A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Gastric or Gastroesophageal Junction Carcinoma (MORPHEUS C-Gastric and Gastroesophageal Junction Carcinoma)
Phase: PHASE1
Conditions: Gastric and Gastroesophageal Junction Carcinoma
Sponsor: Hoffmann-La Roche



CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, 
especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its 
control) and therefore is provided to you in confidence as an investigator, potential investigator, 
or consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional 
Review Board.  It is understood that this information will not be disclosed to others without written 
authorization from Roche except to the extent necessary to obtain informed consent from 
persons to whom the drug may be administered. 
 
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
Protocol YO43408, Version 5 
PROTOCOL 
PROTOCOL TITLE: 
A PHASE Ib/II, OPEN-LABEL, MULTICENTER, 
RANDOMIZED UMBRELLA STUDY EVALUATING 
THE EFFICACY AND SAFETY OF MULTIPLE 
TREATMENT COMBINATIONS IN PATIENTS WITH 
GASTRIC OR GASTROESOPHAGEAL JUNCTION 
CARCINOMA (MORPHEUS CGASTRIC AND 
GASTROESOPHAGEAL JUNCTION CARCINOMA) 
PROTOCOL NUMBER: YO43408 
VERSION NUMBER: 
5 
TEST COMPOUNDS: 
Atezolizumab (RO5541267) 
Tiragolumab (RO7092284) 
STUDY PHASE: 
Phase Ib/II 
REGULATORY 
AGENCY IDENTIFIER 
NUMBERS: 
NCT Number:  NCT05251948 
SPONSOR'S NAME 
AND LEGAL 
REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document. 
 

 
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
2/Protocol YO43408, Version 5 
PROTOCOL HISTORY 
 
Protocol 
Version 
Date Final 
5 
See electronic date stamp on the final 
page of this document. 
4 
2 June 2023 
3 
20 December 2022 
2 
10 January 2022 
1 
10 June 2021 

 
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
3/Protocol YO43408, Version 5 
PROTOCOL AMENDMENT, VERSION 5 
RATIONALE 
Protocol YO43408 has been amended to remove two treatment arms.  In addition, risks 
and management guidelines for atezolizumab have been updated to align with the latest 
Atezolizumab Investigator's Brochure (Version 20).  Substantive changes to the protocol, 
along with a rationale for each change, are summarized below. 
 
The following stage 1 treatment arms have been removed: atezolizumab and 
CAPOX in combination with AB011 (Atezo  CAPOX  AB011), or CAPOX in 
combination with AB011 (CAPOX  AB011).  No patient had been enrolled in any of 
these arms (Section 3.1.2, Table 4, Figure 2, Section 3.1.3, Section 4.1.2, Section 
4.1.2.4, Section 4.3.1, Section 4.5.7, Section 5.3.5.12, Section 5.7, Appendix 6, 
Appendix 9 and Appendix 10). 
 
As a result of the removal of these arms, other changes have been made as follows: 
 
Information about AB011 has been removed (Section 1.3)  
 
Number of participants to be enrolled during Stage 1 has been reduced to 
approximately 4090 patients due to the removal of two arms 
(Section 3.1.2, Section 6.1) 
 
Specific biomarker assessment for claudin-18 isoform 2 [CLDN18.2] is no 
longer required (Section 3.3.3, Section 4.5.7, Appendix 6) 
 
Treponema pallidum antibody test and fecal occult blood test have been 
removed as these were only applicable to AB011 arms.  Stool samples 
have been made optional (Section 3.3.3, Section 4.5.7, Section 4.5.9, 
Appendix 6, Appendix 7, Appendix 8) 
 
Number of FFPE tumor specimen slides has been reduced 
(Section 3.3.3, Section 4.5.7) 
 
Optional tumor biopsy frequency has been reduced to every 8 weeks 
(  7 days) (Section 4.5.8). 
 
It has been made explicit that expedited safety reports are notified to EudraVigilance 
(Section 5.7). 
 
The adverse events management guidelines have been updated to align with the 
Atezolizumab IB, Version 20 (Appendix 5).   
 
The list of approved indications for atezolizumab has been updated to include 
alveolar soft part sarcoma (Appendix 7 and Appendix 8). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.  
 
 

 
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................ 9 
PROTOCOL SYNOPSIS .................................................................................... 10 
1. 
BACKGROUND ............................................................................ 18 
1.1 
Background on Gastric Cancer and Gastroesophageal 
Junction Cancer ....................................................................... 18 
1.2 
First-Line Treatment of GC and GEJC ..................................... 18 
1.3 
Study Rationale ....................................................................... 19 
1.4 
COVID-19 Benefit–Risk Assessment ....................................... 21 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 22 
3. 
STUDY DESIGN ........................................................................... 27 
3.1 
Description of the Study ........................................................... 27 
3.1.1 
Overview of Study Design........................................................ 27 
3.1.2 
Stage 1 .................................................................................... 29 
3.1.3 
Stage 2 .................................................................................... 32 
3.1.4 
Assessments and Monitoring ................................................... 33 
3.1.5 
Internal Monitoring Committee ................................................. 34 
3.2 
End of Study and Length of Study ........................................... 34 
3.3 
Rationale for Study Design ...................................................... 34 
3.3.1 
Rationale for Patient Population .............................................. 34 
3.3.2 
Rationale for Immunotherapy-Based Treatment beyond 
Initial Radiographic Progression .............................................. 35 
3.3.3 
Rationale for Biomarker Assessments ..................................... 36 
4. 
MATERIALS AND METHODS ...................................................... 37 
4.1 
Patients .................................................................................... 37 
4.1.1 
Inclusion Criteria ...................................................................... 37 
4.1.1.1 
Inclusion Criteria for Stage 1.................................................... 37 
4.1.1.2 
Inclusion Criteria for Stage 1 and Stage 2 ............................... 38 
4.1.1.3 
Inclusion Criteria for Stage 2.................................................... 39 
4.1.2 
Exclusion Criteria ..................................................................... 39 
4.1.2.1 
Exclusion Criteria for Stage 1 .................................................. 40 
4.1.2.2 
Exclusion Criteria for Stage 1 and Stage 2 .............................. 40 

 
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4.1.2.3 
Exclusion Criteria for Tiragolumab-Containing Arm ................. 43 
4.2 
Method of Treatment Assignment ............................................ 43 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 44 
4.3.1 
Investigational Medicinal Product Handling and 
Accountability ........................................................................... 44 
4.3.2 
Post-Trial Access to Study Treatment ..................................... 45 
4.4 
Concomitant Therapy and Prohibited Food ............................. 45 
4.5 
Study Assessments ................................................................. 45 
4.5.1 
Informed Consent Forms and Screening ................................. 45 
4.5.2 
Medical History, Molecular Profile, Concomitant 
Medication, and Demographic Data ......................................... 46 
4.5.3 
Physical Examinations ............................................................. 46 
4.5.4 
Vital Signs ................................................................................ 47 
4.5.5 
Electrocardiograms .................................................................. 47 
4.5.6 
Tumor and Response Evaluations ........................................... 47 
4.5.7 
Laboratory, Biomarker, and Other Biological Samples ............ 49 
4.5.8 
Optional Tumor Biopsies ......................................................... 52 
4.5.9 
Optional Stool Samples ........................................................... 52 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 53 
4.6.1 
Study Treatment Discontinuation ............................................. 53 
4.6.2 
Patient Discontinuation from Study .......................................... 54 
4.6.3 
Study Discontinuation .............................................................. 54 
4.6.4 
Site Discontinuation ................................................................. 54 
5. 
ASSESSMENT OF SAFETY ......................................................... 55 
5.1 
Safety Plan .............................................................................. 55 
5.2 
Safety Parameters and Definitions .......................................... 55 
5.2.1 
Adverse Events ........................................................................ 55 
5.2.2 
Serious Adverse Events (Immediately Reportable to 
the Sponsor) ............................................................................ 56 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 57 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 57 

 
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5.3.1 
Adverse Event Reporting Period .............................................. 57 
5.3.2 
Eliciting Adverse Event Information ......................................... 58 
5.3.3 
Assessment of Severity of Adverse Events ............................. 58 
5.3.4 
Assessment of Causality of Adverse Events............................ 59 
5.3.5 
Procedures for Recording Adverse Events .............................. 60 
5.3.5.1 
Infusion-Related Reactions and Cytokine Release 
Syndrome ................................................................................ 60 
5.3.5.2 
Diagnosis versus Signs and Symptoms ................................... 61 
5.3.5.3 
Adverse Events That Are Secondary to Other Events ............. 61 
5.3.5.4 
Persistent or Recurrent Adverse Events .................................. 62 
5.3.5.5 
Abnormal Laboratory Values ................................................... 62 
5.3.5.6 
Abnormal Vital Sign Values ..................................................... 63 
5.3.5.7 
Abnormal Liver Function Tests ................................................ 63 
5.3.5.8 
Deaths ..................................................................................... 64 
5.3.5.9 
Preexisting Medical Conditions ................................................ 64 
5.3.5.10 
Lack of Efficacy or Worsening of Gastric Cancer or 
Gastroesophageal Junction Carcinoma ................................... 64 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ............................ 65 
5.3.5.12 
Cases of Accidental Overdose or Medication Error, Drug 
Abuse, or Drug Misuse ............................................................ 65 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 67 
5.4.1 
Medical Monitors and Emergency Medical Contacts ............... 68 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 68 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation ............. 68 
5.4.2.2 
Events That Occur after Study Treatment Initiation ................. 68 
5.5 
Follow-Up of Patients after Adverse Events............................. 69 
5.5.1 
Investigator Follow-Up ............................................................. 69 
5.5.2 
Sponsor Follow-Up .................................................................. 69 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 69 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 70 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 71 

 
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6.1 
Determination of Sample Size ................................................. 71 
6.2 
Summaries of Conduct of Study .............................................. 71 
6.3 
Summaries of Demographic and Baseline Characteristics ...... 72 
6.4 
Efficacy Analyses ..................................................................... 72 
6.4.1 
Primary Efficacy Endpoint ........................................................ 72 
6.4.2 
Secondary Efficacy Endpoints ................................................. 72 
6.5 
Safety Analyses ....................................................................... 73 
6.6 
Pharmacokinetic Analyses ....................................................... 73 
6.7 
Immunogenicity Analyses ........................................................ 74 
6.8 
Biomarker Analyses ................................................................. 74 
6.9 
Interim Analyses ...................................................................... 74 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 75 
7.1 
Data Quality Assurance ........................................................... 75 
7.2 
Electronic Case Report Forms ................................................. 75 
7.3 
Source Data Documentation .................................................... 75 
7.4 
Use of Computerized Systems ................................................ 76 
7.5 
Retention of Records ............................................................... 76 
8. 
ETHICAL CONSIDERATIONS ...................................................... 77 
8.1 
Compliance with Laws and Regulations .................................. 77 
8.2 
Informed Consent .................................................................... 77 
8.3 
Institutional Review Board or Ethics Committee ...................... 78 
8.4 
Confidentiality .......................................................................... 78 
8.5 
Financial Disclosure ................................................................. 79 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ....................................................................... 79 
9.1 
Study Documentation .............................................................. 79 
9.2 
Protocol Deviations .................................................................. 80 
9.3 
Site Inspections ....................................................................... 80 
9.4 
Administrative Structure ........................................................... 80 
9.5 
Dissemination of Data and Protection of Trade Secrets .......... 80 
9.6 
Protocol Amendments ............................................................. 81 
10. 
REFERENCES.............................................................................. 82 

 
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LIST OF TABLES 
Table 1 
Target and Proposed Mechanism-of-Action Classification for 
Experimental Investigational Medicinal Products ........................ 21 
Table 2 
Objectives and Corresponding Endpoints for Stage 1 ................ 23 
Table 3 
Objectives and Corresponding Endpoints for Stage 2 ................ 25 
Table 4 
Stage 1 Treatment Regimens ..................................................... 30 
Table 5 
Stage 2 Treatment Regimens ..................................................... 32 
Table 6 
Arm-Specific Exclusion Criteria ................................................... 39 
Table 7 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 58 
Table 8 
ASTCT CRS Consensus Grading Scale ..................................... 59 
Table 9 
Causal Attribution Guidance ....................................................... 60 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 28 
Figure 2 
Detailed Study Design ................................................................ 31 
 
 
LIST OF APPENDICES 
Appendix 1 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1).......................................................... 86 
Appendix 2 
ECOG Performance Status Scale ............................................... 95 
Appendix 3 
Preexisting Autoimmune Diseases and Immune Deficiencies .... 96 
Appendix 4 
Anaphylaxis Precautions ............................................................. 97 
Appendix 5 
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with 
Atezolizumab .............................................................................. 98 
Appendix 6 
Schedule of Activities for Screening .......................................... 134 
Appendix 7 
Study Details Specific to Atezo  CAPOX Arm (Control) .......... 137 
Appendix 8 
Study Details Specific to Atezo  CAPOX  Tira Arm ............... 167 
 
 
 

 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
PROTOCOL TITLE: 
A PHASE Ib/II, OPEN-LABEL, MULTICENTER, 
RANDOMIZED UMBRELLA STUDY EVALUATING 
THE EFFICACY AND SAFETY OF MULTIPLE 
TREATMENT COMBINATIONS IN PATIENTS WITH 
GASTRIC OR GASTROESOPHAGEAL JUNCTION 
CARCINOMA (MORPHEUS CGASTRIC AND 
GASTROESOPHAGEAL JUNCTION CARCINOMA) 
PROTOCOL NUMBER: YO43408 
VERSION NUMBER: 
4 
TEST COMPOUNDS: 
Atezolizumab (RO5541267) 
Tiragolumab (RO7092284) 
SPONSOR NAME: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by Fortrea. 

 
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
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PROTOCOL SYNOPSIS 
PROTOCOL TITLE: 
A PHASE Ib/II, OPEN-LABEL, MULTICENTER, RANDOMIZED 
UMBRELLA STUDY EVALUATING THE EFFICACY AND SAFETY 
OF MULTIPLE TREATMENT COMBINATIONS IN PATIENTS WITH 
GASTRIC OR GASTROESOPHAGEAL JUNCTION CARCINOMA 
(MORPHEUS CGASTRIC AND GASTROESOPHAGEAL 
JUNCTION CARCINOMA) 
REGULATORY 
AGENCY IDENTIFIER 
NUMBERS: 
NCT Number:  NCT05251948 
  
STUDY RATIONALE 
The purpose of this study is to evaluate the efficacy and safety of multiple treatment 
combinations in patients with inoperable locally advanced, metastatic, or advanced gastric 
carcinoma (GC) or gastroesophageal junction carcinoma (GEJC), with adenocarcinoma 
confirmed as the predominant histology, who have not received prior systemic therapy for 
advanced or metastatic disease.  The current standard-of-care treatment options for patients 
with GC and GEJC are primarily limited to cytotoxic chemotherapy in combination with 
checkpoint inhibitors and targeted therapy (if applicable).  Cytotoxic agents given as backbone 
treatment are associated with significant toxicities and the majority of patients who received 
standard-of-care treatments will still experience disease progression within 1 year.  Therefore, 
there is a high unmet need for improved medical intervention for patients with inoperable locally 
advanced, metastatic, or advanced GC or GEJC. 
OBJECTIVES AND ENDPOINTS 
The objectives and corresponding endpoints are summarized in Table 1. 

 
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Table 1 
Objectives and Corresponding Endpoints for Stage 1 
Primary Objective 
Primary Efficacy Objective 
Corresponding Endpoint  
 To evaluate the efficacy of treatment 
combinations during Stage 1 
 ORR, defined as the proportion of patients with a 
complete response or a partial response on two 
consecutive occasions  4 weeks apart during 
Stage 1, as determined by the investigator 
according to RECIST v1.1 
Secondary Objectives 
Secondary Efficacy Objective 
Corresponding Endpoints  
 To evaluate the efficacy of treatment 
combinations during Stage 1 
 PFS after randomization, defined as the time from 
randomization to the first occurrence of disease 
progression or death from any cause (whichever 
occurs first) in Stage 1, as determined by the 
investigator according to RECIST v1.1 
 OS after randomization, defined as the time from 
randomization to death from any cause, 
regardless of stage 
 OS at specific timepoints (e.g., 6 and 12 months) 
 DOR, defined as the time from the first occurrence of 
a documented objective response to disease 
progression or death from any cause (whichever 
occurs first) in Stage 1, as determined by the 
investigator according to RECIST v1.1 
 Disease control rate, defined as the proportion of 
patients with stable disease for  12 weeks or a 
complete or a partial response, as determined by 
the investigator according to RECIST v1.1 
Safety Objective 
Corresponding Endpoint 
 To evaluate the safety of treatment 
combinations during Stage 1 
 Incidence and severity of adverse events, with 
severity of all events graded according to 
NCI CTCAE v5.0 and severity for CRS also 
graded according to the ASTCT CRS Consensus 
Grading Scale 
ASTCT  American Society for Transplantation and Cellular Therapy; CRS  cytokine release 
syndrome; DOR  duration of response; NCI CTCAE  National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 5.0; ORR  objective response rate; OS  overall 
survival; PFS  progression-free survival; RECIST v1.1 Response Evaluation Criteria in Solid 
Tumors, Version 1.1. 
Note:  Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1. 
 
 
OVERALL DESIGN AND STUDY POPULATION 
This Phase Ib/II, open-label, multicenter, randomized umbrella study will evaluate the efficacy 
and safety of multiple treatment combinations in patients with advanced GC or GEJC.  The 
study is designed with the flexibility to open new treatment arms as new treatments become 
available, close existing treatment arms that demonstrate minimal clinical activity or 

 
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unacceptable toxicity, and modify the patient population (e.g., with regard to prior anti-cancer 
treatment or biomarker status). 
Several key aspects of the study design and study population are summarized in Table 2. 
Table 2 Study Design and Population 
Phase: 
Phase Ib/II 
Population Type: 
Adult patients 
Control Method: 
Active comparator 
Population Diagnosis 
or Condition: 
Inoperable locally 
advanced, metastatic, 
or advanced GC or 
GEJC 
Interventional 
Model: 
Parallel group 
 
Population Age: 
Age  18 years 
Test Compounds: 
Atezolizumab, 
tiragolumab 
Site Distribution: 
Multi-site 
Active Comparator: Atezolizumab in 
combination with 
capecitabine plus 
oxaliplatin 
Study Intervention 
Assignment Method: 
Randomization 
Number of Arms: 
2 
Number of Participants 
to Be Enrolled: 
Approximately 
4090 patients 
GC  gastric carcinoma; GEJC  gastroesophageal junction carcinoma. 
 
STUDY TREATMENT 
The study treatment is summarized in Table 3. 
Table 3 Study Treatment 
Stage 1 Study Treatments 
Treatment Group 
Dose, Route, and Regimen 
(drugs listed in order of administration) 
Atezo  CAPOX 
(control group 
treatment combination) 
(21-day cycles) 
 Atezolizumab 1200 mg by IV infusion on Day 1 
 Capecitabine 1000 mg/m2 orally twice daily on Days 114 a 
 Oxaliplatin 130 mg/m2 by IV infusion on Day 1 a 
Atezo  CAPOX  Tira 
(treatment combination) 
(21-day cycles) 
 Atezolizumab 1200 mg by IV infusion on Day 1 
 Tiragolumab 600 mg by IV infusion on Day 1 
 Capecitabine 1000 mg/m2 orally twice a day on Days 114 a 
 Oxaliplatin 130 mg/m2 by IV infusion on Day 1 a 
Atezo  atezolizumab; CAPOX  capecitabine plus oxaliplatin; Tira  tiragolumab. 
a Treatment for up to six cycles. 
 
There will be no dose modifications for atezolizumab or tiragolumab in this study. 
Capecitabine Dose Modification 
The capecitabine dose can be modified as presented in Table 4 for the management of drug-
related toxicities.  Once the dose has been reduced, it cannot be increased later.  Omitted 
doses of capecitabine because of toxicity will not be replaced. 

 
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Table 4 Dose Modification for Capecitabine for Drug-Related Toxicities 
Toxicity a 
Action to Be Taken for 
Current Treatment 
Dose Modification for the  
Next Treatment 
(% of Starting Dose) 
Grade 1 
Maintain dose level. 
Maintain dose level. 
Grade 2 
 
 
First occurrence 
Withhold until resolved to Grade 1 
or better. 
100% (1000 mg/m2) 
Second occurrence 
75% (750 mg/m2) 
Third occurrence 
50% (500 mg/m2) 
Fourth occurrence 
Discontinue permanently. 
 
Grade 3 
 
 
First occurrence 
Withhold until resolved to Grade 1 
or better. 
75% (750 mg/m2) 
Second occurrence 
50% (500 mg/m2) 
Third occurrence 
Discontinue permanently. 
 
Grade 4 
 
 
First occurrence 
Discontinue permanently or 
continue at the discretion of the 
investigator once the event has 
resolved to Grade 1 or better. 
50% (500 mg/m2) 
a Graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 5.0. 
 
Oxaliplatin Dose Modification 
Dose Modifications for Patients with Neurotoxicity 
 
For Grade 2 peripheral sensory neuropathy (moderate paresthesia or dysesthesia) or 
limiting instrumental activities of daily living, omit oxaliplatin.  When toxicity resolves to 
Grade 1 or better, resume oxaliplatin to 75% of the initial dose.  If oxaliplatin is omitted for 6 
weeks (two consecutive cycles) for neurologic toxicity, discontinue oxaliplatin. 
 
For Grade 3 and 4 peripheral sensory neuropathy (severe paresthesia or dysesthesia) or 
limiting self-care activities of daily living), discontinue oxaliplatin. 
 
Dose Modifications for Patients with Renal Impairment 
 
For normal renal function or mild to moderate renal impairment (creatinine clearance 
 50 mL/min), the full dose of oxaliplatin can be administered. 
 
For severe renal impairment, the oxaliplatin dose should be reduced to 75% of the initial 
dose. 
 
Dose Modifications for Patients with Hematologic Toxicity 
 
For Grade 2 and 3 thrombocytopenia, the oxaliplatin dose should be reduced to 75% of the 
initial dose.  For Grade 4 thrombocytopenia, the dose should be reduced to 50% of the 
initial dose. 
 
For Grade 3 and 4 neutropenia or febrile neutropenia, the oxaliplatin dose should be 
reduced to 75% of the initial dose. 
 

 
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DURATION OF PARTICIPATION 
Treatment will continue until disease progression per Response Evaluation Criteria in Solid 
Tumors, Version 1.1.  The total length of the study, from screening of the first patient to the end 
of the study, is expected to be approximately 35 years.   
COMMITTEES 
Independent Committees: Not applicable 
Other Committees: 
Internal Monitoring Committee 
 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
5-FU 
5-fluorouracil 
ADA 
anti-drug antibody 
ASTCT 
American Society for Transplantation and 
Cellular Therapy 
Atezo 
atezolizumab 
Atezo  CAPOX 
atezolizumab in combination with capecitabine 
and oxaliplatin 
Atezo  CAPOX  Tira 
atezolizumab in combination with capecitabine, 
oxaliplatin, and tiragolumab 
CAPOX 
capecitabine in combination with oxaliplatin 
CIT 
cancer immunotherapy 
COVID-19 
coronavirus disease 2019 
CPS 
combined positive score 
CRS 
cytokine release syndrome 
CT 
computed tomography 
DOR 
duration of response 
EBV 
Epstein-Barr virus 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
FFPE 
formalin-fixed, paraffin-embedded 
GC 
gastric carcinoma 
GEJ 
gastroesophageal junction 
GEJC 
gastroesophageal junction carcinoma 
HBcAb 
hepatitis B core antibody 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS (cont.) 
 
Abbreviation 
Definition 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor 2 
HR 
hazard ratio 
ICH 
International Council for Harmonisation 
IFN (- 
interferon (- 
IHC 
immunohistochemistry 
IL 
interleukin 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IxRS 
interactive voice or web-based response system 
LPLV 
last patient, last visit 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
NCCN 
National Comprehensive Cancer Network 
NCI CTCAE v5.0 
National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0 
NGS 
next-generation sequencing 
ORR 
objective response rate 
OS 
overall survival 
PD-1 
programmed death1 
PD-L1 
programmed deathligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetic 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SITC 
Society for Immunotherapy of Cancer 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS (cont.) 
 
Abbreviation 
Definition 
TIGIT 
T-cell immunoreceptor with Ig and ITIM domains 
Tira 
tiragolumab 
TNF- 
tumor necrosis factor 
ULN 
upper limit of normal 
VCA 
viral capsid antigen 
WES 
whole exome sequencing 
 

 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON GASTRIC CANCER AND 
GASTROESOPHAGEAL JUNCTION CANCER 
Gastric carcinoma (GC) is the fifth leading cancer and the fourth leading cause of 
cancer-related deaths globally.  The incidence of GC varies with different geographic 
regions, with more than 70% of GCs occurring in developing countries (Global Cancer 
Observatory 2020), and about 50% of these cases are in East Asia, with China the most 
affected country as it accounts for 42.6% of the global incidence and 45% of all 
GC-related deaths (Torre et al. 2015; Wang et al. 2018).  In China, GC remains the 
second in terms of incidence among all malignancies, just below lung cancer (Zheng 
et al. 2017; Chen et al. 2018).  In terms of incidence, GC is ranked second and fifth 
among males and females, respectively.  With respect to mortality, GC is ranked third, 
preceded by lung cancer and liver cancer, whereas the mortality among males and 
females is ranked third and second, respectively (Chen et al. 2018). 
The incidence of proximal GC is rising in the West, and that of non-proximal locations is 
rising in the East, especially in Japan and China.  At diagnosis, GC often presents as 
advanced disease, comprising approximately 40% of newly diagnosed cases in the 
United States and Europe and approximately 20% in Japan and Korea, where early 
detection is common.  However, in China more than 80% of patients with GC are 
already in advanced stages of the disease at the time of diagnosis, and many patients 
may miss the opportunity of radical resection or are at high risk of postoperative 
metastasis and relapse. 
GC, including gastroesophageal junction (GEJ) carcinoma (GEJC), is a heterogeneous 
cancer type with multiple identified risk factors, including environmental, genetic, and 
behavioral risks.  There has been a decline in GC mortality attributable to lifestyle and 
dietary changes globally (Global Burden of Disease 2017 Stomach Cancer Collaborators 
2020) as well as to decreased infection with Helicobacter pylori, which is considered the 
main cause of mortality in Asian countries (Lichtenstein et al. 2000).  However, the 
incidence of GEJ tumors has increased considerably because of increases in risk 
factors, such as smoking, obesity, and gastroesophageal reflux disease (Buas and 
Vaughan 2013; Coleman et al. 2018). 
1.2 
FIRST-LINE TREATMENT OF GC AND GEJC 
GEJ tumors are frequently grouped together with GC and treated in a similar fashion as 
GC due to its anatomical location straddling the distal esophagus and proximal stomach 
and given that the majority of GEJ tumors are adenocarcinomas (Hasegawa and 
Yoshikawa 2010).  Moreover, advanced and metastatic GEJ cancers are treated in a 
similar manner as GC according to oncology guidelines (National Comprehensive 
Cancer Network [NCCN] 2021a). 

 
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Platinum (cisplatin and oxaliplatin) and fluoropyrimidines (5-fluorouracil [5-FU], 
capecitabine, and S-1) doublets are generally considered as standard-of-care treatment 
in the first-line setting of metastatic GC and GEJC across different regions (Japanese 
Gastric Cancer Association 2021; NCCN 2021a, 2021b; Wang et al. 2021).  In patients 
with good performance status who are willing to sacrifice toxicity for higher response 
rates and potentially longer progression-free survival (PFS), triplet regimens consisting 
of fluoropyrimidine, oxaliplatin, and docetaxel can be considered (Lyons 2017).  
Overexpression or amplification of human epidermal growth factor 2 (HER2; also known 
as ERBB2) is present in approximately 15%20% of patients with advanced GC.  
The pivotal Phase III ToGA trial established the addition of trastuzumab to cytotoxic 
chemotherapy as the standard of care in the first-line treatment of patients with 
HER2-positive GC and GEJC (Bang et al. 2010; Lyons 2017). 
Immunotherapeutic approaches have demonstrated clinical efficacy in several advanced 
cancer types, including GC and GEJC.  Two anti-programmed death1 (PD-1) 
monoclonal antibodies, pembrolizumab and nivolumab, have demonstrated improved 
overall survival (OS) in patients with refractory GC that has progressed after two or more 
lines of chemotherapy, and both received regulatory approval for corresponding 
indications in 2017 (Kang et al. 2017; Fuchs et al. 2018).  Recently, 
CheckMate-649 (NCT02872116), a Phase III trial investigating nivolumab plus 
chemotherapy or nivolumab plus ipilimumab compared with chemotherapy alone in the 
first-line treatment of metastatic HER2-negative GC and GEJC, showed improved OS 
(14.4 vs. 11.1 months; hazard ratio [HR]: 0.71) and improved PFS (7.7 vs. 6.1 months; 
HR: 0.74) in patients with a programmed deathligand 1 (PD-L1) combined positive 
score (CPS)  5 receiving nivolumab plus chemotherapy compared with chemotherapy 
alone (Moehler et al. 2020).  An OS benefit (13.8 vs. 11.6 months; HR: 0.80) was also 
seen in an all-randomized population.  With the recent regulatory approval by the 
U.S. Food and Drug Administration, this practice-changing study has established 
chemotherapy plus nivolumab as a new standard of care for the first-line treatment of 
patients with HER2-negative GC and GEJC. 
1.3 
STUDY RATIONALE 
The current standard-of-care treatment for the first-line treatment of patients with 
HER2-negative GC and GEJC with cytotoxic chemotherapy is typically palliative in intent 
and results in poor prognosis, with the duration of median OS ranging from 8 to 
14 months across Asia, the United States, and Europe (Moehler et al. 2020).  In patients 
with GC and GJEC with a PD-L1 CPS  5, nivolumab in combination with chemotherapy 
conferred an additional survival benefit compared with chemotherapy alone.  However, 
the survival benefit in an all-randomized population was marginal and the treatment 
effect in the CPS  5 population remained unclear (Moehler et al. 2020).  In addition, 
cytotoxic agents used as treatment backbone are accompanied by high toxicity, with 
Grade 3 and 4 toxicities reported in up to 77% of patients treated with platinum-doublet 
regimens and in  80% of patients treated with triplet regimens (Van Cutsem et al. 2006; 

 
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Cunningham et al. 2008; Ohtsu et al. 2011; Lordick et al. 2013).  Therefore, new 
treatment options are needed to improve survival and response as well as decrease 
toxicity in the first-line treatment setting of GC and GEJC. 
This Phase Ib/II umbrella study is designed to accelerate the development of treatment 
combinations by identifying early signals and establishing proof-of-concept clinical data 
in patients with GC or GEJC.  The study is designed with the flexibility to open new 
treatment arms as new treatment combinations become available and close existing 
treatment arms that demonstrate minimal clinical activity or unacceptable toxicity.  
Enrollment of multiple experimental arms in a single study, rather than one or two 
experimental arms within multiple studies, will result in an overall reduction in the 
number of patients receiving control arm treatment.  More importantly, this study will 
assess the importance of simultaneously targeting multiple pathways, including immune 
cell priming and activation, tumor infiltration, and/or recognition of tumor cells for 
elimination.  To improve the confidence of clinical signal detection in the experimental 
arms, this study will include a control arm.  In addition, patients who experience disease 
progression with the initial treatment regimen (Stage 1) may be eligible to continue 
treatment with a different treatment regimen (Stage 2), which may advance the scientific 
understanding of treatment resistance mechanisms in patients who do not respond to or 
experience disease progression during treatment. 
This study will enroll patients with inoperable locally advanced, metastatic, or advanced 
GC or GEJC, with adenocarcinoma confirmed as the predominant histology, who have 
not received prior systemic therapy for their disease.  Despite the recently demonstrated 
clinical benefit of nivolumab plus chemotherapy in patients with a PD-L1 CPS  5, there 
remains a high unmet medical need for treatment-naive patients with inoperable locally 
advanced, metastatic, or advanced GC or GEJC, requiring further evaluation of novel, 
more efficacious treatment combinations. 
The target and proposed mechanism-of-action classification for each experimental 
investigational medicinal product (IMP) are presented in Table 1.  The control and 
experimental treatment regimens are described in Sections  3.1.1 and 3.1.2 (see Table 4 
and Table 5).  Background information and a rationale for each treatment combination, 
including a benefitrisk assessment for experimental agent, are provided in the 
respective appendix for that treatment arm, as outlined in Table 4 and Table 5. 

 
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Table 1 
Target and Proposed Mechanism-of-Action Classification for 
Experimental Investigational Medicinal Products 
Experimental 
IMP 
Target 
Proposed  
Mechanism-of-Action Classification 
Atezolizumab 
PD-L1 
Checkpoint inhibitor 
Tiragolumab 
TIGIT 
Checkpoint inhibitor; improves activation and 
effectiveness of T-cell and NK-cell tumor-killing activity a 
IMP  investigational medicinal product; NK  natural killer; TIGIT  T-cell immunoreceptor 
with Ig and ITIM domains. 
a Stanietsky et al. 2009; Yu et al. 2009; Johnston et al. 2014. 
  
1.4 
COVID-19 BENEFIT–RISK ASSESSMENT 
In the setting of the coronavirus disease 2019 (COVID-19) pandemic, patients with 
comorbidities, including those with cancer, are considered a more vulnerable population, 
with the potential for more severe clinical outcomes from severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) infection.  However, it is unclear whether or how 
systemic cancer therapies, such as chemotherapy, targeted therapy, or immunotherapy, 
impact the incidence or severity of SARS-CoV-2 infection. 
A possible consequence of immune checkpoint inhibition may be the modulation of the 
host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses (Wykes and Lewin 2018; Schorer et al. 2020).  
In nonclinical models, PD-1/PD-L1 blockade appears to be associated with serious 
exacerbation of inflammation in the setting of acute (as opposed to chronic) viral 
infection with lymphocytic choriomeningitis virus (Clone 13) (Frebel et al. 2012).  
However, there are insufficient and inconsistent clinical data to assess if outcome from 
SARS-CoV-2 infection is altered by cancer immunotherapy (CIT). 
Severe SARS-CoV-2 infection appears to be associated with a cytokine release 
syndrome (CRS) involving the inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and 
interferon (IFN)- (Merad and Martin 2020).  Although it is not known, there may be a 
potential for an increased risk of an enhanced inflammatory response if a patient 
develops acute SARS-CoV-2 infection while receiving immune checkpoint inhibitor 
therapies (e.g., atezolizumab and/or tiragolumab).  At this time, there is insufficient 
evidence for causal association between atezolizumab or tiragolumab and an increased 
risk of severe outcomes from SARS-CoV-2 infection. 
There may be potential synergy or overlap in clinical and radiologic features for 
immune-mediated pulmonary toxicity with immune checkpoint inhibitor therapies and 
clinical and radiologic features for SARS-CoV-2related interstitial pneumonia.  Thus, 
investigators should use their clinical judgment when evaluating and managing patients 
with pulmonary symptoms.  

 
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There are limited data concerning the possible interactions between CIT treatment and 
COVID-19 vaccination, and it is recognized that human immune responses are highly 
regulated and that immune-modifying therapies may positively or negatively impact the 
efficacy and safety of COVID-19 vaccination (Society for Immunotherapy of Cancer 
[SITC] 2020). 
Per recommendations of the NCCN COVID-19 Vaccination Advisory Committee, 
COVID-19 vaccination is recommended for all patients with cancer receiving active 
therapy (including immune checkpoint inhibitors), with the understanding that there are 
limited safety and efficacy data in such patients (NCCN 2021c).  Given the lack of 
clinical data, currently no recommendations can be made regarding the optimal 
sequence of COVID-19 vaccination in patients who are receiving CIT (SITC 2020).  For 
patients enrolling in this study and receiving CIT, a decision to administer the vaccine to 
a patient should be made on an individual basis by the investigator in consultation with 
the patient. 
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for patients receiving CIT to receive COVID-19 vaccination 
include the following:  the risk of SARS-CoV-2 infection and potential benefit from the 
vaccine, the general condition of the patient and potential complications associated with 
SARS-CoV-2 infection, underlying disease, and the severity of COVID-19 outbreak in a 
given area or region. 
SITC and NCCN recommendations along with institutional guidelines should be used by 
the investigator when deciding on administering COVID-19 vaccines.  When 
administered, COVID-19 vaccines must be given in accordance with the approved or 
authorized vaccine label.  Receipt of the COVID-19 vaccine is considered a concomitant 
medication and should be documented as such (see Section 4.4). 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of multiple treatment 
combinations in patients with advanced GC or GEJC.  Specific objectives and 
corresponding endpoints for the study are outlined below for Stage 1 (see Table 2) and 
Stage 2 (see Table 3). 

 
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Table 2 
Objectives and Corresponding Endpoints for Stage 1 
Primary Efficacy Objective 
Corresponding Endpoint 
 To evaluate the efficacy of treatment 
combinations during Stage 1 
 ORR, defined as the proportion of patients with a 
complete response or a partial response on two 
consecutive occasions  4 weeks apart during Stage 1, 
as determined by the investigator according to 
RECIST v1.1 
Secondary Efficacy Objective 
Corresponding Endpoints 
 To evaluate the efficacy of treatment 
combinations during Stage 1 
 PFS after randomization, defined as the time from 
randomization to the first occurrence of disease 
progression or death from any cause (whichever occurs 
first) in Stage 1, as determined by the investigator 
according to RECIST v1.1 
 OS after randomization, defined as the time from 
randomization to death from any cause, regardless of 
stage 
 OS at specific timepoints (e.g., 6 and 12 months) 
 DOR, defined as the time from the first occurrence of a 
documented objective response to disease progression 
or death from any cause (whichever occurs first) in 
Stage 1, as determined by the investigator according to 
RECIST v1.1 
 Disease control rate, defined as the proportion of 
patients with stable disease for  12 weeks or a complete 
or a partial response, as determined by the investigator 
according to RECIST v1.1 
Safety Objective 
Corresponding Endpoint 
 To evaluate the safety of treatment 
combinations during Stage 1 
 Incidence and severity of adverse events, with severity of 
all events graded according to NCI CTCAE v5.0 and 
severity for CRS also graded according to the ASTCT 
CRS Consensus Grading Scale 
ADA  anti-drug antibody; ASTCT  American Society for Transplantation and Cellular Therapy; 
CRS  cytokine release syndrome; DOR  duration of response; NCI CTCAE  National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 5.0; ORR  objective 
response rate; OS  overall survival; PFS  progression-free survival; PK  pharmacokinetic; 
RECIST v1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1. 
Note:  Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 1). 
  

 
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Table 2 
Objectives and Corresponding Endpoints for Stage 1 (cont.) 
Exploratory 
Pharmacokinetic Objectives 
Corresponding Endpoints 
 To characterize the PK profile of 
drugs that are administered as part of 
a treatment combination during 
Stage 1 
 Plasma or serum concentrations of each drug 
(as appropriate) at specified timepoints 
 To evaluate potential relationships 
between drug exposure during 
Stage 1 and the efficacy and safety 
of treatment combinations 
 Relationship between plasma or serum 
concentrations or PK parameters for each drug 
(as appropriate on the basis of available data) and 
efficacy endpoints 
 Relationship between plasma or serum 
concentrations or PK parameters for each drug 
(as appropriate on the basis of available data) and 
safety endpoints 
Exploratory 
Immunogenicity Objectives 
Corresponding Endpoints 
 To evaluate the immune response to 
drugs that are administered as part of 
a treatment combination during 
Stage 1 
 For drugs for which ADA formation is measured:  
presence of ADAs during the study relative to the 
presence of ADAs at baseline 
 To evaluate potential effects of ADAs 
during Stage 1 
 For drugs for which ADA formation is measured:  
relationship between ADA status and efficacy, safety, 
or PK endpoints 
Biomarker Objective 
Corresponding Endpoint 
 To identify biomarkers during Stage 1 
that are predictive of response to 
study treatment (i.e., predictive 
biomarkers), are associated with 
progression to a more severe 
disease state (i.e., prognostic 
biomarkers), are associated with 
resistance to study treatment, are 
associated with susceptibility to 
developing adverse events 
(i.e., safety biomarkers), can provide 
evidence of study treatment activity 
(i.e., pharmacodynamic biomarkers), 
or can increase the knowledge and 
understanding of disease biology 
 Relationship between biomarkers in blood and tumor 
tissue (listed in Section 4.5.7) and efficacy, safety, 
PK, immunogenicity, or other biomarker endpoints 
ADA  anti-drug antibody; ASTCT  American Society for Transplantation and Cellular Therapy; 
CRS  cytokine release syndrome; DOR  duration of response; NCI CTCAE  National Cancer 
Institute Common Terminology Criteria for Adverse Events, Version 5.0; ORR  objective 
response rate; OS  overall survival; PFS  progression-free survival; PK  pharmacokinetic; 
RECIST v1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1. 
Note:  Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 1). 

 
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Table 3 
Objectives and Corresponding Endpoints for Stage 2 
Exploratory Efficacy Objective 
Corresponding Endpoints 
 To evaluate the efficacy of treatment 
combinations during Stage 2 
 ORR, defined as the proportion of patients with a 
complete response or a partial response on two 
consecutive occasions  4 weeks apart during 
Stage 2, as determined by the investigator according 
to RECIST v1.1 
 PFS after initiation of Stage 2, defined as the time 
from initiation of Stage 2 to the first occurrence of 
disease progression or death from any cause 
(whichever occurs first), as determined by the 
investigator according to RECIST v1.1 
 OS after initiation of Stage 2, defined as the time from 
initiation of Stage 2 to death from any cause, 
regardless of stage 
 DOR, defined as the time from the first occurrence of 
a documented objective response during Stage 2 to 
disease progression or death from any cause 
(whichever occurs first), as determined by the 
investigator according to RECIST v1.1 
 Disease control rate, defined as the proportion of 
patients with stable disease for  12 weeks or a 
complete or a partial response, as determined by the 
investigator according to RECIST v1.1  
Safety Objective 
Corresponding Endpoint 
 To evaluate the safety of treatment 
combinations during Stage 2 
 Incidence and severity of adverse events, with 
severity of all events graded according to NCI 
CTCAE v5.0 and severity for CRS also graded 
according to the ASTCT CRS Consensus Grading 
Scale 
ADA  anti-drug antibody; ASTCT  American Society for Transplantation and Cellular Therapy; 
CRS  cytokine release syndrome; DOR  duration of response; NCI CTCAE v5.0  National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0; ORR  objective 
response rate; OS  overall survival; PFS  progression-free survival; PK  pharmacokinetic; 
RECIST v1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1. 
Note:  Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 1). 
  

 
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Table 3 
Objectives and Corresponding Endpoints for Stage 2 (cont.) 
Exploratory 
Pharmacokinetic Objectives 
Corresponding Endpoints 
 To characterize the PK profile of drugs 
that are administered as part of a 
treatment combination during Stage 2 
 Plasma or serum concentrations of each 
(as appropriate) drug at specified timepoints  
 To evaluate potential relationships 
between drug exposure during 
Stage 2 and the efficacy and safety of 
immunotherapy-based treatment 
combinations 
 Relationship between plasma or serum 
concentrations or PK parameters for each drug 
(as appropriate on the basis of available data) and 
efficacy endpoints  
 Relationship between plasma or serum 
concentrations or PK parameters for each drug 
(as appropriate on the basis of available data) and 
safety endpoints 
Exploratory 
Immunogenicity Objectives 
Corresponding Endpoints 
 To evaluate the immune response to 
drugs that are administered as part of 
a treatment combination during 
Stage 2 
 For drugs for which ADA formation is measured:  
presence of ADAs during the study relative to the 
presence of ADAs at baseline 
 To evaluate potential effects of ADAs 
during Stage 2 
 For drugs for which ADA formation is measured:  
relationship between ADA status and efficacy, 
safety, or PK endpoints 
Biomarker Objective 
Corresponding Endpoint 
 To identify biomarkers during Stage 2 
that are predictive of response to 
study treatment (i.e., predictive 
biomarkers), are associated with 
progression to a more severe disease 
state (i.e., prognostic biomarkers), are 
associated with resistance to study 
treatment, are associated with 
susceptibility to developing adverse 
events (i.e., safety biomarkers), can 
provide evidence of study treatment 
activity (i.e., pharmacodynamic 
biomarkers), or can increase the 
knowledge and understanding of 
disease biology 
 Relationship between biomarkers in blood and tumor 
tissue (listed in Section 4.5.7) and efficacy, safety, 
PK, immunogenicity, or other biomarker endpoints 
ADA  anti-drug antibody; ASTCT  American Society for Transplantation and Cellular Therapy; 
CRS  cytokine release syndrome; DOR  duration of response; NCI CTCAE v5.0  National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0; ORR  objective 
response rate; OS  overall survival; PFS  progression-free survival; PK  pharmacokinetic; 
RECIST v1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1. 
Note:  Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 1). 
  

 
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Table 3 
Objectives and Corresponding Endpoints for Stage 2 (cont.)  
Biomarker Objective 
Corresponding Endpoint 
 To identify biomarkers during Stage 2 
that are predictive of response to 
study treatment (i.e., predictive 
biomarkers), are associated with 
progression to a more severe disease 
state (i.e., prognostic biomarkers), are 
associated with resistance to study 
treatment, are associated with 
susceptibility to developing adverse 
events (i.e., safety biomarkers), can 
provide evidence of study treatment 
activity (i.e., pharmacodynamic 
biomarkers), or can increase the 
knowledge and understanding of 
disease biology 
 Relationship between biomarkers in blood and tumor 
tissue (listed in Section 4.5.7) and efficacy, safety, 
PK, immunogenicity, or other biomarker endpoints 
ADA  anti-drug antibody; ASTCT  American Society for Transplantation and Cellular Therapy; 
CRS  cytokine release syndrome; DOR  duration of response; NCI CTCAE v5.0  National 
Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0; ORR  objective 
response rate; OS  overall survival; PFS  progression-free survival; PK  pharmacokinetic; 
RECIST v1.1 Response Evaluation Criteria in Solid Tumors, Version 1.1. 
Note:  Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 1). 
  
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
This is a Phase Ib/II, open-label, multicenter, randomized umbrella study in patients with 
advanced GC or GEJC.  The study is designed with the flexibility to open new treatment 
arms as new treatments become available, close existing treatment arms that 
demonstrate minimal clinical activity or unacceptable toxicity, and modify the patient 
population (e.g., with regard to prior anti-cancer treatment or biomarker status). 
Cohort 1 will enroll patients with inoperable locally advanced, metastatic, or advanced 
GC or GEJC, with adenocarcinoma confirmed as the predominant histology, who have 
not received prior systemic therapy for advanced or metastatic disease (see Figure 1).  
Eligible patients will initially be randomly assigned to one of the treatment arms (Stage 1; 
see Section 3.1.2).  Patients who experience loss of clinical benefit or unacceptable 
toxicity during Stage 1 may be eligible to receive treatment with a different treatment 
combination (Stage 2; see Section 3.1.3).  When a Stage 2 treatment combination is 
available, this will be introduced by amending the protocol. 

 
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Figure 1 Study Schema 
 
GC  gastric carcinoma; GEJC  gastroesophageal junction carcinoma; R  randomization. 
a See Table 4 for a summary of available Stage 1 treatment regimens. 
b If deemed clinically feasible by the investigator, a biopsy will be performed for patients who discontinue Stage 1 because of unacceptable 
toxicity or loss of clinical benefit, as determined by the investigator (see details on tissue sample collection in Section 4.5.7). 
c See Table 5 for a summary of available Stage 2 treatment regimens. 

 
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3.1.2 
Stage 1 
During Stage 1, patients will be randomly assigned to a control arm (atezolizumab in 
combination with capecitabine and oxaliplatin [CAPOX] [Atezo  CAPOX]) or an 
experimental arm consisting of atezolizumab and CAPOX in combination with 
tiragolumab (Atezo  CAPOX  Tira).  Details on the treatment regimens for Stage 1 are 
provided in Appendix 7 and Appendix 8, as specified in Table 4. 
Approximately 40-90 patients will be enrolled during Stage 1.  Enrollment in the 
experimental arm will take place in two phases:  a preliminary phase, followed by an 
expansion phase.  For most arms, approximately 20 patients will be enrolled during the 
preliminary phase.  If clinical activity is observed in the experimental arm during the 
preliminary phase, approximately 25 additional patients may be enrolled in that arm 
during the expansion phase.  The Sponsor may decide to delay or suspend enrollment 
within a given treatment arm.  If the experimental arm shows minimal clinical activity or 
unacceptable toxicity, then it will not undergo expansion.  Additional patients may be 
enrolled to ensure balance across treatment arms with respect to demographic and 
baseline characteristics, including potential predictive biomarkers, to enable further 
subgroup analyses.  New experimental arms may be added during the study by 
amending the protocol. 
Patients in Stage 1 will be randomly assigned to experimental arms or the control arm, 
and the randomization ratio will depend on the number of experimental arms that are 
open for enrollment (e.g., if an arm is added or enrollment in an arm is suspended 
pending analysis of results from the preliminary phase), with the stipulation that the 
likelihood of being allocated to the control arm will be no more than 50%.  The treatment 
regimen in the control arm may change with emerging data to reflect the evolving 
standard-of-care treatments; new control arm treatment will be updated by amending the 
protocol.  Randomization will take into account arm-specific exclusion criteria.  Patients 
will be ineligible for a specific arm if they meet any of the exclusion criteria outlined for 
that arm (see Section 4.1.2).  Details on treatment assignment and randomization are 
provided in Section 4.2.

 
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Table 4 
Stage 1 Treatment Regimens 
Arm Name 
Study Treatment a 
Number of Patients 
Appendix 
Preliminary 
Phase 
Expansion 
Phase b 
Control (Atezo  CAPOX) c 
Atezolizumab plus capecitabine plus oxaliplatin 
Variable d 
Appendix 7 
Atezo  CAPOX  Tira 
Atezolizumab plus capecitabine plus oxaliplatin plus tiragolumab  
20  
25 
Appendix 8 
Atezo  atezolizumab; CAPOX  capecitabine plus oxaliplatin; Tira  tiragolumab. 
a The Sponsor may decide to delay or suspend enrollment within a given treatment arm.  Thus, all listed experimental arms may not be open for 
enrollment at the same time. 
b If clinical activity is observed in an experimental arm during the preliminary phase, approximately 25 additional patients may be enrolled in that 
arm during the expansion phase.  Experimental arms with minimal clinical activity or unacceptable toxicity will not undergo expansion. 
c The treatment regimen in the control arm may change with emerging data to reflect the evolving standard-of-care treatments, and new control 
arm treatment will be updated by amending the protocol. 
d The randomization ratio will depend on the number of experimental arms that are open for enrollment (e.g., if an arm is added or enrollment in 
an arm is suspended pending analysis of results from the preliminary phase), with the stipulation that the likelihood of being allocated to the 
control arm will be no more than 50% (see Section 3.1.2 for details). 
 

 
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Figure 2 Detailed Study Design 
 
Atezo  atezolizumab; CAPOX  capecitabine plus oxaliplatin; GC  gastric carcinoma; GEJC  gastroesophageal junction carcinoma; 
R  randomization; Tira  tiragolumab. 
a Patients who experience loss of clinical benefit as determined by the investigator (details provided below) or unacceptable toxicity during 
Stage 1 may be eligible to receive a different treatment combination during Stage 2, provided they meet the eligibility criteria and a Stage 2 
arm is open for enrollment.  Details are provided in the respective appendix for each treatment arm (see Appendix 7 and Appendix 8.  
 

 
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Patients in the control and experimental arms will continue to receive treatment until 
unacceptable toxicity or loss of clinical benefit as determined by the investigator after an 
integrated assessment of radiographic and biochemical data, local biopsy results 
(if available), and clinical status (e.g., symptomatic deterioration such as pain secondary 
to disease). 
Because of the possibility of an initial increase in tumor burden caused by immune cell 
infiltration in the setting of a T-cell response (termed pseudoprogression) with 
atezolizumab and other CITs, radiographic progression per Response Evaluation 
Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) may not be indicative of true 
disease progression.  In the absence of unacceptable toxicity, patients who meet 
criteria for disease progression per RECIST v1.1 while receiving treatment with a 
CIT-based combination will be permitted to continue treatment if they meet all of the 
following criteria: 
 
Evidence of clinical benefit, as determined by the investigator following a review of 
all available data 
 
Absence of symptoms and signs (including laboratory values, such as new or 
worsening hypercalcemia) indicating unequivocal progression of disease 
 
Absence of decline in Eastern Cooperative Oncology Group (ECOG) Performance 
Status that can be attributed to disease progression 
 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 
 
3.1.3 
Stage 2 
Patients in a control or experimental arm who experience loss of clinical benefit as 
determined by the investigator (as described above) during Stage 1 will be given the 
option of receiving a different treatment combination during Stage 2, as outlined in 
Table 5, provided they meet eligibility criteria (see Section 3.1.2) and a Stage 2 arm is 
open for enrollment.  Patients who experience unacceptable toxicity during Stage 1 may 
be eligible to receive treatment during Stage 2. 
Stage 2 treatment must begin within 3 months after a patient has experienced loss of 
clinical benefit or unacceptable toxicity in Stage 1 and will continue until unacceptable 
toxicity or loss of clinical benefit as determined by the investigator.  However, it is 
recommended that patients begin Stage 2 treatment as soon as possible. 
Table 5 
Stage 2 Treatment Regimens 
Study Treatment  
Appendix 
No Stage 2 treatment currently available 
 
  

 
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The Sponsor may also decide to discontinue enrollment in the Stage 2 treatment arms 
on the basis of a review of all available safety data, preliminary efficacy data, and 
supportive information (e.g., biomarker research data), as appropriate. 
3.1.4 
Assessments and Monitoring 
All patients will be closely monitored for adverse events throughout the study, and 
adverse events will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0).  Severity for 
CRS will also be graded according to the American Society for Transplantation and 
Cellular Therapy (ASTCT) CRS Consensus Grading Scale. 
Patients will undergo tumor assessments every 6 weeks ( 1 week) during the first 
48 weeks (from Day 1 of Cycle 1) and then every 12 weeks ( 2 weeks) thereafter, 
regardless of dose delays until confirmed radiographic disease progression, except in 
the case of patients who continue treatment after radiographic disease progression; 
such patients will undergo tumor assessments every 6 weeks ( 1 week) until loss of 
clinical benefit as determined by the investigator (see Section 4.5.6).  Response will be 
assessed by the investigator according to RECIST v1.1 (see Appendix 1).  If clinical 
activity is demonstrated in an experimental arm, the Sponsor may request that tumor 
assessment scans for that arm and the corresponding control arm be submitted for 
evaluation by an independent review facility. 
Baseline tumor tissue samples will be collected from all patients, preferably by means of 
a biopsy performed at study entry.  If a biopsy is not deemed feasible by the investigator, 
archival tumor tissue may be submitted, provided the tissue was obtained within 
6 months prior to enrollment and the patient has not received any systemic anti-cancer 
therapy since the time of the procedure.  If deemed clinically feasible by the investigator, 
tumor tissue will also be collected from patients who discontinue Stage 1 because of 
unacceptable toxicity or loss of clinical benefit as determined by the investigator. 
These samples will be utilized for biomarker research (see rationale for biomarker 
assessments in Section 3.3.3 and details on tissue sample collection in Section 4.5.7). 
To characterize the pharmacokinetic (PK) properties and/or immunogenicity of 
atezolizumab and other therapeutic agents, blood samples will be taken at various 
timepoints before and during study treatment administration. 
Based on a review of real-time safety data and available PK data, treatment regimens 
may be modified by the Sponsor as deemed appropriate. 
The schedule of activities for each treatment arm is presented in Appendix 7 and 
Appendix 8. 

 
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3.1.5 
Internal Monitoring Committee 
An Internal Monitoring Committee (IMC) will monitor patient safety throughout the study.  
The IMC will include representatives from Clinical Science, Clinical Safety, and 
Biostatistics.  In addition to the ongoing assessment of the incidence, nature, and 
severity of adverse events, serious adverse events, deaths, and laboratory abnormalities 
performed by the investigator and the Medical Monitor, the IMC will review all necessary 
cumulative data at regular intervals during the study.  At the time of each review, the 
IMC will make appropriate recommendations (e.g., the study should continue as 
planned, enrollment in a specific arm should be discontinued, a treatment regimen 
should be modified, the protocol should be amended, enrollment should be held pending 
further safety evaluations).  Decisions will be made in consideration of the totality of the 
available data.  Ad-hoc meetings may be called in addition to scheduled meetings, as 
necessary, to provide recommendations on management of any new safety issues.  
Specific operational details such as the committee's composition, frequency and timing 
of meetings, and members' roles and responsibilities will be detailed in an IMC Charter. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient completes the last visit 
(last patient, last visit [LPLV]), including survival follow-up visits conducted by telephone 
or in the clinic. 
In addition, the Sponsor may decide to terminate the study at any time. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 35 years. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Patient Population 
This study will enroll patients with inoperable locally advanced, metastatic, or advanced 
GC or GEJC, with adenocarcinoma confirmed as the predominant histology, who have 
not received prior systemic therapy for their advanced or metastatic disease. 
The current standard-of-care treatment for the first-line treatment of patients with 
HER2-negative GC and GEJC with cytotoxic chemotherapy is typically palliative in intent 
and results in poor prognosis, with median OS duration of 8 to 14 months across Asia, 
the United States, and Europe (Cunningham et al. 2008; Ohtsu et al. 2011; Yamada et 
al. 2015).  In patients with GC and GEJC with a PD-L1 CPS  5, nivolumab in 
combination with chemotherapy resulted in additional survival benefit compared with 
chemotherapy alone.  However, the survival benefit in the all-randomized population was 
marginal and the treatment effect in the PD-L1 CPS  5 population remained unclear 
(Moehler et al. 2020).  Moreover, cytotoxic agents given as treatment backbone are 
accompanied by high toxicity, with Grade 3 and 4 toxicities reported in up to 77% of 

 
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patients treated with platinum-doublet regimens and  80% of patients with triplet 
regimens (Van Cutsem et al. 2006; Cunningham et al. 2008; Ohtsu et al. 2011; Lordick 
et al. 2013).  Therefore, despite the recently demonstrated clinical benefit of nivolumab 
plus chemotherapy in patients with a PD-L1 CPS  5, there remains a high unmet 
medical need for treatment-naive patients with inoperable locally advanced, metastatic, 
or advanced GC and GEJC, requiring further evaluation of novel, more efficacious 
treatment combinations to improve survival and response as well as decreased toxicity 
in the first-line setting. 
Patients affected by signet ring cell dominant carcinoma ( 50% of the tumor) will be 
excluded.  This specific histotype differs significantly from the other gastric 
adenocarcinomas with regard to epidemiology (Lauren 1965; Henson et al. 2004), 
oncogenesis (Fukui 2014), and clinical presentation (Taghavi et al. 2012).  In addition, 
signet ring cell carcinoma seems to have a different chemosensitivity profile (Henson 
et al. 2004), and in particular, recent data suggest that a taxane-based therapy could be 
more effective in this histotype (Pernot et al. 2015a, 2015b).  Advanced-stage signet ring 
cell adenocarcinoma is commonly thought to be associated with poor prognosis. 
Patients with HER2-positive carcinoma will be excluded on the basis of the pivotal 
Phase III ToGA trial that established the addition of trastuzumab to cytotoxic 
chemotherapy as the standard-of care treatment in the first-line setting of HER2-positive 
GC and GEJC. 
3.3.2 
Rationale for Immunotherapy-Based Treatment beyond 
Initial Radiographic Progression 
In studies of immunotherapeutic agents, complete response, partial response, and 
stable disease have each been shown to occur after radiographic evidence of an 
apparent increase in tumor burden.  This initial increase in tumor burden caused by 
immune cell infiltration in the setting of a T-cell response has been termed 
pseudoprogression (Hales et al. 2010).  In Study PCD4989g, evidence of tumor growth 
followed by a response was observed in several tumor types.  In addition, in some 
responding patients with radiographic evidence of progression, biopsies of new lesions 
or areas of new growth in existing lesions revealed immune cells and no viable cancer 
cells.  Because of the potential for a response after pseudoprogression, this study will 
allow patients randomly allocated to immunotherapy-based treatment arms to continue 
combination treatment after apparent radiographic progression per RECIST v1.1, 
provided the benefitrisk ratio is judged by the investigator to be favorable 
(see Section 3.1.2 for the criteria).  Patients should be discontinued for unacceptable 
toxicity or loss of clinical benefit as determined by the investigator after an integrated 
assessment of radiographic and biochemical data, local biopsy results (if available), and 
clinical status (see Section 3.1.2 for details). 

 
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3.3.3 
Rationale for Biomarker Assessments 
Blood samples for biomarker assessments will be collected at baseline and during the 
study.  Changes in biomarkers in blood may provide evidence of biologic activity of the 
specific treatment combinations.  Correlations between surrogate biomarkers in blood 
(such as tumor burden markers, cytokines, chemokines, immune cell subpopulations, 
gene expression, and circulating tumor DNA) and drug dose, efficacy, or safety 
endpoints may allow for the development of a blood-based biomarker to help define 
future treatments and predict which patients are more likely to benefit from specific 
treatment combinations. 
Baseline tumor tissue samples will be obtained from all patients, preferably by means of 
a biopsy performed at study entry.  If deemed clinically feasible by the investigator, 
tumor tissue will also be collected from patients who discontinue Stage 1 because of 
unacceptable toxicity or loss of clinical benefit as determined by the investigator 
(see Section 3.1.2 for details) to enable analysis of tumor tissue biomarkers related to 
resistance, disease progression, and clinical benefit of study treatments. 
Tumor samples will be evaluated for biomarkers, such as tumor-infiltrating immune cells, 
PD-L1, CD8, Epstein-Barr virus (EBV) infection, and expression of targets specific to 
each drug combination (e.g., T-cell immunoreceptor with Ig and ITIM domains [TIGIT]).  
Evaluation of the tumor microenvironment in response to treatment within each arm, 
including changes in the number and functional status of tumor-infiltrating immune cells, 
may provide validation of the postulated mechanism of action and confirmation that an 
appropriate dose and exposure for the specific treatment combination have been 
achieved. 
Tumor tissue and blood samples may be analyzed through use of next-generation 
sequencing (NGS), including whole exome sequencing (WES), to identify somatic 
mutations that are predictive of response to study drugs, are associated with progression 
to a more severe disease state, are associated with acquired resistance to study drugs, 
are associated with susceptibility to developing adverse events, or can increase the 
knowledge and understanding of disease biology. 
Optional stool samples will be collected to assess the gut microbiota diversity at 
baseline and during the study.  The gut microbiome has been shown to be a key 
determinant in immune regulation in cancer, in part by influencing T celldriven anti-
tumor responses (Routy et al. 2018).  For example, antibiotic treatment is associated 
with poor survival outcomes to antiPD-1 therapy in non–small cell lung cancer, renal 
cell carcinoma, and urothelial carcinoma (Elkrief et al. 2019).  Conversely, the risk of 
colitis with CITs may be predictive based on a patient’s pretreatment microbiome (Dubin 
et al. 2016; Chaput et al. 2017).  Thus, heterogeneity in microbiome composition across 
patients may be a key driver of safety events in addition to efficacy.  In addition, 
dysbiosis, or altered microbial communities, has been observed in patients with GC 

 
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(Ferreira et al. 2018).  This study will examine whether a patient’s microbiome may be 
used to assess response to a CIT combination, and conversely, whether a CIT 
combination can alter the microbiome to such an extent that changes during treatment to 
the microbiome may be early predictors of adverse events, including colitis. 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
4.1.1 
Inclusion Criteria 
Patients must meet all of the criteria outlined in Sections 4.1.1.1 and 4.1.1.2 to qualify 
for Stage 1.  Patients must meet all of the criteria outlined in Sections 4.1.1.2 and 4.1.1.3 
to qualify for Stage 2. 
4.1.1.1 
Inclusion Criteria for Stage 1 
Patients must meet all of the following criteria to qualify for Stage 1: 
 
Age  18 years at the time of signing Informed Consent Form 
 
ECOG Performance Status of 0 or 1 (see Appendix 2) 
 
Inoperable locally advanced, metastatic, or advanced GC or GEJC, with 
adenocarcinoma confirmed as the predominant histology 
 
No prior systemic treatment (including systemic investigational agents or 
HER2 inhibitors) for advanced or metastatic disease 
Prior adjuvant or neoadjuvant chemotherapy, radiotherapy, or 
chemoradiotherapy for GC and GEJC are permitted as long as the last 
administration of the last dose (whichever was given last) occurred at least 
6 months prior to randomization.  Palliative radiotherapy is allowed and must be 
completed 2 weeks prior to randomization. 
Prior treatment with herbal therapies, including traditional Chinese medicines, 
with anti-cancer activity noted in the label are allowed, provided that the 
medications are discontinued prior to randomization. 
 
Life expectancy  3 months, as determined by the investigator 
 
Availability of a representative tumor specimen that is suitable for determination of 
PD-L1 and/or additional biomarker status by central testing 
Baseline tumor tissue samples will be collected from all patients, preferably by 
means of a biopsy performed at study entry.  If a biopsy is not deemed feasible 
by the investigator, archival tumor tissue may be submitted, provided that the 
tissue was obtained from a previous surgery or biopsy within 6 months prior to 
enrollment and that the patient has not received any anti-cancer therapy since 
the time of the procedure. 
A formalin-fixed, paraffin-embedded (FFPE) tumor specimen 7-18 slides 
(18 slides highly preferred) containing unstained, freshly cut serial sections must 
be submitted along with an associated pathology report.  The number of slides 

 
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4.1.2.1 
Exclusion Criteria for Stage 1 
Patients who meet any of the following criteria will be excluded from Stage 1: 
 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
including, but not limited to, anti-CTLA-4, antiPD-1, antiPD-L1, and anti-TIGIT 
therapeutic antibodies 
 
Treatment with investigational therapy within 28 days prior to initiation of study 
treatment 
 
Any contraindications to any of the study drugs of the chemotherapy regimen 
Investigators should refer to local package insert of the chemotherapy drugs. 
 
Eligible only for the control arm 
 
4.1.2.2 
Exclusion Criteria for Stage 1 and Stage 2 
Patients who meet any of the following criteria will be excluded from Stage 1 and from 
Stage 2: 
 
Patients with a signet ring cells dominant carcinoma ( 50% of the tumor) 
 
Symptomatic, untreated, or actively progressing CNS metastases 
Asymptomatic patients with treated CNS lesions are eligible, provided that all of 
the following criteria are met: 
 
Measurable disease, per RECIST v1.1, must be present outside the CNS. 
 
The patient has no history of intracranial hemorrhage or spinal cord 
hemorrhage. 
 
The patient has not undergone stereotactic radiotherapy within 7 days 
prior to initiation of study treatment, whole-brain radiotherapy within 
14 days prior to initiation of study treatment, or neurosurgical resection 
within 28 days prior to initiation of study treatment. 
 
The patient has no ongoing requirement for corticosteroids as therapy for 
CNS disease.  Anti-convulsant therapy at a stable dose is permitted. 
 
Metastases are limited to the cerebellum or the supratentorial region 
(i.e., no metastases to the midbrain, pons, medulla, or spinal cord). 
 
There is no evidence of interim progression between completion of 
CNS-directed therapy and initiation of study treatment. 
Asymptomatic patients with CNS metastases newly detected at screening are 
eligible for the study after receiving radiotherapy or surgery, with no need to 
repeat the screening brain scan. 
 
History of leptomeningeal disease 
 Uncontrolled tumor-related pain 
Patients requiring pain medication must be on a stable regimen at study entry. 

 
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Symptomatic lesions (e.g., bone metastases or metastases causing nerve 
impingement) amenable to palliative radiotherapy should be treated prior to 
enrollment.  Patients should be recovered from the side effects of radiation.  
There is no required minimum recovery period. 
Asymptomatic metastatic lesions that would likely cause functional deficits or 
intractable pain with further growth (e.g., epidural metastasis that is not 
currently associated with spinal cord compression) should be considered 
for locoregional therapy if appropriate prior to enrollment. 
 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently) 
Patients with indwelling catheters (e.g., PleurX) are allowed. 
 
Uncontrolled or symptomatic hypercalcemia (ionized calcium  1.5 mmol/L, 
calcium  12 mg/dL, or corrected calcium greater than ULN) 
 
Active or history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid 
antibody syndrome, granulomatosis with polyangiitis, Sjögren syndrome, 
Guillain-Barré syndrome, or multiple sclerosis (see Appendix 3 for a more 
comprehensive list of autoimmune diseases and immune deficiencies), with the 
following exceptions: 
Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen 
are eligible for the study. 
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met: 
 
Rash must cover  10% of body surface area. 
 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids. 
 
No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic 
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids 
within the previous 12 months. 
 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of 
active pneumonitis on the screening chest computed tomography (CT) scan 
 
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
Active tuberculosis 

 
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 
Significant cardiovascular disease (such as New York Heart Association Class II 
or greater cardiac disease, myocardial infarction, or cerebrovascular accident) 
within 3 months prior to initiation of study treatment, unstable arrhythmia, or 
unstable angina 
 
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation 
of study treatment, or anticipation of need for a major surgical procedure during 
the study 
 
History of malignancy other than GC or GEJC within 2 years prior to initiation of 
study treatment, with the exception of malignancies with a negligible risk of 
metastasis or death (e.g., 5-year OS rate  90%), such as adequately treated 
carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate 
cancer, ductal carcinoma in situ, or Stage I uterine cancer 
 
Severe infection within 4 weeks prior to initiation of study treatment, including, but 
not limited to, hospitalization for complications of infection, bacteremia, or severe 
pneumonia, or any active infection that, in the opinion of the investigator, could 
impact patient safety 
 
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of 
study treatment 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease exacerbation) are eligible for 
the study. 
 
Prior allogeneic stem cell or solid organ transplantation 
 
Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding that contraindicates the use of an investigational drug, may affect 
the interpretation of the results, or may render the patient at high risk from treatment 
complications 
 
Pregnancy or breastfeeding, or intending to become pregnant during the study 
Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment. 
 
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab or 
tiragolumab treatment, within 5 months after the final dose of atezolizumab, or 
90 days after the final dose of tiragolumab, whichever is later 
 
History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
 
Known hypersensitivity to Chinese hamster ovary cell products or recombinant 
human antibodies 
 
Known allergy or hypersensitivity to any of the study drugs or any of their excipients 

 
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 
Treatment with systemic immunostimulatory agents (including, but not limited to, 
IFN and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) 
prior to initiation of study treatment 
 
Treatment with systemic immunosuppressive medication (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-tumor necrosis factor [TNF] agents) within 2 weeks prior to initiation of study 
treatment or anticipation of need for systemic immunosuppressive medication during 
study treatment, with the following exceptions: 
Patients who received acute, low-dose systemic immunosuppressant 
medication or a one-time pulse dose of systemic immunosuppressant 
medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible 
for the study. 
Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible 
for the study. 
 
For patients entering Stage 2:  immunotherapy-related adverse events that have not 
resolved to Grade 1 or better or to baseline at the time of consent with the following 
exception: 
Patients with ongoing endocrine events that are adequately managed with 
supplemental therapy are eligible. 
 
4.1.2.3 
Exclusion Criteria for Tiragolumab-Containing Arm 
Patients who meet any of the following criteria will be excluded from the 
tiragolumab-containing arm during Stage 1: 
 
Prior treatment with an anti-TIGIT agent 
 
Active EBV infection or known or suspected chronic active EBV infection at 
screening 
Patients with a positive EBV viral capsid antigen (VCA) IgM test at screening are 
excluded from this arm.  An EBV PCR test should be performed as clinically 
indicated to screen for active infection or suspected chronic active infection.  
Patients with a positive EBV PCR test are excluded from this arm. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
This is a randomized, open-label study.  After initial written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient’s 
identification number and Stage 1 treatment assignment from the interactive voice or 
web-based response system (IxRS).  Patients who enroll in Stage 2 will be assigned to 
treatment through use of the IxRS and will retain the same patient identification number 
that is assigned in Stage 1. 

 
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For Stage 1, this study will employ a permuted-block randomization method with 
dynamically changing randomization ratios to account for fluctuation in the number of 
treatment arms that are open for enrollment during the study.  The randomization ratio 
will depend on the number of experimental arms that are open for enrollment (e.g., if an 
arm is added or enrollment in an arm is suspended pending analysis of results from the 
preliminary phase), with the stipulation that the likelihood of being allocated to the 
control arm will be no more than 50%.  The randomization ratios may be altered to 
increase enrollment in a particular experimental arm that has demonstrated promising 
clinical activity. 
Randomization will take into account general exclusion criteria and arm-specific 
exclusion criteria as outlined in Section 4.1.2.  If a patient is eligible only for the control 
arm, the patient will not be enrolled in the study. 
Patients who do not receive at least one dose of each drug for their assigned treatment 
regimen will not be included in the efficacy analyses.  Additional patients may be 
enrolled in Stage 1 to reach the target number of treated patients planned for analysis. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
Details on the therapeutic agents for each treatment arm are provided in the respective 
appendix for that treatment arm, as outlined in Table 4 for Stage 1 and Table 5 for 
Stage 2. 
4.3.1 
Investigational Medicinal Product Handling and Accountability 
The IMPs for this study are atezolizumab and tiragolumab.  All IMPs required for 
completion of this study will be provided by the Sponsor where required by local 
practices.  The study site (i.e., investigator or other authorized personnel 
[e.g., pharmacist]) is responsible for maintaining records of IMP delivery to the site, IMP 
inventory at the site, IMP use by each patient, and disposition or return of unused IMP, 
thus enabling reconciliation of all IMP received, and for ensuring that patients are 
provided with doses specified by the protocol. 
The study site should follow all instructions included with each shipment of IMP.  The 
study site will acknowledge receipt of IMPs supplied by the Sponsor using the IxRS to 
confirm the shipment condition and content.  Any damaged shipments will be replaced.  
The investigator or designee must confirm that appropriate temperature conditions have 
been maintained during transit for all IMPs received and that any discrepancies have 
been reported and resolved before use of the IMPs.  All IMPs must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions, with access limited to the investigator 
and authorized staff. 

 
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Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
All IMPs either will be disposed of at the study site according to the study site’s 
institutional standard operating procedure or will be returned to the Sponsor (if supplied 
by the Sponsor) with the appropriate documentation.  The site’s method of destroying 
Sponsor-supplied IMPs must be agreed to by the Sponsor.  The site must obtain written 
authorization from the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP 
destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on a drug accountability log. 
Refer to the pharmacy manual and/or the applicable Investigator's Brochure for 
information on IMP handling, including preparation and storage, and accountability. 
4.3.2 
Post-Trial Access to Study Treatment 
Currently, the Sponsor does not have any plans to provide study treatments or 
interventions to patients who have completed the study.  The Sponsor may evaluate 
whether to continue providing study treatments in accordance with the Roche Global 
Policy on Continued Access to Investigational Medicinal Product, available at the 
following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
4.4 
CONCOMITANT THERAPY AND PROHIBITED FOOD 
Details on concomitant therapy, prohibited food, and additional restrictions for each 
treatment arm are provided in the respective appendix for that treatment arm, as outlined 
in Table 4 for Stage 1 and Table 5 for Stage 2. 
4.5 
STUDY ASSESSMENTS 
A schedule of activities to be performed during the study is provided for each treatment 
arm (see Appendix 7 and Appendix 8).  All activities must be performed and documented 
for each patient.  Patients will be closely monitored for safety and tolerability throughout 
the study.  Patients should be assessed for toxicity prior to each dose; dosing will occur 
only if the clinical assessment and local laboratory test values are acceptable. 
4.5.1 
Informed Consent Forms and Screening 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. 

 
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Written informed consent must also be obtained before performing screening 
evaluations for Stage 2. 
Screening evaluations for Stage 1 and Stage 2 are to be performed within 28 days prior 
to initiation of study treatment (Day 1).  All screening evaluations must be completed 
and reviewed to confirm that patients meet all eligibility criteria before enrollment 
(see  Appendix 6 for the schedule of activities for Stage 1 screening). 
Patients who fail their first screening for study eligibility (Stage 1 or Stage 2) may qualify 
for two re-screening opportunities (for a total of three screening opportunities per patient) 
at the investigator’s discretion.  Patients must re-sign the consent form prior to 
re-screening.  Results of standard-of-care tests or examinations performed prior to 
obtaining informed consent and within a specified time prior to Day 1 (see the schedule 
of activities for each arm in Appendix 7 and Appendix 8) may be used; such tests do not 
need to be repeated for screening or re-screening. 
4.5.2 
Medical History, Molecular Profile, Concomitant Medication, 
and Demographic Data  
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking 
history, and use of alcohol and drugs of abuse, will be recorded at baseline.  A patient's 
molecular profile for GC and GEJC, if available, will be recorded at screening and 
whenever updated information becomes available during the study.  In addition, all 
medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within a specified 
time prior to initiation of study treatment will be recorded (as outlined for each arm in 
Appendix 7 and Appendix 8).  At the time of each follow-up physical examination, an 
interval medical history should be obtained and any changes in medications and 
allergies should be recorded.  Demographic data will include age, sex, and self-reported 
race/ethnicity. 
4.5.3 
Physical Examinations 
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions electronic Case 
Report Form (eCRF). 
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF. 

 
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During visits when a patient will undergo a tumor assessment, the physical examination 
should include an evaluation of the presence and degree of enlarged lymph nodes, 
hepatomegaly, and splenomegaly. 
Weight will be recorded at specified timepoints during the study. 
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, pulse oximetry, and 
temperature. 
Vital signs should be measured at other specified timepoints as outlined for each arm in 
the schedule of activities in Appendix 7 and Appendix 8. 
4.5.5 
Electrocardiograms 
An ECG is required at screening and as outlined in the schedule of activities.  ECGs for 
each patient should be obtained from the same machine wherever possible.  Lead 
placement should be as consistent as possible.  It is recommended that patients be 
resting in a supine position for at least 10 minutes prior to ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Any morphologic waveform changes or other ECG abnormalities 
must be documented on the eCRF. 
4.5.6 
Tumor and Response Evaluations 
Patients will undergo tumor assessments every 6 weeks ( 1 week) during the first 
48 weeks (from Day 1 of Cycle 1) and then every 12 weeks ( 2 weeks) thereafter, 
regardless of dose delays until confirmed radiographic disease progression, except in 
the case of patients who continue treatment after radiographic disease progression; 
such patients will undergo tumor assessments every 6 weeks ( 1 week) until loss of 
clinical benefit as determined by the investigator (see Section 3.1.2 for details).  Thus, 
tumor assessments are to continue according to schedule in patients who discontinue 
treatment for reasons other than loss of clinical benefit, even if they start a new 
nonprotocol-specified anti-cancer therapy.  At the investigator’s discretion, tumor 
assessments may be repeated at any time if progressive disease is suspected. 
Baseline tumor assessments for Stage 2 must be performed within 28 days prior to 
initiation of Stage 2 treatment (i.e., Day 1 of Cycle 1).  Tumor assessments performed 
prior to or at the time of unacceptable toxicity or loss of clinical benefit during Stage 1 
may serve as baseline assessments for Stage 2, provided the tumor assessments are 
performed within 28 days prior to initiation of Stage 2 treatment. 

 
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All measurable and/or evaluable lesions should be assessed and documented at 
screening (in both Stage 1 and Stage 2).  Brain metastases treated with radiotherapy or 
surgery will not be considered measurable or evaluable but will be documented at 
screening as a site of metastatic disease.  Tumor assessments performed as standard 
of care prior to obtaining informed consent and within 28 days prior to initiation of study 
treatment do not have to be repeated at screening. 
Screening assessments must include CT scans (with IV contrast; with or without oral 
contrast) or magnetic resonance imaging (MRI) scans (with IV contrast) of the chest, 
abdomen, and pelvis.  A spiral CT scan of the chest may be obtained but is not a 
requirement.  If a CT scan with contrast is contraindicated (i.e., in patients with contrast 
allergy or impaired renal clearance), a non-contrast CT scan of the chest may be 
performed and MRI scans (with IV contrast, if feasible) of the abdomen and pelvis 
should be performed.  Bone scans, CT or MRI scans of the neck, and CT or MRI scans 
of the brain should also be performed if clinically indicated.  At the investigator’s 
discretion, other methods of assessment of measurable disease as per RECIST v1.1 
may be used. 
If a CT scan for tumor assessment is performed in a positron emission tomography/CT 
scanner, the CT acquisition must be consistent with the standards for a full-contrast 
diagnostic CT scan. 
All measurable and/or evaluable lesions identified at baseline should be re-assessed at 
subsequent tumor evaluations according to the schedule described above.  Brain 
metastases identified at baseline that have been treated with radiotherapy or surgery will 
not be considered measurable or evaluable unless there is suspected disease 
progression in the brain (i.e., the patient becomes symptomatic).  Thus, subsequent 
head scans are not required unless clinically indicated.  The same radiographic 
procedures used to assess disease sites at screening should be used for subsequent 
tumor assessments (e.g., the same contrast protocol for CT scans).  Tumor 
assessments must be continued after disease progression per RECIST v1.1 for patients 
who receive treatment beyond progression.  This includes continued measurement of 
target lesions, evaluation of non-target lesions (including monitoring for further 
worsening of any non-target lesions that have shown unequivocal progression), and 
evaluation of any newly identified lesions (including measurements, if lesions are 
measurable) at all subsequent assessments. 
Overall response at a single timepoint will be assessed by the investigator using 
RECIST v1.1 (see Appendix 1).  Assessments should be performed by the same 
evaluator, if possible, to ensure internal consistency across visits.  Results must be 
reviewed by the investigator prior to treatment administration. 

 
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and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis). 
 
Urinalysis includes pH, specific gravity, glucose, protein (or albumin), ketones, and 
blood; dipstick permitted 
 
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis: 
 
Serum samples for PK analysis through use of validated assays (see Appendix 7 
and Appendix 8) 
 
Serum samples for immunogenicity analysis through use of validated assays 
(see Appendix 7 and Appendix 8) 
 
Blood, serum, plasma, and WBC samples for biomarker analysis and biomarker 
assay development (see Appendix 7 and Appendix 8) 
Plasma and WBC will be isolated from blood at central laboratory. 
 
Archival or newly collected tumor tissue sample collected at baseline for 
determination of PD-L1 and TIGIT expression, tumor-infiltrating lymphocytes, 
microsatellite instability (MSI) status, EBV infection, gene expression profiling, and 
other biomarkers 
Baseline tumor tissue samples from the primary lesion or a metastatic lesion 
will be collected from all patients, preferably by means of a biopsy performed at 
study entry.  If a biopsy is not deemed feasible by the investigator, archival 
tumor tissue may be submitted, provided that the patient has not received any 
systemic anti-cancer therapy and that the tissue was obtained from a previous 
surgery or biopsy performed within 6 months prior to enrollment. 
A representative FFPE tumor specimen 7-18 slides (18 slides highly preferred) 
containing unstained, freshly cut, serial sections must be submitted along with 
an associated pathology report. 
Tumor tissue should be of good quality based on total and viable tumor content.  
Samples must contain a minimum of 50 viable tumor cells that preserve cellular 
context and tissue architecture regardless of needle gauge or retrieval method.  
Samples collected via resection, core-needle biopsy (1618 gauge preferred, at 
least three cores and embedded in a single paraffin block), or excisional, 
incisional, punch, or forceps biopsy are acceptable.  Fine-needle aspiration 
(defined as samples that do not preserve tissue architecture and yield cell 
suspension and/or smears), brushing, cell pellets from pleural effusion, and 
lavage samples are not acceptable.  Tumor tissue from bone metastases that 
have been decalcified is not acceptable. 
 
Tumor tissue sample collected during Stage 1 at the time of unacceptable toxicity or 
loss of clinical benefit as determined by the investigator (see Section 3.1.2 for 
details), if deemed clinically feasible by the investigator, for biomarkers analysis 

 
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Biopsies should be performed within 40 days after determination of 
unacceptable toxicity, disease progression, or loss of clinical benefit, or prior to 
the next anti-cancer therapy, whichever is sooner.  Samples collected by 
means of resection, core-needle biopsy (at least three cores preferred), or 
excisional, incisional, punch, or forceps biopsy are preferred. 
 
Biomarker research may include, but will not be limited to, analysis of genes or gene 
signatures associated with tumor molecular subtype and tumor immunobiology, PD-L1, 
expression of targets specific to each drug combination (e.g., TIGIT), EBV, tumor 
mutation load, MSI status, lymphocyte subpopulations, T cellreceptor repertoire, or 
cytokines.  Research may involve DNA or RNA extraction, analysis of somatic 
mutations, and use of NGS (including WES).  Biomarker sample collections and 
research are applicable only after approval from the local regulatory authorities.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Biological samples will be destroyed no later than the time of completion of the final 
Clinical Study Report, with the following exceptions: 
 
Serum samples collected for PK or immunogenicity analysis may be needed for 
additional immunogenicity characterization and for PK or immunogenicity assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed. 
 
Plasma, serum, blood, tumor tissue, and stool samples collected for biomarker 
research will be destroyed no later than 5 years after the final Clinical Study Report 
has been completed. 
 
For patients who are not enrolled, remaining archival tissue specimens will be 
returned to the site no later than 6 months after eligibility determination. 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4. 
The aggregate results of any conducted research will be available in accordance with 
the effective Sponsor policy on study data publication. 

 
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4.5.8 
Optional Tumor Biopsies 
Patients will be given the option of consenting to additional tumor biopsies.  Patients 
who consent to optional biopsies will undergo tumor biopsy sample collection 
8 weeks ( 7 days) after treatment initiation, if deemed clinically feasible by the 
investigator.  In addition, patients who consent to optional biopsies may undergo 
additional biopsies during treatment at any other time at the investigator’s discretion. 
Samples collected by means of resection, core-needle biopsy (at least three cores 
preferred), or excisional, incisional, punch, or forceps biopsy are preferred.  
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
The Informed Consent Form will contain a separate section that addresses optional 
biopsies.  A separate, specific signature will be required to document a patient's 
agreement to undergo optional biopsies. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the Optional Biopsy 
Sample Informed Consent eCRF. 
Samples may be used for biomarker analysis as described in Section 4.5.7.  
See Section 4.5.7 for details on sample storage, use of samples after patient withdrawal, 
confidentiality standards for data, and availability of data from biomarker analyses. 
4.5.9 
Optional Stool Samples  
Patients will be given the option of consenting to provide stool samples.  Patients who 
consent to providing optional stool samples will receive the collection device prior to 
baseline and the Day 1, Cycle 3 visit.  For sampling procedures, storage conditions,  
and shipment instructions, see the laboratory manual.  The Informed Consent Form 
will contain a separate section that addresses optional stool samples.  A separate, 
specific signature will be required to document a patient's agreement to provide 
optional stool samples.  
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the Optional Stool 
Sample Informed Consent eCRF.  Samples may be used for biomarker research as 
described in Section 4.5.7.  Refer to Section 4.5.7 for details on sample storage, use of 
samples after patient withdrawal, confidentiality standards for data, and availability of 
data from biomarker analyses. 

 
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4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of 
the following: 
 
Intolerable toxicity related to study treatment, including development of an 
immune-mediated adverse event determined by the investigator to be unacceptable 
given the individual patient’s potential response to therapy and severity of the event 
 
Any medical condition that may jeopardize the patient’s safety if he or she continues 
study treatment 
 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Use of another nonprotocol-specified anti-cancer therapy 
 
Pregnancy 
 
Loss of clinical benefit as determined by the investigator after an integrated 
assessment of radiographic and biochemical data, local biopsy results (if available), 
and clinical status (e.g., symptomatic deterioration such as pain secondary to 
disease) (see Section 3.1.2 for details) 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. 
Patients will return to the clinic for a treatment discontinuation visit  30 days after the 
final dose of study treatment.  The visit at which response assessment shows 
progressive disease or loss of clinical benefit may be used as the treatment 
discontinuation visit.  Patients who discontinue study treatment for any reason other than 
progressive disease or loss of clinical benefit will continue to undergo tumor response 
assessments as outlined in the schedule of activities provided for each arm in 
Appendix 7 and Appendix 8. 
After treatment discontinuation, information on survival follow-up and initiation of a new 
anti-cancer therapy will be collected by means of telephone calls, patient medical 
records, and/or clinic visits approximately every 3 months ( 2 weeks) or more frequently 
until death (unless the patient withdraws consent or the Sponsor terminates the study).  
If a patient requests to be withdrawn from follow-up, this request must be documented in 
the source documents and signed by the investigator.  If the patient withdraws from the 
study, the study staff may use a public information source (e.g., county records) to 
obtain information about survival status only.  For an experimental arm, in which all 
patients discontinued treatment and passed the safety follow-up window, as well as 
approximately 80% of patients discontinued the study, the Sponsor may conclude the 
arm (the remaining approximately 20% of patients will be discontinued from the study). 

 
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4.6.2 
Patient Discontinuation from Study 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
 
Patient withdrawal of consent 
 
Study termination or site closure 
 
Adverse event 
 
Loss to follow-up 
 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients who withdraw from the study will not be replaced. 
If a patient withdraws from the study, the study staff may use a public information source 
(e.g., county records) to obtain information about survival status. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 

 
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5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
A safety plan for each treatment arm, including a summary of risks and management 
guidelines for patients who experience specific adverse events, is provided in the 
respective appendix for that treatment arm, as outlined in Appendix 5, Appendix 7 and 
Appendix 8. 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.  Guidelines for managing patients who experience anticipated 
adverse events, including criteria for dosage modification and treatment interruption or 
discontinuation, are provided in Appendix 5 through Appendix 8.  See Sections 5.25.6 
for details on safety reporting (e.g., adverse events, pregnancies) for this study. 
Patients with active infection will be excluded from study participation.  In the setting of a 
pandemic or epidemic, screening for active infections (including SARS-CoV-2) prior to 
and during study participation should be considered according to local or institutional 
guidelines or guidelines of applicable professional societies (e.g., American Society of 
Clinical Oncology or European Society for Medical Oncology). 
Severe COVID-19 appears to be associated with a CRS involving the inflammatory 
cytokines IL-6, IL-10, IL-2, and IFN- (Merad and Martin 2020).  If a patient develops 
suspected CRS during the study, a differential diagnosis should include COVID-19, 
which should be confirmed or refuted through assessment of exposure history, 
appropriate laboratory testing, and clinical or radiologic evaluations per investigator 
judgment.  If a diagnosis of COVID-19 is confirmed, the disease should be managed as 
per local or institutional guidelines. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 

 
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pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 
and Section 5.3.5.10 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study treatment 
 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to 
the Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
 
Is a congenital anomaly or birth defect in a neonate or infant born to a mother 
exposed to study treatment 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 

 
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Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for each 
treatment arm are listed in the respective appendix for that treatment arm, as outlined in 
Appendix 7 and Appendix 8. 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6). 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study treatment, all adverse events will be reported until 30 days after 
the final dose of study treatment or until initiation of new systemic anti-cancer therapy, 
whichever occurs first, and serious adverse events and adverse events of special 
interest will continue to be reported until 
 days after the final dose of study treatment 
or until initiation of new systemic anti-cancer therapy, whichever occurs first. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 

 
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5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?" 
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 7 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 7 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
  
The ASTCT CRS Consensus Grading Scale (see Table 8) should be used in addition to 
NCI CTCAE when reporting severity of CRS (see Section 5.3.5.1 for details on CRS 
reporting). 

 
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Table 8 
ASTCT CRS Consensus Grading Scale 
Grade 
Symptom(s) 
1 
 Fever a, with or without constitutional symptoms 
 No hypotension 
 No hypoxia 
2 
 Fever a combined with at least one of the following: 
 Hypotension not requiring vasopressors 
 Hypoxia requiring low-flow oxygen b by nasal cannula or 
blow-by 
3 
 Fever a combined with at least one of the following: 
 Hypotension requiring one vasopressor, with or without 
vasopressin 
 Hypoxia requiring high-flow oxygen b by nasal cannula, face 
mask, non-rebreather mask, or Venturi mask 
4 
 Fever a combined with at least one of the following: 
 Hypotension requiring multiple vasopressors (excluding 
vasopressin) 
 Hypoxia requiring oxygen by positive pressure (e.g., CPAP, 
BiPAP, intubation, and mechanical ventilation) 
5 
 Death due to CRS for which the cause is not the principal factor 
leading to this outcome 
ASTCT  American Society for Transplantation and Cellular Therapy; BiPAP  bi-level 
positive airway pressure; CPAP  continuous positive airway pressure; CRS  cytokine 
release syndrome. 
a Fever is defined as temperature  38C not attributable to any other cause.  In patients 
who develop CRS and then receive antipyretic, anti-cytokine, or corticosteroid 
therapy, fever is no longer required when determining CRS severity (grade).  In this 
case, the CRS grade is driven by the presence of hypotension and/or hypoxia. 
b Low flow is defined as oxygen delivered at   6 mL/min, and high flow is defined as 
 6 L/min. 
  
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether 
an adverse event is considered to be related to study treatment, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration 
(see also Table 9): 
 
Temporal relationship of event onset to the initiation of study treatment 
 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study treatment, or reintroduction of study treatment 
(as applicable) 
 
Known association of the event with study treatment or with similar treatments 
 
Known association of the event with the disease under study 

 
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 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
 
Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 9 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by study treatment on the basis of facts, 
evidence, science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of study treatment, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to study treatment; and/or the 
adverse event abates or resolves upon discontinuation of study treatment or dose 
reduction and, if applicable, reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified below.   
Evidence exists that the adverse event has an etiology other than study treatment 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of study treatment (e.g., cancer diagnosed 2 days after 
first dose of study treatment). 
  
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse 
Event eCRF. 
5.3.5.1 
Infusion-Related Reactions and Cytokine Release Syndrome 
There may be significant overlap in signs and symptoms of infusion-related reactions 
(IRRs) and CRS.  While IRRs occur during or within 24 hours after treatment 
administration, time to onset of CRS may vary.  Differential diagnosis should be applied, 
particularly for late-onset CRS (occurring more than 24 hours after treatment 
administration), to rule out other etiologies such as delayed hypersensitivity reactions, 
sepsis or infections, hemophagocytic lymphohistiocytosis, tumor lysis syndrome, early 
disease progression, or other manifestations of systemic inflammation. 
Adverse events that occur during or within 24 hours after study treatment 
administration and are judged to be related to study treatment infusion should be 
captured on the Adverse Event eCRF as a diagnosis (e.g., "infusion-related reaction" 
or "cytokine release syndrome").  Avoid ambiguous terms such as "systemic reaction."  

 
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Cases of late-onset CRS should be reported as "cytokine release syndrome" on the 
Adverse Event eCRF.  Associated signs and symptoms should be recorded on the 
dedicated Infusion-Related Reaction eCRF or Cytokine Release Syndrome eCRF, as 
appropriate. 
If a patient experiences both a local and systemic reaction to a single administration of 
study treatment, each reaction should be recorded separately on the Adverse Event 
eCRF, with associated signs and symptoms also recorded separately on the dedicated 
Infusion-Related Reaction eCRF or Cytokine Release Syndrome eCRF. 
In recognition of the challenges in clinically distinguishing between IRRs and CRS, 
consolidated guidelines for medical management of IRRs and CRS are provided in 
Appendix 5. 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 

 
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All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator’s judgment  
Note:  For oncology trials, certain abnormal values may not qualify as 
adverse events. 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5  ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 

 
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(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3 x ULN for patients with normal baseline liver 
function test or  3  baseline value for patients with abnormal baseline liver function 
tests) in combination with either an elevated total bilirubin ( 2  ULN) or clinical jaundice 
in the absence of cholestasis or other causes of hyperbilirubinemia is considered to be 
an indicator of severe liver injury (as defined by Hy's Law).  Therefore, investigators 
must report as an adverse event the occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  ULN or baseline value in combination with 
total bilirubin  2  ULN (of which  35% is direct bilirubin) 
 
Treatment-emergent ALT or AST  3  ULN or baseline value in combination with 
clinical jaundice 
 

 
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The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2). 
5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of GC or GEJC should be recorded on the 
Death Attributed to Progressive Disease eCRF.  All other deaths that occur during the 
adverse event reporting period, regardless of relationship to study treatment, must be 
recorded on the Adverse Event eCRF and immediately reported to the Sponsor 
(see Section 5.4.2). 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of Gastric Cancer or 
Gastroesophageal Junction Carcinoma 
Medical occurrences or symptoms of deterioration that are anticipated as part of gastric 
cancer or gastroesophageal carcinoma should not be recorded as adverse events.  
However, deterioration that is judged by the investigator to have unexpectedly worsened 

 
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in severity or frequency or changed in nature at any time during the study should be 
recorded as an adverse event.  When recording an unanticipated worsening of gastric 
cancer or gastroesophageal carcinoma on the Adverse Event eCRF, it is important to 
convey the concept that the condition has changed by including applicable descriptors 
(e.g., "accelerated worsening of gastric carcinoma or gastroesophageal carcinoma"). 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as 
outlined below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for respite care 
 
Planned hospitalization required by the protocol (e.g., for study treatment 
administration or performance of an efficacy measurement for the study) 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease. 
The patient has not experienced an adverse event. 
 
Hospitalization due solely to progression of the underlying cancer 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event but should be reported as an adverse 
event instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.3.5.12 
Cases of Accidental Overdose or Medication Error, Drug 
Abuse, or Drug Misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Intentional overdose: intentional administration of a drug in a quantity that is higher 
than the assigned dose 

 
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 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Drug abuse: intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm 
 
Drug misuse: intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the patient. 
 
Special situations are not in themselves adverse events but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).  For atezolizumab and tiragolumab, adverse 
events associated with special situations should be recorded as described below for 
each situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
Drug abuse that does not qualify as an overdose: Enter the adverse event term.  
Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes. 
 

 
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In addition, all special situations associated with atezolizumab and tiragolumab, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
 
Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" box. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 

 
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place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see arm-specific appendices for details on pregnancy reporting 
requirements for each treatment arm) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board or Ethics Committee 
(IRB/EC). 
5.4.1 
Medical Monitors and Emergency Medical Contacts 
To ensure the safety of study patients, access to the Medical Monitors is available 
24 hours per day, 7 days per week.  Details will be provided separately. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Treatment Initiation 
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Adverse Event/Special Situations Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Treatment Initiation 
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported until 
 days after the final dose of study treatment or until 

 
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initiation of new systemic anti-cancer therapy, whichever occurs first.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Adverse 
Event/Special Situations Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system. 
Instructions for reporting serious adverse events that occur after the reporting period are 
provided in Section 5.6. 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study treatment or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome, 
with follow-up information on the infant collected according to procedures outlined in 
Appendix 7 and Appendix 8. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After the end of the reporting period for serious adverse events and adverse events of 
special interest (defined as 
 days after the final dose of study treatment or until 

 
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initiation of new systemic anti-cancer therapy, whichever occurs first), all deaths, 
regardless of cause, should be reported through use of the Long-Term Survival 
Follow-Up eCRF. 
In addition, if the investigator becomes aware of a serious adverse event that is believed 
to be related to prior exposure to study treatment, the event should be reported through 
use of the Adverse Event eCRF.  However, if the EDC system is not available, the 
investigator should report these events directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations Form using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
The Sponsor has a legal responsibility to notify regulatory authorities about the safety 
of a study treatment under clinical investigation.  The Sponsor will comply with 
regulatory requirements for expedited safety reporting to regulatory authorities (which 
includes the use of applicable systems, such as EudraVigilance), IRBs, ECs, and 
investigators. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 
Drug 
Document 
Atezolizumab 
Atezolizumab Investigator's Brochure  
Tiragolumab 
Tiragolumab Investigator's Brochure  
  
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
Certain adverse events are anticipated to occur in the study population at some 
frequency independent of study drug exposure and will be excluded from expedited 
reporting.  Adverse events of special interest for each treatment arm are listed in the 
respective appendix for that treatment arm, as outlined in Appendix 7 and Appendix 8. 

 
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6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The final study analysis will be based on patient data collected through study 
discontinuation.  If not otherwise specified, efficacy analyses will be based on the 
efficacy-evaluable population, defined as all patients who receive at least one dose of 
each drug for their assigned treatment regimen, and safety analyses will be based on 
the safety-evaluable population, defined as all patients who receive any amount of 
study treatment. 
The analysis results will be summarized by the treatment regimen that patients actually 
receive, as well as by stage (Stage 1 or Stage 2).  Data will be described and 
summarized as warranted by sample size.  Continuous variables will be summarized 
through use of means, standard deviations, medians, and ranges.  Categorical variables 
will be summarized through use of counts and percentages.  Listings will be used in lieu 
of tables in the event of small sample sizes. 
New baseline values will be established for the Stage 2 efficacy and safety analyses.  
For evaluation of tumor response, new baseline tumor assessments will be established 
as described in Section 4.5.6.  For other endpoints (e.g., change from baseline in vital 
signs or laboratory test results), the last non-missing value prior to a patient's first dose 
during Stage 2 will serve as the new baseline. 
6.1 
DETERMINATION OF SAMPLE SIZE 
This study is not designed to make explicit power and type I error considerations for a 
hypothesis test.  Instead, this study is designed to obtain preliminary efficacy, safety, 
and PK data on immunotherapy-based treatment combinations when administered to 
patients with GC or GEJC.  Cohort 1 will enroll patients with inoperable locally advanced, 
metastatic, or advanced GC or GEJC with adenocarcinoma confirmed as the 
predominant histology who have not received prior systemic therapy for advanced or 
metastatic disease. 
Approximately 40-90 patients will be randomly allocated to the control and experimental 
arms during the study. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment will be summarized by region, country, and investigator by treatment arm in 
the two stages.  Patient disposition will be summarized by treatment arm in each stage.  
Major protocol deviations, including major deviations with regard to the inclusion and 
exclusion criteria, will be summarized by treatment arm in each stage. 
For safety-evaluable patients, study drug administration data will be tabulated or listed 
by treatment arm in each stage, and any dose modifications will be flagged.  Means and 

 
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standard deviations will be used to summarize the total dose and dose intensity for each 
study drug.  The reasons for discontinuation of study treatment will also be tabulated. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, race/ethnicity, weight, 
malignancy duration, metastatic disease site, and baseline ECOG Performance Status) 
will be summarized overall and by treatment arm in each stage. 
6.4 
EFFICACY ANALYSES 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is objective response rate (ORR) (defined as the 
proportion of patients with an objective response [a complete or a partial response]) 
during Stage 1 based on RECIST v1.1, as defined in Section 2 (see Table 2).  Patients 
with missing or no response assessments will be classified as non-responders. 
ORR, the proportion of patients with a complete or partial response, will be calculated for 
each arm, along with 95% CIs (
).  The difference in ORR 
between the experimental arms and the control arm will also be calculated, along with 
95% CIs using the 
 with continuity correction. 
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are PFS, OS, OS at specific timepoints (e.g., 6 and 
12 months), duration of response (DOR), and disease control during Stage 1, as defined 
in Section 2 (see Table 2).  PFS, DOR, and disease control will be determined by the 
investigator according to RECIST v1.1. 
DOR will be derived for efficacy-evaluable patients with a complete response or a 
partial response. 
For patients who do not have documented disease progression or die, PFS and DOR 
will be censored at the day of the last tumor assessment. 
Patients who are still alive at the time of OS analysis will be censored at the last date 
they were known to be alive. 
The 
 method will be used to estimate the median for PFS, OS, and DOR, 
with 95% CIs constructed through use of the 
 method.  The OS 
rate at specific timepoints will also be estimated using the 
 method, with 
95% CIs calculated based on 
 for variance. 

 
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Disease control rate (the proportion of patients with stable disease for  12 weeks, a 
partial response, or a complete response) will be calculated for each treatment arm, with 
95% CIs estimated using the 
. 
6.5 
SAFETY ANALYSES 
Safety will be assessed through summaries of adverse events, changes in laboratory 
test results, changes in vital signs and ECGs, and exposure to study drugs.  Exposure to 
combination treatment and length of safety follow-up will be summarized by treatment 
arm within each stage. 
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities thesaurus terms, and adverse event severity will be graded according to 
NCI CTCAE v5.0, and severity of CRS will also be graded by the investigator according 
to the ASTCT Consensus Grading (Lee et al. 2019).  All adverse events, serious 
adverse events, adverse events leading to death, adverse events of special interest, and 
adverse events leading to study treatment discontinuation that occur on or after the first 
dose of study treatment (i.e., treatment-emergent adverse events) will be summarized by 
mapped term, appropriate thesaurus level, and severity grade.  For events of varying 
severity, the highest grade will be used in the summaries.  Deaths and causes of death 
will be summarized.  
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, pulse 
oximetry, and temperature), and ECG data will be displayed by time, with grades 
identified where appropriate.  Additionally, a shift table of selected laboratory tests will be 
used to summarize the baseline and maximum postbaseline severity grade.  Changes in 
vital signs and ECGs will be summarized. 
6.6 
PHARMACOKINETIC ANALYSES 
Sparse samples will be collected for potential PK analyses of atezolizumab (patients 
who receive at least one dose of atezolizumab) and specified drugs given in combination 
with atezolizumab (patients who receive at least one dose of the drug).  Serum or 
plasma concentrations of the various study drugs may be reported as individual values 
and summarized (mean, standard deviation, coefficient of variation, median, range, 
geometric mean, and geometric mean coefficient of variation) by treatment arm, and by 
cycle and day when appropriate and as data allow.  Individual and median serum or 
plasma concentrations of the various study drugs may be plotted by treatment arm, 
cycle, and day when appropriate and as data allow.  PK data for combination drugs may 
be compared with available historical data from internal and published previous studies.  
Atezolizumab or other study drug concentration data may be pooled with data from other 
studies using an established population PK model to derive PK parameters such as 
clearance, volume of distribution, and area under the concentrationtime curve. 

 
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6.7 
IMMUNOGENICITY ANALYSES 
Immunogenicity may be assessed for atezolizumab and other study treatments as 
appropriate (refer to arm-specific appendices for details).  The immunogenicity analyses 
will include all patients with at least one anti-drug antibody (ADA) assessment.  Patients 
will be grouped according to treatment received or, if no treatment is received prior to 
study discontinuation, according to treatment assigned. 
For atezolizumab, the numbers and proportions of ADA-positive patients and 
ADA-negative patients at baseline (baseline prevalence) and after baseline 
(postbaseline incidence) will be summarized by treatment group.  When determining 
postbaseline incidence, patients are considered to be ADA positive if they are ADA 
negative or are missing data at baseline but develop an ADA response following study 
drug exposure (treatment-induced ADA response), or if they are ADA positive at 
baseline and the titer of one or more postbaseline samples is at least 0.60 titer unit 
greater than the titer of the baseline sample (treatment-enhanced ADA response).  
Patients are considered to be ADA negative if they are ADA negative or are missing data 
at baseline and all postbaseline samples are negative, or if they are ADA positive at 
baseline but do not have any postbaseline samples with a titer that is at least 0.60 titer 
unit greater than the titer of the baseline sample (treatment unaffected). 
For other study treatments for which ADAs are tested, positivity will be determined 
according to standard methods established for previous studies of these drugs. 
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported using descriptive statistics. 
6.8 
BIOMARKER ANALYSES 
Biomarker analyses will be performed in an effort to understand the association of these 
biomarkers with response to study drugs, taking into account efficacy and safety 
endpoints (see Section 4.5.7 for more details). 
6.9 
INTERIM ANALYSES 
 
 
 
 
 
 
 
 
 
 

 
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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  
Sites will receive training and have access to a manual for appropriate eCRF 
completion.  eCRFs will be submitted electronically to the Sponsor and should be 
handled in accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered on the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies of transcriptions 

 
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that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, patient files, and records 
kept at pharmacies, laboratories, and medico-technical departments involved in a 
clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly on the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered on the eCRFs must not be obliterated or destroyed and must be retained per the 
policy for retention of records described in Section 7.5. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMPs, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study or for the length of time required by 
relevant national or local health authorities, whichever is longer.  After that period of 
time, the documents may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 

 
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Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).   
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Forms (and ancillary sample Informed Consent 
Forms such as a Mobile Nursing Informed Consent Form, if applicable) will be provided 
to each site.  If applicable, they will be provided in a certified translation into the local 
language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 

 
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If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments 
(see Section 9.5). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4 
CONFIDENTIALITY 
Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect such 
data against accidental or unlawful loss, alteration, or unauthorized disclosure or access.  
In the event of a data security breach, appropriate mitigation measures will be 
implemented. 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 

 
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Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Given the complexity and exploratory nature of biomarker analyses, data derived from 
these analyses will generally not be provided to patients unless required by law.  The 
aggregate results of any conducted research will be available in accordance with the 
effective Roche policy on study data publication (see Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data, which may include data on genomic variants, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted Clinical Study Reports 
and other summary reports will be provided upon request (see Section 9.5). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will 
receive the patient data, including an audit trail containing a complete record of all 
changes to data. 

 
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9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.  
Screening and enrollment will occur through an IxRS. 
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker analyses, and PK analyses), as specified in 
Section 4.5.7.  Accredited local laboratories will be used for routine monitoring; local 
laboratory ranges will be collected. 
An IMC will be employed to monitor and evaluate patient safety throughout the study. 
9.5 
DISSEMINATION OF DATA AND PROTECTION OF 
TRADE SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details).  In 
addition, redacted Clinical Study Reports and/or other summaries of clinical study results 
may be available in health authority databases for public access, as required by local 
regulation, and will be made available upon request.  For more information, refer to the 
Roche Global Policy on Sharing of Clinical Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/  
 

 
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The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Any substantial 
amendments to the protocol will require IRB/EC and health authority approval (as locally 
required) before implementation of any changes, with the exception of administrative 
changes or changes necessary to eliminate an immediate hazard to patients. 

 
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10. 
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[SITC] Society for Immunotherapy of Cancer statement on SARS-CoV-2 vaccination and 
cancer Immunotherapy [resource on the Internet]. Press release: 23 December 
2020 [cited: 28 May 2021]. Available from: 
https://www.sitcancer.org/aboutsitc/press-releases/2020/sitc-statement-sars-cov-2-
vaccination-cancer-immunotherapy. 
Stanietsky N, Simic H, Arapovic J, et al. The interaction of TIGIT with PVR and PVRL2 
inhibits human NK cell cytotoxicity. Proc Natl Acad Sci USA 2009;106:1785863. 
Taghavi S, Jayarajan SN, Davey A, et al. Prognostic significance of signet ring gastric 
cancer. J Clin Oncol 2012;30:34938. 
Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 
2015;65:87–108. 
Van Cutsem E, Moiseyenko VM, Tjulandin S, et al. Phase III study of docetaxel and 
cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line 
therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin 
Oncol 2006;24:49917. 
Wang F-H, Zhang X-T, Li Y-F, et al. The Chinese Society of Clinical Oncology (CSCO): 
clinical guidelines for the diagnosis and treatment of gastric cancer, 2021. Cancer 
Commun (Lond) 2021;41:74795. 
Wang W, Sun Z, Deng J-Y, et al. A novel nomogram individually predicting disease-
specific survival after D2 gastrectomy for advanced gastric cancer. 
Cancer Commun 2018;38:23. 
Wykes MN, Lewin SR. Immune checkpoint blockade in infectious disease. Nat Rev 
Immunol 2018;18:91104. 
Yamada Y, Higuchi K, Nishikawa K, et al. Phase III study comparing oxaliplatin plus S-1 
with cisplatin plus S-1 in chemotherapy-naive patients with advanced gastric 
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2013. Chin J Cancer 2017;36:66. 
 

 
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Appendix 1  
Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) 
Selected sections from the Response Evaluation Criteria in Solid Tumors, Version 1.1 
(RECIST v1.1), (Eisenhauer et al. 2009) are presented below, with slight modifications 
from the original publication and the addition of explanatory text as needed for clarity.1 
TUMOR MEASURABILITY 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or 
non-measurable as described below.  All measurable and non-measurable lesions 
should be assessed at screening and at subsequent protocol-specified tumor 
assessment timepoints.  Additional assessments may be performed as clinically 
indicated for suspicion of progression. 
DEFINITION OF MEASURABLE LESIONS 
Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size as follows:  
 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval  5 mm) 
 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 
20 mm by chest X-ray 
 
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be 
 15 mm in the short axis when assessed by CT scan (CT scan slice thickness 
recommended to be  5 mm).  At baseline and follow-up, only the short axis will be 
measured and followed.  Additional information on lymph node measurement is provided 
below (see "Identification of Target and Non-Target Lesions" and "Calculation of Sum of 
Diameters"). 
                                            
 
1 For clarity and for consistency within this document, the section numbers and cross-references 
to other sections within the article have been deleted and minor changes have been made. 

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DEFINITION OF NON-MEASURABLE LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter  10 mm or 
pathological lymph nodes with short axis  10 mm but  15 mm) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques. 
SPECIAL CONSIDERATIONS REGARDING LESION MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions: 
 
Technetium-99m bone scans, sodium fluoride positron emission tomography scans, 
and plain films are not considered adequate imaging techniques for measuring bone 
lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
 
Blastic bone lesions are non-measurable. 
 
Cystic Lesions: 
 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) because 
they are, by definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with Prior Local Treatment: 
 
Tumor lesions situated in a previously irradiated area or in an area subjected to 
other locoregional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion. 
 

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METHODS FOR ASSESSING LESIONS 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during the study.  
Imaging-based evaluation should always be the preferred option. 
CLINICAL LESIONS 
Clinical lesions will only be considered measurable when they are superficial and 
 10 mm in diameter as assessed using calipers (e.g., skin nodules).  For the case of 
skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is suggested. 
CHEST X-RAY 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, because CT is more sensitive than X-ray, particularly in identifying new 
lesions.  However, lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung. 
CT AND MRI SCANS 
CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  In this guideline, the definition of measurability of lesions on 
CT scan is based on the assumption that CT slice thickness is  5 mm.  When CT scans 
have slice thickness of  5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable.  
If prior to enrollment it is known that a patient is unable to undergo CT scans with IV 
contrast because of allergy or renal insufficiency, the decision as to whether a non-
contrast CT or MRI (without IV contrast) will be used to evaluate the patient at baseline 
and during the study should be guided by the tumor type under investigation and the 
anatomic location of the disease.  For patients who develop contraindications to contrast 
after baseline contrast CT is done, the decision as to whether non-contrast CT or MRI 
(enhanced or non-enhanced) will be performed should also be based on the tumor type 
and the anatomic location of the disease, and should be optimized to allow for 
comparison with prior studies, if possible.  Each case should be discussed with the 
radiologist to determine if substitution of these other approaches is possible and, if not, 
the patient should be considered not evaluable from that point forward.  Care must be 
taken in measurement of target lesions and interpretation of non-target disease or new 

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lesions on a different modality, because the same lesion may appear to have a different 
size using a new modality. 
ENDOSCOPY, LAPAROSCOPY, ULTRASOUND, TUMOR MARKERS, 
CYTOLOGY, HISTOLOGY 
Endoscopy, laparoscopy, ultrasound, tumor markers, cytology, and histology cannot be 
utilized for objective tumor evaluation. 
ASSESSMENT OF TUMOR BURDEN 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements. 
IDENTIFICATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one or 
two organ sites involved, a maximum of two lesions (one site) and four lesions (two 
sites), respectively, will be recorded.  Other lesions (albeit measurable) in those organs 
will be considered non-target lesions. 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention because they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of  15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Lymph node size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT, 
this is almost always the axial plane; for MRI, the plane of acquisition may be axial, 
sagittal, or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm  30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis  10 mm 

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but  15 mm) should be considered non-target lesions.  Nodes that have a short axis of 
 10 mm are considered non-pathological and should not be recorded or followed. 
All lesions (or sites of disease) not selected as target lesions (measurable or 
non-measurable), including pathological lymph nodes, should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements are not required.  It is 
possible to record multiple non-target lesions involving the same organ as a single item 
on the Case Report Form (CRF) (e.g., "multiple enlarged pelvic lymph nodes" or 
"multiple liver metastases"). 
CALCULATION OF SUM OF DIAMETERS 
A sum of the diameters (longest diameter for nonlymph node lesions, short axis for 
lymph node lesions) will be calculated for all target lesions at baseline and at each 
subsequent tumor assessment as a measure of tumor burden. 
Measuring Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the node regresses to  10 mm during the study.  Thus, when 
lymph nodes are included as target lesions, the sum of diameters may not be zero even 
if complete response criteria are met, because a normal lymph node is defined as having 
a short axis of  10 mm. 
Measuring Lesions That Become Too Small to Measure 
During the study, all target lesions (lymph node and nonlymph node) recorded at 
baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm).  However, sometimes lesions or lymph 
nodes that are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measurement and may 
report them as being too small to measure.  When this occurs, it is important that a value 
be recorded on the CRF, as follows: 
 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
 
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and "too small to measure" should be 
ticked.  (Note:  It is less likely that this rule will be used for lymph nodes because 
they usually have a definable size when normal and are frequently surrounded by 
fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well, and "too small to measure" should also 
be ticked). 

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To reiterate, however, if the radiologist is able to provide an actual measurement, that 
should be recorded, even if it is  5 mm, and in that case "too small to measure" should 
not be ticked. 
Measuring Lesions That Split or Coalesce on Treatment 
When nonlymph node lesions fragment, the longest diameters of the fragmented 
portions should be added together to calculate the sum of diameters.  Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in 
this instance should be the maximum longest diameter for the coalesced lesion. 
EVALUATION OF NON-TARGET LESIONS 
Measurements are not required for non-target lesions, except that malignant lymph node 
non-target lesions should be monitored for reduction to  10 mm in short axis.  
Non-target lesions should be noted at baseline and should be identified as "present" or 
"absent" and (in rare cases) may be noted as "indicative of progression" at subsequent 
evaluations.  In addition, if a lymph node lesion shrinks to a non-malignant size (short 
axis  10 mm), this should be captured on the CRF as part of the assessment of 
non-target lesions. 
RESPONSE CRITERIA 
CRITERIA FOR TARGET LESIONS 
Definitions of the criteria used to determine objective tumor response for target lesions 
are provided below: 
 
Complete response (CR):  Disappearance of all target lesions 
Any pathological lymph nodes must have reduction in short axis to  10 mm. 
 
Partial response (PR):  At least a 30% decrease in the sum of diameters of all target 
lesions, taking as reference the baseline sum of diameters, in the absence of CR 
 
Progressive disease (PD):  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum of diameters at prior timepoints 
(including baseline)  
In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of  5 mm. 
 
Stable disease (SD):  Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD 
 

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CRITERIA FOR NON-TARGET LESIONS 
Definitions of the criteria used to determine the tumor response for the group of 
non-target lesions are provided below.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints specified in the schedules of activities. 
 
CR:  Disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level 
All lymph nodes must be non-pathological in size ( 10 mm short axis). 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesions and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
 
PD:  Unequivocal progression of existing non-target lesions 
 
SPECIAL NOTES ON ASSESSMENT OF PROGRESSION OF NON-TARGET 
LESIONS 
Patients with Measurable and Non-Measurable Disease 
For patients with both measurable and non-measurable disease to achieve unequivocal 
progression on the basis of the non-target lesions, there must be an overall level of 
substantial worsening in non-target lesions in a magnitude that, even in the presence of 
SD or PR in target lesions, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest increase in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  The 
designation of overall progression solely on the basis of change in non-target lesions in 
the face of SD or PR in target lesions will therefore be extremely rare. 
NEW LESIONS 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some "new" bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a 
"new" cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 

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If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, progression should be declared using the date of the 
initial scan. 
CRITERIA FOR OVERALL RESPONSE AT A SINGLE TIMEPOINT 
Table 1 provides a summary of the overall response status calculation at each response 
assessment timepoint for patients who have measurable disease at baseline. 
Table 1 
Criteria for Overall Response at a Single Timepoint:  Patients 
with Target Lesions (with or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease; PR  partial 
response; SD  stable disease. 
  
MISSING ASSESSMENTS AND NOT-EVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If measurements are made on only a subset of target 
lesions at a timepoint, usually the case is also considered not evaluable at that 
timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesions would not change the assigned timepoint response.  This 
would be most likely to happen in the case of PD.  For example, if a patient had a 
baseline sum of 50 mm with three measured lesions and during the study only two 
lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved 
PD status, regardless of the contribution of the missing lesion. 
SPECIAL NOTES ON RESPONSE ASSESSMENT 
Patients with a global deterioration in health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 

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having "symptomatic deterioration."  Every effort should be made to document objective 
progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target lesions as shown in Table 1. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:22847. 
 

 
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Appendix 2  
ECOG Performance Status Scale 
Grade 
Description 
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 housework or office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about  50% of waking hours. 
3 
Capable of only limited self-care; confined to a bed or chair  50% of 
waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair. 
5 
Dead. 
ECOG  Eastern Cooperative Oncology Group. 
 

 
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Appendix 3  
Preexisting Autoimmune Diseases and Immune Deficiencies 
Patients should be carefully questioned regarding their history of acquired or congenital 
immune deficiencies or autoimmune disease.  Patients with any history of immune 
deficiencies or autoimmune disease listed in the table below are excluded from 
participating in the study.  Possible exceptions to this exclusion could be patients with a 
medical history of such entities as atopic disease or childhood arthralgias where the 
clinical suspicion of autoimmune disease is low.  Patients with a history of 
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study.  In addition, transient autoimmune manifestations of an 
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis).  Caution should be used when considering 
atezolizumab for patients who have previously experienced a severe or life-threatening 
skin adverse reaction or pericardial disorder while receiving another immunostimulatory 
anti-cancer agent.  The Medical Monitor is available to advise on any uncertainty about 
any autoimmune exclusions. 
Autoimmune Diseases and Immune Deficiencies 
 Acute disseminated 
encephalomyelitis 
 Addison disease 
 Ankylosing spondylitis 
 Antiphospholipid antibody 
syndrome 
 Aplastic anemia 
 Autoimmune hemolytic 
anemia 
 Autoimmune hepatitis 
 Autoimmune 
hypoparathyroidism 
 Autoimmune hypophysitis 
 Autoimmune myelitis 
 Autoimmune myocarditis 
 Autoimmune oophoritis 
 Autoimmune orchitis 
 Autoimmune 
thrombocytopenic purpura 
 Behçet disease 
 Bullous pemphigoid 
 Chronic fatigue syndrome 
 Chronic inflammatory 
demyelinating 
polyneuropathy 
 Churg-Strauss syndrome 
 Crohn disease 
 Dermatomyositis 
 Dysautonomia 
 Epidermolysis bullosa 
acquisita 
 Gestational pemphigoid 
 Giant cell arteritis 
 Goodpasture syndrome 
 Granulomatosis with 
polyangiitis 
 Graves disease 
 Guillain-Barré syndrome 
 Hashimoto disease 
 IgA nephropathy 
 Inflammatory bowel disease 
 Interstitial cystitis 
 Kawasaki disease 
 Lambert-Eaton myasthenia 
syndrome 
 Lupus erythematosus 
 Lyme diseasechronic 
 Meniere syndrome 
 Mooren ulcer 
 Morphea 
 Multiple sclerosis 
 Myasthenia gravis 
 Neuromyotonia 
 Opsoclonus myoclonus 
syndrome 
 Optic neuritis 
 Ord thyroiditis 
 Pemphigus 
 Pernicious anemia 
 Polyarteritis nodosa 
 Polyarthritis 
 Polyglandular 
autoimmune syndrome 
 Primary biliary cholangitis 
 Psoriasis 
 Reiter syndrome 
 Rheumatoid arthritis 
 Sarcoidosis 
 Scleroderma 
 Sjögren syndrome 
 Stiff-Person syndrome 
 Takayasu arteritis 
 Ulcerative colitis 
 Vitiligo 
 Vogt-Koyanagi-Harada 
disease 

 
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Appendix 4  
Anaphylaxis Precautions 
EQUIPMENT NEEDED 
 
Oxygen 
 
Epinephrine for SC, IV, and/or endotracheal use in accordance with standard 
practice 
 
Antihistamines 
 
Corticosteroids 
 
Intravenous infusion solutions, tubing, catheters, and tape 
 
PROCEDURES 
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed: 
1. 
Stop the study treatment administration, if possible.  
2. 
Call for additional medical assistance. 
3. 
Maintain an adequate airway. 
4. 
Ensure that appropriate monitoring is in place, with continuous ECG and 
pulse oximetry monitoring if possible. 
5. 
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge. 
6. 
Continue to observe the patient and document observations. 
 

 
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Appendix 5  
Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
Atezolizumab-Specific Adverse Events (cont.) 
  
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
Atezolizumab-Specific Adverse Events (cont.) 
 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
Atezolizumab-Specific Adverse Events (cont.) 
  
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
Atezolizumab-Specific Adverse Events (cont.) 
 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
Atezolizumab-Specific Adverse Events (cont.) 
 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
Atezolizumab-Specific Adverse Events (cont.) 
  
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
Atezolizumab-Specific Adverse Events (cont.) 
 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
Atezolizumab-Specific Adverse Events (cont.) 
  
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
Atezolizumab-Specific Adverse Events (cont.) 
 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
Atezolizumab-Specific Adverse Events (cont.) 
  
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
Atezolizumab-Specific Adverse Events (cont.) 
 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
Atezolizumab-Specific Adverse Events (cont.) 
  
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
Atezolizumab-Specific Adverse Events (cont.) 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
Atezolizumab-Specific Adverse Events (cont.) 
 
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Appendix 5:  Risks Associated with Atezolizumab and Guidelines for Management of 
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REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from antiprogrammed 
death-1 antibody: raising awareness among community oncologist. J Oncol Pract 
2019;15:5024. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematol Am 
Soc Hematol Educ Program 2015;1:1906. 
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:246577. 
Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. 
Biol Blood Marrow Transplant 2019;25:62538. 
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 
29 October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis. 
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for 
monocytes and macrophages. Nat Rev Immunol 2020;20:35562. 
Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of 
cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin 
Risk Manag 2019;15:32335. 
Rotz SJ, Leino D, Szabo S, et al. Severe cytokine release syndrome in a patient 
receiving PD-1-directed therapy. Pediatr Blood Cancer 2017;64:e26642. 
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:290814. 
 

 
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Appendix 6  
Schedule of Activities for Screening 
Table 1 
Schedule of Activities for Stage 1 Screening 
Assessment or Procedure 
Stage 1 Screening a 
(Days –28 to –1) 
Informed consent 
x b 
Demographics (age, sex, and self-reported race/ethnicity) 
x 
Medical history and baseline conditions 
x 
Molecular profile of GC or GEJC (if available) 
x 
Vital signs c 
x 
Weight 
x 
Height 
x 
Complete physical examination d 
x 
ECOG Performance Status 
x 
ECG e 
x 
Hematology f 
x g 
Chemistry h 
x g 
Coagulation (INR and aPTT) 
x g 
TSH, free T3 (or total T3 i), and free T4 
x g 
C-reactive protein 
x g 
Pregnancy test k 
x g 
Urinalysis l 
x g 
Baseline tumor tissue sample m 
x 
Baseline tumor assessments n 
x 
Concomitant medications o 
x 
Adverse events p 
x 
 

 
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Appendix 7  
Study Details Specific to Atezo  CAPOX Arm (Control) 
TABLE OF CONTENTS 
A7–1 
Background on Atezo  CAPOX Arm .................................... 139 
A7–1.1 
Background on Atezolizumab ................................................ 139 
A7–1.2 
Background on CAPOX ......................................................... 139 
A7–2 
Rationale for Atezo  CAPOX ARM ....................................... 140 
A7–2.1 
The PD-L1 Pathway ............................................................... 140 
A7–2.2 
Effect of CAPOX on the Immune Tumor Microenvironment .. 141 
A7–2.3 
Combination Treatment with Atezolizumab and CAPOX ....... 141 
A7–2.4 
Clinical Studies of Atezolizumab in Combination with 
CAPOX .................................................................................. 142 
A7–2.5 
Benefit‒Risk Assessment ...................................................... 143 
A7–3 
Rationale for Dose and Schedule for Atezo  CAPOX Arm ... 143 
A7–3.1 
Rationale for Atezolizumab Dose and Schedule .................... 143 
A7–3.2 
Rationale for CAPOX Dose and Schedule ............................. 143 
A7–4 
Materials and Methods Specific to Atezo  CAPOX Arm ....... 144 
A7–4.1 
Treatment in Atezo  CAPOX Arm ........................................ 144 
A7–4.1.1 
Formulation and Packaging ................................................... 144 
A7–4.1.1.1 
Atezolizumab ......................................................................... 144 
A7–4.1.1.2 
CAPOX .................................................................................. 144 
A7–4.1.2 
Dosage, Administration, and Compliance .............................. 144 
A7–4.1.2.1 
Atezolizumab ......................................................................... 145 
A7–4.1.2.2 
CAPOX .................................................................................. 146 
A7–4.2 
Concomitant Therapy for Atezo  CAPOX Arm ..................... 146 
A7–4.2.1 
Permitted Therapy for Atezo  CAPOX Arm .......................... 146 
A7–4.2.2 
Cautionary Therapy for Atezo  CAPOX Arm ........................ 148 
A7–4.2.2.1 
Corticosteroids, Immunosuppressive Medications, and 
Tumor Necrosis Factor Inhibitors ....................................... 148 
A7–4.2.2.2 
Herbal Therapies ................................................................... 148 
A7–4.2.2.3 
Medications Given with Precaution Concomitantly with 
CAPOX .................................................................................. 148 
A7–4.2.3 
Prohibited Therapy for Atezo  CAPOX Arm ......................... 149 
A7–4.3 
Contraception Requirements for Atezo  CAPOX Arm .......... 149 

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A7–5 
Assessment of Safety for Atezo  CAPOX Arm ..................... 150 
A7–5.1 
Safety Plan for Atezo  CAPOX Arm ..................................... 150 
A7–5.1.1 
Risks Associated with Atezolizumab ...................................... 151 
A7–5.1.2 
Risks Associated with CAPOX ............................................... 151 
A7–5.1.3 
Risks Associated with Combination Use of Atezolizumab 
and CAPOX ........................................................................... 151 
A7–5.1.4 
Management of Patients Who Experience Specific 
Adverse Events in the Atezolizumab  CAPOX Arm ............. 152 
A7–5.1.4.1 
Dose Modifications ................................................................ 152 
A7–5.1.4.2 
Treatment Interruption for Toxicities ...................................... 153 
A7–5.1.4.3 
Management Guidelines for Adverse Events ......................... 154 
...... 154 
A7–5.3 
Reporting Requirements for Pregnancies in 
Atezo  CAPOX Arm ............................................................. 155 
A7–5.3.1 
Pregnancies in Female Patients ............................................ 155 
A7–5.3.2 
Pregnancies in Female Partners of Male Patients ................. 156 
A7–5.3.3 
Abortions................................................................................ 156 
A7–5.3.4 
Congenital Anomalies/Birth Defects ...................................... 157 
A7–6 
Schedule of Activities and Sample Collection for 
Atezo  CAPOX Arm ............................................................. 158 
 
 

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A7–1 
BACKGROUND ON ATEZO  CAPOX ARM 
A7–1.1 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets programmed 
deathligand 1 (PD-L1) and inhibits the interaction between PD-L1 and its receptors, 
programmed death1 (PD-1) and B7-1 (also known as CD80), both of which function as 
inhibitory receptors expressed on T cells.  Therapeutic blockade of PD-L1 binding by 
atezolizumab has been shown to enhance the magnitude and quality of tumor-specific 
T-cell responses, resulting in improved anti-tumor activity (Fehrenbacher et al. 2016; 
Rosenberg et al. 2016).  Atezolizumab has minimal binding to fragment crystallizable 
(Fc) receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy. 
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer (NSCLC), small-cell lung cancer, triple-negative breast cancer, hepatocellular 
carcinoma, melanoma, and alveolar soft part sarcoma. 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and 
clinical studies. 
A7–1.2 
BACKGROUND ON CAPOX 
The combination of capecitabine and oxaliplatin (CAPOX) in the first-line treatment 
setting of human epidermal growth factor 2 (HER2)-negative gastric carcinoma (GC) is 
the standard of care recommended by oncology guidelines (National Comprehensive 
Cancer Network 2021; Wang et al. 2021).  The CAPOX regimen demonstrated survival 
benefit in patients with GC in the first-line treatment Phase II studies, with median 
progression-free survival (PFS) of about 67 months and overall survival (OS) of about 
1213 months (Park et al. 2008; Kim et al. 2012).  In addition, the convenience of the 
CAPOX regimen (oral capecitabine every 2 weeks plus oxaliplatin administered by IV 
infusion in a 3-week cycle) has favored increased implementation of this regimen in 
clinical practice globally. 

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A7–2 
RATIONALE FOR ATEZO  CAPOX ARM 
A7–2.1 
THE PD-L1 PATHWAY 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies 
(Hodi et al. 2010; Kantoff et al. 2010; Chen et al. 2012). 
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is an extracellular protein that downregulates immune responses through binding 
to its two receptors, PD-1 and B7-1.  PD-1 is an inhibitory receptor expressed on T cells 
following T-cell activation, and expression is sustained in states of chronic stimulation 
(Blank et al. 2005; Keir et al. 2008).  B7-1 is a molecule expressed on 
antigen-presenting cells and activated T cells.  Binding of PD-L1 to PD-1 and B7-1 
inhibits T-cell proliferation and activation, cytokine production, and cytolytic activity, 
leading to the functional inactivation or exhaustion of T cells (Butte et al. 2007; 
Yang et al. 2011).  Overexpression of PD-L1 on tumor cells has been reported to impede 
anti-tumor immunity, resulting in immune evasion (Blank and Mackensen 2007).  
Therefore, interruption of the PD-L1 pathway represents an attractive strategy for 
restoring tumor-specific T-cell immunity. 
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies who have failed standard-of-care therapies.  Objective 
responses have been observed across a broad range of malignancies, including 
NSCLC, urothelial carcinoma, renal cell carcinoma, melanoma, colorectal cancer, head 
and neck cancer, GC, breast cancer, and sarcoma (see Atezolizumab Investigator's 
Brochure for detailed efficacy results). 
A number of studies have indicated a role for PD-L1 in gastric carcinogenesis.  In case 
studies, PD-L1 was expressed in tumor cells in 42%65% of patients with GC (Wu et al. 
2006; Geng et al. 2015; Kim et al. 2016).  AntiPD-1 inhibitors (i.e., nivolumab and 
pembrolizumab) have been investigated in the treatment of GC and have demonstrated 
anti-tumor activity.  In the Phase III ATTRACTION-2 study, nivolumab monotherapy 
demonstrated superior OS benefit versus placebo (hazard ratio [HR]: 0.63) in the 
third- or subsequent-line setting of GC and gastroesophageal junction carcinoma 
(GEJC) (Kang et al. 2017).  In the Phase II KEYNOTE-059 study, pembrolizumab 
monotherapy achieved a 33% objective response rate (ORR) by investigator 
assessment and 22% by central data review of patients with GC with PD-L1expressing 
tumors (Bang et al. 2015). 

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A7–2.2 
EFFECT OF CAPOX ON THE IMMUNE TUMOR 
MICROENVIRONMENT 
There is increasing evidence that in addition to causing tumor cell death, certain 
conventional chemotherapies may have immunogenic effects (Zitvogel et al. 2008).  
Oxaliplatin, a component of CAPOX, is one of a limited number of anti-cancer agents 
that has been shown to induce immunogenic cell death, eliciting immune responses as a 
result of calreticulin exposure and release of adenosine triphosphate and high-mobility 
group protein (Green et al. 2009; Tesniere et al. 2010; Michaud et al. 2011).  In a murine 
nonclinical model with transplantable and transgene-driven cancers, oxaliplatin has been 
shown to trigger tumor-targeting immune responses (Shalapour et al. 2015).  
Capecitabine, an orally administered tumor-activated 5-fluorouracil (5-FU) prodrug, is 
metabolized to 5-FU by means of a three-step enzymatic cascade after oral 
administration (Reigner et al. 2001).  The treatment of tumor-bearing mice with 5-FU 
results in selective reduction of myeloid-derived suppressor cells in the tumor bed, 
without significant depletion of T cells, natural killer cells, dendritic cells, or B cells, a 
corresponding increase in interferon- production by CD8-positive tumor-infiltrating 
lymphocytes was observed (Vincent et al. 2010).  These nonclinical results suggesting 
that treatment with oxaliplatin and capecitabine may enhance anti-tumor immunity. 
A7–2.3 
COMBINATION TREATMENT WITH ATEZOLIZUMAB AND 
CAPOX 
Chemotherapy may modulate tumor and immune system interactions in favor of the 
immune system, resulting in tumor cell death with a resultant increase in tumor antigen 
delivery to antigen-presenting cells.  Tumor cell death may also lead to a reduction in 
soluble and membrane-bound factors inhibiting tumor-infiltrating T cells.  Chemotherapy 
may also disrupt immune system regulatory networks by decreasing the number of 
T-regulatory cells.  Immunogenic chemotherapy such as oxaliplatin combined with 
immune checkpoint inhibitors can trigger T-cell infiltration to tumors and provide additive 
or synergistic anti-tumor activity in vivo and is expected to contribute to durable 
anti-tumor responses (Pfirschke and Engblom 2016). 
Recently, CheckMate-649 (NCT02872116), a Phase III trial investigating nivolumab plus 
chemotherapy or nivolumab plus ipilimumab compared with chemotherapy alone in the 
first-line treatment of metastatic HER2-negative GC and GEJC, showed improved OS 
(14.4 vs. 11.1 months; HR: 0.71) and improved PFS (7.7 vs. 6.1 months; HR: 0.74) in 
patients with a PD-L1 combined positive score (CPS)  5 receiving nivolumab plus 
chemotherapy compared with chemotherapy alone (Moehler et al. 2020).  An OS benefit 
(13.8 vs. 11.6 months; HR: 0.80) was also seen in an all-randomized population.  
With the recent regulatory approval by the U.S. Food and Drug Administration, this 
practice-changing study has established chemotherapy plus nivolumab as a new 

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standard of care for the first-line treatment of patients with HER2-negative GC 
and GEJC. 
Nivolumab and atezolizumab are both approved for the treatment of patients with 
metastatic NSCLC who experienced disease progression during or following a 
platinum-containing chemotherapy, irrespective of PD-L1 expression.  Nivolumab 
demonstrated superiority in OS over docetaxel based on two Phase III trials, 
CheckMate-017 for the treatment of squamous NSCLC and CheckMate-057 for the 
treatment of non-squamous NSCLC, and atezolizumab was based on the Phase III OAK 
trial.  Of note, the two drugs showed comparable survival benefit in non-squamous 
populations.  In the CheckMate-057 study (Borghaei et al. 2015), the median OS for 
nivolumab and docetaxel was 12.2 versus 9.4 months (HR: 0.73).  In the OAK study 
(Rittmeyer et al. 2017), the median OS for atezolizumab and docetaxel was 15.6 versus 
11.2 months (HR: 0.73). 
In light of the totality of evidence described above, together with the anticipated 
evaluation of standard of care for the first-line treatment of patients with HER2-negative 
GC and GJEC following the positive readout of CheckMate-649, blockade of the 
PD-L1/PD-1 pathway with atezolizumab in combination with CAPOX chemotherapy may 
result in an enhanced protective anti-tumor immune response, supporting the selection 
of this treatment combination to be a control for other experimental arms with innovative 
combination therapies. 
A7–2.4 
CLINICAL STUDIES OF ATEZOLIZUMAB IN COMBINATION 
WITH CAPOX 
Capecitabine, an orally administered tumor-activated 5-FU prodrug, is metabolized to 
5-FU by means of a three-step enzymatic cascade after oral administration (Reigner 
et al. 2001).  The safety and the preliminary anti-tumor activity of the combination of 
atezolizumab, bevacizumab, and FOLFOX (5-FU in combination with oxaliplatin) have 
been evaluated in the Phase I study GP28328 in oxaliplatin treatmentnaive patients 
with solid tumors, including metastatic colorectal cancer.  Adverse events observed thus 
far are consistent with the known risks of each study treatment.  Atezolizumab in 
combination with cytotoxic chemotherapy has not been associated with additive severe 
(Grade  3) toxicities, indicating that atezolizumab can be safely combined with standard 
chemotherapy. 
As of the clinical cutoff date, 1 September 2015, 23 efficacy-evaluable oxaliplatin 
treatmentnaive patients with metastatic colorectal cancer had been treated in the 
first-line setting.  Investigator-assessed ORR (confirmed response per Response 
Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST v1.1]) was 52.2%, and all 
12 responders had partial responses.  The median investigator-assessed duration of 

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response per RECIST v1.1 for the 12 responders was 11.4 months.  The median 
investigator-assessed PFS per RECIST v1.1 was 14.1 months. 
Detailed clinical study results for atezolizumab can be found in the Atezolizumab 
Investigator's Brochure. 
A7–2.5 
BENEFIT‒RISK ASSESSMENT 
Capecitabine is the prodrug of 5-FU and taking into account the manageable and 
tolerable safety profile of FOLFOX (5-FU in combination with oxaliplatin) plus 
atezolizumab described in Study GP28328, the combination of CAPOX appears to have 
promising therapeutic potential in the treatment of solid tumors such as GC. 
For the evaluation of the impact of the coronavirus disease 2019 (COVID-19) pandemic 
on the benefitrisk assessment, please see Section 1.4. 
A7–3 
RATIONALE FOR DOSE AND SCHEDULE FOR 
ATEZO  CAPOX ARM 
A7–3.1 
RATIONALE FOR ATEZOLIZUMAB DOSE AND SCHEDULE 
Atezolizumab will be administered at a fixed dose of 1200 mg every 3 weeks (Q3W) 
(1200 mg on Day 1 of each 21-day cycle), which is an approved dosage for 
atezolizumab (Tecentriq® U.S. Package Insert). 
A7–3.2 
RATIONALE FOR CAPOX DOSE AND SCHEDULE 
The CAPOX regimen (1000 mg/m2 capecitabine taken orally twice a day for 14 days 
followed by 7 days off and 130 mg/m2 oxaliplatin administered intravenously on Day 1 
Q3W) at the recommended doses has been used in multiple Phase III trials (Boku et al. 
2019; Moehler et al. 2020) represents an acceptable combination of capecitabine and 
oxaliplatin for patients with GC or GEJC. 
Standard treatment for late-stage GC is recommended to be 4–6 months by Chinese 
Society of Clinical Oncology guidelines (Wang et al. 2021).  In this study, the 
discontinuation of chemotherapy beyond Cycle 6 (administered in 21-day cycles) will 
occur because the majority of patients with GC and GEJC achieve maximum tumor 
reduction by Cycle 6 and discontinuation of chemotherapy will improve the tolerability of 
continued dosing with maintenance treatment with atezolizumab. 

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A7–4 
MATERIALS AND METHODS SPECIFIC TO 
ATEZO  CAPOX ARM 
A7–4.1 
TREATMENT IN ATEZO  CAPOX ARM 
A7–4.1.1 
Formulation and Packaging 
A7–4.1.1.1 Atezolizumab 
The atezolizumab drug product will be supplied by the Sponsor as a 
 
-mL glass vial.  The vial contains approximately 
 mL (1200 mg) of 
atezolizumab solution. 
For information on the formulation of atezolizumab, see the pharmacy manual and the 
Atezolizumab Investigator's Brochure. 
A7–4.1.1.2 CAPOX 
Refer to the oxaliplatin and capecitabine prescribing information for details on the 
respective formulations and storage instructions.  Oxaliplatin and capecitabine will be 
either provided by Sponsor or sourced commercially by sites. 
For information on the formulation, packaging, and handling of the CAPOX agents, refer 
to the local prescribing information for each agent. 
A7–4.1.2 
Dosage, Administration, and Compliance 
Patients in the atezolizumab plus CAPOX (Atezo  CAPOX) arm will receive treatment as 
outlined in Table 1 until unacceptable toxicity or loss of clinical benefit as determined by 
the investigator after an integrated assessment of radiographic and biochemical data, 
local biopsy results (if available), and clinical status (e.g., symptomatic deterioration such 
as pain secondary to disease) (see Section 3.1.2 for details). 
 
 
Table 1 
Treatment Regimen for Atezo  CAPOX Arm 
Cycle Length 
Dose, Route, and Regimen 
(drugs listed in order of administration) 
21 days 
 
Atezolizumab 1200 mg by IV infusion on Day 1 
 
Capecitabine 1000 mg/m2 orally twice daily on Days 114 a 
 
Oxaliplatin 130 mg/m2 by IV infusion on Day 1 a 
Atezo  atezolizumab; CAPOX  capecitabine plus oxaliplatin. 
a Treatment for up to six cycles. 
 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 

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Medication errors should be noted on the Study Drug Administration electronic Case 
Report Form (eCRF).  Cases of accidental overdose or medication error, along with any 
associated adverse events, should be reported as described in Section 5.3.5.12.  No 
safety data related to overdosing of atezolizumab are available to date. 
A7–4.1.2.1 Atezolizumab 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle. 
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 4.  
Atezolizumab infusions will be administered per the instructions outlined in Table 2. 
Table 2 
Administration of First and Subsequent Atezolizumab Infusions 
First Infusion 
Subsequent Infusions 
 
No premedication is permitted prior to the 
atezolizumab infusion. 
 
Vital signs (pulse rate, respiratory rate, 
blood pressure, pulse oximetry, and 
temperature) should be recorded within 
60 minutes prior to the infusion. 
 
Atezolizumab should be infused over 
60 ( 15) minutes. 
 
If clinically indicated, vital signs should be 
recorded every 15 ( 5) minutes during the 
infusion and 30 ( 10) minutes after the 
infusion. 
 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
 
If the patient experienced an IRR with 
any previous infusion, premedication with 
antihistamines, antipyretic medications, 
and/or analgesics may be administered 
for subsequent doses at the discretion of 
the investigator. 
 
Vital signs should be recorded within 
60 minutes prior to the infusion. 
 
Atezolizumab should be infused over 
30 ( 10) minutes if the previous infusion 
was tolerated without an IRR, or 
60 ( 15) minutes if the patient 
experienced an IRR with the previous 
infusion. 
 
If the patient experienced an IRR with the 
previous infusion or if clinically indicated, 
vital signs should be recorded during the 
infusion and at 30 ( 10) minutes after the 
infusion. 
IRR  infusion-related reaction. 
 
Guidelines for medical management of infusion-related reactions (IRRs) for 
atezolizumab are provided in Appendix 5. 
No dose modification for atezolizumab is allowed.  Guidelines for treatment interruption 
or discontinuation because of toxicities are provided in Section A7–5.1.4.  Atezolizumab 
treatment may be interrupted for reasons other than toxicity (e.g., surgical procedures).  

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The acceptable length of treatment interruption must be based on the investigator's 
benefitrisk assessment and in alignment with the protocol requirements for the duration 
of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 
A7–4.1.2.2 CAPOX 
Treatment will be administered as follows during each 21-day cycle for up to 6 cycles: 
 
Capecitabine (1000 mg/m2) orally twice a day on Days 114 
 
Oxaliplatin (130 mg/m2) by IV infusion on Day 1 at least 5 minutes after completion 
of the atezolizumab infusion 
 
The rates of drug administration for oxaliplatin may follow the institutional guidelines.  
Patients may be premedicated with 5-HT3receptor antagonists or other 
standard-of-care methods to control nausea and vomiting.  Premedication with steroids 
should be limited when clinically feasible, because of their immunosuppressant effects.  
All medications must be recorded on the appropriate Concomitant Medications eCRF. 
Guidelines for dosage modification and treatment interruption or discontinuation because 
of toxicities are provided in Section A7–5.1.4.  CAPOX treatment may be interrupted for 
reasons other than toxicity (e.g., surgical procedures).  The acceptable length of 
treatment interruption must be based on the investigator's benefitrisk assessment and 
in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed. 
A7–4.2 
CONCOMITANT THERAPY FOR ATEZO  CAPOX ARM 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated study treatment from 
7 days prior to initiation of study treatment to the treatment discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 
A7–4.2.1 
Permitted Therapy for Atezo  CAPOX Arm 
Patients are permitted to use the following therapies during the study: 
 
Oral contraceptives with a failure rate of  1% per year 
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy 
 
Vaccinations (such as influenza, COVID-19) 
Live, attenuated vaccines are not permitted (see A7–4.2.3). 
 
Megestrol acetate administered as an appetite stimulant 

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 
Mineralocorticoids (e.g., fludrocortisone) 
 
Inhaled corticosteroids administered for chronic obstructive pulmonary disease or 
asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below: 
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  Treatment with atezolizumab and 
CAPOX may be continued during palliative radiotherapy. 
 
Radiotherapy to the brain as outlined below: 
Patients whose extracranial tumor burden is stable or responding to study 
treatment and who are subsequently found to have three or fewer brain 
metastases may receive radiotherapy to the brain (either stereotactic 
radiosurgery or whole-brain radiation therapy) provided that all of the following 
criteria are met: 
– 
The patient has no evidence of progression or hemorrhage after completion 
of CNS-directed therapy. 
– 
The patient has no ongoing requirement for corticosteroids as therapy for 
CNS disease. 
Patients who require corticosteroid therapy for more than 7 days after 
completion of radiotherapy must be discontinued from study treatment. 
– 
Anti-convulsant therapy, if required, is administered at a stable dose. 
 
Premedication with antihistamines, antipyretic medications, and/or analgesics may be 
administered for the second and subsequent atezolizumab infusions only, at the 
discretion of the investigator. 
In general, investigators should manage a patient's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies as clinically indicated, per local standard practice.  Patients who 
experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor antagonists 
(e.g., famotidine, cimetidine), or equivalent medications per local standard practice.  
Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists; see Appendix 4). 

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A7–4.2.2 
Cautionary Therapy for Atezo  CAPOX Arm 
A7–4.2.2.1 Corticosteroids, Immunosuppressive Medications, and 
Tumor Necrosis Factor Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and tumor necrosis factor 
(TNF-) inhibitors may attenuate potential beneficial immunologic effects of treatment 
with atezolizumab.  Therefore, in situations in which systemic corticosteroids, 
immunosuppressive medications, or TNF- inhibitors would be routinely administered, 
alternatives, including antihistamines, should be considered.  If the alternatives are not 
feasible, systemic corticosteroids, immunosuppressive medications, and TNF- 
inhibitors may be administered at the discretion of the investigator. 
Systemic corticosteroids or immunosuppressive medications are recommended, at the 
discretion of the investigator, for the treatment of specific adverse events when 
associated with atezolizumab therapy (refer to Appendix 5 for details). 
A7–4.2.2.2 Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer 
(see Section A7–4.2.3) may be used during the study at the discretion of the 
investigator. 
A7–4.2.2.3 Medications Given with Precaution Concomitantly with CAPOX 
The following medications should be used with precaution during treatment with CAPOX: 
 
Anticoagulants:  Patients who receive concomitant capecitabine and oral 
coumadin-derivative anticoagulant therapy such as warfarin should have their 
anticoagulant response (INR or prothrombin time) monitored frequently in order to 
adjust the anticoagulant dose. 
 
Phenytoin:  Monitor phenytoin levels in patients taking capecitabine concomitantly 
with phenytoin.  The phenytoin dose may need to be reduced. 
 
Leucovorin:  The concentration of 5-FU is increased and its toxicity may be 
enhanced by leucovorin. 
 
CYP2C9 substrates:  Patients who are treated with capecitabine and other sensitive 
CYP2C9 substrate or a CYP2C9 substrate with narrow therapeutic index should be 
closely monitored for toxicity. 
 
Because platinum-containing species are eliminated primarily through the kidneys, 
clearance of these products may be decreased by co-administration of potentially 
nephrotoxic compounds.  Co-administration of oxaliplatin with medicinal products 
known to cause nephrotoxicity is not recommended. 
 

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A7–4.2.3 
Prohibited Therapy for Atezo  CAPOX Arm 
Use of the following concomitant therapies is prohibited as described below: 
 
Concomitant therapy intended for the treatment of cancer (including, but not 
limited to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and 
herbal therapy), whether health authorityapproved or experimental, for 
various time periods prior to starting study treatment, depending on the agent 
(see Section 4.1.2), and during study treatment until disease progression is 
documented and the patient has discontinued study treatment, with the exception of 
palliative radiotherapy and radiotherapy to the brain under circumstances outlined in 
Section  A7–4.2.1  
 
Concomitant use of herbal therapies and traditional Chinese medicine with 
anti-cancer activity included in the label 
 
Investigational therapy within 28 days prior to initiation of study treatment and during 
study treatment 
 
Use of allopurinol during treatment with capecitabine 
 
Live, attenuated vaccines (e.g., FluMist) within 4 weeks prior to initiation of study 
treatment, during treatment with atezolizumab, and for 5 months after the final dose 
of atezolizumab 
 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) 
prior to initiation of study treatment and during study treatment because these 
agents could potentially increase the risk for autoimmune conditions when given in 
combination with atezolizumab 
 
A7–4.3 
CONTRACEPTION REQUIREMENTS FOR ATEZO  CAPOX ARM 
Contraception requirements for women and men in the Atezo  CAPOX arm are 
outlined below: 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate 
of  1% per year during the treatment period and for 5 months after the final 
dose of atezolizumab, 6 months after the final dose of capecitabine, and 
9 months after the final dose of oxaliplatin. 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 

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Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for 
3 months after the final dose of capecitabine, and 6 months after the final dose 
of oxaliplatin to avoid exposing the embryo.  Men must refrain from donating 
sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of preventing drug 
exposure.  If required per local guidelines or regulations, information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
Male patients should be advised regarding the conservation of sperm prior to 
treatment because of the possibility of irreversible infertility resulting from 
therapy with capecitabine and oxaliplatin. 
 
A7–5 
ASSESSMENT OF SAFETY FOR ATEZO  CAPOX ARM 
A7–5.1 
SAFETY PLAN FOR ATEZO  CAPOX ARM 
The safety plan for patients in this study is based on clinical experience with 
atezolizumab and CAPOX in completed and ongoing studies.  The anticipated important 
safety risks are outlined below (see Sections A7–5.1.1, A7–5.1.2, and A7–5.1.3).  
Guidelines for management of patients who experience specific adverse events are 
provided in Section A7–5.1.4. 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study. 

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Administration of study treatment will be performed in a monitored setting in which there 
is immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  Adverse events will be reported as described in 
Sections 5.45.6. 
A7–5.1.1 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, facial paresis, myelitis, 
meningoencephalitis, myocarditis, pericardial disorders, nephritis, myositis, and severe 
cutaneous adverse reactions.  In addition, immune-mediated reactions may involve any 
organ system and lead to hemophagocytic lymphohistiocytosis (HLH).  See Appendix 5 
of the protocol and Section 6 of the Atezolizumab Investigator's Brochure for a detailed 
description of anticipated safety risks for atezolizumab. 
A7–5.1.2 
Risks Associated with CAPOX 
In prior clinical trials of capecitabine, the following safety signals were identified:  
diarrhea, nausea, vomiting, stomatitis, cardiotoxicity, hepatotoxicity, hand–foot 
syndrome, and hematologic toxicity.  Patients should be advised to avoid prolonged 
exposure to sunlight because of the risk of photosensitivity with capecitabine. 
In prior clinical trials of oxaliplatin, the following safety signals were identified:  sensory 
and/or motor neuropathy, allergic reactions, pharyngolaryngeal dysesthesia, interstitial 
lung disease and pulmonary fibrosis, hepatotoxicity, and hematologic toxicity. 
For more details regarding the safety profile of capecitabine and oxaliplatin, see the 
respective local prescribing information. 
A7–5.1.3 
Risks Associated with Combination Use of Atezolizumab 
and CAPOX 
The following adverse events are potential overlapping toxicities associated with 
combination use of atezolizumab and CAPOX:  hepatic, gastrointestinal (primarily, 
diarrhea), hepatotoxicity, and pulmonary events. 
Neutropenia and lymphopenia associated with chemotherapy may increase the risk for 
developing infection in patients receiving atezolizumab in combination with 
chemotherapy. 

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A7–5.1.4 
Management of Patients Who Experience Specific Adverse 
Events in the Atezolizumab  CAPOX Arm 
A7–5.1.4.1 Dose Modifications 
Atezolizumab 
There will be no dose modifications for atezolizumab in this study. 
Capecitabine 
The capecitabine dose can be modified as presented in the Table 3 for the management 
of drug-related toxicities.  Once the dose has been reduced, it cannot be increased later.  
Omitted doses of capecitabine because of toxicity will not be replaced. 
Table 3 
Dose Modification for Capecitabine for Drug-Related Toxicities 
Toxicity a 
Action to Be Taken for 
Current Treatment 
Dose Modification for the  
Next Treatment 
(% of Starting Dose) 
Grade 1 
Maintain dose level. 
Maintain dose level. 
Grade 2 
 
 
First occurrence 
Withhold until resolved to Grade 1 
or better. 
100% (1000 mg/m2) 
Second occurrence 
75% (750 mg/m2) 
Third occurrence 
50% (500 mg/m2) 
Fourth occurrence 
Discontinue permanently. 
 
Grade 3 
 
 
First occurrence 
Withhold until resolved to Grade 1 
or better. 
75% (750 mg/m2) 
Second occurrence 
50% (500 mg/m2) 
Third occurrence 
Discontinue permanently. 
 
Grade 4 
 
 
First occurrence 
Discontinue permanently or 
continue at the discretion of the 
investigator once the event has 
resolved to Grade 1 or better. 
50% (500 mg/m2) 
a Graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 5.0. 
  
Oxaliplatin 
Dose Modifications for Patients with Neurotoxicity 
 
For Grade 2 peripheral sensory neuropathy (moderate paresthesia or dysesthesia) 
or limiting instrumental activities of daily living, omit oxaliplatin.  When toxicity 
resolves to Grade 1 or better, resume oxaliplatin to 75% of the initial dose.  
If oxaliplatin is omitted for 6 weeks (two consecutive cycles) for neurologic toxicity, 
discontinue oxaliplatin. 

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 
For Grade 3 and 4 peripheral sensory neuropathy (severe paresthesia or 
dysesthesia) or limiting self-care activities of daily living), discontinue oxaliplatin. 
 
Dose Modifications for Patients with Renal Impairment 
 
For normal renal function or mild to moderate renal impairment (creatinine clearance 
 50 mL/min), the full dose of oxaliplatin can be administered. 
 
For severe renal impairment, the oxaliplatin dose should be reduced to 75% of the 
initial dose. 
 
Dose Modifications for Patients with Hematologic Toxicity 
 
For Grade 2 and 3 thrombocytopenia, the oxaliplatin dose should be reduced to 
75% of the initial dose.  For Grade 4 thrombocytopenia, the dose should be reduced 
to 50% of the initial dose. 
 
For Grade 3 and 4 neutropenia or febrile neutropenia, the oxaliplatin dose should be 
reduced to 75% of the initial dose. 
 
A7–5.1.4.2 Treatment Interruption for Toxicities 
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity 
considered to be related to study treatment.  If corticosteroids are initiated for treatment 
of the toxicity, they must be tapered over  1 month to  10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed.  If atezolizumab is withheld for 
 12 weeks, the patient will be discontinued from atezolizumab.  However, atezolizumab 
may be withheld for  12 weeks to allow patients to taper off corticosteroids prior to 
resuming treatment.  Atezolizumab can be resumed after being withheld for  12 weeks if 
the patient is likely to derive clinical benefit.  The decision to re-challenge patients with 
atezolizumab should be based on the investigator’s benefitrisk assessment and 
documented by the investigator.  The Medical Monitor is available to advise as needed. 
The CAPOX treatment may be temporarily suspended in patients who experience 
toxicity considered to be related to study treatment.  If CAPOX has been withheld for 
 21 days because of toxicity, the patient should be discontinued from CAPOX, unless 
the patient is likely to derive clinical benefit.  The decision to re-challenge patients with 
CAPOX should be based on the investigator’s benefitrisk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
If one component of the combination (atezolizumab or CAPOX) is discontinued, the 
other component may be continued if the patient is likely to derive clinical benefit, as 
determined by the investigator.  The Medical Monitor is available to advise as needed.  
Treatment with CAPOX will continue for up to six cycles and patients will be offered 
continued treatment with atezolizumab as long as they are experiencing clinical benefit 
in the opinion of the investigator.  If oxaliplatin treatment is discontinued during the first 
six cycles, patients are encouraged to continue chemotherapy with capecitabine and 

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atezolizumab, as long as they are experiencing clinical benefit in the opinion of the 
investigator.  The Medical Monitor is available to advise as needed.  If capecitabine 
treatment is discontinued during the first six cycles, patients are encouraged to continue 
chemotherapy with oxaliplatin and atezolizumab, provided they are experiencing 
clinical benefit in the opinion of the investigator.  The Medical Monitor is available to 
advise as needed. 
A7–5.1.4.3 Management Guidelines for Adverse Events 
Appendix 5 provides guidelines for the management of patients who experience 
atezolizumab-associated adverse events.  It is recommended that atezolizumab be 
withheld or discontinued per the guidelines provided in Appendix 5. 
For cases in which management guidelines are not covered in Appendix 5, patients 
should be managed and treatments should be withheld or discontinued as deemed 
appropriate by the investigator according to best medical judgment. 
Guidelines for management of patients who experience specific adverse events related 
to CAPOX regimen are provided in Section A7–5.1.4.1.  The treating physician may use 
discretion in modifying the dose modification guidelines, depending on the severity of 
toxicity and an assessment of the benefit versus risk for the patient, with the goal of 
maximizing patient compliance and access to supportive care. 
Chemotherapy should be discontinued if ANC and platelets do not recover to  1000/L 
and  75,000/L, respectively, after treatment is delayed by 3 weeks. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A7–5.3 
REPORTING REQUIREMENTS FOR PREGNANCIES IN 
ATEZO  CAPOX ARM 
A7–5.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 5 months after the final dose of atezolizumab, 6 months after the final dose of 
capecitabine, or 9 months after the final dose of oxaliplatin.  A paper Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.  Pregnancy should not be recorded on the Adverse 
Event eCRF.  The investigator should discontinue study treatment and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly or birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available. 
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 

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Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
A7–5.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
3 months after the final dose of capecitabine or 6 months after the final dose of 
oxaliplatin.  The investigator should report the pregnancy on the paper Clinical Trial 
Pregnancy Reporting Form and submit the form to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the pregnancy), either by 
faxing or by scanning and emailing the form using the fax number or email address 
provided to investigators.  Attempts should be made to collect and report details of the 
course and outcome of any pregnancy in the partner of a male patient exposed to study 
treatment.  When permitted by the site, the pregnant partner would need to sign an 
Authorization for the Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  If the authorization has been signed, the investigator 
should submit a Clinical Trial Pregnancy Reporting Form with additional information on 
the pregnant partner and the course and outcome of the pregnancy as it becomes 
available. 
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
A7–5.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 

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more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form. 
A7–5.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly or birth defect in a child born to a female patient exposed to 
study treatment or the female partner of a male patient exposed to study treatment 
should be classified as a serious adverse event, recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
 

Appendix 7:  Study Details Specific to Atezo  CAPOX Arm (Control) (cont.) 
  
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
158/Protocol YO43408, Version 5 
A7–6 
SCHEDULE OF ACTIVITIES AND SAMPLE COLLECTION FOR ATEZO  CAPOX ARM 
Table 4 
Schedule of Activities for Atezo  CAPOX Arm 
Assessment or Procedure 
Stage 1 
Screening  
(see 
Appendix 6) 
Treatment Cycles (21-day cycles) a 
Treatment 
Discontinuation c 
Follow-Up  
Cycle 1 b 
Cycles  2 
Days 28 
to 1 
Day 1 
Day 1 
( 3 days) 
Every 3 Months 
Molecular profile of GC or GEJC 
(if available) 
See 
Appendix 6. 
Whenever updated information becomes available  
 
Vital signs d, e 
x 
x 
x 
 
Weight e 
x 
x 
x 
 
Complete physical examination f 
 
 
x 
 
Limited physical examination e, g 
x 
x 
 
 
ECOG Performance Status e 
x 
x 
x 
 
ECG e, h 
Perform as clinically indicated. 
 
 
Hematology i 
x j, k 
x j 
x 
 
Chemistry l 
x j. k 
x j 
x 
 
TSH, free T3 (or total T3),and free T4 m 
x j, k, m 
x 
 
C-reactive protein 
x j, k 
 
 
 
Pregnancy test o 
x j, k 
x j 
x 
x o 
Urinalysis p 
Perform as clinically indicated. 
 
 
 

Appendix 7:  Study Details Specific to Atezo  CAPOX Arm (Control) (cont.) 
  
Table 4 
Schedule of Activities for Atezo  CAPOX Arm (Control) (cont.) 
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
159/Protocol YO43408, Version 5 
Assessment or Procedure 
Stage 1 
Screening  
(see 
Appendix 6) 
Treatment Cycles (21-day cycles) a 
Treatment 
Discontinuation c 
Follow-Up  
Cycle 1 b 
Cycles  2 
Days 28 
to 1 
Day 1 
Day 1 
( 3 days) 
Every 3 Months 
Biomarker sample (blood, serum, plasma, 
and WBC) 
See 
Appendix 6. 
See Table 5. 
 
Tumor biopsy 
x q 
 
Tumor biopsy (optional) 
x r 
 
Stool sample (optional) 
x s 
x s 
 
 
Tumor response assessments 
x t, u 
 
Concomitant medications v 
x 
x 
x 
 
Adverse events w 
x  
x 
x w 
x w 
Atezolizumab administration x, y 
x 
x 
 
 
CAPOX administration x, z 
x 
x 
 
 
Survival follow-up and anti-cancer treatment 
 
 
 
x aa 
Atezo  atezolizumab; CAPOX  capecitabine plus oxaliplatin; CT  computed tomography; ECOG  Eastern Cooperative Oncology Group; 
eCRF  electronic Case Report Form; GC  gastric carcinoma; GEJC  gastroesophageal junction carcinoma;
 
Note:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
a 
If a visit is precluded because of a holiday, vacation, or other circumstance, it can occur outside of the specified window. 
b 
 
c 
Patients who discontinue study treatment will return to the clinic for a treatment discontinuation visit not more than 30 days after the final dose 
of study treatment.  The visit at which loss of clinical benefit is confirmed by the investigator (see Section 3.1.2 for details) may be used as the 
treatment discontinuation visit. 

Appendix 7:  Study Details Specific to Atezo  CAPOX Arm (Control) (cont.) 
  
Table 4 
Schedule of Activities for Atezo  CAPOX Arm (Control) (cont.) 
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
160/Protocol YO43408, Version 5 
d 
Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, pulse oximetry, 
and temperature.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  For the first infusion of 
atezolizumab, vital signs should be measured within 60 minutes prior to the infusion and, if clinically indicated, every 15 ( 5) minutes during 
and 30 ( 10) minutes after the infusion.  For subsequent infusions of atezolizumab, vital signs should be measured within 60 minutes prior to 
the infusion and, if clinically indicated or if symptoms occurred during the previous infusion, during and 30 ( 10) minutes after the infusion. 
e 
Assessment may be performed within 24 hours prior to dosing during the treatment period. 
f 
Complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  During visits when a patient will undergo a tumor 
assessment, the physical examination should include an evaluation of the presence and degree of enlarged lymph nodes, hepatomegaly, and 
splenomegaly.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
g 
Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  During visits when a 
patient will undergo a tumor assessment, the physical examination should include an evaluation of the presence and degree of enlarged lymph 
nodes, hepatomegaly, and splenomegaly.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
h 
It is recommended that patients be resting in a supine position for at least 10 minutes prior to ECG recording. 
i 
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, and other cells). 
j 
Laboratory tests must be performed within 96 hours prior to dosing during the treatment period. 
k 
If screening laboratory assessments were performed within 96 hours prior to Day 1 of Cycle 1, they do not have to be repeated. 
l 
Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if available), sodium, potassium, chloride, glucose, BUN or 
urea, creatinine, total protein, albumin, phosphate (or phosphorus), calcium, total bilirubin, ALP, ALT, AST, and lactate dehydrogenase (if 
available). 
m TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every four cycles 
thereafter (i.e., Cycles 5, 9, 13, and so on). 
n 
o 
All women of childbearing potential will have urine or serum pregnancy tests performed at specified visits during treatment and at 3 months and 
6 months after the final dose of study treatment.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 

Appendix 7:  Study Details Specific to Atezo  CAPOX Arm (Control) (cont.) 
  
Table 4 
Schedule of Activities for Atezo  CAPOX Arm (Control) (cont.) 
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
161/Protocol YO43408, Version 5 
p 
Urinalysis includes pH, specific gravity, glucose, protein (or albumin), ketones, and blood; dipstick permitted. 
q 
Patients will undergo tumor biopsy sample collection at the time of unacceptable toxicity or loss of clinical benefit as determined by the 
investigator (see Section 3.1.2 for details), if deemed clinically feasible by the investigator.  Biopsies should be performed within 40 days after 
determination of unacceptable toxicity, disease progression, or loss of clinical benefit, or prior to the next anti-cancer therapy, whichever is 
sooner.  See Section 4.5.7 for tissue sample requirements. 
r 
Patients who consent to optional biopsies will undergo tumor biopsy sample collection 8 weeks ( 7 days) after treatment initiation, if deemed 
clinically feasible and may undergo additional on-treatment biopsies at any other time at the investigator's discretion. 
s 
Patients who consent to providing optional stool sample will receive the collection device for the stool sample prior to Day1 of Cycle1 and 
Day 1 of Cycle 3.  Samples to be collected by predose (i.e., before the visit).  Patients will be instructed to return the collection device with the 
stool sample to the site on the Day 1, Cycle 1 and Day 1, Cycle 3 ( 1 week) visit.  If a patient does not return the collection device at the Day 1, 
Cycle 3 visit, he or she may return the collection device at the Day 1, Cycle 4 visit. 
t 
Patients will undergo tumor assessments every 6 weeks ( 1 week) during the first 48 weeks (from Day 1 of Cycle 1) and then every 12 weeks 
( 2 weeks) thereafter, regardless of dose delays until confirmed radiographic disease progression, except in the case of patients who continue 
treatment after radiographic disease progression; such patients will undergo tumor assessments every 6 weeks ( 1 week) until loss of clinical 
benefit as determined by the investigator (see Section 4.5.6 for details).  Thus, tumor assessments are to continue according to schedule in 
patients who discontinue treatment for reasons other than loss of clinical benefit, even if they start new nonprotocol-specified anti-cancer 
therapy. 
u 
All measurable and/or evaluable lesions identified at baseline should be re-assessed at subsequent tumor evaluations according to the tumor 
assessment schedule.  Brain metastases identified at baseline that have been treated with radiotherapy or surgery will not be considered 
measurable or evaluable unless there is suspected disease progression in the brain (i.e., the patient becomes symptomatic).  Thus, subsequent 
head scans are not required unless clinically indicated.  The same radiographic procedures used to assess disease sites at screening should 
be used for subsequent tumor assessments (e.g., the same contrast protocol for CT scans). 
v 
Concomitant medication includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, 
nutritional supplements) used by a patient in addition to protocol-mandated study treatment from 7 days prior to initiation of study treatment until 
the treatment discontinuation visit. 

Appendix 7:  Study Details Specific to Atezo  CAPOX Arm (Control) (cont.) 
  
Table 4 
Schedule of Activities for Atezo  CAPOX Arm (Control) (cont.) 
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
162/Protocol YO43408, Version 5 
w 
After initiation of study treatment, all adverse events will be reported until 30 days after the final dose of study treatment or until initiation of a 
new systemic anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of special interest will continue to be 
reported until 
 days after the final dose of study treatment or until initiation of a new systemic anti-cancer therapy, whichever occurs first.  
After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes 
aware of any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6).  The investigator 
should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, 
the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to 
be related to study treatment or trial-related procedures until a final outcome can be reported. 
x 
Treatment will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator (see Section 3.1.2 for details). 
y 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle.  The initial dose of atezolizumab 
will be delivered over 60 ( 15) minutes.  Subsequent infusions will be delivered over 30 ( 10) minutes if the previous infusion was tolerated 
without infusion-associated adverse events, or 60 ( 15) minutes if the patient experienced an infusion-associated adverse event with the 
previous infusion.  See Section A7–4.1.2.1 for details on atezolizumab infusions (including measurement of vital signs). 
z 
Capecitabine (1000 mg/m2) will be administered orally twice daily on Days 114 and oxaliplatin (130 mg/m2) will be administered by IV infusion 
on Day 1 and at least 5 minutes after completion of the atezolizumab infusion.  Treatment will continue for up to six cycles. 
aa After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) 
will be collected by means of telephone calls, patient medical records, and/or clinic visits approximately every 3 months or more frequently until 
death (unless the patient withdraws consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from follow-up, this 
request must be documented in the source documents and signed by the investigator.  If a patient withdraws from the study, the study staff may 
use a public information source (e.g., county records) to obtain information about survival status only.  For an experimental arm, in which all 
patients discontinued treatment and passed the safety follow-up window, as well as approximately 80% of patients discontinued the study, the 
Sponsor may conclude the arm (the remaining approximately 20% of patients will be discontinued from the study). 
 

Appendix 7:  Study Details Specific to Atezo  CAPOX Arm (Control) (cont.) 
 
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
163/Protocol YO43408, Version 5 
Table 5 
Schedule of Pharmacokinetic, Anti-Drug Antibody, and Blood 
Biomarker Samples for AtezoCAPOX Arm 
Visit 
Time 
Sample Type 
Day 1 of Cycle 1 
Prior to infusion 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 Biomarker (serum and blood) 
 Biomarker (plasma and WBC ) a 
30 ( 10) minutes after end 
of atezolizumab infusion 
 Atezolizumab PK (serum) 
Day 1 of Cycles 2, 3, 4, 8, 
12, and 16 
Prior to infusion 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 Biomarker (serum and blood) on 
Day 1 of Cycles 2 and 3 only 
Treatment discontinuation 
visit ( 30 days after final 
dose) 
At visit 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 Biomarker (serum and blood ) 
 Biomarker (plasma) a 
ADA  anti-drug antibody; Atezo  atezolizumab; CAPOX  capecitabine plus oxaliplatin; 
ctDNA  circulating tumor DNA; PK  pharmacokinetic; WES  whole exome sequencing. 
Note:  On the basis of emerging safety or efficacy data, the number of PK and ADA samples 
may be reduced or sample collection may cease altogether.  Additionally, collected samples 
may not be analyzed if not warranted.  Blood collections for biomarker assessment 
(e.g., cytokines, chemokines, gene expression profiling, ctDNA and WES of WBC-derived 
DNA as germline control) are applicable only after approval from local regulatory authorities.  
Based on emerging biomarker data, the number of biomarker samples may be reduced or 
sample collection may cease altogether. 
a 
 Blood collected at site for central processing of plasma and WBC samples. 

Appendix 7:  Study Details Specific to Atezo  CAPOX Arm (Control) (cont.) 
  
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
164/Protocol YO43408, Version 5 
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165/Protocol YO43408, Version 5 
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Appendix 8  
Study Details Specific to Atezo  CAPOX  Tira Arm 
TABLE OF CONTENTS 
A8–1 
Background on Atezo  CAPOX  Tira Arm .......................... 170 
A8–1.1 
Background on Atezolizumab ................................................ 170 
A8–1.2 
Background on CAPOX ......................................................... 170 
A8–1.3 
Background on Tiragolumab .................................................. 170 
A8–2 
Rationale for Atezo  CAPOX  Tira Arm .............................. 171 
A8–2.1 
The PD-L1 Pathway ............................................................... 171 
A8–2.2 
Effect of CAPOX on the Immune Tumor Microenvironment .. 172 
A8–2.3 
The TIGIT Pathway ................................................................ 172 
A8–2.4 
Combination Treatment with Atezolizumab, CAPOX, and 
Tiragolumab ........................................................................... 173 
A8–2.5 
Clinical Studies of Atezolizumab in Combination with 
CAPOX .................................................................................. 174 
A8–2.6 
Clinical Studies of Tiragolumab ............................................. 175 
A8–2.6.1 
Study GO30103 ..................................................................... 175 
A8–2.6.2 
Study GO40290 ..................................................................... 175 
A8–2.7 
Benefit–Risk Assessment ...................................................... 176 
A8–3 
Rationale for Dose and Schedule for 
Atezo  CAPOX  Tira Arm ................................................... 177 
A8–3.1 
Rationale for Atezolizumab Dose and Schedule .................... 177 
A8–3.2 
Rationale for CAPOX Dose and Schedule ............................. 177 
.................... 177 
A8–4 
Materials and Methods Specific to Atezo  CAPOX .............. 178 
A8–4.1 
Treatment in Atezo  CAPOX  Tira Arm .............................. 178 
A8–4.1.1 
Formulation and Packaging ................................................... 178 
A8–4.1.1.1 
Atezolizumab ......................................................................... 178 
A8–4.1.1.2 
CAPOX .................................................................................. 178 
A8–4.1.1.3 
Tiragolumab ........................................................................... 178 
A8–4.1.2 
Dosage, Administration, and Compliance .............................. 178 
A8–4.1.2.1 
Atezolizumab ......................................................................... 179 
A8–4.1.2.2 
CAPOX .................................................................................. 181 
A8–4.1.2.3 
Tiragolumab ........................................................................... 181 

Appendix 8:  Study Details Specific to Atezo  CAPOX  Tira Arm (cont.) 
  
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168/Protocol YO43408, Version 5 
A8–4.2 
Concomitant Therapy for Atezo  CAPOX  Tira Arm ........... 183 
A8–4.2.1 
Permitted Therapy for Atezo  CAPOX  Tira Arm ................ 183 
A8–4.2.2 
Cautionary Therapy for Atezo  CAPOX  Tira Arm .............. 184 
A8–4.2.2.1 
Corticosteroids, Immunosuppressive Medications, and 
Tumor Necrosis Factor Inhibitors ....................................... 184 
A8–4.2.2.2 
Herbal Therapies ................................................................... 184 
A8–4.2.2.3 
Medications Given with Precaution Concomitantly with 
CAPOX .................................................................................. 185 
A8–4.2.3 
Prohibited Therapy for Atezo  CAPOX  Tira Arm ............... 185 
A8–4.3 
Contraception Requirements for Atezo  CAPOX  Tira 
Arm ........................................................................................ 186 
A8–5 
Assessment of Safety for atezo  CAPOX  Tira Arm ........... 187 
A8–5.1 
Safety Plan for Atezo  CAPOX  Tira Arm ........................... 187 
A8–5.1.1 
Risks Associated with Atezolizumab ...................................... 187 
A8–5.1.2 
Risks Associated with CAPOX ............................................... 187 
A8–5.1.3 
Risks Associated with Tiragolumab ....................................... 188 
A8–5.1.3.1 
Infusion-Related Reactions .................................................... 188 
...................................... 188 
...................................... 189 
...................................... 189 
A8–5.1.3.5 
Embryofetal Toxicity .............................................................. 190 
A8–5.1.4 
Risks Associated with Combination Use of Atezolizumab, 
CAPOX, and Tiragolumab ..................................................... 190 
A8–5.1.5 
Management of Patients Who Experience Specific 
Adverse Events in Atezo  CAPOX  Tira Arm ...................... 190 
A8–5.1.5.1 
Dose Modifications ................................................................ 190 
A8–5.1.5.2 
Treatment Interruption for Toxicities ...................................... 192 
A8–5.1.5.3 
Management Guidelines for Adverse Events ......................... 193 
. 193 
A8–5.3 
Reporting Requirements for Pregnancies in 
Atezo  CAPOX  Tira Arm ................................................... 194 
A8–5.3.1 
Pregnancies in Female Patients ............................................ 194 

Appendix 8:  Study Details Specific to Atezo  CAPOX  Tira Arm (cont.) 
  
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169/Protocol YO43408, Version 5 
A8–5.3.2 
Pregnancies in Female Partners of Male Patients ................. 195 
A8–5.3.3 
Abortions................................................................................ 196 
A8–5.3.4 
Congenital Anomalies/Birth Defects ...................................... 196 
A8–6 
Schedule of Activities and Sample Collection for 
Atezo  CAPOX  Tira Arm ................................................... 197 
 
 

Appendix 8:  Study Details Specific to Atezo  CAPOX  Tira Arm (cont.) 
  
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
170/Protocol YO43408, Version 5 
A8–1 
BACKGROUND ON ATEZO  CAPOX  TIRA ARM 
A8–1.1 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab is a humanized IgG1 monoclonal antibody that targets programmed 
deathligand 1 (PD-L1) and inhibits the interaction between PD-L1 and its receptors, 
programmed death1 (PD-1) and B7-1 (also known as CD80), both of which function as 
inhibitory receptors expressed on T cells.  Therapeutic blockade of PD-L1 binding by 
atezolizumab has been shown to enhance the magnitude and quality of tumor-specific 
T-cell responses, resulting in improved anti-tumor activity (Fehrenbacher et al. 2016; 
Rosenberg et al. 2016).  Atezolizumab has minimal binding to fragment crystallizable 
(Fc) receptors, thus eliminating detectable Fc-effector function and associated 
antibody-mediated clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy. 
Atezolizumab is approved for the treatment of urothelial carcinoma, nonsmall cell lung 
cancer (NSCLC), small-cell lung cancer, triple-negative breast cancer, hepatocellular 
carcinoma, melanoma, and alveolar soft part sarcoma. 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and 
clinical studies. 
A8–1.2 
BACKGROUND ON CAPOX 
The combination of capecitabine and oxaliplatin (CAPOX) in the first-line treatment 
setting of human epidermal growth factor 2 (HER2)-negative gastric carcinoma (GC) is 
the standard of care recommended by oncology guidelines (National Comprehensive 
Cancer Network 2021; Wang et al. 2021).  The CAPOX regimen demonstrated survival 
benefit in patients with GC in the first-line treatment Phase II studies, with median 
progression-free survival (PFS) of about 67 months and overall survival (OS) of about 
1213 months (Park et al. 2008; Kim et al. 2012).  In addition, the convenience of the 
CAPOX regimen (oral capecitabine every 2 weeks plus oxaliplatin administered by IV 
infusion in a 3-week cycle) has favored increased implementation of this regimen in 
clinical practice globally. 
A8–1.3 
BACKGROUND ON TIRAGOLUMAB 
Tiragolumab is a fully human IgG1/ monoclonal antibody that binds to T-cell 
immunoreceptor with Ig and ITIM domains (TIGIT) and prevents its interaction with 
CD155 (also known as poliovirus receptor [PVR]).  Therapeutic blockade of TIGIT by 

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tiragolumab represents an attractive strategy for cancer therapy and is expected to 
enhance the magnitude and quality of tumor-specific T-cell responses, which may result 
in improved meaningful anti-tumor activity when tiragolumab is used in combination with 
other cancer immunotherapies and administered with chemotherapy.  The available 
nonclinical and clinical data provide a strong rationale for evaluating the potential clinical 
benefit of tiragolumab in cancer patients. 
Refer to the Tiragolumab Investigator’s Brochure for details on nonclinical and 
clinical studies. 
A8–2 
RATIONALE FOR ATEZO  CAPOX  TIRA ARM 
A8–2.1 
THE PD-L1 PATHWAY 
Encouraging clinical data emerging in the field of tumor immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced malignancies 
(Hodi et al. 2010; Kantoff et al. 2010; Chen et al. 2012). 
The PD-L1 pathway serves as an immune checkpoint to temporarily dampen immune 
responses in states of chronic antigen stimulation, such as chronic infection or cancer.  
PD-L1 is an extracellular protein that downregulates immune responses through binding 
to its two receptors, PD-1 and B7-1.  PD-1 is an inhibitory receptor expressed on T cells 
following T-cell activation, and expression is sustained in states of chronic stimulation 
(Blank et al. 2005; Keir et al. 2008).  B7-1 is a molecule expressed on 
antigen-presenting cells and activated T cells.  Binding of PD-L1 to PD-1 and B7-1 
inhibits T-cell proliferation and activation, cytokine production, and cytolytic activity, 
leading to the functional inactivation or exhaustion of T cells (Butte et al. 2007; 
Yang et al. 2011).  Overexpression of PD-L1 on tumor cells has been reported to impede 
anti-tumor immunity, resulting in immune evasion (Blank and Mackensen 2007).  
Therefore, interruption of the PD-L1 pathway represents an attractive strategy for 
restoring tumor-specific T-cell immunity. 
Targeting the PD-L1 pathway with atezolizumab has demonstrated activity in patients 
with advanced malignancies who have failed standard-of-care therapies.  Objective 
responses have been observed across a broad range of malignancies, including 
NSCLC, urothelial carcinoma, renal cell carcinoma, melanoma, colorectal cancer, head 
and neck cancer, GC, breast cancer, and sarcoma (see Atezolizumab Investigator's 
Brochure for detailed efficacy results). 
A number of studies have indicated a role for PD-L1 in gastric carcinogenesis.  In case 
studies, PD-L1 was expressed in tumor cells in 42%65% of patients with GC (Wu et al. 
2006; Geng et al. 2015; Kim et al. 2016).  AntiPD-1 inhibitors (i.e., nivolumab and 

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pembrolizumab) have been investigated in the treatment of GC and have demonstrated 
anti-tumor activity.  In the Phase III ATTRACTION-2 study, nivolumab monotherapy has 
demonstrated superior OS benefit versus placebo (hazard ratio [HR]: 0.63) in the 
third- and subsequent-line GC and gastroesophageal carcinoma (GEJC) settings 
(Kang et al. 2017).  In the Phase II KEYNOTE-059 study, pembrolizumab 
monotherapy achieved a 33% overall response rate (ORR) by investigator assessment 
and 22% by central data review in patients with GC with PD-L1expressing tumors 
(Bang et al. 2015). 
A8–2.2 
EFFECT OF CAPOX ON THE IMMUNE TUMOR 
MICROENVIRONMENT 
There is increasing evidence that in addition to causing tumor cell death, certain 
conventional chemotherapies may have immunogenic effects (Zitvogel et al. 2008). 
Oxaliplatin, a component of CAPOX, is one of a limited number of anti-cancer agents 
that has been shown to induce immunogenic cell death, eliciting immune responses as a 
result of calreticulin exposure and release of adenosine triphosphate and high-mobility 
group protein (Green et al. 2009; Tesniere et al. 2010; Michaud et al. 2011).  In a murine 
nonclinical model with transplantable and transgene-driven cancers, oxaliplatin has been 
shown to trigger tumor-targeting immune responses (Shalapour et al. 2015).  
Capecitabine, an orally administered tumor-activated 5-fluorouracil (5-FU) prodrug, is 
metabolized to 5-FU by means of a three-step enzymatic cascade after oral 
administration (Reigner et al. 2012).  The treatment of tumor-bearing mice with 5-FU 
results in selective reduction of myeloid-derived suppressor cells in the tumor bed, 
without significant depletion of T cells, natural killer (NK) cells, dendritic cells, or B cells, 
a corresponding increase in interferon- production by CD8-positive tumor-infiltrating 
lymphocytes was observed (Vincent et al. 2010).  The preclinical results suggesting that 
treatment with oxaliplatin and capecitabine may enhance anti-tumor immunity. 
A8–2.3 
THE TIGIT PATHWAY 
TIGIT is an immune inhibitory receptor that is a member of the immunoglobulin 
superfamily.  TIGIT is expressed on the surface of activated T-cell and NK-cell subsets 
and interacts with high affinity with CD155 (also known as PVR) (Yu et al. 2009).  
Genetic ablation of TIGIT in T cells in mice results in exacerbated T-cell responses in 
nonclinical models of autoimmune and viral infections, demonstrating the role of TIGIT in 
inhibiting T-cell responses (Joller et al. 2011; Johnston et al. 2014).  TIGIT expression is 
elevated in the tumor microenvironment in many human tumors, is concordantly 
expressed with other immune checkpoint receptors such as PD-1 on the surface of 
T cells, and is associated with impaired T-cell function and anti-tumor immunity 
(Johnston et al. 2014; Manieri et al. 2017).  Activation of TIGIT on T cells and NK cells 
limits cellular proliferation, effector cytokine production, and killing of target tumor cells 

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(Stanietsky et al. 2009; Yu et al. 2009; Johnston et al. 2014; Wang et al. 2015; 
Manieri et al. 2017). 
TIGIT is expressed in a wide variety of human tumors, including most solid tumors, such 
as NSCLC, breast cancer, hepatocellular carcinoma, and melanoma, and hematologic 
tumors, such as multiple myeloma and non-Hodgkin lymphoma, and 
fluorescence-activated cell sorting analysis of T cells isolated from fresh tumor samples 
revealed that TIGIT and PD-1 are also co-expressed on tumor-infiltrating T cells 
(Johnston et al. 2014; Yadav et al. 2016; He et al. 2017; Yang 2016; Guillerey at al. 
2018; Duan et al. 2019).  TIGIT expression was 30%80% and 50%80% on 
tumor-infiltrating CD4 and CD8 T cells, respectively (Johnston et al. 2014). 
Therefore, TIGIT is a potential target for therapeutic intervention, aimed at restoring the 
immune response against the tumor.  Agents that inhibit TIGIT interaction with PVR may 
inhibit an important source of tumor-associated immune suppression and therefore may 
enhance the activity of other immune-based therapies.  Nonclinical studies using 
blocking antibodies in genetically deficient mice have revealed a key role for TIGIT in 
regulating T-cell responses in cancer.  Together, the data support the hypothesis that 
anti-TIGIT may reactivate anti-tumor immunity and provide clinical benefits to patients 
with cancer. 
A8–2.4 
COMBINATION TREATMENT WITH ATEZOLIZUMAB, CAPOX, 
AND TIRAGOLUMAB 
Chemotherapy may modulate tumor and immune-system interactions in favor of the 
immune system, resulting in tumor cell death with a resultant increase in tumor antigen 
delivery to antigen-presenting cells.  Tumor cell death may also lead to a reduction in 
soluble and membrane-bound factors inhibiting tumor-infiltrating T cells.  Chemotherapy 
may also disrupt immune system regulatory networks by decreasing the number of 
T-regulatory cells.  Immunogenic chemotherapy such as oxaliplatin combination with 
immune checkpoint can trigger T-cell infiltration to tumors and provide additive or 
synergistic anti-tumor activity in vivo and is expected to contribute to durable anti-tumor 
responses (Pfirschke and Engblom 2016). 
Recently, CheckMate-649 (NCT02872116), a Phase III trial investigating nivolumab plus 
chemotherapy or nivolumab plus ipilimumab compared with chemotherapy alone in the 
first-line treatment of patients with metastatic HER2-negative GC and GEJC, showed 
improved OS (14.4 vs. 11.1 months; HR: 0.71) (Moehler et al. 2020).  An OS benefit 
(13.8 vs. 11.6 months; HR: 0.80) was also seen in the all-randomized population.  With 
the recent regulatory approval, this practice changing study has established 
chemotherapy plus nivolumab as a new standard of care for the first-line treatment of 
patients with HER2-negative GC and GEJC. 

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Resistance to PD-L1/PD-1 blockade may result in the expression of multiple co-inhibitory 
receptors on the surface of effector T cells.  Nonclinical tumor models have shown that 
TIGIT selectively suppresses the effector function of chronically stimulated CD8+ T cells 
and that inhibiting both TIGIT and PD-L1/PD-1 results in superior efficacy compared with 
single-agent treatments (Johnston et al. 2014).  Higher levels of PD-1+, TIGIT+, CD8+ 
T cells have been reported in GC and are associated with hyporesponsive anti-tumor 
immunity and poor prognosis (Xu et al. 2020).  Hence, targeting TIGIT and PD-L1 with 
tiragolumab and atezolizumab, respectively, may enhance the efficacy of PD-L1/PD-1 
blockade across different cancer types, including GC and GEJC (see Section A8–2.6 for 
a description of clinical studies of tiragolumab combined with atezolizumab). 
Based on the above-described data, it is hypothesized that combination treatment with 
atezolizumab, CAPOX, and tiragolumab may augment the anti-tumor immune response, 
resulting in improved and more durable clinical benefit in patients with GC and GEJC. 
A8–2.5 
CLINICAL STUDIES OF ATEZOLIZUMAB IN COMBINATION 
WITH CAPOX 
Capecitabine, an orally administered tumor-activated 5-FU prodrug, is metabolized to 
5-FU by means of a three-step enzymatic cascade after oral administration 
(Reigner et al. 2001).  The safety and the preliminary anti-tumor activity of the 
combination of atezolizumab, bevacizumab, and FOLFOX (5-FU  oxaliplatin) have been 
evaluated in the Phase I Study GP28328 in oxaliplatin treatmentnaive patients with 
solid tumors, including metastatic colorectal cancer.  Adverse events observed thus far 
are consistent with the known risks of each study treatment.  Atezolizumab in 
combination with cytotoxic chemotherapy has not been associated with additive severe 
(Grade  3) toxicities, indicating that atezolizumab can be safely combined with standard 
chemotherapy. 
As of the clinical cutoff date, 1 September 2015, 23 efficacy-evaluable oxaliplatin 
treatmentnaive patients with metastatic colorectal cancer had been treated in the 
first-line setting.  Investigator-assessed ORR (confirmed response as assessed by the 
investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 
[RECIST v1.1]) was 52.2% and all 12 responders had partial responses.  The median 
investigator-assessed duration of response per RECIST v1.1 for the 12 responders was 
11.4 months.  The median investigator-assessed PFS according to RECIST v1.1 was 
14.1 months. 
Detailed clinical study results for atezolizumab can be found in the Atezolizumab 
Investigator's Brochure. 

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A8–2.6 
CLINICAL STUDIES OF TIRAGOLUMAB 
Tiragolumab is currently under investigation in two ongoing clinical studies (GO30103 
and GO40290) in patients with solid tumors. 
A8–2.6.1 
Study GO30103 
Study GO30103 is a first-in-human, Phase I, open-label, dose-escalation, and 
dose-expansion study of tiragolumab as a single agent and in combination with 
atezolizumab in patients with locally advanced, recurrent, or metastatic incurable tumors, 
including urothelial carcinoma, renal cell carcinoma, NSCLC, head and neck squamous 
cell carcinoma, esophageal cancer, colorectal cancer, GC, cholangiocarcinoma, and 
triple-negative breast cancer. 
As of 2 December 2020, a total of 236 patients had been enrolled in Study GO30103.  
Of the 236 patients, 42 patents were enrolled in the Phase Ia portion of the study across 
tiragolumab dose levels from 2 mg to 1200 mg every 3 weeks (Q3W) and 217 patients 
were enrolled in the Phase Ib portion of the study across tiragolumab dose levels from 
2 mg to 1200 mg Q3W in combination with 1200 mg atezolizumab Q3W, including 
23 patients who crossed over from the Phase Ia portion.  One patient in the Phase Ib 
portion of the study was enrolled in the study at the 30-mg tiragolumab dose level but 
was not treated with any study drug. 
Overall, from the combined Phase Ia and Ib portions of Study GO30103, the Eastern 
Cooperative Oncology Group (ECOG) Performance Status at screening for the 
safety-evaluable population was 0 or 1 in 29.8% and 70.2% of patients, respectively.  
The most common cancer types reported in  10 patients in this study population were 
NSCLC (19.1%), breast, and head and neck cancer (9.8% each), esophageal and colon 
cancer (8.5% each), ovarian cancer (6.4%), and kidney, melanoma, and stomach cancer 
(4.7% each).  
A8–2.6.2 
Study GO40290 
Study GO40290 is a Phase II, randomized, blinded, placebo-controlled study of 
tiragolumab plus atezolizumab compared with placebo plus atezolizumab in previously 
untreated patients with locally advanced unresectable or metastatic PD-L1positive 
(defined as tumor proportion score [TPS]  1%) NSCLC. 
As of the data cutoff date, 30 June 2019, a total of 135 patients with a PD-L1 TPS  1% 
had received tiragolumab plus atezolizumab (n  67) or placebo plus atezolizumab 
(n  68).  In the intent-to-treat (ITT) population, the confirmed ORR was higher in the 
tiragolumab plus atezolizumab arm (31.3%) than the placebo plus atezolizumab arm 
(16.2%).  In the subgroup of patients with TPS  50%, the confirmed ORR was higher in 
the tiragolumab plus atezolizumab arm (n  29; 55.2% [95% CI: 35.4% to 75.0%]) than 

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the placebo plus atezolizumab arm (n  29; 17.2% [95% CI: 1.8% to 32.7%]).  Of note, 
responders in the tiragolumab plus atezolizumab arm included patients with both 
squamous and non-squamous histology. 
In the ITT population, investigator-assessed PFS was improved in the tiragolumab plus 
atezolizumab arm compared with the placebo plus atezolizumab arm (stratified HR: 0.57 
[95% CI: 0.37 to 0.90]; median PFS: 5.4 vs. 3.6 months, respectively).  In the subgroup 
of patients with TPS  50%, investigator-assessed PFS was improved in the tiragolumab 
plus atezolizumab arm compared with the placebo plus atezolizumab arm (unstratified 
HR: 0.33 [95% CI: 0.15 to 0.72]; median PFS: not estimable vs. 3.9 months, 
respectively). 
As of the data cutoff date, most adverse events have been Grade 1 or Grade 2.  Serious 
adverse events, Grade 35 adverse events, adverse events leading to discontinuation, 
and adverse events leading to death have been balanced between the two treatment 
arms.  Serious and high-grade treatment-related adverse events have also been 
balanced between the two treatment arms.  
 have 
been balanced between the two treatment arms, with the exception of a higher 
frequency of infusion-related reaction (IRR) and rash reported in the atezolizumab plus 
tiragolumab arm. 
 
 
 
 
Overall, tiragolumab in combination with atezolizumab has been well tolerated, adverse 
events have been manageable, and the safety profile seems to be consistent as 
reported across different solid tumor indications. 
Refer to the Tiragolumab Investigator’s Brochure for additional details on all ongoing and 
planned clinical studies. 
A8–2.7 
BENEFIT–RISK ASSESSMENT 
Taking into account the potentially synergistic mechanisms of action of tiragolumab and 
atezolizumab, as well as the preliminary efficacy and manageable safety profiles of the 
above-described combinations, treatment with atezolizumab, CAPOX, and tiragolumab 
(Atezo  CAPOX  Tira) may have therapeutic potential in solid tumors such as GC 
and GEJC. 

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For the evaluation of the impact of the (coronavirus disease 2019) COVID-19 pandemic 
on the benefitrisk assessment, please refer to Section 1.4. 
A8–3 
RATIONALE FOR DOSE AND SCHEDULE FOR 
ATEZO  CAPOX  TIRA ARM 
A8–3.1 
RATIONALE FOR ATEZOLIZUMAB DOSE AND SCHEDULE 
Atezolizumab will be administered at a fixed dose of 1200 mg Q3W (1200 mg on Day 1 
of each 21-day cycle), which is an approved dosage for atezolizumab (Tecentriq U.S. 
Package Insert). 
A8–3.2 
RATIONALE FOR CAPOX DOSE AND SCHEDULE 
The CAPOX regimen (1000 mg/m2 capecitabine taken orally twice a day for 14 days 
followed by 7 days off and 130 mg/m2 oxaliplatin administered intravenously on Day 1 
Q3W) at the recommended doses has been used in multiple Phase III trials (Boku et al. 
2019; Moehler et al. 2020) and represents an acceptable capecitabine/oxaliplatin 
combination for patients with GC and GEJC. 
Standard treatment for late-stage GC is recommended to be 4–6 months according to 
the Chinese Society of Clinical Oncology guidelines (Wang et al. 2021).  In this study, 
the discontinuation of chemotherapy beyond Cycle 6 (administered in 21-day cycles) will 
occur because the majority of patients with GC and GEJC achieve maximum tumor 
reduction by Cycle 6, and discontinuation of chemotherapy will improve the tolerability of 
continued dosing with maintenance treatment with atezolizumab. 

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A8–4 
MATERIALS AND METHODS SPECIFIC TO ATEZO  CAPOX 
A8–4.1 
TREATMENT IN ATEZO  CAPOX  TIRA ARM 
A8–4.1.1 
Formulation and Packaging 
A8–4.1.1.1 Atezolizumab 
The atezolizumab drug product will be supplied by the Sponsor as a 
 
-mL glass vial.  The vial contains approximately 
) of 
atezolizumab solution. 
For information on the formulation of atezolizumab, refer to the pharmacy manual and 
the Atezolizumab Investigator's Brochure. 
A8–4.1.1.2 CAPOX 
Refer to the oxaliplatin and capecitabine prescribing information for details on the 
respective formulations and storage instructions.  Oxaliplatin and capecitabine will be 
either provided by Sponsor or sourced commercially by sites. 
For information on the formulation, packaging, and handling of the CAPOX agents, refer 
to the local prescribing information for each agent. 
A8–4.1.1.3 Tiragolumab 
The tiragolumab drug product will be supplied by the Sponsor in 
-mL glass 
vials.  The vial contains 
 mL of tiragolumab.  The approximate concentration of 
tiragolumab antibody in each vial is 
 mg/mL. 
For information on the formulation of tiragolumab, refer to the pharmacy manual and the 
Tiragolumab Investigator's Brochure. 
A8–4.1.2 
Dosage, Administration, and Compliance 
Patients in the atezolizumab plus CAPOX plus tiragolumab (Atezo  CAPOX  Tira) arm 
will receive treatment as outlined in Table 1 until unacceptable toxicity or loss of clinical 
benefit as determined by the investigator after an integrated assessment of radiographic 
and biochemical data, local biopsy results (if available), and clinical status 
(e.g., symptomatic deterioration such as pain secondary to disease) (see Section 3.1.2 
for details). 
 
 

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Table 1 
Treatment Regimen for Atezo  CAPOX  Tira Arm 
Cycle Length 
Dose, Route, and Regimen 
(drugs listed in order of administration) 
21 days 
 
Atezolizumab 1200 mg by IV infusion on Day 1 
 
Tiragolumab 600 mg by IV infusion on Day 1 
 
Capecitabine 1000 mg/m2 orally twice a day on Days 114 a 
 
Oxaliplatin 130 mg/m2 by IV infusion on Day 1 a 
Atezo  atezolizumab; CAPOX  capecitabine plus oxaliplatin; Tira  tiragolumab. 
a 
Treatment for up to six cycles. 
  
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, 
and administration. 
Medication errors should be noted on the Study Drug Administration electronic Case 
Report Form (eCRF).  Cases of accidental overdose or medication error, along with any 
associated adverse events, should be reported as described in Section 5.3.5.12.  No 
safety data related to overdosing of atezolizumab or tiragolumab are available to date. 
A8–4.1.2.1 Atezolizumab 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle. 
Administration of atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 4.  
Atezolizumab infusions will be administered per the instructions outlined in Table 2. 
 
 

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Table 2 
Administration of First and Subsequent Atezolizumab Infusions 
First Infusion 
Subsequent Infusions 
 
No premedication is permitted prior to the 
atezolizumab infusion. 
 
Vital signs (pulse rate, respiratory rate, 
blood pressure, pulse oximetry, and 
temperature) should be recorded within 
60 minutes prior to the infusion. 
 
Atezolizumab should be infused over 
60 ( 15) minutes. 
 
If clinically indicated, vital signs should be 
recorded every 15 ( 5) minutes during the 
infusion and 30 ( 10) minutes after the 
infusion. 
 
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms. 
 
If the patient experienced an IRR with 
any previous infusion, premedication with 
antihistamines, antipyretic medications, 
and/or analgesics may be administered 
for subsequent doses at the discretion of 
the investigator. 
 
Vital signs should be recorded within 
60 minutes prior to the infusion. 
 
Atezolizumab should be infused over 
30 ( 10) minutes if the previous infusion 
was tolerated without an IRR, or 
60 ( 15) minutes if the patient 
experienced an IRR with the previous 
infusion. 
 
If the patient experienced an IRR with the 
previous infusion or if clinically indicated, 
vital signs should be recorded during the 
infusion and at 30 ( 10) minutes after the 
infusion. 
IRR  infusion-related reaction. 
  
Guidelines for medical management of IRRs for atezolizumab are provided in 
Appendix 5. 
No dose modification for atezolizumab is allowed.  Guidelines for treatment interruption 
or discontinuation because of toxicities are provided in Section A8–5.1.5.  Atezolizumab 
treatment may be interrupted for reasons other than toxicity (e.g., surgical procedures).  
The acceptable length of treatment interruption must be based on the investigator's 
benefitrisk assessment and in alignment with the protocol requirements for the duration 
of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 

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A8–4.1.2.2 CAPOX 
Treatment will be administered as follows during each 21-day cycle for up to six cycles: 
 
Capecitabine (1000 mg/m2) orally twice a day on Days 114 
 
Oxaliplatin (130 mg/m2) by IV infusion on Day 1 and at least 5 minutes after 
completion of the tiragolumab infusion 
 
The rates of drug administration for oxaliplatin may follow the institutional guidelines.  
Patients may be premedicated with 5-HT3receptor antagonists or other standard of care 
methods to control nausea and vomiting.  Premedication with steroids should be limited 
when clinically feasible, because of their immunosuppressant effects.  All medications 
must be recorded on the appropriate Concomitant Medications eCRF. 
Guidelines for dosage modification and treatment interruption or discontinuation because 
of toxicities are provided in Section A8–5.1.5.  CAPOX treatment may be interrupted for 
reasons other than toxicity (e.g., surgical procedures).  The acceptable length of 
treatment interruption must be based on the investigator's benefitrisk assessment and 
in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator.  The Medical Monitor is available to advise as needed. 
A8–4.1.2.3 Tiragolumab 
Tiragolumab will be administered by IV infusion at a fixed dose of 600 mg on Day 1 of 
each 21-day cycle with a post-infusion observation period as described in Table 3.  
On Day 1 of Cycle 1, tiragolumab will be administered 60 minutes after completion of the 
atezolizumab infusion.  The interval between subsequent infusions will be 30 minutes if 
the previous atezolizumab infusion was given without premedication and tolerated 
without an IRR or 60 minutes if the patient experienced an IRR with the previous 
atezolizumab infusion. 
Administration of tiragolumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  For anaphylaxis precautions, see Appendix 4.  
Tiragolumab infusions will be administered per the instructions in Table 3. 

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Guidelines for medical management of IRRs for tiragolumab are provided in Appendix 5. 
No dose modification for tiragolumab is allowed.  Guidelines for treatment interruption or 
discontinuation because of toxicities are provided in Section A8–5.1.5.  Tiragolumab 
treatment may be interrupted for reasons other than toxicity (e.g., surgical procedures).  
The acceptable length of treatment interruption must be based on the investigator's 
benefitrisk assessment and in alignment with the protocol requirements for the duration 
of treatment and documented by the investigator.  The Medical Monitor is available to 
advise as needed. 

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A8–4.2 
CONCOMITANT THERAPY FOR ATEZO  CAPOX  TIRA ARM 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated study treatment from 
7 days prior to initiation of study treatment to the treatment discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 
A8–4.2.1 
Permitted Therapy for Atezo  CAPOX  Tira Arm 
Patients are permitted to use the following therapies during the study: 
 
Oral contraceptives with a failure rate of  1% per year 
 
Hormone-replacement therapy 
 
Prophylactic or therapeutic anticoagulation therapy 
 
Vaccinations (such as influenza, COVID-19) 
 Live, attenuated vaccines are not permitted (see Section A8–4.2.3). 
 
Megestrol acetate administered as an appetite stimulant  
 
Mineralocorticoids (e.g., fludrocortisone) 
 
Inhaled corticosteroids administered for chronic obstructive pulmonary disease 
or asthma 
 
Low-dose corticosteroids administered for orthostatic hypotension or 
adrenocortical insufficiency 
 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic 
relief of pain) as outlined below: 
Palliative radiotherapy is permitted, provided it does not interfere with the 
assessment of tumor target lesions (e.g., the lesion to be irradiated must not be 
the only site of measurable disease).  Treatment with atezolizumab, 
tiragolumab, and CAPOX may be continued during palliative radiotherapy. 
 
Radiotherapy to the brain as outlined below: 
Patients whose extracranial tumor burden is stable or responding to study 
treatment and who are subsequently found to have three or fewer brain 
metastases may receive radiotherapy to the brain (either stereotactic 
radiosurgery or whole-brain radiotherapy) provided that all of the following 
criteria are met: 
– 
The patient has no evidence of progression or hemorrhage after completion 
of CNS-directed therapy. 
– 
The patient has no ongoing requirement for corticosteroids as therapy for 
CNS disease. 

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Patients who require corticosteroid therapy for more than 7 days after 
completion of radiotherapy must be discontinued from study treatment. 
– 
Anti-convulsant therapy, if required, is administered at a stable dose. 
 
Premedication with antihistamines, antipyretic medications, and/or analgesics may be 
administered for the second and subsequent atezolizumab and tiragolumab infusions 
only, at the discretion of the investigator. 
In general, investigators should manage a patient's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies as clinically indicated, per local standard practice.  Patients who 
experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor antagonists 
(e.g., famotidine, cimetidine), or equivalent medications per local standard practice.  
Serious infusion-associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen 
and 2-adrenergic agonists; see Appendix 4). 
A8–4.2.2 
Cautionary Therapy for Atezo  CAPOX  Tira Arm 
A8–4.2.2.1 
Corticosteroids, Immunosuppressive Medications, and 
Tumor Necrosis Factor Inhibitors 
Systemic corticosteroids, immunosuppressive medications, and tumor necrosis factor 
(TNF-) inhibitors may attenuate potential beneficial immunologic effects of treatment 
with atezolizumab and/or tiragolumab.  Therefore, in situations in which systemic 
corticosteroids, immunosuppressive medications, or TNF- inhibitors would be routinely 
administered, alternatives, including antihistamines, should be considered.  If the 
alternatives are not feasible, systemic corticosteroids, immunosuppressive medications, 
and TNF- inhibitors may be administered at the discretion of the investigator. 
Systemic corticosteroids or immunosuppressive medications are recommended, at 
the discretion of the investigator, for the treatment of specific adverse events 
when associated with atezolizumab and/or tiragolumab therapy (refer to Appendix 5 
for details). 
A8–4.2.2.2 Herbal Therapies 
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies not intended for the treatment of cancer (see 
Section A8–4.2.3) may be used during the study at the discretion of the investigator. 

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A8–4.2.2.3 Medications Given with Precaution Concomitantly with CAPOX 
The following medications should be used with precaution during treatment with CAPOX: 
 
Anticoagulants:  Patients who receive concomitant capecitabine and oral 
coumadin-derivative anticoagulant therapy such as warfarin should have their 
anticoagulant response (INR or prothrombin time) monitored frequently in order to 
adjust the anticoagulant dose.  
 
Phenytoin:  Monitor phenytoin levels in patients taking capecitabine concomitantly 
with phenytoin.  The phenytoin dose may need to be reduced. 
 
Leucovorin:  The concentration 5-FU is increased and its toxicity may be enhanced 
by leucovorin. 
 
CYP2C9 substrates:  Patients who are treated with capecitabine and other sensitive 
CYP2C9 substrate or a CYP2C9 substrate with narrow therapeutic index should be 
closely monitored for toxicity. 
 
Because platinum-containing species are eliminated primarily through the kidneys, 
clearance of these products may be decreased by co-administration of potentially 
nephrotoxic compounds.  Co-administration of oxaliplatin with medicinal products 
known to cause nephrotoxicity is not recommended. 
 
A8–4.2.3 
Prohibited Therapy for Atezo  CAPOX  Tira Arm 
Use of the following concomitant therapies is prohibited as described below: 
 
Concomitant therapy intended for the treatment of cancer (including, but not limited 
to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal 
therapy), whether health authorityapproved or experimental, for various time 
periods prior to starting study treatment, depending on the agent 
(see Section 4.1.2), and during study treatment until disease progression is 
documented and the patient has discontinued study treatment, with the exception of 
palliative radiotherapy and radiotherapy to the brain under circumstances outlined in 
Section A8–4.2.1 
 
Concomitant use of herbal therapies and traditional Chinese medicine with 
anti-cancer activity included in the label 
 
Investigational therapy within 28 days prior to initiation of study treatment and during 
study treatment 
 
Use of allopurinol during treatment with capecitabine 
 
Live, attenuated vaccines (e.g., FluMist) within 4 weeks prior to initiation of study 
treatment, during treatment with atezolizumab and/or tiragolumab, and for 5 months 
after the final dose of atezolizumab or 90 days after the final dose of tiragolumab, 
whichever is later 

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 
Systemic immunostimulatory agents (including, but not limited to, interferons and 
interleukin-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) 
prior to initiation of study treatment and during study treatment because such agents 
could potentially increase the risk for autoimmune conditions when given in 
combination with atezolizumab and/or tiragolumab 
 
A8–4.3 
CONTRACEPTION REQUIREMENTS FOR 
ATEZO  CAPOX  TIRA ARM 
Contraception requirements for women and men in the Atezo  CAPOX  Tira arm are 
outlined below: 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate 
of  1% per year during the treatment period and for 90 days after the final dose 
of tiragolumab, 5 months after the final dose of atezolizumab, 6 months after 
the final dose of capecitabine, and 9 months after the final dose of oxaliplatin. 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of contraception.  
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for 
3 months after final dose of capecitabine, 6 months after final dose of 
oxaliplatin, and for 90 days after the final dose of tiragolumab to avoid exposing 
the embryo.  Men must refrain from donating sperm during this same period. 

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The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of preventing drug 
exposure.  If required per local guidelines or regulations, information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
Male patients should be advised regarding the conservation of sperm prior to 
treatment because of the possibility of irreversible infertility resulting from 
therapy with capecitabine and oxaliplatin. 
 
A8–5 
ASSESSMENT OF SAFETY FOR ATEZO  CAPOX  TIRA ARM 
A8–5.1 
SAFETY PLAN FOR ATEZO  CAPOX  TIRA ARM 
The safety plan for patients in this study is based on clinical experience with 
atezolizumab, CAPOX, and tiragolumab in completed and ongoing studies.  The 
anticipated important safety risks are outlined below (see Sections A8–5.1.1, A8–5.1.2, 
A8–5.1.3, and A8–5.1.4).  Guidelines for management of patients who experience 
specific adverse events are provided in Section A8–5.1.5. 
Measures will be taken to ensure the safety of patients participating in this study, 
including the use of stringent inclusion and exclusion criteria and close monitoring of 
patients during the study.   
Administration of study treatment will be performed in a monitored setting in which there 
is immediate access to trained personnel and adequate equipment and medicine to 
manage potentially serious reactions.  Adverse events will be reported as described in 
Sections 5.45.6. 
A8–5.1.1 
Risks Associated with Atezolizumab 
Atezolizumab has been associated with risks such as the following:  IRRs and 
immune-mediated hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, facial paresis, myelitis, 
meningoencephalitis, myocarditis, pericardial disorders, nephritis, myositis, and severe 
cutaneous adverse reactions.  In addition, immune-mediated reactions may involve any 
organ system and lead to hemophagocytic lymphohistiocytosis (HLH).  See Appendix 5 
of the protocol and Section 6 of the Atezolizumab Investigator's Brochure for a detailed 
description of anticipated safety risks for atezolizumab. 
A8–5.1.2 
Risks Associated with CAPOX 
In prior clinical trials of capecitabine, the following safety signals were identified: 
diarrhea, nausea, vomiting, stomatitis, cardiotoxicity, hepatotoxicity, hand–foot 

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syndrome, and hematologic toxicity.  Patients should be advised to avoid prolonged 
exposure to sunlight because of the risk of photosensitivity with capecitabine. 
In prior clinical trials of oxaliplatin, the following safety signals were identified:  sensory 
and/or motor neuropathy, allergic reactions, pharyngolaryngeal dysesthesia, interstitial 
lung disease and pulmonary fibrosis, hepatotoxicity, and hematologic toxicity. 
For more details regarding the safety profile of capecitabine and oxaliplatin, see the 
respective local prescribing information. 
A8–5.1.3 
Risks Associated with Tiragolumab 
 
 While clinical evaluation of tiragolumab is limited and not all risks are 
known, as an antagonist of TIGIT, tiragolumab is anticipated to enhance T-cell and NK-
cell proliferation, survival, and function.  Therefore, tiragolumab may increase the risk of 
autoimmune inflammation (also described as 
 
A8–5.1.3.1 Infusion-Related Reactions 
 
  Clinical signs and symptoms of such reactions may include rigors, chills, 
wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. 
 
The 
majority of events were mild to moderate and manageable. 
To minimize the risk and sequelae of IRRs, 
 
 
Subsequent infusions and observation times may be shortened if the preceding infusion 
was well tolerated.  All infusions of tiragolumab will be administered in an appropriate 
medical setting. 
See Section A8–4.1.2.3 detailed guidance on administration of tiragolumab in this study.  
See Appendix 4 for guidance on anaphylaxis precautions and Appendix 5 for guidance 
on the management of IRRs. 
 
 
 
 

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A8–5.1.3.5 Embryofetal Toxicity 
 
 
 
 
  No reproductive or teratogenicity 
studies in animals have been conducted with tiragolumab.  There are no clinical studies 
of tiragolumab in pregnant women.  Tiragolumab should not be administered to pregnant 
women. 
Refer to Section 6 of the Tiragolumab Investigator’s Brochure for a detailed description 
of embryofetal toxicity. 
A8–5.1.4 
Risks Associated with Combination Use of Atezolizumab, 
CAPOX, and Tiragolumab 
The following adverse events are potential overlapping toxicities associated with 
combination use of atezolizumab with tiragolumab and CAPOX:  
 
 
 
Neutropenia and 
 associated with chemotherapy may aggravate the known 
adverse reaction of 
 for tiragolumab in combination with atezolizumab, and 
increase the risk for developing infection in patients receiving atezolizumab and 
tiragolumab in combination with chemotherapy. 
Given the mechanism of action for atezolizumab and tiragolumab, 
 
 are potential overlapping toxicities associated with combination use of 
these two agents. 
A8–5.1.5 
Management of Patients Who Experience Specific 
Adverse Events in Atezo  CAPOX  Tira Arm 
A8–5.1.5.1 Dose Modifications 
Atezolizumab and Tiragolumab 
There will be no dose modifications for atezolizumab and tiragolumab in this study. 
Capecitabine 
The capecitabine dose can be modified as presented in Table 4 for the management of 
drug-related toxicities.  Once the dose has been reduced, it cannot be increased later.  
Omitted doses of capecitabine because of toxicity will not be replaced. 

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Table 4 
Dose Modifications for Capecitabine Drug-Related Toxicities 
Toxicity a 
Action to Be Taken for 
Current Treatment 
Dose Modification for the 
Next Treatment 
(% of Starting Dose) 
Grade 1 
Maintain dose level. 
Maintain dose level. 
Grade 2 
 
 
First occurrence 
Withhold until resolved to 
Grade 1 or better. 
100% (1000 mg/m2) 
Second occurrence 
75% (750 mg/m2) 
Third occurrence 
50% (500 mg/m2) 
Fourth occurrence 
Discontinue permanently. 
 
Grade 3 
 
 
First occurrence 
Withhold until resolved to 
Grade 1 or better. 
75% (750 mg/m2) 
Second occurrence 
50% (500 mg/m2) 
Third occurrence 
Discontinue permanently. 
 
Grade 4 
 
 
First occurrence 
Discontinue permanently or 
continue at the discretion of 
the investigator until resolved 
to Grade 1 or better. 
50% (500 mg/m2) 
a Graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 5.0. 
  
Oxaliplatin 
Dose Modifications for Patients with Neurotoxicity 
The following dose modifications will be made for patients with neurotoxicity: 
 
For Grade 2 peripheral sensory neuropathy (moderate paresthesia or dysesthesia), 
or limiting instrumental activities of daily living, omit oxaliplatin.  When toxicity 
resolves to Grade 1 or better, resume oxaliplatin to 75% of the initial dose.  
If oxaliplatin is omitted for 6 weeks (two consecutive cycles) for neurologic toxicity, 
discontinue oxaliplatin. 
 
For Grade 3 and 4 peripheral sensory neuropathy (severe paresthesia or 
dysesthesia) or limiting self-care activities of daily living), discontinue oxaliplatin. 
 
Dose Modifications for Patients with Renal Impairment 
The following dose modifications will be made for patients with renal impairment: 
 
For normal renal function or mild to moderate renal impairment (creatinine clearance 
 50 mL/min), the full dose of oxaliplatin can be administered. 
 
For severe renal impairment, the oxaliplatin dose should be reduced to 75% of the 
initial dose. 
 

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Dose Modifications for Patients with Hematologic Toxicity 
The following dose modifications will be made for patients with hematologic toxicity: 
 
For Grade 2 and 3 thrombocytopenia, the oxaliplatin dose should be reduced to 
75% of the initial dose.  For Grade 4 thrombocytopenia, the dose should be reduced 
to 50% of the initial dose. 
 
For Grade 3 and 4 neutropenia or febrile neutropenia, the oxaliplatin dose should be 
reduced to 75% of the initial dose. 
 
A8–5.1.5.2 Treatment Interruption for Toxicities 
The Medical 
Monitor is available to advise as needed. 
On the basis of the available characterization of mechanism of action, tiragolumab may 
cause adverse events similar to, but independent of, atezolizumab.  Tiragolumab may 
also exacerbate the frequency or severity of atezolizumab-related adverse events or 
may have non-overlapping toxicities with atezolizumab.  Because these scenarios may 
not be distinguishable from each other in the clinical setting, 
 
 should generally be attributed to both agents, and dose interruptions or treatment 
discontinuation in response to 
 should be applied to 
both tiragolumab and atezolizumab. 
The CAPOX treatment may be temporarily suspended in patients who experience 
toxicity considered to be related to study treatment.  If CAPOX has been withheld for 
 21 days because of toxicity, the patient should be discontinued from CAPOX, unless 
the patient is likely to derive clinical benefit.  The decision to re-challenge patients with 
CAPOX should be based on the investigator’s benefitrisk assessment and documented 
by the investigator.  The Medical Monitor is available to advise as needed. 
If atezolizumab is withheld or discontinued, tiragolumab should also be withheld or 
discontinued, but CAPOX may be continued if the patient is likely to derive clinical 
benefit, as determined by the investigator per medical judgment.  If CAPOX or 
tiragolumab is discontinued, the other drugs can be continued if the patient is likely to 
derive clinical benefit according to the investigator’s medical judgment.  Treatment with 

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CAPOX will continue for up to six cycles and patients will be offered continued treatment 
with atezolizumab as long as they are experiencing clinical benefit in the opinion of the 
investigator.  If oxaliplatin treatment is discontinued during the first six cycles, patients 
are encouraged to continue chemotherapy with capecitabine, atezolizumab, and 
tiragolumab as long as they are experiencing clinical benefit in the opinion of the 
investigator.  The Medical Monitor is available to advise as needed.  If capecitabine 
treatment is discontinued during the first six cycles, patients are encouraged to continue 
chemotherapy with oxaliplatin, atezolizumab, and tiragolumab as long as they are 
experiencing clinical benefit in the opinion of the investigator, the Medical Monitor is 
available to advise as needed. 
A8–5.1.5.3 Management Guidelines for Adverse Events 
Appendix 5 provides guidelines for the management of patients who experience 
atezolizumab- and/or tiragolumab-associated adverse events.  It is recommended that 
atezolizumab and/or tiragolumab be withheld or discontinued per the guidelines provided 
in Appendix 5. 
For cases in which management guidelines are not covered in Appendix 5, patients 
should be managed and treatments should be withheld or discontinued as deemed 
appropriate by the investigator according to best medical judgment. 
Guidelines for management of patients who experience specific adverse events related 
to CAPOX regimen are provided in Section A8–5.1.5.1.  The treating physician may use 
discretion in modifying the dose modification guidelines, depending on the severity of 
toxicity and an assessment of the benefit versus risk for the patient, with the goal of 
maximizing patient compliance and access to supportive care. 
Chemotherapy should be discontinued if ANC and platelets do not recover to  1000/L 
and  75,000/L, respectively, after treatment is delayed by 3 weeks. 
 
 
 
 
 
 
 
 

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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A8–5.3 
REPORTING REQUIREMENTS FOR PREGNANCIES IN 
ATEZO  CAPOX  TIRA ARM 
A8–5.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 5 months after the final dose of atezolizumab, 90 days after the final dose of 
tiragolumab, 6 months after the final dose of capecitabine, or 9 months after the final 

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dose of oxaliplatin.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study treatment and counsel the patient, discussing the risks of the 
pregnancy and the possible effects on the fetus.  Monitoring of the patient should 
continue until conclusion of the pregnancy.  Any serious adverse events associated with 
the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly or birth defect in the child) should be reported on 
the Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
A8–5.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
3 months after the final dose of capecitabine, 6 months after the final dose of oxaliplatin, 
or 90 days after the final dose of tiragolumab.  The investigator should report the 
pregnancy on the paper Clinical Trial Pregnancy Reporting Form and submit the form to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or by scanning and emailing the form using the fax number 
or email address provided to investigators.  Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study treatment.  When permitted by the site, the pregnant partner 
would need to sign an Authorization for the Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  If the authorization has been 
signed, the investigator should submit a Clinical Trial Pregnancy Reporting Form with 
additional information on the pregnant partner and the course and outcome of the 
pregnancy as it becomes available. 
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 

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would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth. 
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
A8–5.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.   
A8–5.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly or birth defect in a child born to a female patient exposed to 
study treatment or the female partner of a male patient exposed to study treatment 
should be classified as a serious adverse event, recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
 

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A8–6 
SCHEDULE OF ACTIVITIES AND SAMPLE COLLECTION FOR ATEZO  CAPOX  TIRA ARM 
Table 5 
Schedule of Activities for Atezo  CAPOX  Tira Arm 
Assessment/Procedure 
Stage 1 
Screening  
(see 
Appendix 6) 
Treatment Cycles (21-day cycles) a 
Treatment 
Discontinuation c 
Follow-Up  
Cycle 1 b 
Cycles  2 
Days 28 
to 1 
Day 1 
Day 1 
( 3 days) 
Every 
3 Months 
Molecular profile of GC and GEJC (if 
available)  
See 
Appendix 6. 
Whenever updated information becomes available  
 
Vital signs d, e 
x 
x 
x 
 
Weight e 
x 
x 
x 
 
Complete physical examination f 
 
 
x 
 
Limited physical examination e, g 
x 
x 
 
 
ECOG Performance Status e 
x 
x 
x 
 
ECG e, h 
Perform as clinically indicated. 
 
 
Hematology i 
x j, k 
x j 
x 
 
Chemistry l 
x j, k 
x j 
x 
 
TSH, free T3 (or total T3),and  free T4 m 
x j, k, m 
x 
 
C-reactive protein 
x j, k 
 
 
 
Pregnancy test o 
x j, k 
x j 
x 
x o 
Urinalysis p 
Perform as clinically indicated. 
 
 
 

Appendix 8:  Study Details Specific to Atezo  CAPOX Tira Arm (cont.) 
  
Table 5 
Schedule of Activities for Atezo  CAPOX  Tira Arm (cont.) 
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
198/Protocol YO43408, Version 5 
 
Assessment/Procedure 
Stage 1 
Screening  
(see 
Appendix 6) 
Treatment Cycles (21-day cycles) a 
Treatment 
Discontinuation c 
Follow-Up  
Cycle 1 b 
Cycles  2 
Days 28 
to 1 
Day 1 
Day 1 
( 3 days) 
Every 
3 Months 
See 
Appendix 6. 
Blood (for plasma and WBC central 
processing) and serum for biomarkers 
See Table 6. 
 
Tumor biopsy 
x q 
 
Tumor biopsy (optional) 
x r 
 
Stool sample (optional) 
xs 
x s 
 
 
Tumor response assessments 
x t, u 
Concomitant medications v 
x 
x 
x 
 
Adverse events w 
x  
x 
x w 
x w 
Atezolizumab administration x, y 
x 
x 
 
 
CAPOX administration x, z 
x 
x 
 
 
Tiragolumab administration x, aa 
x 
x 
 
 
Survival follow-up and anti-cancer treatment 
 
 
 
x bb 
ADA  anti-drug antibody; Atezo  atezolizumab; CAPOX  capecitabine plus oxaliplatin; CT  computed tomography; ECOG  Eastern Cooperative 
Oncology Group; eCRF  electronic Case Report Form; GC  gastric carcinoma; GEJC  gastroesophageal junction carcinoma;
 IRR  infusion-related reaction; PK  pharmacokinetic. 

Appendix 8:  Study Details Specific to Atezo  CAPOX Tira Arm (cont.) 
  
Table 5 
Schedule of Activities for Atezo  CAPOX  Tira Arm (cont.) 
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
199/Protocol YO43408, Version 5 
 
Note:  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
a 
If a visit is precluded because of a holiday, vacation, or other circumstance, it can occur outside of the specified window. 
b 
 
c 
Patients who discontinue study treatment will return to the clinic for a treatment discontinuation visit not more than 30 days after the final dose 
of study treatment.  The visit at which loss of clinical benefit is confirmed by the investigator (see Section 3.1.2 for details) may be used as the 
treatment discontinuation visit. 
d 
Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, pulse oximetry, 
and temperature.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF.  For the first infusion of 
atezolizumab, vital signs should be measured within 60 minutes prior to the infusion and, if clinically indicated, every 15 ( 5) minutes during 
and 30 ( 10) minutes after the infusion.  For subsequent infusions of atezolizumab, vital signs should be measured within 60 minutes prior to 
the infusion and, if clinically indicated or if symptoms occurred during the previous infusion, during and 30 ( 10) minutes after the infusion. 
e 
Assessment may be performed within 24 hours prior to dosing during the treatment period. 
f 
Complete physical examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurologic systems.  During visits when a patient will undergo a tumor 
assessment, the physical examination should include an evaluation of the presence and degree of enlarged lymph nodes, hepatomegaly, and 
splenomegaly.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
g 
Perform a limited, symptom-directed examination at specified timepoints and as clinically indicated at other timepoints.  During visits when a 
patient will undergo a tumor assessment, the physical examination should include an evaluation of the presence and degree of enlarged lymph 
nodes, hepatomegaly, and splenomegaly.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
h 
It is recommended that patients be resting in a supine position for at least 10 minutes prior to ECG recording. 
i 
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (neutrophils, eosinophils, basophils, 
monocytes, lymphocytes, and other cells). 
j 
Laboratory tests must be performed within 96 hours prior to dosing during the treatment period. 
k 
If screening laboratory assessments were performed within 96 hours prior to Day 1 of Cycle 1, they do not have to be repeated. 
l 
Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if available), sodium, potassium, chloride, glucose, BUN or 
urea, creatinine, total protein, albumin, phosphate (or phosphorus), calcium, total bilirubin, ALP, ALT, AST, and lactate dehydrogenase 
(if available). 
m TSH, free T3 (or total T3 for sites where free T3 is not performed), and free T4 will be assessed on Day 1 of Cycle 1 and every four cycles 
thereafter (i.e., Cycles 5, 9, 13, and so on). 

Appendix 8:  Study Details Specific to Atezo  CAPOX Tira Arm (cont.) 
  
Table 5 
Schedule of Activities for Atezo  CAPOX  Tira Arm (cont.) 
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
200/Protocol YO43408, Version 5 
 
n 
o 
All women of childbearing potential will have urine or serum pregnancy tests performed at specified visits during treatment and at 3 months and 
6 months after the last dose of study treatment.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. 
p 
Urinalysis includes pH, specific gravity, glucose, protein (or albumin), ketones, and blood; dipstick permitted. 
q 
Patients will undergo tumor biopsy sample collection at the time of unacceptable toxicity or loss of clinical benefit as determined by the 
investigator (see Section 3.1.2 for details), if deemed clinically feasible by the investigator.  Biopsies should be performed within 40 days after 
determination of unacceptable toxicity, disease progression, or loss of clinical benefit, or prior to the next anti-cancer therapy, whichever is 
sooner.  Refer to Section 4.5.7 for tissue sample requirements. 
r 
Patients who consent to optional biopsies will undergo tumor biopsy sample collection 8 weeks ( 7 days) after treatment initiation, if deemed 
clinically feasible and may undergo additional on-treatment biopsies at any other time at the investigator's discretion. 
s 
Patients who consent to providing optional stool sample  will receive the collection device for the stool sample prior to Day 1 of Cycle 1 and 
Day 1 of Cycle 3.  Samples to be collected predose (i.e., before the visit).  Patients will be instructed to return the collection device with the stool 
sample to the site on the Day 1, Cycle 1 and Day 1, Cycle 3 ( 1 week) visits.  If a patient does not return the collection device at the Day 1, 
Cycle 3 visit, he or she may return the collection device at the Day 1, Cycle 4 visit. 
t 
Patients will undergo tumor assessments every 6 weeks ( 1 week) during the first 48 weeks (from Day 1 of Cycle 1) and then every 12 weeks 
( 2 weeks) thereafter, regardless of dose delays until confirmed radiographic disease progression, except in the case of patients who continue 
treatment after radiographic disease progression; such patients will undergo tumor assessments every 6 weeks ( 1 week) until loss of clinical 
benefit as determined by the investigator (see Section 4.5.6 for details).  Thus, tumor assessments are to continue according to schedule in 
patients who discontinue treatment for reasons other than loss of clinical benefit, even if they start new nonprotocol-specified anti-cancer 
therapy. 
u 
All measurable and/or evaluable lesions identified at baseline should be re-assessed at subsequent tumor evaluations according to the tumor 
assessment schedule described above.  Brain metastases identified at baseline that have been treated with radiotherapy or surgery will not be 
considered measurable or evaluable unless there is suspected disease progression in the brain (i.e., the patient becomes symptomatic).  Thus, 
subsequent head scans are not required unless clinically indicated.  The same radiographic procedures used to assess disease sites at 
screening should be used for subsequent tumor assessments (e.g., the same contrast protocol for CT scans). 

Appendix 8:  Study Details Specific to Atezo  CAPOX Tira Arm (cont.) 
  
Table 5 
Schedule of Activities for Atezo  CAPOX  Tira Arm (cont.) 
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
201/Protocol YO43408, Version 5 
 
v 
Includes any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) 
used by a patient in addition to protocol-mandated study treatment from 7 days prior to initiation of study treatment until the treatment 
discontinuation visit. 
w 
After initiation of study treatment, all adverse events will be reported until 30 days after the final dose of study treatment or until initiation of a 
new systemic anti-cancer therapy, whichever occurs first, and serious adverse events and adverse events of special interest will continue to be 
reported until 
 days after the final dose of study treatment or until initiation of a new systemic anti-cancer therapy, whichever occurs first.  
After this period, all deaths, regardless of cause, should be reported.  In addition, the Sponsor should be notified if the investigator becomes 
aware of any serious adverse event that is believed to be related to prior exposure to study treatment (see Section 5.6).  The investigator 
should follow each adverse event until the event has resolved to baseline grade or better, the event is assessed as stable by the investigator, 
the patient is lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow all serious adverse events considered to 
be related to study treatment or trial-related procedures until a final outcome can be reported. 
x 
Treatment will continue until unacceptable toxicity or loss of clinical benefit as determined by the investigator (see Section 3.1.2 for details). 
y 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle.  The initial dose of atezolizumab 
will be delivered over 60 ( 15) minutes.  Subsequent infusions will be delivered over 30 ( 10) minutes if the previous infusion was tolerated 
without infusion-associated adverse events, or 60 ( 15) minutes if the patient experienced an infusion-associated adverse event with the 
previous infusion.  See Section A8–4.1.2.1 for details on atezolizumab infusions (including measurement of vital signs). 
z 
Capecitabine (1000 mg/m2) will be administered orally twice daily on Days 114 and oxaliplatin (130 mg/m2) will be administered by IV infusion 
on Day 1 and at least 5 minutes after completion of the tiragolumab infusion.  Treatment will continue for up to six cycles. 
aa Tiragolumab will be administered by IV infusion at a fixed dose of 600 mg on Day 1 of each 21-day cycle.  The initial dose of tiragolumab will be 
delivered over 60 ( 10) minutes.  Subsequent infusions will be delivered over 30 ( 10) minutes if the previous infusion was tolerated without 
infusion-associated adverse events, or 60 ( 10) minutes if the patient experienced an infusion-associated adverse event with the previous 
infusion.  On Day 1 of Cycle 1, tiragolumab will be administered 60 minutes after completion of the atezolizumab infusion.  The interval between 
subsequent infusions will be 30 minutes if the previous atezolizumab infusion was tolerated without an IRR or 60 minutes if the patient 
experienced an IRR with the previous atezolizumab infusion.  See Section A8–4.1.2.3 for details on tiragolumab infusions (including 
measurement of vital signs and patient observation after infusions). 
bb After treatment discontinuation, information on survival follow-up and new anti-cancer therapy (including targeted therapy and immunotherapy) 
will be collected by means of telephone calls, patient medical records, and/or clinic visits approximately every 3 months or more frequently until 
death (unless the patient withdraws consent or the Sponsor terminates the study).  If a patient requests to be withdrawn from follow-up, this 
request must be documented in the source documents and signed by the investigator.  If the patient withdraws from the study, the study staff 
may use a public information source (e.g., county records) to obtain information about survival status only.  For an experimental arm, in which 
all patients discontinued treatment and passed the safety follow-up window, as well as approximately 80% of patients discontinued the study, 
the Sponsor may conclude the arm (the remaining approximately 20% of patients will be discontinued from the study). 

Appendix 8:  Study Details Specific to Atezo CAPOX  Tira Arm (cont.) 
  
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
202/Protocol YO43408, Version 5 
Table 6 
Schedule of Pharmacokinetic, Immunogenicity, and Blood 
Biomarker Samples for Atezo  CAPOX  Tira Arm 
Visit 
Timepoint(s) 
Sample Type(s) 
Day 1 of Cycle 1 
Prior to first infusion 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 
 
 
 
 Biomarker (serum) 
 Biomarker (plasma and WBC) a 
30 ( 10) minutes after end 
of atezolizumab infusion 
 Atezolizumab PK (serum) 
30 ( 10) minutes after end 
of tiragolumab infusion 
 
 
Day 1 of Cycle 2 
Prior to infusion 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 
 
 
 
Day 1 of Cycle 3 
Prior to infusion 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 
 
 
 
 Biomarker (serum) 
Day 1 of Cycle 4 
Prior to infusion 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 
 
 
 
Day 1 of Cycle 8 
Prior to infusion 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 
 
 
 
ADA  anti-drug antibody; Atezo CAPOX  Tira  atezolizumab plus capecitabine plus 
oxaliplatin plus tiragolumab; ctDNA  circulating tumor DNA; PK  pharmacokinetic; 
WES  whole exome sequencing. 
Note:  On the basis of emerging safety or efficacy data, the number of PK and ADA samples 
may be reduced or sample collection may cease altogether.  Additionally, collected samples 
may not be analyzed if not warranted.  Blood collections for biomarker assessment 
(e.g., cytokines, chemokines, ctDNA, and WES of WBC-derived DNA as germline control) 
are applicable only after approval from local regulatory authorities.  Based on emerging 
biomarker data, the number of biomarker samples may be reduced or sample collection 
may cease altogether.  
a Blood collected at site for central processing of plasma and WBC samples. 
 

Appendix 8:  Study Details Specific to Atezo CAPOX  Tira Arm (cont.) 
  
Table 6 
Schedule of Pharmacokinetic, Immunogenicity, and Liquid 
Biomarker Samples for Atezo  CAPOX  Tira Arm (cont.) 
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
203/Protocol YO43408, Version 5 
Visit 
Timepoint(s) 
Sample Type(s) 
Day 1 of Cycles 12 and 16 
Prior to infusion 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 
 
 
 
Treatment discontinuation 
visit ( 30 days after final 
dose) 
At visit 
 Atezolizumab PK (serum) 
 Atezolizumab ADA (serum) 
 
 
 
 
 Biomarker (serum) 
 Biomarker (plasma) a 
ADA  anti-drug antibody; Atezo CAPOX  Tira  atezolizumab plus capecitabine plus 
oxaliplatin plus tiragolumab; ctDNA  circulating tumor DNA; PK  pharmacokinetic; 
WES  whole exome sequencing. 
Note:  On the basis of emerging safety or efficacy data, the number of PK and ADA samples 
may be reduced or sample collection may cease altogether.  Additionally, collected samples 
may not be analyzed if not warranted.  Blood collections for biomarker assessment 
(e.g., cytokines, chemokines, ctDNA, and WES of WBC-derived DNA as germline control) 
are applicable only after approval from local regulatory authorities.  Based on emerging 
biomarker data, the number of biomarker samples may be reduced or sample collection 
may cease altogether.  
a Blood collected at site for central processing of plasma and WBC samples. 

 
GC and GEJC Combinations—F. Hoffmann-La Roche Ltd 
204/Protocol YO43408, Version 5 
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Signature Page for Protocol - YO43408 - BM EM0060 - v5 - Global/Core - Published
System identifier: RIM-CLIN-513175
Approval Task
Company Signatory
01-Dec-2023 21:04:21 GMT+0000