered from any related toxicity.  
3. Subject has received systemic immunosuppressive therapy, including systemic 
corticosteroids within 14 days prior to randomization. Subjects using a physiologic 
replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day 
of hydrocortisone or up to 10 mg per day of prednisone), receiving a single dose of 
systemic corticosteroids or receiving systemic corticosteroids as premedication for 
radiologic imaging contrast use are allowed. 
4. Subject has received other investigational agents or devices within 28 days prior to 
randomization.  
Medical History or Concurrent Disease 
5. Subject has prior severe allergic reaction or intolerance to known ingredients of 
zolbetuximab or other monoclonal antibodies, including humanized or chimeric 
antibodies. 
6. Subject has known immediate or delayed hypersensitivity, intolerance or 
contraindication to any component of study treatment. 
7. Subject has prior severe allergic reaction or intolerance to any component of 
mFOLFOX6. 
8. Subject has known dihydropyrimidine dehydrogenase (DPD) deficiency. (NOTE: 
Screening for DPD deficiency should be conducted per local requirements.) 
9. Subject has a complete gastric outlet syndrome or a partial gastric outlet syndrome 
with persistent/recurrent vomiting. 
10. Per investigator judgment, subject has significant gastric bleeding and/or untreated 
gastric ulcers that would exclude the subject from participation per investigator 
judgment. 
11. Subject has a known history of a positive test for human immunodeficiency virus 
(HIV) infection or known active hepatitis B (positive HBs Ag) or C infection. NOTE: 
Screening for these infections should be conducted per local requirements.  
a. 
For subjects who are negative for HBs Ag, but HBc Ab positive, an HB DNA test 
will be performed and if positive the subject will be excluded. 
b. Subjects with positive hepatitis C virus (HCV) serology, but negative HCV RNA 
test results are eligible. 
c. 
Subjects treated for HCV with undetectable viral load results are eligible. 
12. Subject has an active autoimmune disease that has required systemic treatment within 
the past 3 months prior to randomization.  
13. Subject has active infection requiring systemic therapy that has not completely 
resolved within 7 days prior to randomization. 
14. Subject has significant cardiovascular disease, including any of the following: 

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a. Congestive heart failure (defined as New York Heart Association Class III or IV), 
myocardial infarction, unstable angina, coronary angioplasty, stenting, coronary 
artery bypass graft, cerebrovascular accident or hypertensive crisis within 
6 months prior to randomization. 
b. History of clinically significant ventricular arrhythmias (i.e., sustained ventricular 
tachycardia, ventricular fibrillation or Torsades de Pointes)  
c. QTc interval > 450 msec for male subjects; QTc interval > 470 msec for female 
subjects 
d. History or family history of congenital long QT syndrome 
e. Cardiac arrhythmias requiring anti-arrhythmic medications (Subject with rate 
controlled atrial fibrillation for > 1 month prior to randomization are eligible). 
15. Subject has history of central nervous system metastases and/or carcinomatous 
meningitis from gastric/GEJ cancer.  
16. Subject has known peripheral sensory neuropathy > grade 1 unless the absence of 
deep tendon reflexes is the sole neurological abnormality.  
17. Subject has had a major surgical procedure  28 days prior to randomization.  
a. Subject is without complete recovery from a major surgical procedure  14 days 
prior to randomization. 
18. Subject has psychiatric illness or social situations that would preclude study 
compliance, per investigator judgment. 
19. Subject has another malignancy for which treatment is required per investigator’s 
clinical judgment.   
20. Subject has any concurrent disease, infection or comorbid condition that interferes 
with the ability of the subject to participate in the study, which places the subject at 
undue risk or complicates the interpretation of data in the opinion of the investigator. 
4 
IDENTIFICATION OF STUDY TREATMENT(S)  
4.1 
Zolbetuximab (IMAB362) (Investigational Product) 
The investigational product, zolbetuximab, is a sterile lyophilized powder with the chimeric 
(mouse/human IgG1) monoclonal antibody zolbetuximab as the active pharmaceutical 
ingredient.  
The investigational product is supplied by Astellas in a single-use glass vial containing 
105 mg of zolbetuximab, of which 100 mg is extractable from each vial. All excipients are 
animal component free and of compendial grade (Pharm. Eur. current version). No 
preservatives are contained, since the vial is designed for single use.  
The investigational product should be stored at refrigerated conditions (2°C to 8°C; 36°F to 
46°F). Temperature should be controlled and monitored. Details of investigational product 
receipt, labeling, storage and preparation are provided in the Pharmacy Manual and Infusion 
Guidelines. 
The zolbetuximab used in this study will be prepared, packaged, and labeled under the 
responsibility of qualified staff at Astellas Pharma Global Development, Inc. (APGD), 

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Astellas US Technologies, Inc. or sponsor’s designee in accordance with APGD or sponsor’s 
designee Standard Operating Procedures (SOPs), Good Manufacturing Practices (GMP) 
guidelines, International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
guidelines, and applicable local laws/regulations. 
Each vial and carton will bear a label conforming to regulatory guidelines, GMP and local 
laws and regulations that identifies the contents as investigational drug. 
As required, a qualified person of Astellas Pharma Europe B.V. (APEBV) or sponsor’s 
designee will perform the final release of the medication according to the requirements of the 
EU Directive 2003/94/EC annex 13. 
4.2 
0.9% Sodium Chloride Injection 
0.9% Sodium Chloride Injection will be used for infusion solution preparation in this study 
for both zolbetuximab arm and placebo arm. 0.9% Sodium Chloride Injection will not be 
manufactured or provided to sites by the sponsor. Sites should use their own commercially 
obtained supply of 0.9% Sodium Chloride Injection. Details of preparation of infusion 
solution are provided in the Pharmacy Manual and Infusion Guidelines. SPECIFIC TO 
JAPAN: In this study, 0.9% Sodium Chloride Injection is not considered an ‘investigational 
product’ as defined in J-GCP.   
For manufacturing, formulation, storage, handling and preparation details please refer to the 
package insert, SPC or local product information supplied by the manufacturer. 
4.3 
Comparative Drug (Placebo) 
Placebo will not be manufactured or provided by the sponsor. Sites should use their own 
commercial supply of 0.9% Sodium Chloride Injection, as placebo infusion solution. Details 
of preparation of placebo infusion solution are provided in the Pharmacy Manual and 
Infusion Guidelines. 
4.4 
mFOLFOX6 (Backbone Treatment) 
Oxaliplatin, folinic acid (leucovorin) and 5-FU (mFOLFOX6) are administered in 
combination with zolbetuximab/placebo. If folinic acid is not available it may be replaced by 
levo-folinic acid. mFOLFOX6 products should be given according to institutional standards, 
published guidelines, the respective product package insert(s) or dosed according to this 
protocol. SPECIFIC TO JAPAN: leucovorin (folinic acid) is replaced by levofolinate. 
Backbone treatment will be supplied by the responsible site pharmacy of each investigational 
site or by the sponsor as applicable. Sites are permitted to utilize generic drug that is 
approved by the respective regulatory authority. 
For manufacturing, formulation, storage, handling and preparation details please refer to the 
package insert, SPC or local product information supplied by the manufacturer. 
mFOLFOX6 will be supplied by the responsible site pharmacy of each investigational site or 
by the sponsor, as applicable.  

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If mFOLFOX6 is supplied by the sponsor, mFOLFOX6 used in this study will be, packaged 
and labeled under the responsibility of qualified staff at APGD/Astellas US Technologies, 
Inc. (AUST) sponsor’s designee in accordance with APGD-AUST or sponsor’s designee 
SOPs, GMP guidelines, ICH GCP guidelines, and applicable local laws/regulations. 
Each product will bear a label conforming to regulatory guidelines, GMP and local laws and 
regulations that identifies the contents as investigational drug. 
As required, a qualified person of APEBV or sponsor’s designee will perform the final 
release of the medication according to the requirements of the EU Directive 2003/94/EC 
annex 13. 
4.5 
Other Drug(s)  
4.5.1 
Antiemetic Premedication 
Prophylactic antiemetics will not be provided by the sponsor but rather will be sourced by the 
Sites via commercial supply. 
For manufacturing, formulation, storage, handling and preparation details please refer to the 
package insert, SPC or local product information supplies by the manufacturer. 
4.6 
Study Drug Handling  
Current ICH GCP Guidelines require the investigator to ensure that study treatment and other 
drug deliveries from the sponsor are received by the investigator or designee and that: 
● 
Such deliveries are recorded, 
● 
Study drug is handled and stored according to labeled storage conditions, 
● 
Study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol, and 
● 
Any unused study drug is returned to the sponsor, unless prior approval is received 
from the sponsor allowing local standard procedures for the alternative disposition of 
unused study drug. 
Study drug inventory and accountability records will be kept by the investigator, head of 
study site (SPECIFIC TO SITES IN JAPAN) or designee. Study drug accountability 
throughout the study must be documented and reconciled. The following guidelines are 
therefore pertinent: 
● 
The investigator agrees not to supply study drugs to any persons except the eligible 
subjects in this study in accordance with the protocol. 
● 
The investigator or designee will keep the study drugs in a pharmacy or other locked 
and secure storage facility under controlled storage conditions, accessible only to those 
authorized by the investigator to dispense these study drugs. 
● 
A study drug inventory will be maintained by the investigator or designee. The 
inventory will include details of material received and a clear record of when they were 
dispensed and to which subject. 

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● 
At the conclusion or termination of this study, the investigator or designee agrees to 
conduct a final drug supply inventory and to record the results of this inventory on the 
Drug Accountability Record. It must be possible to reconcile delivery records with 
those of used and/or returned study drug. Any discrepancies must be accounted for and 
documented. Appropriate forms of deliveries and returns must be signed by the site 
staff delegated this responsibility. 
● 
The site staff must return unused study drug to the sponsor or designee at the end of the 
study or upon expiration unless otherwise approved by the sponsor. 
4.7 
Blinding 
See [Appendix 12.10] for unblinding procedures following final OS database lock. 
4.7.1 
Blinding Method  
The clinical study will be conducted as subject and investigator-blinded. Subjects will be 
randomized to receive zolbetuximab or placebo in a blinded fashion such that neither the 
investigator, sponsor’s study management team, clinical staff, nor subject will know which 
agent is being administered.  
Upon the need for unblinding (e.g., real-time assessment of the safety data), the chair of the 
IDMC can ask for the release of the treatment assignment for 1 or more subjects and will 
identify the sponsor staff who will receive the information. 
4.7.2 
Confirmation of the Indistinguishability of the Study Drugs 
The appearance and the final form of both the drug and packaging of zolbetuximab solution 
for infusion are identical to placebo. In order to maintain the blind, the subjects randomized 
to the placebo treatment arm (Arm B) will receive placebo in a volume and route 
corresponding to the appropriate zolbetuximab dose (Arm A). The unblinded 
pharmacist/designee will provide the investigator or designee with blinded study drugs to 
dose the subjects. Refer to the Pharmacy Manual and Infusion Guidelines for detailed 
information. 
4.7.3 
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking  
The randomization list and study drug blind will be maintained by the Interactive Response 
Technology (IRT) system.  
4.7.4 
Breaking the Treatment Code for Emergency  
The treatment code for each randomized subject will be provided by the IRT in the event of a 
medical emergency requiring knowledge of the treatment assigned to the subject. The IRT 
will be programmed with blind-breaking instructions that may only be requested by the 
investigator or sub-investigators designated to have access to perform blind-break. No 
subjects or other study personnel, other than the unblinded pharmacist or designee, will be 
made aware of the treatment given to any subject unless a medical emergency necessitates 
such disclosure. In case of a medical emergency, the investigator has the sole responsibility 

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for determining if unblinding of subject’s treatment assignment is warranted. Subject safety 
must always be the first consideration in making such determination. If the investigator 
decides that unblinding is warranted, the investigator should make every effort to contact the 
sponsor prior to unblinding a subject’s treatment assignment unless this could delay 
emergency treatment for the subject. Any unblinding by the investigators must be reported 
immediately to the sponsor and must include an explanation for the unblinding.  
The investigator must have confirmed functionality to access code-break through the IRT 
system and must have a designated back up (e.g., redundant processes) to support emergency 
unblinding requirements.  
Prior to randomization, subjects should be provided with information that includes the site 
emergency contact number and back-up contact number in case of a medical emergency. Any 
unblinding by the investigational staff must be reported immediately to the sponsor and 
include an explanation of why the study drug was unblinded. If unblinding is associated with 
a SAE the investigator is to follow the instructions in [Section 5.5.5 Reporting of SAE].  
Care should be taken to limit knowledge of the randomization arm in case this could affect 
the blinding of other subjects or future study assessment for the subject.  
The time, date, subject number and reason for obtaining any of these codes, and therefore 
breaking the blind, must be documented in the study file.  
If possible, the sponsor should be contacted prior to unblinding of the study drug. 
4.7.5 
Breaking the Treatment Code by the Sponsor  
The sponsor may break the treatment code for subjects who experience a Suspected 
Unexpected Serious Adverse Reaction (SUSAR), in order to determine if the individual case 
or a group of cases requires expedited regulatory reporting. Individual Emergency Codes will 
be provided to the limited staff who are responsible to break the codes for all SUSAR cases 
for reporting purposes. 
4.8 
Assignment and Allocation 
Subject randomization will be performed by blinded site user via IRT and treatment assigned 
in a 1:1 ratio to zolbetuximab or placebo. Prior to the initiation of the study treatment, the 
unblinded pharmacist/designee will be notified by the IRT system about the randomly 
assigned treatment. The unblinded pharmacist/designee will dispense the treatment according 
to the IRT system’s assignment. Specific procedures for randomization through the IRT are 
contained in the IRT manual.  
Randomization will be stratified by:  
● 
Region (Asia vs Non-Asia) 
● 
Number of organs with metastatic sites (0 to 2 vs ≥ 3) 
● 
Prior gastrectomy (Yes or No) 

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5 
TREATMENTS AND EVALUATION 
5.1 
Dosing and Administration of Study Drug(s) and Other 
Medication(s) 
5.1.1 
Dose/Dose Regimen and Administration Period 
5.1.1.1 Zolbetuximab/Placebo 
Subjects will be administered zolbetuximab/placebo as a minimum 2-hour IV infusion. 
Guidance for slowing the initial infusion to minimize toxicity can be found in the 
Pharmacy Manual and Infusion Guidelines. Subjects will be administered a loading dose 
of 800 mg/m2 on zolbetuximab/placebo on C1D1 followed by subsequent doses of 
600 mg/m2 every 3 weeks starting from C1D22 (i.e., C1D22, C2D1, C2D22, etc.). If both 
zolbetuximab/placebo and mFOLFOX6 are to be administered during the same visit, 
zolbetuximab/placebo should be administered prior to mFOLFOX6. Flow rate data will be 
collected in the eCRF. 
IV infusion may be interrupted or slowed down to manage toxicity. Please refer to the 
Pharmacy Manual and Infusion Guidelines for more detailed information.  
Once the product is commercially marketed and locally accessible, participants should 
complete the study and transition to commercial supply and follow the local label for 
treatment. 
Astellas is planning to close the clinical trial when zolbetuximab (Vyloy) is commercially 
marketed in all countries with active patients and all patients have successfully transitioned to 
an alternative means of drug supply. 
5.1.1.2 Antiemetics 
Antiemetic premedication (prophylactic antiemetics) should be administered prior to each 
study treatment. 
(NOTE: Subjects receiving zolbetuximab do not need to be premedicated for prevention of 
IRRs; however, subjects should be closely monitored for IRRs to facilitate early 
identification and management.)  
● 
Antiemetic premedication 
o 
IV antiemetic premedication should be initiated prior to treatment, or 
o 
Oral antiemetic premedication should be initiated at a minimum of 30 minutes prior 
to treatment.  
● 
On days when zolbetuximab/placebo and mFOLFOX6 are administered together, 
antiemetic premedication should be given prior to zolbetuximab/placebo administration.  
● 
It is recommended that the prophylactic antiemetic regimen include (but is not limited to) 
the following agents: 
o 
NK-1 receptor blockers  
o 
5-HT3 receptor blockers* 

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* To minimize the risk of Torsades de Pointes, administer 5-HT3 receptor blockers with 
caution to subjects who have or may develop QTc prolongation.  
Antiemetic premedication should be administered according to institutional standard of care, 
published guidelines and the respective product package insert(s).  
Corticosteroids: 
● 
The impact of corticosteroids on the potential efficacy of zolbetuximab is not known. 
Therefore, consideration should be given to avoid or minimize the use of corticosteroids 
as a prophylactic antiemetic, if possible.  
● 
For a subject’s first dose of zolbetuximab/placebo, it is recommended that the 
prophylactic use of corticosteroids be avoided. 
5.1.1.3 mFOLFOX6 
Subjects will receive up to 12 treatments of mFOLFOX6 (or components of mFOLFOX6 if 
some components are discontinued due to toxicity) over 4 or more cycles (each cycle is 
approximately 42 days) in which mFOLFOX6 is administered on Days 1, 15 and 29.  
After 12 treatments, subjects may continue to receive 5-FU and folinic acid at the 
investigator’s discretion until the subject meets study treatment discontinuation criteria. 
mFOLFOX6 (or components) should be administered after zolbetuximab/placebo on visits 
when both treatments are to be administered on the same day (e.g., C1D1, C2D1, etc.). 
● 
Oxaliplatin: 85 mg/m2 IV infusion over 2 hours or longer per institutional standard of 
care every 2 weeks for 4 cycles (3 treatments each cycle), for a maximum of 12 doses. 
(NOTE: ECG is required to be performed and assessed locally prior to every oxaliplatin 
infusion [before any antiemetic treatment] and following completion of every 
oxaliplatin infusion. ECG should be performed up to 48 hours prior to and up to 6 hours 
following every oxaliplatin infusion. Oxaliplatin administration and electrolyte levels 
should be managed according to the investigator’s judgement for subjects with grade 1 
or 2 hypokalemia, hypomagnesemia and/or hypocalcemia.) 
● 
Folinic Acid: 400 mg/m2 IV infusion over 2 hours or longer per institutional standard of 
care every 2 weeks for 4 cycles (3 treatments each cycle). Folinic acid can be continued 
beyond 4 cycles based on investigator’s judgement. SPECIFIC TO JAPAN: Or, 
Levofolinate 200 mg/m2 IV infusion over 2 hours or longer per institutional standard of 
care every 2 weeks for 4 cycles. Levofolinate can be continued beyond 4 cycles based 
on investigator’s judgement. Or, levo-folinic acid may be given as deemed appropriate 
by the investigator in accordance with institutional standard of care. 
● 
5-FU Bolus: 400 mg/m2 IV bolus over 5 to 15 minutes or per institutional standard of 
care every 2 weeks for 4 cycles (3 treatments each cycle). 5-FU can be continued 
beyond 4 cycles based on investigator’s judgement. 
● 
5-FU Infusion: 2400 mg/m2 IV infusion over 46 to 48 hours or per institutional standard 
of care every 2 weeks for 4 cycles (3 treatments each cycle). 5-FU can be continued 
beyond 4 cycles based on investigator’s judgement. 

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Participants who discontinue zolbetuximab and continue to receive mFOLFOX6 or 
components of mFOLFOX6 should complete procedures on the study and transition to 
commercially marketed and locally accessible mFOLFOX6 product(s). 
5.1.2 
Study Treatment Dose Modifications, Delays And Interruptions 
5.1.2.1 Increase or Reduction of Zolbetuximab/Placebo 
Dose increase or dose reduction for zolbetuximab/placebo is not allowed. Body surface area 
should be recalculated at minimum if there is a weight change of at least 10% since the last 
dose calculation. 
5.1.2.2 Zolbetuximab/Placebo Interruption or Permanent Discontinuation 
There is a + 6 calendar day allowable window for dosing zolbetuximab/placebo. If 
zolbetuximab/placebo treatment is delayed 7 or more calendar days then it should be 
administered with the next scheduled mFOLFOX6 treatment, which would now be 
considered Day 1 of the next cycle. The timing of subsequent doses should be scheduled 
using the date of the last dose administration.  Refer to the Pharmacy Manual and Infusion 
Guidelines for further detail on incomplete dosing.  
A delay of zolbetuximab/placebo treatment for > 28 days from when the next study treatment 
was scheduled (> 49 days from last dose of zolbetuximab/placebo) to be administered due to 
unresolved toxicity associated with zolbetuximab/placebo will result in the subject 
discontinuing zolbetuximab/placebo. 
Radiologic imaging schedule of every 9 weeks (± 7 days) counting from C1D1 for the first 
54 weeks, and then every 12 weeks (± 7 days) thereafter, should be maintained regardless of 
treatment delay. 
Note: IV infusion of zolbetuximab/placebo should be administered as a minimum 2-hour 
infusion. IV infusion may be interrupted or slowed down to manage toxicity. Please refer to 
the Pharmacy Manual and Infusion Guidelines for more detailed information. 
Guidelines for zolbetuximab/placebo treatment modification due to non-hematologic and 
hematologic toxicities, regardless of investigator assessment of relationship to 
zolbetuximab/placebo, are described below in [Table 2] and [Table 3], respectively. 
One case of PRES has been reported in subjects receiving zolbetuximab. Discontinue 
zolbetuximab/placebo if PRES is suspected. Confirm PRES diagnosis by brain imaging, 
preferably by MRI.  

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Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Action 
Continue treatment 
Withhold treatment.  
Follow standard 
treatment guidelines. 
Transfuse if indicated. 
Recheck blood counts 
weekly until Hgb 
recovers to > 8.0 g/dL 
(≤ grade 2) before 
restarting treatment.  
Discontinue 
zolbetuximab/ placebo 
if Hgb remains 
< 8.0 g/dL (≥ grade 3) 
after a ≥ 28-day 
treatment delay from 
when the next study 
treatment was scheduled 
to be administered. 
Withhold treatment. 
Urgent intervention 
required following 
standard treatment 
guidelines and 
transfuse blood.  
The subject may be 
discontinued after 
discussion with 
Medical Monitor. 
ANC: absolute neutrophil count; LLN: lower limit of normal; PLT: platelet count; Hgb: hemoglobin 
† At the investigator’s discretion growth factors may be used according to standard practice guidelines. 
5.1.2.3 Guidelines for Infusion-Related Reactions for Zolbetuximab/Placebo 
Subjects should be closely monitored for IRRs to facilitate early identification and 
management. 
The management of such toxicities should be based on investigator utilizing institutional 
standard of care, published guidelines, and the general guidelines provided in [Table 4] 
below. 
A subject with an infusion reaction should be evaluated specifically for the symptoms and 
signs that are highly suggestive of anaphylaxis (urticaria, repetitive cough, wheeze and throat 
tightness/change in voice). A careful examination of the skin is advised in order to detect 
urticaria, which often appears first in the neck, trunk, abdomen and axillae. 
Not all anaphylactic reactions manifest as anaphylactic shock. Because anaphylaxis can recur 
and worsen with re-exposure, permanently discontinue zolbetuximab/placebo for any subject 
having a reaction with features (even if mild) that are highly suggestive of anaphylaxis.  
Note: IV infusion of zolbetuximab/placebo should be administered as a minimum 2-hour 
infusion. IV infusion may be interrupted or slowed down to manage toxicity. Please refer to 
Pharmacy Manual and Infusion Guidelines for more detailed information.  

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5.1.2.9 Oxaliplatin-Induced Laryngopharyngeal Dysesthesia 
Oxaliplatin has also been associated with laryngopharyngeal dysesthesia, which is an unusual 
loss of sensation of breathing (acute respiratory distress) without any objective evidence of 
respiratory distress (hypoxia, laryngospasm or bronchospasm). Laryngopharyngeal 
dysesthesia may be induced or exacerbated upon exposure to cold. 
Subjects developing laryngopharyngeal dysesthesia should have their oxygen saturation 
evaluated via a pulse oximeter. If results are normal, reassurance should be provided, a 
benzodiazepine or other anxiolytic agent should be considered, and the subject should remain 
for observation in the clinic until the episode has resolved. After resolution, the oxaliplatin 
infusion may then be continued at one-third the rate. 
Because laryngopharyngeal dysesthesia may be associated with the rate of oxaliplatin 
infusion, subsequent infusions of oxaliplatin should be prolonged from a normal 2-hour 
infusion to a 6-hour infusion. 
Subjects receiving oxaliplatin should avoid consuming cold drinks or ice chips on Day 1 of 
each cycle, as this may exacerbate oral or throat dysesthesia, as well as laryngopharyngeal 
dysesthesia. Administration of prophylactic medication such as Mg2+/Ca2+ infusions or others 
is at the discretion of the investigator. 
The symptoms and treatments of laryngopharyngeal dysesthesia and platinum HSRs are 
compared in [Table 9]. 
Table 9 
Comparison of the Symptoms and Treatment of Laryngopharyngeal and 
Platinum Hypersensitivity Reactions 
Clinical Symptoms 
Laryngopharyngeal Dysesthesia 
Platinum Hypersensitivity 
Dyspnea 
Present 
Present 
Bronchospasm 
Absent 
Present 
Laryngospasm 
Absent 
Present 
Anxiety 
Present 
Present 
O2 saturation 
Normal 
Decreased 
Difficulty swallowing 
Present (loss of sensation) 
Absent 
Pruritus 
Absent 
Present 
Urticaria/rash 
Absent 
Present 
Cold-induced symptoms 
Yes 
No 
Blood pressure 
Normal or increased 
Normal or decreased 
Treatment 
Reassurance, anxiolytics, observation in a 
controlled clinical setting until symptoms 
abate or at the physician’s discretion 
Oxygen, steroids, epinephrine, 
bronchodilators; fluids and 
vasopressors, if appropriate 
5.1.2.10 Allergic Reaction to Oxaliplatin 
Subjects developing grade 1 or 2 allergic reaction to oxaliplatin should receive premedication 
according to institutional practice prior to further administration of oxaliplatin. Appropriate 
premedication should also be given if grade 1 to 2 allergic reaction persists into the next 
cycle. Oxaliplatin should be discontinued in subjects developing grade 3 to 4 allergic 
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Oxaliplatin should be interrupted pending further investigation in subjects experiencing 
respiratory symptoms indicative of pulmonary fibrosis such as nonproductive cough, dyspnea, 
crackles, rales, hypoxia, tachypnea or radiological pulmonary infiltrates. Oxaliplatin should be 
permanently discontinued in subjects with confirmed interstitial pulmonary fibrosis. 
5.1.2.11 Extravasation of Oxaliplatin 
Necrosis has been seen in conjunction with extravasation of oxaliplatin. Subjects with 
suspected extravasation should have their infusion stopped and the drug administered at 
another site. Extravasation should be treated according to institutional guidelines. 
5.1.3 
Treatment Compliance 
The dose and schedule of zolbetuximab/placebo and mFOLFOX6 administered to each 
subject will be recorded on the appropriate eCRF at every cycle. Reasons for dose delay or 
omission will also be recorded. This information will be used to assess compliance with the 
treatment.  
5.1.4 
Criteria for Continuation of Treatment  
In case of premature termination, zolbetuximab may be made available to subjects who are 
still receiving and benefitting from study treatment until a study-defined treatment 
discontinuation criterion is met.  
Once the product is commercially marketed and locally accessible, participants should 
complete the study and transition to commercial supply and follow the local label for 
treatment. 
Astellas is planning to close the clinical trial when zolbetuximab (Vyloy) is commercially 
marketed in all countries with active patients, and all patients have successfully transitioned 
to an alternative means of drug supply. 
5.1.4.1 Discontinuation of mFOLFOX6 (All Components) and Continuation of 
Zolbetuximab/Placebo 
If a subject discontinues mFOLFOX6 (or components of mFOLFOX6) due to any reason 
other than locally-confirmed or IRC-confirmed disease progression, they may continue on 
zolbetuximab/placebo at the discretion of the investigator and until zolbetuximab is 
commercially marketed and locally accessible, provided that all of the following have been 
met: 
● the subject completed at least 1 cycle (42 days; 3 doses of mFOLFOX6) of mFOLFOX6 
treatment; 
● the subject will not receive another systemic chemotherapy, immunotherapy, 
radiotherapy or other treatment intended for antitumor activity; and 
● in the investigator’s opinion the subject continues to derive clinical benefit with 
acceptable toxicity. 
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), 
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follow the Study Treatment Period Schedule of Assessments [Table 11]. Under Protocol 
Version 6.1 or earlier (e.g., Original Protocol Version 1 through 6.1), radiological disease 
progression was determined by IRC and subjects followed the Study Treatment Period 
Schedule of Assessments [Table 1]. 
5.1.4.2 Discontinuation of Zolbetuximab/Placebo and Continuation of mFOLFOX6 
(Some or All Components) 
If zolbetuximab/placebo is permanently discontinued first for reasons other than PD as 
confirmed locally or by IRC and no other anticancer treatment is started, subjects may 
continue to receive mFOLFOX6/5-FU and folinic acid until treatment discontinuation criteria 
are met.  
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), 
radiological disease progression will be determined locally and subjects should continue to 
follow the Study Treatment Period Schedule of Assessments [Table 11]. Under Protocol 
Version 6.1 or earlier (e.g., Original Protocol Version 1 through 6.1), radiological disease 
progression was determined by IRC and subjects followed the Study Treatment Period 
Schedule of Assessments [Table 1]. 
Participants who discontinue zolbetuximab and continue to receive mFOLFOX6 or 
components of mFOLFOX6 should complete procedures on the study and transition to 
commercially marketed and locally accessible mFOLFOX6 product(s). 
5.1.4.3 If Both Zolbetuximab/Placebo and mFOLFOX6 (All Components) are 
Discontinued 
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), if both 
zolbetuximab/placebo and mFOLFOX6 (all components) are discontinued for reasons other 
than locally or IRC confirmed radiological PD, the subject should enter 30-day safety 
follow-up and continue to undergo imaging assessments if clinically indicated per Schedule 
of Assessments [Table 11]. Under Protocol Version 6.1 or earlier (e.g., Original Protocol 
Version 1 through 6.1), if both zolbetuximab/placebo and mFOLFOX6 (all components) are 
discontinued for reasons other than IRC-confirmed radiological PD, the subject should enter 
the Post-Treatment Follow-Up Period and continue to undergo imaging assessments per 
Schedule of Assessments [Table 1]. 
5.1.5 
Previous and Concomitant Treatment (Medication and Non-Medication 
Therapy 
All medications and concomitant treatments administered from the time of full main 
informed consent through the 90-day safety follow-up visit must be recorded in the eCRF. 
Documentation will include the medication name, indication, route and dates of 
administration. 

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Prohibited Concomitant Treatment  
The following are strictly prohibited: 
● 
Sorivudine or analogs (during 5-FU treatment). 
● 
Concurrent nonsteroid systemic immunosuppressive agents (for systemic corticosteroids, 
see cautionary concomitant treatment below). 
● 
Live vaccines should be avoided during the treatment period in which subject is 
receiving oxaliplatin or 5-FU and up to 6 months after final oxaliplatin or 5-FU dose. In 
cases where a live vaccine is needed for COVID-19 prevention and allowed per local 
regulations, please contact the Medical Monitor for discussion.  
● 
Other systemic chemotherapy, immunotherapy, radiotherapy, herbal medications or other 
treatments intended for antitumor activity.  
o Palliative radiotherapy for peripheral bone metastases is allowed.  
o For gastric bleeding, palliative radiotherapy is prohibited, but 
esophagogastroduodenoscopy with epinephrine injection is allowed. 
● 
Investigational products or therapy other than zolbetuximab. 
Cautionary Concomitant Treatment  
Considerations should be given to avoid or minimize the use of the following concomitant 
medications, if possible, during zolbetuximab/placebo treatment: 
● 
Systemic corticosteroids, because their impact on the potential efficacy of zolbetuximab 
is not known. 
o Systemic corticosteroids should be avoided or minimized while subject is on study 
treatment unless required for management of an emergent medical condition (e.g., 
severe nausea/vomiting or hypersensitivity reaction).  
o For a subject’s first dose of zolbetuximab/placebo, it is recommended that the 
prophylactic use of corticosteroids be avoided. 
o Inhaled, intranasal, ophthalmic, otic and topically applied steroids are allowed. 
● 
Subjects are allowed to use a physiologic replacement dose of hydrocortisone or its 
equivalent (defined as up to 30 mg/day of hydrocortisone or up to 10 mg/day of 
prednisone), receive a single dose of systemic corticosteroids or receive systemic 
corticosteroids as pre-medication for radiologic imaging contrast use. 
● 
Administer 5-HT3 blockers with caution in subjects who have or may develop QTc 
prolongation. 
● 
Nonsteroidal anti-inflammatory drugs (NSAIDs) because of the potential to cause gastric 
ulcers and covert bleeding.  
o In such cases where NSAID use is necessary, the use of NSAIDs with lower 
gastric ulcerogenic potential is preferred and concomitant gastric protection with 
proton pump inhibitors is recommended.  
The following should be avoided or used with caution and closely monitored during  5-FU 
administration:  
● 
CYP2C9 substrates  

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● 
Metronidazole and cimetidine 
● 
Anti-epileptic medications (e.g., phenobarbital, phenytoin and primidone)  
The following should be avoided or used with caution during oxaliplatin treatment and 
appropriate monitoring should be conducted: 
● 
Medications known to prolong the QT or QTc interval (refer to 
https://www.crediblemeds.org for a list of these medications) 
Prohibited and cautionary treatments are described in [Appendix 12.4]. 
5.2 
Demographics and Baseline Characteristics 
5.2.1 
Demographics 
Demographic information will be collected for all subjects and will include initials (where 
permitted), age, date of birth (where permitted), sex, race (where permitted) and ethnicity 
(where permitted). 
5.2.2 
Medical History 
Medical history includes all significant medical conditions per the judgement of the 
investigator that have resolved prior to informed consent or are ongoing at the time of full 
main consent. Details that will be collected include the onset date and recovery date and 
CTCAE v4.03 grade, if applicable for ongoing conditions. 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease  
A complete medical history of the target disease will be recorded during Screening. This will 
include the subject’s medical condition, date of initial diagnosis, tumor location, and other 
disease specific information as designated in the eCRF. 
5.3 
Efficacy Assessments 
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), 
radiologic imaging will be evaluated locally [Table 11]. Under Protocol Version 6.1 or earlier 
(e.g., Original Protocol Version 1 through 6.1), radiographic imaging was evaluated centrally 
by IRC.  
Radiologic imaging will be evaluated at Screening (within 28 days prior to randomization) 
and every 9 weeks (± 7 days) counting from C1D1 for the first 54 weeks and then every 
12 weeks (± 7 days) thereafter until subject develops radiological disease progression per 
RECIST 1.1 by local confirmation or IRC confirmation or starts other systemic anticancer 
treatment, whichever comes earlier.  
All radiologically evaluable disease (measurable and/or non-measurable), per local 
assessment, must be documented at Screening and re-assessed at each subsequent radiologic 
evaluation. Imaging will include CT scans with contrast of the thorax, abdomen, and pelvis. 
If CT scan with contrast is medically not feasible, MRI may be used for imaging. Bone scans 
(or focal X-ray) or brain imaging should be performed if metastatic disease in bone or brain 
is suspected, respectively. The same mode of imaging should be utilized throughout the study 

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unless medical necessity requires a change. For randomized subjects, screening images 
should be sent to the central imaging vendor no later than at time of submission of the first 
on-treatment imaging. All imaging acquired post randomization will be sent to the local or 
central imaging vendor within 7 days of scanning for the blinded independent central 
assessment of radiological tumor response based on RECIST 1.1 [Eisenhauer et al, 2009]. 
The investigator should make every effort to immediately submit radiologic assessments for 
local or IRC review when PD is suspected. Refer to Imaging Acquisition Guidelines for 
further detail on scan modality and contrast options. 
5.4 
Safety Assessment 
5.4.1 
Vital Signs 
Vital signs, including systolic and diastolic blood pressures (mmHg) and radial pulse rate 
(beats/minute) and temperature, will be obtained and recorded at the times specified in the 
Schedule of Assessments [Table 1]. All vital sign measurements will be obtained in a 
consistent manner (sitting or supine) throughout their study participation. Height and weight 
will be measured using normal institutional standards. 
If clinically significant vital sign changes from baseline (pretreatment) are noted, the changes 
will be documented as AEs on the AE page of the eCRF. Clinical significance will be defined 
as a variation in vital signs, which has medical relevance as deemed by the investigator that 
could result in an alteration in medical care. For clinically significant vital sign changes, the 
investigator will continue to monitor the subject until the parameter returns to grade ≤ 1, or to 
the baseline (pretreatment) value, or until the investigator determines that follow up is no 
longer medically necessary. 
5.4.2 
Observation Period Following Zolbetuximab/Placebo Infusion 
Following the first dose of zolbetuximab/placebo on C1D1, the subject must be observed for 
2 hours post zolbetuximab/placebo infusion. The post-infusion observation period can be 
conducted during the mFOLFOX6 administration. If ≥ grade 2 AEs are observed during 
infusion or during the post-infusion observation period, subsequent zolbetuximab/placebo 
infusion times should be extended and subjects should continue to be observed for 2 hours 
post zolbetuximab/placebo infusion. If the subject does not develop any ≥ grade 2 AEs, the 
subject should be observed for 1 hour post-infusion for their subsequent 
zolbetuximab/placebo infusions. The subject should be instructed to notify site personnel if 
they develop any AEs during this post-infusion observation time period. 
In the event of an IRR with features of anaphylaxis (regardless of grade) or grade 3 or 4 IRR, 
blood samples for cytokine/chemokine panel and serum total tryptase level (levels typically 

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peak within 3 hours after the onset of symptoms) should be collected once the subject has 
stabilized for shipment to the central laboratory.  
5.4.3 
Laboratory Assessments 
Below is a table of the laboratory tests that will be performed during the conduct of the study.  
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), 
laboratory tests will be performed according to the Schedule of Assessments [Table 11] and 
must be sent to the local laboratory for analysis.  
Under Protocol Version 6.1 or earlier (e.g., Original Protocol Version 1 through 6.1), 
laboratory tests will be performed according to the Schedule of Assessments [Table 1] and 
must be sent to the central laboratory for analysis. Eligibility can be determined based on 
central and/or local laboratory testing. 
● 
The most recent laboratory data must be used to confirm the subject’s eligibility. In the 
case of multiple sample collections within 14 days prior to randomization, the most 
recent sample collection with available results should be used to determine eligibility. 
o 
Central labs must be collected and submitted to the central laboratory during the 
Screening period.  
o 
If retesting of lab values is necessary to confirm eligibility, local labs can be 
used without requiring additional sample collection for central laboratory 
submission. 
o 
The screening labs used to determine eligibility should be collected within 
14 days prior to randomization.  
● 
Laboratory test results (central or local) will be reviewed by the investigator prior to any 
study treatment. Clinical significance of out of range laboratory findings is to be 
determined and documented by the investigator/subinvestigator who is a qualified 
physician. 
● 
Local laboratory results may be used for treatment decisions; however, central laboratory 
samples must also be drawn per protocol and sent to the central laboratory, unless 
otherwise approved by sponsor. 
● 
Central and local labs may be collected up to 48 hours prior to study treatment. 
● 
Holidays and weekends should be taken into account when scheduling these sample 
collections. 
● 
Additional assessments may be done centrally or locally to monitor AEs or as clinically 
indicated.  

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Panel/Assessment 
Parameters to be Analyzed 
Hematology 
Hematocrit (Hct) 
Hemoglobin (Hgb) 
Red Blood Cell Count (RBC) 
White Blood Cell Count (WBC) 
WBC differential 
Absolute Neutrophil Count (ANC) 
Platelets 
Mean Corpuscular Volume (MCV) 
Mean Corpuscular Hemoglobin (MCH) 
Mean Corpuscular Hemoglobin Concentration (MCHC) 
Biochemistry 
Albumin  
Blood Urea Nitrogen (BUN)  
Calcium  
Bicarbonate 
Chloride  
Creatinine  
Glucose  
Magnesium 
Phosphate 
Potassium  
Sodium  
Total Bilirubin  
Total Protein  
Alanine Aminotransferase (ALT)  
Alkaline Phosphatase (ALP)  
Aspartate Aminotransferase (AST) 
Creatinine Clearance 
Urinalysis 
Color  
Clarity/turbidity  
pH  
Specific gravity  
Glucose  
Ketones  
Nitrites  
Leukocyte esterase  
Bilirubin  
Urobilinogen  
Blood  
Protein  
RBCs  
WBCs   

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Panel/Assessment 
Parameters to be Analyzed 
Coagulation 
Prothrombin time (PT) (sec) 
Partial Thromboplastin Time (PTT) 
International normalized ratio (INR) 
Thyroid Function Test 
Thyroid stimulating hormone (TSH) 
Free T4 (thyroxine) 
Urine Pregnancy Test 
Human chorionic gonadotropin (HCG) 
Serum Pregnancy Test 
Human chorionic gonadotropin (HCG) 
Grade 3 or 4 infusion-related reaction 
(IRR) 
Cytokine/Chemokine Panel† 
Serum total tryptase† 
Any reaction with features of 
anaphylaxis† 
Cytokine/Chemokine Panel† 
Serum Total Tryptase 
Dihydropyrimidine dehydrogenase 
(DPD) deficiency screening† 
DPD deficiency alleles 
†As applicable 
5.4.4 
Physical Examination  
Physical examinations will be conducted at visits as outlined in the Schedule of Assessments 
[Table 1]. Each physical exam should include height (at Screening only), weight and ECOG 
performance status. A full physical exam is required at Screening. The physical exam only 
needs to be repeated on C1D1 if clinically significant changes from Screening are observed 
(in the opinion of the investigator). For all cycles, the physical examination, weight and 
ECOG performance status assessments can be completed up to 48 hours prior to 
zolbetuximab/placebo administration. Targeted (symptom driven) physical exams should be 
conducted every 3 weeks on zolbetuximab/placebo visit days. If clinically significant 
worsening of findings from baseline is noted at any study visit, the changes will be 
documented as AEs on the AE eCRF. Clinical significance is defined as any variation in 
physical findings, which has medical relevance that could result in an alteration in medical 
care. The investigator will continue to monitor the subject until the parameter returns to grade 
≤ 1, or to the baseline condition, or until the investigator determines that follow up is no 
longer medically necessary. 
5.4.5 
Electrocardiogram  
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), a single 
12-lead ECG will be performed at the time points outlined in the Schedule of Assessments 
[Table 11].   
Under Protocol Version 6.1 or earlier (e.g., Original Protocol Version 1 through 6.1), a single 
12-lead ECG will be performed at the time points outlined in the Schedule of Assessments 
[Table 1]. Prior to performing ECG, subjects should rest in supine position for 10 minutes. 
When collected on the same day, ECG should be collected prior to pharmacokinetic samples. 
Additional ECG may be performed based on medical history and investigator medical 

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judgement. ECGs will be read locally. Clinically significant findings should be recorded as 
an AE. 
5.4.6 
Performance Status 
The ECOG Scale [Oken et al, 1982] will be used to assess performance status. Refer to 
[Appendix 12.8]. 
5.5 
Adverse Events and Other Safety Aspects 
AEs and SAEs, regardless of causality will be collected from the time of full main informed 
consent through 90 days following the last dose of zolbetuximab/placebo and mFOLFOX6 
(all components). If a participant transitions to commercially marketed zolbetuximab or 
mFOLFOX6 and has discontinued from the study, the 30- and 90-day safety follow up visits 
are not required.  
Once participants have transitioned to commercially marketed zolbetuximab, safety 
assessment and reporting should continue as per post-marketing product requirements. 
AEs will be documented at each clinic visit, but can be collected at any time. Any AE that 
meets the definition of an SAE will also be reported on a separate form to the sponsor.  
5.5.1 
Definition of Adverse Events  
An AE is any untoward medical occurrence in a subject administered a study drug, and which 
does not necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom or disease (new or exacerbated) temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
In order to identify any events that may be associated with study procedures and could lead to 
a change in the conduct of the study, Astellas collects AEs even if the subject has not 
received study drug treatment. AE collection begins after the signing of the informed consent 
and will be collected until 90 days after the last dose of study treatment or the subject is 
determined to be a screen failure.  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrences. 
5.5.1.1 Abnormal Laboratory Findings 
Any abnormal laboratory test result (e.g., hematology, clinical chemistry or urinalysis) or 
other safety assessment (e.g., ECGs, radiology scans, vital signs measurements, physical 
examination), including those that worsen from baseline, that is considered to be clinically 
significant in the medical and scientific judgement of the investigator and not related to 
underlying disease, is to be reported as an (S)AE. 

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Any clinically significant abnormal laboratory finding or other abnormal safety assessment 
which is associated with the underlying disease does not require reporting as an (S)AE, 
unless judged by the investigator to be more severe than expected for the subject’s condition. 
Repeating an abnormal laboratory test or other safety assessment, in the absence of any of the 
above criteria, does not constitute an AE. Any abnormal test result that is determined to be an 
error does not require reporting as an AE. 
5.5.1.2 Potential Cases of Drug-Induced Liver Injury 
Refer to [Appendix 12.5 Liver Safety Monitoring and Assessment] for detailed instructions 
on drug induced liver injury. Abnormal values in AST and/or ALT concurrent or with 
abnormal elevations in total bilirubin that meet the criteria outlined in [Appendix 12.5 Liver 
Safety Monitoring and Assessment], in the absence of other causes of liver injury, are 
considered potential cases of drug-induced liver injury (potential Hy’s Law cases) and are 
always to be considered important medical events and reported per [Section 5.5.5 Reporting 
of Serious Adverse Events]. 
5.5.1.3 Disease Progression and Study Endpoints 
Under this protocol, the following event(s) will not be considered as an(S)AE: 
● 
Disease Progression: events including defined study endpoints that are clearly consistent 
with the expected pattern of progression of the underlying disease are not to be recorded 
as AEs. These data will be captured as efficacy assessment data as outlined in 
[Section 5.3 Efficacy Assessments]. If there is any uncertainty as to whether an event is 
due to anticipated disease progression and/or if there is evidence suggesting a causal 
relationship between the study treatment and the event, it should be reported as an 
(S)AE. All deaths up to 90 days after the last dose of study drug must be reported as an 
SAE, even if attributed to disease progression. 
● 
Disease progression can be considered as the worsening of a subject’s condition 
attributable to Gastric or GEJ cancer. It may be an increase in the severity of the disease 
under study and/or increases in the symptoms of the disease. The development of new, or 
progression of existing metastases to the primary cancer under study should be 
considered as disease progression not an AE. Events which are unequivocally due to 
disease progression should not be reported as an AE during the study. 
5.5.2 
Definition of Serious Adverse Events 
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes:  
● 
Results in death 
● 
Is life-threatening (an AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death) 

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● 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions  
● 
Results in congenital anomaly, or birth defect 
● 
Requires inpatient hospitalization (except for planned procedures as allowed per study) 
or leads to prolongation of hospitalization (except if prolongation of planned 
hospitalization is not caused by an AE). Hospitalization for 
treatment/observation/examination caused by AE is to be considered as serious. 
● 
Other medically important events (defined in paragraph below) 
Medical and scientific judgement should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent 1 of the other outcomes listed in the definition 
above. These events, including those that may result in disability/incapacity, usually are 
considered serious. Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse.  
5.5.2.1 Important Medical Events 
If an AE occurs that the sponsor determines to be an Important Medical Event, additional 
information on the event (e.g., investigator confirmation of seriousness, causality) will be 
requested.  
Progression of Gastric or GEJ cancer, including signs and symptoms of progression, should 
not be reported as an SAE unless it results in death within 90 days of the last dose of study 
treatment. For progression-related death reported as an SAE, there should be available 
immediate cause of death reported as the event term. “Death due to disease progression” 
should be recorded as the AE term only when the cause of death cannot be otherwise 
determined. 
5.5.3 
Criteria for Causal Relationship to Study Treatment 
A medically-qualified investigator is obligated to assess the relationship between each study 
treatment and each occurrence of each (S)AE. This medically-qualified investigator will use 
medical judgement, as well as the RSI to determine the relationship. The causality assessment 
is one of the criteria used when determining regulatory reporting requirements.  
The medically qualified investigator is requested to provide an explanation for the causality 
assessment for each (S)AE and must document in the medical notes that he/she has reviewed 
the (S)AE and has provided an assessment of causality. 
Following a review of the relevant data, the causal relationship between the study treatment 
and each (S)AE will be assessed by answering ‘yes’ or ‘no’ to the question “Do you 
consider that there is a reasonable possibility that the event may have been caused by 
the study treatment”. 

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When making an assessment of causality, the following factors are to be considered when 
deciding if there is evidence and/or arguments to suggest there is a ‘reasonable possibility’ 
that an (S)AE may have been caused by the study treatment (rather than a relationship cannot 
be ruled out) or if there is evidence to reasonably deny a causal relationship: 
● 
Plausible temporal relationship between exposure to the study treatment and (S)AE onset 
and/or resolution. Has the subject actually received the study treatment? Did the (S)AE 
occur in a reasonable temporal relationship to the administration of the study treatment?  
● 
Plausibility; i.e., could the event have been caused by the study treatment? Consider 
biologic and/or pharmacologic mechanism, half-life, literature evidence, drug class, 
preclinical and clinical study data, etc. 
● 
Dechallenge/Dose reduction/Rechallenge:  
o 
Did the (S)AE resolve or improve after stopping or reducing the dose of the suspect 
drug? Also consider the impact of treatment for the event when evaluating a 
dechallenge experience.  
o 
Did the (S)AE reoccur if the suspected drug was reintroduced after having been 
stopped?  
● 
Laboratory or other test results; a specific lab investigation supports the assessment of 
the relationship between the (S)AE and the study treatment (e.g., based on values pre-, 
during and post-treatment) 
● 
Available alternative explanations independent of study treatment exposure; such as 
other concomitant drugs, past medical history, concurrent or underlying disease, risk 
factors including medical and family history, season, location, etc. and strength of the 
alternative explanation 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important that 
the medically-qualified investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the sponsor. With limited or insufficient 
information about the event to make an informed medical judgment and in absence of any 
indication or evidence to establish a causal relationship, a causality assessment of ‘no’ is to 
be considered. In such instance, the investigator is expected to obtain additional information 
regarding the event as soon as possible and to re-evaluate the causality upon receipt of 
additional information. The medically qualified investigator may revise his/her assessment of 
causality in light of new information regarding the SAE and shall send an SAE follow-up 
report and update the eCRF with the new information and updated causality assessment.  
5.5.4 
Criteria for Defining the Severity of an Adverse Event 
AEs, including abnormal clinical laboratory values, will be graded using the NCI-CTCAE 
v4.03 guidelines. The items that are not stipulated in the NCI-CTCAE v4.03 will be assessed 
according to the criteria below and entered into the eCRF.  

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Grade 
Assessment Standard 
1-Mild 
Asymptomatic or mild symptoms, clinical or diagnostic 
observations noted; intervention not indicated. 
2-Moderate 
Local or noninvasive intervention indicated. 
3-Severe 
Medically significant but not immediately life threatening, 
hospitalization or prolonged hospitalization. 
4-Life Threatening 
Life threatening consequences, urgent intervention indicated 
5-Death 
Death related to AE 
5.5.5 
Reporting of Serious Adverse Events 
The collection of AEs and the expedited reporting of SAEs will start following receipt of the 
signed full main informed consent and will continue to until 90 days after the last dose of 
study treatment or the subject is determined to be a screen failure. Once patients have 
transitioned to commercially marketed zolbetuximab, safety assessment and reporting should 
continue as per post-marketing product requirements. 
In the case of a SAE, the investigator must contact the sponsor by fax or email immediately 
(within 24 hours of awareness). 
The investigator must complete and submit a SAE worksheet containing all information that 
is required by local and/or regional regulations to the sponsor by email or fax immediately 
(within 24 hours of awareness).  
The SAE worksheet must be signed by a medically qualified investigator (as identified on 
Delegation of Authority Log). Signature confirms accuracy and completeness of the SAE 
data as well as the investigator causality assessment including the explanation for the 
causality assessment. 
If the SAE is associated with emergency unblinding as outlined in Section 4.7.4 Breaking the 
Treatment Code for Emergency this is to be recorded on the SAE worksheet. Within the SAE 
worksheet, the investigator is to include when unblinding took place in association with the 
SAE. 
JAPAN SITES ONLY: In the case of a SAE, the investigator or sub-investigator must report 
to the head of the study site and must contact the sponsor by email or fax immediately (within 
24 hours of awareness). The investigator should complete and submit JUTOKUNA 
YUUGAIJISHOU HOUKOKUSHO containing all information that is required by the 
Regulatory Authorities to the sponsor by email or fax immediately (within 24 hours of 
awareness) and to the head of the hospital. If the faxing of JUTOKUNA YUUGAIJISHOU 
HOUKOKUSHO is not possible or is not possible within 24 hours, the sponsor should be 
informed by phone. After marketing authorization in Japan, the sponsor collects all AEs and 
the following special situations in accordance with Good Post-marketing Study Practice. 
● 
Drug Exposure During Pregnancy 
● 
Drug Exposure via Breast Milk 

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● 
Lack of Efficacy 
● 
Medication Error 
● 
Abuse, Misuse, Overdose 
● 
Off-Label Use 
● 
Occupational Exposure 
● 
Drug-Drug Interaction 
● 
Unexpected Benefit 
For contact details, see [Section II Contact Details of Key Sponsor's Personnel]. Fax or email 
the SAE and Special Situations Worksheet to:  
Astellas Pharma Global Development, Inc. 
Pharmacovigilance 
North American Fax: +1-888-396-3750 
(North America Alternate Fax: +1-847-317-1241) 
International Fax: +44-800-471-5263 
Email: safety-us@us.astellas.com 
UNIQUE TO JAPAN REGION: JUTOKUNA YUUGAIJISHOU HOUKOKUSHO the SAE 
and Special Situations Worksheet to: 
PAREXEL International 
Fax number: 03-6888-5798 
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor's Medical Monitor/Study Physician or his/her designee [Section II Contact Details of 
Key Sponsor’s Personnel].  
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification (UNIQUE TO JAPAN REGION: within 2 days for the initial notification). 
Full details of the SAE or Special Situation should be recorded on the medical records, SAE 
or Special Situation Worksheet and on the (e)CRF.  
The following minimum information is required: 
● International Study Number (ISN)/Study number,  
● Subject number, sex and age, 
● The date of report, 
● A description of the SAE (event, seriousness criteria),  
● Causal relationship to the study treatment (including reason), and 
● The drug provided (if any). Note: blinded regimen is also an option.  
The sponsor or sponsor's designee will medically evaluate the SAE and determine if the 
report meets the requirements for expedited reporting based on seriousness, causality, and 
expectedness of the events (e.g., Suspected Unexpected Serious Adverse Reaction (SUSAR) 
reporting) according to current local/regional regulatory requirements in participating 
countries. The sponsor or sponsor’s designee will submit expedited safety reports (e.g., IND 
Safety Reports, Council for International Organizations of Medical Sciences I Form) to 

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Competent Authorities (CA) and concerned Ethics Committee per current local regulations, 
and will inform the investigators of such regulatory reports as required. Investigators must 
submit safety reports as required by their IRB/local IEC within timelines set by regional 
regulations (e.g., EU, (e)CTD, FDA) where required. Documentation of the submission to 
and receipt by the IRB/ local IEC of expedited safety reports should be retained by the study 
site. 
The sponsor will notify all investigators responsible for ongoing clinical studies with the 
study treatment of all SUSARs, which require submission per local requirements IRB/local 
IEC/ head of the study site (as applicable). 
The heads of the study sites (if applicable) and investigators should provide written 
documentation of IRB/IEC notification for each report to the sponsor. 
5.5.6 
Follow-up of Adverse Events 
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized by the investigator.  
If after the protocol defined AE collection period [see Section 5.5.1 Definition of Adverse 
Event], an AE progresses to a SAE, or the investigator learns of any (S)AE including death, 
where he/she considers there is reasonable possibility it is related to the study treatment or 
study participation, the investigator must promptly notify the sponsor. Once patients have 
transitioned to commercially marketed zolbetuximab, safety assessment and reporting should 
continue as per post-marketing product requirements. 
5.5.7 
Monitoring of Common Serious Adverse Events 
Common SAEs are SAEs commonly anticipated to occur in the study population independent 
of drug exposure. SAEs classified as “common” are provided in [Appendix 12.6 Common 
Serious Adverse Events] for reference. The list does NOT change the investigator’s reporting 
obligations, nor his obligations to perform a causality assessment, or prevent the need to 
report an AE meeting the definition of an SAE as detailed above. The purpose of this list is to 
alert the investigator that some events reported as SAEs may not require expedited reporting 
to the regulatory authorities based on the classification of “common SAEs” as specified in 
[Appendix 12.6 Common Serious Adverse Events]. The sponsor will monitor these events 
throughout the course of the study for any change in frequency. Any changes to this list will 
be communicated to the participating investigational sites. Investigators must report 
individual occurrences of these events as stated in [Section 5.5.5 Reporting of Serious 
Adverse Events].  
5.5.8 
Adverse Events of Special Interest 
In case of zolbetuximab induced nausea, vomiting or hypersensitivity/IRR, infusion rate of 
zolbetuximab/placebo may be reduced or infusion paused or discontinued based on 
investigator’s clinical judgement about severity of toxicity and local standard of care. See 

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[Section 5.1.2 Study Treatment Dose Modifications, Delays and Interruption] and the 
Pharmacy Manual and Infusion Guidelines. 
If the AEs of interest are classified as serious, they are to be collected via the SAE worksheet 
and reported within 24 hours as described in [Section 5.5.5 Reporting of Serious Adverse 
Events].  
5.5.9 
Special Situations  
Certain Special Situations observed in association with the study treatment(s), such as 
incorrect administration (e.g., wrong dose of study treatment, comparator or background 
therapy) are collected in the eCRF, as Protocol Deviations per [Section 8.2 Major Protocol 
Deviations] or may require special reporting, as described below. These Special Situations 
are not considered AEs, but do require to be communicated to Astellas as per the timelines 
defined below. 
If a Special Situation is associated with, or results in, an AE, the AE is to be assessed 
separately from the Special Situation and captured as an AE in the eCRF. If the AE meets the 
definition of a SAE, the SAE is to be reported as described in [Section 5.5.5 Reporting of 
Serious Adverse Events] and the details of the associated Special Situation are to be included 
in the clinical description on the Special Situation worksheet.  
The Special Situations are: 
● Pregnancy 
● Medication error, Overdose and “Off label use” 
● Misuse/abuse 
● Occupational exposure 
● (Suspicion of) Transmission of infectious agent  
● Suspected Drug-Drug interaction 
5.5.9.1 Pregnancy 
If a female subject becomes pregnant during the study dosing period or within 9 months after 
the final administration of oxaliplatin and 6 months after the final administration of all other 
study drugs, or if a partner of a male subject becomes pregnant during the study dosing 
period or within 6 months from the discontinuation of dosing, the investigator is to report the 
information to the sponsor according to the timelines in [Section 5.5.5 Reporting of Serious 
Adverse Events] using the Pregnancy Reporting Form and in the eCRF. 
The expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated conception date, pregnancy result and neonatal data etc., should be included in this 
information. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
termination (including elective termination) of a pregnancy is to be reported for a female 
study subject as an AE in the eCRF or SAE per [Section 5.5.5 Reporting of Serious Adverse 
Events]. For (S)AEs experienced by a female partner of a male subject, (S)AEs are to be 
reported via the Pregnancy Reporting Form.  

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Additional information regarding the outcome of a pregnancy when also categorized as an 
SAE is mentioned below: 
● 
"Spontaneous abortion" includes miscarriage, abortion and missed abortion. 
● 
Death of a newborn or infant within 1 month after birth is to be reported as an SAE 
regardless of its relationship with the study drug. 
● 
If an infant dies more than 1 month after the birth, is to be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the investigator. 
● 
Congenital anomaly (including anomaly in miscarried fetus) 
Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, the 
embryo or fetus should be assessed for congenital defects by visual examination. (S)AEs 
experienced by the newborn/infant should be reported via the Pregnancy Reporting Form. 
Generally, follow up will be no longer than 6 to 8 weeks following the estimated delivery 
date. 
5.5.9.2 Medication Error, Overdose and “Off-Label Use” 
If a Medication Error, Overdose or “Off label Use” (i.e., use outside of what is stated in the 
protocol) is suspected [refer to Section 8.2 Major Protocol Deviations]. Any associated 
(S)AEs are to be reported in the eCRF. If the AE meets the definition of a SAE, the SAE is 
also to be reported as described in [Section 5.5.5 Reporting of Serious Adverse Events] 
together with the details of the medication error, overdose or “Off-Label Use”. 
There is no antidote for overdose of the study drug. In the event of suspected zolbetuximab 
overdose, the subject should receive supportive care and monitoring (including, but not 
limited to, inpatient hospitalization). The Medical Monitor should be contacted as applicable. 
In the event of suspected mFOLFOX6 overdose, refer to the approved package insert, SPC or 
local product information supplied by the manufacturer for each agent. 
5.5.9.3 Misuse/Abuse 
If misuse or abuse of the study drug(s) is suspected, the investigator must forward the Special 
Situation worksheet to the sponsor/delegated contract research organization (CRO) by fax or 
email immediately (within 24 hours of awareness). Any associated (S)AEs are to be reported 
in the eCRF. If the AE meets the definition of a SAE, the SAE is also to be reported as 
described in [Section 5.5.5 Reporting of Serious Adverse Events] together with details of the 
misuse or abuse of the study drug(s). 
5.5.9.4 Occupational Exposure 
If occupational exposure (e.g., inadvertent exposure to the study drug(s) of site staff whilst 
preparing it for administration to the subject) to the study drug(s) occurs, the investigator 
must forward the Special Situation worksheet to the sponsor/delegated CRO by fax or email 
immediately (within 24 hours of awareness). Any associated (S)AEs occurring to the 
individual associated with or resulting from the Special Situation are to be reported on the 
Special Situations worksheet. 

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5.5.9.5 Suspected Drug-Drug Interaction 
If a suspected drug-drug interaction associated with the study drug(s) is suspected, the 
investigator must forward the Special Situation worksheet to the sponsor/delegated CRO by 
fax or email immediately (within 24 hours of awareness). Any associated (S)AEs are to be 
reported in the eCRF. If the AE meets the definition of a SAE, the SAE is also to be reported 
as described in [Section 5.5.5 Reporting of Serious Adverse Events] together with details of 
the suspected drug-drug interaction. 
5.5.10 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available necessary for conducting the clinical study 
properly, the sponsor will inform all investigators involved in the clinical study as well as the 
regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed.  
The investigator will also inform the subjects, who will be required to sign an updated ICF in 
order to continue in the clinical study. 
UNIQUE TO JAPAN REGION: 
1. When information is obtained regarding serious and unexpected adverse drug reactions 
(or other) that are specified in Article 273 of the Act on Securing Quality, Efficacy and 
Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy 
Products, Gene Therapy Products, and Cosmetics, in compliance with Article 80-2 
Paragraph 6 of the Pharmaceutical Affairs Law, the sponsor should inform all the 
investigators involved in the clinical study, the head of the study site, and the regulatory 
authorities of such information. The head of the study site who receives such information 
will decide whether the clinical study should be continued after hearing the opinions of 
the IRB. The investigator will supply the new information to the subjects, in compliance 
with [Section 12.1.4.2 Supply of New and Important Information Influencing the 
Subject’s Consent and Revision of the Written Information.] 
2. 
In addition to the above item (1), when the head of the study site receives the revisions 
of the IB, protocol or written information, information on the matters covering the 
quality of the study drug, efficacy and safety, information necessary for conducting the 
clinical study properly, or documents to be examined by the IRB these documents 
should be sent to the IRB. 
5.5.11 
Urgent Safety Measures 
An Urgent Safety Measure (USM) is an intervention, which is not defined by the protocol 
and can be put in place with immediate effect without needing to gain prior approval by the 
sponsor, relevant CA, IRB/IEC, where applicable, in order to protect study participants from 
any immediate hazard to their health and/or safety. Either the investigator or the sponsor can 
initiate a USM. The cause of a USM can be safety, product or procedure related. 

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5.5.12 
Reporting Urgent Safety Measures 
In the event of a potential USM, the investigator must contact the Astellas Study Physician 
and/or – unique for JP region – Astellas team member (within 24 hours of awareness). Full 
details of the potential USM are to be recorded in the subject’s medical records. The sponsor 
may request additional information related to the event to support their evaluation.  
If the event is confirmed to be an USM the sponsor will take appropriate action to ensure the 
safety and welfare of the patients. These actions may include but are not limited to a change 
in study procedures or study treatment, halting further enrollment in the study, or stopping 
the study in its entirety. The sponsor or sponsor's designee will notify CA and central Ethics 
Committee within the timelines required per current local regulations, and will inform the 
investigators as required. When required, investigators must notify their IRB/IEC within 
timelines set by regional regulations. 
5.6 
Test Drug Concentration 
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), 
pharmacokinetic sampling will no longer be collected at the 30-Day Safety Follow-up visit or 
90-Day Follow-up visit; see the Schedule of Assessments in [Table 11] in [Section 13].  
Under Protocol Version 6.1 or earlier (e.g., Original Protocol Version 1 through 6.1), test 
drug concentration was evaluated as outlined in [Table 1]. Serum concentrations of 
zolbetuximab will be measured. Samples will be collected as outlined in the Schedule of 
Assessments. Blood sampling, processing, storage and shipment instructions will be provided 
in the Laboratory Manual. Samples will be shipped to and analyzed by a sponsor-designated 
analytical laboratory using validated analytical methods. Please refer to the Laboratory 
Manual for more detailed information. 
Samples remaining after pharmacokinetic assessments may be used for additional biomarker 
analysis described in [Section 5.7.1 Biomarkers]. 
5.7 
Other Measurements, Assessments or Methods 
5.7.1 
Biomarkers 
Tumor tissue and blood/serum/plasma samples described in [Sections 5.7.2 Blood, Serum 
and Plasma Samples and 5.7.3 Tumor Tissue Samples] may be used for research purposes as 
allowed per local policy to identify genomic and/or other biomarkers that may be associated 
with clinical outcome or dynamic changes associated with zolbetuximab treatment (in terms 
of dose, safety, tolerability and efficacy). Since the identification of exploratory biomarkers 
that correlate with the efficacy or safety of zolbetuximab treatment may continue to evolve as 
new findings become available, additional analyses related to zolbetuximab activity on tumor 
signaling pathways or clinical outcomes may be conducted as allowed per local policy. 
Tumor tissue and blood/serum samples remaining after the specified biomarker assessments 
(e.g., aliquots of tumor cell RNA or DNA) may be used for re-testing, additional analyses as 
defined above or developing, and validating assays related to prediction of response or 
dynamic changes associated with zolbetuximab treatment. The tumor tissue and 

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blood/serum/plasma samples (e.g., aliquots of tumor cell RNA or DNA, peripheral blood 
mononuclear cells) will be stored at the study sponsors’ facility or a contract laboratory 
facility for up to 15 years after database closure, at which time the samples will be destroyed. 
The procedures for the collection, handling and shipping of laboratory samples being 
submitted to the local or central laboratory will be specified in a laboratory manual. 
5.7.2 
Blood, Serum and Plasma Samples 
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), blood, 
serum and plasma samples will be collected as allowed per local policy according to the 
Schedule of Assessments [Table 11].  Under Protocol Version 6.1 or earlier (e.g., Original 
Protocol Version 1 through 6.1), blood, serum and plasma samples will be collected as 
allowed per local policy according to the Schedule of Assessments [Table 1] for exploratory 
biomarker measurements. Blood, serum and plasma samples may be analyzed for biomarkers 
including but not limited to chemokines, cytokines, CDC activation, circulating DNA soluble 
factors and genetic markers.  
5.7.3 
Tumor Tissue Samples 
FFPE tumor tissue samples will be obtained for all subjects and sent for central IHC testing 
to evaluate for CLDN18.2, and HER2 status if a previously documented HER2 test result is 
not available. Tissue from the primary site is preferred; however, if a metastatic site is used 
(excluding bone metastasis), the sample should be gastric or GEJ in origin. Archival tumor 
tissue is preferred, but if the specimen is insufficient or unavailable, a biopsy may be 
performed to obtain a primary tumor tissue or tumor tissue from metastatic site (excluding 
bone metastasis). Sponsor preapproval is required when a biopsy procedure is needed for the 
sole purpose of determining study eligibility. Optional post-progression tumor tissue sample 
for exploratory biomarker analysis may be collected, as allowed per local policy following 
local or IRC confirmation of disease progression and prior to initiation of subsequent 
anticancer therapy for subjects who sign a separate ICF. Tumor specimens may be analyzed 
for exploratory biomarkers including but not limited to CLDN18.2 expression, immune cells, 
genetic markers and gene/protein expression, as allowed per local policy. 
The investigator, in consultation with other specialists, as needed (e.g., radiology staff) will 
assess the risk associated with obtaining a tumor tissue sample and determine if the subject is 
an appropriate candidate for the procedure. Biopsies should be obtained in accordance with 
institutional policies/guidelines to minimize risk. Procedures requiring general anesthesia 
should not be performed to obtain a tumor tissue sample; however, if a surgical procedure 
under general anesthesia is performed for a clinical indication, excess tumor tissue may be 
used for research purposes with the consent of the subject.  

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Tumor Tissue Requirements  
Visit 
Tumor Tissue Requirement 
Screening  
A minimum of 1 FFPE tumor tissue block (preferred) OR a minimum* of 
15 FFPE unstained slides are required, as allowed per local policy.  
If local HER2 results are available, a minimum* of 12 slides are required 
along with the pathology report/documented test results. If local HER2 results 
are unavailable, follow guidance above. 
(Unique to China: Five FFPE unstained slides are required, as allowed per 
local policy. The slides should be freshly cut from the FFPE block within the 
time frame described in the laboratory manual.) 
Post-Progression 
(optional) 
A minimum of 1 FFPE tumor tissue block (preferred) OR a minimum* of 
15 FFPE unstained slides are required, as allowed per local policy. 
(Unique to China: Option is not available for China.) 
FFPE: formalin-fixed paraffin embedded; HER2: human epidermal growth factor receptor 2 
*If the required minimum number of slides is not able to be submitted, sponsor notification and approval is 
required. 
5.7.4 
Immunogenicity Assessment (ADA) 
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), serum 
samples to assess the formation of ADAs against zolbetuximab will be collected as outlined 
in the Schedule of Assessments [Table 11]. Under Protocol Version 6.1 or earlier (e.g., 
Original Protocol Version 1 through 6.1), serum samples to assess the formation of ADAs 
against zolbetuximab will be collected as outlined in the Schedule of Assessments [Table 1]. 
Blood sampling, processing, storage and shipment instructions will be provided in the 
Laboratory Manual. Samples will be shipped to and analyzed by a sponsor designated 
analytical laboratory using validated analytical methods. Please refer to the Laboratory 
Manual for more detailed information. 
Samples remaining after immunogenicity assessments may be used for additional biomarker 
analysis, as allowed per local policy, as described in [Section 5.7.1 Biomarkers].  
5.7.5 
Optional Samples for Future Pharmacogenomic Analysis  
For subjects who signed a separate ICF, an optional whole blood sample for 
pharmacogenomics (PGx) will be collected at C1D1 prior to first study drug administration, 
as allowed per local policy. PGx research may be conducted in the future to analyze or 
determine genes of relevance to clinical response, pharmacokinetics and toxicity/safety 
issues. A sample of whole blood for possible retrospective PGx analysis will be collected and 
processed, as allowed per local policy. Blood sampling, processing, storage and shipment 
instructions will be provided in the Laboratory Manual. Samples will be shipped to a 
sponsor-designated analytical storage laboratory. Please refer to the Laboratory Manual for 
more detailed information. 
See [Appendix 12.7, Retrospective PGx Sub-study] for further details on the banking 
procedures.  

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5.7.6 
Electronic Clinical Outcome Assessments (HRQoL and HRU)  
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), all 
eCOAs are discontinued as outlined in the Schedule of Assessments [Table 11].  
Under Protocol Version 6.1 or earlier (e.g., Original Protocol Version 1 through 6.1), subjects 
were asked to complete HRQoL and HRU questionnaires as specified in the Schedule of 
Assessments [Table 1].  The electronic Clinical Outcomes Assessment (eCOA) 
questionnaires should be completed by the subject at Screening (except HRU), on day 1 and 
day 22 of each cycle (or up to 48 hours) before any antiemetic or drug treatment and before 
the disease status is discussed with the subject using the electronic device provided. When 
completion by the subject is not possible, the questionnaires may be administered to the 
subject by site personnel using the electronic tablet device. For subjects with low literacy or 
situations where required translation is not available, please contact the sponsor for further 
guidance. Assessments will also be collected at study treatment discontinuation and 30 and 
90 days post zolbetuximab/placebo treatment. HRQoL and HRU questionnaires are not 
required at mFOLFOX6 dosing visits (if different from zolbetuximab/placebo dosing visit), 
mFOLFOX6 treatment discontinuation, 30 day safety follow-up and 90 day safety follow-up 
visits. A combined visit can be completed if zolbetuximab/placebo and all components of 
mFOLFOX6 are discontinued on the same day and HRQoL and HRU questionnaires should 
be completed for a combined visit. HRQoL will be measured by EORTC QLQ-C30, QLQ-
OG25, GP and the EQ5D-5L.  
5.7.6.1 Quality of Life Questionnaire C30 (QLQ-C30) 
The EORTC-QLQ-C30 is a 30-item cancer-specific instrument consisting of 5 functional 
scales (physical, role, emotional, social and cognitive), 9 symptom scales/items (fatigue, 
nausea/vomiting, general pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and 
financial difficulties) and a global health status scale. For functional scales, higher scores 
indicate better functioning, while for symptom scales/items, higher scores indicate worse 
symptoms. 
5.7.6.2 Oesophago-Gastric Module 25 (OG-25) 
The EORTC QLQ-OG25 questionnaire is a 25-item instrument that evaluates gastric and 
GEJ cancer-specific symptoms. This module consists of 6 scales: dysphagia (3 items), eating 
restrictions (4 items), reflux (2 items), odynophagia (2 items), pain and discomfort (2 items) 
and anxiety (2 items), as well as 10 single items: eating in front of others, dry mouth, trouble 
with taste, body image, trouble swallowing saliva, choked when swallowing, trouble with 
coughing, trouble talking, weight loss and hair loss. For symptom scales/items, higher scores 
indicate worse symptoms. 
5.7.6.3 Global Pain (GP) 
The GP instrument is a single assessment of overall pain. 

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5.7.6.4 EuroQOL Five Dimensions Questionnaire (EQ-5D-5L) 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome 
consisting of 6 items that cover 5 main domains (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) and a general visual analog scale for health status. 
5.7.6.5 Health Resource Utilization 
The HRU questionnaire is used to assess the number of office visits, hospital stays, and other 
healthcare resource utilization that occur outside of the clinical trial. 
5.8 
Total Amount of Blood 
The total amount of blood collected for study assessments for each subject will vary 
depending on how long they stay on treatment.  
At any time during the study, if any laboratory abnormalities are found for a subject or for 
disease assessment, additional blood may be drawn for monitoring. 
Additional blood beyond standard monitoring that will be drawn for this study will include 
draws for eligibility assessment, hematology, chemistry, and coagulation at specific study 
defined time points, pharmacokinetics, and biomarker sampling. 
The maximum amount of blood collected is approximately 81 mL in Cycle 1, and less in 
subsequent cycles. (Unique to China: The maximum amount of blood collected is 
approximately 30 mL in Cycle 1, and less in subsequent cycles.) 
6 
DISCONTINUATION 
6.1 
Discontinuation of Individual Subject(s) From Study Treatment 
A subject who enrolled in the study and for whom study treatment (zolbetuximab/placebo 
and all components mFOLFOX6) is permanently discontinued for any reason will be 
assessed as having met study treatment discontinuation criteria.  
As survival is the secondary end-point of the study, all subjects will be followed for survival 
after meeting study treatment discontinuation criteria unless the subject withdraws consent or 
is considered lost to follow-up after repeated attempts to contact or if the sponsor 
discontinues the study.  
A subject is free to withdraw from the study treatment and/or study for any reason and at any 
time without giving reason for doing so and without penalty or prejudice. The investigator is 
also free to terminate a subject's involvement in the study at any time if the subject's clinical 
condition warrants it. 
A subject will be discontinued from study treatment (zolbetuximab/placebo and all 
components mFOLFOX6) if any of the following occur: 
● 
Investigator determines it is in the subject’s best interest to discontinue study treatment  
● 
Subject develops radiological disease progression per RECIST 1.1 criteria based on 
assessment locally or by IRC. 

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o If the investigator believes that the subject is continuing to derive clinical benefit 
(asymptomatic and/or without worsening of performance status or overall health) 
from study treatment, and an increase in tumor burden is not likely to affect vital 
organ function, the subject may remain on study treatment until an additional 
radiologic assessment is completed (≤ 9 weeks from previous radiologic 
assessment). 
▪ If the additional radiologic assessment locally or by IRC indicates PD per 
RECIST 1.1 then the subject must be discontinued from study treatment. 
▪ If the additional radiologic assessment locally or by IRC does not confirm 
the initial assessment of PD, the subject may continue study treatment. 
● 
Subject develops clinical progression per investigator assessment and radiologic 
assessment is not medically feasible to confirm radiologic progression due to the 
subject’s condition.  
● 
Subject starts another systemic anticancer treatment chemotherapy, immunotherapy, 
radiotherapy or other treatment intended for antitumor activity. 
● 
Subject starts another investigational agent or device  
● 
Subject develops unacceptable toxicity. 
● 
Subject has a delay of study treatment (zolbetuximab/placebo and all components 
mFOLFOX6) for > 28 days from when the next study treatment was scheduled to be 
administered (> 49 days from when the last dose of zolbetuximab/placebo and > 42 days 
from when the last dose of mFOLFOX began). 
● 
Subject develops inter-current illness that the investigator determines may jeopardize the 
subject’s safety if the subject continues to receive study treatment. 
● 
Female subject becomes pregnant. 
● 
Significant deviation from the protocol or eligibility criteria as determined by the 
sponsor. 
● 
Subject declines further treatment. 
● 
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject. 
● 
Subject is noncompliant with the protocol based on investigator or Medical Monitor 
assessment. 
Note: If a subject discontinues mFOLFOX6 and/or zolbetuximab/placebo due to any reason 
other than locally confirmed or IRC confirmed disease progression (and is not receiving any 
other anticancer therapy), the subject must be followed according to the protocol-specified 
radiologic assessment schedule until radiological disease progression per RECIST 1.1 criteria 
is confirmed locally or by IRC assessment. 
Study Discontinuation Criteria 
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), the 
Post-Treatment Follow-up Period (for PFS) is discontinued with radiological disease 
progression determined locally; see the Schedule of Assessments [Table 11] in [Section 13].  

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Participation in the study will end when subjects transition to the commercially marketed and 
locally accessible product (zolbetuximab and/or mFOLFOX6). 
Subjects that completed the 90-Day Safety Follow up Visit(s) treatment period under 
Protocol Version 6.1 or earlier (e.g., Original Protocol Version 1 through 6.1) were eligible 
for the Post-Treatment Follow-up Period (for PFS) and were to remain in the study through 
the Survival Follow-up Period (OS is a key secondary study endpoint) and followed as 
outlined in Protocol Version 6.1 [Table 1]. A subject will be discontinued from the Post-
Treatment, Long Term and Survival Follow-up Periods if any of the following occur: 
● 
Subject declines further study participation (i.e., withdraws consent)  
● 
Subject is lost to follow-up despite reasonable efforts by the investigator to locate the 
subject 
● 
Death (from any cause) 
● 
Study termination by the sponsor 
6.2 
Discontinuation of the Site 
If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the sponsor and, SPECIFIC TO SITES IN JAPAN, the head of the 
study site must also be informed immediately. 
6.3 
Discontinuation of the Study 
If the study is prematurely terminated or suspended the sponsor or designee shall promptly 
inform the investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. 
The study may also be terminated if it is not possible for the sponsor to make a necessary 
adjustment to the maximum insurance sum as required by local law/regulation. 
In case of premature study termination, zolbetuximab may be made available to subjects who 
are still receiving and benefitting from study treatment until a study defined treatment 
discontinuation criterion is met. 
Astellas is planning to close the study when zolbetuximab (Vyloy) is commercially marketed 
in all countries with active participants. 
7 
STATISTICAL METHODOLOGY 
A statistical analysis plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced. The SAP will be finalized before 
the randomization of the first subject. Any changes from the analyses planned in SAP will be 
justified in the clinical study report. 
Prior to database lock, a final review of data and tables, listings and figures meeting (final 
DRM) will be held to allow a review of the clinical trial data and to verify the data that will 

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be used for analysis set classification. A meeting to determine analysis set classifications may 
also be held prior to database lock. 
In general, continuous data will be summarized with descriptive statistics (number of 
subjects, mean, standard deviation, minimum, median and maximum) for continuous 
variables, and frequency and percentage for categorical variables.  
Baseline will be defined as the last observation prior to first dose, unless otherwise specified. 
7.1 
Sample Size 
Approximately 550 subjects will be randomized in a 1:1 ratio to receive zolbetuximab in 
combination with mFOLFOX6 chemotherapy (Arm A) or placebo in combination with 
mFOLFOX6 chemotherapy (Arm B). The planned 300 PFS events during the study will 
provide 93.4% power to detect a difference in PFS between Arm A (zolbetuximab + 
mFOLFOX6) with the assumption of 9 months median PFS time and Arm B (placebo + 
mFOLFOX6) with the assumption of 6 months median PFS time (hazard ratio = 0.67) at the 
overall 1-sided 0.025 significance level. Similarly, the planned 396 OS events during the 
study will provide 81% power to detect a difference in OS between Arm A (zolbetuximab + 
mFOLFOX6) with the assumption of 14.7 months median survival time and Arm B (placebo 
+ mFOLFOX6) with the assumption of 11 months median survival time (hazard ratio = 0.75) 
at the overall 1-sided 0.025 significance level. 
7.2 
Analysis Sets 
The allocation of subjects to analysis sets will be determined prior to database hard-lock. For 
each treatment group, the number and percentage of subjects will be characterized for all 
randomized subjects and by each analysis set. 
7.2.1 
Full Analysis Set 
The FAS will consist of all subjects who are randomized to 1 of the treatment arms. Subjects 
will be analyzed according to the treatment arm to which they were randomized. The FAS 
will be used for description of baseline characteristics and all efficacy analyses. 
7.2.2 
Safety Analysis Set 
The safety analysis set (SAF) will consist of all subjects who received at least 1 dose of any 
study drug (zolbetuximab/placebo/mFOLFOX6). The safety analysis set will be used for all 
safety analyses. Subjects would be analyzed according to the actual treatment they received. 
7.2.3 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set (PKAS) consists of the subset of the SAF for which at least 
1 concentration data is available. Additional subjects may be excluded from the PKAS at the 
discretion of the Pharmacokineticist. The PKAS would be used for description of 
pharmacokinetic data. 

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7.3 
Demographics and Baseline Characteristics  
Demographics and other baseline characteristics will be summarized by treatment group and 
overall for FAS and SAF. 
7.3.1 
Subject Disposition  
The number and percentage of subjects who discontinued treatment and reasons for treatment 
discontinuation will be presented for FAS by treatment group and overall. Similar tables for 
subjects who do not have a PFS event and subjects who do not have observed death will also 
be presented. All disposition details and dates of first and last evaluations for each subject 
will be listed. 
7.3.2 
Previous and Concomitant Medications  
All previous and concomitant medications will be presented in a listing. 
All previous and concomitant medications will be presented in a listing. The frequency of 
concomitant medications (prescription, over-the-counter, and nutritional supplements) will be 
summarized. Any component of mFOLFOX6 is not considered concomitant medications. 
7.3.3 
Medical History  
Medical history for each subject will be presented in a listing and summarized. 
7.4 
Analysis of Efficacy  
Efficacy analysis will be conducted on the FAS. The interpretation of results from statistical 
tests will be primarily based on the FAS. All randomized subjects will be analyzed according 
to the treatment to which they are randomized. 
7.4.1 
Analysis of Primary Endpoint  
7.4.1.1 Primary Analysis 
The primary endpoint is PFS assessed by the blinded IRC. For each subject, PFS is defined as 
the time from the date of randomization until the date of radiological disease progression 
(i.e., PFS) assessed by IRC, or until death due to any cause, whichever is earlier. If a subject 
has neither progressed nor died, the subject will be censored at the date of last radiological 
assessment. Subjects who receive new anticancer therapy before radiological progression will 
be censored at the date of the last radiological assessment before the new anticancer therapy 
started. If progression or death occurs after missing 2 or more scheduled radiological 
assessments, the subject will be censored at the date of last radiological assessment or at the 
date of randomization if no post-baseline radiological assessment is available. 
The primary analysis will be performed when approximately 300 PFS events have been 
observed. 
The distribution of PFS will be estimated for each treatment arm using Kaplan-Meier 
methodology and compared between Arm A and Arm B using log-rank test stratified by: 
● 
Region (Asia vs Non-Asia) 

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● 
Number of organs with metastatic sites (0 to 2 vs ≥ 3) 
● 
Prior gastrectomy (Yes or No) 
The hypothesis testing on the primary analysis will be performed at an overall 1-sided 0.025 
significance level to test the null hypothesis that PFS is not prolonged in Arm A compared to 
Arm B versus the alternative hypothesis that PFS is prolonged in Arm A compared to Arm B. 
In addition, stratified Cox proportional hazard model will be used to estimate the hazard ratio 
and the corresponding 95% CI. 
The primary analysis will be performed using the FAS. 
7.4.1.2 Sensitivity Analyses 
Sensitivity analyses with different censoring rules will be described in the SAP. 
7.4.1.3 Subgroup Analysis  
The analysis described in [Section 7.4.1.1 Primary Analysis] will be conducted in the 
subgroups using the FAS. Subgroups defined by baseline factors will be described in the 
SAP.  
Forest plot will be presented to illustrate the strength of treatment effects across subgroups. 
7.4.2 
Analysis of Secondary Endpoints  
7.4.2.1 Overall Survival 
A key secondary endpoint OS is defined as the time from the date of randomization until the 
documented date of death from any cause. All events of death will be included, regardless of 
whether the event occurred while the subject is still taking study drug or after the subject 
discontinue study drug. Subjects who are still alive at the time of analysis will be censored at 
the last day known to be alive. 
The distribution of OS will be estimated for each treatment arm using Kaplan-Meier 
methodology and compared between Arm A and Arm B using the log-rank test stratified by 
the same stratification factors used for PFS analysis. To maintain the overall Type I error rate 
at the 0.025 significance level, the hypothesis testing on OS will be performed only if the null 
hypothesis on the primary analysis is rejected at the overall 1-sided 0.025 significance level. 
In addition, stratified Cox proportional hazard model will be used to estimate the hazard ratio 
and the corresponding 95% CI. 
7.4.2.2 PF, OG25-Pain, and GHS/QoL Scores 
A key secondary endpoint, TTCD, is defined for the following 3 HRQoL domains: physical 
functioning (PF) and Global Health Status/Quality of Life (GHS/QoL) as collected in the 
EORTC QLQ-C30, and abdominal pain and discomfort (OG25-Pain) as collected in the 
EORTC QLQ-OG25). TTCD is defined as the time from the date of randomization until the 
date of first clinically meaningful deterioration that is confirmed at a next scheduled 
assessment or followed by drop-out resulting in missing data.  

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Clinically meaningful deterioration will be defined if a subject’s change from baseline 
exceeds a pre-specified threshold denoting a clinically meaningful change. While clinically 
meaningful thresholds have been derived for EORTC QLQ-30 for some domains (e.g., 10 for 
GHS/QoL in Osoba 1998), an appropriate threshold for this population and for all domains of 
interest will be derived using the study’s data. A separate analysis plan will be developed 
where methods for the estimation of the clinically meaningful threshold will be defined in 
detail and signed off before database lock. The execution of these analysis and derivation of 
the threshold value to be used in the TTCD analysis will also be performed before database 
lock, and the resulting value will be inserted in the clinical SAP in a last amendment again 
before the study is unblinded.  
Subjects who did not experience a confirmed deterioration will be censored at the last eCOA 
assessment. Subjects who have no baseline or post-baseline assessment, or are not able to 
show deterioration due to their baseline value will be censored at randomization. For 
example, if a subject has a baseline GHS/QoL value of 5 and the clinically meaningful 
threshold proves to be 8, then this subject will be censored at baseline. Death or disease 
progression will not be considered as an event. 
Similarly to PFS and OS endpoints, the distribution of TTCD will be estimated for each 
treatment arm using Kaplan-Meier methodology and compared between Arm A and Arm B 
using the log-rank test stratified by the same stratification factors used for PFS and OS 
analysis. To maintain the overall Type I error rate at the 0.025 significance level, the 
hypothesis testing on TTCD will be performed only if the null hypothesis on the OS is 
rejected at the overall 1-sided 0.025 significance level. Specifically, if the null hypothesis on 
the OS is rejected at the overall 1-sided 0.025 significance level, then the TTCD will be 
tested using the gatekeeping procedure with the following order: 
1. Non-inferiority testing for TTCD in PF at 0.025 significance level 
2. Non-inferiority testing for TTCD in OG25-Pain at 0.025 significance level 
3. Non-inferiority testing for TTCD in GHS/QoL at 0.025 significance level 
4. Superiority testing for TTCD in PF at 0.025 significance level 
5. Superiority testing for TTCD in OG25-PA at 0.025 significance level 
6. Superiority testing for TTCD in GHS/QoL at 0.025 significance level 
A stratified Cox proportional hazard model will be used to estimate the hazard ratio and the 
corresponding 95% CI for the three time-to-event eCOA endpoints. 
7.4.2.3 Objective Response Rate 
Best overall response (BOR) is determined once all tumor response data for the subject is 
available. Subjects will be classified by BOR on study as outlined in RECIST V1.1 criteria. 
For BOR of SD, SD must be documented as present at least once after study entry and at least 
8 weeks after first dose. 
The ORR is defined as the proportion of subjects with a BOR of complete response (CR) or 
partial response (PR) based on IRC per RECIST V1.1.  

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The comparison of ORR between Arm A and Arm B will be performed using stratified 
Cochran-Mantel-Haenszel (CMH) test with the same stratification factor used for the PFS 
analysis. In addition, ORR for each arm will be estimated and corresponding 95% CI will be 
constructed. 
In addition, percent of subjects with CR will be summarized. 
7.4.2.4 Duration of Response 
DOR is defined as the time from the date of the first response of CR or PR (whichever is first 
recorded) as assessed by IRC to the date of radiological progression or death, whichever is 
earlier. If a subject has not progressed, the subject will be censored at the date of last 
radiological assessment or at the date of first CR/PR if no post-baseline radiological 
assessment is available. Other censoring used for the PFS analysis will apply to DOR too.  
The distribution of DOR will be estimated for each treatment arm using Kaplan-Meier 
methodology and compared between Arm A and Arm B using the log-rank test stratified by 
the same stratification factors used for the PFS analysis. In addition, stratified Cox 
proportional hazard model will be used to estimate the hazard ratio and the corresponding 
95% CI. 
7.4.2.5 Health-Related Quality of Life 
HRQoL endpoints will be summarized by descriptive statistics with respect to change from 
baseline for the FAS for each treatment arm. Completion rate for each questionnaire will be 
summarized by time point. Additional analyses will be described in the SAP.  
7.4.3 
Analysis of Exploratory Endpoints  
7.4.3.1 Time to Progression 
TTP is defined as the time from the date of randomization until the date of PD (per RECIST 
1.1 by IRC). TTP does not include deaths as event. For deaths before the first documented 
PD by IRC, subjects will be censored at the time of last radiological assessment. The TPP 
analysis assumes the pre-PD deaths are not related to tumor progression and estimates the 
TTP for pre-PD deaths if the subjects had not died. Kaplan-Meier and log-rank methods will 
be applied to TTP endpoint. 
7.4.3.2 Progression Free Survival After Subsequent Therapy (PFS2) 
PFS2 is defined as the time from the date of randomization until the date of PD (per 
investigator) following subsequent anticancer therapy, death from any cause or start of any 
other anticancer therapy, whichever is earliest. In cases where PFS2 cannot be reliably 
determined, discontinuation of subsequent anticancer treatment may be used as the event 
date. Otherwise, subjects will be censored. Subjects who are alive and for whom a PFS2 
event date has not been observed should be censored at the last time known to be alive and 
without second objective disease progression.  
The distribution of PFS2 will be estimated for each treatment arm using Kaplan-Meier 
methodology and compared between Arm A and Arm B using stratified log-rank test with the 

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same stratification factors used for the PFS analysis. In addition, stratified Cox proportional 
hazard model will be used to estimate the hazard ratio and the corresponding 95% CI. 
7.4.3.3 Disease Control Rate 
The DCR is defined as the proportion of subjects with a BOR of SD, CR or PR based on 
RECIST 1.1 by IRC.  
The comparison of DCR between Arm A and Arm B will be performed using CMH test with 
the same stratification factor used for PFS analysis. In addition, DCR for each arm will be 
estimated and corresponding 95% CI will be constructed. 
7.4.3.4 Biomarkers 
Biomarkers may be summarized graphically or descriptively, and summary statistics may be 
tabulated. Associations between biomarkers and clinical (e.g., efficacy, safety or 
pharmacodynamics, pharmacokinetics) measures may be performed on subjects who have 
sufficient baseline and on-study measurements to provide interpretable results for specific 
parameters. Additional post-hoc statistical analyses may be outlined in the SAP. 
7.4.3.5 Health Resource Utilization 
HRU variables will be summarized for each treatment arm.  
7.5 
Analysis of Safety 
All treated subjects will be analyzed according to the treatment they received.  
7.5.1 
Adverse Events  
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
graded using NCI-CTCAE v4.03.  
Treatment emergent adverse event (TEAE) is defined as an AE observed after starting 
administration of the study treatment and within 30 days after the last dose of study 
treatment. Late SAE and/or AE is defined as (S)AE that is collected after 30 days post last 
dose of study drug.  
A study drug-related TEAE is defined as any TEAE with a causal relationship of YES by the 
investigator. 
AEs of special interest described in [Section 5.5.8 Adverse Events of Special Interest] will be 
summarized. 
The number and percentage of AEs, SAEs, AEs leading to interruption/ discontinuation, AEs 
leading to death and AEs related to study drug will be summarized by SOC, preferred term 
for SAF. The number and percentage of AEs by toxicity grade will also be summarized. Late 
(S)AEs will be summarized. All AEs will be listed. 
7.5.2 
Laboratory Assessments  
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline for subjects in the SAF by treatment group and time point.  

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Incidences of subjects with shifts from baseline to worse grade based on NCI CTCAE v4.03 
in laboratory tests will be summarized by treatment group, time point and grade. 
7.5.3 
Vital Signs  
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
for subjects in the SAF by treatment group and time point.  
7.5.4 
Routine 12-lead Electrocardiograms 
The 12-lead ECG results will be summarized by treatment group and time point. 
7.5.5 
Eastern Cooperative Oncology Group Performance Status 
Summary statistics (number and percent of subjects) for each category of the ECOG 
performance status at each assessment will be provided. The change from baseline to final 
visit or early termination will also be summarized. Negative change scores indicate an 
improvement. Positive scores indicate a decline in performance. 
7.6 
Analysis of Pharmacokinetics 
Descriptive statistics (e.g., number of subjects, mean, standard deviation, minimum, median, 
maximum, coefficient of variation [CV], geometric mean, and geometric CV) will be 
provided.  
7.6.1 
Serum Concentrations 
Serum concentrations of zolbetuximab will be listed and summarized using descriptive 
statistics by scheduled time point. Box and whisker plots of trough concentrations against 
cycle and dosing day will be provided. 
7.6.2 
Immunogenicity 
Immunogenicity of zolbetuximab will be summarized using the frequency of ADA positive 
subjects. The potential relationship between zolbetuximab immunogenicity and zolbetuximab 
pharmacokinetics, efficacy, safety profile in subjects may be assessed.  
Additional model-based analyses may be performed and reported separately. 
7.7 
Major Protocol Deviations and Other Analyses 
Major protocol deviations as defined in [Section 8.2 Major Protocol Deviations] will be 
summarized for all randomized subjects by treatment group and total as well as by site. A 
data listing will be provided by site and subject.   
The major protocol deviation criteria will be uniquely identified in the summary table and 
listing. 
7.8 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
To evaluate whether zolbetuximab + mFOLFOX6 (Arm A) is beneficial compared to the 
concurrent placebo + mFOLFOX6 (Arm B) while the study is ongoing, a formal OS interim 
analysis is planned when the final PFS analysis occurs with the pre-specified number of PFS 

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events. A group sequential design using the O’Brien-Fleming type alpha-spending function 
[Lan & DeMets, 1983] will be utilized to control the overall 1-sided 0.025 significance level 
(East®) for the OS analysis.  
The IDMC may recommend terminating the trial for favorable or unfavorable results at the 
formal efficacy interim analysis using PFS and OS. If the PFS is not significant at 0.025 
1-sided alpha, the trial may be terminated for failure. In the case of favorable results, the 
1-sided significance level for superiority is 0.0082, assuming about 72% of the target number 
of OS events is obtained, for the interim OS analysis and 0.0225 for the final OS analysis 
(Note: The OS significance level will be adjusted depending on the number of OS events at 
the time of interim analysis). If the 1-sided P value of the interim OS analysis is less than the 
significance level (and PFS is also significant at 1-sided 0.025 alpha), the IDMC may 
recommend terminating the trial for success. If the study is not stopped after the interim 
analysis, a final OS analysis will occur after 100% of the planned death events have been 
observed. 
The interim OS analysis will be conducted by an Independent Data Analysis Center for 
IDMC. In addition, safety data reviews during the trial will be conducted by the IDMC on a 
periodic basis. For example, the IDMC will have its first safety data review 6 weeks after the 
40th subject has been randomized and on study drug for 1 cycle (6 weeks) and meetings will 
be conducted regularly thereafter, as determined by the IDMC.  
The full procedures for IDMC safety review will be described in a separate IDMC Charter. 
The analysis for the eCOA endpoints will be performed as the final analysis once OS is 
significant either at the interim OR or at final OS analysis hence there is no interim analysis 
planned for eCOA endpoints. 
7.9 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
Imputation for missing data, if applicable, will be addressed in the SAP. 
8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS 
8.1 
Procedure for Clinical Study Quality Control 
8.1.1 
Data Collection 
The investigator or site designee will enter data collected using an electronic data capture 
system. In the interest of collecting data in the most efficient manner, the investigator or site 
designee should record data (including laboratory values, if applicable) in the eCRF within 
5 days after the subject visit. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. These documents should be appropriately maintained by the 
site. 

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Local laboratory results may be used for treatment decisions; however, central laboratory 
samples must also be drawn per protocol and send to the central laboratory, unless otherwise 
approved by sponsor. Central Laboratory data will be transferred electronically to the sponsor 
or designee at predefined intervals during the study. The Central laboratory will provide the 
sponsor or designee with a complete and clean copy of the data.  
Imaging results are read by a local or central imaging laboratory. Central imaging data will 
be transferred electronically to the sponsor or designee at predefined intervals during the 
study. The central imaging laboratory will provide the sponsor or designee with a complete 
and clean copy of the data. 
For Screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF. 
8.1.1.1 Collection of Data Via Electronic Source  
All procedures conducted under the protocol must be documented. For screen failures, the 
minimum demographic data (sex, birth date, race and informed consent date), outcome of 
eligibility assessment (inclusion and exclusion criteria), reason for screen failure and AEs 
details must be documented. 
The investigator or designee will be responsible for eCRF completion and for ensuring the 
source data are attributable, legible, contemporaneous, original, accurate and complete 
whether the data are handwritten on paper or entered electronically. If source data are created 
(first entered), modified, maintained, archived, retrieved or transmitted electronically via 
computerized systems (and/or other kind of electronic devices) as part of regulated study 
activities, such systems must be compliant with all applicable laws and regulations governing 
use of electronic records and/or electronic signatures. Such systems may include, but are not 
limited to, electronic medical/health records, protocol-related assessments, AE tracking, 
electronic clinical outcome assessment and/or drug accountability. 
Electronic data sources and any supporting documents should be available for 
review/retrieval by the sponsor/designee at any given time. 
Study monitors will perform ongoing source data review to confirm that the safety and rights 
of participants are being protected; and that the study is being conducted in accordance with 
the currently approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
8.1.1.2 Electronic Clinical Outcomes Assessment 
Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), eCOA 
assessments will be discontinued according to the Schedule of Assessments [Table 11]. 
Under Protocol Version 6.1 or earlier (e.g., Original Protocol Version 1 through 6.1), eCOA 
assessments will be performed according to the Schedule of Assessments [Table 1]. Subject 
HRQoL and HRU questionnaires will be completed by the subject or, if not possible, 
administered to the subject by site personnel on an electronic tablet device for subject visits. 
The subject questionnaire responses captured on the electronic device will be transferred to 

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the eCOA vendor’s central portal (web portal). The investigator or site designee should 
review the questionnaire data on the web portal for correct completion while the subject is at 
the site. The questionnaire data will be transferred electronically to sponsor or designee at 
predefined intervals during the study. Sponsor/CRO staff also have access to the vendor web 
portal for continuous review of the data and access to reports. The vendor will provide 
sponsor or designee with a complete and clean copy of the data. 
For further details please refer to the eCOA guidelines/manual (e.g., ERT Site Guide to 
eCOA Product). 
8.2 
Major Protocol Deviations 
A major protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. All deviations from the protocol are to be 
recorded. A protocol waiver is a documented prospective approval of a request from an 
investigator to deviate from the protocol. Protocol waivers are strictly prohibited. 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol and must protect the rights, safety, and 
welfare of subjects. The investigator should not implement any deviation from, or changes of, 
the protocol, unless it is necessary to eliminate an immediate hazard to study subjects.  
When a major deviation from the protocol is identified for an individual subject, the 
investigator or designee must ensure the sponsor is notified. The sponsor will follow up with 
the investigator, as applicable, to assess the deviation and the possible impact to the safety of 
the subject to determine subject continuation in the study.  
Major protocol deviation criteria will be summarized at the end of the study. 
The investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
sponsor and maintained within the trial master file.  
9 
END OF TRIAL IN ALL PARTICIPATING COUNTRIES 
The end of the study is defined as the last visit or scheduled procedure shown in the Schedule 
of Assessments [Table 1] and [Table 11] for the last study participant in the study. 
Study completion is defined as the conclusion of data collection for the defined study 
endpoints. The study may be closed within a participating country per local regulations once 
the study has completed and if all subjects enrolled in the country are no longer receiving 
study treatment. In addition, the sponsor may prematurely terminate the study for reasonable 
cause at any time. 

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10 
STUDY ORGANIZATION 
10.1 
Independent Data Monitoring Committee 
An IDMC will evaluate the unblinded safety data of subjects enrolled on a periodic basis 
during this study. IDMC members will be clinicians with expertise in gastric cancer trials and 
a statistician and are not investigators participating in this trial or Astellas employees. A 
separate charter will outline the activities of this committee. 
10.2 
Other Study Organization 
SPECIFIC TO SITES IN JAPAN: The Japan site contact list is kept as a separate 
attachment to the protocol. 

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11 
REFERENCES  
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phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or 
gastroesophageal adenocarcinoma study: the FLAGS trial. J Clin Oncol. 2010;28:1547-53. 
Ajani JA. Standard chemotherapy for gastric carcinoma: is it a myth? J Clin Oncol. 2000;18:4001-3. 
Amiri M, Janssen F, Kunst AE. The decline in stomach cancer mortality: exploration of future trends 
in seven European countries. Eur J Epidemiol. 2011;26:23-8. 
Bang Y, Chung H, Xu J, Lordick F, Sawaki A, Al-Sakaff N, et al. Pathological features of advanced 
gastric cancer (GC): Relationship to human epidermal growth factor receptor 2 (HER2) 
positivity in the global screening programme of the ToGA trial. J Clin Oncol. 
2009;27(155):4556.  
Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A. Trastuzumab in combination 
with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced 
gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised 
controlled trial. Lancet. 2010;376:687-97. 
Cancer Fact Sheet. World Health Organization; February 2018. 
CYRAMZA Prescribing Information. Indianapolis, IN: Eli Lilly and Company; 2017. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-47. 
Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, 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;383:31-39. 
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009.  
Gunzel D, Yu SL. Claudins of the modulation of tight junction permeability. Physiol. Rev. 
2013;93(2):525-69. 
HERCEPTIN (trastuzumab) [package insert]. South San Francisco, CA: Genentech, Inc.; 2016.  
Karanjawala ZE, Illei PB, Ashfaq R, Infante JR, Murphy K, Pandey A, et al. New markers of 
pancreatic cancer identified through differential gene expression analyses: claudin 18 and 
annexin A8. Am J Surg Pathol. 2008;32:188-96. 
Kim NK, Park YS, Heo DS, Suh C, Kim SY, Park KC, et al. A phase III randomized study of 
5-fluorouracil and cisplatin versus 5-fluorouracil, doxorubicin and mitomycin C versus 
5-fluorouracil alone in the treatment of advanced gastric cancer. Cancer. 1993;71:3813–18. 
Lan KKG and De Mets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70:659-63.  

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Lederman L. Gastric Cancer: local and global burden. Supplement: the current and future 
management of gastric cancer. Am J Manag Care. June 29, 2017:2-5. 
Lee HH, Hur H, Kim SH, Park AR, Kim W, Jeon HM. Outcomes of Modified FOLFOX-6 as First 
Line Treatment in Patients with Advanced Gastric Cancer in a Single Institution; Retrospective 
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Lee JH, Kim KS, Kim TJ, Hong SP, Song SY, Chung JB, et al. Immunohistochemical analysis of 
claudin expression in pancreatic cystic tumors. Oncol Rep. 2011;25:971-78. 
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN 
Guidelines): Gastric cancer. National Comprehensive Cancer Network (NCCN). 2017; version 
1.2017. 
Niimi T, Nagashima K, Ward JM, Minoo P, Zimonjic DB, Popescu NC, et al. claudin-18, a novel 
downstream target gene for the T/EBP/NKX2.1 homeodomain transcription factor, encodes 
lung- and stomach-specific isoforms through alternative splicing. Mol Cell Biol. 
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Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, et al. Bevacizumab in combination 
with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, 
placebo-controlled phase III study. J Clin Oncol. 2011;29:3968-76. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response 
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol.1982;5(6):649-55. 
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in health-
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Pasini F, Fraccon AP, De Manzoni G. The role of chemotherapy in metastatic gastric cancer. Cancer 
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Pennathur A, Gibson MK, Jobe BA, Luketich JD. Oesophageal carcinoma. Lancet. 2013;381:400-12. 
Sahin U, Koslowski M, Dhaene K, Usener D, Brandenburg G, Seitz G, et al. Claudin-18 splice variant 
2 is a pan-cancer target suitable for therapeutic antibody development. Clin Cancer Res. 
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Sanada Y, Hirose Y, Osada S, Tanaka Y, Takahashi T, Yamaguchi K, et al. Immunohistochemical 
study of claudin 18 involvement in intestinal differentiation during the progression of 
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Temple R. Hy’s law: Predicting Serious Hepatotoxicity. Pharmacoepidemiol Drug Saf. 
2006;15(Suppl 4):241-43. 
Waddell T, Chau I, Cunningham D, Gonzalez D, Okines AF, Wotherspoon A, et al. Epirubicin, 
oxaliplatin, and capecitabine with or without panitumumab for patients with previously 
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Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel 
versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-

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oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. 
Lancet Oncol. 2014;15:1224-35. 
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IMAB362 antibody in pancreatic neoplasms. Int J Cancer. 2014;134:731-9. 

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12 
APPENDICES 
12.1 
Ethical, Regulatory, and Study Oversight Considerations 
12.1.1 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, ICH guidelines, all applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  
12.1.2 Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Competent Authorities (CA) 
GCP requires that the clinical protocol, any protocol amendments, the IB, the informed 
consent and all other forms of subject information related to the study (e.g., advertisements 
used to recruit subjects) and any other necessary documents be reviewed by an IEC/IRB. The 
IEC/IRB will review the ethical, scientific and medical appropriateness of the study before it 
is conducted. IEC/IRB approval of the protocol, informed consent and subject information 
and/or advertising, as relevant, will be obtained prior to the authorization of drug shipment to 
a study site. 
Any substantial amendments to the protocol will require IRB/IEC approval before to 
implementation, except for changes necessary to eliminate an immediate hazard to subjects. 
The investigator will be responsible for the following: 
1. Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
2. Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
3. Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
12.1.3 Protocol Amendment and/or Revision 
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or non-substantial amendments. 
Depending on the nature of the amendment, either IRB/IEC, CA approval or notification may 
be required. The changes will become effective only after the approval of the sponsor, the 
investigator, the regulatory authority, and the IRB/IEC (if applicable).  
Amendments to this protocol must be signed by the sponsor and the investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented. 
Modifications to the protocol that are administrative in nature do not require IRB/IEC 
approval, but will be submitted to the IRB/IEC for their information, if required by local 
regulations. 

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If there are changes to the informed consent, written verification of IRB/IEC approval must 
be forwarded to the sponsor. An approved copy of the new informed consent must also be 
forwarded to the sponsor. 
12.1.4 Informed Consent of Subjects 
12.1.4.1 Subject Information and Consent 
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative (if applicable), and answer all questions regarding this 
study.  
An optional partial screening ICF may be available to allow central testing of tissue for 
CLDN18.2 and HER2 only.  
Prior to any study-related screening procedures being performed on the subject, the informed 
consent statement will be reviewed and signed (UNIQUE TO JAPAN REGION: place a 
personal seal) and dated by the subject or his/her guardian or legal representative, the person 
who administered the informed consent and any other signatories according to local 
requirements. A copy of the signed (UNIQUE TO JAPAN REGION: or sealed) ICF will be 
given to the subject and the original will be placed in the subject’s medical record. An entry 
must also be made in the subject’s dated source documents to confirm that informed consent 
was obtained prior to any study-related procedures and that the subject received a signed 
copy.  
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request. 
12.1.4.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information 
1. The investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the 
study (e.g., report of serious drug adverse drug reaction). The communication must be 
documented in the subject’s medical records and whether the subject is willing to 
remain in the study or not must be confirmed and documented.  
2. The investigator must update their ICF and submit it for approval to the IRB/IEC. The 
investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout their participation in the study. The 
investigator or his/her designee must re-consent subjects with the updated ICF even if 
relevant information was provided orally. The investigator or his/her representative 
who obtained the written informed consent and the subject should sign and date the 
ICF (UNIQUE TO JAPAN REGION: place a personal seal). A copy of the signed 
(UNIQUE TO JAPAN REGION: or sealed) ICF will be given to the subject and the 
original will be placed in the subject’s medical record. An entry must be made in the 
subject’s records documenting the re-consent process. 

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12.1.5 Source Documents 
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.  
The investigator is responsible for ensuring the source data are attributable, legible, 
contemporaneous, original, accurate and complete whether the data are hand-written on paper 
or entered electronically. If source data are created (first entered), modified, maintained, 
achieved, retrieved or transmitted electronically via computerized systems (and/or other kind 
of electric devices) as part of regulated clinical study activities, such systems must be 
compliant with all applicable laws and regulations governing use of electronic records and/or 
electronic signatures. Such systems may include, but are not limited to, electronic 
medical/health records, protocol related assessments, AE tracking, and/or drug 
accountability.  
Paper records from electronic systems used in place of electronic format must be certified 
copies. A certified copy must be an exact copy and must have all the same attributes and 
information as the original. Certified copies must include signature and date of the individual 
completing the certification. Certified copies must be a complete and chronological set of 
study records (including notes, attachments, and audit trail information (if applicable). All 
printed records must be kept in the subject file and available for archive. 
12.1.6 Record Retention 
The investigator will archive all study data (e.g., subject identification code list, source data, 
eCRFs and investigator's file) and relevant correspondence. These documents are to be kept 
on file for the appropriate term determined by local regulation (for US sites, two years after 
approval of the NDA or discontinuation of the IND). The sponsor will notify the 
site/investigator if the NDA/MAA/J-NDA is approved or if the IND/IMPD/CHIKEN 
TODOKE is discontinued. The investigator agrees to obtain the sponsor's agreement prior to 
disposal, moving, or transferring of any study-related records. The sponsor will archive and 
retain all documents pertaining to the study according to local regulations. 
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes. 
12.1.7 Subject Confidentiality and Privacy 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited unless otherwise the subject provides 
written consent or approval. Additional medical information may be given only after 
approval of the subject to the investigator or to other appropriate medical personnel 
responsible for the subject's well-being. 
The sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons. 

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Even though any individuals involved in the study, including the study monitors and auditors, 
may get to know matters related to subject's privacy due to direct access to source documents, 
or from other sources, they may not leak the content to third parties.  
The sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number will identify subject data retrieved by the sponsor. However, 
the sponsor requires the investigator to permit the sponsor, sponsor's representative(s), the 
IRB/IEC and when necessary, representatives of the regulatory health authorities to review 
and/or to copy any medical records relevant to the study. 
The sponsor agrees to comply and process personal data in accordance with all applicable 
privacy laws and regulations, including, without limitation, the Personal Information 
Protection Law in Japan and Privacy laws in the US. If the services will involve the 
collection or processing of personal data (as defined by applicable data protection legislation) 
within the European Economic Area (EEA), then sponsor shall serve as the controller of such 
data, as defined by the European Union (EU) Data Protection Directive, and Investigator 
and/or third party shall act only under the instructions of the sponsor in regard to personal 
data. If sponsor is not based in the EEA, sponsor must appoint a third party to act as its local 
data protection representative or arrange for a co-controller established in the EU for data 
protection purposes in order to comply with the Directive. 
12.1.8 Arrangement for Use of Information and Publication of the Clinical Study 
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the IB and other pertinent information is confidential and remains the property of the 
sponsor. Details should be disclosed only to the persons involved in the approval or conduct 
of the study. The investigator may use this information for the purpose of the study only. It is 
understood by the investigator that the sponsor will use the information obtained during the 
clinical study in connection with the development of the drug and therefore may disclose it as 
required to other clinical investigators or to regulatory agencies. In order to allow for the use 
of the information derived from this clinical study, the investigator understands that he/she 
has an obligation to provide the sponsor with all data obtained during the study. 
Publication of the study results is discussed in the clinical study agreement. 
12.1.9 Insurance of Subjects and Others (UNIQUE TO JAPAN REGION/STUDIES 
ENROLLING SUBJECTS IN EU) 
If a subject suffers any study-related injury, the sponsor will compensate appropriately 
according to the severity and duration of the damage. However, if it was caused intentionally 
or was due to gross negligence by the study site, the sponsor will consult with the study site 
about handling the injury, based on the agreed study contract. Compensation for the study-
related injury is provided by the following procedures: 
1. If a subject incurs an injury as a result of participation in the clinical study, the study 
site should provide medical treatment and other necessary measures. The sponsor 
should be notified of the injury.  

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2. When the subject claims compensation from the study site for the above study-related 
injury, or such compensation may be claimed, the study site should immediately 
communicate the fact to the sponsor. Both parties should work together towards 
compensation settlement.  
3. The sponsor shall pay compensation or indemnification and bear expenses necessary 
for the settlement as provided in the clinical contract.  
4. The sponsor shall make an arranging for insurance and take measures necessary to 
ensure the compensation or indemnification mentioned above. 
The sponsor has covered this study by means of an insurance of the study according to 
national requirements. The name and address of the relevant insurance company, the 
certificate of insurance, the policy number and the sum insured are provided in the 
investigator's file.  
12.1.10 Signatory Investigator for Clinical Study Report 
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report, which forms part of a marketing authorization application, be signed by the 
representative for the coordinating investigator(s) or the principal investigator(s). The 
representative for the coordinating investigator (s) or the principal investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for 
coordinating investigator(s) or the principal investigator(s) will be selected from the 
participating investigators by the sponsor prior to database lock. 
 
 

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12.2 
Procedures for Clinical Study Quality Control 
12.2.1 Clinical Study Monitoring 
The sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with 
study-related records such as source documents. The sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring. They will monitor the study in 
accordance with planned monitoring procedures.  
12.2.2 Direct Access to Source Data/Documents 
The investigator and the study site must accept monitoring and auditing by the sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records, including source documents 
when they are requested by the sponsor monitors and auditors, the IRB/IEC or regulatory 
authorities. The confidentiality of the subject's identities shall be well protected consistent 
with local and national regulations when the source documents are subject to direct access. 
Remote source data review will be used when needed. It will focus on the quality control of 
critical data such as primary efficacy data and important safety data. Important secondary 
efficacy data will be monitored simultaneously, provided this does not result in a need to 
access additional documents and therefore increase the burden for site staff. The sponsor will 
determine the extent and nature of remote source data review that is needed for any 
exceptional situations and will carefully weigh it against the extra burden that introduction of 
any alternative measures would put on site staff and facilities. 
12.2.3 Data Management 
Data Management will be coordinated by the Data Science of the sponsor in accordance with 
the SOPs for data management. All study-specific processes and definitions will be 
documented by Data Management. eCRF completion will be described in the eCRF 
instructions. Coding of medical terms and medications will be performed using MedDRA 
and World Health Organization (WHO) Drug Dictionary, respectively. 
12.2.4 Quality Assurance 
The sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that studies are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s). Where applicable, the quality assurance and quality control systems and 
written SOPs of the CRO will be applied. 
The sponsor or sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, case report forms, and source documents. Direct access to these documents will 
be required by the auditors.   

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12.3 
Contraception Requirements 
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Schedule of Assessments [Table 1] and [Table 11]. 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND METHODS OF 
CONTRACEPTION DEFINITIONS (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.  
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
o 
Documented hysterectomy 
o 
Documented bilateral salpingectomy 
o 
Documented bilateral oophorectomy 
3. Postmenopausal 
Documentation of any of these categories can come from the site personnel’s review of the 
female subject’s medical records, medical examination, or medical history interview. 
A postmenopausal state is defined as at least 12 months after last regular menstrual bleeding 
without an alternative medical cause.  
1. In case the last regular menstrual bleeding cannot be clearly determined, confirmation 
with repeated FSH measurements of at least > 40 IU/L (or higher per local 
institutional guidelines), is required.  
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-estrogen hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status by repeated FSH measurements before study enrollment. 
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD 
BEARING POTENTIAL 
One of the highly effective methods of contraception listed below is required at the time of 
informed consent and until the end of relevant systemic exposure, defined as 9 months after 
the final administration of oxaliplatin and 6 months after the final administration of all other 
study drugsa.  
Highly Effective Contraceptive Methods (Failure rate of <1% per year when used 
consistently and correctly)b 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation 
1. oral 
2. intravaginal 

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3. transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
1. oral 
2. injectable 
3. implantable  
Hormonal methods of contraception containing a combination of estrogen and progesterone, 
vaginal ring, injectables, implants and intrauterine hormone-releasing system (IUS) 
1. intrauterine device (IUD) 
2. bilateral tubal occlusion 
Vasectomized partner (A vasectomized partner is a highly effective contraception method 
provided that the partner is the sole male sexual partner of the WOCBP and the absence of 
sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used.) 
Sexual abstinence (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 drug. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant. It is not 
necessary to use any other method of contraception when complete abstinence is elected.) 
a Local laws and regulations may require use of alternative and/or additional contraception 
methods. 
b Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies. 
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) 
OF CHILD BEARING POTENTIAL. 
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to the following during treatment and until the end of relevant systemic exposure 
defined as 6 months after final drug administration. 
1. Inform any and all partner(s) of their participation in a clinical drug study and the 
need to comply with contraception instructions as directed by the investigator. 
2. Male participants are required to use a condom during treatment and until end of 
relevant systemic exposure defined as 6 months after final drug administration. 
3. Female partners of male participants who have not undergone a vasectomy with the 
absence of sperm confirmed or a bilateral orchiectomy should consider use of 
effective methods of contraception until the end of relevant systemic exposure, 
defined as 6 months after final drug administration. 

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12.4 
Concomitant Medication Restrictions or Requirements 
Prohibited Concomitant Treatment  
The following are strictly prohibited: 
● 
Sorivudine or analogs (during 5-FU treatment) 
● 
Concurrent non-steroid systemic immunosuppressive agents (for systemic 
corticosteroids, see cautionary concomitant treatment below).  
● 
Live vaccines should be avoided during the treatment period in which subject is 
receiving oxaliplatin or 5-FU and up to 6 months after final oxaliplatin or 5-FU dose. In 
cases where a live vaccine is needed for COVID-19 prevention and allowed per local 
regulations, please contact the Medical Monitor for discussion.  
● 
Other systemic chemotherapy, immunotherapy, radiotherapy, herbal medications or other 
treatments intended for antitumor activity.  
o Palliative radiotherapy for peripheral bone metastases is allowed. 
o For gastric bleeding, palliative radiotherapy is prohibited, but 
esophagogastroduodenoscopy with epinephrine injection is allowed. 
● 
Investigational products or therapy other than zolbetuximab. 
Cautionary Concomitant Treatment  
Considerations should be given to avoid or minimize the use of the following concomitant 
medications, if possible, during zolbetuximab/placebo treatment: 
● 
Systemic corticosteroids, because of their impact on the potential efficacy of 
zolbetuximab is not known. 
o Systemic corticosteroids should be avoided or minimized while subject is on 
study treatment unless required for management of an emergent medical condition 
(e.g., severe nausea/vomiting or HSR).  
o For a subject’s first dose of zolbetuximab/placebo, it is recommended that the 
prophylactic use of corticosteroids be avoided. 
o Inhaled, intranasal, ophthalmic, otic and topically applied steroids are allowed. 
o Subjects are allowed to use a physiologic replacement dose of hydrocortisone or 
its equivalent (defined as up to 30 mg/day of hydrocortisone or up to 10 mg/day 
of prednisone), receive a single dose of systemic corticosteroids or receive 
systemic corticosteroids as pre-medication for radiologic imaging contrast use. 
● 
Administer 5-HT3 blockers with caution in subjects who have or may develop QTc 
prolongation. 
● 
NSAIDs because of the potential to cause gastric ulcers and covert bleeding.  
o In such cases where NSAID use is necessary, the use of NSAIDs with lower 
gastric ulcerogenic potential is preferred and concomitant gastric protection with 
proton pump inhibitors is recommended.  
The following should be avoided or used with caution during 5-FU treatment and appropriate 
monitoring should be conducted:  
● 
CYP2C9 substrates  
● 
Metronidazole and cimetidine  
● 
Anti-epileptic medications (e.g., phenobarbital, phenytoin and primidone) 

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The following should be avoided or used with caution during oxaliplatin treatment and 
appropriate monitoring should be conducted: 
● 
Medications known to prolong the QT or QTc interval (refer to 
https://www.crediblemeds.org for a list of these medications) 

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12.5 
Liver Safety Monitoring and Assessment  
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases to > 3 × ULN (to > 5 x ULN in subjects with liver metastases) or 
bilirubin > 2 × ULN should undergo detailed testing for liver enzymes (including at least 
ALT, AST, alkaline phosphatase [ALP] and total bilirubin). Testing should be repeated 
within 72 hours of notification of the test results. For studies for which a local or central 
laboratory is used, alerts will be generated by the local or central laboratory regarding 
moderate and severe liver abnormality to inform the investigator, study monitor and study 
team. Subjects should be asked if they have any symptoms suggestive of hepatobiliary 
dysfunction.  
Definition of Liver Abnormalities 
Confirmed abnormalities will be characterized as moderate and severe where ULN: 
  
ALT or AST 
 
Total Bilirubin 
Moderate 
> 3 x ULN (in subjects without liver 
metastases), > 5 x ULN (in subjects with 
liver metastases) 
or 
> 2 x ULN 
 
 
 
 
Severe* 
> 3 x ULN 
and 
> 2 x ULN 
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following: 
● 
ALT or AST > 8 × ULN. 
● 
ALT or AST > 5 × ULN for more than 2 weeks (in the absence of liver metastases). 
● 
ALT or AST > 3 × ULN and International Normalized Ratio (INR) > 1.5 (If INR testing 
is applicable/evaluated). 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).  
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring and 
follow-up. 
Follow-up Procedures 
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination and laboratory tests. The site staff is to complete the LA-CRF. Subjects with 
confirmed abnormal liver function testing should be followed as described below.  
Confirmed moderately abnormal LFTs should be repeated 2 to 3 times weekly then weekly or 
less if abnormalities stabilize or the study treatment has been discontinued and the subject is 
asymptomatic.  

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Severe hepatic liver function abnormalities as defined above, in the absence of another etiology 
may be considered an important medical event and may be reported as a SAE. The sponsor 
should be contacted and informed of all subjects for whom severe hepatic liver function 
abnormalities possibly attributable to study treatment are observed. 
To further assess abnormal hepatic laboratory findings, the investigator is expected to: 
● Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new-onset diseases is to be recorded as “AEs” in the (e)CRF. Illnesses and 
conditions such as hypotensive events, and decompensated cardiac disease that may lead 
to secondary liver abnormalities should be noted. Nonalcoholic steatohepatitis is seen in 
obese hyperlipoproteinemic, and/or diabetic subjects and may be associated with 
fluctuating AT levels. The investigator should ensure that the medical history form 
captures any illness that predates study enrollment that may be relevant in assessing 
hepatic function.  
● 
Obtain a history of concomitant drug use (including nonprescription medication, 
complementary and alternative medications), alcohol use, recreational drug use and 
special diets. Medications, including dose, is to be entered in the (e)CRF. Information on 
alcohol, other substance use and diet should be entered on the LA-CRF or an appropriate 
document. 
● 
Obtain a history of exposure to environmental chemical agents. 
● 
Based on the subject’s history, other testing may be appropriate including:  
o Acute viral hepatitis (A, B, C, D, E or other infectious agents),  
o Ultrasound or other imaging to assess biliary tract disease, 
o Other laboratory tests including INR, direct bilirubin. 
● 
Consider gastroenterology or hepatology consultations. 
● 
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document. 
Study Treatment Discontinuation 
In the absence of an explanation for increased LFT’s, such as viral hepatitis, preexisting or 
acute liver disease, presence of liver metastases or exposure to other agents associated with 
liver injury, the subject may be discontinued from study treatment. The investigator may 
determine that it is not in the subject’s best interest to continue study enrollment. 
Discontinuation of study treatment should be considered if: 
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks (in subjects without liver metastases 
● 
ALT or AST > 3 × ULN and total bilirubin > 2 × ULN or INR > 1.5 (If INR testing is 
applicable/evaluated) 
● 
ALT or AST > 5 × ULN and (total bilirubin > 2 × ULN in subjects with liver metastases) 
● 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%) 

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In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, study treatment should be discontinued. 
*Hy’s Law Definition—The two “requirements” for Hy’s Law are:  
1. Evidence that a drug can cause hepatocellular-type injury, generally shown by a higher rate 
than control of people with 3 X and greater transaminase elevations over the upper limit of 
normal (2 X elevations are too common in treated and untreated subjects to be 
discriminating). 
2. Cases of increased bilirubin (to at least 2X ULN) in people with concurrent transaminase 
elevation to at least 3 X ULN (but it is almost invariably higher) and no evidence of intra-
or extra-hepatic bilirubin obstruction (elevated ALP) or Gilbert’s syndrome. [Temple, 
2006] 
FDA Guidance for Industry, “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
2009: 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST than the (non-hepatotoxic) control drug 
or placebo. 
2. Among trial subjects showing such AT elevations, often with ATs much greater than 
3 x ULN, 1 or more also show elevation of serum total bilirubin to > 2 x ULN, without 
initial findings of cholestasis (elevated serum ALP). 
3. No other reason can be found to explain the combination of increased AT and total 
bilirubin, such as viral hepatitis A, B or C; preexisting or acute liver disease; or another 
drug capable of causing the observed injury.  
References 
Temple R. Hy’s law: Predicting Serious Hepatotoxicity. Pharmacoepidemiol Drug Saf. 
2006 April;15(Suppl 4):241-3. 
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009. 
 

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12.6 
Common Serious Adverse Events 
The following is a list of SAEs that the sponsor considers to be associated with the disease 
state being studied. The list does NOT change your reporting obligations or prevent the need 
to report an AE meeting the definition of an SAE as detailed in [Section 5.5.2 Definition of 
Serious Adverse Events]. The purpose of this list is to alert the investigator that some events 
reported as SAEs may not require expedited reporting to the regulatory authorities based on 
the classification of “common SAEs”. The investigator is required to follow the requirements 
detailed in [Section 5.5.5 Reporting of Serious Adverse Events]. 
For IND safety reporting, single occurrences of the following events may be excluded from 
expedited reporting to the FDA. If aggregate analysis of these events indicates they occur 
more frequently with study treatment, an expedited IND safety report may be submitted to 
the FDA.  
AEs most likely related to Gastric or GEJ adenocarcinoma: 
● Gastric reflux 
● Abdominal pain 
● Abdominal distention 
● Dysphagia 
● Loss of appetite 
 

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12.7 
Pharmacogenomic Analysis with Banked Samples (Optional) 
INTRODUCTION 
Pharmacogenomic (PGx) research aims to provide information regarding how naturally 
occurring changes in a subject’s gene and/or expression based on genetic variation may 
impact what treatment options are best suited for the subject. Through investigation of PGx 
by technologies such as genotyping, gene sequencing, statistical genetics and Genome-Wide 
Association Studies, the relationship between gene profiles and a drug’s kinetics, efficacy or 
toxicity may be better understood. As many diseases may be influenced by 1 or more genetic 
variations, PGx research may identify which genes are involved in determining the way a 
subject may or may not respond to a drug. Samples for PGx are optional and will only be 
collected as allowed per local policy.  
OBJECTIVES 
The PGx research that may be conducted in the future with acquired blood samples is 
exploratory. The objective of this research will be to analyze or determine genes of relevance 
to clinical response, pharmacokinetics and toxicity/safety issues. 
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to treatment in terms of efficacy and/or toxicity. 
SUBJECT PARTICIPATION 
Subjects who have consented to participate in this study may participate in this PGx sub-
study, if applicable per local policy. As part of this sub-study, subjects must provide written 
consent prior to providing any blood samples that may be used at a later time for genetic 
analysis. 
SAMPLE COLLECTION AND STORAGE 
Subjects who consent to participate in this sub-study will provide 1 approximately 4–6 mL 
tube of whole blood per Astellas’ instructions. Each sample will be identified by the unique 
subject number. Samples will be shipped to a designated banking CRO as directed by 
Astellas. 
PGx ANALYSIS 
Details on the potential PGx analysis cannot be established yet. Astellas may initiate the PGx 
analysis if evidence suggests that genetic variants may be influencing the drug’s kinetics, 
efficacy and/or safety.  
DISPOSAL OF PGx SAMPLES/DATA 
All PGx samples collected will be stored for a period of up to 15 years following study 
database hard-lock. If there is no requirement for analysis, the whole blood sample will be 
destroyed after the planned storage period. The subject has the right to withdraw consent at 
any time. When a subject’s withdraw notification is received, the PGx sample will be 
destroyed. The results of any PGx analysis conducted on a sample prior to its withdrawal will 
be retained at Astellas indefinitely unless otherwise specified by local regulation. 

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INFORMATION DISCLOSURE TO THE SUBJECTS 
Exploratory PGx analysis may be conducted following the conclusion of the clinical study, if 
applicable. The results of the PGx analysis will not be provided to any investigators or 
subjects, nor can the results be requested at a later date. Any information that is obtained 
from the PGx analysis will be the property of Astellas.  

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12.8 
Eastern Cooperative Oncology Group Performance Status Scale 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light house work, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Dead 
Reference: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
 

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12.9 
Clinical Study Continuity  
INTRODUCTION 
The purpose of this appendix is to provide acceptable alternate methods to assess safety and 
efficacy parameters, as appropriate, in the event the clinical study is interrupted at the 
country, state, site or participant level during any crisis (e.g., natural disaster, pandemic).    
BENEFIT-RISK RATIONALE 
Maintaining the safety of clinical study participants and delivering continuity of care in the 
clinical study setting is paramount during any crisis. The site is expected to follow the 
protocol and associated Schedule of Assessments [Table 1] and [Table 11] unless the site PI 
determines the need to implement the alternate measures. The PI should notify Astellas 
and/or their CRA when these alternate measures are needed.  
The approach outlined within this appendix defines which assessments are required to 
maintain a favorable benefit/risk to the participant, to maintain overall study integrity and to 
provide acceptable alternate methods to complete the study required assessments and 
procedures if study activities are unable to be performed as described in [Table 1] and 
[Table 11] due to a crisis. 
INFORMED CONSENT 
Participants who need to follow any or all of the alternate measures outlined in this Appendix 
will be required to provide informed consent which explicitly informs them of the nature of, 
and rationale for these changes, and gain their agreement to continue participation in the 
study prior to the implementation of any of these changes. In the event the urgency of 
implementing the alternate measures does not allow for the participant to provide written 
consent prior to implementation, the PI or designee will obtain oral agreement from the 
subject followed by written documentation as soon as is feasible. A separate addendum to the 
study informed consent will be provided to document the participant’s consent of the 
changes. 
PARTICIPANT PROCEDURES ASSESSMENT 
Sites with participants who are currently enrolled into this clinical study may consider 
implementing the alternate methods outlined below if one or more of the following 
conditions are met due to the crisis: 
● 
Regional or local travel has been restricted, inclusive of mandatory shelter in place 
measures, which makes participant travel to/from the study site nearly impossible 
● 
Site facilities have been closed for clinical study conduct  
● 
Site has been restricted to treating patients with conditions outside of the scope of the 
study 
● 
Site personnel have temporarily relocated the conduct of the study to a location that 
place a burden on the participant with respect to time and travel 
● 
Participant(s) have temporarily relocated from the current study site to an alternate study 
site to avoid placing a burden on the participant with respect to travel 

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● 
Participant(s) have temporarily relocated from their home location and the new distances 
from the site would cause undue burden with respect to time and travel 
● 
Participant has risk factors for which traveling to the site poses an additional risk to the 
participant’s health and safety 
 

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ADA: anti-drug antibodies; AE: adverse event; βhCG: beta human chorionic gonadotropin; C1D1: Cycle 1 Day 1; CLDN: Claudin; CT: computerized tomography; ECG: 
electrocardiogram; eCOA: electronic Clinical Outcomes Assessment; ECOG: Eastern Cooperative Oncology Group; eCRF: electronic case report form; EOI: end of infusion; FFPE: 
formalin fixed paraffin embedded; HER2: human epidermal growth factor receptor 2; HRQoL: health-related quality of life; HRU: Health Resource Utilization; ICF: informed consent 
form: INR: international normalized ratio; IRC: independent review committee; IRR: infusion-related reaction; IV: intravenous; mFOLFOX6: 5-fluorouracil, folinic acid and 
oxaliplatin; MRI: magnetic resonance imaging; OS: overall survival; PD: progressive disease; PFS: progression free survival; PFS2: progressive disease following 2nd line therapy; 
PGx: pharmacogenomics; PT: prothrombin time; PTT: partial thromboplastin time; QoL: quality of life; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: serious adverse 
event; T4: thyroxine; TSH: thyroid stimulating hormone 
†In case subjects are unable to be evaluated in person on Day 1 of each cycle, the site will contact the subject by phone for a safety assessment at the time the next visit would be due. 
††Additional non-protocol-specific testing may be required per local regulations. Local and/or regional protocols or precautions for COVID-19 management should be followed as 
applicable. 
*+ 6 calendar day visit window does not apply to C1D1. 
1. Screening: The Screening period is 45 days from full main ICF signature. Re-testing of lab values is allowed within the 45-day screening period. Re-screening outside of the 45-
day window under a new subject number may be allowed once and upon discussion with the Medical Monitor. CT scans and MRIs conducted as part of a subject’s routine clinical 
management (i.e., standard of care) obtained prior to signing the ICF may be utilized for screening or baseline purposes, provided the procedures met the protocol-specified criteria 
and were performed within the Screening period.  
• Optional Partial Screening: A partial screening ICF may be available for central testing of tissue for CLDN18.2 and HER2 only. 
• Laboratory testing: 
Eligibility can be determined based on central and/or local testing, however: 
o 
The most recent laboratory tests with available results must be used to confirm the subject’s eligibility. 
o 
Central labs must be collected and submitted to the central laboratory during the Screening period. 
o 
If retesting of lab values is necessary to confirm eligibility, local labs can be used without requiring additional sample collection for central laboratory submission.  
o 
The screening labs used to determine eligibility should be collected within 14 days prior to randomization.    
• Radiologic imaging used to confirm eligibility must be conducted within 28 days prior to randomization.  
2. CLDN18.2 and HER2 Testing: FFPE tumor tissue will be collected for central testing to determine CLDN18.2 and HER2 status. (Unique to China: FFPE tumor tissue will be 
collected for central testing to determine CLDN18.2 status.) Archival tumor tissue from the primary tumor (gastric or GEJ) is preferred. If primary tumor tissue is not available, 
tumor tissue from a metastatic site (excluding bone metastasis) may be used. A minimum of 1 FFPE tumor tissue block (preferred) OR a minimum of 15 FFPE unstained slides are 
required, as allowed per local policy. If slides are submitted, the slides should be freshly cut from the FFPE block within the time frame described in the laboratory manual. If local 
HER2 results are already available from local testing, a minimum of 12 FFPE unstained slides are required to be submitted to the central lab, as allowed per local policy. If the 
specimen is insufficient or unavailable, a biopsy may be performed to obtain primary tumor tissue (preferred) or tumor tissue from metastatic site (excluding bone metastasis). 
Sponsor pre-approval is required when the sole purpose of the biopsy procedure is to assess eligibility for this study. (Unique to China: Five FFPE unstained slides are required, as 
allowed per local policy.) See [Section 5.7.3 Tumor Tissue Samples]. 
If the required number of slides cannot be provided, the sponsor or designee should be contacted for further guidance.  
3. Randomization: After confirmation of eligibility, the blinded site user will perform the randomization IRT transaction. The unblinded pharmacist/designee will be notified by the 
IRT system about the randomly assigned treatment. Confirmation of Inclusion/Exclusion Criteria must be completed prior to randomization. Randomization may be performed 

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prior to C1D1. If C1D1 cannot be performed within 5 calendar days from Randomization, please contact the Medical Monitor. Details of infusion preparation and storage 
requirements are defined in the Pharmacy Manual and Infusion Guidelines. 
4. Antiemetic Pre-treatment: Antiemetic premedication (prophylactic antiemetics) should be administered prior to each study treatment. IV antiemetic premedication should be 
initiated prior to treatment, or oral antiemetic premedication should be initiated at a minimum of 30 minutes prior to treatment. Antiemetic premedication should be given 
according to institutional standard of care, published guidelines and the respective product package insert(s). For further details, see [Section 5.1.1.2 Antiemetics].  
5. Zolbetuximab/placebo will be administered as a minimum 2-hour IV infusion every 3 weeks starting on C1D1 (i.e., C1D1, C1D22, C2D1, etc.). Please refer to the Pharmacy 
Manual and Infusion Guidelines for more detailed information. If both zolbetuximab/placebo and mFOLFOX6 are to be administered during the same visit, zolbetuximab/placebo 
should be administered prior to mFOLFOX6. For further details, see [Section 5.1.1.1 Zolbetuximab/Placebo]. 
6. Post-Infusion Observation Period: Following the first dose of zolbetuximab/placebo in C1, the subject must be observed for 2 hours post-zolbetuximab/placebo infusion. The post-
infusion observation period can be conducted during the mFOLFOX6 administration. If any ≥ grade 2 AEs are observed during infusion or during the post-infusion observation 
period, subsequent zolbetuximab/placebo infusion times should be extended and subjects should continue to be observed for 2 hours post zolbetuximab/placebo infusion. If the 
subject does not develop any ≥ grade 2 AEs, the subject should be observed for 1 hour post-infusion for their subsequent zolbetuximab/placebo infusions. The subject should be 
instructed to notify site personnel if they develop any AEs during this observation time period. In the event of an IRR with features of anaphylaxis (regardless of grade) or grade 3 
or 4 IRR, blood samples for cytokine/chemokine panel and serum total tryptase level (levels typically peak within 3 hours after the onset of symptoms) should be collected once 
the subject has stabilized for shipment to the central laboratory. See Observation Period following zolbetuximab/placebo [Section 5.4.2] for further details.   
7. mFOLFOX6 will be administered every 2 weeks starting at C1D1 (i.e., C1D1, C1D15, C1D29, etc.) for 4 cycles (up to 12 treatments). A maximum of 12 doses of oxaliplatin can 
be administered. If both zolbetuximab/placebo and mFOLFOX6 are to be administered during the same visit, zolbetuximab/placebo should be administered prior to mFOLFOX6. 
See [Section 5.1.1.3 mFOLFFOX6]. 
8. 5-FU and Folinic Acid may continue to be administered at the discretion of the investigator after completion of 12 treatments of mFOLFOX6. If 5-FU is not continued after 
12 treatments of mFOLFOX6, then day 15 and day 29 visits are not required. If both zolbetuximab/placebo and 5-FU and folinic acid are to be administered during the same visit, 
zolbetuximab/placebo should be administered first. See [Section 5.1.1.1 Zolbetuximab/Placebo]. 
9. Physical Exam: should include height (at Screening only), weight and ECOG performance status. A full physical exam is required at Screening. The physical exam only needs to 
be repeated on C1D1 if clinically significant changes from Screening are observed (in the opinion of the investigator). For all cycles, the physical examination, weight and ECOG 
performance status assessments can be completed up to 48 hours prior to zolbetuximab/placebo administration. Targeted (symptom driven) physical exams should be conducted 
every 3 weeks on zolbetuximab/placebo visit days. For further details, see [Section 5.4.4 Physical Examination]. 
10. Vital signs (pulse, blood pressure, temperature) should be taken during every visit at the following time points (see [Section 5.4.1 Vital Signs]): 
o Pre-dose at every visit  
o C1D1: Every 30 (± 10) minutes during zolbetuximab/Placebo infusion  
o If the subject did not develop any ≥ grade 2 AEs during the C1D1 zolbetuximab/placebo infusion or the Post-Infusion Observation Period, the site may do the following for 
subsequent zolbetuximab/placebo infusions: 
▪ 
The post-infusion observation period can be 1 hour for subsequent visits after C1D1 
▪ 
The vital signs can be assessed every 60 minutes for subsequent visits after C1D1 
o Every 60 (±10) minutes post zolbetuximab/placebo infusion during the Post-Infusion Observation Period (for 1 or 2 hours. See footnote 6) 
o Unscheduled if clinically indicated 

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11. ECGs: ECGs will be locally read. When collected on the same day, ECG should be collected prior to pharmacokinetic samples. For further details, see [Section 5.4.5 
Electrocardiogram]. A single ECG will be performed at the following time points: 
o Screening 
o Up to 48 hours prior to every oxaliplatin infusion (before any antiemetic treatment) 
o Up to 6 hours following completion of every oxaliplatin infusion 
o Zolbetuximab/placebo study treatment discontinuation visit 
o Zolbetuximab/placebo 30-day safety follow-up visit 
o If clinically indicated and/or per local requirements  
12. Imaging Assessments: Radiologic imaging will be evaluated at Screening (must be conducted within 28 days prior to randomization) and every 9 weeks (± 7 days) counting from 
C1D1 for the first 54 weeks and then every 12 weeks (± 7 days) thereafter until subject develops radiological disease progression per RECIST 1.1 by IRC or starts other systemic 
anticancer treatment, whichever comes earlier. Imaging schedule should be maintained regardless of treatment delay. Imaging will include CT scans with contrast of the thorax, 
abdomen, and pelvis. If CT scan with contrast is medically not feasible, MRI may be used for imaging. Bone scans (or focal X-ray) or brain imaging should be performed if 
metastatic disease in bone or brain is suspected, respectively. The same mode of imaging should be utilized throughout the study unless medical necessity requires a change. For 
randomized subjects, screening imaging should be sent to the central imaging vendor no later than submission of the first on-treatment imaging. All imaging acquired post 
randomization will be sent to the central imaging vendor within 7 days of scanning for the blinded independent central assessment of radiological tumor response based on 
RECIST 1.1. The investigator should make every effort to immediately submit radiologic assessments for IRC review when PD is suspected. See [Section 5.3 Efficacy 
Assessments]. Refer to Imaging Acquisition Guidelines for further detail on scan modality and contrast options. 
13. Laboratory Assessments: See [Section 5.4.3 Laboratory Assessments] for list of laboratory assessments. Laboratory tests must be sent to the central laboratory for analysis unless 
otherwise approved by the sponsor. For screening/eligibility laboratory assessments, see footnote 1.   
o Laboratory test results (central or local) will be reviewed by the investigator prior to any study treatment. Clinical significance of out-of-range laboratory findings is to be 
determined and documented by the investigator/sub-investigator who is a qualified physician.  
o Local laboratory results may be used for treatment decisions; however, central laboratory samples must also be drawn per protocol and sent to the central laboratory unless 
otherwise approved by the sponsor.   
o Central and local labs may be collected up to 48 hours prior to study treatment. 
o Holidays and weekends should be taken into account when scheduling these blood draws. 
o Additional assessments may be done centrally or locally to monitor AEs or as clinically indicated. 
14. Coagulation (PT, PTT and INR): Coagulation tests should be done at Screening and during study treatment period if clinically indicated. Local or central lab results may be used to 
confirm eligibility. Ongoing evaluation should be continued for Subjects who are receiving therapeutic anticoagulation according to local standard of care. See [Section 5.4.3 
Laboratory Assessments]. 
15. Serum Pregnancy Test: Serum pregnancy tests will be collected for female subjects of child bearing potential only. Serum pregnancy tests collected at Screening, during study 
treatment period and if clinically indicated or per local requirements. Serum pregnancy test can be completed up to 48 hours prior to zolbetuximab/placebo administration. (Note: 
For Screening, subjects with elevated serum βHCG and a demonstrated non-pregnant status through additional testing are eligible.) Local or central laboratory results may be used 
to confirm eligibility. 

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16. Urine Pregnancy Test: for female subjects of child bearing potential only. Local urine pregnancy tests to be performed during the treatment period every 3 weeks at 
zolbetuximab/placebo visits and at the zolbetuximab/placebo Study Treatment Discontinuation and 30-Day Safety Follow up Visits. Urine pregnancy test can be completed up to 
48 hours prior to zolbetuximab/placebo administration. Additional urine pregnancy testing for up to 9 months after the final study treatment administration may be applied based 
on local requirements. 
17. HRQoL and HRU questionnaires: eCOA questionnaires are to be completed by the subject at Screening (except HRU), on day 1 and day 22 of each cycle (or up to 48 hours) 
before any antiemetic or drug treatment and before the disease status is discussed with the subject using the electronic tablet device provided. When completion by the subject is 
not possible, the questionnaires may be administered to the subject by site personnel using the electronic tablet device. For subjects with low literacy, situations where translations 
are unavailable or other circumstances preventing the screening questionnaires to be completed, please contact the sponsor for further guidance. 
18. Study Treatment Discontinuation Visit (End of Study Treatment): The Study Treatment Discontinuation Visits will take place ≤ 7 days following the decision to discontinue all 
study treatment (zolbetuximab/placebo and mFOLFOX6 [all components]). If zolbetuximab/placebo and mFOLFOX6 (all components) are discontinued on a different day, 
subjects will have a separate Study Treatment Discontinuation Visit following each treatment’s discontinuation. Laboratory tests must be sent to the central laboratory for analysis. 
HRQoL and HRU questionnaires are not required at mFOLFOX6 treatment discontinuation visit. A combined visit can be completed if zolbetuximab/placebo are discontinued on 
the same day. If necessary during a crisis, this visit can be completed remotely for safety assessments and the required laboratory samples should be collected as soon as the crisis 
permits. 
19. 30-Day Safety Follow-up Visit: A 30-Day Safety Follow-up visit should occur 30 days after the last dose of zolbetuximab/placebo and will include the assessments as shown in 
the Schedule of Assessments above. A 30-Day Safety Follow-Up Visit should occur 30 days after the last dose of mFOLFOX6 (all components) and may be conducted by phone if 
the subject is unable to visit the site and will require only contact for AE/SAE collection. HRQoL and HRU questionnaires are not required at mFOLFOX6 30-day safety follow up 
visit. A combined visit can be completed if zolbetuximab/placebo and all components of mFOLFOX6 are discontinued on the same day and HRQoL and HRU questionnaires 
should be completed for a combined visit. If necessary during a crisis, this visit can be completed remotely for safety assessments and the required laboratory samples should be 
collected as soon as the crisis permits. 
20. 90-Day Safety Follow-up Visits: A 90-Day Safety Follow-up visit should occur 90 days after the last dose of zolbetuximab/placebo and will include the assessments as shown in 
the Schedule of Assessments above. A 90-Day Safety Follow-Up Visit should occur 90 days after the last dose of mFOLFOX6 (all components) and may be conducted by phone if 
the subject is unable to visit the site and will require only contact for AE/SAE collection. HRQoL and HRU questionnaires are not required at mFOLFOX6 90-day safety follow up 
visit. A combined visit can be completed if zolbetuximab/placebo and all components of mFOLFOX6 are discontinued on the same day and HRQoL and HRU questionnaires 
should be completed for a combined visit. 
21. Post-Treatment Follow-up: if a subject discontinues all study treatments (zolbetuximab/placebo and all components of mFOLFOX6) prior to IRC confirmed radiological disease 
progression, the subject will enter the Post-Treatment Follow-up Period and continue to undergo imaging assessments every 9 weeks (or every 12 weeks if subject has been on 
study over 54 weeks) until radiologic disease progression (i.e., PFS) or the subject starts subsequent anticancer treatment, whichever occurs earlier. If study treatment 
(zolbetuximab/placebo and all components of mFOLFOX6) is discontinued due to PD, the subject will enter the Long Term and Survival Follow-up Period.   
22. Long Term and Survival Follow-up Period: Following disease progression on 1st line treatment or start of subsequent anticancer treatment, subjects will be followed in the Long-
Term and Survival Follow-up Period per institutional guidelines, but not less frequently than every 12 weeks. Radiologic imaging will be done per standard of care and read 
locally. Survival Follow-up Period will continue until death (from any cause). All post-progression details including subsequent anticancer treatment and date and site of 
progression will be recorded on the eCRF. Subject contact by phone or other remote methods is sufficient during Long Team and Survival Follow-up.  
23. Pharmacokinetic (Serum) for zolbetuximab/placebo samples will be taken at the below timepoints and sent to the central laboratory. The date and time of each blood sample 
collection will be recorded to the nearest minute. 
o Cycle 1 Day 1: End of zolbetuximab/placebo infusion  

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o Cycle 1 Day 22: Predose  
o Cycle 2 Day 1: End of zolbetuximab/placebo infusion  
o Pre-dose on Day 1 of Cycles 3, 5, 7 and 9 
o Zolbetuximab/placebo 30-Day Safety Follow-up visit   
o Zolbetuximab/placebo 90-Day Follow-up visit  
o Unscheduled pharmacokinetic blood samples may be taken at any time during the study to evaluate drug exposure following a safety event 
Pharmacokinetic Sampling Window:  
o Predose: within 60 minutes prior to dosing 
o End of Infusion: within 10 minutes after the end of the infusion 
24. Anti-Drug Antibodies (ADA): Blood samples (Serum) for ADA will be taken at the below timepoints and sent to the central laboratory.  
o Cycle 1 Day 1: Predose  
o Cycle 1 Day 22: Predose  
o Pre-dose on Day 1 of Cycle 3, 5, 7 and 9 
o Zolbetuximab/placebo 30-Day Safety Follow-up visit  
o Zolbetuximab/placebo 90-Day Follow-up visit  
ADA Sampling Window: Predose: within 60 minutes prior to dosing 
25. Genetic Immune Polymorphism: To be collected per local policy. Whole blood sample taken at C1D1 will be sent to the central laboratory. Samples may be collected up to 
48 hours prior to study treatment. 
26. Exploratory Biomarker (Serum and Plasma): To be collected per local policy. Samples should be taken at the below timepoints and sent to the central laboratory: 
o Cycle 1 Day 1: Predose  
o Cycle 1 Day 22: Predose 
o Cycle 2 Day 1: Predose 
o Cycle 2 Day 22: Predose 
o Cycle 3 Day 1: Predose  
o Cycle 3 Day 22: Predose 
o Cycle 4 Day 22: Predose 
o Zolbetuximab/placebo Study Treatment Discontinuation Visit 
Exploratory Biomarker samples may be collected up to 48 hours prior to study treatment 
27. Optional PGx: for subjects who signed a separate ICF, an optional whole blood sample for PGx for exploratory biomarker analysis may be collected up to 48 hours prior to first 
study drug administration at C1D1. Sample collection is optional and only collected as allowed per local policy. 
28. Optional Post-Progression Tumor Sample: for subjects who signed a separate ICF, an optional post-progression tumor sample for exploratory biomarker analysis may be collected 
following IRC confirmation of disease progression and prior to initiation of subsequent anticancer therapy. Sample collection is optional and only collected as allowed per local 
policy. 
29. Concomitant medications: Concomitant medications will be collected from the time of full main informed consent through 90 days following the last dose of study treatment. 

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30. AEs/SAEs: AEs/SAEs (regardless of causality) will be collected from the time of full main informed consent through 90 days following the last dose of study treatment. See 
[Section 5.5.5 Reporting of Serious Adverse Event].  
31. With implementation of Protocol Version 7.0, please refer to [Table 11] for the Protocol Version 7.0 and later Schedule of Assessments. 

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IMP SUPPLY 
If any of the conditions outlined above in the Participants Procedures Assessment are met, one or all of the following mitigating strategies will be 
employed, as needed, to ensure continuity of IMP supply to the participants:  
● 
Increase stock of IMP on site to reduce number of shipments required, if site space will allow, as cold storage space is needed.  
DATA COLLECTION REQUIREMENTS 
Additional data may be collected in order to indicate how participation in the study may have been affected by a crisis and to accommodate data 
collection resulting from alternate measures implemented to manage the conduct of the study and participant safety.  
● 
Critical assessments for safety and efficacy based on study endpoints to be identified as missing or altered (performed virtually, at alternative 
locations, out of window, or other modifications) due to the crisis. 
 
 
 

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12.10 Unblinding Procedures Following Final Overall Survival Database Lock 
Following completion of the final OS database lock, all principal investigators will be unblinded and informed of the treatment arm for each participant. 
Participant unblinding will be at the discretion of the principal investigator. Participants allocated to the placebo arm will be given the option to continue 
with the mFOLFOX backbone chemotherapy treatment according to protocol, or discontinue from the study and enter the follow-up period. As the study 
has achieved the primary objective and key secondary objectives, participants allocated to zolbetuximab may continue on study treatment until 
discontinuation criteria is met [Section 6.1]. 
 
 

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4. 5-FU and Folinic Acid may continue to be administered at the discretion of the investigator after completion of 12 treatments of mFOLFOX6. If 5-FU is not continued after 
12 treatments of mFOLFOX6, then day 15 and day 29 visits are not required. If both zolbetuximab/placebo and 5-FU and folinic acid are to be administered during the same visit, 
zolbetuximab/placebo should be administered first. See [Section 5.1.1.1 Zolbetuximab/Placebo].  
5. Physical Exam: should include weight and ECOG performance status. For all cycles, the physical examination, weight and ECOG performance status assessments can be 
completed up to 48 hours prior to zolbetuximab/placebo administration. Targeted (symptom driven) physical exams should be conducted every 3 weeks on zolbetuximab/placebo 
visit days. For further details, see [Section 5.4.4 Physical Examination]. 
6. Vital signs (pulse, blood pressure, temperature) should be taken during every visit at the following time points (see [Section 5.4.1 Vital Signs]): 
o Pre-dose at every visit  
o If the subject did not develop any ≥ grade 2 AEs during the C1D1 zolbetuximab/placebo infusion or the Post-Infusion Observation Period, the site may do the following for 
subsequent zolbetuximab/placebo infusions: 
▪ 
The post-infusion observation period can be 1 hour for subsequent visits after C1D1 
▪ 
The vital signs can be assessed every 60 minutes for subsequent visits after C1D1 
o Every 60 (±10) minutes post zolbetuximab/placebo infusion during the Post-Infusion Observation Period (for 1 or 2 hours. See footnote 3) 
o Unscheduled if clinically indicated 
7. ECGs: ECGs will be locally read. When collected on the same day, ECG should be collected prior to pharmacokinetic samples. For further details, see [Section 5.4.5 
Electrocardiogram]. A single ECG will be performed at the following time points: 
o Up to 48 hours prior to every oxaliplatin infusion (before any antiemetic treatment) 
o Up to 6 hours following completion of every oxaliplatin infusion 
o Zolbetuximab/placebo study treatment discontinuation visit 
o Zolbetuximab/placebo 30-day safety follow-up visit (if clinically indicated) 
o If clinically indicated and/or per local requirements  
8. Imaging Assessments: Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), radiologic imaging will be evaluated locally. Under Protocol Version 
6.1 or earlier (e.g., Original Protocol Version 1 through 6.1), radiographic imaging was evaluated centrally by IRC [Table 1]. Radiologic imaging will be evaluated every 9 weeks 
(± 7 days) counting from C1D1 for the first 54 weeks and then every 12 weeks (± 7 days) thereafter until subject develops radiological disease progression per RECIST 1.1 
confirmed locally or by IRC assessment or starts other systemic anticancer treatment, whichever comes earlier. Imaging schedule should be maintained regardless of treatment 
delay. Imaging will include CT scans with contrast of the thorax, abdomen, and pelvis. If CT scan with contrast is medically not feasible, MRI may be used for imaging. Bone 
scans (or focal X-ray) or brain imaging should be performed if metastatic disease in bone or brain is suspected, respectively. The same mode of imaging should be utilized 
throughout the study unless medical necessity requires a change. All imaging acquired post randomization will be sent to the local vendor within 7 days of scanning for the blinded 
independent assessment of radiological tumor response based on RECIST 1.1. The investigator should make every effort to immediately submit radiologic assessments for local or 
IRC review when PD is suspected. See [Section 5.3 Efficacy Assessments]. Refer to Imaging Acquisition Guidelines for further detail on scan modality and contrast options. 

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9. Laboratory Assessments: See [Section 5.4.3 Laboratory Assessments] for list of laboratory assessments. Laboratory tests must be sent to the local laboratory for analysis unless 
otherwise approved by the sponsor.  
o Laboratory test results (local) will be reviewed by the investigator prior to any study treatment. Clinical significance of out-of-range laboratory findings is to be determined 
and documented by the investigator/sub-investigator who is a qualified physician.  
o Local laboratory results are to be used for treatment decisions.  
o Local labs may be collected up to 48 hours prior to study treatment. 
o Holidays and weekends should be taken into account when scheduling these sample collections. 
o Additional assessments should be done locally to monitor AEs or as clinically indicated. 
10. Coagulation (PT, PTT and INR): Coagulation tests should be done during study treatment period if clinically indicated. Ongoing evaluation should be continued for Subjects who 
are receiving therapeutic anticoagulation according to local standard of care. See [Section 5.4.3 Laboratory Assessments].  
11. Serum Pregnancy Test: Serum pregnancy tests will be collected for female subjects of child bearing potential only. Serum pregnancy tests collected at Screening, during study 
treatment period and if clinically indicated or per local requirements. Serum pregnancy test can be completed up to 48 hours prior to zolbetuximab/placebo administration.  
12. Urine Pregnancy Test: for female subjects of child bearing potential only. Local urine pregnancy tests to be performed during the treatment period every 3 weeks at 
zolbetuximab/placebo visits and at the zolbetuximab/placebo Study Treatment Discontinuation and 30-Day Safety Follow up Visits. Urine pregnancy test can be completed up to 
48 hours prior to zolbetuximab/placebo administration. Additional urine pregnancy testing for up to 9 months after the final study treatment administration may be applied based 
on local requirements. 
13. Study Treatment Discontinuation Visit (End of Study Treatment): The Study Treatment Discontinuation Visits will take place ≤ 7 days following the decision to discontinue all 
study treatment (zolbetuximab/placebo and mFOLFOX6 [all components]). If zolbetuximab/placebo and mFOLFOX6 (all components) are discontinued on a different day, 
subjects will have a separate Study Treatment Discontinuation Visit following each treatment’s discontinuation. Laboratory tests must be sent to the local laboratory for analysis. A 
combined visit can be completed if zolbetuximab/placebo are discontinued on the same day. The Study Treatment Discontinuation Visit is not required if the participant has 
transitioned to commercially available zolbetuximab and/or mFOLFOX6. Safety reporting should continue as per post-marketing requirements in this case. 
14. 30-Day Safety Follow-up Visit: A 30-Day Safety Follow-up visit should occur 30 days after the last dose of zolbetuximab/placebo and will include the assessments as shown in 
the Schedule of Assessments above. A 30-Day Safety Follow-Up Visit should occur 30 days after the last dose of mFOLFOX6 (all components) and may be conducted by phone if 
the subject is unable to visit the site and will require only contact for AE/SAE collection. A combined visit can be completed if zolbetuximab/placebo and all components of 
mFOLFOX6 are discontinued on the same day. The 30-Day Safety Follow-up visit is not required if the participant has transitioned to commercially available zolbetuximab and/or 
mFOLFOX6. Safety reporting should continue as per post-marketing requirements in this case. 
15. 90-Day Safety Follow-up Visits: A 90-Day Safety Follow-up visit should occur 90 days after the last dose of zolbetuximab/placebo and will include the assessments as shown in 
the Schedule of Assessments above. A 90-Day Safety Follow-Up Visit should occur 90 days after the last dose of mFOLFOX6 (all components) and may be conducted by phone. 
A combined visit can be completed if zolbetuximab/placebo and all components of mFOLFOX6 are discontinued on the same day. The 90-Day Safety Follow-up visit is not 
required if the participant has transitioned to commercially available zolbetuximab and/or mFOLFOX6. Safety reporting should continue as per post-marketing requirements in 
this case. 

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16. Pharmacokinetic (Serum) for zolbetuximab/placebo samples will be taken at the below timepoints and sent to the central laboratory. The date and time of each blood sample 
collection will be recorded to the nearest minute. 
o Pre-dose on Day 1 of Cycles 5, 7 and 9 
o Unscheduled pharmacokinetic blood samples may be taken at any time during the study to evaluate drug exposure following a safety event 
Pharmacokinetic Sampling Window:  
o Predose: within 60 minutes prior to dosing 
o End of Infusion: within 10 minutes after the end of the infusion 
17. Anti-Drug Antibodies (ADA): Blood samples (Serum) for ADA will be taken at the below timepoints and sent to the central laboratory.  
o Pre-dose on Day 1 of Cycles 5, 7 and 9 
ADA Sampling Window: Predose: within 60 minutes prior to dosing 
18. Optional Post-Progression Tumor Sample: for subjects who signed a separate ICF, an optional post-progression tumor sample for exploratory biomarker analysis may be collected 
following local or IRC confirmation of disease progression and prior to initiation of subsequent anticancer therapy. Sample collection is optional and only collected as allowed per 
local policy.  
19. Concomitant medications: Concomitant medications will be collected from the time of full main informed consent through 90 days following the last dose of study treatment. 
20. AEs/SAEs: AEs/SAEs (regardless of causality) will be collected from the time of full main informed consent through 90 days following the last dose of study treatment. See 
[Section 5.5.5 Reporting of Serious Adverse Events]. 
21. Collection by phone. 
22. Participants assigned to Arm B (mFOLFOX6 chemotherapy in combination with placebo) who continue in the study are not required to receive placebo (and may receive the 
chemotherapy components without placebo), and are not required to attend Day 22 visits. 
 
 
 

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†In case subjects are unable to be evaluated in person on Day 1 of each cycle, the site will contact the subject by phone for a safety assessment at the time the next visit would be due. 
1. Antiemetic Pre-treatment: Antiemetic premedication (prophylactic antiemetics) should be administered prior to each study treatment. IV antiemetic premedication should be 
initiated prior to treatment, or oral antiemetic premedication should be initiated at a minimum of 30 minutes prior to treatment. Antiemetic premedication should be given 
according to institutional standard of care, published guidelines and the respective product package insert(s). For further details, see [Section 5.1.1.2 Antiemetics]. 
2. Zolbetuximab/placebo will be administered as a minimum 2-hour IV infusion every 3 weeks starting on C1D1 (i.e., C1D1, C1D22, C2D1, etc.). Please refer to the Pharmacy 
Manual and Infusion Guidelines for more detailed information. If both zolbetuximab/placebo and mFOLFOX6 are to be administered during the same visit, zolbetuximab/placebo 
should be administered prior to mFOLFOX6. For further details, see [Section 5.1.1.1 Zolbetuximab/Placebo]. 
3. Post-Infusion Observation Period: Following the first dose of zolbetuximab/placebo in C1, the subject must be observed for 2 hours post-zolbetuximab/placebo infusion. The post-
infusion observation period can be conducted during the mFOLFOX6 administration. If any ≥ grade 2 AEs are observed during infusion or during the post-infusion observation 
period, subsequent zolbetuximab/placebo infusion times should be extended and subjects should continue to be observed for 2 hours post zolbetuximab/placebo infusion. If the 
subject does not develop any ≥ grade 2 AEs, the subject should be observed for 1 hour post-infusion for their subsequent zolbetuximab/placebo infusions. The subject should be 
instructed to notify site personnel if they develop any AEs during this observation time period. In the event of an IRR with features of anaphylaxis (regardless of grade) or grade 3 
or 4 IRR, blood samples for cytokine/chemokine panel and serum total tryptase level (levels typically peak within 3 hours after the onset of symptoms) should be collected once 
the subject has stabilized. See Observation Period following zolbetuximab/placebo [Section 5.4.2] for further details.   
4. 5-FU and Folinic Acid may continue to be administered at the discretion of the investigator after completion of 12 treatments of mFOLFOX6. If 5-FU is not continued after 
12 treatments of mFOLFOX6, then day 15 and day 29 visits are not required. If both zolbetuximab/placebo and 5-FU and folinic acid are to be administered during the same visit, 
zolbetuximab/placebo should be administered first. See [Section 5.1.1.1 Zolbetuximab/Placebo].  
5. Physical Exam: should include weight and ECOG performance status. For all cycles, the physical examination, weight and ECOG performance status assessments can be 
completed up to 48 hours prior to zolbetuximab/placebo administration. Targeted (symptom driven) physical exams should be conducted every 3 weeks on zolbetuximab/placebo 
visit days. For further details, see [Section 5.4.4 Physical Examination]. 
6. Vital signs (pulse, blood pressure, temperature) should be taken during every visit at the following time points (see [Section 5.4.1 Vital Signs]): 
a. Pre-dose at every visit   
b. If the subject did not develop any ≥ grade 2 AEs during the C1D1 zolbetuximab/placebo infusion or the Post-Infusion Observation Period, the site may do the following for 
subsequent zolbetuximab/placebo infusions: 
i. The post-infusion observation period can be 1 hour for subsequent visits after C1D1 
ii. The vital signs can be assessed every 60 minutes for subsequent visits after C1D1 
c. Every 60 (±10) minutes post zolbetuximab/placebo infusion during the Post-Infusion Observation Period (for 1 or 2 hours. See footnote 3) 
d. Unscheduled if clinically indicated 

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7. ECGs: ECGs will be locally read. When collected on the same day, ECG should be collected prior to pharmacokinetic samples. For further details, see [Section 5.4.5 
Electrocardiogram]. A single ECG will be performed at the following time points: 
o Up to 48 hours prior to every oxaliplatin infusion (before any antiemetic treatment) 
o Up to 6 hours following completion of every oxaliplatin infusion 
o Zolbetuximab/placebo study treatment discontinuation visit 
o Zolbetuximab/placebo 30-day safety follow-up visit (if clinically indicated).  
8. Imaging Assessments: Effective with implementation of Protocol Version 7.0 (Substantial Amendment 6), radiologic imaging will be evaluated locally. Under Protocol Version 
6.1 or earlier (e.g., Original Protocol Version 1 through 6.1), radiographic imaging was evaluated centrally by IRC [Table 1]. Radiologic imaging will be evaluated every 9 weeks 
(± 7 days) counting from C1D1 for the first 54 weeks and then every 12 weeks (± 7 days) thereafter until subject develops radiological disease progression per RECIST 1.1 by 
local or IRC or starts other systemic anticancer treatment, whichever comes earlier. Imaging schedule should be maintained regardless of treatment delay. Imaging will include CT 
scans with contrast of the thorax, abdomen, and pelvis. If CT scan with contrast is medically not feasible, MRI may be used for imaging. Bone scans (or focal X-ray) or brain 
imaging should be performed if metastatic disease in bone or brain is suspected, respectively. The same mode of imaging should be utilized throughout the study unless medical 
necessity requires a change. All imaging acquired post randomization will be sent to the local imaging vendor within 7 days of scanning for the blinded independent local 
assessment of radiological tumor response based on RECIST 1.1. The investigator should make every effort to immediately submit radiologic assessments for local or IRC review 
when PD is suspected. See [Section 5.3 Efficacy Assessments]. Refer to Imaging Acquisition Guidelines for further detail on scan modality and contrast options. 
9. Laboratory Assessments: See [Section 5.4.3 Laboratory Assessments] for list of laboratory assessments. Laboratory tests must be sent to the local laboratory for analysis unless 
otherwise approved by the sponsor.   
o Laboratory test results (local) will be reviewed by the investigator prior to any study treatment. Clinical significance of out-of-range laboratory findings is to be determined 
and documented by the investigator/sub-investigator who is a qualified physician.  
o Local laboratory results may be used for treatment decisions.  
o Local labs may be collected up to 48 hours prior to study treatment. 
o Holidays and weekends should be taken into account when scheduling these blood draws. 
o Additional assessments may be done locally to monitor AEs or as clinically indicated. 
10. Coagulation (PT, PTT and INR): Coagulation tests should be done if clinically indicated. Ongoing evaluation should be continued for Subjects who are receiving therapeutic 
anticoagulation according to local standard of care. See [Section 5.4.3 Laboratory Assessments]. 
11. Serum Pregnancy Test: Serum pregnancy tests will be collected for female subjects of child bearing potential only. Serum pregnancy tests will be collected if clinically indicated 
or per local requirements. Serum pregnancy test can be completed up to 48 hours prior to zolbetuximab/placebo administration.  
12. Urine Pregnancy Test: for female subjects of child bearing potential only. Local urine pregnancy tests to be performed during the treatment period every 3 weeks at 
zolbetuximab/placebo visits and at the zolbetuximab/placebo Study Treatment Discontinuation and 30-Day Safety Follow up Visits. Urine pregnancy test can be completed up to 
48 hours prior to zolbetuximab/placebo administration. Additional urine pregnancy testing for up to 9 months after the final study treatment administration may be applied based 
on local requirements. 
13. Study Treatment Discontinuation Visit (End of Study Treatment): The Study Treatment Discontinuation Visits will take place ≤ 7 days following the decision to discontinue all 
study treatment (zolbetuximab/placebo and mFOLFOX6 [all components]). If zolbetuximab/placebo and mFOLFOX6 (all components) are discontinued on a different day, 
subjects will have a separate Study Treatment Discontinuation Visit following each treatment’s discontinuation. A combined visit can be completed if zolbetuximab/placebo are 
discontinued on the same day. If necessary during a crisis, this visit can be completed remotely for safety assessments and the required laboratory samples should be collected as 

Sponsor:  APGD 
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soon as the crisis permits. The Study Treatment Discontinuation Visit is not required if the participant has transitioned to commercially available zolbetuximab and/or 
mFOLFOX6. Safety reporting should continue as per post-marketing requirements in this case. 
14. 30-Day Safety Follow-up Visit: A 30-Day Safety Follow-up visit should occur 30 days after the last dose of zolbetuximab/placebo and will include the assessments as shown in 
the Schedule of Assessments above. A 30-Day Safety Follow-Up Visit should occur 30 days after the last dose of mFOLFOX6 (all components) and may be conducted by phone if 
the subject is unable to visit the site. A combined visit can be completed if zolbetuximab/placebo and all components of mFOLFOX6 are discontinued on the same day. If 
necessary during a crisis, this visit can be completed remotely for safety assessments and the required laboratory samples should be collected as soon as the crisis permits. The 30-
Day Safety Follow-up visit is not required if the participant has transitioned to commercially available zolbetuximab and/or mFOLFOX6. Safety reporting should continue as per 
post-marketing requirements in this case. 
15. 90-Day Safety Follow-up Visits: A 90-Day Safety Follow-up visit should occur 90 days after the last dose of zolbetuximab/placebo and will include the assessments as shown in 
the Schedule of Assessments above. A 90-Day Safety Follow-Up Visit should occur 90 days after the last dose of mFOLFOX6 (all components) and may be conducted by phone. 
A combined visit can be completed if zolbetuximab/placebo and all components of mFOLFOX6 are discontinued on the same day. The 90-Day Safety Follow-up visit is not 
required if the participant has transitioned to commercially available zolbetuximab and/or mFOLFOX6. Safety reporting should continue as per post-marketing requirements in 
this case. 
16. Pharmacokinetic (Serum) for zolbetuximab/placebo samples will be taken at the below timepoints and sent to the central laboratory. The date and time of each blood sample 
collection will be recorded to the nearest minute. 
o Pre-dose on Day 1 of Cycles 5, 7 and 9 
o Unscheduled pharmacokinetic blood samples may be taken at any time during the study to evaluate drug exposure following a safety event 
Pharmacokinetic Sampling Window:  
o Predose: within 60 minutes prior to dosing 
o End of Infusion: within 10 minutes after the end of the infusion 
17. Anti-Drug Antibodies (ADA): Blood samples (Serum) for ADA will be taken at the below timepoints and sent to the central laboratory.  
o Pre-dose on Day 1 of Cycles 5, 7 and 9 
ADA Sampling Window: Predose: within 60 minutes prior to dosing 
18. Optional Post-Progression Tumor Sample: for subjects who signed a separate ICF, an optional post-progression tumor sample for exploratory biomarker analysis may be collected 
following local or IRC confirmation of disease progression and prior to initiation of subsequent anticancer therapy. Sample collection is optional and only collected as allowed per 
local policy. 
19. Concomitant medications: Concomitant medications will be collected from the time of full main informed consent through 90 days following the last dose of study treatment. 
20. AEs/SAEs: AEs/SAEs (regardless of causality) will be collected from the time of full main informed consent through 90 days following the last dose of study treatment. See 
[Section 5.5.5 Reporting of Serious Adverse Event].  
21. Collection by phone 
22. Participants assigned to Arm B (mFOLFOX6 chemotherapy in combination with placebo) who continue in the study are not required to receive placebo (and may receive the 
chemotherapy components without placebo), and are not required to attend Day 22 visits. 
 

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14 
COORDINATING INVESTIGATOR’S SIGNATURE  
A Phase 3, Global, Multi-Center, Double-Blind, Randomized, Efficacy Study of 
Zolbetuximab (IMAB362) Plus mFOLFOX6 Compared with Placebo Plus 
mFOLFOX6 as First-line Treatment of Subjects with Claudin (CLDN)18.2-
Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric 
or Gastroesophageal Junction (GEJ) Adenocarcinoma  
ISN/Protocol 8951-CL-0301 
Version 8.0 Incorporating Substantial Amendment 7 
14 Nov 2024 
I have read all pages of this clinical study protocol for which Astellas is the sponsor. I agree that it 
contains all the information required to conduct this study. 
Coordinating Investigator: 
 
Signature: 
 
 
 
<Insert name, department/affiliation, name of institution> 
 
Date (DD Mmm YYYY) 
 
Printed Name: 
 
 
 
 
Address: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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15 
SPONSOR’S SIGNATURES 
Astellas Signatories 
(Electronic signatures are attached at the end of the document.) 
 
 
Development, Immuno-Oncology 
 
 
Statistical Science, Immuno-
Oncology 
 
 
 
 
 
 
Post-marketing Study Supervisor 
 
PPD
PPD
PPD