A Phase II, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) and Trastuzumab in Combination With Capecitabine and Oxaliplatin (Xelox) in Patients With HER2 Positive Locally Advanced Resectable Gastric Cancer of Adenocarcinoma of Gastroesophageal Junction (GEJ)
Phase: PHASE2
Conditions: Gastric Cancer, Gastroesophageal Junction Adenocarcinoma
Sponsor: Hoffmann-La Roche

 
Official Title: 
A Phase II, Randomized Study of Atezolizumab (Anti-PD-L1 
Antibody) and Trastuzumab in Combination With Capecitabine and 
Oxaliplatin (Xelox) in Patients With HER2 Positive Locally Advanced 
Resectable Gastric Cancer of Adenocarcinoma of Gastroesophageal 
Junction (GEJ) 
NCT Number: 
NCT04661150 
Document Date: 
Protocol Amendment Version 7: 22-February-2024 
 
 
 

 
FINAL PROTOCOL APPROVAL 
 
 
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document, especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or 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. 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
Protocol ML42058, Version 7, Jan 2024 
 
PROTOCOL 
TITLE: 
A PHASE II, RANDOMIZED STUDY OF 
ATEZOLIZUMAB(ANTI-PD-L1 ANTIBODY) AND 
TRASTUZUMAB IN COMBINATION WITH 
CAPECITABINE AND OXALIPLATIN (XELOX)  IN 
PATIENTS WITH HER2 POSITIVE LOCALLY 
ADVANCED RESECTABLE GASTRIC CANCER OR 
ADENOCARCINOMA OF GASTROESOPHAGEAL 
JUNCTION (GEJ) 
PROTOCOL NUMBER: ML42058 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
Not applicable 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
Trastuzumab (RO0452317) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
See electronic date stamp below 

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PROTOCOL HISTORY 
Protocol 
Version 
Date Final 
7 
See electronic date stamp on title page 
6 
21-Feb-2023 
5 
10-Aug-2022 (internal drop) 
4 
24 Feb 2022. 
3 
10 Feb 2021 
2 
17 June 2020 
1 
29 April 2020 
 

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PROTOCOL AMENDMENT, VERSION 7: 
RATIONALE 
Protocol ML42058, Version 7.0, has been amended to align the adverse event management 
guidelines for atezolizumab with the Atezolizumab Investigator’s Brochure, Version 20. 
Substantive changes to the protocol, along with a rationale for each change, are summarized 
below. 
To align with the Atezolizumab IB, Version 20, the following changes have been 
made: 
- 
The list of approved indications for atezolizumab has been updated to include alveolar soft 
part sarcoma (Section 1.3). 
- 
The risks and adverse event management guidelines have been updated to align with the 
Atezolizumab IB, Version 20 (Appendix 8). 
- 
The risk description in the adverse event management guidelines have been updated to 
align with the Atezolizumab IB, Version 20 (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. 
 

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TABLE OF CONTENTS 
PROTOCOL 
SYNOPSIS 
111.
 
BACKGROUND
 
271.1
 
Background on Locally Advanced Gastric Cancer 
(LAGC) 
271.2 
 
Neoadjuvant or Perioperative Chemotherapy for 
LAGC 
281.3
 
Background on 
ATEZOLIZUMAB 
291.4
 
Background on 
TRASTUZUMAB 
291.5
 
Study Rationale and Benefit-Risk 
Assessment 
302.
 
OBJECTIVES AND 
ENDPOINTS 
332.1
 
Efficacy 
Objectives 
332.1.1
 
                    Primary Efficacy 
Objective 
332.1.2
 
                    Secondary Efficacy 
Objective 
332.1.3  
 
Exploratory Efficacy 
Objective 
342.2
 
Safety 
Objective 
343.
 
STUDY 
DESIGN 
353.1
 
Description of the 
Study 
353.1.1 
 
Overview of Study 
Design 
353.1.2 
 
Internal Monitoring 
Committee 
373.2
 
End of Study and Length of 
Study 
373.3
 
Rationale for Study 
Design 
373.3.1 
 
Rationale for Atezolizumab and Trastuzumab Dose and 
Schedule 
373.3.2 
 
Rationale for Patient 
Population 
383.3.3 
 
Rationale for Open-Label 
Study 
383.3.4 
 
Rationale for pathological complete regression (pCR) rate as Primary 
Endpoint 
41 
4. 
MATERIALS AND 
METHODS 
394.1
 
Patients

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394.1.1 
 
Inclusion 
Criteria 
394.1.2 
 
Exclusion 
Criteria 
414.2
 
Method of Treatment 
Assignment 
454.3
 
Study Treatment and Other Treatments Relevant to the Study 
Design 
454.3.1 
 
Study Treatment Formulation, Packaging, and 
Handling 
47 
4.3.2  
Study Treatment Dosage, Administration, and 
Compliance 
48 
4.3.3  
Supportive medications 
494.3.4 
 
Investigational Medicinal Product 
Accountability 
494.3.5 
 
Surgery
 
504.4
 
Concomitant 
Therapy 
514.4.1 
 
Permitted 
Therapy 
514.4.2 
 
Cautionary 
Therapy 
524.4.3 
 
Prohibited 
Therapy 
534.5
 
Study 
Assessments 
534.5.1 
 
Informed Consent Forms and Screening 
Log 
544.5.2 
 
Medical History, Concomitant Medication, and Demographic 
Data 
57 
4.5.3  
Physical Examinations 
544.5.4 
 
Vital 
Signs 
544.5.5 
 
Tumor and Response 
Evaluations 
554.5.6 
 
Laboratory, Biomarker, and Other Biological 
Samples 
564.5.7 
 
Evaluation of left ventricular ejection 
fraction 
584.5.8 
 
Electrocardiograms
 
584.5.9 
 
Esophageal-gastro-
duodenoscopy 
584.5.10
 
Histopathological 
assessment 
594.5.11
 
Optional 
Procedure 
594.6
 
Treatment, Patient, Study, and Site 

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Discontinuation 
594.6.1 
 
Study Treatment 
Discontinuation 
594.6.2 
 
Patient Discontinuation from the 
Study 
604.6.3 
 
Study 
Discontinuation 
614.6.4 
 
Site 
Discontinuation 
615.
 
ASSESSMENT OF 
SAFETY 
615.1
 
Safety 
Plan 
615.1.1 
 
Risks Associated with 
Atezolizumab 
625.1.2 
 
Risks Associated with 
Trastuzumab 
625.1.3 
 
Risks Associated with 
Capecitabine 
625.1.4 
 
Risks Associated with 
Oxaliplatin 
625.1.5 
 
Risks Associated with Combination Use of Atezolizumab, 
Trastuzumab and XELOX 
66 
5.1.6  
Risk Associated with 
Surgery 
635.2
 
Safety Parameters and 
Definitions 
635.2.1 
 
Adverse 
Events 
635.2.2 
 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
68 
5.2.3  
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
68 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters 
655.3.1 
 
Adverse Event Reporting 
Period 
655.3.2 
 
Eliciting Adverse Event 
Information 
665.3.3 
 
Assessment of Severity of Adverse 
Events 
665.3.4 
 
Assessment of Causality of Adverse 
Events 
675.3.5 
 
Procedures for Recording 
Adverse Events 
675.4
 
Immediate Reporting Requirements from Investigator to 
Sponsor 
735.4.1 
 
Emergency Medical 
Contacts 
735.4.2 

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Reporting Requirements for Serious Adverse Events and Adverse 
Events of Special Interest 
79 
5.4.3  
Reporting Requirements for 
Pregnancies 
745.5
 
Follow-Up of Patients after 
Adverse Events 
765.5.1 
 
Investigator Follow-
Up 
765.5.2 
 
Sponsor Follow-
Up 
765.6
 
Adverse Events That Occur after the Adverse Event Reporting 
Period 
765.7
 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Ethics 
Committees 
776.
 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
PLAN 
776.1
 
Determination of Sample 
Size 
776.2
 
Summaries of Conduct of 
Study 
776.3
 
Summaries of Demographic and Baseline 
Characteristics 
776.4
 
Efficacy 
Analyses 
786.4.1 
 
Primary Efficacy 
Endpoint 
786.4.2 
 
Secondary Efficacy 
Endpoints 
786.4.3 
 
Exploratory Efficacy 
Endpoints 
806.5
 
Safety 
Analyses 
806.6
 
Biomarker 
Analyses 
806.7
 
Interim 
Analysis 
807.
 
DATA COLLECTION AND 
MANAGEMENT 
817.1
 
Data Quality 
Assurance 
817.2
 
Electronic Case Report 
Forms 
817.3
 
Source Data 
Documentation 
817.4
 
Use of Computerized 
Systems 
827.5
 
Retention of 
Records 
828.
 
ETHICAL 
CONSIDERATIONS 
828.1

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Compliance with Laws and 
Regulations 
828.2
 
Informed 
Consent 
838.3
 
Institutional Review Board or 
Ethics Committee 
838.4
 
Confidentiality
 
848.5
 
Financial 
Disclosure 
849.
 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
859.1
 
Study 
Documentation 
859.2
 
Protocol 
Deviations 
859.3
 
Site 
Inspections 
859.4
 
Administrative 
Structure 
859.5
 
Dissemination of Data and Protection of Trade 
Secrets 
859.6
 
Protocol 
Amendments 
8610.
 
REFERENCES
 
87 
 
LIST OF TABLES 
Table 1 
Administration of First and Subsequent Atezolizumab Infusions 
47Table 2
 
Timing for Vital Sign Measurements for First and Subsequent Infusions
 
55Table 3 Adverse Event Severity Grading Scale 
for Events Not Specifically Listed in NCI CTCAE 
66Table 4
 
Causal Attribution Guidance 
67 
 
LIST OF FIGURES 
Figure 1 
Study Schema 
37 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Activities 
97 
Appendix 2 
The tumor regression grade (TRG) score of the 8th American Joint 
Committee on Cancer (AJCC)  
102 
Appendix 3 
Evaluation and scoring criteria for HER2 immunohistochemical 
staining of gastric cancer  
103 

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Appendix 4 
 Response Evaluation Criteria in Solid Tumors, 
Version 1.1 (RECIST v1.1) 
105 
Appendix 5 
 Anaphylaxis Precautions 
115 
Appendix 6 
 Risks Associated with Atezolizumab and Guidelines for 
Management of Adverse Events Associated with Atezolizumab 
116 
Appendix 7 
 Risks Associated with Trastuzumab and Guidelines for 
Management of Adverse Events Associated with Trastuzumab 
143 
Appendix 8 
Capecitabine Dose Calculation  
146 
Appendix 9 
Dose Modifications for Chemotherapy Treatment for Specific 
Toxicities  
147 
Appendix 10 
ECOG Performance Status as developed by the Eastern 
Cooperative Oncology Group (Oken et al. 1982)  
153 
Appendix 11      Preexisting Autoimmune Diseases and Immune Deficiencies 
 
 
157 
 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE II, RANDOMIZED STUDY OF 
ATEZOLIZUMAB(ANTI-PD-L1 ANTIBODY) AND 
TRASTUZUMAB IN COMBINATION WITH 
CAPECITABINE AND OXALIPLATIN (XELOX)  IN 
PATIENTS WITH HER2 POSITIVE LOCALLY 
ADVANCED RESECTABLE GASTRIC CANCER OR 
ADENOCARCINOMA OF GASTROESOPHAGEAL 
JUNCTION (GEJ) 
PROTOCOL NUMBER: ML42058 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
Not applicable 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
Trastuzumab (RO0452317) 
MEDICAL MONITOR: 
  
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 

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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 your local study monitor. 
  

 
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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE II, RANDOMIZED STUDY OF ATEZOLIZUMAB(ANTI-PD-
L1 ANTIBODY) AND TRASTUZUMAB IN COMBINATION WITH 
CAPECITABINE AND OXALIPLATIN (XELOX)  IN PATIENTS WITH 
HER2 POSITIVE LOCALLY ADVANCED RESECTABLE GASTRIC 
CANCER OR ADENOCARCINOMA OF GASTROESOPHAGEAL 
JUNCTION(GEJ) 
PROTOCOL NUMBER: 
ML42058 
VERSION NUMBER: 
7 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
Not applicable 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
Trastuzumab (RO0452317) 
PHASE: 
II 
INDICATION: 
Resectable, HER2 positive gastric cancer or adenocarcinoma of 
gastroesophageal junction 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
This study will evaluate the efficacy and safety of perioperative trastuzumab+XELOX with / 
without atezolizumab in patients eligible for surgery with locally advanced HER2-positive gastric 
cancer or adenocarcinoma of GEJ.  Specific objectives and corresponding endpoints for the 
study are outlined below. 

 
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Primary Efficacy Objective 
Corresponding Endpoint 
● To evaluate the efficacy of study 
treatments on the basis of the 
endpoint: pathological complete 
regression (pCR) rate 
● Pathological complete regression (pCR) rate 
pCR is defined as no evidence of vital residual tumor 
cells on hematoxylin and eosin evaluation of the 
complete resected gastric/gastroesophageal junction 
(GEJ) specimen and all sampled regional lymph nodes 
following completion of neoadjuvant systemic therapy 
(NAST) (i.e., ypT0N0 in the current AJCC staging 
system, 8th edition). 
pCR status of surgery specimens will be analyzed by 
local pathologists at each site according to the tumor 
regression grade (TRG) score of the 8th AJCC (See 
Appendix 2).   pCR rate will be analyzed in the 
intention-to-treat (ITT) population, defined as all 
patients who were randomly assigned to a treatment, 
regardless of whether they had surgery. It will be 
additionally assessed in a pre-specified sensitivity 
analysis in the per-protocol (PP) population. This 
population is defined as all patients who are centrally 
confirmed as HER2 positive and underwent resection.  
 
Secondary Efficacy Objective 
Corresponding Endpoints 
● To evaluate the efficacy of study 
treatments on the basis of the 
endpoints: event-free survival 
(EFS), disease-free survival 
(DFS), overall survival (OS), major 
pathologic response (MPR), 
objective response rate (ORR) and 
R0 resection rate 
● Event-free survival (EFS), defined as the time from 
randomization to the first documented disease 
recurrence, unequivocal tumor progression determined 
by the investigator according to RECIST v1.1, or death 
from any cause, whichever occurs first. 
● Disease-free survival (DFS), defined as the time from 
surgery to the first documented disease recurrence or 
death from any cause, whichever occurs first. 
● Overall survival (OS), defined as the time from 
randomization to death from any cause in all patients. 
● Major pathologic response (MPR), defined as < 10% 
residual tumor per tumor bed based on evaluation of 
the resected primary esophagogastric specimen by a 
local pathologist. 
● Objective response rate (ORR), defined as the 
proportion of patients with a complete response (CR) 
or partial response (PR) during NAST, as determined 
by the investigator according to RECIST v1.1. 
● R0 resection rate defined as the proportion of patients 
with a microscopically margin-negative resection, in 
which no gross or microscopic tumor remains in the 
primary tumor bed and/or sampled regional lymph 
nodes based on evaluation by the local pathologist. 

 
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Exploratory Efficacy Objectives 
Corresponding Endpoints 
● To monitor the effects of 
treatments by detecting HER2 
copy number in circulating tumor 
DNA (ctDNA).  
● HER2 copy number in circulating tumor DNA 
Blood samples are collected at several time points 
indicated in Appendix 1(ctDNA analysis,HER2 copy 
number) and circulating DNA is extracted for detecting 
HER2 copy number centrally using droplet digital PCR.  
● To explore the effects of treatment 
on HER2 status by detecting 
HER2 expression in surgical 
resected samples. 
● HER2 status in surgical resected samples 
HER2 will also be evaluated centrally using surgical 
resected samples to explore the effects of treatment on 
HER2 status. 
● To evaluate measures of efficacy 
based upon mismatch repair 
(MMR) status, PD-L1 expression 
and stromal tumor-infiltrating 
lymphocytes (sTIL) infiltration.  
● MMR status 
MMR is the repair of normal nucleotide sequences in 
DNA molecules containing mismatched bases. 
Deficient MMR (dMMR) is defined as a loss of 
expression in ≥1 mismatch repair proteins (MLH1, 
PMS2, MSH2 or MSH6). 
MMR status will be assessed centrally or locally using 
biopsy samples by IHC. 
● PD-L1 expression 
Expression of PD-L1 will be assessed both in pre-
treatment tumor biopsy and surgical resected samples 
by the immunohistochemistry assay (PD-L1, 22C3; 
Agilent Technologies) in the central laboratory. Tumors 
will be considered PD-L1 positive if the combined 
positive score (number of PD-L1–positive cells [tumor 
cells, macrophages, lymphocytes] divided by the total 
number of tumor cells, multiplied by 100) is 1 or 
greater. Subgroups based on PD-L1 expression status 
will be evaluated. 
● stromal tumor-infiltrating lymphocytes (sTIL) infiltration  
sTIL signature will be assessed by multiplex 
immunohistochemistry staining  on pre-treatment 
tumor tissue by central pathologist. Briefly, 4-5 m 
sections of FFPE will be applied with several 
antibodies (FoxP3, CD56, CD4, CD3, CD8, HER2, 
CD68, CD163, IRF8, CD20, PD-1, PD-L1) to label 
different kinds of cells. TILs are reported for the 
stromal compartment (% stromal TILs, sTIL) in all 
areas containing invasive tumor cells on the H&E slide 
containing the most invasive tumor. 
 

 
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Safety Objective 
Corresponding Endpoint 
● To evaluate the safety of study 
treatments 
● Incidence, nature and severity of adverse events(AEs), 
with severity determined according to the National 
Cancer  Institute Common Terminology Criteria for 
Adverse Events version 5.0 (NCI CTCAE v5.0). 
● Changes from baseline in targeted vital signs and 
physical findings. 
● Changes from baseline in targeted clinical laboratory 
test results. 
 
Study Design 
Description of Study 
This is a phase II, multicenter, randomized, open-label study designed to evaluate the efficacy 
and safety of perioperative trastuzumab+XELOX with / without atezolizumab in patients eligible 
for surgery with locally advanced HER2-positive gastric cancer or adenocarcinoma of GEJ. The 
study will enroll approximately 42 patients in China. 
Patients who have histologically confirmed, HER2 positive, locally advanced (cT3/T4a/T4b or N+, 
M0, AJCC 8th edition) gastric cancer or adenocarcinoma of GEJ (Siewert I-III) are eligible. HER2 
status of the primary gastric/GEJ tumor will be assessed in local laboratory and mandatory sent 
to the central laboratory for HER2 positivity confirmation. Patients without centrally confirmed 
HER2-positive result will be included in ITT analysis but not in PP analysis.  
Eligible patients will be enrolled and 1:1 randomized to perioperative treatment with either 
trastuzumab plus atezolizumab withXELOX (Arm A) or trastuzumab alone with XELOX (Arm B).  
Arm A: Atezolizumab plus Trastuzumab with XELOX 
Patients randomized to treatment Arm A will receive atezolizumab + trastuzumab + XELOX for 3 
treatment cycles prior to surgery, 3 weeks each cycle, as described below. Following surgery, 
patients will receive 5 further cycles of this regimen. 
• 
Atezolizumab 1200mg IV day 1 every 3 weeks Q3W  
• 
Trastuzumab 6 mg/kg IV day 1 (8 mg/kg as loading dose at 1st administration pre- and 
post-operation) Q3W 
• 
XELOX: Capecitabine 1000mg/m2 PO bid, days 1-14 Q3W 
                      Oxaliplatin 130mg/m2 IV day 1 Q3W 
 
Arm B: Trastuzumab with XELOX 
Patients randomized to treatment Arm B will receive trastuzumab + XELOX for 3 treatment cycles 
prior to surgery, 3 weeks each cycle, as described below. Following surgery, patients will receive 
5 further cycles of this regimen.  
• 
Trastuzumab 6 mg/kg IV day 1 (8 mg/kg as loading dose at 1st administration pre- and 
post-operation) Q3W 
• 
XELOX: Capecitabine 1000mg/m2 PO bid, days 1-14 Q3W 
                      Oxaliplatin 130mg/m2 IV day 1 Q3W 
 
Surgery is recommended to be performed 3 to 6 weeks after the last dose of neoadjuvant study 
treatment. The first dose of postoperative treatment is recommended to initiate within 8 weeks 

 
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after surgery. Surgical approaches will be tailored to the individual patient according to local 
standards with the goal of achieving R0 resection.  
Note: there will be a Safety Run-in Phase comprising the first 10 patients enrolled into both arms 
who have completed neoadjuvant treatment and surgery. All available safety data (including 
perioperative morbidity and mortality) of the first 10 patients will be reviewed by the internal 
monitoring committee (IMC) for providing a recommendation whether to continue, modify or 
terminate the study.  
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 electronic Case Report Form (eCRF) and in the patient's 
medical record to facilitate source data verification. Following completion of the treatment of the 
study, every effort should be made to follow up all subjects for their disease and survival status 
until subject death or termination by the Sponsor, except withdrawing ICF. Patients who 
discontinue neoadjuvant therapy early as a result of disease progression or who receives non-
protocol therapy prior to surgery must be discontinued from all study treatment, and will be 
managed per local practice. These patients will remain on study for survival follow-up. 
Patients who discontinue treatment for reasons other than disease progression (e.g., toxicity) will 
continue scheduled tumor assessments until disease progression, withdrawal of consent, study 
termination by Sponsor, or death, whichever occurs first.  In the absence of disease progression, 
tumor assessments should continue regardless of whether patients start a new anti-cancer 
therapy, unless consent is withdrawn.  All patients will be followed for survival unless consent is 
withdrawn.   
Tumor specimens (by pre-operative biopsy and surgical resection) from eligible patients will be 
prospectively tested for biomarkers. ctDNA will also be collected for HER2 copy number 
monitoring. These samples will enable analysis of tumor tissue biomarkers related to clinical 
benefits. 
Number of Patients 
Approximately 42 patients will be enrolled in this study. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
1. 
Signed Informed Consent Form 
2. 
Aged  18 and ≤ 75 years 
3. 
Ability to comply with the study protocol, in the investigator's judgment 
4. 
Histologically confirmed (by enrolling center) gastric cancer or adenocarcinoma of GEJ 
(Siewert I-III)  
5. 
HER2-positive status defined as either IHC score of 3+ or IHC 2+ (See Appendix 3) with 
amplification proven by in situ hybridization (ISH) as assessed by local review based on 
pretreatment endoscopic biopsies. ISH positivity is defined as a ratio of  2.0 for the number 
of HER2 gene copies to the number of signals for chromosome 17 copies (HER2/CEP17). 

 
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6. 
Clinical stage at presentation: cT3/T4a/T4b, or N+, M0 as determined by AJCC staging 
system, 8th edition 
a. 
An esophageal-gastro-duodenoscopy is mandatory 
b. 
Diagnostic laparoscopy and endoscopic ultrasonography are recommended 
7. 
Avaliability of formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block 
(preferred) or at least 16 available and of good quality biopsy tissue slides containing 
unstained, freshly cut, serial sections must be submitted for central assessment of HER2, 
PD-L1, MMR and sTIL signature. Agree to provide blood samples after enrollment. 
a. 
For MMR, there is no need to submit for central assessment if local lab is available.  
8. 
Physical condition and organ function allowing to undergo appropriate surgical management 
9. 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
10. Baseline LVEF  55% measured by echocardiogram (ECHO) or multiple-gated acquisition 
(MUGA) scans 
11. Life expectancy  12 weeks 
12. Adequate hematologic and end-organ function, defined by the following laboratory test 
results, obtained within 7 days prior to initiation of study treatment: 
a. 
Absolute neutrophil count (ANC)   1.5  109/L (1500/L) without granulocyte colony-
stimulating factor support 
b. 
Lymphocyte count  0.5  109/L (500/L) 
c. 
Platelet count  100  109/L (100,000/L) without transfusion  
d. 
Hemoglobin  90 g/L (9 g/dL). Patients may be transfused to meet this criterion 
e. 
AST, ALT, and alkaline phosphatase (ALP)  2.5  upper limit of normal (ULN) 
f. 
Serum total bilirubin  1.5  ULN with the following exception: 
Patients with known Gilbert disease:  serum total bilirubin level  3  ULN 
g. 
Serum creatinine  1  ULN or Creatinine clearance (CCr)  60mL/min (calculated using 
the Cockcroft-Gault formula): 
(140-age)  Weight (kg)  
CCr (ml/min) =                                               (Female 0.85) 
72   SCr (mg/dL) 
 
(140-age)  Weight (kg)  
OR  CCr (ml/min) =                                             (Female 0.85) 
0.818   SCr (umol/L)  
h. 
Serum albumin  30 g/L (3.0 g/dL) 

 
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i. 
For patients not receiving therapeutic anticoagulation:  INR or aPTT  1.5  ULN 
j. 
For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen and 
stable INR 
13. For female patients of childbearing potential, agreement (by patient) to remain abstinent 
(refrain from heterosexual intercourse) or to use highly effective form(s) of contraception 
(i.e., one that results in a low failure rate [<1% per year] when used consistently and 
correctly) during the treatment period and to continue its use for at least i) 5 months after the 
last dose of atezolizumab, ii) 7 months after the last dose of trastuzumab, or iii)  6 months 
after the last dose of capecitabine or oxaliplatin, whichever is longer. 
a. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (<12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus) 
b. 
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 
c. 
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 acceptable methods of contraception 
14. For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below: 
a. 
With female partners of childbearing potential or pregnant female partners, men who 
are not surgically sterile must remain abstinent or use a condom plus an additional 
contraceptive method that together result in a failure rate of <1% per year during the 
treatment period and for at least i) 7 months after the last dose of trastuzumab, ii)  3 
months after the last dose of capecitabine, or iii) 6 months after the last dose of 
oxaliplatin, whichever is longer.. Men must refrain from donating sperm during this 
same period 
b. 
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 acceptable methods of contraception 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. 
Stage IV (metastatic) or unresectable gastric/GEJ cancer determined by investigators 
2. 
Prior systemic therapy for treatment of gastric cancer 
3. 
History of malignancy other than GC within 5 years prior to screening, 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 
4. 
Cardiopulmonary dysfunction as defined by any of the following prior to randomization: 

 
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a. 
History of congestive heart failure of any classification 
b. 
Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not 
controlled by adequate medication, severe conduction abnormality, or clinically 
significant valvular disease 
c. 
High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate > 100/min at 
rest, significant ventricular arrhythmia [ventricular tachycardia], or higher-grade 
atrioventricular [AV]-block [second-degree AV-block Type 2 [Mobitz 2] or third degree 
AV-block]) 
d. 
Significant symptoms (Grade  2) relating to left ventricular dysfunction, cardiac 
arrhythmia, or cardiac ischemia 
e. 
Myocardial infarction within 12 months prior to randomization 
f. 
Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood 
pressure > 100 mmHg) 
g. 
Evidence of transmural infarction on ECG 
h. 
Requirement for oxygen therapy 
5. 
Dyspnea at rest 
6. 
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, 
Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis 
(see protocol Appendix 11 for a more comprehensive list of autoimmune diseases and 
immune deficiencies), with the following exceptions: 
a. Patients with a history of autoimmune-mediated hypothyroidism who are on thyroid-
replacement hormone are eligible for the study. 
b. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for the study. 
c. 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: 
i. 
Rash must cover  10% of body surface area 

 
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ii. 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 
iii. 
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 
7. 
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest CT scan 
8. 
Active tuberculosis 
9. 
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 course of the 
study  
10. Severe infections within 4 weeks prior to initiation of study treatment, including, but not 
limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia 
11. Treatment with therapeutic antibiotics within 2 weeks (IV antibiotics) or 5 days (oral 
antibiotics) prior to initiation of study treatment 
a. 
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or 
chronic obstructive pulmonary disease exacerbation) are eligible for the study. 
12. Prior allogeneic stem cell or solid organ transplantation 
13.  
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 
14. 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 treatment or within 5 months 
after the final dose of atezolizumab 
15. Current treatment with anti-viral therapy for HBV 
16. Positive test for HIV 
17. Patients with active hepatitis B (defined as having a positive hepatitis B surface antigen 
[HBsAg] test at screening) 
a. 
Patients with past HBV infection or resolved HBV infection (defined as having a 
negative HBsAg test or a positive antibody to hepatitis B core antigen [anti-HBc] 
antibody followed by a negative HBV-DNA test at screening) are eligible. 
18. Patients with active hepatitis C 
a. 
Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA. 

 
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19. Evidence of significant uncontrolled concomitant disease that could affect compliance with 
the protocol or interpretation of results, including significant liver disease (such as cirrhosis, 
uncontrolled major seizure disorder, or superior vena cava syndrome) 
20. Treatment with any approved anti-cancer therapy, 5 half-lives prior to initiation of study 
treatment 
21. Treatment with investigational therapy within 28 days prior to initiation of study treatment 
22. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
anti CTLA-4, anti PD-1, and anti PD-L1 therapeutic antibodies  
23. Treatment with systemic immunostimulatory agents (including but not limited to interferons or 
interleukin-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to 
initiation of study treatment 
24. Treatment with systemic immunosuppressive medications (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), inhaled or low‑dose 
corticosteroids for COPD or asthma, or low-dose corticosteroids for orthostatic hypotension 
or adrenal insufficiency are eligible for the study. 
25. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins 
26. Known hypersensitivity to Chinese hamster ovary cell products or to any component of the 
atezolizumab formulation  
27. Known allergy or hypersensitivity to any component of trastuzumab, capecitabine or 
oxaliplatin formulations 
28. Known dihydropyrimidine dehydrogenase (DPD) deficiency or history of severe and 
unexpected reactions to fluoropyrimidine therapy in patients selected to receive capecitabine 
29. Have a significant impact on oral drug absorption factors, such as unable to swallow, chronic 
diarrhea and intestinal obstruction 
30. Requirement for concurrent use of the antiviral agent sorivudine (antiviral) or chemically 
related analogues, such as brivudine in patients selected to receive capecitabine. Use of 
these drugs is not allowed within 4 weeks prior to study treatment that includes capecitabine 
31. Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or 
within i) 5 months after the last dose of atezolizumab, ii) 7 months after the last dose of 
trastuzumab, or iii)  6 months after the last dose of capecitabine or oxaliplatin, whichever is 
longer 

 
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a. 
Women of childbearing potential must have a negative serum pregnancy test result 
within 7 days prior to initiation of study treatment. 
End of Study 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs.  The 
end of the study is expected to occur approximately 40 months after the last patient is enrolled 
(36 months after the last patient receives surgery). 
In addition, the Sponsor may decide to terminate the study. 
Length of Study 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 52 months, assuming a recruitment period of approximately 12 
months plus 40 months from the date of enrollment of the last patient. 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
The investigational medicinal products (IMPs) for this study are atezolizumab and trastuzumab. 
Atezolizumab (Tecentriq ®) 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-
day cycle for 3 cycles prior to surgery and 5 cycles after surgery.  
Atezolizumab should be administered as the first infusion. 
Treatment will continue as scheduled unless progression, recurrence of disease, or 
unmanageable toxicity, whichever occurs first. 
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 5. Atezolizumab infusions will be 
administered per the instructions outlined in the protocol.  
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  However, 
patients who experience an infusion-related reaction (IRR) with Cycle 1 of atezolizumab may 
receive premedication with antihistamines or antipyretics/analgesics (e.g., acetaminophen) for 
subsequent infusions.  Metamizole (dipyrone) is prohibited in treating atezolizumab-associated 
IRRs because of its potential for causing agranulocytosis. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.  
Guidelines for medical management of infusion-related reactions (IRRs) are provided in Appendix 
6. 
No dose modification for atezolizumab is allowed. Guidelines for atezolizumab interruption or 
discontinuation for patients who experience adverse events are provided in Appendix 6.  
Trastuzumab (Herceptin ®) 
Trastuzumab is given as an 8 mg/kg IV loading dose and then 6 mg/kg IV on Day 1 of a 21-day 
cycle for 3 cycles before surgery, and administration will continue after surgery. The first 
administration of trastuzumab after surgery should also be given at the loading dose of 8 mg/kg. 
Trastuzumab should be administered after atezolizumab and prior to oxaliplatin. 

 
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Weight should be recorded during screening and on Day 1 of each cycle for all patients. The 
initial baseline weight for a patient will be that measured on Cycle 1, Day 1. The amount of 
trastuzumab to be administered must be recalculated if the patient’s body weight has changed 
by > 10% (increased or decreased) from the Cycle 1, Day 1 weight. Weight at the time the dose 
is recalculated will be considered as baseline for subsequent evaluations of degree of weight 
change with respect to trastuzumab dose modification requirements. The amount of trastuzumab 
administered is calculated according to the patient’s actual body weight, with no upper limit. 
The initial dose of trastuzumab will be administered over 90 (+/-10) minutes, and patients will be 
observed for at least 30 minutes from the end of the infusion for infusion-related symptoms such 
as fever or chills. Interruption or slowing of the infusion may help control such symptoms and may 
be resumed when symptoms abate. If the infusion is well tolerated, subsequent infusions may be 
administered over 30 (+/-10) minutes, and patients will be observed for a further 30 minutes. All 
infusion-related symptoms must have resolved before chemotherapy is given or the patient is 
discharged.  
Anti-emetic premedication and supportive care will be given according to local/international 
standards. For patients who have experienced mild, moderate or severe infusion reactions after 
the first administration of trastuzumab, trastuzumab therapy can be resumed. Subsequent 
trastuzumab infusion is generally well tolerated. Premedications of corticosteroids, antihistamine 
and antipyretics can be used before trastuzumab therapy at the discretion of investigators. 
Patients can be administrated with premedication (e.g. phenothiazines, antihistaminics, or 
anticholinergic agents) to control nausea/vomiting per local practice standards. 
Guidelines for trastuzumab interruption or discontinuation are provided in Appendix 7. No dose 
modification is allowed for trastuzumab. If the patient misses a dose of trastuzumab by one week 
or less, then the usual dose of trastuzumab (6 mg/kg) should be given as soon as possible (do 
not wait until the next planned cycle). Subsequent maintenance trastuzumab doses of 6 mg/kg 
are then given every 3 weeks, according to the previous schedule. If the patient misses a dose of 
trastuzumab by more than one week, a re-loading dose of trastuzumab should be given (8 mg/kg 
over 90 minutes). In general, subsequent maintenance trastuzumab doses of 6 mg/kg are then 
given every 3 weeks, starting 3 weeks later. 
The patients who are diagnosed to be recurrent must be discontinued the treatment with study 
drug. The treatment for recurrent is at the investigators’ discretion but must be recorded in the 
CRFs. 
Non-Investigational Medicinal Products 
Chemotherapy 
XELOX is the chemotherapy regimen used in this trial, which will be administered in the 3 cycles 
before surgery (neoadjuvant) and 5 cycles after surgery (adjuvant) as follows: 
• 
Capecitabine 1000 mg/m2 administered twice orally on days 1–14, repeated every 3 
weeks(21[+/-3]days); The first dose of capecitabine is given on the evening of day 1 and the 
last dose is given on the morning of day 15 of each cycle;  
• 
Oxaliplatin 130mg/m2 IV on day 1 of a 21-day cycle; infusion over 2 hours. 
The dose of chemotherapy is calculated according to the patient’s BSA. The BSA and the amount 
of drug administered must be recalculated if the patient’s body weight has changed by > 10% 
(increased or decreased) from baseline. Recalculation of the amount of drug administered on the 
basis of smaller changes in body weight or BSA is at the investigators’ discretion. 

 
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In case the oxaliplatin treatment should be discontinued due to its specific toxicity (such as 
neurotoxicity), then capecitabine can be continued alone for up to 8 cycles (including preoperative 
chemotherapy cycles). If capecitabine is discontinued, oxaliplatin won't be continued. 
There is no mandatory delay between atezolizumab/trastuzumab and oxaliplatin, assuming the 
infusion is well tolerated. If local policy is to give the atezolizumab/ trastuzumab on day one and 
start the oxaliplatin the next day, (still within a 24 hour period), this is acceptable on an 
exceptional basis. 
Appendix 8 provides the dosage calculation of capecitabine. For the other information of dosage 
and administration of capecitabine and oxaliplatin, please refer to the local prescribing 
information.  
Supportive medications 
Supportive medications (anti-emetics, antihistamines, and analgesics) will be administered per 
local practice standards. 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  However, 
patients who experience an infusion-related reaction (IRR) with Cycle 1 of atezolizumab may 
receive premedication with antihistamines, antipyretics, and/or analgesics (e.g., acetaminophen) 
for subsequent infusions.  Metamizole (dipyrone) is prohibited in treating IRRs because of its 
potential for causing agranulocytosis. 
Oxaliplatin can be administrated with premedication (e.g. phenothiazines, antihistaminics, or 
anticholinergic agents) at each cycle to control nausea/vomiting per local practice standards. 
Patients who experience mild, moderate or severe infusion reactions on the first dose may be 
retreated with trastuzumab. Subsequent trastuzumab infusions are generally well tolerated. 
Premedication with corticosteroids, antihistamines, and antipyretics may be used before 
subsequent trastuzumab infusions at the Investigator’s discretion. 
Statistical Methods 
Primary Analysis 
The primary efficacy endpoint for this study is pCR rate. pCR is defined as no evidence of vital 
residual tumor cells on hematoxylin and eosin evaluation of the complete resected stomach/GEJ 
specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic 
therapy (NAST) (i.e., ypT0N0 in the current AJCC staging system, 8th edition). The primary 
efficacy endpoint will be established following completion of neoadjuvant therapy and surgery.  
pCR status of surgery specimens will be analyzed by local pathologists at each site.  
This primary endpoint will be analyzed in the intention-to-treat (ITT) population, defined as all 
patients who were randomly assigned to a treatment arm, regardless of whether they had 
surgery. An estimate of the pCR rate and its 95% confidence Interval (CI) will be calculated for 
each treatment arm. The CIs for each treatment arm will be calculated with the Clopper-Pearson 
exact method. The difference in pCR rates will be provided with 90% CIs, using the normal 
approximation to the binomial distribution. P value of comparison between two arms will be 
calculated with Chi-square test. 

 
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Determination of Sample Size   
The sample size calculation of this study is based on the primary endpoint, the pCR rate.  
Assuming mean difference between two arms is 22% and pCR rate is 10% for control arm (arm 
B), sample size of 19 per each group could provide the precision (half width) of 90%CI of 0.21.  
It is planned to recruit 42 patients (21 patients in each group) into this study assuming a 10% 
drop-out rate. 
Interim Analyses  
There will be no formal interim efficacy analysis for the primary endpoint of pCR, although data 
on efficacy may be provided to the IMC upon request in order to evaluate benefit-risk for 
patients. Interim analyses of EFS, DFS, and OS at the time of and/or after the primary analysis 
of pCR may be conducted as needed and/or requested by Health Authorities. 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
Anti-HBc 
antibody to hepatitis B core antigen 
ANC 
Absolute neutrophil count 
APTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AV-block 
Atrioventricular-block 
BFI 
Brief Fatigue Inventory 
bid 
bis in die 
CCr 
Creatinine clearance 
COVID-19 
Coronavirus 2019 
CR 
complete response 
CRO 
contract research organization 
CRS 
cytokine-release syndrome 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
DFS 
disease-free survival 
DLT 
dose-limiting toxicities 
dMMR 
Deficient mismatch repair 
DPD 
dihydropyrimidine dehydrogenase 
EC 
Ethics Committee 
ECF 
epirubicin, cisplatin and 5-fluorouracil 
ECHO 
echocardiogram 
ECG 
Electrocardiograph 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EFS 
Event-free survival 
FDA 
Food and Drug Administration 
FFPE 
formalin fixed paraffin-embedded 
GC 
gastric cancer 
GEJ 
gastroesophageal junction 
HBV 
hepatitis B virus 
HBsAg 
hepatitis B surface antigen 

 
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HCV 
hepatitis C virus 
H&E 
Hematoxylin-eosin 
HER2 
human epidermal growth factor receptor 2 
HGRAC 
Human Genetic Resources Administration Office of China 
HIV 
human immunodeficiency virus 
HLH 
hemophagocytic lymphohistiocytosis 
ICH 
International Council for Harmonisation 
IHC 
Immunohistochemistry 
IMC 
internal monitoring committee 
IMP 
investigational medicinal product 
INR 
International Normalized Ratio 
IND 
Investigational New Drug (Application) 
IRB 
IRR 
Institutional Review Board 
infusion-related reaction 
ISH 
in situ hybridization 
ITT 
intention-to-treat 
IV 
intravenous 
LAGC 
Locally advanced gastric cancer 
LPLV 
last patient, last visit 
LVEF 
left ventricular ejection fraction 
MAS 
macrophage activation syndrome 
MDT 
muti-disciplinary treatment 
MMR 
mismatch repair 
MPR 
Major pathologic response 
MRI 
Magnetic Resonance Imaging 
MUGA 
multiple-gated acquisition 
NACT 
Neoadjuvant chemotherapy 
NAST 
NCCN 
neoadjuvant systemic therapy 
National Cancer Comprehensive Network 
NCI CTCAE 
v{XX}.0 
National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version {XX}.0  
NSCLC 
Non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PCR 
polymerase chain reaction 
pCR 
Pathological complete regression 
PD 
Progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PO 
per os 

 
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PP 
per-protocol 
PR 
partial response 
PRO 
patient-reported outcome 
Q3W 
every 3 weeks 
RBR 
Research Biosample Repository 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SCLC 
SITC 
small cell lung cancer 
Society for Immunotherapy for Cancer 
sTIL 
stromal tumor-infiltrating lymphocytes 
TNF-α 
anti-tumor necrosis factor-α 
ULN 
upper limit of normal 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
XELOX 
capecitabine plus oxaliplatin 
 
1. 
BACKGROUND 
1.1 
BACKGROUND ON LOCALLY ADVANCED GASTRIC CANCER (LAGC) 
With an estimated over one million new cases in 2018, gastric cancer (GC) ranks the 5th 
most common malignancy and the 3rd leading cause of cancer-related mortality 
worldwide (Bray et al., 2018). While the prevalence of GC is known to be higher in East 
Asian countries than Western countries, histological types of GC are similar between 
Asian and Western countries and the most common type is adenocarcinoma. China has 
the largest number of GC patients in the world, accounting for 42.6% and 45.0% of the 
global GC incidence and mortality (Ferlay et al., 2015). It is estimated that there are 
679.1 thousands newly diagnosed cases and 498.0 thousands deaths of GC in 2015 
(Ferlay et al., 2015), both ranking the 2nd place of all cancer types. 
At present, radical resection is still the only possible cure method for gastric cancer. In 
Japan and Korea, mass screening programs to detect early-stage disease and operative 
technique improvement with meticulous regional lymph node dissection, patients’ 
survival has been much improved. In contrast, early diagnosis rate of GC is rather low 
due to difficulties of disease screening in China. Therefore, more than half of Chinese 
GC patients have already been in locally advanced stage at presentation (Zhang et al., 
2012). Even for patients with localized resectable gastric cancer, the prognosis is poor 
with 5-year overall survival (OS) rate ranging from 18% to 53% (Shu et al., 2017). 
Postoperative adjuvant chemotherapy for GC is intended to prevent disease relapse due 
to a residual microtumor after radical resection. The phase III ACTS-GC trial conducted 
in Japan tested S-1 (an oral fluoropyrimidine) as adjuvant chemotherapy in patients with 
stage II or III gastric cancer who had undergone D2 lymphadenectomy (Sakuramoto et 
al., 2007). The 3-year overall survival (OS) rate of S-1 treatment group was 80.1%, while 
that of the surgery only group was 70.1% (HR=0.68, 95%CI 0.52-0.87; P=0.003) 

 
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(Sakuramoto et al., 2007). CLASSIC study [7] is another phase III randomized controlled 
trial undertaken in 37 centres in South Korea and China (including Taiwan). It 
investigated the effect on disease-free survival of adjuvant chemotherapy with 
capecitabine plus oxaliplatin (XELOX) after D2 gastrectomy compared with D2 
gastrectomy only in patients with stage II–IIIB (AJCC 6.0th edition) GC (Bang et al., 
2012). The 3-year disease-free survival (DFS) was 74% (95% CI 69–79) in the XELOX 
group and 59% (95% CI 53–64) in the surgery only group (HR=0.56, 95% CI 0.44-0.72; 
P<0.0001) (Bang et al., 2012). In Japan, D2 gastrectomy plus adjuvant chemotherapy 
(ACT) using S-1 is the standard treatment for [6]; whereas in some others, like China, the 
standard is D2 gastrectomy with postoperative capecitabine plus oxaliplatin (CapeOX) 
(Wang et al., 2019). However, even with current ACT, the long-term survival for GC 
patients is not satisfactory, further development of treatment strategy and novel drugs is 
in urgent need. 
1.2 
NEOADJUVANT OR PERIOPERATIVE CHEMOTHERAPY FOR LAGC 
Neoadjuvant chemotherapy (NACT) or perioperative chemotherapy are proposed as 
another approach to improve the outcomes, which can increase R0 resection rate by 
shrinking tumor size. Moreover, potential prognosis-related factors like micrometastases 
can be better addressed by chemotherapy prior to surgery.  Neoadjuvant treatment has 
gradually become a standard of care for locally advanced, resectable GC and 
adenocarcinoma of the GEJ. 
The MAGIC and FLOT studies have shown a possible survival benefit due to 
preoperative treatment (Cunningham et al., 2006; Al-Batran et al., 2017). However, the 
best and personalized regimen of NACT remains to be determined. 
Definitive support for the favorable effect of perioperative chemotherapy in gastric, 
esophageal, and gastroesophageal junction (GEJ) adenocarcinoma was provided by the 
MAGIC study (Cunningham et al., 2006). The study observed a 5-year survival benefit 
for perioperative chemotherapy in patients with gastric and GEJ cancer. In the MAGIC-
trial (Cunningham et al. 2006), patients with clinical stage II or III GC (75%) or 
adenocarcinoma of the gastroesophageal junction (GEJ) (25%) were either treated with 
three cycles of epirubicin, cisplatin and 5-fluorouracil (ECF) pre- and post-surgery or with 
surgery alone (Cunningham et al., 2006). Patients in the chemotherapy arm had a 
clinically relevant and statistically significant improvement of PFS and OS in comparison 
to patients without chemotherapy (Cunningham et al., 2006). Benefit in 5-year survival 
was 13% (5-year OS, 36% with perioperative chemotherapy versus 23% with surgery 
alone). Patients treated with chemotherapy had smaller primaries and a favorable 
pathological tumor stage. No differences were seen between the two treatment groups 
regarding surgical mortality and morbidity, and hospitalization time (Cunningham et al., 
2006). A third trial (French ACCORD/FFCD 9703), including predominantly GEJ cancers 
(GEJ, 76%; stomach, 24%) showed similar results. In the FFCD trial, patients received 
2-3 cycles of cisplatin/5-FU, followed by surgery, or surgery alone. After surgery, 
patients in the chemotherapy arm who responded to the preoperative therapy received 
additional cycles of chemotherapy. Treatment with neoadjuvant or perioperative 
chemotherapy resulted in significantly improved rates of margin-free resection (R0) and 
prolonged relapse-free and overall survival. The survival benefit at five years was 14% 
(Ychou et al., 2011). In the most recent AIO-FLOT4 phase III trial, which was presented 
at ASCO 2017, 716 patients with gastric (44%) or adenocarcinoma of the GEJ (56%) 
were randomized to receive either perioperative ECF/ECX or FLOT (a docetaxel-based 
triple combination consisting of 5-FU, leucovorin, oxaliplatin and docetaxel) (Al-Batran et 

 
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al., 2017). FLOT improved PFS and OS (5-year OS rate, 45% vs. 36%) compared to 
ECF or ECX. No increase in mortality or perioperative complications was observed (Al-
Batran et al., 2017). It is important to note that neither study found that preoperative 
chemotherapy increased morbidity or mortality over surgery alone.However, despite 
these advances, the outcome of patients with advanced gastric or GEJ cancer remains 
unsatisfactory. Considerable investigation is still required to improve perioperative 
protocols and their efficacy. 
1.3 
BACKGROUND ON ATEZOLIZUMAB  
Atezolizumab (Tecentriq®, RO5541267) is a humanized IgG1 monoclonal antibody that 
targets PD-L1 and inhibits the interaction between PD-L1 and its receptors, 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 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 has been approved for the treatment of urothelial carcinoma, non small 
cell lung cancer (NSCLC), small cell lung cancer (SCLC) ,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. 
1.4 
BACKGROUND ON TRASTUZUMAB 
Trastuzumab (Herceptin®, RO0452317) is a recombinant, humanized, anti-p185HER2 
monoclonal antibody that binds specifically and with high affinity to the extracellular 
domain of the human epidermal growth factor receptor 2 (HER2). Trastuzumab has 
been shown to inhibit the proliferation of human tumor cells overexpressing HER2 both 
in vitro and in vivo. 
Trastuzumab 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.  
Trastuzumab 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. 
Trastuzumab has been approved for the treatment of HER2-overexpressing metastatic 
breast cancer, HER2-overexpressing operable early breast cancer, and HER2-
overexpressing metastatic gastric cancer. 

 
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Refer to the Trastuzumab Investigator's Brochure for details on nonclinical and clinical 
studies. 
1.5 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
HER2 dysregulation is associated with tumorigenesis and poor outcomes of gastric/GEJ 
cancer. In China, approximately 12.0% of patients with gastric and GEJ cancer are HER-
2 positive (Huang et al., 2013).  
Trastuzumab, a monoclonal antibody that acts against HER2, which is an effective and 
well-tolerated treatment for HER2-positive GC and GEJ cancer. The NEOHX study, a 
Spanish, multicenter, open-label phase II study, evaluated the efficacy and toxicity 
profile of perioperative treatment with trastuzumab in combination with XELOX 
(capecitabine and oxaliplatin) in patients with HER2-positive resectable stomach or 
esophagogastric junction adenocarcinoma (Rivera et al., 2013). The data shows 
promising activity of the regimen (trastuzumab plus XELOX) with pCR of 8%, 18-month 
DFS of 71% (95% CI: 53-83%),2-year DFS of 60% (Rivera et al., 2013). The update 
result of NEOHX study shows in 31 patients who received surgery 9.6% had a pCR and 
benefit in 5-year survival was 58% (Rivera et al, 2021). The HerFLOT study showed a 
pCR of 21% in patients with HER2-positive advanced gastric or GEJ cancer who 
received XELOX and trastuzumab as perioperative treatment (Available 
online:http://www.clinicaltrials.gov/ct2/show/NCT01472029?term = NCT01472029&rank 
= 1). In addition, two phase II trials, both performed specifically in Asiatic population, 
have reported a favourable toxic profile and high efficacy of XELOX–trastuzumab (Ryu 
et al., 2015; Gong et al., 2016). In the ad-hoc analysis of the phase III Trastuzumab for 
Gastric Cancer (ToGA) study, trastuzumab in combination with a fluoropyrimidine and 
cisplatin versus chemotherapy alone was evaluated as first-line therapy in patients with 
locally advanced or metastatic HER2-positive adenocarcinoma of the stomach including 
the gastroesophageal junction. The patients received trastuzumab achieved the greatest 
OS benefit compared with those received chemotherapy alone (16.0 vs. 11.8 months). 
The most common adverse events in both groups were nausea (trastuzumab plus 
chemotherapy, 197 [67%] vs. chemotherapy alone, 184 [63%]), vomiting (147 [50%] vs. 
134 [46%]), and neutropenia (157 [53%] vs. 165 [57%]). Rates of overall grade 3 or 4 
adverse events (201 [68%] vs. 198 [68%]) and cardiac adverse events (17 [6%] vs. 18 
[6%]) did not differ between groups (Bang et al., 2010). These data have shown the high 
efficacy and tolerance of XELOX–trastuzumab in GC patients. 
At present, immune checkpoint inhibitors, especially immune-combination therapies 
have resulted in a significant survival benefit in patients with advanced malignancies. 
Lots of evidence has shown that targeting the PD-1/PD-L1 pathway prolongs the survival 
in patients with different types of cancer, including NSCLC, gastric, bladder, and skin 
cancer. Pre-clinical research indicated synergetic effect on tumor reduction when 
combining anti-HER2 and anti-PD-1 (Müller et al., 2015). Moreover, 2019 ASCO GI 
reported a phase II single-arm study (NCT02954536) investigating the activity and 
tolerability of pembrolizumab and trastuzumab plus XELOX in treatment-naïve 
metastatic GC, showing ORR and DCR as 87% and 100% respectively (Janjigian et al., 
2019). Recently, 2022 ASCO GI reported the latest result of one single-arm, phase II 
study (NCT03950271) which showed neoadjuvant combination of SHR1210 (PD-1 
inhibitor), transtuzumab and XELOX is a safe and efficacious treatment option. Among 
sixteen patients who experienced D2 resection, 5 (31.3%) achieved pCR (Li et al, 2022). 
These primary data suggest a role for immune regulation of response to targeted and 

 
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chemotherapy, which support the combination strategy of anti-HER2 and anti-PD-1 plus 
XELOX to be investigated in more settings for HER2-positive GC patients.  
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).  
Regarding perioperative chemotherapy for LAGC, no consensus on standard regimen 
exists so far. In the current study, XELOX is chosen as chemotherapy backbone 
regarding its recommendation in adjuvant (1A) and palliative (2B for HER2 positive) 
settings in CSCO guideline and also wide use in Chinese GC patients. 
Based on the considerations mentioned above, this study is designed to investigate the 
potential of atezolizumab plus trastuzumab in combination with XELOX in HER2-positive 
LAGC Chinese patients. We aim to explore the efficacy and safety of the regimen in this 
special GC population, and hopefully provide valuable data for further research. 
Atezolizumab has been generally well tolerated.  Adverse events with potentially 
immune-mediated causes consistent with an immunotherapeutic agent, including rash, 
influenza-like illness endocrinopathies, hepatitis or transaminitis, pneumonitis colitis, and 
myasthenia gravis, have been observed (see Atezolizumab Investigator's Brochure for 
detailed safety results).  To date, these events have been manageable with treatment or 
interruption of atezolizumab treatment. In addition, the safety of the regimen of 
trastuzumab plus XELOX is acceptable and manageable, which has been proved in the 
previous studies (Bang et al., 2010; Rivera et al., 2013). 
This trial will enroll patients with HER2 positive GC or adenocarcinoma of 
gastroesophageal junction.  Given the relatively poor prognosis and limited treatment 
options for these patients, this population is considered appropriate for trials of novel 
therapeutic candidates.  The benefit-risk ratio for atezolizumab in combination with 
trastuzumab and XELOX is expected to be acceptable in this setting. 
In the setting of the coronavirus 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 inhibiting the PD-1/PD-L1 pathway may be the modulation of 
the host immune response to acute infection, which may result in immunopathology or 
dysregulated immune system defenses.  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. 

 
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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).  While it is not known, there may be a 
potential for an increased risk of an enhanced inflammatory response if a patient 
develops acute severe acute respiratory syndrome corona virus 2 (SARS CoV-2) 
infection while receiving atezolizumab.  At this time, there is insufficient evidence for 
causal association between atezolizumab 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 atezolizumab and clinical and radiologic features for 
SARS CoV-2related interstitial pneumonia.  Thus, investigators should use their clinical 
judgment when evaluating and managing patients with pulmonary symptoms. 
There are limited data concerning the possible interactions between cancer 
immunotherapy 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 for Cancer [SITC] 2020). 
Per recommendations of the National Comprehensive Cancer Network (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 2021).  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 cancer immunotherapy (SITC 2020).  For patients enrolling in this study and 
receiving atezolizumab treatment, 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 atezolizumab treatment 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 4.4.1).      
Neutropenia and lymphopenia associated with chemotherapy may increase the risk for 
developing an infection in patients receiving atezolizumab in combination with 
chemotherapy. 

 
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2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy and safety of atezolizumab when given in 
combination with trastuzumab+XELOX (Arm A: atezolizumab trastuzumab with XELOX) 
compared with trastuzumab+XELOX (Arm B: trastuzumab with XELOX) in patients 
eligible for surgery with locally advanced HER2 positive gastric cancer or 
adenocarcinoma of gastroesophageal junction.  Specific objectives and corresponding 
endpoints for the study are outlined below. 
In this protocol, "study treatment" refers to the combination of treatments assigned to 
patients as part of this study (i.e., trastuzumab+XELOX with / without atezolizumab). 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the efficacy of study 
treatments on the basis of the following endpoint: 
● 
Pathological complete regression (pCR) rate 
pCR is defined as no evidence of vital residual tumor cells on hematoxylin and eosin 
evaluation of the complete resected gastric/GEJ specimen and all sampled regional 
lymph nodes following completion of neoadjuvant systemic therapy (NAST) (i.e., 
ypT0N0 in the current AJCC staging system, 8th edition). 
pCR status of surgery specimens will be analyzed by local pathologists at each site 
according to the tumor regression grade (TRG) score of the 8th AJCC (See 
Appendix 2).   pCR rate will be analyzed in the intention-to-treat (ITT) population, 
defined as all patients who were randomly assigned to a treatment, regardless of 
whether they had surgery. It will be additionally assessed in a pre-specified 
sensitivity analysis in the per-protocol (PP) population. This population is defined as 
all patients who are centrally confirmed as HER2 positive and underwent resection.  
 
2.1.2 
Secondary Efficacy Objective 
The secondary efficacy objectives for this study will be analyzed in ITT population, 
including: 
● 
Event-free survival (EFS), defined as the time from randomization to the first 
documented disease recurrence, unequivocal tumor progression determined by the 
investigator according to RECIST v1.1, or death from any cause, whichever occurs 
first. 
● 
Disease-free survival (DFS), defined as the time from surgery to the first 
documented disease recurrence or death from any cause, whichever occurs first. 
● 
Overall survival (OS), defined as the time from randomization to death from any 
cause in all patients. 
● 
Major pathologic response (MPR), defined as < 10% residual tumor per tumor bed 
based on evaluation of the resected primary esophagogastric specimen by a local 
pathologist. 
● 
Objective response rate (ORR), defined as the proportion of patients with a 
complete response (CR) or partial response (PR) during NAST, as determined by 
the investigator according to RECIST v1.1. 

 
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● 
R0 resection rate, defined as the proportion of patients with a microscopically 
margin-negative resection, in which no gross or microscopic tumor remains in the 
primary tumor bed and/or sampled regional lymph nodes based on evaluation by the 
local pathologist. 
 
2.1.3 
Exploratory Efficacy Objective 
The following exploratory analyses are currently planned, but may be adapted taking into 
account new research data and approval of Human Genetic Resources Administration 
Office of China (HGRAC): 
● 
To monitor the effects of treatments by detecting HER2 copy number in circulating 
tumor DNA (ctDNA). Blood samples are collected at several time points indicated in 
Appendix 1 (ctDNA analysis,HER2 copy number) and circulating DNA is extracted 
for detecting HER2 copy number centrally using droplet digital polymerase chain 
reaction (PCR). 
● 
To explore the effects of treatment on HER2 status. HER2 will be evaluated 
centrally using surgical resected samples to explore the effects of treatment on 
HER2 status. 
● 
To evaluate measures of efficacy based upon mismatch repair (MMR) status, PD-L1 
expression and stromal tumor-infiltrating lymphocytes (sTIL) infiltration. 
MMR status will be assessed centrally or locally using biopsy samples. Deficient 
MMR (dMMR) is defined by immunohistochemistry (IHC) as a loss of expression in 
≥1 mismatch repair proteins (MLH1, PMS2, MSH2 or MSH6). MMR results will be 
collected for subgroup analysis. 
Expression of PD-L1 will be assessed both in pre-treatment tumor biopsy and 
surgical resected samples by the IHC assay (PD-L1, 22C3; Agilent Technologies) in 
the central laboratory. Tumors will be considered PD-L1 positive if the combined 
positive score (number of PD-L1–positive cells [tumor cells, macrophages, 
lymphocytes] divided by the total number of tumor cells, multiplied by 100) is 1 or 
greater. Subgroups based on PD-L1 expression status will be evaluated.  
sTIL signature will be assessed by multiplex immunohistochemistry staining  on pre-
treatment tumor tissue by central pathologist. Briefly, 4-5 m sections of FFPE will 
be applied with several antibodies (FoxP3, CD56, CD4, CD3, CD8, HER2, CD68, 
CD163, IRF8, CD20, PD-1, PD-L1) to label different kinds of cells. TILs are reported for 
the stromal compartment (% stromal TILs, sTIL) in all areas containing invasive 
tumor cells on the H&E slide containing the most invasive tumor. 
 
2.2 
SAFETY OBJECTIVE 
The safety objective for this study is to evaluate the safety of study treatments on the 
basis of the following endpoints:  
● 
Incidence, nature and severity of adverse events (AEs), with severity determined 
according to the National Cancer  Institute Common Terminology Criteria for 
Adverse Events version 5.0 (NCI CTCAE v5.0). 
● 
Changes from baseline in targeted vital signs and physical findings. 
● 
Changes from baseline in targeted clinical laboratory test results. 

 
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
This is a phase II, multicenter, randomized, open-label study designed to evaluate the 
efficacy and safety of perioperative trastuzumab+XELOX with / without atezolizumab in 
patients eligible for surgery with locally advanced HER2-positive gastric cancer or 
adenocarcinoma of GEJ. The study will enroll approximately 42 patients in China. 
Patients who have histologically confirmed, HER2 positive, locally advanced 
(cT3/T4a/T4b or N+, M0, AJCC 8th edition) gastric cancer or adenocarcinoma of GEJ 
(Siewert I-III) are eligible. HER2 status of the primary gastric/GEJ tumor will be assessed 
in local laboratory and mandatory sent to the central laboratory for HER2 positivity 
confirmation. Patients without centrally confirmed HER2-positive result will be included in 
ITT analysis but not in PP analysis.  
Eligible patients will be enrolled and 1:1 randomized to perioperative treatment with 
either trastuzumab plus atezolizumab with XELOX (Arm A) or trastuzumab alone with 
XELOX (Arm B).  
Arm A: Atezolizumab plus Trastuzumab with XELOX 
Patients randomized to treatment Arm A will receive atezolizumab + trastuzumab + 
XELOX for 3 treatment cycles prior to surgery, 3 weeks each cycle, as described below. 
Following surgery, patients will receive 5 further cycles of this regimen. 
• 
Atezolizumab 1200mg IV day 1 every 3 weeks Q3W  
• 
Trastuzumab 6 mg/kg IV day 1 (8 mg/kg as loading dose at 1st administration pre- 
and post-operation) Q3W 
• 
XELOX: Capecitabine 1000mg/m2 PO bid, days 1-14 Q3W 
              Oxaliplatin 130mg/m2 IV day 1 Q3W 
 
Arm B: Trastuzumab with XELOX 
Patients randomized to treatment Arm B will receive trastuzumab + XELOX for 3 
treatment cycles prior to surgery, 3 weeks each cycle, as described below. Following 
surgery, patients will receive 5 further cycles of this regimen.  
• 
Trastuzumab 6 mg/kg IV day 1 (8 mg/kg as loading dose at 1st administration pre- 
and post-operation) Q3W 
• 
XELOX: Capecitabine 1000mg/m2 PO bid, days 1-14 Q3W 
              Oxaliplatin 130mg/m2 IV day 1 Q3W 
 
Surgery is recommended to be performed 3 to 6 weeks after the last dose of 
neoadjuvant study treatment. The first dose of postoperative treatment is recommended 
to initiate within 8 weeks after surgery. Surgical approaches will be tailored to the 
individual patient according to local standards with the goal of achieving R0 resection.  
Note: there will be a Safety Run-in Phase comprising the first 10 patients enrolled into 
both arms who have completed neoadjuvant treatment and surgery. All available safety 
data (including perioperative morbidity and mortality) of the first 10 patients will be 
reviewed by the internal monitoring committee (IMC) for providing a recommendation 
whether to continue, modify or terminate the study.  

 
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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 
electronic Case Report Form (eCRF) and in the patient's medical record to facilitate 
source data verification. Following completion of the treatment of the study, every effort 
should be made to follow up all subjects for their disease and survival status until subject 
death or termination by the Sponsor, except withdrawing consent. Patients who 
discontinue neoadjuvant therapy early as a result of disease progression or who 
receives non-protocol therapy prior to surgery must be discontinued from all study 
treatment, and will be managed per local practice. These patients will remain on study 
for survival follow-up. 
Patients who discontinue treatment for reasons other than disease progression (e.g., 
toxicity) will continue scheduled tumor assessments until disease progression, 
withdrawal of consent, study termination by Sponsor, or death, whichever occurs first.  In 
the absence of disease progression, tumor assessments should continue regardless of 
whether patients start a new anti-cancer therapy, unless consent is withdrawn.  All 
patients will be followed for survival unless consent is withdrawn.   
Tumor specimens (by pre-operative biopsy and surgical resection) from eligible patients 
will be prospectively tested for biomarkers. ctDNA will also be collected for HER2 copy 
number monitoring. These samples will enable analysis of tumor tissue biomarkers 
related to clinical benefits. 
Figure 1 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1. 

 
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Figure 1 
Study Schema 
 
AJCC= American Joint Committee on Cancer; GEJ  gastroesophageal junction ; d  day; IHC= 
immunohistochemistry; IV  intravenous; PO = per os; PS= Performance Status; Q3W= every 3 
weeks  
 
3.1.2 
Internal Monitoring Committee  
An internal Monitoring Committee (IMC) will evaluate all available safety data (including 
perioperative morbidity and mortality) of the first 10 patients during the study for 
providing a recommendation whether to continue, modify or terminate the study. The 
IMC is a Roche internal committee and consists of the statistician, safety scientist and 
representatives from clinical science. 
Any outcomes of these data reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of their respective Institutional Review 
Boards/Ethics Committees (IRBs/ECs). 
The operation of IMC will follow the IMC agreement. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of this study is defined as the date when the last patient, last visit (LPLV) 
occurs.  The end of the study is expected to occur approximately 40 months after the 
last patient is enrolled (36 months after the last patient receives surgery). 
In addition, the Sponsor may decide to terminate the study. 
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 52 months, assuming a recruitment period of 
approximately 12 months plus 40 months from the date of enrollment of the last patient. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Atezolizumab and Trastuzumab 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 the approved dosage for atezolizumab (Tecentriq U.S. 
Package Insert).  Anti-tumor activity has been observed across doses ranging from 1 
mg/kg to 20 mg/kg Q3W.  In Study PCD4989g, the maximum tolerated dose of 
atezolizumab was not reached and no dose-limiting toxicities (DLTs) were observed at 

 
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any dose.  The fixed dose of 1200 mg Q3W (equivalent to an average body 
weight based dose of 15 mg/kg Q3W) was selected on the basis of both nonclinical 
studies (Deng et al. 2016) and available clinical pharmacokinetic, efficacy, and safety 
data. In the study PCD4989g, patients receiving 10 to 20 mg/kg atezolizumab, including 
the fixed 1200 mg dose, maintained geometric mean Cmin that was in excess of both the 
LOQ and the target serum concentration of 6 μg/mL (Deng et al. 2016) . Treatment with 
atezolizumab at a fixed dose of 1200 mg Q3W as a single agent or in combination with 
other therapeutic agents results in anti-tumor activity across a range of tumor types and 
hematologic malignancies (including pediatric-type tumors), across lines of therapy, and 
across PD-L1 expression subgroups. The safety data indicate that atezolizumab is well 
tolerated and the observed AEs are consistent with the known mechanism of action of 
atezolizumab or the underlying disease. Please refer to the Atezolizumab Investigator's 
Brochure for details. 
Trastuzumab will be administered at an 8 mg/kg IV loading dose and then 6 mg/kg IV on 
Day 1 of a 21-day cycle, which is the approved dosage for HER2+ advanced GC. In 
Study BO27798 (HELOISE), 16/28 HER2+ advanced GC patients received trastuzumab 
at an 8 mg/kg IV loading dose and then 6 mg/kg IV on Day 1 of a 21-day cycle had 
serum trastuzumab concentrations of ≥12 μg/mL at Cycle 2 Day 21. Median OS was 
12.5 months, and median PFS was 5.7 months. No new safety signals was detected. 
Please refer to the Trastuzumab Investigator's Brochure for details. 
3.3.2 
 Rationale for Patient Population 
This study will enroll patients eligible for surgery with locally advanced HER2-positive 
GC or adenocarcinoma of GEJ. 
In China, more than 80% of gastric cancer patients are already in advanced stages at 
the time of diagnosis (Wang et al., 2019). Patients with advanced disease (locally 
advanced or metastatic) have a somber prognosis. For LAGC, the overall 5-year survival 
rate in China is only 18-70% (Wang et al., 2016), and the HER2+ subgroup is much 
worse.  
However, there are no standard perioperative/neoadjuvant regimens for the HER2+ GC 
population yet. In the previous perioperative trials, the efficacy for LAGC is unsatisfying, 
especially in the HER2+ LAGC patients. Thus, this study plans to recuit patients eligible 
for surgery with locally advanced HER2-positive GC or adenocarcinoma of GEJ to 
receive perioperative trastuzumab+XELOX with / without atezolizumab, which is 
expected to provide efficacy and safety data for further research.   
3.3.3 
Rationale for Open-Label Study 
An open-label study design was chosen for this trial for a number of reasons.  Given the 
known toxicities associated with atezolizumab, patients assigned to atezolizumab-
containing arms, as well as physicians, may be capable of identifying treatment 
assignment in a blinded study.  Furthermore, because of the potential for 
pseudoprogression in patients randomized to atezolizumab-containing arms, a blinded 
study would require all patients to continue treatment until loss of clinical benefit 
regardless of whether they were receiving atezolizumab.  This could then delay 
subsequent treatment with approved therapies in patients assigned to the control arm, 
as well as increase the complexity of treatment decisions. 

 
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The strategy and timing for final analysis of the primary endpoint, including censoring 
rules and methods for handling missing data, have been prespecified in the protocol. 
3.3.4 
Rationale for pathological complete regression (pCR) rate as Primary 
Endpoint 
In this study, the primary efficacy endpoint will be local pathologists-assessed pCR.   
pCR is defined as no evidence of vital residual tumor cells on hematoxylin and eosin 
evaluation of the complete resected stomach/GEJ specimen and all sampled regional 
lymph nodes following completion of neoadjuvant systemic therapy (NAST) (i.e., ypT0N0 
in the current AJCC staging system, 8th edition). 
pCR is considered as a surrogate endpoint index to predict EFS, DFS and OS, and it is 
often used as the primary efficacy endpoint in clinical trials of neoadjuvant therapy 
(Homann et al., 2012; Issa et al., 2012). Furthermore, the whole trial period can be 
shorten, and sample size can be decreased if pCR used as the primary efficacy 
endpoint. As a result, pCR is used as the primary endpoint in this study. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 42 patients eligible for surgery with locally advanced HER2-positive 
gastric cancer or adenocarcinoma of GEJ will be enrolled in this study. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
1. Signed Informed Consent Form 
2. Aged  18 and ≤ 75 years 
3. Ability to comply with the study protocol, in the investigator's judgment 
4. Histologically confirmed (by enrolling center) gastric cancer or adenocarcinoma of 
GEJ (Siewert I-III)  
5. HER2-positive status defined as either IHC score of 3+ or IHC 2+ (See Appendix 3) 
with amplification proven by in situ hybridization (ISH) as assessed by local review 
based on pretreatment endoscopic biopsies. ISH positivity is defined as a ratio of  
2.0 for the number of HER2 gene copies to the number of signals for chromosome 
17 copies (HER2/CEP17). 
6. Clinical stage at presentation: cT3/T4a/T4b, or N+, M0 as determined by AJCC 
staging system, 8th edition 
a. An esophageal-gastro-duodenoscopy is mandatory 
b. Diagnostic laparoscopy and endoscopic ultrasonography are recommended 
7. 
Avaliability of formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin 
block (preferred) or at least 16 available and of good quality biopsy tissue slides 
containing unstained, freshly cut, serial sections must be submitted for central 

 
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assesment of HER2, PD-L1, MMR and sTIL signature.  Agree to provide blood 
samples after enrollment. 
a. For MMR, there is no need to submit for central assessment if local lab is available. 
8. Physical condition and organ function allowing to undergo appropriate surgical 
management 
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
10. Baseline left ventricular ejection fraction (LVEF)  55% measured by 
echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scans 
11. Life expectancy  12 weeks 
12. Adequate hematologic and end-organ function, defined by the following laboratory 
test results, obtained within 7 days prior to initiation of study treatment: 
a. Absolute neutrophil count (ANC)   1.5  109/L (1500/L) without granulocyte 
colony-stimulating factor support 
b. Lymphocyte count  0.5  109/L (500/L) 
c. 
Platelet count  100  109/L (100,000/L) without transfusion  
d. Hemoglobin  90 g/L (9 g/dL). Patients may be transfused to meet this criterion 
e. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and 
alkaline phosphatase (ALP)  2.5  upper limit of normal (ULN) 
f. 
Serum total bilirubin  1.5  ULN with the following exception: 
Patients with known Gilbert disease:  serum total bilirubin level  3  ULN 
g. Serum creatinine  1  ULN or Creatinine clearance (CCr)  60mL/min 
(calculated using the Cockcroft-Gault formula): 
(140-age)  Weight (kg)  
CCr (ml/min) =                                             (Female 0.85) 
72   SCr (mg/dL) 
 
(140-age)  Weight (kg)  
OR  CCr (ml/min) =                                             (Female 0.85) 
0.818   SCr (umol/L)  
h. Serum albumin  30 g/L (3.0 g/dL) 
i. 
For patients not receiving therapeutic anticoagulation:  INR or aPTT  1.5  ULN 
j. 
For patients receiving therapeutic anticoagulation:  stable anticoagulant 
regimen and stable INR 
13. For female patients of childbearing potential, agreement (by patient) to remain 
abstinent (refrain from heterosexual intercourse) or to use highly effective form(s) of 
contraception (i.e., one that results in a low failure rate [<1% per year] when used 

 
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consistently and correctly) during the treatment period and to continue its use for at 
least i) 5 months after the last dose of atezolizumab, ii) 7 months after the last dose 
of trastuzumab, or iii)  6 months after the last dose of capecitabine or oxaliplatin, 
whichever is longer.  
a. A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (<12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus) 
b. 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 
c. 
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 acceptable methods of contraception 
14. For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below: 
a. 
With female partners of childbearing potential or pregnant female partners, men 
who are not surgically sterile must remain abstinent or use a condom plus an 
additional contraceptive method that together result in a failure rate of <1% per 
year during the treatment period and for at least, i) 7 months after the last dose 
of trastuzumab, ii)  3 months after the last dose of capecitabine, or iii) 6 months 
after the last dose of oxaliplatin, whichever is longer. Men must refrain from 
donating sperm during this same period 
b. 
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 acceptable methods of contraception 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Stage IV (metastatic) or unresectable gastric/GEJ cancer determined by 
investigators 
2. Prior systemic therapy for treatment of gastric cancer 
3. History of malignancy other than GC within 5 years prior to screening, 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 
4. Cardiopulmonary dysfunction as defined by any of the following prior to 
randomization: 

 
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a. History of congestive heart failure of any classification 
b. Angina pectoris requiring anti-anginal medication, serious cardiac 
arrhythmia not controlled by adequate medication, severe conduction 
abnormality, or clinically significant valvular disease 
c. 
High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate > 
100/min at rest, significant ventricular arrhythmia [ventricular tachycardia], 
or higher-grade atrioventricular [AV]-block [second-degree AV-block Type 2 
[Mobitz 2] or third degree AV-block]) 
d. Significant symptoms (Grade  2) relating to left ventricular dysfunction, 
cardiac arrhythmia, or cardiac ischemia 
e. Myocardial infarction within 12 months prior to randomization 
f. 
Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or 
diastolic blood pressure > 100 mmHg) 
g. Evidence of transmural infarction on electrocardiograph (ECG) 
h. Requirement for oxygen therapy 
5. Dyspnea at rest 
6. 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, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré 
syndrome, or multiple sclerosis (see protocol Appendix 11 for a more 
comprehensive list of autoimmune diseases and immune deficiencies), with the 
following exceptions: 
a. Patients with a history of autoimmune-mediated hypothyroidism who are on 
thyroid-replacement hormone are eligible for the study. 
b. Patients with controlled Type 1 diabetes mellitus who are on an insulin 
regimen are eligible for the study. 
c. 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: 
i. 
Rash must cover  10% of body surface area 
ii. 
Disease is well controlled at baseline and requires only low-potency topical 
corticosteroids 

 
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iii. 
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 
7. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan 
8. Active tuberculosis 
9. 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 
course of the study  
10. Severe infections within 4 weeks prior to initiation of study treatment, including, but 
not limited to, hospitalization for complications of infection, bacteremia, or severe 
pneumonia 
11. Treatment with therapeutic antibiotics within 2 weeks (IV antibiotics) or 5 days (oral 
antibiotics) prior to initiation of study treatment 
a. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract 
infection or chronic obstructive pulmonary disease exacerbation) are eligible for 
the study. 
12. Prior allogeneic stem cell or solid organ transplantation 
13.  
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 
14. 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 treatment 
or within 5 months after the final dose of atezolizumab 
15. Current treatment with anti-viral therapy for hepatitis B virus (HBV) 
16. Positive test for human immunodeficiency virus (HIV) 
17. Patients with active hepatitis B (defined as having a positive hepatitis B surface 
antigen [HBsAg] test at screening) 
a. Patients with past HBV infection or resolved HBV infection (defined as having a 
negative HBsAg test or a positive antibody to hepatitis B core antigen [anti-HBc] 
antibody followed by a negative HBV-DNA test at screening ) are eligible. 
18. Patients with active hepatitis C 
a. Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is 
negative for HCV RNA. 
19. Evidence of significant uncontrolled concomitant disease that could affect 
compliance with the protocol or interpretation of results, including significant liver 
disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena 
cava syndrome) 
20. Treatment with any approved anti-cancer therapy, 5 half-lives prior to initiation of 
study treatment 

 
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21. Treatment with investigational therapy within 28 days prior to initiation of study 
treatment 
22. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
including anti CTLA-4, anti PD-1, and anti PD-L1 therapeutic antibodies  
23. Treatment with systemic immunostimulatory agents (including but not limited to 
interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is 
shorter, prior to initiation of study treatment 
24. Treatment with systemic immunosuppressive medications (including, but not limited 
to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and 
anti-tumor necrosis factor-α[TNF-α] 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), inhaled 
or low dose corticosteroids for COPD or asthma, or low-dose corticosteroids for 
orthostatic hypotension or adrenal insufficiency are eligible for the study. 
25. History of severe allergic anaphylactic reactions to chimeric or humanized 
antibodies or fusion proteins 
26. Known hypersensitivity to Chinese hamster ovary cell products or to any component 
of the atezolizumab formulation  
27. Known allergy or hypersensitivity to any component of trastuzumab, capecitabine or 
oxaliplatin formulations 
28. Known dihydropyrimidine dehydrogenase (DPD) deficiency or history of severe and 
unexpected reactions to fluoropyrimidine therapy in patients selected to receive 
capecitabine 
29. Have a significant impact on oral drug absorption factors, such as unable to 
swallow, chronic diarrhea and intestinal obstruction 
30. Requirement for concurrent use of the antiviral agent sorivudine (antiviral) or 
chemically related analogues, such as brivudine in patients selected to receive 
capecitabine. Use of these drugs is not allowed within 4 weeks prior to study 
treatment that includes capecitabine 
31. Pregnancy or breastfeeding, or intention of becoming pregnant during study 
treatment or within i) 5 months after the last dose of atezolizumab, ii) 7 months after 

 
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the last dose of trastuzumab, or iii)  6 months after the last dose of capecitabine or 
oxaliplatin, whichever is longer 
a. Women of childbearing potential must have a negative serum pregnancy test 
result within 7 days prior to initiation of study treatment. 
 
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 treatment assignment from an interactive voice or web-based 
response system (IxRS). 
Patients will be randomly assigned to one of two treatment arms: atezolizumab plus 
trastuzumab with XELOX or trastuzumab with XELOX.  Randomization will occur in a 1:1 
ratio using a permuted-block randomization method to ensure a balanced assignment to 
each treatment arm. 
 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT TO THE STUDY 
DESIGN 
The investigational medicinal products (IMPs) for this study are atezolizumab and 
trastuzumab. 
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
4.3.1.1 
Atezolizumab and trastuzumab 
Atezolizumab will be supplied by the Sponsor as sterile liquid in a single-use, 20-mL 
glass vial. The vial contains approximately 20 mL (1200 mg) of atezolizumab solution. 
Atezolizumab is formulated in histidine acetate buffered at pH 5.8 containing sucrose 
and polysorbate 20. No preservative is used in the atezolizumab Drug Product or the 
diluent; therefore, the vial is intended for single use only. For intravenous administration, 
atezolizumab will be administered in IV infusion bags containing 0.9% sodium chloride 
(NaCl) and infusion lines equipped with 0.2 or 0.22 μm in-line filters. 
Trastuzumab will be supplied by the Sponsor as a lyophilized formulation in multi-dose 
(440 mg) vial. Trastuzumab is formulated in histidine/histidine-HCl monohydrate (buffer), 
α,α-trehalose dihydrate (tonicity adjuster), and polysorbate 20 (stabilizer/emulsifier). 
Following reconstitution in bacteriostatic water for injection for the multi-dose 
preparation, trastuzumab is further diluted in 250 mL 0.9% sodium chloride solution for 
administration.  
Please refer to the pharmacy manual for details of atezolizumab and trastuzumab 
formulation, packaging, and handling. 
4.3.1.2 
Chemotherapy 
XELOX (capecitabine and oxaliplatin) is the chemotherapy regimen used in this trial.  
Capecitabine will be supplied by the Sponsor as biconvex, oblong film-coated tablets for 
oral administration. Each peach-colored tablet contains 500 mg capecitabine. The 
inactive ingredients in capecitabine include: anhydrous lactose, croscarmellose sodium, 

 
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hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate, and 
purified water. The peach or light peach film coating contains hydroxypropyl 
methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides..  
Oxaliplatin will be supplied by the Sponsor as lyophilized lump or powder in a glass vial 
which contains 50 mg of oxaliplatin lyophilized lump or powder. Excipients contain 
lactose hydrate and water for injection. For intravenous administration, oxaliplatin should 
be dissolved in 5% glucose solution 250ml to 500ml (for a concentration of 0.2mg/ml or 
above). The vial is intended for single use only. 
For information on the formulation, packaging, and handling of capecitabine and 
oxaliplatin, refer to the local prescribing information for the chemotherapy regimen. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Any dose modification should be noted on the Study Drug Administration 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. 
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Appendix 6, Appendix 7 and 
Appendix 9. 
4.3.2.1 
Atezolizumab and Trastuzumab 
Atezolizumab 
Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of 
each 21-day cycle for 3 cycles prior to surgery and 5 cycles after surgery. 
Atezolizumab should be administered as the first infusion. 
Treatment will continue as scheduled unless progression, recurrence of disease, or 
unmanageable toxicity, whichever occurs first. 
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 5.  
Atezolizumab infusions will be administered per the instructions outlined in Table 1. 

 
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Table 1 
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, and temperature) should 
be measured within 60 minutes prior to the 
infusion. 
● Atezolizumab should be infused over 
60 ( 15) minutes. 
● If clinically indicated, vital signs should be 
measured every 15 ( 5) minutes during the 
infusion and at 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 infusion-
related reaction with any previous 
infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator. 
● Vital signs should be measured within 
60 minutes prior to the infusion. 
● Atezolizumab should be infused over 
30 ( 10) minutes if the previous infusion 
was tolerated without an infusion-related 
reaction, or 60 ( 15) minutes if the 
patient experienced an infusion-related 
reaction with the previous infusion. 
● If the patient experienced an infusion-
related reaction with the previous infusion 
or if clinically indicated, vital signs should 
be measured during the infusion and at 
30 ( 10) minutes after the infusion. 
 
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
the Appendix 6. 
No dose modification for atezolizumab is allowed. Guidelines for atezolizumab 
interruption or discontinuation for patients who experience adverse events are provided 
in Appendix 6. 
Trastuzumab 
Trastuzumab is given as an 8 mg/kg IV loading dose and then 6 mg/kg IV on Day 1 of a 
21-day cycle for 3 cycles before surgery, and administration will continue after surgery. 
The first administration of trastuzumab after surgery should also be given at the loading 
dose of 8 mg/kg. 
Trastuzumab should be administered after atezolizumab and prior to oxaliplatin. 
Weight should be recorded during screening and on Day 1 of each cycle for all patients. 
The initial baseline weight for a patient will be that measured on Cycle 1, Day 1. The 
amount of trastuzumab to be administered must be recalculated if the patient’s body 
weight has changed by > 10% (increased or decreased) from the Cycle 1, Day 1 weight. 
Weight at the time the dose is recalculated will be considered as baseline for 
subsequent evaluations of degree of weight change with respect to trastuzumab dose 
modification requirements. The amount of trastuzumab administered is calculated 
according to the patient’s actual body weight, with no upper limit. 
The initial dose of trastuzumab will be administered over 90 (+/-10) minutes, and 
patients will be observed for at least 30 minutes from the end of the infusion for infusion-
related symptoms such as fever or chills. Interruption or slowing of the infusion may help 

 
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control such symptoms and may be resumed when symptoms abate. If the infusion is 
well tolerated, subsequent infusions may be administered over 30 (+/-10) minutes, and 
patients will be observed for a further 30 minutes. All infusion-related symptoms must 
have resolved before chemotherapy is given or the patient is discharged. Patients can 
be administrated with premedication (e.g. phenothiazines, antihistaminics, or 
anticholinergic agents) to control nausea/vomiting per local practice standards.  
Guidelines for treatment interruption or discontinuation for trastuzumab are provided in 
the Appendix 7. No dose modifications are allowed for trastuzumab. If the patient misses 
a dose of trastuzumab by one week or less, then the usual dose of trastuzumab (6 
mg/kg) should be given as soon as possible (do not wait until the next planned cycle). 
Subsequent maintenance trastuzumab doses of 6 mg/kg are then given every 3 weeks, 
according to the previous schedule. If the patient misses a dose of trastuzumab by more 
than one week, a re-loading dose of trastuzumab should be given (8 mg/kg over 90 
minutes). In general, subsequent maintenance trastuzumab doses of 6 mg/kg are then 
given every 3 weeks, starting 3 weeks later. 
The patients who are diagnosed to be recurrent must be discontinued the study 
treatment. The treatment for recurrent is at the investigators’ discretion but must be 
recorded in the eCRFs. 
4.3.2.2 
Chemotherapy 
XELOX is the chemotherapy regimen used in this trial, which will be administered in the 
3 cycles before surgery (neoadjuvant) and 5 cycles after surgery (adjuvant) as follows: 
• 
Capecitabine 1000 mg/m2 administered twice orally on days 1–14, repeated 
every 3 weeks(21[+/-3]days); The first dose of capecitabine is given on the evening of 
day 1 and the last dose is given on the morning of day 15 of each cycle.  
Capecitabine shall be orally taken within 30 minutes after the meal (breakfast or 
dinner), bid, taking tablets with 200 ml water (juice is not allowed). 
Capecitabine dose is the combined dose of 500mg tablets. Total dose in each day 
is divided into two times to take with approximately 12 hours of interval. Two doses shall 
be separated in order to take a whole tablet. Appendix 8 provides the dosage calculation 
of capecitabine. 
• 
Oxaliplatin 130mg/m2 IV on day 1 of a 21-day cycle; infusion over 2 hours.  
Oxaliplatin should not be mixed with any other solutions (especially 5-fluorouracil, 
alkaline solutions, tromethamine or folic acid drugs containing tromethamine), or 
administered simultaneously with them through the same vein. The infusion pipeline 
should be flushed after oxaliplatin infusion.  
It needs to be noted that patients should avoid cold exposure during oxaliplatin 
administration or for several hours after administration, and avoid eating raw/cold food 
or/and cold drinks. 
The dose of chemotherapy is calculated according to the patient’s body surface area 
(BSA). The BSA and the amount of drug administered must be recalculated if the 
patient’s body weight has changed by > 10% (increased or decreased) from baseline. 

 
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Recalculation of the amount of drug administered on the basis of smaller changes in 
body weight or BSA is at the investigators’ discretion. 
In case the oxaliplatin treatment should be discontinued due to its specific toxicity (such 
as neurotoxicity), then capecitabine can be continued alone for up to 8 cycles (including 
preoperative chemotherapy cycles). If capecitabine is discontinued, oxaliplatin won't be 
continued. 
Guidelines for dosage modification and treatment interruption or discontinuation for 
capecitabine and oxaliplatin are provided in Appendix 9. 
There is no mandatory delay between atezolizumab/trastuzumab and oxaliplatin, 
assuming the infusion is well tolerated. If local policy is to give the atezolizumab/ 
trastuzumab on day one and start the oxaliplatin the next day, (still within a 24 hour 
period), this is acceptable on an exceptional basis. 
4.3.3 
Supportive medications 
Supportive medications (anti-emetics, antihistamines, and analgesics) will be 
administered per local practice standards. 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) with Cycle 1 of 
atezolizumab may receive premedication with antihistamines, antipyretics, and/or 
analgesics (e.g., acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is 
prohibited in treating IRRs because of its potential for causing agranulocytosis. 
Oxaliplatin can be administrated with premedication (e.g. phenothiazines, 
antihistaminics, or anticholinergic agents) at each cycle to control nausea/vomiting per 
local practice standards. 
Patients who experience mild, moderate or severe infusion reactions on the first dose 
may be retreated with trastuzumab. Subsequent trastuzumab infusions are generally 
well tolerated. Premedication with corticosteroids, antihistamines, and antipyretics may 
be used before subsequent trastuzumab infusions at the Investigator’s discretion. 
4.3.4 
Investigational Medicinal Product Accountability 
All IMPs (i.e. atezolizumab and trastuzumab) required for completion of this study will be 
provided by the Sponsor.  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. 
Used IMPs will either be disposed of at the study site according to the study site's 
institutional standard operating procedure or be returned to the Sponsor with the 
appropriate documentation. Unused IMPs will be returned to the Sponsor. 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 the Drug Inventory Log. 

 
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4.3.5 
Surgery 
Surgery is recommended to be performed 3 to 6 weeks after the last dose of neoadjuvant 
study treatment. Surgical approaches will be tailored to the individual patient according to 
local standards with the goal of achieving R0 resection. 
White blood cell count should be above 3.5109/L, platelet more than 100109/L, drug 
treatment-related adverse reactions have been recovered to meet surgical requirements 
(according to guidelines). The surgical procedure will be carried out according to the 
CSCO clinical guidelines for the diagnosis and treatment of gastric cancer 2019 (Wang et 
al., 2019). 
Surgery will be under general anesthesia supported by epidural anesthesia. Open 
surgery is considered to be the standard approach. Laparoscopic and robotic-assisted 
surgery is allowed only after discussion with the principal investigator if the surgical team 
has significant expertise in the minimally invasive approach with morbidity, mortality, and 
oncologic results that are comparable to the open approach. Trial laparoscopy may be 
considered by the surgical team to have an initial assessment of the extent and 
resectability of the tumor and evidence of distant metastases. 
Please refer to the surgical guidelines for more details. 
4.3.5.1 
Resection 
A sufficient distance between tumor bed and longitudinal resection margin should be 
ensured. The proximal and distal margins of resection will be based on the location of the 
tumor. The recommendations for an adequate distance of resection margin for Borrmann 
I–II gastric cancers are to be ≥ 3 cm, and for Borrmann III–IV it should be ≥ 5 cm. If the 
tumor has invaded the esophagus or pylorus, a resection margin of 5 cm is not obligatory 
only when R0 resection can be assured and the frozen pathological examinations of the 
resection margins are negative.  
For EGJ adenocarcinoma which has invaded < 3 cm into the esophagus or the body of 
the stomach, non-endoscopic surgery is recommended. 
4.3.5.2 
Lymphadenectomy 
The extent of the lymphadenectomy depends on the type of resection. D2 lymph node 
dissection is the standard recommendation for resectable gastric cancer classified as 
being cT1N+ and cT2-4N-/+. It is recommended that ≥ 16 lymph nodes should be 
pathologically examined to ensure accurate staging and prognostication. The lymph node 
dissection should follow the recommendations of the CSCO clinical guidelines for the 
diagnosis and treatment of gastric cancer 2019 (Wang et al., 2019).  
The extent of resection and lymphadenectomy will be documented on the eCRF.  

 
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4.4 
CONCOMITANT THERAPY 
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 treatment from 7 days prior the initiation of 
study treatment until the treatment discontinuation visit or 30 days after the last study 
treatment (whichever occurs first).  All such medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF.  New cancer 
treatment should be recorded in survival follow up phase. 
4.4.1 
Permitted Therapy  
Patients are permitted to use the following therapies during the study: 
● 
Oral contraceptives 
● 
Hormone-replacement therapy 
● 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin) 
● 
Vaccinations (such as influenza , COVID-19) 
Live, attenuated vaccines are not permitted (see Section 4.4.3).      
● 
Megestrol acetate administered as an appetite stimulant  
● 
Mineralocorticoids (e.g., fludrocortisone) 
● 
Corticosteroids administered for COPD or asthma 
● 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency 
 
For atezolizumab, premedication with antihistamines, antipyretics, and/or analgesics 
may be administered for the second and subsequent atezolizumab infusions only, at the 
discretion of the investigator (see Section 4.3.3). 
Oxaliplatin can be administrated with premedication (e.g. phenothiazines, 
antihistaminics, or anticholinergic agents) at each cycle to control nausea/vomiting per 
local practice standards (see Section 4.3.3). 
Patients who experience mild, moderate or severe infusion reactions on the first dose 
may be retreated with trastuzumab. Subsequent trastuzumab infusions are generally 
well tolerated. Premedication with corticosteroids, antihistamines, and antipyretics may 
be used before subsequent trastuzumab infusions at the Investigator’s discretion. 
In general, investigators should manage a patient's care (including preexisting 
conditions) with supportive therapies other than those defined as cautionary or 
prohibited therapies (see Sections 4.4.2 and 4.4.3) 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 8). 

 
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In addition, a primary prophylaxis with G-CSF is not required, although permitted after 
balancing benefits and risks in the individual patient by the investigator. Upon 
occurrence of complicated neutropenia (e.g. either febrile neutropenia or infection during 
neutropenia), therapeutic and prophylactic actions according to local standards (e.g. 
administration of antibiotics and growth factors) should be applied. In order to avoid 
treatment delays, secondary prophylaxis with G-CSF will be required for all subsequent 
cycles if one of the following criteria is applicable: 
● 
Occurrence of febrile neutropenia or infection in neutropenia at any time or 
● 
Occurrence of grade 4 (NCI CTCAE v5.0) neutropenia or 
● 
Delay of one therapy cycle due to leucopenia or neutropenia by more than 3 days 
Anemia and thrombocytopenia should be managed according to local standards. 
4.4.2 
Cautionary Therapy  
● 
Systemic corticosteroids and TNF- inhibitors: Systemic corticosteroids and TNF- 
inhibitors may attenuate potential beneficial immunologic effects of treatment with 
atezolizumab.  Therefore, in situations in which systemic corticosteroids or TNF- 
inhibitors would be routinely administered, alternatives, including antihistamines, 
should be considered.  If the alternatives are not feasible, systemic corticosteroids 
and TNF- inhibitors may be administered at the discretion of the investigator. 
● 
Systemic corticosteroids are recommended, at the discretion of the investigator, for 
the treatment of specific adverse events when associated with atezolizumab therapy 
(refer to Appendix 6 for details). 
● 
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 4.4.3) may be used during the study at the discretion of the 
investigator. 
● 
Anticoagulants: patients treated with capecitabine should have their anticoagulant 
response (INR or prothrombin time) monitored frequently in order to adjust the 
anticoagulant dose accordingly. The use of low molecular weight heparin instead of 
coumarin is strongly recommended, but at the discretion of the Investigator. 
● 
Phenytoin: patients taking phenytoin concomitantly with capecitabine should be 
regularly monitored for increased phenytoin plasma concentrations and associated 
clinical symptoms. 
● 
Care needs to be taken if a patient is taking both capecitabine and cimetidine. 
● 
Interactions between capecitabine and drugs known to be metabolized by 
cytochrome p-450 2C9 have not been formally investigated. Thus, using of these 
drugs concomitantly with capecitabine should be cautious. 
● 
Leucovorin has an effect on the pharmacodynamics of capecitabine and may 
increase the toxicity of capecitabine. 

 
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● 
Anthracyclines should be avoided whenever possible within 7 months of 
trastuzumab withdrawal.When anthracyclines are needed, the patient's heart 
function should be closely monitored. 
4.4.3 
Prohibited Therapy 
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, is prohibited 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. 
● 
Investigational therapy is prohibited within 28 days prior to initiation of study 
treatment and during study treatment. 
● 
Live, attenuated vaccines are prohibited within 4 weeks prior to initiation of study 
treatment, during atezolizumab treatment, and for 5 months after the final dose of 
atezolizumab. 
● 
Systemic immunostimulatory agents (including, but not limited to, interferons and IL-
2) are prohibited within 4 weeks or 5 half-lives of the drug (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. 
● 
Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) are prohibited 
during study treatment because these agents could potentially alter the efficacy and 
safety of atezolizumab. 
● 
The antiviral agent sorivudine (antiviral) or chemically related analogues, such as 
brivudine, are prohibited within 4 weeks prior to initiation of capecitabine treatment 
and during capecitabine treatment. 
● 
Treatment with therapeutic antibiotics is prohibited within 2 weeks (IV antibiotics) or 
5 days (oral antibiotics) prior to initiation of study treatment. Treatment with 
prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic 
obstructive pulmonary disease exacerbation) is permitted. 
● 
Drugs with potential nephrotoxicity should be avoided during treatment with 
chemotherapy. 
● 
Allopurinol: interactions with allopurinol have been observed for 5-FU; with possible 
decreased efficacy of 5-FU. Concomitant use of allopurinol with capecitabine should 
be avoided. 
  
4.5 
STUDY ASSESSMENTS  
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should 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. 

 
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4.5.1 
Informed Consent Forms and Screening Log 
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. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. Patients who fail their first screening for study eligibility 
may qualify for one re-screening opportunity (for a total of two screenings per patient) at 
the investigator’s discretion.  All re-screening requests should be discussed with the 
Medical Monitor or designee. 
4.5.2 
Medical History, 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.  In addition, 
all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 7 days prior 
to initiation of study treatment will be recorded.  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 eCRF. Height and 
weight should be measured and recorded in the eCRF. 
Limited, symptom-directed physical examinations should be performed by the 
investigator or qualified designee 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.  
4.5.4 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure, and temperature.  Record abnormalities observed at baseline 
on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, 
record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
Vital signs should be measured within 60 minutes prior to each study treatment infusion 
and, if clinically indicated, during or after the infusion as outlined in Table 2.  In addition, 

 
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vital signs should be measured at other specified timepoints as outlined in the schedule 
of activities (see Appendix 1). 
Table 2 
Timing for Vital Sign Measurements for First and Subsequent Infusions 
Drug 
Timing for Vital Sign Measurements 
First Infusion 
Subsequent Infusions 
Atezolizumab ● Within 60 minutes prior to the 
atezolizumab infusion 
● Record patient's vital signs during or 
after the infusion if clinically 
indicated. 
● Within 60 minutes prior to the 
atezolizumab infusion 
● Record patient's vital signs during or 
after the infusion if clinically indicated 
Trastuzumab ● Within 60 minutes prior to the 
trastuzumab infusion 
● At least 30 minutes from the end of 
the infusion 
● Within 60 minutes prior to the 
trastuzumab infusion 
● At least 30 minutes from the end of the 
infusion 
Oxaliplatin 
● Within 60 minutes prior to the 
oxaliplatin infusion 
● Record patient's vital signs during or 
after the infusion if clinically 
indicated. 
● Within 60 minutes prior to the 
oxaliplatin infusion 
● Record patient's vital signs during or 
after the infusion if clinically indicated. 
 
4.5.5 
Tumor and Response Evaluations 
Patients will undergo tumor assessments at baseline, within 2 weeks  
 (+7 days)  before surgery, every 6 months until 3 years after surgery regardless of dose 
delays, until radiographic disease progression or recurrence per RECIST v1.1.  Thus, 
tumor assessments are to continue according to schedule in patients who discontinue 
treatment for reasons other than disease progression until disease progression, 
withdrawal of consent, study termination by Sponsor, or death, whichever occurs first.  In 
the absence of disease progression, tumor assessments should continue regardless of 
whether patients start a new anti-cancer therapy, unless consent is withdrawn. 
Additional assessment can be performed by the investigator as clinically indicated. If 
signs or symptoms indicate a possible disease progression or recurrence, they need to 
be confirmed by the investigator after an integrated assessment of radiographic, 
pathologic (if available) and/or biochemical examinations.  In that case, the time of 
progression or recurrence should be based on the time of first documented signs or 
symptoms.  Abnormal laboratory test results alone should not be used as a criterion to 
determine progression or recurrence. 
All measurable and evaluable lesions should be assessed and documented at 
screening.  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 oral or IV contrast) or MRI scans of 
the chest, abdomen, and pelvis as clinically indicated/determined by the investigators. If 
a CT scan with contrast is contraindicated (e.g., in patients with impaired renal 

 
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clearance), a non-contrast CT scan of the chest may be performed and MRI scans of the 
abdomen and pelvis should be performed.   
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a full-
contrast diagnostic CT scan. 
All measurable and evaluable lesions identified at baseline should be re-assessed at 
each subsequent tumor evaluation, and results must be reviewed by the investigator 
before dosing at the next cycle. 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).  
Objective response during NAST at a single timepoint will be determined according to 
RECIST v1.1 (see Appendix 4).  Assessments should be performed by the same 
evaluator, if possible, to ensure internal consistency across visits. 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples 
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis: 
● 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes) 
● 
Chemistry panel (serum):  bicarbonate or total carbon dioxide (if considered 
standard of care for the region), sodium, potassium, chloride, glucose, BUN or urea, 
creatinine, total protein, albumin, phosphate, calcium, total bilirubin, ALP, ALT, AST, 
and LDH 
● 
Coagulation:  INR, and aPTT 
● 
Thyroid function testing:  thyroid-stimulating hormone, free triiodothyronine (FT3) (or 
total T3 for sites where free T3 is not performed), and free thyroxine (also known as 
FT4) 
● 
HIV serology 
● 
HBV serology:  HBsAg, total HbcAb; if a patient has a negative HBsAg test and a 
positive total HBcAb test at screening, an HBV DNA test must also be performed to 
determine if the patient has an HBV infection. 
● 
HCV serology:  HCV antibody; if a patient has a positive HCV antibody test at 
screening, an HCV RNA test must also be performed to determine if the patient has 
an HCV infection. 
● 
Pregnancy test 
All women of childbearing potential will have a serum pregnancy test within 7 
days before the first dose of study treatment and repeated at any time during 
the study if pregnancy is suspected. During the study treatment period, 
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy 
test. 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
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, 

 
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and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis). 
● 
Urinalysis (pH, specific gravity, glucose, protein, ketones, and blood); dipstick 
permitted  
 
The following samples will be mandatory: 
● 
Pretreatment endoscopic biopsy sample obtained at baseline and surgery sample 
obtained after surgery for determination of HER2 status  
- 
A formalin-fixed paraffin-embedded (FFPE) biopsy specimen in a paraffin block 
(preferred) or a minimum of 4 biopsy tissue slides containing unstained, freshly cut, 
serial sections must be submitted for central confirmation of HER2 positivity. A 
prespecified sensitivity analysis will be conducted in the centrally confirmed HER2 
positive population. 
- 
A formalin-fixed paraffin-embedded (FFPE) surgery specimen in a paraffin block 
(preferred) or a minimum of 4 surgery tissue slides containing unstained, freshly cut, 
serial sections must be submitted for central determination of HER2 status. 
● 
Pretreatment endoscopic biopsy sample obtained at baseline and surgery sample 
obtained after surgery for exploratory research on PD-L1 expression. 
- 
A formalin-fixed paraffin-embedded (FFPE) surgery/biopsy specimen in a paraffin 
block (preferred) or a minimum of 4 slides (2 biopsy and 2 surgery respectively) 
containing unstained, freshly cut, serial sections must be submitted for central 
evaluation of PD-L1 expression. 
● 
Pretreatment endoscopic biopsy sample obtained at baseline for exploratory 
research on MMR status and sTIL signature. 
- 
A formalin-fixed paraffin-embedded (FFPE) biopsy specimen in a paraffin block 
(preferred) or a minimum of 6 slides containing unstained, freshly cut, serial sections 
must be evaluated centrally/locally for MMR status. 
- 
A formalin-fixed paraffin-embedded (FFPE) biopsy specimen in a paraffin block 
(preferred) or a minimum of 4 slides containing unstained, freshly cut, serial sections 
must be submitted for central evaluation of sTIL signature. 
● 
Surgery sample (i.e. the complete resected stomach/GEJ specimen and regional 
lymph nodes) obtained after surgery for the primary endpoint pCR evaluation by 
local pathologists at each site.  
● 
Blood samples collected at several time points (i.e. Day 1of Cycle 1, Day 1-35 after 
the last dose of Cycle 3, Day 1-56 after surgery, Day 1 of Cycle 6, treatment 
discontinuation visit, and during survival follow-up if clinically necessary) for 
exploratory research on HER2 copy number in circulating tumor DNA. 
 
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, 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. 

 
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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
The leftover biological samples will be returned to the site as per the site requirement or 
destroyed when the final Clinical Study Report has been completed, with the following 
exception: 
● 
Blood and tissue samples collected for biomarker research will be destroyed no later 
than 5 years after the final Clinical Study Report has been completed.   
 
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. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law or HGRAC.  The aggregate results of any conducted 
research will be available in accordance with the effective Sponsor policy on study data 
publication. 
4.5.7 
Evaluation of left ventricular ejection fraction 
LVEF will be measured using MUGA scan or ECHO, using the same technique 
throughout the study in an individual patient. Baseline LVEF assessments should be 
done within 28 days prior to the start of treatment. LVEF measurement should then be 
done every 12 weeks (and more often if clinically indicated) during treatment and at most 
every 6 months following discontinuation of treatment until 24 months from the last 
administration of trastuzumab. 
4.5.8 
Electrocardiograms 
An ECG is required at screening, before the treatment of each cycle and surgery, and at 
the time of treatment discontinuation.  An ECG may be conducted if clinically necessary 
at any time after the initiation of the study treatment. ECGs for each patient should be 
obtained from the same machine wherever possible.  Lead placement should be as 
consistent as possible.  ECG recordings must be performed after the patient has been 
resting in a supine position for at least 10 minutes. 
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. 
4.5.9 
Esophageal-gastro-duodenoscopy 
An esophageal-gastro-duodenoscopy is mandatory at screening to confirm clinical 
stage. 

 
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4.5.10 
Histopathological assessment 
Histopathological tumor regression should be analyzed by local pathologists at each site 
after surgery according to AJCC staging system, 8th edition. Appendix 2 provides the 
tumor regression grade (TRG) score of the 8th AJCC. 
4.5.11 
Optional Procedure 
Diagnostic laparoscopy and endoscopic ultrasonography are recommended to confirm 
clinical stage of indication at screening. Although they are optional procedures, the 
investigator should recommend the patients to complete them. 
4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment 
(atezolizumab+trastuzumab+XELOX or trastuzumab+XELOX) 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 determination that treatment discontinuation is in the best 
interest of the patient 
● 
Use of another non-protocol 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 3.1.1 for details) 
● 
Radiographic disease progression or recurrence per RECIST v1.1 or symptomatic 
deterioration attributed to disease progression.  
● 
Any event that meets stopping criteria defined in Appendix 6, Appendix 7 and 
Appendix 9 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
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 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 (see Appendix 1). 

 
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After treatment discontinuation, information on survival follow-up and new anti-cancer 
therapy will be collected via telephone calls, patient medical records, and/or clinic visits 
approximately once every 6 months in the first 3 years, followed by once a year until 5 
years after surgery or until death (unless the patient withdraws consent or the Sponsor 
terminates the study). 
4.6.1.1 
Handling Disease Progression Prior To Surgery 
Progressive disease prior to surgery occurs when patients experience a progression of 
the primary tumor (as assessed by endoscopy for example) or develop metastases prior 
to surgery. Investigators will stop the study treatment for these patients. If surgical 
intervention is still reasonable (investigator decision), patients may proceed to surgery 
and the related information will be documented in the eCRF. After surgery, patients will 
be removed from the study treatment and will enter the survival follow-up phase. If 
surgery is not possible or not recommended, patients will be removed from the study 
treatment and enter the survival follow-up phase. The investigator will define the 
subsequent therapy for this patient according to local clinical practice. All related data 
will be collected in the eCRF and follow-up will be performed for OS assessment. 
4.6.1.2 
Handling Inoperability Defined During Surgery and R1/2 Resection 
If metastatic disease is diagnosed during surgery (e.g. liver metastases or peritoneal 
carcinomatosis), resection can be performed if considered possible and reasonable by 
investigator. Patients found to be non-resectable during surgery as well as patients 
receiving palliative resection only will be removed from the study treatment. The 
investigator will define the subsequent therapy for these patients according to local 
clinical practice. After surgery, study treatment can be continued only if the investigator 
determines that the benefits outweigh the risks of continuing treatment for patients.  All 
related data will be collected in the eCRF and survival follow-up will be performed. Any 
subsequent anti-tumor therapy should be documented in the eCRF. 
4.6.2 
Patient Discontinuation from the 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 a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced. 

 
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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) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
The safety plan for patients in this study is based on clinical experience with 
atezolizumab, trastuzumab, capecitabine and oxaliplatin in completed and ongoing 
studies.  The anticipated important safety risks are outlined below (see Sections 5.1.1, 
5.1.2, 5.1.3, 5.1.4, 5.1.5 and 5.1.6.   
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 atezolizumab, trastuzumab, capecitabine 
and oxaliplatin 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.  Guidelines for managing patients who experience 
anticipated adverse events, including criteria for dosage modification and treatment 
interruption or discontinuation, are provided in Appendix 6, Appendix 7 and Appendix 9.  
Refer to Sections 5.2 5.6 for details on safety reporting (e.g., adverse events, 
pregnancies) for this study. 
Severe SARS CoV 2 infection 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 
SARS CoV 2 infection, which should be confirmed or refuted through assessment of 
exposure history, appropriate laboratory testing, and clinical or radiologic evaluations per 

 
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investigator judgment.  If a diagnosis of SARS CoV 2 infection is confirmed, the disease 
should be managed as per local or institutional guidelines. 
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, pericardial disorders, myocarditis, and nephritis, myositis, and 
severe cutaneous adverse reactions.  In addition, immune-mediated reactions may 
involve any organ system and lead to hemophagocytic lymphohistiocytosis (HLH).  Refer 
to Section 6 of the Atezolizumab Investigator's Brochure for a detailed description of 
anticipated safety risks for atezolizumab.   
5.1.2 
Risks Associated with Trastuzumab  
Trastuzumab has been associated with risks such as the following: infusion/ARRs and 
hypersensitivity, cardiac dysfunction, pulmonary adverse drug reactions, 
neutropenia/febrile neutropenia. Refer to Sections 5 and 6 of the trastuzumab 
Investigator's Brochure for a detailed description of anticipated safety risks for 
trastuzumab. 
5.1.3 
Risks Associated with Capecitabine  
Capecitabine has been associated with risks such as the following: diarrhea, 
dehydration, hand-foot-syndrome, neutropenia/febrile neutropenia, leukopenia, 
thrombocytopenia, anemia and hyperbilirubinemia. Refer to the local prescribing 
informaion of capecitabine for a detailed description of anticipated safety risks for 
capecitabine.  
5.1.4 
Risks Associated with Oxaliplatin  
Oxaliplatin has been associated with risks such as the following: 
anaphylactic/anaphylactoid reactions, peripheral sensory neuropathy, acute 
neurosensory symptoms, pulmonary fibrosis and hematological toxicity. Refer to the 
local prescribing informaion of oxaliplatin for a detailed description of anticipated safety 
risks for oxaliplatin. 
5.1.5 
Risks Associated with Combination Use of Atezolizumab, 
Trastuzumab and XELOX 
The risk of overlapping toxicities between atezolizumab, trastuzumab and XELOX is 
anticipated to be controllable.  Nevertheless, the attribution and management of certain 
adverse events that have been associated with each agent separately (e.g. cardiac 
dysfunction, hypothyroidism, hyperthyroidism and neuropathy) may not be unambiguous 
when the agents are administered together.  It is theoretically possible that allergic or 
inflammatory adverse events associated with trastuzumab and oxaliplatin could be 
exacerbated by the immunostimulatory activity of atezolizumab. On the basis of the 
frequency of adverse events associated with either atezolizumab, trastuzumab or  

 
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capecitabine, the following adverse events are potential overlapping toxicities associated 
with combination use of atezolizumab, traszumab and capecitabine: cardiovascular, 
gastrointestinal (particularly diarrhea), renal, and hematologic toxicity. 
Toxicities should initially be managed according to the recommendations in Appendix 6, 
Appendix 7 and Appendix 9 with dose holds and modifications (if applicable) applied to 
the component of the study treatment judged to be the primary cause.  If individual 
component causality for the toxicity cannot be adequately determined, then the most 
conservative management recommendation should be applied.  
5.1.6 
Risk Associated with Surgery 
In this study, the included patients will undergo the gastrectomy, therefore, the risk 
associated with surgery exists, such as the risk of anesthesia, bleeding and weakened 
the digestive function of the stomach. 
Prior to the surgery, the laboratory tests are required to conducted, and drug treatment-
related adverse reactions have been recovered to meet surgical requirements 
(according to guidelines). The surgical procedure will be carried out according to the 
CSCO clinical guidelines for the diagnosis and treatment of gastric cancer 2019 (Wang 
et al., 2019). 
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 International Council for Harmonisation (ICH) guideline for Good 
Clinical Practice, an adverse event is any untoward medical occurrence in a clinical 
investigation subject administered a 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 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 

 
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● 
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/birth defect in a neonate/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 
v5.0; see Section 5.3.3); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings). 
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 this study 
are as follows: 
● 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7) 
● 
Suspected transmission of an infectious agent by the study treatment, as defined 
below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 

 
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considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of study treatment is suspected. 
● 
Systemic lupus erythematosus 
● 
Events suggestive of hypersensitivity, infusion-related reactions (IRR), cytokine-
release syndrome (CRS), Hemophagocytic lymphohistiocytosis (HLH),  and MAS 
● 
Nephritis 
● 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
● 
Grade ≥  2 cardiac disorders 
● 
Vasculitis 
● 
Autoimmune hemolytic anemia 
● 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, 
toxic epidermal necrolysis) 
● 
Congestive Heart Failure 
● 
Myelitis 
● 
Facial paresis  
  
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, 5.5, 5.6 and 
5.7. 
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 last 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 

 
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interest will continue to be reported until 90 days after the last 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. 
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 3 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 3 
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. 
 

 
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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 4): 
● 
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 
● 
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 4 
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? 
YE
S 
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 
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 as a 
diagnosis (e.g., "infusion-related reaction") on the Adverse Event eCRF.  Avoid 
ambiguous terms such as "systemic reaction."  Associated signs and symptoms should 

 
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be recorded on the dedicated Infusion-Related Reaction eCRF.  If a patient experiences 
both a local and systemic reaction to the same dose of study treatment, each reaction 
should be recorded separately on the Adverse Event eCRF, with signs and symptoms 
also recorded separately on the dedicated Infusion-Related Reaction eCRF. 
There may be significant overlap in signs and symptoms of IRRs and cytokine-release 
syndrome (CRS).  In recognition of the challenges in clinically distinguishing between 
these two events, consolidated guidelines for medical management of IRRs and CRS 
are provided in Appendix 6. 
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. 
 
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 

 
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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:  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., alkaline phosphatase 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 
(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  

 
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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  ULN) 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 in combination with total bilirubin 
 2  ULN 
● 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
 
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 adenocarcinoma of GEJ 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. 

 
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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 adenocarcinoma 
of GEJ  
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on RECIST v1.1.  In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration.  However, every effort should 
be made to document progression through use of objective criteria.  If there is any 
uncertainty as to whether an event is due to disease progression, it should be reported 
as an adverse event. 
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 
 

 
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5.3.5.12 
Cases of Accidental Overdose, or Medication Error 
Overdose (accidental or intentional) and medication error (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 
● 
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. 
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, 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 trastuzumab, 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. 
● 
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. 
In addition, all special situations associated with atezolizumab and trastuzumab, 
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. 
● 
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. 
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. 
All these special situations associated with atezolizumab and trastuzumab regardless of 
whether they result in an adverse event and AEs associated with special situations 
should be reported to the Sponsor within 30 calendar days. 

 
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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 
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 Section 5.4.3 for details on reporting requirements) 
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 IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information for site location 
Medical Monitor (Roche): 
 
Telephone No.: 
/ 
Mobile Telephone No.: 
 
 
Medical Monitor (CRO): 
  
Telephone No.: 
/ 
Mobile Telephone No.: 
 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators.  

 
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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 Serious Adverse Event/Adverse Event of Special Interest 
Reporting 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 90 days after the final dose of study treatment or until 
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. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 5 months after the last 
dose of atezolizumab, 7 months after the last dose of trastuzumab, or 6 months after the 
last dose of capecitabine or oxaliplatin, whichever is longer.  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/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.   

 
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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 
5.4.3.2 
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 7 
months after the last dose of trastuzumab, 3 months after the last dose of capecitabine, 
or 6 months after the last dose of oxaliplatin, whichever is longer.  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.  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 will need to sign an 
Authorization for 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 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. 
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. 
5.4.3.3 
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. 

 
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All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/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). 
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. 
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 all of serious adverse events and adverse events 
of special interest (defined as 90 days after the final dose of study treatment or until 
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 
Situation Form using the fax number or email address provided to investigators. 

 
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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. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents: 
● 
Atezolizumab Investigator's Brochure 
● 
Trastuzumab Investigator's Brochure  
● 
Prescribing Information of Capecitabine 
● 
Prescribing Information of Oxaliplatin 
 
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. 
 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
6.1 
DETERMINATION OF SAMPLE SIZE 
The sample size calculation of this study is based on the primary endpoint, the pCR rate.  
Assuming mean difference between two arms is 22% and pCR rate is 10% for control 
arm (arm B), sample size of 19 per each group could provide the precision (half width) of 
90%CI of 0.21.  
It is planned to recruit 42 patients (21 patients in each group) into this study assuming a 
10% drop-out rate.   
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Descriptive statistics will be used in evaluating the conduct of the study. 
Enrollment, study drug administration, and discontinuation from the study will be 
summarized by treatment arm.  The reasons for study drug discontinuation will also be 
tabulated.  Major protocol deviations, including major deviations with regard to the 
inclusion and exclusion criteria, will be summarized by treatment arm. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographic and baseline characteristics (including age, sex, self reported 
race/ethnicity) will be summarized using means, standard deviations, medians, and 
ranges for continuous variables and proportions for categorical variables, as appropriate.  
Summaries will be presented overall and by treatment group. 

 
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6.4 
EFFICACY ANALYSES 
The analysis population for the efficacy analyses will consist of all randomized patients, 
with patients grouped according to their assigned treatment. 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy objective for this study is to evaluate the efficacy of study 
treatments on the basis of the following endpoint: 
● 
Pathological complete regression (pCR) rate 
pCR is defined as no evidence of vital residual tumor cells on hematoxylin and eosin 
evaluation of the complete resected stomach/GEJ specimen and all sampled 
regional lymph nodes following completion of neoadjuvant systemic therapy (NAST) 
(i.e., ypT0N0 in the current AJCC staging system, 8th edition). 
The primary efficacy endpoint will be established following completion of neoadjuvant 
therapy and surgery.  
pCR status of surgery specimens will be analyzed by local pathologists at each site. 
pCR rate will be analyzed in the intention-to-treat (ITT) population, defined as all patients 
who were randomly assigned to a treatment, regardless of whether they had surgery. An 
estimate of the pCR rate and its 95% CI will be calculated for each treatment arm. The 
CIs for each treatment arm will be calculated with the Clopper-Pearson exact method. 
The difference in pCR rates will be provided with 90% CIs, using the normal 
approximation to the binomial distribution. P value of comparison between two arms will 
be calculated with Chi-square test. It will be additionally assessed in a pre-specified 
sensitivity analysis in the per-protocol (PP) population. This population is defined as all 
patients who are centrally confirmed as HER2 positive and underwent resection.  
6.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints for this study will be analyzed in ITT population, 
including: event-free survival (EFS), disease-free survival (DFS), overall survival (OS), 
major pathologic response (MPR), objective response rate (ORR) and R0 resection rate. 
6.4.2.1 
Event-Free Survival (EFS) 
Event-free survival (EFS), defined as the time from randomization to the first 
documented disease recurrence, unequivocal tumor progression determined by the 
investigator according to RECIST v1.1, or death from any cause, whichever occurs first. 
Patients who have not experienced disease recurrence, progression or death at the time 
of analysis will be censored at the time of the last tumor assessment. Patients with no 
post-baseline tumor assessment will be censored at the date of randomization. 
The Kaplan-Meier estimates will be presented by each treatment arm including median 
time and its corresponding 95%CI if applicable. The 95%CI of median time will be 
calculated according to the Brookmeyer-Crowley methodology (Brookmeyer and 
Crowley 1982). 
6.4.2.2 
Disease-Free Survival (DFS) 
Disease-free survival (DFS), defined as the time from surgery to the first documented 
disease recurrence or death from any cause, whichever occurs first. 

 
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DFS will be analyzed in a similar manner as EFS. 
6.4.2.3 
Overall Survival (OS) 
Overall survival (OS), defined as the time from randomization to death from any cause in 
all patients. 
Patients who are alive at the time of the analysis data cutoff will be censored at the last 
date they were known to be alive. Patients with no post-baseline information will be 
censored at the date of randomization. 
The Kaplan-Meier estimates will be presented by each treatment arm including median 
time and its corresponding 95%CI if applicable. The 95%CI of median time will be 
calculated according to the Brookmeyer-Crowley methodology (Brookmeyer and 
Crowley 1982). 
6.4.2.4 
Major Pathologic Response (MPR) 
Major pathologic response (MPR), defined as < 10% residual tumor per tumor bed 
based on evaluation of the resected primary esophagogastric specimen by a local 
pathologist. 
MPR will be analyzed in a similar manner as primary endpoint. 
6.4.2.5 
Objective Response Rate (ORR) 
Objective response rate (ORR), defined as the proportion of patients with a complete 
response (CR) or partial response (PR) during NAST, as determined by the investigator 
according to RECIST v1.1. Patients without any post-baseline tumor assessment, will be 
considered non-responders. 
ORR will be analyzed in a similar manner as primary endpoint. 
6.4.2.6 
R0 Resection Rate 
R0 resection rate, defined as the proportion of patients with a microscopically margin-
negative resection, in which no gross or microscopic tumor remains in the primary tumor 
bed and/or sampled regional lymph nodes based on evaluation by the local pathologist. 
Patients who will not undergo surgery or will not have a resection will be considered as 
treatment failures (not having R0 resection). R0 resection rates will be analyzed in a 
similar manner as primary endpoint. 

 
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6.4.3 
Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints are planned to include HER2 copy number in ctDNA, 
MMR status, PD-L1 expression and sTIL infiltration. 
Descriptive statistics will be provided for each exploratory efficacy endpoint. Subgroup 
analysis based on these exploratory endpoints will be conducted if applicable.  
More details about exploratory efficacy endpoints analyses will be specified in the SAP 
finalized before database lock. 
6.5 
SAFETY ANALYSES 
The safety analysis population will consist of all randomized patients who received at 
least one dose of study treatment, with patients grouped according to treatment 
received.  
Safety will be assessed through summaries of exposure to study treatment, adverse 
events, changes in laboratory test results, and changes in vital signs and ECGs. 
Study treatment exposure (such as treatment duration, total dose received, and number 
of cycles and dose modifications) will be summarized with descriptive statistics. 
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to NCI CTCAE v5.0.  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 Preferred Term (PT), 
System Organ Class (SOC), and severity grade.  For events of varying severity, the 
highest grade will be used in the summaries.  Deaths and cause 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 
BIOMARKER ANALYSES 
Although no formal statistical analysis of exploratory biomarkers will be performed, data 
may be analyzed in the context of this study and in aggregate with data from other 
studies. 
6.7 
INTERIM ANALYSIS 
There will be no formal interim efficacy analysis for the primary endpoint of pCR, 
although data on efficacy may be provided to the IMC upon request in order to evaluate 
benefit-risk for patients. Interim analyses of EFS, DFS, and OS at the time of and/or after 
the primary analysis of pCR may be conducted as needed and/or requested by Health 
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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
A contract research organization (CRO) will be responsible for the 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 CRO will request data clarification 
from the sites, which the sites will resolve electronically in the EDC system.   
The Sponsor will perform oversight of the data management of this study.  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 CRO, using the 
CRO'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 that must be kept with the study records.  Acknowledgement of receipt 
of the data 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 into 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, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions 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 into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 

 
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Source documents that are required to verify the validity and completeness of data 
entered into 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 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for 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. 
Roche will retain study data for 25 years after the final study results have been reported 
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 applicable 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).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws. 

 
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8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form will be provided to each site.  If 
applicable, it will be provided in a certified translation of 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. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  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 9.6). 

 
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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 Investigational New 
Drug (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 
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. 
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 exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor 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 (see definition of end of 
study in Section 3.2). 

 
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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. 
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. 
Approximately 10-12 sites in China will participate to randomize approximately 42 
patients.   
Central facilities will be used for certain study assessments throughout the study (e.g., 
biomarker analyses), as specified in Section 4.5.6.  Accredited local laboratories will be 
used for routine monitoring; local laboratory ranges will be collected. 
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), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
Data at the following website: 
www.roche.com/roche global policy on sharing of clinical study information.pdf 

 
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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.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 

 
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10. 
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and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or 
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adenocarcinoma (FLOT4-AIO): A multicenter, randomized phase 3 trial. J Clin 
Oncol 2017;35:4004. 
Bang YJ, Kim YW, Yang HK, et al. Adjuvant capecitabine and oxaliplatin for gastric 
cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised 
controlled trial. Lancet 2012;379:315-21. 
Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with 
chemotherapy versus chemotherapy alone for treatment of HER2-positive 
advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-
label, randomised controlled trial. Lancet 2010;376:687-697. 
Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN 
Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. 
CA Cancer J Clin 2018;68:394-424. 
Brookmeyer, R. and Crowley, J. A confidence interval for the median survival time. 
Biometrics 1982;38:29-41. 
Cunningham D, Allum WH, et al. Perioperative chemotherapy versus surgery alone for 
resectable gastroesophageal cancer. N Engl J Med 2006;355:11-20. 
Deng R, Bumbaca D, Pastuskovas CV, et al. Preclinical pharmacokinetics, 
pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 
monoclonal antibody, an immune checkpoint inhibitor. MAbs 2016;8:593 603.  
Explorative phase II study of perioperative treatment in patients with adenocarcinoma of 
the gastroesophageal junction or stomach (HerFLOT) [Internet]. 2014. Available 
online: 
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Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients 
with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-
label, phase 2 randomised controlled trial. Lancet 2016;387:1837 46. 
Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: 
sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 
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Frebel H, Nindl V, Schuepbach RA, et al. Programmed death 1 protects from fatal 
circulatory failure during systemic virus infection of mice. J Exp Med 
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Gong J, Liu T, Fan Q, et al. Optimal regimen of trastuzumab in combination with 
oxaliplatin/ capecitabine in first-line treatment of HER2-positive advanced gastric 
cancer (CGOG1001): a multicenter, phase II trial. BMC Cancer 2016;16:68. 
Huang D, Lu N, and Fan Q, et al. HER2 Status in Gastric and Gastroesophageal 
Junction Cancer Assessed by Local and Central Laboratories: Chinese Results of 
the HER-EAGLE Study. PLoS ONE 2013;8: e80290. 
Homann N, Pauligk C, Luley K, et al. Pathological complete remission in patients with 
oesophagogastric cancer receiving preoperative 5-fluorouracil, oxaliplatin and 
docetaxel. Int J Cancer 2012;130:1706-13. 
Issa N , Murninkas A , Powsner E , et al. Long-term Outcome of Local Excision after 
Complete Pathological Response to Neoadjuvant Chemoradiation Therapy for 
Rectal Cancer. World J Surg 2012;36:2481-2487. 
Janjigian YY,et al. First-line pembrolizumab (P), trastuzumab (T), capecitabine (C) and 
oxaliplatin (O) in HER2-positive metastatic esophagogastric adenocarcinoma. 
2019 ASCO Abstract 4011. 
Li N, Li Z, Fu Q, et al. Phase II study of SHR1210 and trastuzumab in combination with 
CAPOX for neoadjuvant treatment of HER2-positive gastric or gastroesophageal 
junction (GEJ) adenocarcinoma. Journal of Clinical Oncology 2022 40:4_suppl, 
296-296 
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. 
Müller P, Kreuzaler M, Khan T, et al. Trastuzumab emtansine (T-DM1) renders HER2+ 
breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci Transl Med 
2015;7: 315ra188. 
Rivera F, Jimenez P, Garcia Alfonso P, et al. NeoHx study: Perioperative treatment with 
trastuzumab in combination with capecitabine and oxaliplatin (XELOX-T) in 
patients with HER2 resectable stomach or esophagogastric junction (EGJ) 
adenocarcinoma--R0 resection, pCR, and toxicity analysis. J Clin Oncol 2013;31. 
Rivera F, Izquierdo-Manuel M, García-Alfonso P, et al. Perioperative trastuzumab, 
capecitabine and oxaliplatin in patients with HER2-positive resectable gastric or 
gastro-oesophageal junction adenocarcinoma: NEOHX phase II trial. Eur J 
Cancer. 2021;145:158-167. 
Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally 
advanced and metastatic urothelial carcinoma who have progressed following 
treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 
trial. Lancet 2016;387:1909 20. 

 
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Ryu MH, Yoo C, Kim JG, et al. Multicenter phase II study of trastuzumab in combination 
with capecitabine and oxaliplatin for advanced gastric cancer. Eur J Cancer 
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Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer 
with S-1, an oral fluoropyrimidine. N Engl J Med 2007;357:1810- 20. 
Shu P, Qin J, Shen KT, et al. The IGCA staging system is more accurate than AJCC7 
system in stratifying survival of patients with gastric cancer in stage III. BMC 
Cancer. 2017;17:238–43. 
Wang FH, Shen L, Li J, et al. The Chinese Society of Clinical Oncology (CSCO): clinical 
guidelines for the diagnosis and treatment of gastric cancer. Cancer Commun 
2019;39:1-31. 
Wang W, Sun Z, Deng J, et al. Integration and analysis of associated data in surgical 
treatment of gastric cancer based on multicenter, high volume databases. Chin J 
Gastrointest Surg 2016;19:179-85. 
Ychou M, Boige V, Pignon J-P, et al. Perioperative chemotherapy compared with 
surgery alone for resectable gastroesophageal adeno-carcinoma: an FNCLCC and 
FFCD multicenter phase III trial. J Clin Oncol 2011;29:1715–21. 
Zhang SL, Liu CL, Wang SP, et al. Advances in the treatment of gastric cancer with 
molecular targeted drugs. Guangdong Medical 2012;33:1026-1029. 

 
Appendix 1: Schedule of Activities 
  
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8. 
At screening, HIV, HBV and HCV serology should be conducted in all of patients who have signed ICF. Results of a test performed prior to the 
participant signing consent as part of routine clinical management are acceptable in lieu of a screening test if performed within the specified 
time frame (e.g., within 28 days prior to the first dose of trial treatment). 
● 
HBV serology:  HBsAg, total HBcAb; if a patient has a negative HBsAg test and a positive total HBcAb test at screening, an HBV DNA test 
must also be performed to determine if the patient has an HBV infection. 
● 
HCV serology:  HCV antibody; if a patient has a positive HCV antibody test at screening, an HCV RNA test must also be performed to 
determine if the patient has an HCV infection. 
9. 
For female patients who have childbearing potential. Serum pregnancy test should be done within 7 days before the first dose of study 
treatment and repeated at any time during the study if pregnancy is suspected. During the study treatment, if a urine test is positive or not 
evaluable, a serum test will be required. Participants must be excluded/discontinued from the study in the event of a positive serum test result.  
10. Recommended, not mandatory. 
11. LVEF will be measured using multiple-gated acquisition (MUGA) scan or echocardiogram (ECHO), using the same technique throughout the 
study in an individual patient. Baseline LVEF assessments should be done within 28 days prior to the start of treatment. LVEF measurement 
should then be done every 12 weeks±7days (and more often if clinically indicated) during treatment (including the recovery period of less 
than or equal to 8 weeks after surgery, and it is possible to test for LVEF before C8.) and at most every 6 months (+7days) following 
discontinuation of treatment until 24 months from the last administration of trastuzumab. 
12. Patients should receive their first dose of study drug on the day of randomization (no later than 3 days after randomization). 
13. Tumor assessment should consist of CT and/or MRI and include chest, abdomen and pelvis as clinically indicated/determined by the 
investigators. For each patient, the same radiographic procedures and technique must be used throughout the study, and results must be 
reviewed by the investigator before dosing at the next cycle. Tumor response will be evaluated according to RECIST v1.1.  
14. Tumor assessment and multi-disciplinary treatment (MDT) evaluation should be performed within 2 weeks(+7 days) before surgery. 
15. Tumor assessment should performed every 6 months±7days until 3 years after surgery. Additional assessment can be performed if signs or 
symptoms indicate a possible recurrence or development of a new gastric cancer. During treatment phase, the visit at which response 
assessment shows progressive disease may be used as the treatment discontinuation visit. 
16. Biomarker testing can use biopsy sample at screening and surgical sample at surgery. MMR and sTIL testing use biopsy sample; PD-L1 
testing use biopsy sample and surgical sample. 

 
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17. Histopathological tumor regression should be analyzed by local pathologists at each site. Instruction manuals will be provided for all local 
laboratory assessments. 
18. After informed consent has been obtained but prior to initiation of study drug, only serious adverse events (SAEs) caused by a protocol-
mandated intervention should be reported. After initiation of study drug, all AEs will be reported until 30 days after the last dose of study 
treatment or until initiation of new systemic anti-cancer therapy, whichever occurs first. SAEs and adverse events of special interest (AESIs) 
will continue to be reported until 90 days after the last dose of study treatment or until initiation of 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). 
19. 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 treatment should be recorded from 7 days prior the initiation of 
study treatment until the treatment discontinuation visit or 30 days after the last study treatment (whichever occurs first). New cancer treatment 
should be recorded in survival follow up phase. 
20. If clinically necessary. 
21. Surgery is recommended to be performed 3 to 6 weeks after the last dose of neoadjuvant study treatment, after completing other "C3 After" 
visit procedures.   
 

Appendix 4: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
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Appendix 4 
 
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"). 
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. 
 
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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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) since 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 loco-regional therapy are usually not considered measurable unless there has 
been demonstrated progression in the lesion.   
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, since 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. 

 
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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 
intravenous (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 the prior studies if possible.  Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions and interpretation of non-
target disease or new lesions on a different modality, since 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 
used 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 should 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 since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 

 
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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 
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 electronic Case Report Form (eCRF) (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, since 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 eCRF, 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 since they 
usually have a definable size when normal and are frequently surrounded by fat 
such as in the retroperitoneum; however, if a lymph node is believed to be present 

 
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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). 
 
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 eCRF 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 schedule 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. 
Patients with Non-Measurable Disease Only  
For patients with non-measurable disease only, the same general concepts apply as 
noted above.  However, in this instance there is no measurable disease assessment to 
factor into the interpretation of an increase in non-measurable disease burden.  Because 
worsening in non-measurable disease cannot be easily quantified (by definition, if all 
lesions are truly non-measurable), a useful test that can be applied when assessing 
patients for unequivocal progression is to consider if the increase in overall disease 
burden based on the change in non-measurable disease is comparable in magnitude to 
the increase that would be required to declare PD for measurable disease, that is, an 
increase in tumor burden representing an additional 73% increase in volume (which is 
equivalent to a 20% increase in diameter in a measurable lesion).  Examples include an 
increase in a pleural effusion from "trace" to "large" or an increase in lymphangitic 
disease from localized to widespread  If unequivocal progression is seen, the patient 
should be considered to have had overall PD at that point.  While it would be ideal to 
have objective criteria to apply to non-measurable disease, the very nature of that 
disease makes it impossible to do so; therefore, the increase must be substantial. 
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 

 
Appendix 4: Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) 
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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. 
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. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to 
be used. 
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. 
 

 
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Table 2 
Criteria for Overall Response at a Single Timepoint:  Patients with Non-
Target Lesions Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR  complete response; NE  not evaluable; PD  progressive disease. 
a "Non-CR/non-PD" is preferred over "stable disease" for non-target 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some trials; thus, assigning "stable disease" 
when no lesions can be measured is not advised. 
 
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 
"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 and Table 2. 
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 5 
 
Anaphylaxis Precautions 
These guidelines are intended as a reference and should not supersede pertinent local 
or institutional standard operating procedures. 
REQUIRED EQUIPMENT AND MEDICATION 
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion: 
● 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
● 
Oxygen 
● 
Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines 
● 
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 infusion. 
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. 

Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
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Appendix 6 
 
Risks Associated with Atezolizumab and Guidelines for Management of Adverse 
Events Associated with Atezolizumab 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology, 
when clinically indicated. 
Although most immune-mediated adverse events observed with atezolizumab have 
been mild and self-limiting, such events should be recognized early and treated promptly 
to avoid potential major complications.  Discontinuation of atezolizumab may not have 
an immediate therapeutic effect, and in severe cases, immune-mediated toxicities may 
require acute management with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents.  
Patients and family caregivers should receive timely and up-to-date information about 
immunotherapies, their mechanism of action, and the clinical profile of possible immune-
related adverse events prior to initiating therapy and throughout treatment and survival 
follow-up.  There should be a high level of suspicion that new symptoms are treatment 
related. 
The following are general recommendations for management of any other adverse 
events that may occur and are not specifically listed in subsequent subsections.  
• 
In general, atezolizumab therapy should be continued with close monitoring for 
Grade 1 toxicities, with the exception of some neurologic toxicities. 
• 
Consider withholding atezolizumab for most Grade 2 toxicities and resume when 
symptoms and/or laboratory values resolve to Grade 1 or better.  Corticosteroids (initial 
dose of 0.5-1 mg/kg/day of prednisone or equivalent) may be administered. 
• 
For Grade 2 recurrent or persistent (lasting for more than 5 days) events, treat as 
a Grade 3 event.   
• 
Withhold atezolizumab for Grade 3 toxicities and initiate treatment with high-dose 
corticosteroids (1-2 mg/kg/day oral prednisone or equivalent).  Corticosteroids should be 
tapered over 1 month to 10 mg/day oral prednisone or equivalent, before atezolizumab 
can be resumed.  If symptoms do not improve within 48 to 72 hours of high-dose 
corticosteroid use, other immunosuppressants may be offered for some toxicities. 
• 
In general, Grade 4 toxicities warrant permanent discontinuation of atezolizumab 
treatment, with the exception of endocrinopathies that are controlled by hormone 
replacement therapy. 
The investigator should consider the benefit risk balance for a given patient prior 
to further administration of atezolizumab.  Resumption of atezolizumab may be 
considered in patients who are deriving benefit and have fully recovered from the 
immune-mediated event. The decision to re-challenge patients with atezolizumab should 
be based on investigator’s benefit risk assessment and documented by the investigator.  
The Medical Monitor is available to advise as needed.  

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TREATMENT INTERRUPTION 
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 the equivalent of  10 mg/day oral 
prednisone before atezolizumab can be resumed.  If atezolizumab is withheld for 
 12 weeks after event onset, the patient will be discontinued from atezolizumab.  
However, atezolizumab may be withheld for  12 weeks to allow for patients to taper off 
corticosteroids prior to resuming treatment.  Atezolizumab can be resumed after being 
withheld for  12 weeks the patient is likely to derive clinical benefit. The decision to re-
challenge patients with atezolizumab should be based on investigator’s assessment of 
benefit-risk and documented by the investigator.  The Medical Monitor is available to 
advise as needed. Atezolizumab treatment may be suspended for reasons other than 
toxicity (e.g., surgical procedures).  The acceptable length of treatment interruption must 
be based on an assessment of benefit risk by the investigator 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. 
MANAGEMENT GUIDELINES 
PULMONARY EVENTS 
Pulmonary events may present as new or worsening, cough, chest pain, fever, dyspnea, 
fatigue, hypoxia, pneumonitis, and pulmonary infiltrates.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will have computed 
tomography (CT) scans of the chest performed at every tumor assessment.   
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension. COVID-19 evaluation should be performed per institutional guidelines 
where relevant. Management guidelines for pulmonary events are provided in Table 1. 

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Table 1 
Management Guidelines for Pulmonary Events, Including Pneumonitis 
Event 
Management 
Pulmonary event, 
Grade 1  
● Continue atezolizumab and monitor closely. 
● Re-evaluate on serial imaging. 
● Consider patient referral to pulmonary specialist. 
● For Grade 1 pneumonitis, consider withholding atezolizumab. 
● 
Consider resuming on radiographic evidence of improvement. 
Pulmonary event, 
Grade 2 
● Withhold atezolizumab for up to 12 weeks after event onset. a 
● Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL with or without transbronchial biopsy. 
● Initiate treatment with corticosteroids equivalent to 1 2 mg/kg/day oral 
prednisone. 
● If event resolves to Grade 1 or better, resume atezolizumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c,d 
● 
For recurrent events, or events with no improvement after 48–72 
hours of corticosteroids, treat as a Grade 3 or 4 event. 
Pulmonary event, 
Grade 3 or 4 
● Permanently discontinue atezolizumab and contact Medical Monitor. c, d 
● Oral or IV broad-spectrum antibiotics should be administered in parallel 
to the immunosuppressive treatment. 
● Bronchoscopy or BAL with or without transbronchial biopsy is 
recommended. 
● Initiate treatment with corticosteroids equivalent to 1 2 mg/kg/day IV 
methylprednisolone. 
● If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
● If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
 

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BAL  bronchoscopic alveolar lavage. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefit-risk by the investigator 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. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re challenge 
patients with atezolizumab should be based on investigator’s assessment of benefit-risk and 
documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed. 
d 
In case of pneumonitis, atezolizumab should not be resumed after permanent 
discontinuation. 
 
 
HEPATIC EVENTS 
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment.  Management guidelines for hepatic events are provided in Table 2. 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug. 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate. 
Table 2 
Management Guidelines for Hepatic Events 
Event 
Management 
Hepatic event, 
Grade 1 
● Continue atezolizumab. 
● Monitor LFTs until values resolve to within normal limits or to 
baseline values.  
Hepatic event, 
Grade 2 
All events: 
● Monitor LFTs more frequently until return to baseline values.  
Events of   5 days’ duration: 
● Withhold atezolizumab for up to 12 weeks after event onset. a 
● Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day oral prednisone. 
● If event resolves to Grade 1 or better, resume atezolizumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c 

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LFT  liver function tests. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on an assessment of benefit-risk by the investigator 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. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event. The decision to re 
challenge patients with atezolizumab should be based on investigator’s assessment 
of benefit-risk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed.  
 
Table 2 
Management Guidelines for Hepatic Events (cont.)  
Event 
Management 
Hepatic event, 
Grade 3 or 4 
● Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
● Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury.  
● Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day oral prednisone. 
● If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
● If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
LFT  liver function tests. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of  10 mg/day oral prednisone.  The acceptable length of the 
extended period of time must be based on an assessment of benefit-risk by the 
investigator 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. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event.  The decision 
to re challenge patients with atezolizumab should be based on investigator’s 
assessment of benefit-risk and documented by the investigator (or an appropriate 
delegate).  The Medical Monitor is available to advise as needed. 
 

Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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GASTROINTESTINAL EVENTS 
Management guidelines for diarrhea or colitis are provided in Table 3. 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis.  
Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
● Continue atezolizumab. 
● Initiate symptomatic treatment. 
● Endoscopy is recommended if symptoms persist for  7 days. 
● Monitor closely. 
Diarrhea or 
colitis, Grade 2 
● Withhold atezolizumab for up to 12 weeks after event onset. a 
● Initiate symptomatic treatment. 
● 
If strong clinical suspicion for immune-mediated colitis, initiate 
empiric IV corticosteroids while waiting for definitive diagnosis.. 
● Patient referral to GI specialist is recommended. 
● For recurrent events or events that persist  5 days, initiate treatment 
with corticosteroids equivalent to 1 2 mg/kg/day oral prednisone. 
Ifevent does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
● If event resolves to Grade 1 or better, resume atezolizumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Diarrhea or 
colitis, Grade 3 
● Withhold atezolizumab for up to 12 weeks after event onset. a 
● Refer patient to GI specialist for evaluation and confirmatory biopsy. 
● Initiate treatment with corticosteroids equivalent to 1 2 mg/kg/day IV 
methylprednisolone and convert to 1 2 mg/kg/day oral prednisone or 
equivalent upon improvement. If the event does not improve within 48 
hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
● If event resolves to Grade 1 or better, resume atezolizumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
 

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GI  gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on an assessment of benefit-risk by the investigator 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. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re challenge 
patients with atezolizumab should be based on investigator’s assessment of benefit-risk 
and documented by the investigator (or an appropriate delegate). The Medical Monitor is 
available to advise as needed. 
 
Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) (cont.) 
 
Event 
Management 
Diarrhea or 
colitis, Grade 4 
● Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
● Refer patient to GI specialist for evaluation and confirmatory 
biopsy. 
● Initiate treatment with corticosteroids equivalent to 1 2 mg/kg/day 
IV methylprednisolone and convert to 1 2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
● If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
● If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
GI  gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on an assessment of benefit-risk by the investigator 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. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to re 
challenge patients with atezolizumab should be based on investigator’s assessment of 
benefit-risk and documented by the investigator (or an appropriate delegate).  The 
Medical Monitor is available to advise as needed.  
 
ENDOCRINE EVENTS 
Management guidelines for endocrine events are provided in Table 4. 

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Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  TSHand free triiodothyronine and 
thyroxine levels should be measured to determine whether thyroid abnormalities are 
present.  Pituitary hormone levels and function tests (e.g., TSH, growth hormone, 
luteinizing hormone, follicle-stimulating hormone, testosterone, prolactin, 
adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and magnetic 
resonance imaging (MRI) of the brain (with detailed pituitary sections) may help to 
differentiate primary pituitary insufficiency from primary adrenal insufficiency. 
 

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Table 4 
Management Guidelines for Endocrine Events 

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Event 
Management 
hypothyroidism 
Grade 1 
● Continue atezolizumab. 
● Initiate treatment with thyroid replacement hormone. 
● Monitor TSH closely . 
hypothyroidism 
Grade 2 
● Consider withholding atezolizumab. 
● Initiate treatment with thyroid replacement hormone. 
● Monitor TSH closely. 
● Consider patient referral to endocrinologist. 
● Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
hypothyroidism 
Grade 3 or 4 
● Withhold atezolizumab. 
● Initiate treatment with thyroid replacement hormone. 
● Monitor TSH closely . 
● Refer patient to  endocrinologist. 
● Admit patient to the hospital for developing myxedema 
(bradycardia, hypothermia, and altered mental status). 
● Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
● Permanently discontinue atezolizumab and contact the 
Medical Monitor for life-threatening immune-mediated 
hypothyroidism. c 
hyperthyroidism 
Grade 1  
TSH  0.1 mU/L and  0.5 mU/L: 
● Continue atezolizumab. 
● Monitor TSH every 4 weeks. 
● Consider patient referral to endocrinologist. 
TSH  0.1 mU/L: 
● Follow guidelines for Grade 2 hyperthyroidism. 
● Consider patient referral to endocrinologist.      
hyperthyroidism 
Grade 2  
● Consider withholding atezolizumab. 
● Initiate treatment with anti-thyroid drugs such as 
methimazole or carbimazole as needed. 
● Consider patient referral to endocrinologist. 
● Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
hyperthyroidism 
Grade 3 or 4  
● Withhold atezolizumab. 
● Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed. 
● Refer patient to endocrinologist. 
● Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
● Permanently discontinue atezolizumab and contact Medical 
Monitor for life-threatening immune-mediated 
hyperthyroidism. c 

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MRI  magnetic resonance imaging;  
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on an assessment of benefit-risk by the investigator 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. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event. The decision to re 
challenge patients with atezolizumab should be based on investigator’s assessment of 
benefit-risk and documented by the investigator (or an appropriate delegate).  The 
Medical Monitor is available to advise as needed.  
 
 
 

Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 4 
Management Guidelines for Endocrine Events (cont.) 
 
Event 
Management 
Symptomatic adrenal 
insufficiency, 
Grade 2 4  
● Withhold atezolizumab for up to 12 weeks after event onset. 
a 
● Refer patient to endocrinologist. 
● Perform appropriate imaging. 
● Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day IV methylprednisolone and convert to 
1 2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
● If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b 
● If event does not resolve to Grade 1 or better or patient is 
not stable on replacement therapy while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c 
Hyperglycemia, 
Grade 1 or 2  
● Continue atezolizumab. 
● Investigate for diabetes.  If patient has Type 1 diabetes, treat 
as a Grade 3 event.  If patient does not have Type 1 
diabetes, treat as per institutional guidelines. 
● Monitor for glucose control. 
Hyperglycemia, 
Grade 3 or 4 
● Withhold atezolizumab. 
● Initiate treatment with insulin. 
● Evaluate for diabetic ketoacidosis and manage as per 
institutional guidelines. 
● Monitor for glucose control. 
● Resume atezolizumab when symptoms resolve and glucose 
levels are stable. 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on an assessment of benefit-risk by the investigator 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. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to re 
challenge patients with atezolizumab should be based on investigator’s assessment of 
benefit-risk and documented by the investigator (or an appropriate delegate).  The 
Medical Monitor is available to advise as needed. 

Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 4 
Management Guidelines for Endocrine Events (cont.) 
 
Event 
Management 
Hypophysitis (pan-
hypopituitarism), 
Grade 2 or 3  
● Withhold atezolizumab for up to 12 weeks after event onset. 
a 
● Refer patient to endocrinologist. 
● Perform brain MRI (pituitary protocol). 
● Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day IV methylprednisolone and convert to 
1 2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
● Initiate hormone replacement if clinically indicated. 
● If event resolves to Grade 1 or better, resume 
atezolizumab. b 
● If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c 
● For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis (pan-
hypopituitarism), 
Grade 4  
● Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
● Refer patient to endocrinologist. 
● Perform brain MRI (pituitary protocol). 
● Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day IV methylprednisolone and convert to 
1 2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
● Initiate hormone replacement if clinically indicated. 
MRI  magnetic resonance imaging;  
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on an assessment of benefit-risk by the investigator 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. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to re 
challenge patients with atezolizumab should be based on investigator’s assessment of 
benefit-risk and documented by the investigator (or an appropriate delegate).  The 
Medical Monitor is available to advise as needed. 
 

Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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OCULAR EVENTS 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5. 
Table 5 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
● Continue atezolizumab. 
● Patient referral to ophthalmologist is strongly recommended. 
● Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
● If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
● Withhold atezolizumab for up to 12 weeks after event onset. a 
● Patient referral to ophthalmologist is strongly recommended. 
● Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
● If event resolves to Grade 1 or better, resume atezolizumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
● Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
● Refer patient to ophthalmologist. 
● Initiate treatment with corticosteroids equivalent to 1 2 mg/kg/day 
oral prednisone.   
● If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time must 
be based on an assessment of benefit-risk by the investigator 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. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re challenge 
patients with atezolizumab should be based on investigator’s assessment of benefit-risk 
and documented by the investigator (or an appropriate delegate).  The Medical Monitor 
is available to advise as needed.  
 

Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
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IMMUNE-MEDIATED CARDIAC EVENTS 
In high-risk patients (including those with abnormal baseline cardiac troponin levels, 
when available), transthoracic echocardiogram (TTE) monitoring should be considered, 
as clinically indicated, and based on local clinical practice.  Management guidelines for 
cardiac events are provided in Table 6. 
IMMUNE-MEDIATED MYOCARDITIS 
Immune-mediated myocarditis should be suspected in any patient presenting with signs 
or symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., 
troponin, B-type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest 
pain, palpitations, fatigue, decreased exercise tolerance, or syncope. Myocarditis may 
also be a clinical manifestation of myositis or associated with pericarditis (see section on 
immune-mediated pericardial disorders below) and should be managed accordingly. 
Immune-mediated myocarditis needs to be distinguished from myocarditis resulting from 
infection (commonly viral, e.g., in a patient who reports a recent history of 
gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy.   
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, a TTE for evaluation of left ventricular 
injection fraction and global longitudinal strain, and a cardiac MRI as appropriate per 
institutional guidelines.  A cardiologist should be consulted.  An endomyocardial biopsy 
may be considered to enable a definitive diagnosis and appropriate treatment, if clinically 
indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6. 
Immune-Mediated pericardial disorders 
Immune-mediated pericarditis should be suspected in any patient presenting with chest 
pain and may be associated with immune-mediated myocarditis (see section on 
immune-mediated myocarditis above). 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in 
any patient presenting with chest pain associated with dyspnea or hemodynamic 
instability.  
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer (e.g., metastatic disease), cancer treatment (e.g., chest 
radiotherapy), cardiac injury (e.g., injury due to myocardial infarction or iatrogenesis), 
 and autoimmune disorders, and should be managed accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by 
performing an ECG, chest X-ray, TTE, and cardiac MRI as appropriate per institutional 
guidelines.  A cardiologist should be consulted.  Pericardiocentesis should be 
considered for diagnostic or therapeutic purposes, if clinically indicated. 

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Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac 
tamponade, in the absence of an identified alternate etiology, should be treated 
according to the guidelines in Table 6.  Withhold treatment with atezolizumab for 
Grade 1 pericarditis and conduct a detailed cardiac evaluation to determine the etiology 
and manage accordingly. 
 
Table 6 
Management Guidelines for Immune-Mediated Myocarditis 
Event 
Management 
Immune-mediated 
myocarditis, Grades 2-
4 
or 
Immune-mediated 
pericardial disorders, 
Grades 2-4 
● Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
● Refer patient to cardiologist. 
● Initiate treatment as per institutional guidelines and consider anti-
arrhythmic drugs, temporary pacemaker, ECMO, VAD, or 
pericardiocentesis as appropriate. 
● Initiate treatment with corticosteroids equivalent to 1 g/day IV 
methylprednisolone for 3-5 days and convert to 1 2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
● If event does not improve within 24 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
● If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
ECMO  extracorporeal membrane oxygenation; VAD  ventricular assist device. 
 
 
INFUSION-RELATED REACTIONS AND CYTOKINE-RELEASE SYNDROME 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction (IRR) with Cycle 1 of 
atezolizumab may receive premedication with antihistamines, anti-pyretic medications, 
and/or analgesics (e.g., acetaminophen) for subsequent infusions.  Metamizole 
(dipyrone) is prohibited in treating atezolizumab-associated IRRs because of its potential 
for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with atezolizumab. These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of 
atezolizumab administration and are generally mild to moderate in severity. 
CRS is defined as a supraphysiologic response following administration of any immune 
therapy that results in activation or engagement of endogenous or infused T cells and/or 
other immune effector cells. Symptoms can be progressive, always include fever at the 
onset, and may include hypotension, capillary leak (hypoxia), and end-organ dysfunction 
(Lee et al. 2019). CRS has been well documented with chimeric antigen receptor T-cell 
therapies and bispecific T-cell engager antibody therapies but has also been reported 

Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek and 
Feldman 2019), including atezolizumab. 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in 
recognition of the challenges in clinically distinguishing between the two, consolidated 
guidelines for medical management of IRRs and CRS are provided in Table 7.   
Severe SARS-CoV-2 infection appears to be associated with a CRS involving the 
inflammatory cytokines interleukin (IL)-6, IL-10, IL-2, and interferon- (Merad and Martin 
2020).  If a patient develops suspected CRS during the study, a differential diagnosis 
should include SARS-CoV-2 infection, which should be confirmed or refuted through 
assessment of exposure history, appropriate laboratory testing, and clinical or radiologic 
evaluations per investigator’s judgment.  If a diagnosis of SARS-CoV-2 infection is 
confirmed, the disease should be managed as per local or institutional guidelines. 
 
 
 
 
Table 7 
Management Guidelines for Infusion-Related Reactions and Cytokine-
Release Syndrome 
Event 
Management 
Grade 1 a 
Fever b with or 
without 
constitutional 
symptoms 
● Immediately interrupt infusion. 
● Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset. 
● If the infusion is tolerated at the reduced rate for 30 minutes, the infusion 
rate may be increased to the original rate. 
● If symptoms recur, discontinue infusion of this dose. 
● Administer symptomatic treatment, c including maintenance of IV fluids 
for hydration. 
● In case of rapid decline or prolonged CRS (> 2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2. 
● 
For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretic medications, and/or 
analgesics, and monitor closely for IRRs and/or CRS.  

Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Grade 2 a 
Fever b with 
hypotension not 
requiring 
vasopressors 
and/or 
Hypoxia requiring 
low-flow oxygen d 
by nasal cannula or 
blow-by 
● Immediately interrupt infusion. 
● Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset. 
● If symptoms recur, discontinue infusion of this dose. 
● Administer symptomatic treatment. c 
● For hypotension, administer IV fluid bolus as needed. 
● Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate). Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional practice. 
● Rule out other inflammatory conditions that can mimic CRS (e.g., 
sepsis). If no improvement within 24 hours, initiate workup and assess 
for signs and symptoms of HLH or MAS. 
● Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
● Consider anti-cytokine therapy. e 
● Consider hospitalization until complete resolution of symptoms. If no 
improvement within 24 hours, manage as per Grade 3, that is, 
hospitalize patient (monitoring in the ICU is recommended), permanently 
discontinue atezolizumab, and contact Medical Monitor. 
● If symptoms resolve to Grade 1 or better for 3 consecutive days, the 
next dose of atezolizumab may be administered. For subsequent 
infusions, consider administration of oral premedication with 
antihistamines, anti-pyretic medications, and/or analgesics and monitor 
closely for IRRs and/or CRS. 
● If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact Medical Monitor.  

Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
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Table 7 Management Guidelines for Infusion-Related Reactions and Cytokine-
Release Syndrome (cont.) 
Event 
Management 
Grade 3 a 
Fever b with 
hypotension 
requiring a 
vasopressor (with 
or without 
vasopressin) 
and/or 
Hypoxia requiring 
high-flow oxygen d 
by nasal cannula, 
face mask, 
non-rebreather 
mask, or venturi-
mask 
● Permanently discontinue atezolizumab and contact Medical Monitor. f 
● Administer symptomatic treatment. c 
● For hypotension, administer IV fluid bolus and vasopressor as needed. 
● Monitor cardiopulmonary and other organ function closely; monitoring 
in the ICU is recommended. Administer IV fluids as clinically indicated, 
and manage constitutional symptoms and organ toxicities as per 
institutional practice. 
● Rule out other inflammatory conditions that can mimic CRS (e.g., 
sepsis). If no improvement within 24 hours, initiate workup and assess 
for signs and symptoms of HLH or MAS. 
● Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
● Consider anti-cytokine therapy. e 
● Hospitalize patient until complete resolution of symptoms. If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients 
who are refractory to anti-cytokine therapy, experimental treatments 
may be considered at the discretion of the investigator and in 
consultation with the Medical Monitor.  
Grade 4 a 
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
Hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
● Permanently discontinue atezolizumab and contact Medical Monitor. f 
● Administer symptomatic treatment. c 
● Admit patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed. Monitor other 
organ function closely. Manage constitutional symptoms and organ 
toxicities as per institutional practice. 
● Rule out other inflammatory conditions that can mimic CRS (e.g., 
sepsis). If no improvement within 24 hours, initiate workup and assess 
for signs and symptoms of HLH or MAS. 
● Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
● Consider anti-cytokine therapy. e  For patients who are refractory to 
anti-cytokine therapy, experimental treatments g may be considered at 
the discretion of the investigator and in consultation with the Medical 
Monitor. 
● Hospitalize patient until complete resolution of symptoms.  
 
 

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Adverse Events Associated with Atezolizumab 
 
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Table 7 Management Guidelines for Infusion-Related Reactions and Cytokine-
Release Syndrome (cont.) 
ASTCT American Society for Transplantation and Cellular Therapy; BiPAP bi-level 
positive airway pressure; CAR chimeric antigen receptor; CPAP continuous positive 
airway pressure; CRS cytokine-release syndrome; CTCAE Common Terminology 
Criteria for Adverse Events; eCRF electronic Case Report Form; HLH hemophagocytic 
lymphohistiocytosis; ICU intensive care unit; IRR infusion-related reaction; 
MAS macrophage activation syndrome; NCCN National Cancer Comprehensive 
Network; NCI National Cancer Institute. 
Note: The management guidelines have been adapted from NCCN guidelines for 
management of CAR T-cell related toxicities (Version 2.2019). 
a. 
Grading system for management guidelines is based on ASTCT consensus grading for 
CRS. NCI CTCAE (v5.0) should be used when reporting severity of IRRs, CRS, or organ 
toxicities associated with CRS on the Adverse Event eCRF. Organ toxicities associated with 
CRS should not influence overall CRS grading. 
b. 
Fever is defined as temperature 38C not attributable to any other cause. In patients who 
develop CRS and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is 
no longer required when subsequently determining event severity (grade). In this case, the 
grade is driven by the presence of hypotension and/or hypoxia. 
c. 
Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, 
bronchodilators, and/or oxygen. For bronchospasm, urticaria, or dyspnea, additional 
treatment may be administered as per institutional practice. 
d. 
Low flow is defined as oxygen delivered at 6 L/min, and high flow is defined as oxygen 
delivered at 6 L/min. 
e. 
There are case reports where anti-cytokine therapy has been used for treatment of CRS 
with immune checkpoint inhibitors (Rotz et al. 2017; Adashek and Feldman 2019), but data 
are limited, and the role of such treatment in the setting of antibody-associated CRS has not 
been established. 
f. 
Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event. The decision to re-challenge 
patients with atezolizumab should be based on investigator’s assessment of benefit-risk 
and documented by the investigator (or an appropriate delegate) .Medical Monitor is 
available to advise as needed. For subsequent infusions, administer oral premedication with 
antihistamines, anti-pyretics, and/or analgesics, and monitor closely for IRRs and/or CRS. 
Premedication with corticosteroids and extending the infusion time may also be considered 
after assessing the benefit risk ratio. 
g. 
Refer to Riegler et al. (2019) for information on experimental treatments for CRS. 
 
 

Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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128/Protocol ML42058, Version 7, Jan 2024 
 
PANCREATIC EVENTS 
The differential diagnosis of acute abdominal pain should include pancreatitis.  
Appropriate workup should include an evaluation for ductal obstruction, as well as serum 
amylase and lipase tests.  Management guidelines for pancreatic events, including 
pancreatitis, are provided in Table 8. 
Table 8 
Management Guidelines for Pancreatic Events, Including Pancreatitis  
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase  1.5 2.0  ULN: 
● Continue atezolizumab. 
● Monitor amylase and lipase weekly. 
● For prolonged elevation (e.g.,  3 weeks), consider 
treatment with corticosteroids equivalent to 10 mg/day oral 
prednisone. 
Asymptomatic with amylase and/or lipase  2.0 5.0  ULN: 
● Treat as a Grade 3 event. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
● Withhold atezolizumab for up to 12 weeks after event onset. 
a 
● Refer patient to GI specialist. 
● Monitor amylase and lipase every other day. 
● If no improvement, consider treatment with corticosteroids 
equivalent to 1 2 mg/kg/day oral prednisone. 
● If event resolves to Grade 1 or better, resume 
atezolizumab. b 
● If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c 
● For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c 
GI  gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefit-risk by the investigator 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. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re challenge 
patients with atezolizumab should be based on investigator’s assessment of benefit-risk and 
documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.  

Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
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Table 8 
Management Guidelines for Pancreatic Events, Including Pancreatitis 
(cont.) 
 
Event 
Management 
Immune-mediated 
pancreatitis, Grade 2 or 3 
 
● Withhold atezolizumab for up to 12 weeks after event onset. 
a 
● Refer patient to GI specialist. 
● Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day IV methylprednisolone and convert to 
1 2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
● If event resolves to Grade 1 or better, resume 
atezolizumab. b 
● If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c 
● For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c  
Immune-mediated 
pancreatitis, Grade 4 
● Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
● Refer patient to GI specialist. 
● Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day IV methylprednisolone and convert to 
1 2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
● If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
● If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
GI  gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefit-risk by the investigator 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. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent 
of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event. The decision to re challenge patients 
with atezolizumab should be based on investigator’s assessment of benefit-risk and 
documented by the investigator (or an appropriate delegate).  The Medical Monitor is 
available to advise as needed.  
 

Appendix 6: Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
130/Protocol ML42058, Version 7, Jan 2024 
 
DERMATOLOGIC EVENTS 
The majority of cases of rash reported with the use of atezolizumab were mild in severity 
and self limited, with or without pruritus.  Although uncommon, cases of severe 
cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal 
necrolysis have been reported with atezolizumab.  A dermatologist should evaluate 
persistent and/or severe rash or pruritus.  A biopsy should be considered unless 
contraindicated.  Management guidelines for dermatologic events are provided in 
Table 9. 
Table 9 
Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic 
event, Grade 1  
● Continue atezolizumab. 
● Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic 
event, Grade 2  
● Continue atezolizumab. 
● Consider patient referral to dermatologist for evaluation and, if 
indicated, biopsy. 
● Initiate treatment with topical corticosteroids. 
● Consider treatment with higher-potency topical corticosteroids if 
event does not improve. 
● If unresponsive to topical corticosteroids, consider oral 
prednisone 0.5 mg/kg/day. 
Dermatologic 
event, Grade 3  
● Withhold atezolizumab for up to 12 weeks after event onset. a 
● Refer patient to dermatologist for evaluation and, if indicated, 
biopsy. 
● Initiate treatment with corticosteroids equivalent to 10 mg/day 
oral prednisone, increasing dose to 1 2 mg/kg/day if event does 
not improve within 48 72 hours. 
● If event resolves to Grade 1 or better, resume atezolizumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c 
Dermatologic 
event, Grade 4 
● Permanently discontinue atezolizumab and contact Medical 
Monitor. c 

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Adverse Events Associated with Atezolizumab 
Atezolizumab—F. Hoffmann-La Roche Ltd 
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131 
 
  
Stevens 
Johnson 
syndrome or 
toxic epidermal 
necrolysis, (any 
grade) 
Additional guidance for Stevens Johnson syndrome or toxic 
epidermal necrolysis 
● Withhold atezolizumab for suspected Stevens Johnson 
syndrome or toxic epidermal necrolysis. 
● Confirm diagnosis by referring patient to a specialist 
(dermatologist, ophthalmologist or urologist as relevant), and, if 
indicated, biopsy. 
● Follow the applicable treatment and management guidelines 
above. 
●  If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue atezolizumab. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefit-risk by the investigator 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. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before atezolizumab can be resumed. 
c 
Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-mediated event. The decision to re 
challenge patients with atezolizumab should be based on investigator’s assessment of 
benefit-risk and documented by the investigator (or an appropriate delegate).  The 
Medical Monitor is available to advise as needed. 
NEUROLOGIC DISORDERS 
Patients may present with signs and symptoms of sensory and/or motor neuropathy.  
Diagnostic workup is essential for an accurate characterization to differentiate between 
alternative etiologies.  Myasthenia may be associated with myositis (see section on 
immune-mediated myositis) and patients should be managed accordingly.  Management 
guidelines for neurologic disorders are provided in Table 10, with specific guidelines for 
myelitis provided in Table 11. 
Table 10 
Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-
mediated 
neuropathy, 
Grade 1 
● Continue atezolizumab. 
● Investigate etiology. 
● Any cranial nerve disorder (including facial paresis) should be 
managed as per Grade 2 management guidelines below. 
Immune-
mediated 
neuropathy, 
including facial 
paresis, Grade 2  
● Withhold atezolizumab for up to 12 weeks after event onset. a 
● Investigate etiology and refer patient to neurologist. 
● Initiate treatment as per institutional guidelines. 
● For general immune-mediated neuropathy: 
-If event resolves to Grade 1 or better, resume atezolizumab. b 
-If event does not resolve to Grade 1 or better while withholding 

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atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
● For facial paresis: 
- Initial observation OR initiate prednisone 1-2 mg/kg/day (if 
progressing from mild).  Initiate treatment with gabapentin, 
pregabalin, or duloxetine, for pain. 
- If event resolves fully, resume atezolizumab. b 
- If event does not resolve fully while withholding atezolizumab, 
permanently discontinue atezolizumab and contact the Medical 
Monitor. c 
Immune-
mediated 
neuropathy, 
including facial 
paresis, Grade 3 
or 4 
● Permanently discontinue atezolizumab and contact Medical 
Monitor. c  
● Refer patient to neurologist 
● Initiate treatment as per institutional guidelines and proceed as 
per Guillain-Barré syndrome management. 
Myasthenia 
gravis and 
Guillain-Barré 
syndrome (any 
grade) 
● Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
● Refer patient to neurologist. 
● Initiate treatment as per institutional guidelines. 
● Consider initiation of corticosteroids equivalent to 1 2 mg/kg/day 
oral or IV prednisone. 
● Consider IVIG or plasmapheresis in patients with rapid 
progression with development of bulbar and/or respiratory 
symptoms. 
● In life-threatening cases, consider IV methylprednisone 1 g/day 
for 3 5 days and consider other immunosuppressive agent. 
IVIG: intravenous immunoglobulin. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
 10 mg/day oral prednisone.  The acceptable length of the extended period of time 
must be based on an assessment of benefit-risk by the investigator 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. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event. The decision to re 
challenge patients with atezolizumab should be based on investigator’s assessment 
of benefit-risk and documented by the investigator (or an appropriate delegate).  The 
Medical Monitor is available to advise as needed.  
Table 11 
Management Guidelines for Immune-Mediated Myelitis 
Event 
Management 
Immune-
mediated 
myelitis, 
Grade 1 
● 
Continue atezolizumab unless symptoms worsen or 
do not improve. 
● 
Investigate etiology and refer patient to neurologist.  

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Immune-
mediated 
myelitis, 
Grade 2 
● 
Permanently discontinue atezolizumab and contact 
the Medical Monitor.  
● 
Investigate etiology and refer patient to a 
neurologist. 
● 
Rule out infection. 
● 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
Immune-
mediated 
myelitis, 
Grade 3 or 4 
● 
Permanently discontinue atezolizumab and contact 
the Medical Monitor. 
● 
Initiate non-opioid treatment (e.g., pregabalin, 
gabapentin, duloxetine) for pain. 
● 
Hospitalize patient. 
o 
Initiate treatment with corticosteroids 
equivalent to 1 g/day IV methylprednisolone. 
o 
If event does not improve or there is 
worsening of symptoms within 3 days, 
consider IVIG or plasmapheresis and 
manage as per institutional guidelines.  
 
● 
Refer patient to a neurologist. 
● 
 
IVIG: intravenous immunoglobulin. 
 
IMMUNE-MEDIATED MENINGOENCEPHALITIS 
Immune-mediated meningoencephalitis should be suspected in any patient presenting 
with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and 
altered or depressed level of consciousness.  Encephalopathy from metabolic or 
electrolyte imbalances needs to be distinguished from potential meningoencephalitis 
resulting from infection (bacterial, viral, or fungal) or progression of malignancy, or 
secondary to a paraneoplastic process.   
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted. 

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Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 12. 
Table 12 
Management Guidelines for Immune-mediated Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
● Permanently discontinue atezolizumab and contact Medical 
Monitor.  
● Refer patient to neurologist. 
● Initiate treatment with corticosteroids equivalent to 1 2 mg/kg/day 
IV methylprednisolone and convert to 1 2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
● If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
● If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
 
 
RENAL EVENTS 
Eligible patients must have adequate renal function. Renal function, including serum 
creatinine, should be monitored throughout study treatment.  Patients with abnormal 
renal function should be evaluated and treated for other more common etiologies 
(including prerenal and postrenal causes, and concomitant medications such as non-
steroidal anti-inflammatory drugs).  Refer the patient to a renal specialist if clinically 
indicated.  A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 13. 
Table 13 
Management Guidelines for Renal Events  
Event 
Management 
Renal event, 
Grade 1 
● Continue atezolizumab. 
● Monitor kidney function closely, including creatinine and urine 
protein, until values resolve to within normal limits or to 
baseline values.  
Renal event, 
Grade 2 
● Withhold atezolizumab for up to 12 weeks after event onset. a 
● Refer patient to renal specialist. 
● Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day oral prednisone. 
● If event resolves to Grade 1 or better, resume atezolizumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c 

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Renal event, 
Grade 3 or 4 
● Permanently discontinue atezolizumab and contact Medical 
Monitor.  
● Refer patient to renal specialist and consider renal biopsy. 
● Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day oral prednisone. 
● If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
● If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on an assessment of benefit-risk by the investigator 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. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event. The decision to re 
challenge patients with atezolizumab should be based on investigator’s assessment 
of benefit-risk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed.  
 
IMMUNE-MEDIATED MYOSITIS 
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, skin rash in dermatomyositis), biochemical (serum creatine kinase/creatine 
phosphokinase increase), and imaging (electromyography/MRI) features, and is 
confirmed with a muscle biopsy. Patients may initially present with low grade nondescript 
symptoms including mild pain and weakness; thus, there should be a low threshold for 
suspicion of myositis.  Patients with possible myositis should be referred to a 
rheumatologist or neurologist.  Patients with possible myositis should be monitored for 
signs of myocarditis (see section on immune-mediated myocarditis) and myasthenia 
gravis (bulbar symptoms such as dysphagia, dysphonia, and dyspnea; see section on 
neurologic disorders). 
Patients with signs and symptoms of myositis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 14. 
Table 14 
Management Guidelines for Immune-mediated Myositis 
Event 
Management 
Immune-
mediated 
myositis, Grade 1 
● Continue atezolizumab. 
● Refer patient to rheumatologist or neurologist.  
● Initiate treatment as per institutional guidelines. 

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Immune-
mediated 
myositis, Grade 2 
● Withhold atezolizumab for up to 12 weeks after event onset a 
and contact Medical Monitor. 
● Refer patient to rheumatologist or neurologist. 
● Initiate treatment as per institutional guidelines. 
● Consider treatment with corticosteroids equivalent to 
1 2 mg/kg/day IV methylprednisolone and convert to 
1 2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
● If corticosteroids are initiated and event does not improve 
within 48 hours after initiating corticosteroids, consider adding 
an immunosuppressive agent. 
● If event resolves to Grade 1 or better, resume atezolizumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c 
 
Table 14 
Management Guidelines for Immune-mediated Myositis (cont.) 
 
Immune-
mediated 
myositis, Grade 3 
● Withhold atezolizumab for up to 12 weeks after event onset a 
and contact Medical Monitor. 
● Refer patient to rheumatologist or neurologist. 
● Initiate treatment as per institutional guidelines.   
● Respiratory support may be required in more severe cases. 
● Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 1 2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
● Consider IVIG or plasmapheresis. 
● If event does not improve within 24 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
● If event resolves to Grade 1 or better, resume atezolizumab. b 
● If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c 
● For recurrent events, treat as a Grade 4 event. Permanently 
discontinue atezolizumab and contact the Medical Monitor. c 

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Immune-
mediated 
myositis, Grade 4 
● Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
● Refer patient to rheumatologist or neurologist. 
● Initiate treatment as per institutional guidelines.   
● Respiratory support may be required in more severe cases. 
● Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 1 2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
● Consider IVIG or plasmapheresis. 
● If event does not improve within 24 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
● If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
IVIG: intravenous immunoglobulin. 
a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of  10 mg/day oral prednisone.  The acceptable length of the extended period of 
time must be based on an assessment of benefit-risk by the investigator 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. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the 
equivalent of  10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-mediated event.  The decision to re 
challenge patients with atezolizumab should be based on investigator’s assessment 
of benefit-risk and documented by the investigator (or an appropriate delegate).  
The Medical Monitor is available to advise as needed. 
 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS  
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH).  
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.   
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014).  A patient should be classified as having HLH if five of the 
following eight criteria are met: 
● 
Fever  38.5°C 
● 
Splenomegaly 
● 
Peripheral blood cytopenia consisting of at least two of the following: 
– 
Hemoglobin  90 g/L (9 g/dL) ( 100 g/L [10 g/dL] for infants  4 weeks old) 

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– 
Platelet count  100  109/L (100,000/L) 
– 
ANC  1.0  109/L (1000/L) 
● 
Fasting triglycerides  2.992 mmol/L (265 mg/dL) and/or fibrinogen  1.5 g/L 
(150 mg/dL) 
● 
Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
● 
Low or absent natural killer cell activity 
● 
Ferritin  500 mg/L (500 ng/mL) 
● 
Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated  2 standard deviations 
above age-adjusted laboratory-specific norms 
 
Patients with suspected HLH should be treated according to the guidelines in Table 15.  
Table 15 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis  
Event 
Management 
Suspected HLH  
● Permanently discontinue atezolizumab and contact Medical 
Monitor. 
● Consider patient referral to hematologist. 
● Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
● Consider initiation of IV corticosteroids, an immunosuppressive 
agent, and/or anti-cytokine therapy. 
● If event does not respond to treatment within 24 hours, contact 
Medical Monitor and initiate treatment as appropriate according to 
published guidelines (La Rosée 2015; Schram and Berliner 2015; 
La Rosée et al. 2019). 
● If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
HLH  hemophagocytic lymphohistiocytosis 

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Adverse Events Associated with Atezolizumab 
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139 
REFERENCES 
Adashek ML, Feldman M. Cytokine release syndrome resulting from anti-programmed 
death-1 antibody: raising awareness among community oncologist. J Oncol 
Practice 2019;15:502 4. 
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram 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 Apr;25(4):625-638. 
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. 
 

Appendix 7: Risks Associated with Trastuzumab and Guidelines for Management of 
Adverse Events Associated with Trastuzumab 
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Appendix 7 
 
Risks Associated with Trastuzumab and Guidelines for Management of Adverse 
Events Associated with Trastuzumab 
General considerations 
There are no dose adjustments of trastuzumab foreseen for toxicity. If a patient cannot 
tolerate trastuzumab infusions, trastuzumab treatment will be stopped completely. 
To ensure continuity of study treatment, patients had to restart trastuzumab within 3 
cycles (≤ 63 days after Day 1 of the previous cycle). If trastuzumab is delayed by more 
than 2 cycles, the patient will be permanently discontinued from trastuzumab 
treatment, unless the investigator considers that the benefit outweighs the risk to the 
patient. 
During neo-adjuvant treatment: If any of the individual study drugs must be delayed 
for a day or more, generally all agents should be delayed in the same timeframe.  
During adjuvant treatment: if this is considered to be in the patient’s best interest by 
the investigator, in patients in whom resolution of a chemotherapy-induced AE seems 
unlikely within one week, administration of trastuzumab, alone or in combination with 
atezolizumab according to the treatment arm but without chemotherapy at the scheduled 
date is possible. In this case, if the patient has been treated with the antibodies but 
without chemotherapy for one cycle, the next treatment cycle of antibodies in 
combination with chemotherapy may be given only three weeks later according to the 
treatment regimen. 
 
Infusion-Related Reactions 
Patients who experience a life-threatening infusion reaction to the first dose of 
trastuzumab (e.g. tachypnoea, bronchospasm, hypotension, hypoxia) should 
immediately discontinue trastuzumab and be given appropriate therapy. They will not be 
re-challenged and will be taken off trastuzumab. 
Patients who experience severe or moderate infusion reactions should be managed by: 
– slowing or stopping the trastuzumab infusion 
– supportive care with oxygen, beta agonists, antihistamines, corticosteroids as 
appropriate at the Investigator's discretion. 
Patients who experience mild or moderate infusion symptoms may be treated with 
antipyretics and antihistamines. 
Patients who experience mild, moderate or severe infusion reactions on the first dose 
may be retreated with trastuzumab. Subsequent trastuzumab infusions are generally 
well tolerated. Premedication with corticosteroids, antihistamines, and antipyretics may 
be used before subsequent trastuzumab infusions at the Investigator’s discretion.  
Cardiotoxicity 
Heart failure (New York Heart Association [NYHA] class II-IV) has been observed in 
patients receiving trastuzumab therapy alone or in combination with paclitaxel or 
docetaxel, particularly following anthracycline- (doxorubicin or epirubicin) containing 
chemotherapy. This may be moderate to severe and has been associated with death. In 

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addition, caution should be exercised in treating patients with increased cardiac risk 
(e.g., hypertension, documented coronary artery disease, CHF, diastolic dysfunction, 
older age).  Population pharmacokinetic model simulations indicate that trastuzumab 
may persist in the circulation for up to 7 months after stopping Herceptin IV treatment.  
Patients who receive anthracycline after stopping Herceptin may also be at increased 
risk of cardiac dysfunction. 
If possible, physicians should avoid anthracycline-based therapy for up to 7 months after 
stopping Herceptin. If anthracyclines are used, the patient’s cardiac function should be 
monitored carefully. 
All candidates for treatment with trastuzumab, should undergo cardiac assessment 
according to the protocol requirements including history, physical examination and 
cardiac assessment (ECG and echocardiogram or MUGA scan). A careful risk-benefit 
assessment should be made before deciding to treat with trastuzumab. 
In this study, all patients must have a baseline LVEF value  55%, and LVEF is to be 
monitored every 12 weeks during antibody treatment and at most every 6 months 
following discontinuation of treatment until 24 months from the last administration of 
trastuzumab. To ensure patient safety, if an investigator assesses that an AE may be 
related to cardiac dysfunction, an additional LVEF measurement should be performed, 
as well as other appropriate procedures such as chest X-ray, and the scheduled cardiac 
toxicity assessments will continue unchanged. 
If symptomatic Left ventricular systolic dysfunction (LVSD) is confirmed by a 
cardiologist’s evaluation in any patient, trastuzumab should be permanently 
discontinued, and the patient should be discontinued from study treatment on account 
of unacceptable toxicity. Symptomatic LVSD should be treated and monitored according 
to standard medical practice. 
At the present time, there are inadequate data available to assess the prognostic 
significance of clinically asymptomatic decreases in LVEF values. However, If LVEF drops 
10 ejection points from baseline and to below 50%, Herceptin should be withheld and a 
repeat LVEF assessment performed within approximately 3 weeks.  If LVEF has not 
improved, or declined further, or clinically significant CHF has developed, discontinuation 
of Herceptin should be strongly considered, unless the benefits for the individual patient 
are deemed to outweigh the risks.  Patients who develop asymptomatic cardiac 
dysfunction may benefit from more frequent monitoring (e.g. every 6-8 weeks).  If patients 
have a continued decrease in left ventricular function, but remain asymptomatic, the 
physician should consider discontinuing therapy if no clinical benefit of Herceptin therapy 
has been seen.  The safety of continuation or resumption of trastuzumab in patients who 
experience cardiac dysfunction has not been prospectively studied.  If symptomatic 
cardiac failure develops during Herceptin therapy, it should be treated with standard 
medications for heart failure (HF).  In the pivotal trials, most patients who developed HF 
or asymptomatic cardiac dysfunction improved with standard HF treatment consisting of 
an angiotensin converting enzyme inhibitor or angiotensin receptor blocker and a β-

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blocker.  The majority of patients with cardiac symptoms and evidence of a clinical benefit 
of Herceptin treatment continued with Herceptin without additional clinical cardiac events. 
Risk factors for a cardiac event identified in four large adjuvant studies included advanced 
age (> 50 years), low level of baseline and declining LVEF (< 55%), low LVEF prior to or 
following the initiation of paclitaxel treatment, Herceptin treatment, and prior or concurrent 
use of anti-hypertensive medications.  In patients receiving Herceptin after completion of 
adjuvant chemotherapy the risk of cardiac dysfunction was associated with a higher 
cumulative dose of anthracycline given prior to initiation of Herceptin and a high body 
mass index (BMI > 25 kg/m2). 
Treatment with chemotherapy should be continued if considered in the patient's best 
interest as considered by the investigator. All such patients should be referred for 
assessment and follow up by a cardiologist.

Appendix 8: Capecitabine Dose Calculation 
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Appendix 8 
Capecitabine Dose Calculation 
For a starting dose of capecitabine 1000 mg/m2, the following tables describe the 
calculation of standard and reduced doses according to body surface area: the following 
tables apply to 500 mg tablet only, where 100% dose level is twice-daily 1000 mg/m2 
(total daily dose of 2000 mg/m2). 
100% Dose Level 
Twice Daily 1000 mg/m2/dose 
Number of 500 mg Tablets to be Taken 
Surface Area (m2) 
Average Dose per 
Administration 
(mg) 
In the Morning 
In the Evening 
≤1.15 
1000 
2 
2 
1.16-1.40 
1250 
2 
3 
1.41-1.65 
1500 
3 
3 
1.66-1.90 
1750 
3 
4 
≥1.91 
2000 
4 
4 
 
75% Dose Level 
Number of 500 mg Tablets to be Taken 
Surface Area (m2) 
Average Dose per 
Administration 
(mg) 
In the Morning 
In the Evening 
≤1.15 
750 
1 
2 
1.16-1.40 
1000 
2 
2 
1.41-1.90 
1250 
2 
3 
≥1.91 
1500 
3 
3 
 
50% Dose Level 
Number of 500 mg Tablets to be Taken 
Surface Area (m2) 
Average Dose per 
Administration 
(mg) 
In the Morning 
In the Evening 
≤1.15 
500 
1 
1 
1.16-1.90 
750 
1 
2 
≥1.91 
1000 
2 
2 

Appendix 9: Dose modifications for chemotherapy treatment for specific toxicities 
 
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Appendix 9 
Dose Modifications for Chemotherapy Treatment for Specific Toxicities 
 
General considerations 
Capecitabine dosing interruptions are regarded as lost treatment days, and missed 
doses should not be replaced.  
Capecitabine dose reductions for a given patient are permanent reductions for that 
patient.  
If capecitabine must be permanently discontinued due to capecitabine-specific toxicity, 
oxaliplatin should also be permanently discontinued. Thus, patients may not continue on 
oxaliplatin monotherapy alone. During preoperative treatment, these patients need to 
proceed to surgery as rapidly as possible after recovery from toxicity.  
If oxaplatin must be discontinued due to oxaliplatin-specific toxicity, capecitabine can be 
continued. If capecitabine is discontinued, oxaliplatin won't be continued. 
During neo-adjuvant treatment: If any of the individual study drugs must be delayed 
for a day or more, generally all agents should be delayed in the same timeframe.  If a 
patient requires a dose delay of chemotherapy for  3 weeks due to toxicity, 
chemotherapy will be definitively discontinued for neoadjuvant treatment for 
unacceptable toxicity. These patients should proceed to surgery as soon as possible 
after recovery from toxicity, to avoid a risk of tumor progression due to administration of 
insufficient chemotherapy doses before surgery. 
During adjuvant treatment: if this is considered to be in the patient’s best interest by 
the investigator, in patients in whom resolution of a chemotherapy-induced AE seems 
unlikely within one week, administration of trastuzumab, alone or in combination with 
atezolizumab according to the treatment arm but without chemotherapy at the scheduled 
date is possible. In this case, if the patient has been treated with the antibodies but 
without chemotherapy for one cycle, the next treatment cycle of antibodies in 
combination with chemotherapy may be given only three weeks later according to the 
treatment regimen.  
General considerations for dose modification 
The latest body weight is used to calculate body surface area for chemotherapy doses. If 
the body weight change is > 10%, the body surface area needs to be recalculated. 
Chemotherapy doses should not be modified for any body weight change of ≤ 10%. 
Hematologic toxicity 
Capecitabine is not expected to worsen, nor to unduly prolong episodes of neutropenia. 
Administration of capecitabine should be interrupted if grade 3 or 4 neutropenia 
develops. In case of fever or infection with neutropenia, the patients should be instructed 
to stop taking capecitabine immediately. When the ANC has recovered to  1.5 109/L 
and the fever or infection has resolved, patients may re-start treatment with a dose 
reduction according to the following guidelines: 

Appendix 9: Dose modifications for chemotherapy treatment for specific toxicities 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
145/Protocol ML42058, Version 7, Jan 2024 
 
Table 15  Dose modifications for FEBRILE NEUTROPENIA occurring anytime 
during treatment with capecitabine and oxaliplatin 
Grade 3 
ANC < 1.0 x 109/L with a single 
temperature ≥ 38.3°C or persistent 
temperature ≥ 38°C for one hour 
Grade 4 
life threatening and need emergency 
treatment 
1st occurrence 
Capecitabine 75% of original 
dose, and oxaliplatin 85 mg/m2 
Stop treatment permanently unless it is 
in the best interest of the patient to treat 
with capecitabine at 50% of original 
dose, and oxaliplatin 85 mg/m2 
2nd occurrence Stop treatment permanently 
unless it is in the best interest of 
the patient to treat with 
capecitabine at 50% of original 
dose, and oxaliplatin 85 mg/m2. 
Stop treatment permanently. 
 
Table 16 Dose modifications for AFEBRILE NEUTROPENIA occurring anytime 
during treatment with capecitabine and oxaliplatin  
Grade 2 
1.0 ≤ ANC < 1.5 
x109/L 
Grade 3 
0.5 ≤ ANC< 1.0 x109/L 
Grade 4 
ANC < 0.5 x109/L 
Laboratory values before the beginning of the chemotherapy cycle: delay 
chemotherapy until ANC 1.5 x109/L, platelet 75 x109/L, and non-hematologic toxicity is 
restored to baseline or ≤ grade 1, followed by chemotherapy at the following dose: 
1st occurrence No dose adjustment Capecitabine 75% of original 
dose, and oxaliplatin 100 
mg/m2. 
Capecitabine 50% 
of original dose, and 
oxaliplatin 85 
mg/m2. 
2nd 
occurrence 
No dose adjustment Capecitabine 75% of original 
dose, oxaliplatin 85 mg/m2. 
Stop treatment 
permanently. 
3rd occurrence No dose adjustment Stop treatment permanently 
unless it is in the best interest
of the patient to treat with 
capecitabine monotherapy at 
75% of original dose. 
Not applicable. 
 
 

Appendix 9: Dose modifications for chemotherapy treatment for specific toxicities 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
146/Protocol ML42058, Version 7, Jan 2024 
 
Table 17 Dose modifications for thrombocytopenia occurring anytime during 
treatment with capecitabine and oxaliplatin 
Thrombocytopenia 
Platelets 
≥ 50 to <75 x 109/L 
Platelets 
≥ 25 to <50 x 109/L 
Platelets 
< 25 x 109/L 
Laboratory values before the beginning of the chemotherapy cycle: delay 
chemotherapy until ANC 1.5 x109/L, platelet 75 x109/L, and non-hematologic toxicity is 
restored to baseline or ≤ grade 1, followed by chemotherapy at the following dose: 
1st occurrence 
Oxaliplatin 100 
mg/m2, and no 
dose adjustment for 
capecitabine   
Capecitabine 75% 
of original dose, 
and oxaliplatin 100 
mg/m2. 
Capecitabine 50% of 
original dose, and 
oxaliplatin 85 mg/m2. 
2nd occurrence 
Oxaliplatin 100 
mg/m2, and no 
dose adjustment for 
capecitabine 
Capecitabine 75% 
of original dose, 
and oxaliplatin 85 
mg/m2. 
Stop treatment 
permanently unless it is 
in the best interest of the 
patient to treat with 
capecitabine 
monotherapy at 50% of 
original dose. 
3rd occurrence 
Oxaliplatin 85 
mg/m2, and no 
dose adjustment for 
capecitabine 
Capecitabine 50% 
of original dose, 
and oxaliplatin 85 
mg/m2. 
Stop treatment 
permanently. 
 
No dose modifications or interruptions will be required for anaemia (non-haemolytic) as it 
can be satisfactorily managed by transfusions. 
Please note: the aforementioned rules for dose modifications are based on the blood 
counts before each treatment cycle. Blood counts during treatment cycles are not 
mandatory. However, if – according to institutional guidelines or other clinical reasons – 
the investigator decides to perform additional blood counts during the treatment cycle, 
and hematologic grade 3 or 4 toxicity (neutropenia or thrombopenia) or other non-
hematological toxicities greater than grade I are diagnosed, treatment with capecitabine 
should be interrupted until recovery to grade 0 or 1. The indication to reduce the dose of 
capecitabine in subsequent treatment cycles should be decided by the investigator. 
Non-hematologic toxicity  
In general, dose modifications for capecitabine-associated, non-hematological toxicities 
should be conducted according to Table 18. 
If Grade 2, 3, or 4 non-hematologic toxicity occurs (except for toxicity related solely 
to oxaliplatin), capecitabine dosing should be interrupted immediately and the 
instructions shown in Table 18 (below) should be followed.  
The recommendations in this section apply to toxicities typically considered to be related 
to capecitabine treatment (e.g., neurotoxicity or ototoxicity does not require capecitabine 
dose modification). 
Capecitabine dosing interruptions are regarded as lost treatment days, and missed 
doses should not be replaced.  

Appendix 9: Dose modifications for chemotherapy treatment for specific toxicities 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
147/Protocol ML42058, Version 7, Jan 2024 
 
Capecitabine dose reductions for a given patient are permanent reductions for that 
patient.  
Table 18  Dose modification for capecitabine for non-hematologic toxicities 
 
Grade 2 
Grade 3 
Grade 4 
1st 
occurrence 
Interrupt treatment 
until resolved to 
Grade  1, then resume 
at 100% of original 
dose with prophylaxis 
if possible 
Interrupt treatment 
until resolved to 
Grade  1, then 
resume at 75% of 
original dose with 
prophylaxis 
if possible 
Permanently 
discontinue 
capecitabine or re-
treat at 50% of 
original dose after 
discussion with study 
medical monitors 
2nd 
occurrence 
of same 
toxicity 
Interrupt treatment 
until resolved to 
Grade  1, then resume 
at 75% of original dose 
Interrupt treatment 
until resolved 
to Grade  1, 
then resume at 50% 
of original dose 
Permanently 
discontinue 
capecitabine 
3rd 
occurrence 
of same 
toxicity 
Interrupt treatment until 
resolved to Grade  1, 
then resume at 50% of 
original dose 
Permanently 
discontinue 
capecitabine 
/ 
4th 
occurrence 
of same 
toxicity 
Permanently 
discontinue 
capecitabine 
/ 
/ 
 
Grade 2 or 3 Palmar–plantar dysesthesia (Hand–Foot Syndrome) 
Manage toxicity according to Table 18. Treat symptomatically (use of emollients is 
recommended) according to local standards. 
Grade 2 or 3 diarrhea 
Capecitabine can induce diarrhea, which can be severe. In general, diarrhea should be 
managed according to grade. Infectious diarrhea should be ruled out, and patients 
should be carefully monitored. If they become dehydrated, they should be given fluid and 
electrolyte replacement. Anti-diarrhea treatments (e.g.loperamide) should be initiated as 
medically appropriate and as early as possible.  
In case of grade 2 or 3 diarrhea, capecitabine should be stopped and symptomatic 
treatment with loperamide should be started. Restart at 100% of previous dose if 
considered adequately controlled within 2 days of initiation of treatment. If control takes 
longer, then the dose should be modified according to Table 18. Any diarrhea 
of  2 days duration requires medical evaluation including relevant diagnostic 
procedures, alternative treatment and possible investigation of dihydropyrimidine 
dehydrogenase deficiency. Capecitabine cannot be restarted until the diarrhea has 
resolved to Grade 0 or 1, with the last loperamide dose given at least 24 hours 
beforehand. 
If the AE recurs despite prophylaxis, dose modifications should be followed as outlined 
in Table 18. If a patient experiences recurrent Grade 2 toxicity at the end of the 2-week 

Appendix 9: Dose modifications for chemotherapy treatment for specific toxicities 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
149/Protocol ML42058, Version 7, Jan 2024 
 
In case of Grade 2 cardiac toxicity attributable to capecitabine, capecitabine should be 
permanently discontinued.  
For a first occurrence of a Grade 4 toxicity, please contact the study medical monitor to 
assess the possibility of continuing treatment at reduced dose (50% of original dose). 
In the presence of unexplained respiratory symptoms, such as dry cough without 
sputum, dyspnea, alveolar rales, or radiographic evidence of lung infiltration, the use of 
oxaliplatin should be discontinued until further pulmonary examination confirms that the 
possibility of interstitial pneumonia has been ruled out. 
If it is not certain that abnormalities in liver function test results or portal hypertension are 
caused by liver metastasis, the possibility of rare hepatic vascular abnormalities caused 
by oxaliplatin should be considered. 
 

Appendix 11:  Preexisting Autoimmune Diseases and Immune Deficiencies 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
151/Protocol ML42058, Version 7, Jan 2024 
 
Appendix 11 
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 lifethreatening skin adverse 
reaction or pericardial disorder while receiving another immunostimulatory anti cancer 
agent. The Medical Monitor is available to advise on any uncertainty over autoimmune 
exclusions. 
Autoimmune Diseases and Immune Deficiencies 
● Acute disseminated 
encephalomyelitis 
● Addison disease 
● Ankylosing spondylitis 
● Anti-phospholipid 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 
● Diabetes mellitus type 1 
● Dysautonomia 
● Epidermolysis bullosa 
acquisita 
● Gestational pemphigoid 
● Giant cell arteritis 
● Goodpasture syndrome 
● 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 
● Wegener granulomatosis 
 

Signature Page for Protocol - ML42058 - TECENTRIQ - v7 - China
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Approval Task
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