Clinical trial NCT04732494
Conditions: Esophageal Squamous Cell Carcinoma
Sponsor: BeiGene
Start date: 2021-03-31; Completion date: 2023-12-26
Enrollment: 125 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A study of tislelizumab (BGB-A317) plus ociperlimab versus tislelizumab plus placebo as second-line treatment in participants with programmed cell death protein-ligand 1 (PD-L1) tumor area positivity (TAP) ≥ 10% unresectable, locally advanced, recurrent or metastatic esophageal squamous cell carcinoma.

Detailed description:

Arms: arm 1: Participants received 200 milligrams (mg) tislelizumab plus 900 mg ociperlimab intravenously once every 3 weeks until disease progression, unacceptable toxicity, or withdrawal of informed consent, whichever occurred first. arm 2: Participants received 200 mg tislelizumab plus placebo intravenously once every 3 weeks until disease progression, unacceptable toxicity, or withdrawal of informed consent, whichever occurred first.
Interventions: intervention 1: Tislelizumab intervention 2: Ociperlimab intervention 3: Placebo
Intervention descriptions: intervention 1: Tislelizumab is a monoclonal antibody formulated for intravenous injection. intervention 2: Ociperlimab is a monoclonal antibody formulated for intravenous injection. intervention 3: Ociperlimab placebo injection is a sterile, preservative-free solution for infusion formulated in the same buffer as ociperlimab active drug.

Protocol documents:
Prot_000.pdf: 
BGB-A317-A1217-203 (AdvanTIG-203) 
BeiGene 
Protocol Amendment 2.0 
27 February 2023 
CONFIDENTIAL 
Page 1 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Phase 2, Multicenter, Randomized, Placebo-Controlled Study to 
Compare the Efficacy of Anti-PD-1 Monoclonal Antibody 
Tislelizumab (BGB-A317) Plus Anti-TIGIT Monoclonal Antibody 
Ociperlimab (BGB-A1217) Versus Tislelizumab Plus Placebo as 
Second-Line Treatment in Patients With PD-L1 Tumor Area 
Positivity (TAP) ≥ 10% Unresectable, Locally Advanced, Recurrent 
or Metastatic Esophageal Squamous Cell Carcinoma   
Protocol Number: 
BGB-A317-A1217-203 (AdvanTIG-203) 
Phase: 
2 
Investigational Products: 
Ociperlimab (BGB-A1217) and Tislelizumab (BGB-A317) 
Reference Number 
EudraCT 2020-004658-32 
Proposed Indication(s): 
PD-L1 TAP ≥ 10% Unresectable, Locally Advanced, Recurrent or 
Metastatic Esophageal Squamous Cell Carcinoma (ESCC)   
Sponsor: 
BeiGene, Ltd.  
c/o BeiGene USA, Inc.  
1840 Gateway Drive, Third Floor 
San Mateo, CA 94404, USA 
Sponsor Medical Monitor: 
 
 
  
Original Protocol 
Version 0.0: 
16 September 2020 
Protocol Amendment 1.0: 
03 June 2022 
Protocol Amendment 2.0:  
 27 February 2023 
Confidentiality Statement 
This Document Is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene, Ltd., and its 
subsidiaries.  This document is for use by individuals and their designated representatives for their 
review, consideration, and/or participation in investigational trial(s).  This document may not be copied or 
distributed for review by any unauthorized individuals without the prior written authorization of 
BeiGene, Ltd., or one of its subsidiaries.  Your acceptance of this document constitutes agreement that 
you will not disclose the information contained herein to others without prior written authorization from 
BeiGene, Ltd., or one of its subsidiaries. 
NCT Number: NCT04732494


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Page 2 
FINAL PROTOCOL APPROVAL SHEET  
 
A Phase 2, Multicenter, Randomized, Placebo-Controlled Study to Compare the Efficacy of 
Anti-PD-1 Monoclonal Antibody Tislelizumab (BGB-A317) Plus Anti-TIGIT Monoclonal 
Antibody Ociperlimab (BGB-A1217) Versus Tislelizumab Plus Placebo as Second-Line 
Treatment in Patients With PD-L1 Tumor Area Positivity (TAP) ≥ 10% Unresectable, Locally 
Advanced, Recurrent or Metastatic Esophageal Squamous Cell Carcinoma 
BeiGene, Ltd., Approval: 
 


BGB-A317-A1217-203 (AdvanTIG-203) 
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Protocol Amendment 2.0 
27 February 2023 
 
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Page 3 
INVESTIGATOR SIGNATURE PAGE  
 
Protocol Title: 
A Phase 2, Multicenter, Randomized, Placebo-Controlled Study to 
Compare the Efficacy of Anti-PD-1 Monoclonal Antibody Tislelizumab 
(BGB-A317) Plus Anti-TIGIT Monoclonal Antibody Ociperlimab 
(BGB-A1217) Versus Tislelizumab Plus Placebo as Second-Line 
Treatment in Patients With PD-L1 Tumor Area Positivity (TAP) ≥ 10% 
Unresectable, Locally Advanced, Recurrent or Metastatic Esophageal 
Squamous Cell Carcinoma 
 
Protocol Identifier: 
BGB-A317-A1217-203 
 
This protocol is a confidential communication of BeiGene, Ltd., and its subsidiaries. I confirm 
that I have read this protocol, I understand it, and I will work according to this protocol and the 
terms of the clinical study agreement governing the study. I will also work consistently with the 
ethical principles that have their origin in the Declaration of Helsinki and that are consistent with 
good clinical practices and the applicable laws and regulations. Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from BeiGene, Ltd., or one of its subsidiaries. 
 
Instructions for Investigator: Please SIGN and DATE this signature page. PRINT your 
name, title, and the name and address of the center in which the study will be conducted.  
 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator: 
_______________________________ Date: _____________ 
Printed Name: 
_______________________________ 
Investigator Title: 
_______________________________ 
Name/Address of Center: 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
FINAL PROTOCOL APPROVAL SHEET ....................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES .........................................................................................................................11 
LIST OF FIGURES .......................................................................................................................11 
SYNOPSIS ....................................................................................................................................12 
LIST OF ABBREVIATIONS AND TERMS ................................................................................19 
1. 
INTRODUCTION AND RATIONALES ..................................................................21 
1.1. 
Background Information on Esophageal Carcinoma ..................................................21 
1.2. 
Current Treatment of Squamous Esophageal Carcinoma ...........................................21 
1.3. 
Ociperlimab as a TIGIT Inhibitor ...............................................................................24 
1.3.1. 
Nonclinical Experience ...............................................................................................26 
1.3.1.1. 
Pharmacology .............................................................................................................26 
1.3.1.2. 
Toxicology ..................................................................................................................26 
1.3.2. 
Clinical Experience .....................................................................................................27 
1.3.2.1. 
Clinical Experience With Other TIGIT Inhibitors ......................................................27 
1.3.2.2. 
Preliminary Safety Profile ..........................................................................................28 
1.3.2.3. 
Clinical Pharmacology ................................................................................................29 
1.3.2.4. 
Efficacy .......................................................................................................................30 
1.4. 
Tislelizumab as a PD-1 Inhibitor ................................................................................30 
1.4.1. 
Pharmacology .............................................................................................................30 
1.4.2. 
Toxicology ..................................................................................................................30 
1.4.3. 
Clinical Pharmacology ................................................................................................31 
1.4.4. 
Prior Clinical Experience of Tislelizumab .................................................................31 
1.4.4.1. 
Pooled Safety Assessment of Monotherapy Studies ..................................................31 
1.4.4.2. 
Efficacy Assessment of Tislelizumab .........................................................................32 
1.5. 
Study Rationale ...........................................................................................................32 
1.5.1. 
Rationale for Dose Selection ......................................................................................32 
1.5.1.1. 
Rationale for the Selection of Ociperlimab Dose in Combination with 
Tislelizumab ...............................................................................................................32 
1.5.1.2. 
Rationale for the Selection of Tislelizumab Dose ......................................................33 


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1.5.2. 
Rationale for Combination of Ociperlimab and Tislelizumab as Second-Line 
Treatment in Unresectable, Locally Advanced, Recurrent or Metastatic 
ESCC ..........................................................................................................................34 
1.5.3. 
Biomarker Strategy Rationale.....................................................................................34 
1.6. 
Benefit-Risk Assessment ............................................................................................35 
1.7. 
Study Conduct ............................................................................................................36 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................37 
2.1. 
Study Objectives .........................................................................................................37 
2.1.1. 
Primary Objectives .....................................................................................................37 
2.1.2. 
Secondary Objectives .................................................................................................37 
2.1.3. 
Exploratory Objectives ...............................................................................................37 
2.2. 
Study Endpoints ..........................................................................................................38 
2.2.1. 
Primary Endpoints ......................................................................................................38 
2.2.2. 
Secondary Endpoints ..................................................................................................38 
2.2.3. 
Exploratory Endpoints ................................................................................................39 
3. 
STUDY DESIGN .......................................................................................................40 
3.1. 
Summary of Study Design ..........................................................................................40 
3.2. 
Prescreening Period ....................................................................................................42 
3.3. 
Screening Period .........................................................................................................42 
3.4. 
Treatment Period ........................................................................................................42 
3.5. 
End of Treatment/Safety Follow-up ...........................................................................43 
3.6. 
Survival Follow-up .....................................................................................................44 
3.7. 
Discontinuation From the Study Treatment or From the Study .................................44 
3.7.1. 
Patient Discontinuation From Study Treatment .........................................................44 
3.7.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient) ..........45 
3.8. 
End of Study ...............................................................................................................45 
4. 
STUDY POPULATION .............................................................................................47 
4.1. 
Inclusion Criteria ........................................................................................................47 
4.2. 
Exclusion Criteria .......................................................................................................48 
5. 
STUDY TREATMENT ..............................................................................................52 
5.1. 
Formulation, Packaging, and Handling ......................................................................52 
5.1.1. 
Ociperlimab ................................................................................................................52 
5.1.2. 
Tislelizumab ...............................................................................................................52 


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5.1.3. 
Matched Placebo .........................................................................................................52 
5.2. 
Dosage, Administration, and Compliance ..................................................................53 
5.3. 
Incorrect Administration or Overdose ........................................................................54 
5.4. 
Investigational Medicinal Product Accountability .....................................................54 
5.5. 
Dose Delay or Modification .......................................................................................54 
5.5.1. 
Dose Modifications for Study Drugs ..........................................................................55 
5.6. 
Blinding ......................................................................................................................55 
6. 
PRIOR AND CONCOMITANT THERAPY .............................................................57 
6.1. 
Prior Therapy ..............................................................................................................57 
6.2. 
Permitted Concomitant Medications/Procedures .......................................................57 
6.2.1. 
Systemic Corticosteroids ............................................................................................57 
6.2.2. 
Hepatitis B Treatment .................................................................................................57 
6.2.3. 
Radiation Therapy ......................................................................................................57 
6.2.4. 
COVID-19 Vaccines ...................................................................................................58 
6.3. 
Prohibited Concomitant Medications/Procedures ......................................................58 
6.4. 
Restricted Concomitant Medications/Procedures .......................................................58 
6.5. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications .................................................................................................................59 
7. 
STUDY ASSESSMENT AND PROCEDURES ........................................................60 
7.1. 
Prescreening ................................................................................................................60 
7.2. 
Screening Period .........................................................................................................60 
7.2.1. 
Informed Consent and Screening Log ........................................................................61 
7.2.2. 
Demographic Data and Medical History ....................................................................61 
7.2.3. 
Females of Childbearing Potential and Contraception ...............................................61 
7.2.4. 
Pulmonary Function Tests ..........................................................................................62 
7.3. 
Enrollment ..................................................................................................................62 
7.3.1. 
Confirmation of Eligibility .........................................................................................62 
7.3.2. 
Patient Numbering ......................................................................................................62 
7.3.3. 
Randomization ............................................................................................................62 
7.4. 
Study Drug Dispensation ............................................................................................62 
7.5. 
Safety Assessment ......................................................................................................62 
7.5.1. 
Vital Signs ..................................................................................................................62 
7.5.2. 
Physical Examinations ................................................................................................63 


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7.5.3. 
Eastern Cooperative Oncology Group Performance Status ........................................63 
7.5.4. 
Laboratory Safety Tests ..............................................................................................63 
7.5.4.1. 
Cardiac Enzyme Monitoring .......................................................................................63 
7.5.5. 
Electrocardiograms .....................................................................................................64 
7.5.6. 
Adverse Events ...........................................................................................................64 
7.5.7. 
Hepatitis B and C Testing ...........................................................................................64 
7.6. 
Tumor and Response Evaluations ..............................................................................64 
7.7. 
Pharmacokinetic and Antidrug Antibody Assessments ..............................................66 
7.8. 
Tumor Tissue and Biomarker Assessment Procedures ..............................................66 
7.9. 
Health-Related Quality of Life/Quality of Life ..........................................................67 
7.10. 
Visit Windows ............................................................................................................67 
7.11. 
Unscheduled Visits .....................................................................................................67 
8. 
SAFETY MONITORING AND REPORTING .........................................................68 
8.1. 
Risks Associated With Study Drugs ...........................................................................68 
8.1.1. 
Risks Associated With Ociperlimab and Tislelizumab ..............................................68 
8.1.2. 
Risks Associated With Placebo ..................................................................................68 
8.2. 
General Plan to Manage Safety Concerns ..................................................................68 
8.2.1. 
Eligibility Criteria .......................................................................................................68 
8.2.2. 
Safety Monitoring Plan ...............................................................................................69 
8.3. 
Adverse Events ...........................................................................................................69 
8.3.1. 
Definitions and Reporting ...........................................................................................69 
8.3.2. 
Assessment of Severity ...............................................................................................70 
8.3.3. 
Assessment of Causality .............................................................................................70 
8.3.4. 
Follow-up of Adverse Events .....................................................................................71 
8.3.5. 
Laboratory Test Abnormalities ...................................................................................71 
8.4. 
Definition of a Serious Adverse Event .......................................................................72 
8.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................73 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................73 
8.6.1. 
Adverse Event Reporting Period ................................................................................73 
8.6.2. 
Reporting Serious Adverse Events .............................................................................74 
8.6.2.1. 
Prompt Reporting of Serious Adverse Events ............................................................74 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report ........................74 


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8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................75 
8.6.3. 
Eliciting Adverse Events ............................................................................................75 
8.6.4. 
Disease Progression ....................................................................................................75 
8.6.5. 
Deaths .........................................................................................................................76 
8.6.6. 
Pregnancies .................................................................................................................76 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional 
Review Boards, and Independent Ethics Committees ................................................76 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events ...................................76 
8.6.9. 
Recording Infusion-Related Reactions .......................................................................77 
8.7. 
Management of Adverse Events of Special Interest ...................................................77 
8.7.1. 
Infusion-Related Reactions .........................................................................................77 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms .....................................78 
8.7.3. 
Immune-Mediated Adverse Events ............................................................................79 
9. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION .................81 
9.1. 
Statistical Analysis ......................................................................................................81 
9.1.1. 
Analysis Sets ...............................................................................................................81 
9.1.2. 
Patient Disposition ......................................................................................................81 
9.1.3. 
Demographic and Other Baseline Characteristics ......................................................81 
9.1.4. 
Prior and Concomitant Medications ...........................................................................82 
9.2. 
Efficacy Analyses .......................................................................................................82 
9.2.1. 
Primary Efficacy Analysis ..........................................................................................82 
9.2.2. 
Secondary Efficacy Analysis ......................................................................................83 
9.3. 
Safety Analyses ..........................................................................................................84 
9.3.1. 
Extent of Exposure .....................................................................................................84 
9.3.2. 
Adverse Events ...........................................................................................................84 
9.3.3. 
Laboratory Analyses ...................................................................................................85 
9.3.4. 
Vital Signs ..................................................................................................................85 
9.4. 
Pharmacokinetic Analyses ..........................................................................................85 
9.5. 
Immunogenicity Analyses ..........................................................................................85 
9.6. 
Other Exploratory Analyses .......................................................................................86 
9.7. 
Sample Size Consideration .........................................................................................86 
9.8. 
Interim Analyses .........................................................................................................86 
10. 
STUDY COMMITTEES AND COMMUNICATION ..............................................87 


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10.1. 
Blinded Independent Review Committee ...................................................................87 
11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS ...............................................................................................88 
11.1. 
Access to Information for Monitoring ........................................................................88 
11.2. 
Access to Information for Auditing or Inspections ....................................................88 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................89 
12.1. 
Regulatory Authority Approval ..................................................................................89 
12.2. 
Quality Assurance .......................................................................................................89 
12.3. 
Study Site Inspections.................................................................................................89 
12.4. 
Drug Accountability ...................................................................................................89 
13. 
ETHICS/PROTECTION OF HUMAN SUBJECTS ..................................................90 
13.1. 
Ethical Standard ..........................................................................................................90 
13.2. 
Institutional Review Board/Independent Ethics Committee ......................................90 
13.2.1. 
Protocol Amendments ................................................................................................90 
13.3. 
Informed Consent .......................................................................................................90 
13.4. 
Patient and Data Confidentiality .................................................................................91 
13.5. 
Financial Disclosure ...................................................................................................92 
14. 
DATA HANDLING AND RECORD KEEPING ......................................................93 
14.1. 
Data Collection and Management Responsibilities ....................................................93 
14.1.1. 
Data Entry in the Electronic Case Report Form .........................................................93 
14.1.2. 
Data Collection ...........................................................................................................93 
14.1.3. 
Data Management/Coding ..........................................................................................93 
14.2. 
Data Integrity and In-house Blinding .........................................................................94 
14.3. 
Study Records Retention ............................................................................................94 
14.4. 
Protocol Deviations ....................................................................................................95 
14.5. 
Study Report and Publications....................................................................................95 
14.6. 
Study and Study Center Closure .................................................................................95 
14.7. 
Information Disclosure and Inventions ......................................................................96 
15. 
REFERENCES ...........................................................................................................98 
16. 
APPENDICES ..........................................................................................................103 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................104 
APPENDIX 2. FLOWCHART FOR DETERMINING THE LINE OF TREATMENT 
IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA .......................................110 


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APPENDIX 3. CLINICAL LABORATORY ASSESSMENTS ..............................................111 
APPENDIX 4. EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
STATUS ...................................................................................................................112 
APPENDIX 5. PRE-EXISTING IMMUNE DEFICIENCIES OR AUTOIMMUNE 
DISEASES ................................................................................................................113 
APPENDIX 6. CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL,” “NO CHILDBEARING 
POTENTIAL” ...........................................................................................................114 
APPENDIX 7. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ..................................................................................................116 
APPENDIX 8. EORTC-QLQ-C30 QUESTIONNAIRE ..........................................................117 
APPENDIX 9. EORTC QLQ-OES18 QUESTIONNAIRE ......................................................119 
APPENDIX 10. EQ-5D-5L QUESTIONNAIRE......................................................................120 
APPENDIX 11. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION .......................................................122 
APPENDIX 12. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION AND 
MANAGEMENT .....................................................................................................123 
APPENDIX 13. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 ................................................................133 
 


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LIST OF TABLES  
Table 1: 
Second-Line Treatment and Outcomes for Esophageal Squamous Cell 
Carcinoma ...................................................................................................................23 
Table 2: 
Overview of Treatment-Emergent Adverse Events (Safety Analysis Set) .................29 
Table 3: 
Planned Dose, Frequency of Administration, and Route of Administration 
for Study Drugs ...........................................................................................................53 
Table 4: 
Administration of Study Drugs and Monitoring Time ...............................................53 
Table 5: 
Guidance for Duration of Recording New or Worsening Adverse Events in 
Both Arms ...................................................................................................................74 
Table 6: 
Time Frames and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee .............................................................................74 
Table 7: 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drugs ................................................................................................................77 
Table 8: 
Immune-Mediated Adverse Events ............................................................................79 
 
LIST OF FIGURES  
Figure 1: Study Schema .................................................................................................................41 
 


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SYNOPSIS  
Name of 
Sponsor/Company: 
BeiGene, Ltd 
Investigational 
Product(s):  
Ociperlimab (also known as BGB-A1217) and tislelizumab (BGB-A317) 
Title of Study: 
A Phase 2, Multicenter, Randomized, Placebo-Controlled Study to Compare 
the Efficacy of Anti-PD-1 Monoclonal Antibody Tislelizumab (BGB-A317) 
Plus Anti-TIGIT Monoclonal Antibody Ociperlimab (BGB-A1217) Versus 
Tislelizumab Plus Placebo as Second-Line Treatment in Patients With PD-L1 
Tumor Area Positivity (TAP) ≥ 10% Unresectable, Locally Advanced, 
Recurrent or Metastatic Esophageal Squamous Cell Carcinoma  
Protocol Identifier: 
BGB-A317-A1217-203 (AdvanTIG-203) 
Phase of 
development: 
2 
Planned Number of 
Patients: 
Approximately 120 patients  
Study Centers: 
Approximately 100 centers globally 
Study Objectives: 
Primary: 
• 
To compare the objective response rate (ORR) as assessed by the investigator according to 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), of tislelizumab plus 
ociperlimab with tislelizumab plus placebo as second-line treatment in patients with 
programmed cell death ligand-1 (PD-L1) TAP ≥ 10% unresectable, locally advanced, recurrent 
or metastatic esophageal squamous cell carcinoma (ESCC) in the Intent-to-Treat (ITT) 
Analysis Set. 
Secondary: 
• 
To compare the overall survival (OS) of tislelizumab plus ociperlimab with tislelizumab plus 
placebo as second-line treatment in patients with PD-L1 TAP ≥ 10% ESCC in the ITT 
Analysis Set. 
• 
To compare the following endpoints between tislelizumab plus ociperlimab and tislelizumab 
plus placebo based on tumor assessments per RECIST v1.1: 
• 
Progression-free survival (PFS) assessed by both the Independent Review Committee (IRC) 
and the investigator.  
• 
Duration of response (DOR), disease control rate (DCR), and clinical benefit rate (CBR) 
assessed by both the IRC and the investigator. 
• 
ORR assessed by the IRC. 
• 
To compare the safety and tolerability between tislelizumab plus ociperlimab and tislelizumab 
plus placebo. 


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• 
To compare the health-related quality of life (HRQoL) via cancer-specific patient-reported 
outcomes (PROs) between tislelizumab plus ociperlimab and tislelizumab plus placebo.  
Exploratory: 
• 
To evaluate the potential association of biomarkers with patient prognosis, response or 
resistance to tislelizumab plus ociperlimab and tislelizumab plus placebo. 
• 
To characterize the pharmacokinetics (PK) of ociperlimab and tislelizumab. 
• 
To assess host immunogenicity to ociperlimab and tislelizumab. 
• 
To compare the quality of life (QoL) via a generic PRO between tislelizumab plus ociperlimab 
and tislelizumab plus placebo.   
Study Endpoints: 
Primary: 
• 
ORR, defined as the proportion of patients in the ITT Analysis Set who have confirmed 
complete response (CR) or partial response (PR) as assessed by the investigator per RECIST 
v1.1. 
Secondary: 
• 
OS, defined as the time from the date of randomization until the date of death due to any cause 
in patients in the ITT Analysis Set. 
• 
ORR, defined as above and assessed by the IRC per RECIST v1.1 in the ITT Analysis Set. 
• 
PFS, defined as the time from the date of randomization to the date of first documentation of 
progressive disease (PD) assessed by both the IRC and investigator per RECIST v1.1 or death, 
whichever occurs first in the ITT Analysis Set. 
• 
DOR, defined as the time from the first determination of an objective response until the first 
documentation of PD as assessed by both the IRC and the investigator per RECIST v1.1, or 
death, whichever comes first in the ITT Analysis Set. 
• 
DCR, defined as the proportion of patients in the ITT Analysis Set who have confirmed CR, 
confirmed PR, and stable disease assessed by both the IRC and the investigator per RECIST 
v1.1. 
• 
CBR, defined as the proportion of patients who achieve confirmed CR, confirmed PR, and 
durable stable disease (stable disease ≥24 weeks).  
• 
HRQoL, measured by the Global Health Status (GHS)/QoL and Physical Function scales of 
European Organization for Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire-Core 30 (QLQ-C30) and scores of Dysphagia, Eating, Reflux and Pain of 
EORTC Quality of Life Oesophageal Cancer Questionnaires 18 (QLQ-OES18). 
• 
Adverse events (AEs) and serious adverse events (SAEs) as characterized by type, frequency, 
severity (as graded by the National Cancer Institute-Common Terminology Criteria for 
Adverse Events [NCI-CTCAE] version 5.0 [v5.0]), timing, seriousness, and relationship to 
study drugs, physical examinations, electrocardiograms (ECGs), and laboratory assessments. 


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Exploratory: 
• 
Evaluate status of exploratory biomarkers including but not limited to expression of TIGIT, 
CD226, CD155, CD112 and PD-L1, gene expression profiling (GEP), tumor mutation burden 
(TMB)/gene mutation/microsatellite instability (MSI), tumor infiltrating immune cells in 
archival and/or fresh tumor tissue and blood before and after study treatment or at 
PD/reoccurrence, and the association between these biomarkers and clinical efficacy, disease 
status, and resistance. 
• 
Serum ociperlimab and tislelizumab concentrations at specified timepoints.  
• 
Immunogenic responses to ociperlimab and tislelizumab, evaluated through the detection of 
antidrug antibodies (ADAs). 
• 
QoL, measured by assessment of European Quality of Life 5-Dimensional 5-Level 
(EQ-5D-5L) and visual analog scale (VAS) in the ITT Analysis Set. 
Study Design 
This is a multicenter, randomized, investigator- and patient-blinded, sponsor-unblinded, placebo-
controlled global Phase 2 study to compare the efficacy, as measured by ORR of anti-programmed cell 
death protein 1 (anti-PD-1) monoclonal antibody tislelizumab (BGB-A317) plus anti-TIGIT 
monoclonal antibody ociperlimab versus tislelizumab plus placebo as second-line treatment in patients 
with PD-L1 TAP ≥ 10% unresectable, locally advanced, recurrent or metastatic ESCC. 
After providing written informed consent, completing all prescreening and screening assessments, and 
being confirmed as eligible for study participation, approximately 120 patients will be randomized at a 
1:1 ratio to receive 1 of the following treatment regimens: 
• 
Arm A: tislelizumab + ociperlimab 
• 
Arm B: tislelizumab + placebo 
Eligible patients will be stratified by the following factors: 
• 
Eastern Cooperative Oncology Group Performance Status (ECOG PS) score (0 versus 1) 
• 
Number of organs with metastases (≤1 versus ≥2) 
• 
Region (Asia versus non-Asia) 
Study drugs (including placebo) will be administered until PD per RECIST v1.1, unacceptable toxicity, 
or withdrawal of informed consent, whichever occurs first. 
No crossover between Arm A and Arm B will be allowed. 
The study design schema is provided in Figure 1, Section 3.1.  
Study Assessments: 
Tumor Assessment: 
Tumor imaging will be performed at baseline (≤ 28 days before randomization).  During the study, 
tumor imaging will be performed approximately every 6 weeks (± 7 days) for the first 54 weeks and 
every 12 weeks (± 7 days) thereafter. 
Response will be assessed using RECIST v1.1. If a patient can continue to benefit from study drugs 
after PD per RECIST v1.1, the patient may continue the study treatment at the investigator’s discretion. 
The following criteria must be met in order to treat patients who may continue to benefit from study 
treatment after PD:  


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• 
Absence of clinical symptoms and signs of PD (including clinically significant worsening of 
laboratory values). 
• 
Stable ECOG PS ≤ 1.  
• 
Absence of rapid PD or of progressive tumor at critical anatomical sites (eg, spinal cord 
compression) that requires urgent alternative medical intervention. 
• 
Investigators must obtain written informed consent for treatment after radiologic PD and 
inform patients that this practice is not considered standard in the treatment of cancer. 
The decision to continue study drugs after initial PD must be agreed to by the medical monitor and 
documented in the study records. Patients who receive the study treatment after PD will undergo tumor 
assessments according to the original schedule until study treatment discontinuation. 
A patient who discontinues study drugs early for reasons other than PD (eg, treatment toxicity) will 
continue to undergo tumor assessments according to the original plan until the patient experiences PD, 
withdraws consent, is lost to follow-up, dies, or until the study terminates, whichever occurs first.  
PROs will be collected using the EORTC QLQ-C30, EORTC QLQ-OES18, and EQ-5D-5L before 
dosing of every treatment cycle, and at the on-site Safety Follow-up Visit. 
Safety Assessment: 
Patients will be evaluated for any AEs and SAEs occurring up to 30 days after the last dose of study 
drugs (all severity grades, per NCI-CTCAE v5.0) or initiation of a new anticancer therapy, whichever 
occurs first, and immune-mediated AEs (imAEs) occurring up to 90 days after the last dose of study 
drugs regardless of initiation of a subsequent anticancer therapy. All drug-related SAEs will be 
recorded by the investigator after treatment discontinuation until patient death, withdrawal of consent, 
or loss to follow-up, whichever occurs first, and will be followed until they resolve to baseline or 
≤ Grade 1, are assessed by the investigator as stable and unlikely to improve, or the patient is lost to 
follow-up, whichever occurs first. 
Duration of Patient Participation: 
Duration of patient participation will vary by patient. Each patient’s visit course will include: 
prescreening (up to 56 days before randomization) and screening (up to 28 days before randomization), 
treatment (until PD, intolerable toxicity, or withdrawal of informed consent), safety follow-up (30 
[± 7], 60 [± 14], and 90 [± 14] days after the last dose of study drugs), and survival follow-up 
(approximately every 3 months ± 14 days after the last Safety Follow-up Visit). 
Study Population:  
The study will enroll approximately 120 patients who meet the inclusion/exclusion criteria, with 
approximately 60 patients in Arm A (tislelizumab plus ociperlimab) and 60 patients in Arm B 
(tislelizumab plus placebo). 
Key Eligibility Criteria: 
The population under study consists of adult patients (>18 years of age or the legal age of consent in 
the jurisdiction in which the study is taking place) with histologically confirmed diagnosis of ESCC 
with tumor progression during or after first-line systemic treatment for unresectable, locally advanced, 
recurrent or metastatic disease. Patients must submit qualified archival tumor tissue with an associated 
pathology report or agree to a tumor biopsy for determination of PD-L1 expression and other 
biomarker analyses. Patients must have PD-L1 TAP ≥ 10% in tumor tissues tested by the central lab. 
Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, TIGIT or any 
other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways are excluded. 


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All patients are also required to have measurable disease per RECIST v1.1 within 28 days before 
randomization, an ECOG PS score of 0 or 1, life expectancy ≥ 12 weeks, and adequate organ function. 
Investigational Product, Dose and Mode of Administration: 
Tislelizumab, 200 mg administered by intravenous infusion once every 3 weeks. 
Ociperlimab, 900 mg administered by intravenous infusion once every 3 weeks. 
Reference Therapy, Dose, and Mode of Administration: 
Tislelizumab, 200 mg administered by intravenous infusion once every 3 weeks. 
Ociperlimab Placebo, administered by intravenous infusion once every 3 weeks. 
Statistical Methods: 
  
Analysis Sets 
• 
The ITT Analysis Set, which includes all randomized patients, will be the primary analysis 
population for all efficacy analyses. 
• 
The Safety Analysis Set (SAS), which includes all patients who received ≥ 1 dose of study 
drugs, will be the primary analysis set for safety analyses. 
• 
The PK Analysis Set, which includes all patients who receive ≥ 1 dose of any component of 
study drugs per the protocol, and for whom any postdose PK data are available.  
• 
The Immunogenicity Analysis Set, which includes all patients who receive at least 1 dose of 
any component of study drugs and for whom both baseline antidrug antibody and 
≥ 1 postbaseline ADA results are available. 
Efficacy Analyses: 
The primary endpoint ORR will be tested at a 1-sided alpha of 0.025. If the null hypothesis for ORR in 
the ITT Analysis Set is rejected, the secondary endpoint OS in the ITT Analysis Set will be tested.   
Primary Efficacy Analysis 
Overall Response Rate by the Investigator’s Review 
ORR, assessed by the investigator per RECIST v1.1, will be compared between Arm A and Arm B. 
Patients with no postbaseline response assessment for any reason will be considered nonresponders. 
The null hypothesis to be tested is:  
H0: ORR in Arm A ≤ ORR in Arm B 
against the alternative:  
H1: ORR in Arm A > ORR in Arm B 
The statistical significance of the difference in ORR between the 2 treatment arms in the ITT Analysis 
Set will be evaluated using the Cochran-Mantel-Haenszel method, adjusted by the selected 
stratification factors at randomization (ie, ECOG PS score [0 versus 1] and the number of organs with 
metastases [≤1 versus ≥2]). The difference in ORR will be calculated, as will the Clopper-Pearson 
95% CIs for the ORR within each arm.  
The final analysis of ORR will be performed at approximately 4 months after the last patient is 
randomized. 
Secondary Efficacy Analysis 
OS will be analyzed in the ITT Analysis Set. In the absence of death, patients will be censored either at 
the date when the patient is last known to be alive or the date of data cutoff, whichever comes earlier. 
A log-rank test stratified by the actual value of selected stratification factors at randomization (ie, 
ECOG PS score [0 versus 1] and the number of organs with metastases [≤1 versus ≥2]) will be used to 


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test the differences in OS between the 2 treatment arms. The median OS and the cumulative probability 
of OS at every 3 months, if estimable, will be calculated for each treatment arm and presented with 2 
sided 95% CIs. Kaplan-Meier survival probabilities over time for each arm will be plotted. The 
treatment effect of OS will be estimated by fitting a Cox regression model with treatment arm adjusted 
by the selected stratification factors at randomization (ie, ECOG PS score [0 versus 1] and number of 
organs with metastases [≤1 versus ≥2]). From this model, the HR of OS will be estimated and 
presented with a 2-sided 95% CI. The final analysis of OS will take place when approximately 72 
deaths (ie, 60% of the total sample size) have been observed. 
ORR assessed by the IRC per RECIST v1.1 in the ITT Analysis Set will be analyzed similarly to the 
corresponding analysis of ORR assessed by the investigator. The 2-sided 95% CIs for the odds ratio 
and the difference in ORR will be calculated, as will the Clopper-Pearson 95% CIs for the ORR within 
each arm.  
PFS based on assessment by the IRC and the investigator per RECIST v1.1 will be analyzed in the ITT 
Analysis Set. The PFS censoring rule will follow the United States (US) Food and Drug 
Administration (FDA) Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer 
Drugs and Biologics (FDA 2018). The median PFS and the cumulative probability of PFS at every 
3 months, if estimable, will be calculated for each treatment arm and presented with 2-sided 95% CIs. 
Kaplan-Meier survival probabilities over time for each arm will be plotted. The treatment effect will be 
estimated by fitting a Cox regression model with treatment arm adjusted by the selected stratification 
factors at randomization (ie, ECOG PS score [0 versus 1] and the number of organs with metastases 
[≤1 versus ≥2]). From this model, the HR of PFS will be estimated and presented with a 2-sided 
95% CI. 
DOR will be analyzed among the responders in the ITT Analysis Set using methods similar to that 
described for PFS, based on assessment by the IRC and the investigator. 
DCR and CBR assessed by the IRC and investigator per RECIST v1.1 will be summarized similarly as 
ORR in the ITT Analysis Set. 
HRQoL is an assessment of a patient’s health state using the scores of Global Health Status 
(GHS)/QoL and Physical Function of QLQ-C30 and Dysphagia, Eating, Reflux and Pain of OES18. 
Safety Analyses 
Extent of exposure to each study drug will be summarized by duration, dosage, and dose intensity for 
each arm. 
Verbatim description of AEs will be mapped to the Medical Dictionary for Regulatory Activities 
(MedDRA) terms and graded per NCI-CTCAE v5.0. All treatment-emergent AEs (TEAEs) will be 
summarized. A TEAE is defined as an AE that had an onset date or a worsening in severity from 
baseline (pretreatment) on or after the first dose of study drug up to 30 days after study drug 
discontinuation or initiation of a new anticancer therapy, whichever occurs first. Immune-mediated 
AEs will be identified from all AEs that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drug and up to 90 days from the last dose of 
ociperlimab (or placebo) and/or tislelizumab, regardless of whether the patient starts a new anticancer 
therapy. If an imAE occurs outside of the above-mentioned TEAE window, it will not be classified as a 
TEAE. All imAEs will be reported separately. 
Clinical laboratory data with values outside of the normal ranges will be identified. Selected laboratory 
values will be summarized by grade. Changes in vital signs will also be summarized by visit. 
Pharmacokinetic Analyses 
Tislelizumab and ociperlimab serum concentration data will be tabulated and summarized by visit 
and/or cycle at which these concentrations are collected. Descriptive statistics will include means, 


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medians, ranges, and standard deviations, as appropriate. Additional PK analyses may be conducted as 
appropriate. 
Sample Size 
The sample size calculation is based on the primary efficacy analysis of ORR between Arm A and Arm 
B in the ITT Analysis Set.   
With 120 randomized patients, the study has at least 80% power to detect a 24% difference in ORR 
(45% versus 21% in Arm A and Arm B, respectively) at a 1-sided type I error of 0.025. 
The sample size is calculated by EAST (version 6.4.1). 
 


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LIST OF ABBREVIATIONS AND TERMS  
Abbreviation 
Definition 
ADAs 
antidrug antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
 
AST 
aspartate aminotransferase 
BOR 
best overall response 
CD 
cluster of differentiation 
CR 
complete response 
CT 
computed tomography 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
EDC 
electronic data capture (system) 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of Treatment (Visit) 
EQ-5D-5L 
European Quality of Life 5-Dimensional 5-Level  
ESCC 
esophageal squamous cell carcinoma 
FDG 
fluorine-18 [F-18] fluorodeoxyglucose 
GCP 
Good Clinical Practice 
GEP 
gene expression profiling 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HR 
hazard ratio 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
imAE 
immune-mediated adverse event 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
ITT 
Intent-to-Treat (Analysis Set) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
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Abbreviation 
Definition 
NK 
natural killer (cells) 
NSCLC 
non-small cell lung cancer 
QLQ-C30 
Quality of Life Questionnaire-Core 30 
QLQ-OES18 
Quality of Life Oesophageal Cancer Questionnaires 18 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PD 
progressive disease 
PD-1 
programmed cell death protein-1 
PD-L1 
programmed cell death protein-ligand 1 
PET 
positron-emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PVR 
poliovirus receptor 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
TAP 
tumor area positivity 
TEAE 
treatment-emergent adverse event 
TIGIT 
T-cell immunoreceptor with Ig and ITIM domains 
Tregs 
regulatory T (cells)  
BGB-A317 
Tislelizumab  
TIL 
tumor-infiltrating lymphocyte 
ULN 
upper limit of normal 
 


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1. 
INTRODUCTION AND RATIONALES  
1.1. 
Background Information on Esophageal Carcinoma  
Esophageal cancer is the seventh most common cancer worldwide and the sixth most common 
cause of death from cancer. Globally, there were an estimated 572,000 cases and over 
508,000 deaths in 2018 (GloboCan 2018). The global incidence of esophageal cancer shows 
wide geographic variation, with a 60-fold difference between high- and low- incidence regions. 
The highest incidence area, often referred to as the “esophageal cancer belt,” spans from northern 
Iran through the Central Asian republics and into northern China. Other high-prevalence areas 
include southern and Eastern Africa and Northern France. In contrast, esophageal cancer is one 
of the least commonly diagnosed cancers in North America. Esophageal cancers are 
histologically classified as esophageal squamous cell carcinoma (ESCC) or adenocarcinoma 
(EAC), which differ from one another in the pathology, tumor location, and prognosis. ESCC is 
the most common histology in eastern Europe and Asia, while adenocarcinoma is the most 
common in North America and western Europe.  
Recognized risk factors for developing both adenocarcinoma and squamous cell esophageal 
carcinoma include poor nutritional status, low intake of fruits and vegetables, alcohol 
consumption, smoking tobacco, chewing betel quid, drinking liquids at high temperatures, 
obesity, and chronic gastroesophageal reflux disease. Esophageal cancer of either histology is 
much more prevalent in men and more common in an older patient population (Shah 2015).  
Advanced esophageal cancer is a rapidly fatal disease. More than two-thirds of patients 
diagnosed with esophageal cancer will have advanced or metastatic disease, with a median 
survival of 8 to 10 months and an expected 5-year survival rate < 5% (Drahos et al 2013; 
Lin et al 2016). These data, combined with the relative lack of highly effective treatment, are 
indicative of the large unmet medical need in patients diagnosed with esophageal cancer. 
1.2. 
Current Treatment of Squamous Esophageal Carcinoma  
The primary treatment of ESCC is based on tumor histology and the extent of disease at 
presentation. Therapeutic treatment modalities include endoscopic resection for focal disease or 
esophagectomy with lymph node resection for larger tumors in patients who are considered 
medically fit (Stahl et al 2009; Lordick et al 2016). Chemoradiation therapy may be given to 
those with larger tumors in the neoadjuvant, periadjuvant or in the adjuvant setting. 
Postoperative chemotherapy or chemoradiation is commonly given to patients who have 
microscopic or macroscopic residual cancer (R1 and R2 resection, respectively) after surgery. 
Systemic regimens given in the preoperative or perioperative setting commonly include 
chemotherapy doublets which include taxanes, platinum agents, fluorouracil, or irinotecan. 
Triplet combinations may also be considered but are more toxic and restricted to those patients 
who are medically fit (NCCN Guideline Version 2 2022). 
For first-line therapy for unresectable locally advanced, recurrent or metastatic ESCC where 
local therapy is not indicated, the main recommendations is for a 2-drug cytotoxic regimen 
because of lower toxicity compared with three-drug regimens. However, 3-drug regimens should 
be reserved for medically fit patients with good performance status and access to frequent 
toxicity evaluation. Preferred regimens include fluoropyrimidines (either fluorouracil or 


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capecitabine) in combination with either cisplatin or oxaliplatin; other recommended regimens 
include fluorouracil and irinotecan, paclitaxel with cisplatin or carboplatin, docetaxel with 
cisplatin, DCF (docetaxel, platinum, fluorouracil) and ECF (epirubicin, platinum, fluorouracil). 
The objective response rate (ORR) to the first-line chemotherapy for advanced or metastatic 
disease ranges from 20% to 48% and 5-year survival rates of < 30% and with significant toxicity 
rates (Grunberger et al 2007). 
For patients who progressed after first-line therapy, regimen selection is dependent upon prior 
therapy and performance status. Current recommendations for second-line treatment include 
single agent chemotherapy (eg, docetaxel, paclitaxel, irinotecan) or immunotherapy (ie, 
anti-programmed cell death protein-1 [PD-1] antibodies). Table 1 summarizes the second-line 
treatment and efficacy outcomes for ESCC. Generally, the ORR and median survival appear 
comparable and limited with treatment of paclitaxel, docetaxel, or irinotecan.  
In 2019, pembrolizumab was approved by the United States (US) Food and Drug Administration 
(FDA) for the treatment of patients who have recurrent locally advanced or metastatic ESCC 
whose tumors express programmed cell death protein-ligand 1 (PD-L1) (Combined Positive 
Score [CPS] ≥10, with progressive disease (PD) after ≥ 1 prior lines of systemic therapy 
(pembrolizumab USPI 2020). The efficacy of pembrolizumab as the second-line treatment was 
investigated in KEYNOTE-181 (NCT02564263), a multicenter, randomized, open-label, 
active-controlled trial that enrolled 628 patients with recurrent locally advanced or metastatic 
esophageal cancer who progressed on or after one prior line of systemic treatment for advanced 
disease. Of these 628 enrolled patients, 167 (27%) had ESCC that expressed PD-L1 with a CPS 
≥10. Of these 167 patients, 85 were randomized to pembrolizumab and 82 to the investigator’s 
treatment of choice (paclitaxel [n=50], docetaxel [n=19], or irinotecan [n=13]). Most patients 
were Asian (68%) and had distant metastasis of disease (90%). The result showed a significant 
improvement in the primary endpoint overall survival (OS) in patients randomized to 
pembrolizumab as compared with chemotherapy (10.3 months versus 6.7 months, hazard ratio 
[HR] 0.62; 95% confidence interval [CI]: 0.46 to 0.90). Improved ORR was also observed in the 
pembrolizumab arm (22% versus 7%) (Kim et al 2019). In 2020, nivolumab was approved by 
FDA for the treatment of patients with unresectable advanced, recurrent or metastatic ESCC after 
prior fluoropyrimidine- and platinum-based chemotherapy, regardless of PD-L1 expression 
status (nivolumab USPI 2020). In ATTRACTION-3 (NCT02569242), a multicenter, randomized 
(1:1), active-controlled, open-label trial, 419 patients with unresectable advanced, recurrent, or 
metastatic ESCC, who couldn’t tolerate ≥ 1 fluoropyrimidine- and platinum-based regimen were 
randomized to receive either nivolumab or  the investigator’s choice of treatment (docetaxel: 
65 patients, 31%; paclitaxel: 144 patients, 69%). Most patients (96%) were Asian. The results 
demonstrated a statistically significant improvement in the primary endpoint OS for patients 
treated with nivolumab as compared with the investigator’s choice of taxane chemotherapy 
(10.9 months versus 8.4 months, HR, 0.77; 95% CI: 0.62 to 0.96). OS benefit was observed 
regardless of PD-L1 expression level (Kato et al 2019). In 2020, camrelizumab was approved by 
China National Medical Products Administration as second-line therapy for advanced or 
metastatic ESCC. In ESCORT, a multicenter, randomized, open-label, Phase 3 study, 
457 patients were randomly assigned (1:1) to receive camrelizumab (200 mg intravenously 
administered every 2 weeks) or chemotherapy with docetaxel (75 mg/m² intravenously 
administered every 3 weeks) or irinotecan (180 mg/m² intravenously administered every 


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2 weeks). As of data cutoff on May 6, 2019, the median OS was 8.3 months (95% CI: 6.8 to 9.7) 
in the camrelizumab group and 6.2 months (95% CI: 5.7 to 6.9) in the chemotherapy group (HR, 
0.71; 95% CI: 0.57 to 0.87; 2-sided p=0.0010) (Huang et al 2020). 
Table 1: 
Second-Line Treatment and Outcomes for Esophageal Squamous Cell 
Carcinoma 
Agent 
(Reference) 
Sample Size 
by 
Histology 
 (n) 
Treatment 
Setting 
Regimen 
ORR (%) 
OS 
(median 
months) 
Paclitaxel 
(Ilson DH 2007) 
ESCC  
(n=32) 
1st/2nd line 
80 mg/m2 weekly x 
4 weeks every 28 
days 
13% (1L);  
8% (2L) 
NR for 
ESCC subset 
Paclitaxel 
(Mizota A 2011) 
ESCC 
(n=35) 
EAC (n=3) 
2nd line 
80 -100 mg/m2 Day 
1, 8, 15 every 28 days 
25.7%* 
7.2* 
Paclitaxel 
(Kato K 2011) 
ESCC 
(n=52) 
EAC (n=1) 
NR** 
100 mg/m2 Days 1, 8, 
15, 22, 29, and 36 
every 49 days 
44% 
10.4 
Paclitaxel 
(Shirakawa T 
2014) 
ESCC 
(n= 31) 
2nd line 
100 mg/m2 weekly x 
6  
1-week rest 
19.4% 
 
6.1 
 
Docetaxel 
(Song ZB 2014) 
ESCC  
(n=41) 
2nd line 
Not specified 
19.5% 
 
5.2 
Docetaxel 
(Mizota A 2011) 
ESCC 
(n=84) 
EAC (n=2) 
2nd line 
60- 70 mg/m2  
Q3W 
10.3%* 
6.1* 
Docetaxel 
(Shirakawa T 
2014) 
ESCC  
n=132 
2nd line 
70 mg/m2   
Q3W 
5.3% 
5.5 
Docetaxel 
(Muro K 2004) 
ESCC 
(n=46) 
EAC (n=1) 
Other (n=1) 
Advanced 
70 mg/m2   
Q3W 
20% 
8.1 
Irinotecan 
(Mühr-
Wilkenshoff F 
2003) 
ESCC 
(n=10) 
EAC (n=3) 
1st/2nd line 
125 mg/m2 Weekly x 
4 with 2 weeks’ rest 
20% 
ESCC only 
6.4* 
Irinotecan 
(Burkart C 2007) 
ESCC (n=7) 
EAC (n=7) 
2nd line 
100 mg/m2 Weekly x 
3 every 4 weeks 
15%* 
5* 
Irinotecan 
(Fukushima R 
2014) 
ESCC 
n=29 
NR** 
Not specified 
4% 
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Abbreviations: EAC, esophageal adenocarcinoma; ESCC, esophageal squamous cell carcinoma; NR, not reported; 
ORR, objective response rate; OS, overall survival; Q3W, every 3 weeks. 
*Combined ESCC and EAC histology 
** line of therapy not specified; all patients received prior treatment for esophageal cancer 
1.3. 
Ociperlimab as a TIGIT Inhibitor  
Ociperlimab is a humanized immunoglobulin G (IgG) 1 monoclonal antibody binding to T-cell 
immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) 
under clinical development for the treatment of human malignancies.  
TIGIT, also known as VSIG9, VSTM3, or WUCAM, is a 26 kDa type I transmembrane 
glycoprotein and an immune checkpoint receptor, a member of the poliovirus receptor 
(PVR)/nectin family that plays an important role in promoting T-cell exhaustion in both chronic 
viral infections and tumor escape from immune surveillance (Yu et al 2009; Boles et al 2009; 
Stanietsky et al 2009; Levin et al 2011; Johnston et al 2014). TIGIT was initially discovered in a 
genomic search for genes specifically expressed in T cells that had a protein domain that 
consisted of inhibitory signaling motifs. The genes and circulating DNAs (cDNAs) coding for 
TIGIT were cloned and characterized in mouse and human cells (Yu et al 2009). Mature human 
TIGIT contains 223 amino acid residues (National Center for Biotechnology Information 2022). 
Its extracellular domain consists of amino acid residues 1 to 120, and the transmembrane domain 
and cytoplasmic C-terminal tail comprises residues 121 to 223. 
TIGIT-deficient mice (TIGIT-/-) showed increased susceptibility to an experimental autoimmune 
model (Joller et al 2014). Natural killer (NK) cells which overexpressed TIGIT produced less 
interferon-gamma (IFN-γ) upon TIGIT/PVR ligation. In contrast, NK cells form TIGIT-deficient 
mice produced more IFN-γ in the presence of PVR-expressing target cells (Li et al 2014). 
Agonistic anti-TIGIT antibody could reduce the production of proinflammatory cytokines 
including IFN-γ and IL-17 by antigen-restimulated splenocytes and antigen-specific 
proliferation. Consistent with these observations, a blockade of the TIGIT pathway in vivo by 
TIGIT blocking antibody alone or in combination with an anti- programmed cell death protein 1 
(PD-1) antibody reduced tumor growth in syngeneic mouse models (College of American 
Pathologist [CAP] guidelines 2018; Argast et al 2018; Dixon et al 2018). These findings strongly 
suggest that TIGIT is a critical immune checkpoint receptor in the maintenance of immune 
tolerance. 
TIGIT is primarily expressed on immune cells, such as T cells, and NK cells (Manieri et al 
2017).  When expressed on effector T cells (cluster of differentiation [CD] 4+ [CD4+] and 
CD8+), activation of TIGIT has been shown to reduce cytokine production and T-cell 
proliferation; the reduction of cytokine production and T-cell proliferation could be rescued by 
TIGIT blocking antibodies or TIGIT expression knockdown (Lozano et al 2012; Joller et al 
2014; Chauvin et al 2015). A similar phenomenon was also observed for NK cells (Stanietsky et 
al 2009; Zheng et al 2017). 
TIGIT is also expressed on FoxP3+ regulatory T (Treg) cells, especially in tumor tissues 
(Joller et al 2014; Kurtulus et al 2015). TIGIT-positive Treg cells demonstrated greater 
suppressive functions when compared to TIGIT-negative Treg cells, with higher expression of 
effector molecules, such as IL-10, granzymes, and Fgl2 (Joller et al 2014). A high TIGIT/CD226 
ratio in Treg cells is associated with increased Treg frequencies in tumors and poor clinical 


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outcome upon immune checkpoint blockade (Fourcade et al 2018). Some studies have also 
shown that TIGIT suppresses immune responses mediated by dendritic cells by binding with 
PVR, especially in enhancement of IL-10 production and the inhibition of IL-12 production (Yu 
et al 2009). 
As an immune “checkpoint” molecule, TIGIT initiates inhibitory signaling in immune cells when 
engaged by its ligands, PVR (CD155) and PVR–related 2 (PVR-L2) (CD112, or nectin-2). These 
ligands are primarily expressed on antigen-presenting cells  and tumor cells (Casado et al 2009; 
Stanietsky et al 2009; Yu et al 2009; Levin et al 2011). The binding affinity of TIGIT to PVR 
(equilibrium dissociation constant [KD]: approximately 1 nM) is much higher than to PVR-L2 
and whether the TIGIT: PVR-L2 interaction is functionally relevant in mediating inhibitory 
signals remains to be determined. The co-stimulatory receptor, CD226, binds to the same ligands 
with lower affinity (KD: approximately 100 nM) but delivers a positive signal and enhances 
cytotoxicity of T cells and NK cells (Bottino et al 2003; Stanietsky et al 2009). High affinity 
binding of TIGIT to PVR could compete off CD226-PVR interaction, therefore reducing T cells 
or NK cells activation (Stanietsky et al 2009). 
The cytoplasmic tail of TIGIT has an inhibitory ITIM and an immunoreceptor tail tyrosine-like 
motif. In NK cells, TIGIT engagement induces the phosphorylation of tyrosine residues in its 
ITIM and immunoreceptor tail tyrosine-like motifs through the Src kinases Fyn and Lck. Then 
the phosphorylations of TIGIT would lead to binding of Grb2 and β-arrestin 2 and subsequently 
recruitment of SHIP-1 and SHP-2 to terminate PI3K and NK-κB signaling in the NK cells 
(Stanietsky et al 2009; Liu et al 2013). Engagement of agonistic TIGIT antibody induced T-cell 
receptor complex disruption (Stanietsky et al 2009). In addition, interaction between TIGIT and 
PVR on dendritic cells could lead to phosphorylation of PVR and modulation of ERK activation 
in dendritic cells (Yu et al 2009).  
Up-regulation of TIGIT expression in tumor-infiltrating lymphocytes (TILs) has been reported in 
many types of cancers, such as lung (Tassi et al 2017), stomach (He et al 2017), breast (Gil Del 
Alcazar et al 2017; Gandara et al 2018), esophageal (Xie et al 2016), brain (Hung et al 2018), 
acute myeloid leukemia (Kong et al 2016), and melanoma (Mahnke and Enk 2016). 
Interestingly, TIGIT expression appears to be minimally expressed by peripheral effector cells 
while significantly up-regulated by tumor localized effector cells, which strongly suggests that 
the tumor microenvironment utilizes TIGIT signaling to further suppress/evade 
immune-mediated tumor cytotoxicity (Johnston et al 2014). Further, up-regulation of TIGIT 
signaling plays an important role in immune tolerance to cancer, similar to its function in the 
presence of chronic viral infections (Chauvin et al 2015; Yin et al 2018). The blockade of the 
TIGIT receptor alone or in combination with PD-1/PD-L1 blockade has been shown both in vitro 
and in vivo to rescue functionally “exhausted” T cells (Johnston et al 2014; Chauvin et al 2015). 
In mouse models, TIGIT blockade in combination with anti–PD-1/PD-L1 antibodies 
demonstrated significantly better antitumor efficacy than either monotherapy (Johnston et al 
2014; Dixon et al 2018).  
In mouse models, Fc with effector functions is critical for TIGIT antibody-mediated antitumor 
activity (College of American Pathologist [CAP] guidelines 2018; Argast et al 2018; Leroy et al 
2018). In the CT26.WT mouse colon cancer model, anti-mouse TIGIT antibody of mIgG2a 
isotype (antibody-dependent cellular cytotoxicity [ADCC] enabling) demonstrated potent 
antitumor activity in monotherapy and in combination with anti-PD-1 antibody. In contrast, 


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anti-TIGIT antibody with Fc devoid of effector functions did not show any of the antitumor 
efficacies in the same model, indicating that Fc-mediated effector functions are required for 
TIGIT antibody-mediated antitumor effects. In addition, the observed efficacy was associated 
with an increased activity of effector T cells (CD8+ and CD4+) and also with Treg depletion 
within the tumor microenvironment. Argast and colleagues activity (CAP guidelines 2018; 
Argast et al 2018), also observed that effector functions were critical for TIGIT antibody-induced 
in vivo efficacy. Waight and colleagues (Waight et al 2018) reported that the interaction of 
anti-TIGIT with gamma fragment crystallizable region (Fc) receptor (FcγR) on 
antigen-presenting cells enhanced antigen-specific T cell responses and antitumor activity. 
Taken as a whole, targeting TIGIT provides a potential mechanism to rescue immune cells 
(eg, T cells, NK cells, and dendritic cells) from the immunosuppressive tumor 
microenvironment, thereby inducing an efficient antitumor immune response. Blocking 
antibodies which target at the PD-1/PD-L1 pathway have achieved remarkable results in the 
treatment of many different tumor types. However, based upon the rate of primary and secondary 
resistance to PD-1 blockade, it is apparent that additional immuno-regulatory mechanism(s) 
underlie tumor immune escape. Indeed, research shows that the TIGIT pathway cooperates with 
PD-1 to maximize the suppression of effector TILs and promote resistance to anti-PD-1 therapy. 
Therefore, TIGIT represents an ideal target with the potential to significantly improve and/or 
extend the therapeutic benefit of anti-PD-1 therapy to a greater number of patients. 
1.3.1. 
Nonclinical Experience  
1.3.1.1. 
Pharmacology  
Ociperlimab binds to the extracellular domain of human TIGIT with high specificity and affinity 
(equilibrium dissociation constant [KD] = 0.135 nM), as demonstrated by target-binding assays 
and surface plasmon resonance (SPR) characterization. In in vitro cell-based assays, ociperlimab 
consistently and dose-dependently enhances the functional activities of activated human 
peripheral blood mononuclear cells (PBMCs). In the MC-38 mouse colon cancer model in 
humanized TIGIT knock-in mice, ociperlimab in combination with antimouse PD-1 enhanced 
the inhibition of tumor growth compared with either monotherapy. 
Refer to the Ociperlimab Investigator’s Brochure for detailed information regarding 
pharmacology studies. 
1.3.1.2. 
Toxicology  
Overall, no apparent toxicity was observed in the 13-week cynomolgus monkey or in the 4-week 
humanized TIGIT knock-in mouse studies. No specific tissue cross-reactivity was detected in 
normal human tissues. The safety profile of ociperlimab was considered adequate to support 
human studies. 
Refer to the Ociperlimab Investigator’s Brochure for detailed information regarding toxicology 
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1.3.2. 
Clinical Experience  
1.3.2.1. 
Clinical Experience With Other TIGIT Inhibitors  
To date, first-in-human Phase 1 and Phase 2 clinical studies have been initiated for 6 anti-TIGIT 
antibodies: MTIG7192A from Genentech/Roche (NCT02794571 and NCT03563716), 
BMS-986207 from Bristol-Myers Squibb (NCT02913313), MK-7684 from Merck Sharp & 
Dohme (NCT02964013), OMP-313M32 from OncoMed (NCT03119428), ASP8374 from 
Astellas/Potenza (NCT03260322), and AB-154 from Arcus (NCT03628677). The goals for these 
clinical studies are to evaluate the safety and efficacy of anti-TIGIT antibodies alone and/or in 
combination with anti-PD-1 or anti-PD-L1 antibodies. 
To date, clinical data have been released for OncoMed’s OMP-313M32 (Sharma et al 2018), 
Merck’s MK-7684 (Golan et al 2018), and Genentech/Roche’s tiragolumab (Bendell et al 2020; 
Rodriguez-Abreu et al 2020). A total of 68 patients have been treated with MK-7684 alone or 
MK-7684 in combination with pembrolizumab (an anti–PD-1 antibody) in a Phase 1 study 
sponsored by Merck Sharp & Dohme, with doses of MK-7684 ranging from 2.1 mg to 700 mg. 
The preliminary results showed that MK-7684 was well tolerated in the dose escalation phase of 
the study, with no dose-limiting toxicity (DLT). Adverse events (AEs) that occurred in > 15% of 
patients were fatigue (n = 5, 15%) for MK-7684 monotherapy and pruritus (n = 10, 21%) for 
MK-7684 and pembrolizumab combination therapy. Furthermore, only 2 treatment-related AEs 
≥ Grade 3 were reported (Grade 3 anemia and Grade 3 diarrhea) for monotherapy and 5 
treatment-related AEs ≥ Grade 3 were reported for combination with pembrolizumab 
(5 Grade 3: alanine aminotransferase [ALT] increased, colitis, Gamma-glutamyl transferase 
[γGT] increased, hypersensitivity, and rash maculopapular). Of the 34 evaluable patients treated 
with MK-7684 alone, one partial response (PR) (1/34 [3.0%]) and a 35% disease control 
rate (DCR) were observed. For combination of MK-7684 and pembrolizumab, 6 PRs 
(6/34 [18%]) and a 48% DCR were observed. In addition, pharmacokinetic (PK) findings were 
linear above 200 mg. 
Eighteen patients have been treated with OMP-313M32 alone in a Phase 1 study sponsored by 
OncoMed, with doses ranging from 0.3 mg/kg to 20 mg/kg. The preliminary results showed that 
OMP-313M32 was well tolerated in the dose escalation phase of the study, with no DLT. 
Treatment-related AEs that occurred in > 15% of patients were rash (n = 5; 27.8%), fatigue 
(n = 3, 16.7%), nausea (n = 3, 16.7%), and pruritus (n = 3, 16.7%) for OMP-313M32 
monotherapy. Grade ≥ 3 treatment-related AEs included rash (n = 3, 16.7%), fatigue (n = 1, 
5.6%), hypophosphatemia (n = 1, 5.6%), and autoimmune hepatitis (n = 1, 5.6%). Based upon 
the safety profile of OMP-313M32 monotherapy, OncoMed has initiated the dose expansion 
with the combination of OMP-313M32 and nivolumab (an anti–PD-1 antibody) in patients with 
non-small cell lung, head and neck, esophageal, gastric, cervical, triple negative breast, anal, and 
hepatocellular cancers or with microsatellite instability-high tumors (NCT03119428).  
The Phase 1 data for tiragolumab was released at the 2020 American Association of Cancer 
Research meeting (Bendell et al 2020). No objective responses occurred in 24 patients treated 
with tiragolumab monotherapy in Phase 1a. However, in Phase 1b, 5 of 44 patients (11.4%) 
treated with tiragolumab combined with atezolizumab had achieved PR (Bendell et al 2020). In 
the Phase 1a (tiragolumab monotherapy) cohort, there were no Grade 3-5 immune-mediated AEs 
(imAEs). Grade 1-2 imAEs included infusion-related reaction (n = 2, 8%), rash (n = 2, 8%), 


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hepatitis (n = 1, 4%), and pancreatitis (n = 1, 4%). In the Phase 1b (tiragolumab combined with 
atezolizumab) cohort, 4% of patients experienced Grade 3-5 imAEs; no Grade 5 imAEs were 
associated with tiragolumab and/or atezolizumab. These imAEs included infusion-related 
reaction (n = 4, 8%), rash (n = 14, 29%), hepatitis (n = 10, 20%), pancreatitis (n = 1, 2%), 
hyperthyroidism (n = 4, 8%), hypothyroidism (n = 3, 6%), and anemia (n = 1, 2%). 
A total of 135 patients with previously untreated PD-L1–selected non-small cell lung cancer 
(NSCLC) were treated with tiragolumab 600 mg by intravenous infusion once every 3 weeks 
plus atezolizumab 1200 mg by intravenous infusion once every 3 weeks (n = 67) or atezolizumab 
1200 mg by intravenous infusion once every 3 weeks plus placebo by intravenous infusion once 
every 3 weeks (n = 68) in a Phase 2 study (CITYSCAPE) sponsored by Genentech/Roche. 
Patients were randomly assigned to 1 of these treatment groups and were stratified by tumor 
proportion score (TPS) (1% to 49% or ≥ 50%), histology (squamous versus nonsquamous), and 
tobacco use (yes or no). Preliminary efficacy results showed a clinically meaningful 
improvement in ORR and PFS in patients treated with tiragolumab plus atezolizumab 
(ORR, 31%; PFS, 5.42 months) compared with those treated with atezolizumab plus placebo 
(ORR, 16%; PFS, 3.58 months). This improvement was still observed 6 months later: 
tiragolumab plus atezolizumab (ORR, 37%; PFS, 5.55 months) compared with atezolizumab plus 
placebo (ORR, 21%; PFS, 3.88 months). In addition, analysis at this 6-month follow-up 
timepoint showed a greater improvement in ORR in patients in the PD-L1 TPS ≥ 50% subgroup 
who received tiragolumab plus atezolizumab (ORR, 66%) compared with atezolizumab plus 
placebo (ORR, 24%). Preliminary safety results showed that study treatment with tiragolumab 
plus atezolizumab was well tolerated; results were generally similar between the 2 treatment 
groups. More patients in the tiragolumab plus atezolizumab group experienced imAEs compared 
with those in the atezolizumab plus placebo group (46 [69%] versus 32 [47%]); most imAEs 
were Grade 1 or Grade 2 events of infusion-related reaction and rash and were manageable. 
Based on these observed efficacy and safety results, Genentech/Roche is conducting an ongoing 
Phase 3 study (SKYSCRAPER-01) in first-line PD-L1 TPS ≥ 50% NSCLC (NCT04294810). 
All of these findings support further development of anti-TIGIT antibody in combination with 
existing therapeutic modalities. 
1.3.2.2. 
Preliminary Safety Profile  
As of 28 July 2021, 6 studies with ociperlimab are ongoing and 3 studies have been planned 
(Ociperlimab Investigator’s Brochure). Of the 6 ongoing studies, 2 (AdvanTIG-105 and 
AdvanTIG-202) have preliminary data available. For more detailed information on ociperlimab 
safety and efficacy data refer to the most recent edition of the Ociperlimab Investigator’s 
Brochure. 
A pooled analysis of monotherapy and combination therapies was conducted to provide a 
comprehensive safety assessment. As of the data cutoff date of 28 July 2021, a total of 
133 patients received ociperlimab treatment in Study AdvanTIG-105 and Study AdvanTIG-202.  
An overview of TEAEs, including serious TEAEs, TEAEs leading to discontinuation of 
ociperlimab, and TEAEs leading to death, is shown in Table 2. 
Overall, of the 133 patients in the Safety Analysis Set, 117 (88%) experienced ≥ 1 TEAE and 
77 patients (57.9%) experienced ≥ 1 TEAE related to ociperlimab. TEAEs ≥ Grade 3 in severity 


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were experienced by 53 of 133 patients (39.8%), and 8 patients (6.0%) experienced ≥ Grade 3 
TEAE related to ociperlimab. Forty-seven patients (35.3%) had serious TEAEs, 7 (5.3%) of 
these were considered related to ociperlimab. Nine patients (6.8%) experienced TEAEs that led 
to discontinuation of ociperlimab. Six patients (4.5%) experienced TEAEs that led to death, but 
none of them were assessed as related to ociperlimab. No TEAEs were considered to be DLTs. 
Table 2: 
Overview of Treatment-Emergent Adverse Events (Safety Analysis Set)  
Ociperlimab 
Monotherapy  
(N = 9)  
 n (%) 
Ociperlimab + 
Tislelizumab  
(N = 99)  
 n (%) 
Ociperlimab + 
Tislelizumab + 
Chemotherapy  
(N = 25)  
 n (%) 
Total 
(N = 133)  
 n (%) 
Patients with any TEAE 
8 (88.9) 
88 (88.9) 
21 (84.0) 
117 (88.0) 
Related to Ociperlimab 
7 (77.8) 
57 (57.6) 
13 (52.0) 
 77 (57.9) 
≥ Grade 3 TEAE 
4 (44.4) 
38 (38.4) 
11 (44.0) 
 53 (39.8) 
Related to Ociperlimab 
1 (11.1) 
 5 (5.1) 
 2 (8.0) 
  8 (6.0) 
Serious TEAE 
4 (44.4) 
33 (33.3) 
10 (40.0) 
 47 (35.3) 
Related to Ociperlimab 
0 (0.0) 
 6 (6.1) 
 1 (4.0) 
  7 (5.3) 
TEAE Leading to Discontinuation of 
Ociperlimab 
1 (11.1) 
 7 (7.1) 
 1 (4.0) 
  9 (6.8) 
Related to Ociperlimab 
0 (0.0) 
 1 (1.0) 
 1 (4.0) 
  2 (1.5) 
TEAE Leading to Death 
2 (22.2) 
 2 (2.0) 
 2 (8.0) 
  6 (4.5) 
Related to Ociperlimab 
0 (0.0) 
 0 (0.0) 
 0 (0.0) 
  0 (0.0) 
Dose-Limiting Toxicity Event 
0 (0.0) 
 0 (0.0) 
 0 (0.0) 
  0 (0.0) 
Source: Ociperlimab Investigator’s Brochure. 
Abbreviations: AE, adverse event; TEAE, treatment-emergent adverse event.  
Note: A patient with multiple occurrences of an AE is counted only once in the AE category.  
 
1.3.2.3. 
Clinical Pharmacology  
Preliminary pharmacokinetic (PK) data are available from a total of 51 patients treated with 
ociperlimab at 50-, 150-, 450-, 900-, and 1800-mg dose levels in combination with tislelizumab 
at 200 mg in the dose-escalation and dose-verification portions of Study AdvanTIG-105. In 
Cycle 1, ociperlimab exposures (AUC and Cmax) increased approximately dose proportionally 
from the 50 mg to the 1800 mg dose. Across dose groups, serum concentrations of ociperlimab 
decreased in a biexponential manner after administration. The mean elimination half-life ranged 
from 7.1 to 10.5 days. Postdose PK sampling duration may not be sufficient for robust 
characterization of elimination half-life using noncompartmental analysis (NCA); hence, the 
reported half-life values should be interpreted with caution. 
Peripheral TIGIT receptor occupancy data were available for 32 enrolled patients treated with 
ociperlimab at 50-, 150-, 450-, 900-, and 1800-mg dose levels in Study AdvanTIG-105. 
Complete TIGIT receptor occupancy (100%) at all tested dose levels was observed on CD8+, 
CD4+, and regulatory T cells in peripheral blood. 
Refer to the Ociperlimab Investigator’s Brochure for detailed information on ociperlimab clinical 
PK and pharmacodynamics.  


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1.3.2.4. 
Efficacy  
Preliminary efficacy data for ociperlimab are available from Study AdvanTIG-105, which is a 
Phase 1/1b study of ociperlimab in combination with tislelizumab with or without chemotherapy 
in patients with unresectable locally advanced or metastatic solid tumors. The ociperlimab dose 
of 900 mg once every 3 weeks combined with tislelizumab 200 mg once every 3 weeks was 
selected as the recommended Phase 2 dose (RP2D) for further investigation based on data from 
the ongoing Phase 1/1b Study AdvanTIG-105. 
Refer to Ociperlimab Investigator’s Brochure further details on the efficacy of ociperlimab. 
1.4. 
Tislelizumab as a PD-1 Inhibitor  
1.4.1. 
Pharmacology  
Tislelizumab (also known as BGB-A317) is a humanized, immunoglobulin G4 (IgG4)-variant 
monoclonal antibody against PD-1 under clinical development for the treatment of several 
human malignancies. 
Tislelizumab acts by binding to the extracellular domain of human PD-1 with high specificity as 
well as high affinity (dissociation constant [KD] = 0.15 nM). It competitively blocks binding 
efforts by both PD-L1 and programmed cell death protein ligand-2 (PD-L2), thus inhibiting 
PD-1-mediated negative signaling in T cells. In in vitro cell-based assays, tislelizumab was 
observed to consistently and dose-dependently enhance the functional activity of human T cells 
and pre-activated, primary PBMC. Tislelizumab has demonstrated in-vivo antitumor activity in 
several allogeneic xenograft models, in which PBMC were co-injected with human cancer cells 
(A431 [epidermoid carcinoma]) or tumor fragments (BCCO-028 [colon cancer]) into 
immunocompromised mice.  
Tislelizumab is an IgG4-variant antibody with low affinity to FcγRs such as FcγRI and 
FcγRIIIA, and complement 1q (C1q), a subunit of complement 1. In vitro assays with 
tislelizumab suggest either low or no ADCC, antibody-dependent cellular phagocytosis, or 
complement-dependent cytotoxicity effects in humans (Labrijn et al 2009). Tislelizumab was 
specifically engineered to abrogate these potential mechanisms of T-cell clearance and potential 
resistance to anti-PD-1 therapy. 
Please refer to the Tislelizumab Investigator’s Brochure for additional details regarding 
nonclinical studies of tislelizumab. 
1.4.2. 
Toxicology  
The toxicity and safety profile of tislelizumab was characterized in single-dose toxicology 
studies in mice and cynomolgus monkeys, and in a 13-week, repeat-dose toxicology study in 
cynomolgus monkeys. Tissue cross-reactivity was evaluated in normal frozen tissues from both 
humans and monkeys. The cytokine release assays were conducted using fresh human whole 
blood cells. The single-dosing regimens spanned from the intended human doses to 10-fold 
higher than the maximum of the intended human doses, and the repeated-dosing regimens 
spanned to 3-fold higher than the maximum of the intended human dose. The cynomolgus 
monkey was the only relevant species based on the target sequence homology and binding 
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Overall, no apparent toxicity was noted in mouse or monkey toxicity studies. No tissue 
cross-reactivity was found in either human or monkey tissues, nor was any effect on cytokine 
release observed in the human whole-blood assay. The toxicokinetic profile was well 
characterized, with dose proportional increases in systemic exposure without apparent 
accumulation or sex difference. Immunogenicity was observed without apparent immunotoxicity 
or effect on the systemic exposure. The NOAEL of tislelizumab in the 13-week monkey toxicity 
study was considered to be 30 mg/kg. The safety profile of tislelizumab is considered adequate to 
support the current study BGB-A317-A1217-203. 
Please refer to the Tislelizumab Investigator’s Brochure for more detailed information on the 
toxicology of tislelizumab. 
1.4.3. 
Clinical Pharmacology  
Based on pooled data from 2596 patients across 12 clinical studies, the PK of tislelizumab was 
best characterized using a 3-compartmental linear population PK model with linear clearance 
mechanisms.  No time-varying clearance was observed in tislelizumab PK.  The Cmax and AUC 
increased in a nearly dose-proportional manner from 0.5 mg/kg to 10 mg/kg.  The terminal half-
life (t1/2) was estimated to be approximately 23.8 days, and the steady state is expected to be 
reached in 12 weeks.  
Refer to the Tislelizumab Investigator’s Brochure for more detailed information on the clinical 
pharmacology of tislelizumab 
1.4.4. 
Prior Clinical Experience of Tislelizumab  
As of 20 May 2021, 33 studies with tislelizumab are ongoing and 9 studies have been completed. 
Of these, 15 studies have preliminary data available in the Investigator’s Brochure Edition 9.0, 
20 October 2021: 6 monotherapy studies, 2 chemotherapy combination therapy studies, and 
7 investigational agent combination therapy studies. 
Refer to the Tislelizumab Investigator’s Brochure for more detailed information on tislelizumab 
safety and efficacy data when given as monotherapy or in combination with chemotherapy. 
1.4.4.1. 
Pooled Safety Assessment of Monotherapy Studies  
A pooled analysis of monotherapy studies was conducted to provide a comprehensive safety 
assessment separate from combination therapy. Data from patients with solid tumors were 
analyzed separately from patients with hematologic malignancies. 
As of May 2021, data are available from patients treated in 7 pooled solid tumor monotherapy 
studies (Tislelizumab Investigator's Brochure).  
For monotherapy, the safety profile of tislelizumab was considered adequate, and tislelizumab 
was well tolerated. In pooled solid tumor studies, the majority of AEs were Grade 1 or 2, and 
most ≥ Grade 3 TEAEs were assessed as unrelated to tislelizumab. Adverse events were 
generally reversible and manageable. The percentage of patients with ≥ Grade 3 immune-
mediated adverse events (imAEs), ≥ Grade 3 infusion-related AEs, and TEAEs leading to 
tislelizumab discontinuation was small.  


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The data collected shows that tislelizumab monotherapy has an adequate safety profile. The 
safety profile for single-agent tislelizumab is similar to that observed with other PD-1 inhibitors 
in solid tumors. 
For more detailed information on the safety of tislelizumab when given as monotherapy or in 
combination with chemotherapy, refer to the Tislelizumab Investigator's Brochure. 
1.4.4.2. 
Efficacy Assessment of Tislelizumab  
Efficacy data are available from 6 monotherapy studies and 8 combination therapy studies. 
Among these 14 studies, 12 studies were in patients with solid tumors, and 2 studies were in 
patients with hematologic malignancies.  
The data collected show that tislelizumab monotherapy can result in antitumor activity across a 
variety of tumor types, and the antitumor activity has been observed across the dose ranges 
evaluated in patients.  
Please refer to the Tislelizumab Investigator's Brochure for detailed efficacy information. 
1.5. 
Study Rationale  
As described earlier, despite the wealth of evidence supporting the role of TIGIT in promoting 
tumor immune tolerance, TIGIT blockade alone (ie, ociperlimab monotherapy) is unlikely to 
result in an effective antitumor response according to existing anti-TIGIT clinical data (see 
Section 1.3). Therefore, the clinical development of ociperlimab focuses on rational 
combinations, such as with tislelizumab. Taking this into account, the combinations of 
ociperlimab plus tislelizumab and tislelizumab plus placebo are designed to evaluate the effect of 
combining ociperlimab with tislelizumab to maximize the patient’s potential therapeutic benefit 
while simultaneously achieving the clinical objective of characterizing the safety and efficacy of 
ociperlimab combined with tislelizumab. 
1.5.1. 
Rationale for Dose Selection  
1.5.1.1. 
Rationale for the Selection of Ociperlimab Dose in Combination with 
Tislelizumab  
The ociperlimab dose of 900 mg once every 3 weeks combined with tislelizumab 200 mg once 
every 3 weeks was selected as the RP2D for further investigation based on clinical safety, 
tolerability, PK, and pharmacodynamic data from the ongoing Phase 1/1b Study AdvanTIG-105.  
Complete TIGIT receptor occupancy was observed in circulating T cells in peripheral blood at 
all the tested doses of ociperlimab in Study AdvanTIG-105. However, the correlation between 
TIGIT receptor occupancy in the periphery and in tumor tissues is unknown. In a previous 
Phase 1 study of tiragolumab, another anti-TIGIT antibody, complete peripheral receptor 
occupancy was reached at the 30 mg dose level, but the clinical dose of 600 mg was determined 
as the RP2D, which was 20 times the 30 mg dose (Bendell et al 2020). Similarly, although 
complete peripheral receptor occupancy was observed at the 50 mg dose level of ociperlimab, 
the RP2D of 900 mg is approximately 20 times the dose of 50 mg, to ensure sufficient TIGIT 
occupancy in the tumor tissue. 


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As of February 2021, a total of 3 patients were assessed to have a confirmed PR, 1 patient each 
in the 450 mg, 900 mg, and 1800 mg cohorts. Ociperlimab exposure in all 3 patients with a PR is 
consistent with that expected at the 900 mg dose level. The confirmed disease control rates 
observed in the 450 mg, 900 mg, and 1800 mg cohorts were 60% (3 of 5 patients), 64.3% 
(9 of 14 patients), and 60% (3 of 5 patients), respectively.  
Although the best overall response rate and disease control rate were numerically comparable at 
the 450 mg and 900 mg dose levels, the 900 mg dose was chosen as the RP2D for the following 
reasons: 
• 900 mg was well tolerated in patients enrolled in Study AdvanTIG-105 
• Exposure in all 3 patients with a PR was consistent with that expected at the 900 mg 
dose 
• Lack of sufficient information on the impact of immunogenicity on ociperlimab PK 
• An overall intent to minimize exposure overlap with doses < 450 mg. 
1.5.1.2. 
Rationale for the Selection of Tislelizumab Dose  
The dosage of 200 mg intravenously once every 3 weeks was selected based on the safety, 
efficacy, and PK assessments in the first-in-human Study BGB-A317_Study_001. A wide range 
of dosages were investigated in this study, including 2 mg/kg or 5 mg/kg on schedules of once 
every 2 weeks or once every 3 weeks. For the once every 3 weeks schedule, a fixed dose of 200 
mg was also investigated, and was ultimately selected for the following reasons: 
• All dosages tested, including 200 mg once every 3 weeks, were tolerated. The 
maximum tolerated dose was not reached with dosages up to 10 mg/kg once every 2 
weeks. The observed serum concentration after 200 mg dosing was within the range 
seen after 2 mg/kg and 5 mg/kg dosing. 
• Preliminary clinical activity was observed at this dosage. 
• Exposure-response relationships were flat for ORR and safety endpoints across a 
variety of tumor types (data from Studies BGB-A317_Study_001, BGB-A317-102, 
BGB-A317-203, and BGB-A317-204). In addition, population PK analysis based on 
2596 cancer patients demonstrated that no covariates had clinically relevant effect on 
tislelizumab PK, suggesting no dose modification is needed based on patient 
demographics and characteristics. 
• Compared with doses based on patient weight, a fixed dose simplifies dose 
administration and reduces the chance of medical errors. 
• Compared with a once every 2 weeks schedule, a once every 3 weeks schedule allows 
for more convenient integration with common chemotherapeutic regimens and 
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1.5.2. 
Rationale for Combination of Ociperlimab and Tislelizumab as Second-Line 
Treatment in Unresectable, Locally Advanced, Recurrent or Metastatic ESCC   
Esophageal cancer is the seventh most common cancer worldwide and the sixth most common 
cause of death from cancer. The highest incidence area spans from northern Iran through the 
Central Asian republics and into northern China. The most common histologic type of 
esophageal cancer is ESCC, which is even more common in Eastern Europe and Asia. More than 
two-thirds of patients diagnosed with esophageal cancer will have advanced or metastatic 
disease, with a median survival of 8 to 10 months and an expected 5-year survival rate < 5%. 
These data, combined with the relative lack of highly effective treatment, are indicative of the 
large unmet medical need in patients diagnosed with esophageal cancer. 
Anti-PD-1 therapies have shown superior efficacy compared with chemotherapy as the 
second-line treatment of ESCC. In KEYNOTE-181 trial that enrolled 628 patients with recurrent 
locally advanced or metastatic esophageal cancer who progressed on or after one prior line of 
systemic treatment for advanced disease, a significant improvement was observed in the primary 
endpoint OS in patients treated with pembrolizumab as compared with chemotherapy 
(10.3 months versus 6.7 months, HR, 0.62; 95% CI: 0.46 to 0.90). In ATTRACTION-3 trial that 
enrolled 419 patients with unresectable advanced, recurrent, or metastatic ESCC, who were 
refractory or intolerant to ≥ 1 fluoropyrimidine-and platinum-based regimen, a significant 
improvement was reported in the primary endpoint OS for patients treated with nivolumab as 
compared with the investigator’s choice of taxane chemotherapy (10.9 months versus 
8.4 months; HR, 0.77; 95% CI: 0.62 to 0.96). OS benefit was observed regardless of PD-L1 
expression level. Potential efficacy was also observed in ESCC treated with tislelizumab. 
BGB-A317_Study_001 and BGB-A317-102 showed potential efficacy of tislelizumab in 
esophageal cancer as mentioned above. The efficacy of tislelizumab in ESCC is under further 
investigation in Study BGB-A317-302, a randomized, controlled, open-label, global Phase 3 
study comparing the efficacy of tislelizumab versus chemotherapy as second-line treatment in 
patients with advanced unresectable/metastatic ESCC. 
As described earlier, targeting TIGIT provides a potential mechanism to rescue immune cells 
from the immunosuppressive tumor microenvironment, thereby inducing an efficient antitumor 
immune response. Research shows that the TIGIT pathway cooperates with PD-1 to maximize 
the suppression of effector TILs as well as promote resistance to anti-PD-1 therapy. Blocking 
antibodies targeting the PD-1/PD-L1 pathway have achieved remarkable results in the treatment 
of ESCC as mentioned above. Therefore, TIGIT represents an ideal target with the potential to 
significantly improve and/or extend the therapeutic benefit of anti-PD-1 therapy in ESCC. 
Given the promising anti-tumor activity of anti-PD-1 antibodies reported in ESCC and given the 
scientific rationale that TIGIT may improve the therapeutic benefit of anti-PD-1 therapy, the 
combination of ociperlimab and tislelizumab may bring significant clinical benefit in this 
indication and support further clinical development.  
1.5.3. 
Biomarker Strategy Rationale  
Biomarker analyses including but not limited to PD-L1 expression, TIGIT pathway molecules, 
gene expression profiling (GEP), tumor mutations, and tumor infiltration immune cells will be 


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performed to explore the association with patient prognosis, response, and potential resistance to 
tislelizumab plus ociperlimab and tislelizumab plus placebo.  
PD-L1 was expressed in tumor and tumor-infiltrating immune cells in ESCC, and its expression 
level was shown to be correlated with clinical efficacy of anti-PD-1 treatment in multiple studies 
(KEYNOTE-181, ATTRACTION-3). The potential predictive role of PD-L1 in checkpoint 
blockade was first reported in KEYNOTE-181 study, in which the HR for OS in patients with 
ESCC whose tumors expressed PD-L1 CPS ≥10 was 0.64 (95% CI: 0.46 to 0.90), and the 
median OS was 10.3 months (95% CI: 7.0 to 13.5) and 6.7 months (95% CI: 4.8 to 8.6) in the 
pembrolizumab and control arms, respectively. Clinical efficacy in PD-L1 positive (PD-L1+) 
patients was superior to PD-L1 negative (PD-L1-) patients. Although the predictive role of PD-
L1 in combination treatment of anti-PD-1 and anti-TIGIT with esophageal squamous cell 
carcinoma is still not clear, there is a hint based on CITYSCAPE study which compares 
atezolizumab (anti-PD-L1) plus tiragolumab (anti-TIGIT) with atezolizumab alone in NSCLC 
patients. It was reported that only patients with high PD-L1 levels showed better ORR in 
combination therapy than monotherapy, suggesting PD-L1 is probably a predictive biomarker for 
PD-1 and TIGIT pathway co-targeting treatment. Here in this study, another PD-L1 score 
algorithm, named Tumor Area Positivity (TAP) score (previously known as visually estimated 
CPS [vCPS] in the original protocol) will be assessed centrally and its predictive role will be 
assessed in patients treated with tislelizumab plus ociperlimab and tislelizumab plus placebo. 
In addition to PD-L1, high TIGIT/CD226 ratio on Treg cells correlated with poor clinical 
outcome upon anti-PD1 or anti-PD-L1 antibody treatment in melanoma patients, which suggest 
signaling through TIGIT pathway in tumor tissues might contribute to resistance to current 
immune checkpoint inhibitors targeting PD-1 or PD-L1 (Fourcade et al 2018). Furthermore, 
clinical data from various studies suggested tumor mutational burden, abundance and location of 
TILs and immune related gene expression profile are a few factors associated with response to 
immunotherapies including anti-PD-1 antibodies in different cancers (Vilain et al 2017; 
Goodman et al 2017; Gandara et al 2018; Jiang et al 2018). Therefore, expression of TIGIT 
pathway molecules (eg, TIGIT, CD226, CD155, CD112), as well as tumor mutation, TILs and 
GEP will be studied to explore the relationship with clinical response to tislelizumab plus 
ociperlimab and tislelizumab plus placebo, and to explore potential predictive biomarkers.  
Beside biomarkers, mechanisms of resistance to immunotherapy are also not well understood 
and need more exploration. Identification tumor and immune-mediated features that are 
associated with PD or acquired resistance to ociperlimab and tislelizumab might increase our 
understanding of disease pathobiology and collecting biological evidence for combination 
strategies. 
1.6. 
Benefit-Risk Assessment  
Patients with unresectable, locally advanced, recurrent or metastatic ESCC whose disease 
progressed on first-line chemotherapy represent a population with a great unmet medical need. 
Anti-PD-1 therapies such as pembrolizumab and nivolumab have shown superior efficacy 
compared with chemotherapy as the second-line treatment of ESCC. Tislelizumab has been 
approved in China by the National Medical Products Administration (NMPA) for second-line 
treatment of patients with ESCC whose disease progressed after chemotherapy. 


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The safety profile of tislelizumab monotherapy is considered as acceptable based on previous 
nonclinical and clinical data. Ociperlimab combined with tislelizumab 200 mg once every 
3 weeks is safe and well-tolerated, with no DLTs, no treatment related SAEs, or high-grade AEs 
occurred during the treatment period for each dose level in the ongoing Study AdvanTIG-105 
Phase 1/1b study as of 28 July 2021. 
Given the unmet medical need and limited treatment options in this indication, the benefit/risk 
assessment, based on the available safety data of anti-TIGIT monoclonal antibodies in 
combination of anti-PD-1/PD-L1 antibodies and the available efficacy data from the PD-1 
antibodies in this indication, the combination of tislelizumab and ociperlimab is considered 
favorable. This Phase 2 study will be conducted in order to compare the potential benefit and 
safety of tislelizumab plus ociperlimab and tislelizumab plus placebo.  
1.7. 
Study Conduct  
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) and in accordance with Good 
Clinical Practice (GCP) standards. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS  
2.1. 
Study Objectives  
2.1.1. 
Primary Objectives  
• To compare the objective response rate (ORR), as assessed by the investigator 
according to RECIST v1.1, of tislelizumab plus ociperlimab with tislelizumab plus 
placebo as second-line treatment in patients with PD-L1 TAP ≥ 10% unresectable, 
locally advanced, recurrent or metastatic ESCC in the Intent-to-Treat (ITT) Analysis 
Set. 
2.1.2. 
Secondary Objectives  
• To compare the overall survival (OS) of tislelizumab plus ociperlimab with 
tislelizumab plus placebo as second-line treatment in patients with PD-L1 
TAP ≥ 10% ESCC in the ITT Analysis Set. 
• To compare the following endpoints between tislelizumab plus ociperlimab and 
tislelizumab plus placebo based on tumor assessments per RECIST v1.1: 
− Progression-free survival (PFS) assessed by both Independent Review Committee 
(IRC) and the investigator.  
− Duration of response (DOR), DCR, and clinical benefit rate (CBR) assessed by 
both the IRC and the investigator.  
− ORR assessed by the IRC. 
• To compare the safety and tolerability between tislelizumab plus ociperlimab and 
tislelizumab plus placebo. 
• To compare the health-related quality of life (HRQoL) via cancer-specific 
patient-reported outcomes (PROs) between tislelizumab plus ociperlimab and 
tislelizumab plus placebo.   
2.1.3. 
Exploratory Objectives  
• To evaluate the potential association of biomarkers with patient prognosis, response 
or resistance to tislelizumab plus ociperlimab and tislelizumab plus placebo. 
• To characterize the PK of ociperlimab and tislelizumab. 
• To assess host immunogenicity to ociperlimab and tislelizumab. 
• To compare the quality of life (QoL) via a generic PRO between tislelizumab plus 
ociperlimab and tislelizumab plus placebo. 
 


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2.2. 
Study Endpoints  
2.2.1. 
Primary Endpoints  
• ORR, defined as the proportion of patients who have confirmed CR or PR by the 
investigator’s review per RECIST v1.1 in the ITT Analysis Set. 
2.2.2. 
Secondary Endpoints  
• OS, defined as the time from the date of randomization until the date of death due to 
any cause in all randomized patients in the ITT Analysis Set. 
• ORR, defined as above and assessed by the IRC per RECIST v1.1 in the ITT 
Analysis Set. 
• PFS, defined as the time from the date of randomization to the date of first 
documentation of PD assessed by both the IRC and the investigator per RECIST v1.1 
or death, whichever occurs first in the ITT Analysis Set. 
• DOR, defined as the time from the first determination of an objective response until 
the first documentation of PD as assessed by both the IRC and the investigator per 
RECIST v1.1, or death, whichever comes first in the ITT Analysis Set. 
• DCR, defined as the proportion of patients who have confirmed CR, confirmed PR, 
and stable disease assessed by both the IRC and the investigator per RECIST v1.1 in 
the ITT Analysis Set. 
• CBR, defined as the proportion of patients who achieve confirmed CR, confirmed 
PR, and durable stable disease (stable disease ≥ 24 weeks).  
• HRQoL, assessed by the scores of Global Health Status (GHS)/QoL and Physical 
Function of European Organization for Research and Treatment of Cancer (EORTC) 
Quality of Life Questionnaire-Core 30 (QLQ-C30) and scores of Dysphagia, Eating, 
Reflux and Pain scales of EORTC Quality of Life Oesophageal Cancer 
Questionnaires 18 (QLQ-OES18). 
• AEs and SAEs as characterized by type, frequency, severity (as graded by National 
Cancer Institute Common Terminology Criteria for Adverse Event [NCI-CTCAE] 
version 5.0 [v5.0]), timing, seriousness, and relationship to study drugs, physical 
examinations, electrocardiograms (ECGs), and laboratory assessments.  


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2.2.3. 
Exploratory Endpoints  
• Evaluate status of exploratory biomarkers including but not limited to expression of 
TIGIT, CD226, CD155, CD112 and PD-L1, GEP, tumor mutation burden 
(TMB)/gene mutation/microsatellite instability (MSI), tumor infiltrating immune cells 
in archival and/or fresh tumor tissue and blood before and after study treatment or at 
PD/reoccurrence, and the association between these biomarkers and clinical efficacy, 
disease status, and resistance. 
• Serum ociperlimab and tislelizumab concentrations at specified timepoints.  
• Immunogenic responses to ociperlimab and tislelizumab, evaluated through the 
detection of ADAs. 
• QoL, defined as assessment of the European Quality of Life 5-Dimensional 5-Level 
(EQ-5D-5L) and visual analog scale (VAS) in the ITT Analysis Set.  


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3. 
STUDY DESIGN  
3.1. 
Summary of Study Design  
This is a multicenter, randomized, investigator- and patient-blinded, sponsor-unblinded, placebo-
controlled global Phase 2 study in which ORR are measured to compare the efficacy of anti-PD-
1 monoclonal antibody tislelizumab (BGB-A317) plus anti-TIGIT monoclonal antibody 
ociperlimab versus tislelizumab plus placebo as second-line treatment in patients with PD-L1 
TAP ≥ 10% unresectable, locally advanced, recurrent or metastatic ESCC. 
After providing written informed consent, completing all prescreening and screening 
assessments, and being confirmed as eligible for study participation, approximately 120 patients 
will be randomized at a 1:1 ratio to receive 1 of the following treatment regimens: 
• Arm A: tislelizumab + ociperlimab 
• Arm B: tislelizumab + placebo 
Eligible patients will be stratified by the following factors: 
• ECOG PS score (0 versus 1) 
• Number of organs with metastases (≤1 versus ≥2) 
• Region (Asia versus non-Asia) 
Study drugs (including placebo) will be administered until PD per RECIST v1.1, unacceptable 
toxicity, or withdrawal of informed consent, whichever occurs first. 
No crossover between Arm A and Arm B will be allowed. 
The study design schema is in Figure 1. 
 


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Figure 1: Study Schema 
 
Abbreviations: ADA, antidrug antibody; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group Performance 
Status; ESCC, esophageal squamous cell carcinoma; HRQoL, Health Related Quality of Life; INV, investigator; IRC, Independent Review Committee; IV, 
intravenously; ORR, objective response rate; OS, overall survival; PD-L1, programmed cell death protein-ligand 1 (PD-L1); PFS, progression-free survival; PK, 
pharmacokinetics; Q3W, once every 3 weeks; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1; TAP; Tumor Area Positivity. 
Note: The initial infusion (Cycle 1 and Cycle 2, Day 1) will be administered over a period of 60 minutes. If this infusion is well tolerated, subsequent infusions 
may be administered over 30 minutes. After infusion, patients will be further monitored for at least 1 hour during Cycles 1 and 2. From Cycle 3 onward, a 
postinfusion monitoring period of at least 30 minutes will be required. 
At the discretion of the investigator, patients may continue tislelizumab and ociperlimab or tislelizumab alone after PD under protocol defined conditions. 
 


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3.2. 
Prescreening Period  
All patients regardless of PD-L1 expression status are required to provide tumor tissues for 
central confirmation of PD-L1 expression during the prescreening period (defined as ≤ 56 days 
before randomization). A separate prescreening informed consent must be obtained.  
Patients must submit qualified archival tumor tissue (formalin-fixed paraffin-embedded [FFPE] 
block containing tumor [preferred] or approximately 15 [≥ 6] unstained slides) with an 
associated pathology report, or agree to a tumor biopsy for determination of PD-L1 expression 
and other exploratory biomarker analyses (fresh tumor biopsies are strongly recommended at 
baseline in patients who have readily accessible tumor lesions and who consent to the biopsies) 
(Section 7.8). If no archival samples are available, a fresh tumor biopsy at baseline is mandatory. 
3.3. 
Screening Period  
Screening evaluations will be performed within 28 days before randomization. Patients whose 
tumors express PD-L1 TAP ≥ 10% in prescreening period and agree to participate in this study 
will sign the informed consent form (ICF) before undergoing any screening procedure. Screening 
evaluations may be repeated as needed within the screening period; the investigator is to assess 
preliminary patient eligibility according to the latest screening assessment results. 
3.4. 
Treatment Period  
After providing written informed consent, completing all prescreening and screening 
assessments, and being confirmed as eligible for study participation, approximately 120 patients 
will be randomized at a 1:1 ratio to receive 1 of the following treatment regimens: 
• Arm A: tislelizumab 200 mg + ociperlimab 900 mg intravenously once every 3 weeks 
until PD assessed by the investigator per RECIST v1.1, unacceptable toxicity, or 
withdrawal of informed consent, whichever should occur first.  
• Arm B: tislelizumab 200 mg + placebo intravenously once every 3 weeks until PD 
assessed by the investigator per RECIST v1.1, unacceptable toxicity, or withdrawal of 
informed consent, whichever should occur first.  
No crossover between Arm A and Arm B will be allowed. 
Eligible patients will be stratified by the following factors: 
• ECOG PS (0 versus 1) 
• Number of organs with metastases (≤1 versus ≥2) 
• Region (Asia versus non-Asia) 
Tumor imaging will be performed at baseline (≤ 28 days before randomization). During the 
study, tumor imaging will be performed approximately every 6 weeks (± 7 days) for the first 
54 weeks and every 12 weeks (± 7 days) thereafter. 
Patients who discontinue the study treatment for reasons other than radiographic PD (eg, 
toxicity) will continue with the scheduled tumor assessments until radiographic PD per 


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RECIST v1.1, withdrawal of consent, loss to follow-up, study termination by sponsor, start of a 
new anticancer therapy, or death, whichever occurs first. 
Response will be assessed using RECIST v1.1. If a patient can continue to benefit from study 
drugs after PD per RECIST v1.1, the patient may continue the study treatment at the 
investigator’s discretion. The following criteria must be met in order to treat patients who may 
continue to benefit from study treatment after PD:  
• Absence of clinical symptoms and signs of PD (including clinically significant worsening 
of laboratory values). 
• Stable ECOG PS score ≤ 1.  
• Absence of rapid PD or of progressive tumor at critical anatomical sites (eg, spinal cord 
compression) that requires urgent alternative medical intervention. 
• Investigators must obtain written informed consent for treatment after radiologic PD. and 
inform patients that this practice is not considered standard in the treatment of cancer. 
The decision to continue study drugs after initial PD must be agreed to by the medical monitor 
and documented in the study records. Patients who receive study treatment after PD will undergo 
tumor assessments according to the original schedule until study treatment discontinuation. 
PROs will be collected using EORTC QLQ-C30, EORTC QLQ-OES18, and EQ-5D-5L 
questionnaires (provided in Appendix 8, Appendix 9, and Appendix 10, respectively) before 
dosing on Day 1 of every other treatment cycle during the first 54 weeks, Day 1 of every 4 cycles 
thereafter, and at the on-site Safety Follow-up Visit (defined in Section 3.5). 
To determine the PK properties of tislelizumab and ociperlimab, and host immunogenic response 
to tislelizumab and ociperlimab, blood samples will be collected at various timepoints as outlined 
in Appendix 1. 
An optional blood sample will be taken at baseline (predose on Day 1 of Cycle 1), at the time of 
first tumor response (predose on Day 1 of the following cycle) and at the End of Treatment 
(EOT) Visit after PD (10 mL each timepoint) for all randomized patients to explore the 
association of blood-based biomarkers with response, prognosis, and resistance to tislelizumab in 
combination with ociperlimab/placebo.  
Safety will be assessed throughout the study by monitoring AEs, SAEs (toxicity grades assigned 
per NCI-CTCAE v5.0), and laboratory results. Vital signs, physical examinations, ECOG PS 
change, ECG results, and other examinations will also be used for safety assessments. Safety 
assessments are further detailed in Section 7.5 and the Schedule of Assessments (Appendix 1).  
3.5. 
End of Treatment/Safety Follow-up  
The EOT Visit is conducted when the investigator determines that study drugs will no longer be 
used. If routine laboratory tests (eg, hematology, serum chemistry) are completed within 7 days 
before the EOT Visit, these tests need not be repeated. Tumor assessment is not required at the 
EOT Visit, and should follow the regular schedule of assessment in Appendix 1.  
Patients who discontinue from study treatment for any reason will be asked to return to the clinic 
for the EOT Visit, which must be conducted within 7 days of the EOT decision is made unless 


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otherwise specified or before the initiation of a new anticancer treatment, whichever occurs first. 
An on-site Safety Follow-up Visit at 30 days (± 7 days) after last dose of study drugs is required. 
If the time windows of this Safety Follow-up Visit and EOT Visit are overlapped, this safety 
follow-up visit can be exempted and the tests required at the on-site Safety Follow-up Visit will 
be conducted at the EOT Visit.  
Additional Safety Follow-up Visits at 60, 90, and 120 days (this visit is only required for women 
of childbearing potential) can be required (in clinic or over the phone, as needed based on 
assessments required). Patients will be contacted by telephone to assess imAEs and relevant 
concomitant medications (ie, those associated with an imAE or any new anticancer therapy). 
These contacts should be made at 60 days (± 14 days) and 90 days (± 14 days) after the last dose 
of study treatment, regardless of whether the patient starts a new anticancer therapy. For women 
of childbearing potential (see Appendix 6), an additional visit to perform a pregnancy test will 
occur at approximately 120 days after the last dose of study treatment. If a patient reports a 
suspected imAE at a telephone follow-up contact, the investigator should arrange an unscheduled 
visit if further assessment is indicated. 
All AEs, including SAEs, will be collected as described in Section 8.6. 
Patients who discontinue from study treatment before PD will need to undergo tumor 
assessments as outlined in Section 7.6. 
If clinically feasible, it is highly recommended to obtain a tumor biopsy from accessible tumor 
sites at the EOT Visit for patients with confirmed PD during the study (see Section 7.8). 
See Appendix 1 for assessments to be performed at the EOT/Safety Follow-up Visits. 
3.6. 
Survival Follow-up  
Patients will be followed for survival and further anticancer therapy information after 
discontinuation of study treatment (for reasons other than PD [eg, toxicity] or death) via 
telephone calls, patient medical records, and/or clinic visits approximately every 3 months 
(± 14 days) after the last Safety Follow-up Visit or as directed by the sponsor until death, loss to 
follow-up, withdrawal of consent, or study completion by the sponsor.  
3.7. 
Discontinuation From the Study Treatment or From the Study  
3.7.1. 
Patient Discontinuation From Study Treatment  
Patients have the right to discontinue study treatment at any time for any reason. In addition, the 
investigator has the right to discontinue a patient from study treatment at any time. Patients who 
discontinue from study treatment for reasons other than PD should be followed for an assessment 
of antitumor activity (Section 7.6), safety (Section 7.5) and survival (Section 3.6), if possible. 
If the decision to discontinue from study treatment is made, both study drugs should be 
discontinued.  
The primary reason for discontinuation from the study treatment should be documented on the 
appropriate electronic case report form (eCRF). Patients may discontinue from study treatment 
for reasons that include, but are not limited to, the following: 


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• Radiographic PD per RECIST v1.1 
• Adverse event 
• Patient decision 
• Pregnancy 
• Any medical condition that the investigator or sponsor determines may jeopardize the 
patient’s safety, if he or she were to continue the study treatment 
• Use of any concurrent anticancer therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents [including Chinese (or other 
country) herbal medicine and Chinese (or other country) patent medicines] for the 
treatment of cancer) (Section 6.3) 
• Patient noncompliance 
Investigative site staff should first counsel patients who are significantly 
noncompliant (eg, missing 2 treatment cycles) on the importance of study drug 
compliance and drug accountability. The investigator may, in consultation with the 
medical monitor, discontinue patients from treatment if they are consistently 
noncompliant. 
3.7.2. 
Patient Discontinuation From Study (End of Study for an Individual Patient)  
Patients may discontinue from the study for reasons that include, but are not limited to, the 
following:  
• Patient withdrawal of consent 
• Death 
• Loss to follow up 
• Patients have completed all study assessments 
3.8. 
End of Study  
The end of study is defined as the timepoint when the final data point is collected from the last 
patient in the study. This is when the last patient dies, withdraws consent, completes all study 
assessments, or is lost to follow up. Alternatively, the end of study is when the sponsor decides 
to terminate the study. 
The sponsor has the right to terminate this study at any time. Reasons for terminating the study 
early may include, but are not limited to, the following: 
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients 
• Overall patient enrollment is unsatisfactory 
The sponsor will notify each investigator if a decision is made to terminate the study. Should this 
be necessary, prematurely discontinued patients should be seen as soon as possible for an EOT 
Visit (within 7 days).  


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The investigators may be informed of additional procedures to be followed to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs) of the early termination of the study. 
At the end of study, any patients who, in the opinion of the investigator, continue to benefit from 
study drugs at study termination, will be offered the option to continue the study drug(s) in a 
company-sponsored clinical trial (if available in that patient’s country) or patient supply 
treatment program until it is commercially available in the country of the patient’s residence. 
The sponsor has the right to close a site at any time. The decision will be communicated to the 
site in advance. 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 
• GCP noncompliance 
• Study activity is completed (ie, all patients have completed all scheduled study 
procedures and all obligations have been fulfilled.) 


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4. 
STUDY POPULATION  
The specific eligibility criteria for selection of patients are provided in Section 4.1 and 
Section 4.2. The sponsor will not grant any eligibility waivers. 
4.1. 
Inclusion Criteria  
Each patient eligible to participate in this study must meet all the following criteria 
1. Able to provide written informed consent and can understand and agree to comply with 
the requirements of the study and the schedule of assessments. 
2. Age ≥ 18 years on the day of signing the informed consent form (or the legal age of 
consent in the jurisdiction in which the study is taking place). 
3. Histologically confirmed diagnosis of ESCC. 
4. Have PD during or after first-line of systemic treatment for unresectable, locally 
advanced, recurrent or metastatic ESCC (Appendix 2).  
a. Patients with PD that occurs during treatment or within ≤ 6 months (180 days) 
after cessation of neoadjuvant/adjuvant treatment (chemotherapy or 
chemoradiotherapy) using standard of care agents are eligible if all other criteria 
are met.  
b. A line of treatment begins with the administration of the first agent in a regimen 
and ends with PD. Regimen might be changed due to toxicities/intolerability but 
the changed regimen will not constitute a new line of therapy.  
c. Patients who can’t tolerate the most recent regimen due to Grade 4 hematologic 
toxicity or Grade 3 or 4 non-hematologic toxicity may also be eligible. 
5. Have measurable disease as assessed by RECIST v1.1.  
Note: A lesion in an area subjected to prior locoregional therapy, including previous 
radiotherapy, is not considered measurable unless there has been demonstrated 
progression in the lesion as defined by RECIST v1.1 since the therapy. 
6. Have confirmed PD-L1 TAP ≥ 10% in tumor tissues tested by the central lab.  
Note: Patients must submit qualified archival tumor tissue (FFPE block containing tumor 
[preferred] or approximately 15 [≥ 6] unstained slides) with an associated pathology 
report, or agree to a tumor biopsy for determination of PD-L1 expression and other 
biomarker analyses (fresh tumor biopsies are strongly recommended at baseline in 
patients with readily accessible tumor lesions and who consent to the biopsies). If no 
archival samples are available, a fresh tumor biopsy at baseline is mandatory.  
PD-L1 expression will be assessed centrally. PD-L1 TAP ≥ 10% is determined using the 
VENTANA PD‑L1 (SP263) Assay.  
Note: The TAP score is defined as the total percentage of the tumor area (tumor and any 
desmoplastic stroma) covered by tumor cells with PD-L1 membrane staining at any 
intensity and tumor-associated immune cells with PD-L1 staining at any intensity, as 
visually estimated. 
7. ECOG PS score of 0 or 1. 


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8. Life expectancy of ≥ 12 weeks. 
9. Patient must have adequate organ function as indicated by the following screening 
laboratory values obtained ≤ 7 days before randomization: 
a. Patients must not have required blood transfusion or growth factor support 
≤ 14 days before sample collection at screening for the following: 
i. 
Absolute neutrophil count ≥ 1.5 × 109/L 
ii. 
Platelets ≥ 75 × 109/L  
iii. 
Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L  
b. Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or estimated glomerular 
filtration rate ≥ 60 mL/min/1.73 m2 using the Chronic Kidney Disease 
Epidemiology Collaboration equation (Appendix 11). 
c. Serum total bilirubin ≤ 1.5 × ULN (total bilirubin must be < 3 × ULN for patients 
with Gilbert syndrome). 
d. AST and ALT ≤ 2.5 × ULN or ≤ 5 × ULN if hepatic metastases are present. 
10. Females of childbearing potential must be willing to use a highly effective method of 
birth control for the duration of the study, and for ≥ 120 days after the last dose of study 
drug, and they must have a negative urine or serum pregnancy test ≤ 7 days before 
randomization (see Appendix 6).  
11.  Nonsterile males must be willing to use a highly effective method of birth control for the 
duration of the study and for ≥ 120 days after the last dose of study drugs. 
a. A sterile male is defined as one for whom azoospermia has been previously 
demonstrated in a semen sample examination as definitive evidence of infertility. 
b. Males with known “low sperm counts” (consistent with “subfertility”) are not to 
be considered sterile for purposes of this study. 
4.2. 
Exclusion Criteria  
Patients who meet any of the following criteria are not eligible to enroll: 
1. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, TIGIT or any other antibody or 
drug specifically targeting T-cell costimulation or checkpoint pathways. 
2. Prior randomization in a tislelizumab or ociperlimab study, regardless of the treatment 
arm, until the primary and key secondary endpoints of the study have read out. 
3. Patients with evidence of fistula (either esophageal/bronchial or esophageal/aorta). 
4. Evidence of complete esophageal obstruction not amenable to treatment. 
5. Active leptomeningeal disease or uncontrolled, untreated brain metastasis.  
Note: Patients with a history of treated and, at the time of screening, stable central 
nervous system (CNS) metastases are eligible, provided that they meet all the following: 
a. Brain imaging at screening shows no evidence of PD, is clinically stable for at 
least 2 weeks and have no evidence of new brain metastases. 


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b. Have measurable and/or evaluable disease outside the CNS. 
c. No ongoing requirement for corticosteroids as therapy for CNS disease; is off 
steroids for ≥ 3 days before randomization; anticonvulsants at a stable dose are 
allowed. 
d. No stereotactic radiation or whole-brain radiation within 14 days before 
randomization. 
6. Active autoimmune diseases or history of autoimmune diseases that may relapse (see 
Appendix 5). 
Note: Patients with the following diseases are not excluded and may proceed to further 
screening: 
a. Controlled type I diabetes. 
b. Hypothyroidism (provided it is managed with hormone replacement therapy 
only). 
c. Controlled celiac disease. 
d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia). 
e. Any other disease that has resolved and is not expected to recur in the absence of 
external triggering factors. 
7. Any active malignancy ≤ 2 years before randomization except for the specific cancer 
under investigation in this study and any locally recurring cancer that has been treated 
curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, 
carcinoma in situ of the cervix or breast). 
8. Any condition that requires systemic treatment with either corticosteroids (> 10 mg daily 
of prednisone or equivalent) or other immunosuppressive medication ≤ 14 days before 
randomization. 
Note: Patients who are currently or have previously been on any of the following steroid 
regimens are not excluded: 
a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent). 
b. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal 
systemic absorption. 
c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for 
contrast dye allergy) or for the treatment of a non-autoimmune condition (eg, 
delayed-type hypersensitivity reaction caused by contact allergen). 
9. Uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, sodium, or 
corrected calcium despite standard medical management or ≥ Grade 3 hypoalbuminemia 
≤ 14 days before randomization. 
Note: If corrected calcium is not reported in a laboratory report, it is required to calculate 
corrected calcium irrespective of the presence of hypoalbuminemia at screening. Please 
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laboratory unit used (mmol/L or mg/dL). A web-based formula is available via 
https://www.mdapp.co/hypoalbuminemia-corrected-calcium-calculator-103/  
• Corrected Calcium (in mmol/L) = Serum Calcium (in mmol/L) + 
0.02 x (40 – Albumin [in g/L]) or  
• Corrected Calcium (in mg/dL) = Serum Calcium (in mg/dL) + 0.8 x (4 – Albumin [in 
g/dL])  
10. Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent 
drainage (recurrence within 2 weeks after intervention). 
11. History of interstitial lung disease, noninfectious pneumonitis or uncontrolled lung 
diseases including pulmonary fibrosis, acute lung diseases, etc.  
Note: Patients with significantly impaired pulmonary function, or who require 
supplemental oxygen at baseline must undergo an assessment of pulmonary function at 
screening. 
12. Infection (including tuberculosis infection, etc) that requires systemic antibacterial, 
antifungal or antiviral therapy within 14 days before randomization or patients who tested 
positive for COVID-19 antigen by a licensed test during screening. 
Note: Antiviral therapy is permitted for patients who have chronic hepatitis B virus 
(HBV) infection. 
13. Untreated chronic hepatitis B or chronic HBV carriers with HBV DNA > 500 IU/mL 
(or > 2500 copies/mL) at screening. 
Note: Patients who are inactive hepatitis B surface antigen (HBsAg) carriers, or who have 
treated and stable hepatitis B (HBV DNA < 500 IU/mL or < 2500 copies/mL) can be 
enrolled. Patients with detectable HBsAg or detectable HBV DNA should be managed 
per treatment guidelines. Patients receiving antivirals at Screening should have been 
treated for > 2 weeks before randomization. 
14. Patients with active hepatitis C. 
Note: Patients with a negative HCV antibody test at screening or positive HCV antibody 
test followed by a negative HCV RNA test at screening are eligible. The HCV RNA test 
will be performed only for patients who test positive for HCV antibody. Patients 
receiving antivirals at screening should have been treated for > 2 weeks before 
randomization. 
15. Known history of human immunodeficiency virus (HIV) infection. 
16. Any major surgical procedure ≤ 28 days before randomization.  
Note: Patients must have recovered adequately from the toxicity and/or complications 
from the intervention before randomization if any major surgical procedure was 
performed > 28 days before randomization. 
17. Prior allogeneic stem cell transplantation or organ transplantation. 
18. Any of the following cardiovascular risk factors: 
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of 
daily living, ≤ 28 days before randomization. 
b. Pulmonary embolism ≤ 28 days before randomization. 
c. Any history of acute myocardial infarction ≤ 6 months before randomization. 


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d. Any history of heart failure meeting New York Heart Association (NYHA) 
Classification III or IV (Appendix 7) ≤ 6 months before randomization. 
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before 
randomization. 
f. Any history of cerebrovascular accident ≤ 6 months before randomization. 
g. Uncontrolled hypertension that cannot be managed by standard antihypertension 
medications ≤ 28 days before randomization. 
Note: For France only, specify: Uncontrolled hypertension is defined as systolic 
pressure ≥ 140 mmHg or diastolic pressure ≥ 90 mmHg on repeated 
measurements. 
h. Any episode of syncope or seizure ≤ 28 days before randomization. 
19. A history of severe hypersensitivity reactions to other monoclonal antibodies. 
20. Has received any chemotherapy, immunotherapy (eg, interleukin, interferon, thymosin, 
etc) or any investigational therapies within 14 days or 5 half-lives (whichever is longer) 
before the first dose of study drug. Or has received palliative radiation treatment or other 
local regional therapies within 14 days before the first dose of study drug. 
21. Patients with toxicities (as a result of prior anticancer therapy) that have not recovered to 
≤Grade 2 or stabilized, except for AEs not considered a likely safety risk (eg, alopecia, 
neuropathy, and specific laboratory abnormalities). 
22. Has received a live vaccine ≤ 28 days before randomization. 
Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. 
Intranasal vaccines are live vaccines and are not allowed. 
23. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug 
abuse or dependence that will be unfavorable for the administration of study drugs, or 
affect the explanation of drug toxicity or AEs, or result in insufficient or impaired 
compliance with study conduct. 
24. Women who are pregnant or breastfeeding. 
25. Concurrent participation in another therapeutic clinical study. 
Note: Concurrent participation in observational or noninterventional studies is allowed. 
In addition, patients who have completed active treatment in a clinical study and are in 
the follow-up period can be enrolled in this study. 
 


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5. 
STUDY TREATMENT  
5.1. 
Formulation, Packaging, and Handling  
5.1.1. 
Ociperlimab  
Ociperlimab is a monoclonal antibody formulated for intravenous infusion in a single-use vial 
(20 mL glass vial, USP type I) containing a total of 200 mg antibody in 10 mL (or 300 mg 
antibody in 15 mL) of buffered isotonic solution. Ociperlimab has been aseptically filled in 
single-use vials with a Flurotec-coated butyl rubber stopper and an aluminum cap. Each vial is 
packaged into a single-carton box. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature and conditions specified on the label. Shaking 
should be avoided. 
Refer to the Pharmacy Manual for details regarding intravenous administration, accountability, 
and disposal. Refer to the Ociperlimab Investigator’s Brochure for other details regarding 
ociperlimab. 
5.1.2. 
Tislelizumab  
Tislelizumab is a monoclonal antibody formulated for intravenous infusion in a single-use vial 
(20R glass, USP type I), containing a total of 100 mg of antibody in 10 mL of isotonic solution. 
Tislelizumab has been aseptically filled in single-use vials with a Flurotec-coated butyl rubber 
stopper and an aluminum cap. Each vial is packaged into a single-carton box. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
The study drug must be kept at the temperature and conditions specified on the label. Shaking 
should be avoided. 
Refer to the Pharmacy Manual for details regarding intravenous administration, accountability, 
and disposal. Refer to the Tislelizumab Investigator’s Brochure for other details regarding 
tislelizumab. 
5.1.3. 
Matched Placebo  
All personnel at the study sites and all patients will be blinded to study treatment. 
Ociperlimab placebo is a sterile, preservative-free solution for infusion formulated in the same 
buffer as ociperlimab active drug. All excipients used for the manufacture of the placebo are of 
pharmacopeial grade. No animal-derived components are used in the manufacture of placebo. 
The placebo will be provided in a single-use vial (20R glass, USP type I), containing 10 mL (or 
15 mL) of isotonic solution. These single-use vials contain a Flurotec-coated butyl rubber 
stopper and an aluminum cap. Each vial is packaged into a single carton box.  
The contents of the label will be in accordance with all applicable local regulatory requirements. 
Refer to the Pharmacy Manual for details regarding intravenous administration, accountability, 
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5.2. 
Dosage, Administration, and Compliance  
Planned dosage and dosing frequency for tislelizumab plus ociperlimab (Arm A) and 
tislelizumab plus placebo (Arm B) are presented in Table 3.  
The first dose of study drugs is to be administered within 2 business days after randomization. 
The initial infusion (Day 1, Cycle 1 and Cycle 2) will be delivered over 60 minutes for each dose 
of tislelizumab, ociperlimab, and placebo; if this is well tolerated, then the subsequent infusions 
of each drug may be administered over 30 minutes, which is the shortest period permissible for 
infusion (see Table 4).  
Accurate records of all study drugs received, dispensed, returned, and disposed of should be 
maintained in the site’s Drug Inventory Log. Refer to the Pharmacy Manual for details of study 
drug management, drug preparation, storage, and administration.  
Table 3: 
Planned Dose, Frequency of Administration, and Route of Administration 
for Study Drugs  
Study drugs 
Dose 
Timing of Administration 
Route of 
Administration 
Duration of 
Treatment 
Ociperlimab 
900 mg  
Day 1 of each 21-day cycle 
Intravenous 
Refer to Section 3.4.  
Tislelizumab 200 mg  
Day 1 of each 21-day cycle 
Intravenous 
Refer to Section 3.4.  
Placebo 
N/A 
Day 1 of each 21-day cycle 
Intravenous 
Refer to Section 3.4.  
Table 4: 
Administration of Study Drugs and Monitoring Time 
Cycle 
Tislelizumab Plus Ociperlimab/Tislelizumab Plus Placebo  
Day 1, Cycle 1 and 
Cycle 2 
Tislelizumab infusion over 60 (± 5) minutes followed by ociperlimab 
(Arm A) or placebo (Arm B) infusion over 60 (± 5) minutes 
Patient monitoring for ≥ 120 minutes 
Day 1, Cycle 3 
onwards 
Tislelizumab infusion over 30 (± 5) minutes followed by ociperlimab 
(Arm A) or placebo (Arm B) infusion over 30 (± 5) minutes 
Patient monitoring for ≥ 30 minutes 
Patients will receive tislelizumab 200 mg on Day 1 of each 21-day cycle (ie, once every 3 weeks) 
followed by the administration of ociperlimab 900 mg (Arm A) or placebo (Arm B). The study 
drugs must be administered by intravenous infusion through an intravenous line containing a 
sterile, nonpyrogenic, low-protein-binding 0.2- or 0.22-micron in-line or add-on filter. Specific 
instructions for product preparation and administration are provided in the Pharmacy Manual. 
Use of a volumetric pump is recommended to control the infusion speed and to avoid potential 
infusion reactions associated with too rapid administration. The pump may not be needed if the 
infusion speed is controlled through alternative means and is consistent with approved 
institutional procedures.  
At the end of the infusion period, flush the line with enough normal saline to make sure that all 
of the study drugs are administered to the patient. 


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As a routine precaution, after infusion of the study drugs on Day 1 of Cycle 1 and Cycle 2, 
patients must be monitored for ≥ 120 minutes afterward in an area with resuscitation equipment 
and emergency agents. From Cycle 3 onward, a ≥ 30‑minute monitoring period is required in an 
area with resuscitation equipment and emergency agents. 
The study drugs must not be concurrently administered with any other drug.  
All patients will be monitored continuously for AEs. Treatment modifications (eg, dose delay, 
interruption or discontinuation) will be based on specific laboratory and AE criteria, as described 
in Section 5.5. Guidelines for dose modification, treatment interruption, or discontinuation and 
for managing imAEs and infusion-related reactions are provided in Section 8.7 and Appendix 12.  
5.3. 
Incorrect Administration or Overdose  
Any incorrect administration of ociperlimab or overdose of tislelizumab (defined as ≥ 600 mg in 
a 24-hour period) should be noted in the patient’s chart and on the appropriate eCRF. 
AEs associated with an incorrect administration or overdose of study drugs will be recorded on 
the AE eCRF. Any SAEs associated with an incorrect administration or overdose must be 
reported within 24 hours of awareness via the SAE reporting process as described in 
Section 8.6.2. Supportive-care measures should be administered as appropriate. 
5.4. 
Investigational Medicinal Product Accountability  
The investigational medicinal products (IMPs) required for completion of this study 
(ociperlimab, tislelizumab, and ociperlimab placebo) will be provided by the sponsor. The 
investigational site will acknowledge receipt of the IMPs. Any damaged shipments will be 
replaced.  
Accurate records of all IMPs received, dispensed, returned, and disposed of should be recorded 
on the site’s Drug Inventory Log. Refer to the Pharmacy Manual for details on managing IMPs.  
5.5. 
Dose Delay or Modification  
Every effort should be made to administer the study drugs according to the planned dose and 
schedule. In the event of significant toxicities, dosing may be delayed and/or interrupted based 
on the guidelines provided below. Reasons for dose interruptions or delays, the supportive 
measures taken, and the outcome will be documented in the patient's chart and recorded in the 
eCRF. 
Guidelines for treatment modification or discontinuation as well as the management of 
infusion-related reactions are provided in Section 8.7 and Appendix 12.  
For AEs that are assessed as related to tislelizumab and/or ociperlimab, the following general 
guidance should be followed unless otherwise specified: 
• AEs ≤ Grade 2: Maintain dose level. 
• AEs of Grade 3: Hold dose until resolved to ≤ Grade 1 or baseline except for alopecia 
or AEs that, in the opinion of the investigator, are not considered a safety risk for the 
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• AEs of Grade 4: Permanent discontinuation of the patient from the study. Exceptions 
may be considered following consultation with the medical monitor. 
5.5.1. 
Dose Modifications for Study Drugs  
No dose reduction is allowed for any of the 3 study drugs in this study. 
A dose interruption is an interruption of an infusion that has begun. A dose delay is a deviation 
from prescribed dosing schedule (ie, the drug is withheld after the visit window).  
If a dose delay is required, both study drugs are to be delayed (ie, tislelizumab and ociperlimab 
or tislelizumab and placebo must both be delayed and restarted at the same time if applicable). 
Exceptions may be considered after consultation between the investigator and the medical 
monitor. 
If treatment is delayed due to TEAEs, treatment may resume only after the AEs have returned to 
baseline or ≤ Grade 1 severity, excluding alopecia or any AE that, in the opinion of the 
investigator, are not considered a safety risk to the patient. If a treatment delay is due to 
worsening of hematologic or biochemical parameters, the frequency of relevant blood tests 
should be increased as clinically indicated. 
In general, dose delays for reasons other than management of AEs are prohibited. A dose delay 
of ≤ 12 weeks is allowed under the following guidance and at the discretion of the investigator 
after consultation with the medical monitor or designee. 
If a dose is delayed for the study drugs for ≤ 10 days during a planned dosing cycle (eg, Cycle 3 
Day 1), the drugs should be administered at the end of the delay. If the delay is > 10 days, the 
patient should skip the study drugs. The study drugs will be administered on Day 1 of the next 
planned cycle (eg, Cycle 4 Day 1). 
If treatment-related AEs are persistent without any improvement for more than 12 weeks, 
permanent discontinuation of the study drugs should be considered. In this situation, both 
assigned study drugs should be discontinued because the causality may not be distinguished from 
one study drug to the other.  
If the patient recovers from the treatment-related AE after 12 weeks, reinitiation of study drugs is 
permitted only in patients who are deemed to be deriving clinical benefit per the opinion of the 
investigator after agreement between the investigator and the medical monitor. 
Management guidelines for imAEs and infusion-related reactions in patients are presented in 
Section 8.7 and Appendix 12, respectively. 
The tumor assessment schedule will not be altered even if the administration of study drugs is 
delayed.  
5.6. 
Blinding  
This is a randomized, investigator- and patient-blinded, sponsor-unblinded, placebo-controlled 
Phase 2 study. Patients will be randomized to receive tislelizumab plus ociperlimab versus 
tislelizumab plus placebo. Patients, investigators, and site staff will remain blinded to study 
treatments but the sponsor will remain unblinded. 


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The following actions should be taken in case of unblinding: 
• Emergency unblinding  
Emergency unblinding for AEs may be performed through an Interactive Web Response 
System. 
In an emergency, the investigator has the sole responsibility for determining if unblinding of 
a patient’s treatment assignment is warranted. Patient safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the medical monitor before 
unblinding a patient’s treatment assignment unless doing so could delay emergency treatment 
of the patient. If a patient’s treatment assignment is unblinded, the sponsor must be notified 
immediately. 
• Inadvertent unblinding  
Every effort will be made to blind both the patient and the investigator to the identity of 
ociperlimab or placebo, but the inadvertent unblinding of a patient may occur. If an 
investigator, site personnel performing assessments, or the patient is unblinded, the 
unblinding will not be sufficient cause (in and of itself) for that patient to be discontinued 
from study therapy or excluded from any safety or efficacy analyses. 
Additionally, there may be ethical reasons to have the patient remain on the study treatment. 
For patients to continue on study treatment in the event of unblinding, the investigator must 
obtain specific approval from the medical monitor for the patient to continue in the study. 


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6. 
PRIOR AND CONCOMITANT THERAPY  
6.1. 
Prior Therapy  
The exclusion criteria (Section 4.2) specify that patients should not have received prior therapies 
targeting PD-1, PD-L1, PD-L2, TIGIT, T-cell costimulation or checkpoint pathways, or 
chemotherapy, immunotherapy (eg, interleukin, interferon, or thymosin), or investigational 
therapy within 14 days or 5 half-lives (whichever is longer) before the first dose of study drugs. 
6.2. 
Permitted Concomitant Medications/Procedures  
Unless noted otherwise, most concomitant medications and therapies are allowed at the 
discretion of the investigator if they are deemed necessary and are in keeping with local 
standards of medical care for supportive care (eg, antiemetics, antidiarrheals, hematopoietic 
growth factors, red blood cell/platelet transfusions) and in a patient’s interest. Opiates and other 
medication required for palliative management of patients are allowed. Patients must notify the 
investigator of all concurrent medications used during the study.  
All concomitant medications will be recorded on the eCRF, including all prescription and 
over-the-counter medicines, herbal supplements, and intravenous medications and fluids.  
Bisphosphonates and receptor activator of NF-kB ligand (RANKL) inhibitors are allowed for 
bone metastases if initiated before enrollment and at a stable dose. Bisphosphonates are 
permitted during the study for a nonmalignant indication. Use of potentially hepatotoxic drugs in 
patients who have impaired hepatic function is allowed but should be carefully monitored. 
6.2.1. 
Systemic Corticosteroids  
Systemic corticosteroids administered for the control of imAEs must be tapered gradually (see 
Appendix 12) and must be administered at nonimmunosuppressive doses (≤ 10 mg/day of 
prednisone or equivalent) before the next administration of the study drugs. The short-term use 
of steroids as prophylactic treatments (eg, patients with contrast allergies to diagnostic imaging 
contrast dyes) is permitted.  
6.2.2. 
Hepatitis B Treatment  
Management of prophylactic antiviral therapy for patients with inactive, treated, and stable 
hepatitis B (HBV DNA < 500 IU/mL) is at the discretion of the investigator as aligned with local 
guidance. Such medications must be documented in the patient’s chart and recorded in the eCRF. 
Patients receiving antivirals at screening should be treated for > 2 weeks before enrollment and 
continue treatment during the study and for 6 months after study drug discontinuation. 
6.2.3. 
Radiation Therapy  
Palliative (limited-field) radiation therapy is permitted, but only for pain control or prophylaxis 
of bone fracture to sites of bone disease present at baseline if the following criteria are met: 
• Repeat imaging demonstrates no new sites of bone metastases; 
• The lesion being considered for palliative radiation is not a target lesion per 
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• The case is discussed with the medical monitor and he/she agrees that the conditions 
required to receive palliative radiation are met. 
Additionally, palliative radiation or other focally ablative therapy for other nontarget sites of the 
disease is permitted if clinically indicated per the investigator’s discretion and after consultation 
with the medical monitor. Whenever possible, these patients should have a tumor assessment of 
the lesion(s) before receiving the radiation therapy to rule out PD. It is not required to withhold 
study drugs during palliative radiotherapy. 
6.2.4. 
COVID-19 Vaccines  
Vaccines for COVID-19 are allowed except for any live vaccine that may be developed. It is 
recommended to avoid COVID-19 vaccination within 72 hours before or after study drug 
administration during the first 2 treatment cycles, and within 24 hours before or after study drug 
administration thereafter (ie, from Cycle 3 onwards). 
Vaccinations are considered a concomitant medication and hence should be entered on the eCRF. 
Instead of generic language (eg, “COVID-19 vaccination”), the specific COVID-19 vaccine 
should be recorded, mRNA-1273 vaccine (Moderna), BioNTech vaccine (Pfizer), etc. 
6.3. 
Prohibited Concomitant Medications/Procedures  
The following medications are prohibited: 
• Any concurrent anticancer therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, or standard or investigational agents including Chinese [or other 
country] herbal medicine and Chinese [or other country] patent medicines for the 
treatment of cancer [regardless of cancer type]) ≤14 days (or ≤5 half-lives, whichever 
is longer) before the first dose of study drugs and during the study.  
• Live vaccines within 28 days before the first dose of study drugs and 60 days after the 
last dose of study drugs. 
• Herbal remedies with immune-stimulating properties (eg, mistletoe extract) or that 
are known to potentially interfere with liver or other major organ functions 
(eg, hypericin) within 14 days (or within 5 half-lives, whichever is longer) before the 
first dose of study drugs and during the study. Patients must notify the investigator of 
all herbal remedies used during the study.  
6.4. 
Restricted Concomitant Medications/Procedures  
The following medications are restricted during the study: 
• Immunosuppressive agents (except to treat a drug-related AE). 
• Systemic corticosteroids > 10 mg daily (prednisone or equivalent), except to treat or 
control a drug-related AE (per protocol) or for short-term use as prophylactic 
treatment. 
• Patients should not abuse alcohol or other drugs during the study.  


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• Use of potentially hepatotoxic drugs in patients with impaired hepatic function should 
be carefully monitored. 
• Radiation therapy is not allowed, except for palliative radiation therapy described in 
Section 6.2.3.  
6.5. 
Potential Interactions Between the Study Drugs and Concomitant 
Medications  
Information regarding clinical drug interactions with ociperlimab is not available and no 
dedicated drug-drug interaction studies are planned. However, the potential for drug-drug 
interaction between the study drugs (ociperlimab and tislelizumab) and other drug products is 
very low because ociperlimab and tislelizumab are therapeutic monoclonal antibodies. Because 
ociperlimab and tislelizumab are expected to be degraded into amino acids and recycled into 
other proteins, they unlikely influence drug-metabolizing enzymes or transporters. 


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7. 
STUDY ASSESSMENT AND PROCEDURES  
A table of scheduled study assessments is provided in Appendix 1. Patients will be closely 
monitored for safety and tolerability throughout the study. All assessments must be performed 
and documented in the medical record for each patient. 
Dosing will occur only if the clinical assessment and local laboratory test values (that must be 
available before any dosing) have been reviewed and found to be acceptable per protocol 
guidelines.   
7.1. 
Prescreening  
Patients must undergo examination of PD-L1 expression in tumor tissues by a central laboratory 
within 56 days before randomization. The details for collection, storage, shipment, and analysis 
of tissue block are detailed in the laboratory manual.  
At prescreening period, the following criteria are a prerequisite for the confirmation of 
randomization by the central laboratory:  
• Adult patients (>18 years of age or the legal age of consent in the jurisdiction in 
which the study is taking place) with histologically confirmed diagnosis of ESCC 
with tumor progression during or after first-line systemic treatment for unresectable, 
locally advanced, recurrent or metastatic disease.  
• Mandatory availability for shipment of FFPE, tumor-containing tissue blocks 
(preferred) or approximately 15 (≥ 6) unstained tumor specimen slides from primary 
tumor and/or metastatic site. Information on previous histopathology reports and 
previous molecular analysis (if applicable) is required to accompany the tissue 
samples. Fresh tumor biopsies are strongly recommended at baseline in patients with 
readily accessible tumor lesions and who consent to the biopsies. If archival tumor 
tissues are not available, a fresh tumor biopsy is mandatory at baseline. 
Written informed consent for collection, storage and analysis of tissue block must be obtained 
from the patient according to International Council for Harmonisation (ICH) GCP, and 
national/local regulations. 
7.2. 
Screening Period  
Screening evaluations will be performed ≤ 28 days before randomization. A patient whose tumor 
tissues have PD-L1 TAP ≥ 10% in prescreening and agrees to participate in this study will sign 
the ICF before undergoing any screening assessment. The screening period begins on the first 
day that a screening assessment is conducted. Screening evaluations may be repeated as needed 
within the screening period. The investigator is to assess patient eligibility according to the latest 
screening assessment results. 
Results of standard-of-care tests or examinations performed before informed consent has been 
obtained and ≤ 28 days before randomization may be used for the purposes of screening rather 
than repeating the standard-of-care tests unless otherwise indicated. 
Procedures conducted only during the Screening Visit are described in this section. For the 
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study, refer to Safety Assessments (Section 7.5), Tumor and Response Evaluations (Section 7.6), 
PK and ADA Assessments (Section 7.7), and Tumor Tissue and Biomarker Assessment 
Procedures (Section 7.8). 
Rescreening under limited conditions may be allowed after consultation with the sponsor 
(eg, when a patient’s laboratory result narrowly misses laboratory criterion and it is correctable 
and not due to rapidly deteriorating condition or progression of disease). Rescreening is allowed 
only once.  
7.2.1. 
Informed Consent and Screening Log  
Voluntary, written informed consent for participation in the study must be obtained before any 
study-specific procedures are performed. The ICFs for enrolled patients and for patients who are 
screened but not 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 the first dose of study drugs. 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.  
After obtaining informed consent, study site personnel will access the Interactive Response 
Technology (IRT) system to assign a unique patient number to a potential study participant. 
7.2.2. 
Demographic Data and Medical History  
Demographic data will include age or date of birth, sex, and self-reported race or ethnicity.  
Medical history includes any history of clinically significant disease, surgery, or cancer history; 
reproductive status (ie, of childbearing potential or no childbearing potential); history of alcohol 
consumption and tobacco (ie, never, previous, and current); and all medications (eg, prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by 
the patient within 30 days before the first dose of study drugs.  
Cancer history will include an assessment of prior surgery, prior radiotherapy, and prior drug 
therapy including start and stop dates, best response, and reason for discontinuation. 
Radiographic studies performed before study entry may be collected for review by the 
investigator. 
7.2.3. 
Females of Childbearing Potential and Contraception  
Childbearing potential is defined as having the physiological ability to become pregnant. Refer to 
Appendix 6 for contraception guidelines and definitions of “women of childbearing potential” 
and “women of no childbearing potential.” 


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7.2.4. 
Pulmonary Function Tests  
Patients who are suspected of having or known to have serious and/or severe respiratory 
conditions, or who exhibit significant respiratory symptoms unrelated to the underlying cancer, 
or who have a history of thoracic radiotherapy will undergo pulmonary function testing that may 
include but is not limited to spirometry and assessment of diffusion capacity done during the 
screening period to assist the determination of suitability for the study. 
The test may be repeated as clinically indicated while on study (refer to Appendix 1 for details). 
7.3. 
Enrollment  
7.3.1. 
Confirmation of Eligibility  
The investigator is responsible for ensuring that each patient meets the eligibility criteria for this 
study. All results from the screening procedures and relevant medical history must be available 
before eligibility can be determined. No eligibility waivers will be granted.  
The sponsor’s medical monitor will support the investigator and/or site staff by answering any 
queries or questions relating to protocol eligibility criteria.  
7.3.2. 
Patient Numbering  
After obtaining informed consent, study site personnel will access the IRT system to assign a 
unique patient number to a potential study participant.  
7.3.3. 
Randomization  
Site personnel will access the IRT system to randomize the patient and assign study drugs by 
permuted block stratified randomization. Study treatment must commence within 2 business days 
after randomization and treatment assignment. 
The stratified randomization will be produced, reviewed, and approved by an independent 
statistician. 
7.4. 
Study Drug Dispensation  
Tislelizumab, ociperlimab, and placebo will be dispensed and administered as described in 
Section 5.2.  
7.5. 
Safety Assessment  
7.5.1. 
Vital Signs  
Vital signs will include measurements of body temperature (˚C), pulse rate, respiratory rate, and 
blood pressure (systolic and diastolic). Pulse rate and blood pressure will be measured while the 
patient is in a seated position after resting for 10 minutes. If coinciding with administration of 
study drugs, the patient’s vital signs are required to be recorded within 60 minutes before, 
during, and 30 minutes after the first cycle of study drug administration. For subsequent cycles, 
vital signs will be collected within 60 minutes before study drug infusion and if clinically 
indicated, during and 30 minutes after study drug infusion. Height should only be measured and 


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recorded during screening. Weight will be measured before study drug administration in every 
cycle. 
7.5.2. 
Physical Examinations  
During the Screening Visit, a complete physical examination will be conducted, including 
evaluations of 1) head, eyes, ears, nose, and throat; 2) cardiovascular; 3) dermatological; 
4) musculoskeletal; 5) respiratory; 6) gastrointestinal; and 7) neurological systems. Any 
abnormality identified during screening will be graded according to NCI-CTCAE v5.0 and 
recorded on the eCRF with appropriate disease/condition terms. 
At subsequent visits (and as clinically indicated), limited, symptom-directed physical 
examinations will be performed. New or worsened clinically significant abnormalities are to be 
recorded as AEs on the eCRF. Refer to Section 8.3 regarding AE definitions and reporting and 
follow-up requirements.  
7.5.3. 
Eastern Cooperative Oncology Group Performance Status  
ECOG PS (Appendix 4) will be assessed during the study. 
7.5.4. 
Laboratory Safety Tests  
Local and/or central laboratory assessments of clinical chemistry, hematology, coagulation, and 
urinalysis will be conducted, of which certain elements will be collected as specified in 
Appendix 3. 
If laboratory tests at screening are not performed ≤ 7 days before study drug administration on 
Day 1 of Cycle 1, these tests should be repeated and reviewed before study drug administration. 
After Cycle 1, results are to be reviewed within 48 hours before study drug administration.  
Thyroid assessments will be performed as specified in Appendix 1. 
Details about sample collection and shipment will be provided in a separate instruction manual. 
Investigators should use results from the same local laboratories for assessing eligibility, safety 
monitoring, and dosing decision for each patient.  
7.5.4.1. 
Cardiac Enzyme Monitoring   
Although immune-mediated myocarditis is a rare complication of immune checkpoint inhibitors, 
serum creatine kinase (CK) and CK-MB are monitored in all tislelizumab studies to protect study 
patients and to quantify the risk of muscle inflammation (see Appendix 1 for the blood collection 
schedule and Appendix 12 for guidelines for management of suspected immune-mediated 
myocarditis, respectively).  
CK and CK-MB testing will be implemented for all patients at screening, predose on Day 1 of 
every cycle, the EOT Visit, and the on-site Safety Follow-up Visit (30 days after the last dose). If 
CK-MB fractionation is not available, serum troponins (troponin I and/or T) measurements will 
be performed instead per local guidelines if used consistently throughout the study.  


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7.5.5. 
Electrocardiograms  
The ECG recordings will be obtained during screening, the EOT Visit, the on-site Safety 
Follow-up Visit, and as clinically indicated.  
For safety monitoring purposes, the investigator must review, sign, and date all ECG tracings. 
Paper or electronic copies of ECG tracings will be kept as part of the patient’s permanent study 
file at the site. 
The patient should rest in semirecumbent supine position for ≥ 10 minutes in the absence of 
environmental distractions that may induce changes in heart rate (eg, television, radio, 
conversation, etc) before each ECG collection. 
7.5.6. 
Adverse Events  
AEs will be graded and recorded throughout the study according to NCI-CTCAE v5.0. 
Characterization of toxicities will include severity, duration, and time to onset.  
All AEs, including SAEs, will be collected as described in Section 8.3.4. 
7.5.7. 
Hepatitis B and C Testing  
Testing will be performed by a central laboratory and/or the local laboratory at screening (and as 
clinically indicated) and will include HBV/HCV serology (HBsAg, hepatitis B surface antibody 
[HBsAb], hepatitis B core antibody [HBcAb], and HCV antibody) and viral load assessment 
(HBV DNA and HCV RNA), which will be assessed only when HBsAg or HCV antibody is 
positive, respectively. For patients who have detectable HBV DNA at screening, a respective 
viral load test will be performed every 4 cycles (ie, Day 1 of Cycle 5, 9, 13, etc) starting from 
Cycle 5.) 
7.6. 
Tumor and Response Evaluations  
Tumor imaging will be performed ≤ 28 days before randomization. Results of standard-of-care 
tests or examinations performed before obtaining informed consent and ≤ 28 days before 
randomization may be used for the purposes of screening rather than repeating the 
standard-of-care tests. During the study, tumor imaging will be performed approximately every 
6 weeks (± 7 days), from Day 1 of Cycle 1, for the first 54 weeks and every 12 weeks (± 7 days) 
thereafter, based on RECIST v1.1. If a tumor assessment is missed or conducted outside of the 
specified assessment window, all subsequent scans should be conducted according to the planned 
schedule. 
Screening assessments and each subsequent assessment must include computed tomography 
(CT) scans (with oral/intravenous contrast) of the neck, chest, abdomen, and pelvis. If a 
contraindication exists, other modalities can be allowed after consultation with the medical 
monitor (eg, magnetic resonance imaging [MRI], CT without contrast); bone scan or 
positron-emission tomography (PET) is required if clinically indicated. Other known or 
suspected sites of disease must be included in the imaging assessments (brain, etc). For patients 
who are suspected to have CNS metastases, CT/MRI of the head is required at baseline. 
All measurable and evaluable lesions should be assessed and documented at the Screening Visit 
and reassessed at each subsequent tumor evaluation. The same radiographic procedure used to 


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assess disease sites at screening must be used throughout the study (eg, the same contrast 
protocol for CT scans). 
• If a patient is known to have a contraindication to CT contrast media or develops a 
contraindication during the study, a noncontrast CT of the chest plus a 
contrast-enhanced MRI (if possible) of abdomen and pelvis should be performed. 
• If a CT scan for tumor assessment is performed on a PET/CT scanner, the CT 
acquisition must be consistent with the standards of a diagnostic CT scan. 
• Bone scans (Technetium-99m [TC-99m]) or PET should be performed at screening if 
clinically indicated. If bone metastases are present at screening and cannot be seen on 
CT or MRI scans, TC-99m or PET bone scans should be repeated when a CR is 
suspected in target lesion or when progression in bone is suspected. 
• CT scans of the head or extremities should be performed at screening only if 
clinically indicated and should be repeated throughout the study if there is evidence 
of metastatic disease in these regions at screening.  
• At the investigator’s discretion, other methods of assessment of target lesion and 
non-target lesions per RECIST v1.1 may be used. 
Response will be assessed by the investigator and IRC using RECIST v1.1 (see Appendix 13). 
The same evaluator should perform assessments, if possible, to ensure internal consistency 
across visits.  
After first documentation of response (CR or PR), confirmation of tumor response should occur 
at 4 weeks or later after the first response or at the next scheduled assessment timepoint. 
If, at the investigator’s discretion, a patient could continue to benefit from study drugs after PD 
per RECIST v1.1 criteria, the patient may continue the study treatment. The following criteria 
must be met in order to treat patients who may continue to benefit from study treatment after PD:  
• Absence of clinical symptoms and signs of PD (including clinically significantly 
worsening of laboratory values) 
• Stable ECOG PS ≤ 1 
• Absence of rapid PD or of progressive tumor at critical anatomical sites (eg, cord 
compression) that requires urgent alternative medical intervention 
• Investigators must obtain written informed consent for treatment after radiologic 
progression of disease and inform patients that this practice is not considered standard 
in the treatment of cancer. 
The decision to continue study drugs after initial PD must be agreed to by the medical monitor 
and documented in the study records.  
Tumor assessment should continue as planned in patients receiving study drug(s) after initial 
investigator-assessed PD. Tumor assessment in such patients should continue until study 
treatment discontinuation.  
A patient who discontinues study drugs early for reasons other than PD (eg, toxicity) will 
continue to undergo tumor assessments in accordance with the original plan until the patient 


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experiences PD, withdraws consent, is lost to follow-up, dies, or until the study terminates, 
whichever occurs first. 
Tumor assessments must be performed on schedule regardless of whether study treatment has 
been administered or withheld. That is, they should not be adjusted for delays in cycles.  
7.7. 
Pharmacokinetic and Antidrug Antibody Assessments  
Ociperlimab and tislelizumab may elicit an immune response. Patients with signs of any 
potential immune response will be closely monitored. Validated screening and confirmatory 
assays will be employed to detect ADAs at multiple timepoints throughout the study. In addition, 
blood samples will be collected for characterization of ociperlimab and tislelizumab PK at the 
timepoints specified in the Schedule of Assessments (Appendix 1).  
PK and ADA assays of ociperlimab and tislelizumab will be managed through a central 
laboratory. Serum samples will be assayed for ociperlimab and tislelizumab concentrations using 
validated immunoassays. Placebo samples will be collected but not analyzed. 
• ADA assays: serum samples will be tested for the presence of ADAs to ociperlimab 
and tislelizumab using a validated immunoassay 
• PK assays: serum samples will be assayed for ociperlimab and tislelizumab 
concentrations with a validated immunoassay 
Refer to the laboratory manual for instructions regarding sample collection, handling, labeling, 
storage, and shipping of laboratory samples. 
7.8. 
Tumor Tissue and Biomarker Assessment Procedures  
Shipping, storage, and handling of blood as well as archival tumor and/or fresh tumor tissues for 
the assessment of biomarkers will be handled by a central laboratory. Refer to the laboratory 
manual for details of sample handling and the Schedule of Assessments (Appendix 1) for 
timepoints. 
Patients are required to provide tumor tissues (archival tumor tissues [FFPE blocks or 
approximately 15 [≥ 6] freshly cut unstained slides] or fresh biopsy) for biomarker analysis (eg, 
TIGIT, CD226, CD155, CD112 and PD-L1), GEP, TMB/gene mutation/MSI, tumor infiltrating 
immune cells, and GEP signatures before and after study treatment or at PD/reoccurrence, and 
the association between these biomarkers and clinical efficacy, disease status, and resistance. If 
no archival samples are available, a fresh tumor biopsy at baseline is mandatory. Acceptable 
fresh biopsy samples include core needle biopsies for deep tumor tissue or excisional, incisional, 
punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions.  
If clinically feasible, it is highly recommended to obtain a tumor biopsy from accessible tumor 
sites at the EOT Visit for the patients who have confirmed PD, which could be used to explore 
the immune- or tumor-related biomarkers and biological changes that might drive PD or acquired 
resistance to study drugs. If feasible, any follow-up biopsy should, ideally, be taken from the 
same tumor lesion as the baseline biopsy. Written informed consent is required for fresh tumor 
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An optional blood sample will be taken at baseline (predose on Day 1 of Cycle 1), at the time of 
first tumor response (predose on Day 1 of the following cycle) and at the EOT Visit after PD 
(10 mL each timepoint) (Appendix 1) to explore association of blood-based biomarkers with 
response, resistance and prognosis.  
Written informed consent is required for any of the fresh tumor biopsies. Tumor tissue should be 
of good quality in terms of total and viable tumor content. Fine needle aspiration, brushing, cell 
pellets from pleural effusion, and lavage samples are not acceptable. 
7.9. 
Health-Related Quality of Life/Quality of Life  
Patients will be asked to complete the EORTC QLQ-C30, EORTC QLQ-OES18, and EQ-5D-5L 
questionnaires before any clinical activities are performed during on-study clinic visits according 
to the schedule in Appendix 1. The questionnaires will be provided in the patient’s preferred 
language. 
7.10. 
Visit Windows  
All visits must occur within ± 3 days from the scheduled date, unless otherwise noted (see 
Appendix 1). All assessments will be performed on the day of the specified visit unless an 
acceptable time window is specified. Assessments scheduled on the day of study treatment 
administration (Day 1) of each cycle should be performed before any study treatment is given 
unless otherwise noted. Laboratory results must be reviewed before dosing. 
If the timing of a protocol-mandated study visit coincides with a holiday, weekend, or other 
events, the visit should be scheduled for the nearest feasible date (the visit window is provided in 
Appendix 1), with subsequent visits conducted according to the planned schedule every 3 weeks 
from Day 1 of Cycle 1.  
7.11. 
Unscheduled Visits  
Unscheduled visits may be performed at any time at the patient’s or the investigator’s request 
and may include vital signs/physical examination; ECOG PS; AE review; concomitant 
medications and procedure reviews; radiographic assessments; physical examination of liver, 
spleen, and lymph nodes; disease-related constitutional symptoms; and hematology and clinical 
chemistry laboratory assessments. The date and reason for the unscheduled visit must be 
recorded in the source documentation. 
If an unscheduled visit is necessary to assess toxicity or for suspected PD, then diagnostic tests 
may be performed based on the investigator assessment as appropriate, and the results of these 
tests should be entered on the unscheduled visit eCRF. 


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8. 
SAFETY MONITORING AND REPORTING  
The investigator is responsible for the monitoring and documentation of events that meet the 
criteria and definition of an AE or SAE as provided in this protocol. 
8.1. 
Risks Associated With Study Drugs  
8.1.1. 
Risks Associated With Ociperlimab and Tislelizumab  
Ociperlimab and tislelizumab are investigational agents that are currently in clinical 
development. Limited safety data are available in patients, and the full safety profile has not been 
characterized. The following recommendation is based on results from nonclinical and clinical 
studies with tislelizumab and ociperlimab and published data on other molecules within the same 
biologic class. 
The PD-L1/PD-1 pathway is involved in peripheral immune tolerance; therefore, such therapy 
may increase the risk of imAEs, specifically the induction or enhancement of autoimmune 
conditions. AEs observed with anti-PD-1 therapy are presented in Section 8.7.3. 
Ociperlimab-mediated TIGIT inhibition may increase the risk of immune mediated AEs. 
However, no apparent immunotoxicity, or toxicity in general, has been observed in animal 
models treated with ociperlimab. Furthermore, in the absence of activation, peripheral effector T-
cells do not typically express TIGIT, thereby minimizing any potential negative additive effect as 
it relates to peripheral immune tolerance. 
Although most imAEs observed with immunomodulatory agents have been mild and 
self-limiting, such events should be recognized early and treated promptly to avoid potential 
major complications. Suggested workup procedures for suspected imAEs are provided in 
Appendix 12.  
8.1.2. 
Risks Associated With Placebo  
There are no specific risks associated with the placebo.  
8.2. 
General Plan to Manage Safety Concerns  
8.2.1. 
Eligibility Criteria  
Eligibility criteria were selected to guard the safety of patients in this study. Results from the 
nonclinical toxicology studies and clinical data with ociperlimab and tislelizumab, as well as the 
nonclinical/clinical data from other PD-L1/PD-1 inhibitors, were considered. Specifically, 
patients who are at risk for study-emergent active autoimmune diseases or who have a history of 
autoimmune diseases that may relapse, patients who have undergone allogeneic stem cell or 
organ transplantation, and patients who have received a live viral vaccine ≤ 28 days before 
randomization are excluded from the study. Refer to Section 4.2 for the full list of exclusion 
criteria.  


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8.2.2. 
Safety Monitoring Plan  
Safety will be evaluated in this study through the monitoring of all AEs, defined and graded 
according to NCI-CTCAE v5.0. Patients will be assessed for safety (including laboratory values) 
according to the schedule in Appendix 1.  
All enrolled patients will be evaluated clinically and with standard laboratory tests at regular 
intervals during their participation in this study. Safety evaluations will consist of medical 
interviews, recording of AEs (see Table 5), physical examinations, laboratory measurements 
(hematology, clinical chemistry, etc), and other assessments including those listed in 
Appendix 1. In addition, patients will be closely monitored for the development of any signs or 
symptoms of autoimmune conditions or infection. 
At the start of each cycle, study drug(s) will be administered only after clinical laboratory results 
have been reviewed. Administration of study drugs will be performed in a setting where 
emergency medical equipment and staff who are trained to respond to medical emergencies are 
available (for additional information, see Section 5.2).  
Serum samples will be drawn for determination of ADAs to ociperlimab and tislelizumab in all 
randomized patients.  
Investigators are instructed to report all AEs (including pregnancy-related AEs). 
The potential safety issues anticipated in this study, as well as measures intended to avoid or 
minimize such toxicities, are outlined in Section 8.7. 
8.3. 
Adverse Events  
8.3.1. 
Definitions and Reporting  
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
drugs, whether considered related to study drugs or not. 
Examples of AEs include:  
• Worsening of a chronic or intermittent pre-existing condition, including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse 
outcome 
• New conditions detected or diagnosed after study drug administration even though 
the condition might have been present before the start of the study 
• Signs, symptoms, or clinical sequelae of a suspected interaction 
• Signs, symptoms, or clinical sequelae of a suspected overdose of either study drugs or 
a concurrent medication (overdose per se should not be reported as an AE or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory results, and diagnostics reports) relative to 
the AE or SAE. The investigator will then record all relevant information regarding an AE or 
SAE in the eCRF. However, there may be instances when copies of medical records for certain 


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cases are requested by the sponsor. In this instance, all patient identifiers will be obscured on the 
copies of the medical records before submission to the sponsor. 
8.3.2. 
Assessment of Severity  
The investigator will assess the severity of each AE and SAE reported during the study. AEs and 
SAEs should be assessed and graded based upon NCI-CTCAE v5.0. 
Toxicities that are not specified in NCI-CTCAE will be defined as follows: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care, activities of daily living 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death related to AE 
Note: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity 
(for example, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or 
life-threatening [Grade 4]); whereas seriousness is classified by the criteria based on the 
regulatory definitions. Seriousness serves as the guide for defining regulatory reporting 
obligations from the sponsor to applicable regulatory authorities as described in Section 8.6.2. 
8.3.3. 
Assessment of Causality  
The investigator is obligated to assess the relationship between the study drugs and the 
occurrence of each AE or SAE using their best clinical judgement. Alternative causes, such as 
natural history of the underlying diseases, concomitant therapy, and other risk factors, and the 
temporal relationship of the AE or SAE to the study drugs should be considered and investigated. 
The investigator should consult the Tislelizumab Investigator’s Brochure and Ociperlimab 
Investigator’s Brochure in the determination of his/her assessment. 
There may be situations when an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important that the 
investigator always assesses causality for every SAE before transmission of the SAE report to 
the sponsor because the causality assessment is one of the criteria used when determining 
regulatory reporting requirements. The investigator may change his/her opinion of causality after 
considering follow-up information, amending the SAE report accordingly. 
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related.” An AE is considered related if there is “a reasonable possibility” that the AE may 
have been caused by the study drugs (ie, there are facts, evidence, or arguments to suggest 
possible causation). A number of factors should be considered in making this assessment 
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• Temporal relationship of the AE to the administration of study treatment/study 
procedure 
• Whether an alternative etiology has been identified 
• Mechanism of action of the study drugs 
• Biological plausibility 
An AE should be considered “related” to study drugs if any of the following are met; otherwise, 
the event should be assessed as “not related”: 
• There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. 
• There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely. 
• There is some evidence to suggest a causal relationship (eg, the AE occurred within a 
reasonable time after administration of the study drug[s]). However, the influence of 
other factors may have contributed to the AE (eg, the patient’s clinical condition or 
other concomitant AEs). 
8.3.4. 
Follow-up of Adverse Events  
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide further information to the sponsor on the patient’s condition. 
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow-up, or the patient 
withdraws consent. The investigator will ensure that follow-up includes any supplemental 
investigations as may be indicated to elucidate the nature and/or causality of the AE or SAE. 
This may include additional laboratory tests or investigations, histopathological examinations, 
radiographic imaging, or consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the AE or SAE. The investigator is obligated to assist. If a patient dies during participation in the 
study or during a recognized follow-up period, the sponsor will be provided with a copy of any 
postmortem findings, including histopathology. 
New or updated information should be reported to the sponsor according to the SAE instructions 
provided by the sponsor within the time frames outlined in Section 8.6.2. 
8.3.5. 
Laboratory Test Abnormalities  
Abnormal laboratory findings (eg, clinical chemistry, complete blood count, coagulation, or 
urinalysis) or other abnormal assessments (eg, ECGs, x-rays, or vital signs) that are judged by 
the investigator as clinically significant will be recorded as AEs or SAEs. This includes clinically 
significant abnormal laboratory findings or other abnormal assessments that are present at 


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baseline and that worsen significantly during the study. The definition of clinically significant is 
based on the judgement of the investigator. In general, these are the laboratory test abnormalities 
or other abnormal assessments that:  
• are associated with clinical signs or symptoms, or  
• require active medical intervention, or  
• lead to dose interruption or discontinuation, or 
• require close observation, more frequent follow-up assessments, or further diagnostic 
investigation. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome (eg, alkaline 
phosphatase and bilirubin 5 × ULN associated with cholestasis), only the diagnosis (ie, 
cholestasis) should be recorded on the Adverse Event eCRF.  
If the laboratory abnormality can be characterized by a precise clinical term per standard 
definitions, the clinical term should be recorded as the AE. For example, an elevated serum 
potassium level of 7.0 mEq/L (or mmol/L) should be recorded as “hyperkalemia.”  
Observations of the same clinically significant laboratory abnormality from visit to visit should 
not be repeatedly recorded on the Adverse Event eCRF, unless the etiology changes. The initial 
severity of the event should be recorded, and the severity or seriousness should be updated any 
time the event worsens. 
8.4. 
Definition of a Serious Adverse Event  
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE. It does not refer to an AE 
that hypothetically might have caused death if it were more severe. 
• Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the patient was admitted (usually 
involving at least an overnight stay) to the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. 
• Results in disability/incapacity 
Note: The term “disability” means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance, such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle), which may 
interfere with or prevent everyday life functions but do not constitute a substantial 
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• Is a congenital anomaly/birth defect 
• Is considered a significant medical AE by the investigator based on medical 
judgement (eg, may jeopardize the patient or may require medical/surgical 
intervention to prevent the outcomes listed above) 
The following are NOT considered SAEs: 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline 
• Hospitalization for social/convenience considerations 
• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
8.5. 
Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is 
both unexpected (ie, not present in the study drug’s reference safety information [RSI]) and 
meets the definition of an serious adverse drug reaction (SADR), the specificity or severity of 
which is not consistent with those noted in the Tislelizumab Investigator’s Brochure and the 
Ociperlimab Investigator’s Brochure. 
8.6. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events  
8.6.1. 
Adverse Event Reporting Period  
After the ICF has been signed, but before the administration of the study drugs, only SAEs 
should be reported to the sponsor. 
After initiation of study drugs, all AEs and SAEs, regardless of relationship to study drugs, will 
be reported until either 30 days after last dose of study drugs or initiation of subsequent 
anticancer therapy, whichever occurs first. Serious or nonserious imAEs should be reported until 
90 days after the last dose of study drugs, regardless of whether the patient starts a subsequent 
anticancer therapy. All SAEs considered related to the study drug(s) that are brought to the 
attention of the investigator should be reported regardless of time since the last dose of treatment.  
AEs and SAEs should be recorded according to the details in Table 5. For the follow-up period 
for AEs, see Section 8.3.4. For the definition of TEAEs, see Section 9.3.2. 


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Table 5: 
Guidance for Duration of Recording New or Worsening Adverse Events in 
Both Arms  
Event Type 
Record New or Worsening Events That Occur During This Period 
Begin 
End 
SAEsa             
Signing of informed 
consent 
Up to 30 days after last dose, initiation of a 
new anticancer therapy, death, withdrawal of 
consent, or loss to follow-up, whichever 
occurs first 
Nonserious AEs due to PD 
Do not record (see Section 8.6.4) 
All nonserious AEs, 
except those due to PD 
First dose of study drug 
Up to 30 days after last dose, initiation of a 
new anticancer therapy, death, withdrawal of 
consent, or loss to follow-up, whichever 
occurs first 
Immune-mediated AEs 
(serious or nonserious) 
First dose of study drug 
Up to 90 days after last dose (regardless of 
initiation of new anticancer therapy), death, 
withdrawal of consent, or loss to follow-up, 
whichever occurs first 
Abbreviations: AE, adverse event; PD, progressive disease; SAE, serious adverse event. 
a All SAEs considered related to the study drug(s) that are brought to the attention of the investigator should be 
reported regardless of time since the last dose of treatment. 
8.6.2. 
Reporting Serious Adverse Events  
8.6.2.1. 
Prompt Reporting of Serious Adverse Events  
As soon as the investigator determines that an AE meets the protocol definition of an SAE, the 
event must be reported promptly (within 24 hours) to the sponsor or designee as described in 
Table 6. 
Table 6: 
Time Frames and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee  
 
Time Frame 
for Making 
Initial Report 
Documentation 
Method 
Time Frame 
for Making 
Follow-up 
Report 
Documentation 
Method 
Reporting 
Method 
All SAEs 
Within 
24 hours after 
first 
knowledge of 
the AE 
SAE report 
As 
expeditiously 
as possible 
SAE report 
Email or fax 
SAE form or 
pregnancy 
form 
Abbreviations: AE, adverse event; SAE, serious adverse event. 
8.6.2.2. 
Completion and Transmission of the Serious Adverse Event Report  
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours, as outlined above in Section 8.6.2.1. The SAE report 


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should always be completed as thoroughly as possible, including all available details of the 
event, and forwarded to the sponsor or designee within the designated time frames. 
If the investigator does not have all information regarding an SAE, he/she is not to wait to 
receive additional information before notifying the sponsor or designee of the SAE and 
completing the form. The form will be updated when additional information is received. 
The investigator must always provide an assessment of causality for each SAE as described in 
Section 8.3.3. 
The sponsor will provide contact information for SAE receipt. 
8.6.2.3. 
Regulatory Reporting Requirements for Serious Adverse Events  
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 8.6.2.1. The sponsor has a legal responsibility to notify, as appropriate, both 
the local regulatory authority and other regulatory agencies about the safety of a drug under 
clinical investigation. 
The investigator, or other responsible person according to local requirements, will comply with 
the applicable local regulatory requirements related to the reporting of SAEs to regulatory 
authorities and the IRB/IEC. 
All SUSARs (as defined in Section 8.5) will be submitted to all applicable regulatory authorities 
and investigators for ociperlimab and tislelizumab studies. 
When a study center receives an initial or follow-up safety report or other safety information 
(eg, revised Investigator’s Brochure) from the sponsor, the investigator or designated responsible 
person is required to promptly notify his/her IRB or IEC. The investigator should place copies of 
safety reports from the sponsor in the investigator site file. 
8.6.3. 
Eliciting Adverse Events  
The investigator or designee will ask patients about AEs by asking the following standard 
questions: 
• How are you feeling? 
• Have you had any medical problems since your last visit? 
• Have you taken any new medicines since your last visit? 
8.6.4. 
Disease Progression  
PD, which is expected in this study population and measured as an efficacy endpoint, should not 
be recorded as an AE term. Similarly, nonserious AEs that are clearly consistent with the pattern 
of progression of the underlying disease and are considered unequivocally due to PD should not 
be recorded. However, if there is any uncertainty as to whether a nonserious AE is due to PD, it 
should be recorded as an AE. All SAEs and deaths regardless of relatedness to PD should be 
recorded and reported (see Section 8.6.2).  


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8.6.5. 
Deaths  
Death is an outcome and not usually considered an AE. If the only information available is death 
and the cause of death is unknown, then the death is reported as an event (eg, “death,” “death of 
unknown cause,” or “death unexplained”). 
8.6.6. 
Pregnancies  
If a female patient or the partner of a male patient becomes pregnant while receiving study drugs 
or within 120 days after the last dose of study drugs, a pregnancy report form must be completed 
and expeditiously submitted to the sponsor to facilitate outcome follow-up. Information on the 
status of the mother and child will be forwarded to the sponsor. Generally, follow-up will be no 
longer than 6 to 8 weeks after the estimated delivery date. Any premature termination of the 
pregnancy will be reported. 
While pregnancy itself is not considered to be an AE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
An abortion, whether accidental, therapeutic, or spontaneous, should always be reported as an 
SAE. Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
study drugs should be recorded and reported as an SAE. 
8.6.7. 
Expedited Reporting to Health Authorities, Investigators, Institutional Review 
Boards, and Independent Ethics Committees  
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, 
IRBs, and IECs based on applicable legislation. 
To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following reference safety information documents:  
• Tislelizumab Investigator’s Brochure 
• Ociperlimab Investigator’s Brochure 
8.6.8. 
Assessing and Recording Immune-Mediated Adverse Events  
Because treatment with anti-PD-1 or immune checkpoint inhibitors can cause autoimmune 
disorders, AEs considered by the investigator to be immune-mediated (see Section 8.7.3) should 
be classified as imAEs and identified as such on the eCRF AE page until Day 90 after treatment 
discontinuation.  
Investigators should consult the guidance on diagnostic evaluation and management of imAEs, 
which are commonly seen with immune checkpoint inhibitors, in Appendix 12. 
An extensive list of potential imAEs appears in Section 8.7.3, Table 8. All conditions like those 
listed should be evaluated to determine whether they are imAEs based on a similar diagnostic 
process to those reactions that are presented in more detail in Appendix 12. 


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8.6.9. 
Recording Infusion-Related Reactions  
The symptoms of infusion-related reactions may include, but are not limited to, fever, 
chills/rigor, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, 
vomiting, myalgia, dizziness, or hypertension. Severe reactions may include acute respiratory 
distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. Each 
individual sign and symptom of an infusion reaction should be recorded each as a separate AE in 
the eCRF and identified as an infusion-related reaction. Refer to the eCRF completion guidelines 
for details. 
8.7. 
Management of Adverse Events of Special Interest  
As a routine precaution, after infusion of the study drugs on Day 1 of Cycle 1 and Cycle 2, 
patients must be monitored for ≥ 120 minutes afterwards in an area with resuscitation equipment 
and emergency agents. From Cycle 3 onward, at least a 30-minute monitoring period is required 
in an area with resuscitation equipment and emergency agents. 
The management for infusion-related reactions, severe hypersensitivity reactions, and imAEs 
according to the NCI-CTCAE criteria are outlined in the following subsections. 
8.7.1. 
Infusion-Related Reactions  
Patients should be closely monitored for infusion-related reactions. Immediate access to an 
Intensive Care Unit or equivalent environment and appropriate medical therapy (including 
epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen) must be 
available to treat infusion-related reactions. 
Treatment modification for symptoms of infusion-related reactions due to study drugs is 
provided in Table 7. 
Table 7: 
Treatment Modification for Symptoms of Infusion-Related Reactions Due to 
Study Drugs  
NCI-CTCAE Grade 
Treatment Modification for Study Drugs  
Grade 1 - mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease infusion rate by 50%. Any worsening is 
closely monitored. Medical management as 
needed.  
Grade 2 - moderate 
Therapy or infusion interruption indicated but the 
patient responds promptly to symptomatic 
treatment (eg, antihistamines, nonsteroidal 
anti-inflammatory drugs, narcotics, intravenous 
fluids); prophylactic medications indicated for 
≤ 24 hours. 
Stop infusion. Infusion may be resumed at 50% of 
previous rate after infusion-related reactions have 
resolved or decreased to Grade 1 in severity. Any 
worsening is closely monitored. Proper medical 
management should be instituted as described in 
the text that follows this table.  
Grade 3 – severe 
Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms after initial 
Immediately stop the infusion. Proper medical 
management should be instituted as described in 
the text that follows this table. 
The patient should be withdrawn from study drug 
treatment. 


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NCI-CTCAE Grade 
Treatment Modification for Study Drugs  
improvement; hospitalization indicated for 
clinical sequelae. 
Grade 4 – life-threatening 
Life-threatening consequences; urgent 
intervention indicated. 
Immediately stop the infusion. Proper medical 
management should be instituted as described in 
the text that follows this table. 
The patient should be withdrawn from study drug 
treatment. 
Hospitalization is recommended. 
Abbreviations: NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events. 
After the infusion rate has been decreased by 50% or suspended due to an infusion-related 
reaction, it must remain decreased for all subsequent infusions. If the patient has a second 
infusion-related reaction (≥ Grade 2) on the slower infusion rate, the infusion should be 
discontinued and the patient should be withdrawn from assigned study drugs.  
NCI-CTCAE Grade 1 or 2 infusion reactions: Proper medical management should be 
instituted, as indicated per the type of reaction. This includes but is not limited to an 
antihistamine (eg, diphenhydramine or equivalent), antipyretic (eg, paracetamol or equivalent), 
and, if considered indicated, oral or intravenous glucocorticoids, epinephrine, bronchodilators, 
and oxygen. In the next cycle, the patient should receive oral premedication with an 
antihistamine (eg, diphenhydramine or equivalent) and an antipyretic (eg, paracetamol or 
equivalent), and the patient should be closely monitored for clinical signs and symptoms of an 
infusion reaction. 
NCI-CTCAE Grade 3 or 4 infusion reactions: Proper medical management should be 
instituted immediately, as indicated per type and severity of the reaction. This includes but is not 
limited to oral or intravenous antihistamine, antipyretic, glucocorticoids, epinephrine, 
bronchodilators, and oxygen. 
8.7.2. 
Severe Hypersensitivity Reactions and Flu-Like Symptoms  
If hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice as described in the complete guideline for emergency treatment of anaphylactic 
reactions according to the Working Group of the Resuscitation Council (United Kingdom) 
(Soar et al 2008). Patients should be instructed to report any delayed reactions to the investigator 
immediately. 
If a systemic anaphylactic/anaphylactoid reaction occurs, the infusion must be stopped 
immediately and the patient discontinued from the study. Systemic anaphylactic/anaphylactoid 
reactions typically manifest within minutes after the administration of the drug/antigen and are 
characterized by respiratory distress, laryngeal edema, and/or intense bronchospasm, and are 
often followed by vascular collapse or shock without antecedent respiratory difficulty; cutaneous 
manifestations such as pruritus and urticaria with/without edema; and gastrointestinal 
manifestations such as nausea, vomiting, crampy abdominal pain, and diarrhea. 
Epinephrine injection and dexamethasone infusion will be administered to patients if 
hypersensitivity reaction is observed, and then the patient should be placed on monitor 
immediately and an Intensive Care Unit should be alerted for possible transfer if needed. 


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For prophylaxis of flu-like symptoms, a dose of 25 mg indomethacin or a comparable dose of 
nonsteroidal anti-inflammatory drugs (ie, 600 mg ibuprofen, 500 mg naproxen sodium) may be 
administered 2 hours before and 8 hours after the start of each dose of study drug infusion. 
Alternative treatments for fever (ie, paracetamol) may be administered to the patient at the 
discretion of the investigator. 
8.7.3. 
Immune-Mediated Adverse Events  
Immune-mediated AEs are of special interest in this study. If the events listed below or similar 
events occur, the investigator should exclude alternative explanations (eg, combination drugs, 
infectious disease, metabolic, toxin, PD, or other neoplastic causes) with appropriate diagnostic 
tests that may include but are not limited to serologic, immunologic, and histologic (biopsy) data. 
If alternative causes have been ruled out, the AE required the use of systemic steroids, other 
immunosuppressants, or endocrine therapy and is consistent with an immune-mediated 
mechanism of action, the imAE indicator on the eCRF AE page should be checked. 
A list of potential imAEs is shown below in Table 8. All conditions similar to those listed should 
be evaluated in patients to determine whether they are immune-mediated. 
Recommendation for diagnostic evaluation and management of imAEs is based on European 
Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) 
guidelines (Haanen et al 2017; Brahmer et al 2018) and common immune-mediated toxicities are 
detailed in Appendix 12. For any AEs not included in Appendix 12, refer to the ASCO Clinical 
Practice Guideline (Brahmer et al 2018) for further guidance on diagnostic evaluation and 
management of immune-mediated toxicities. 
Table 8: 
Immune-Mediated Adverse Events  
Body System Affected 
Events 
Skin (mild-common) 
pruritus or maculopapular rash; vitiligo 
Skin (moderate) 
follicular or urticarial dermatitis; erythematous/lichenoid rash; Sweet 
syndrome 
Skin (severe-rare) 
full-thickness necrolysis/Stevens-Johnson syndrome 
Gastrointestinal 
colitis (includes diarrhea with abdominal pain or endoscopic/radiographic 
evidence of inflammation); pancreatitis; hepatitis; aminotransferase 
(ALT/AST) elevation; bowel perforation 
Endocrine 
thyroiditis, hypothyroidism, hyperthyroidism; hypophysitis with features of 
hypopituitarism (eg, fatigue, weakness, weight gain); insulin-dependent 
diabetes mellitus; diabetic ketoacidosis; adrenal insufficiency 
Respiratory 
pneumonitis/diffuse alveolitis 
Eye 
episcleritis; conjunctivitis; iritis/uveitis 
Neuromuscular 
arthritis; arthralgia; myalgia; neuropathy; Guillain-Barre syndrome; aseptic 
meningitis; myasthenic syndrome/myasthenia gravis; meningoencephalitis; 
myositis 
Blood 
anemia; leukopenia; thrombocytopenia 


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Body System Affected 
Events 
Renal 
interstitial nephritis; glomerulonephritis; acute renal failure 
Cardiac 
pericarditis; myocarditis; heart failure 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. 
Recommendations for managing imAEs are detailed in Appendix 12. 
If a toxicity does not resolve to ≤ Grade 1 within 12 weeks, study drugs should be discontinued 
after consultation with the sponsor. Patients who experience a recurrence of any event at the 
same or higher severity grade with rechallenge should permanently discontinue treatment. 
 


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9. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION  
The statistical analyses will be performed by the sponsor or designee after the data collection is 
completed and the database is locked and released. Details of the statistical analyses will be 
included in a separate Statistical Analysis Plan (SAP).  
9.1. 
Statistical Analysis  
The following descriptive statistics will be used to summarize the study data on the basis of their 
nature unless otherwise specified: 
• Continuous variables: number of nonmissing observations, mean, standard deviation, 
median, minimum, and maximum  
• Categorical variables: frequencies and percentages 
• Time-to-event variables: the number of nonmissing observations (N), median, 
minimum and maximum. Kaplan-Meier event rates may also be provided if 
applicable for specific time to event variables 
9.1.1. 
Analysis Sets  
The following analysis sets will be used for analysis in this study:  
• The ITT Analysis Set, which includes all randomized patients, will be the primary 
analysis population for all efficacy analyses, including HRQoL analysis. 
• The Safety Analysis Set (SAS), which includes all patients who received ≥ 1 dose of 
study drugs, will be the primary analysis set for safety analyses. 
• The PK Analysis Set, which includes all patients who receive ≥ 1 dose of any 
component of study drugs per the protocol, and for whom any postdose PK data are 
available.  
• The Immunogenicity Analysis Set, which includes all patients who receive ≥ 1 dose 
of any component of study drugs and for whom both baseline antidrug antibody and 
at least 1 postbaseline antidrug antibody result are available. 
9.1.2. 
Patient Disposition  
The number of patients randomized, treated, and discontinued from study drugs and/or study and 
those with critical protocol deviations will be counted. The primary reason for study drug and/or 
the study discontinuation will be summarized according to the categories in the eCRF. The 
end‑of‑study status (alive, dead, withdrew consent or lost to follow-up) at the data cutoff date 
will be summarized using the data from the eCRF. 
Critical protocol deviations will be summarized and listed by each category. 
9.1.3. 
Demographic and Other Baseline Characteristics  
Demographic and other baseline characteristics will be summarized using descriptive statistics in 
the ITT Analysis Set. Continuous variables include age, weight, vital signs, time since initial 
cancer diagnosis, time since advanced/metastatic disease diagnosis, etc. Categorical variables 


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include age (≤ 65 years old and >65 years old), sex, ECOG PS, region/country, race, TNM 
Classification of Malignant Tumors staging, smoking status (never, previous, and current), 
alcohol consumption (never, previous, and current), primary tumor location (cervical, upper, 
middle, and lower), and previous treatment (chemotherapy, radiation therapy, and surgery), 
anatomic locations of metastases, and number of metastatic lesions (≤ 1 site versus ≥ 2 sites), etc.  
9.1.4. 
Prior and Concomitant Medications  
Prior medications will be defined as medications that stopped before the day of the first dose of 
study drugs. Concomitant medications will be defined as medications that 1) started before the 
first dose of study drugs and were continuing at the time of the first dose of study drugs, 
or 2) started on or after the date of the first dose of study drugs up to 30 days after the patient’s 
last dose (as of the on-site Safety Follow-up Visit).   
Concomitant medications will be coded using the World Health Organization Drug Dictionary 
drug codes and further coded to the appropriate Anatomical Therapeutic Chemical code 
indicating therapeutic classification. Prior and concomitant medications will be summarized and 
listed by drug and drug class in the clinical study report (CSR) for this protocol.   
9.2. 
Efficacy Analyses  
The primary endpoint ORR will be tested at a 1-sided alpha of 0.025. If the null hypothesis for 
ORR in the ITT Analysis Set is rejected, the secondary endpoint OS in the ITT Analysis Set will 
be tested.   
9.2.1. 
Primary Efficacy Analysis  
Overall Response Rate by the Investigator’s Review 
ORR will be compared between Arm A and Arm B. Patients with no postbaseline response 
assessment (for any reason) will be considered nonresponders. 
The null hypothesis to be tested is:  
H0: ORR in Arm A ≤ ORR in Arm B 
against the alternative:  
H1: ORR in Arm A > ORR in Arm B 
The statistical significance of the difference in ORR between the 2 treatment arms in the ITT 
Analysis Set will be evaluated using the Cochran-Mantel-Haenszel method, adjusted by the 
selected stratification factors at randomization (ie, ECOG PS score [0 versus 1] and the number 
of organs with metastases [≤1 versus ≥2]). The difference in ORR will be calculated, as will 
the Clopper-Pearson 95% CIs for the ORR within each arm.  
The final analysis of ORR will be performed at approximately 4 months after the last patient is 
randomized.  
 
 


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9.2.2. 
Secondary Efficacy Analysis  
Overall Survival 
OS will be analyzed in the ITT analysis set. In the absence of death, patients will be censored 
either at the date when the patient is last known to be alive or the date of data cutoff, whichever 
comes earlier. A log-rank test adjusted by the selected stratification factors at randomization (ie, 
ECOG PS score [0 versus 1] and the number of organs with metastases [≤1 versus ≥2]) will be 
used to test the differences in OS between the 2 treatment arms. The median OS and the 
cumulative probability of OS at every 3 months, if estimable, will be calculated for each 
treatment arm and presented with 2-sided 95% CIs. Kaplan-Meier survival probabilities over 
time for each arm will be plotted. 
The treatment effect of OS will be estimated by fitting a Cox regression model with the treatment 
arm adjusted by selected stratification factors at randomization (ie, ECOG PS score [0 versus 1] 
and the number of organs with metastases [≤1 versus ≥2]). From this model, the HR of OS will 
be estimated and presented with a 2-sided 95% CI. 
The final analysis of OS will take place when approximately 72 deaths (ie, 60% of the total 
sample size) have been observed.  
Overall Response Rate  
ORR assessed by the IRC per RECIST v1.1 in the ITT Analysis Set will be analyzed similarly to 
the corresponding analysis of ORR assessed by the investigator. The 2-sided 95% CIs for the 
odds ratio and the difference in ORR will be calculated, as will the Clopper-Pearson 95% CIs for 
the ORR within each arm.  
Progression-Free Survival  
PFS based on assessment by the IRC and the investigator per RECIST v1.1 will be analyzed in 
the ITT Analysis Set. The PFS censoring rule will follow the US FDA Guidance for Industry: 
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (FDA 2018). The 
median PFS and the cumulative probability of PFS at every 3 months, if estimable, will be 
calculated for each treatment arm and presented with 2-sided 95% CIs. Kaplan-Meier survival 
probabilities over time for each arm will be plotted. The treatment effect will be estimated by 
fitting a Cox regression model with treatment arm adjusted by the actual value of selected 
stratification factors at randomization (ie, ECOG PS score [0 versus 1] and the number of organs 
with metastases [≤1 versus ≥2]). From this model, the HR of PFS will be estimated and 
presented with a 2-sided 95% CI. 
Duration of Response  
DOR will be analyzed among the responders in the ITT Analysis Set using methods similar to 
that described for PFS, based on assessment by the IRC and the investigators. 
Disease Control Rate and Clinical Benefit Rate   
DCR and CBR assessed by the IRC and investigator per RECIST v1.1 will be summarized 
similarly as ORR in the ITT Analysis Set. 


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Health-Related Quality of Life  
HRQoL is defined as assessment of a patient’s overall health status using the EORTC QLQ-C30 
and EORTC QLQ-OES18. The postbaseline scores will be summarized for the 2 arms, and the 
changes from the baseline scores will be summarized descriptively. 
The proportion of patients showing clinically meaningful change at each assessment timepoint 
will be calculated. Completion and compliance rates will be summarized at each timepoint.  
Time to deterioration (TTD) is defined as at least 10-point change on GHS of QLQ-C30 and will 
be calculated using Kaplan-Meier estimates.  
9.3. 
Safety Analyses  
Safety will be assessed by monitoring and recording of all AEs graded by NCI-CTCAE v5.0. 
laboratory values (eg, hematology, clinical chemistry, urinalysis), vital signs, ECGs, and 
physical examinations will also be used to assess the safety profile. Descriptive statistics will be 
used to analyze all safety data in the SAS. 
9.3.1. 
Extent of Exposure  
Extent of exposure to each study drug will be summarized descriptively as the number of cycles 
received (the number and percentage of patients), duration of exposure (days), cumulative total 
dose received per patient (mg), and dose intensity. 
The number (percentage) of patients requiring dose interruption, dose delay, and drug 
discontinuation because of AEs will be summarized for each study drug. Reasons for above dose 
modifications and discontinuation will be summarized as well. 
Patient data listings will be provided for all dosing.  
9.3.2. 
Adverse Events  
The AE verbatim descriptions (investigator’s description from the eCRF) will be classified into 
standardized medical terminology using MedDRA. AEs will be coded to MedDRA (version 24.0 
or higher) lowest level term closest to the verbatim term, preferred term (PT), and primary 
system organ class (SOC). 
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drugs up to 30 days of study drugs after last dose 
or initiation of subsequent anticancer therapy, whichever comes first. Only those AEs that were 
treatment emergent will be included in summary tables of TEAE.  Immune-mediated AEs will be 
identified from all AEs that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drug and up to 90 days from the last dose of 
ociperlimab (or placebo) and/or tislelizumab, regardless of whether the patient starts a new 
anticancer therapy. If an imAE occurs outside of the above-mentioned TEAE window, it will not 
be classified as a TEAE. All imAEs will be reported separately. All AEs, treatment emergent or 
otherwise, will be presented in patient data listings.  
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC and PT. A patient will be counted only once by the highest severity grade per 


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NCI-CTCAE v5.0 within an SOC and PT, even if the patient experienced > 1 TEAE within a 
specific SOC and PT.  
SAEs, deaths, ≥ Grade 3 TEAEs, imAE, treatment-related TEAEs, and TEAEs that led to 
treatment discontinuation, dose interruption or dose delay will be summarized. 
9.3.3. 
Laboratory Analyses  
Clinical laboratory (eg, hematology, clinical chemistry, coagulation, and urinalysis) values will 
be evaluated for each laboratory parameter as appropriate. Abnormal laboratory values will be 
flagged and identified as those outside (above or below) the normal range. Reference (normal) 
ranges for laboratory parameters will be included in the clinical study report for this protocol. 
Descriptive summary statistics (eg, n, mean, standard deviation, median, minimum, and 
maximum for continuous variables; n [%] for categorical variables) for laboratory parameters 
and their changes from baseline will be calculated. Laboratory values will be summarized by 
visit and by worst postbaseline change. 
Laboratory parameters that are graded in NCI-CTCAE v5.0 or higher will be summarized by 
NCI-CTCAE grade. In the summary of laboratory parameters by NCI-CTCAE grade, parameters 
with NCI-CTCAE grading in both high and low directions (eg, calcium, glucose, magnesium, 
potassium, and sodium) will be summarized separately. 
9.3.4. 
Vital Signs  
Descriptive statistics for vital sign parameters (body temperature, pulse rate, respiratory rate, and 
blood pressure [systolic and diastolic]) and weight and their changes from baseline will be 
presented by visit.  
9.4. 
Pharmacokinetic Analyses  
Pharmacokinetic samples will be collected in this study as outlined in Appendix 1. 
Tislelizumab and ociperlimab serum concentration data will be tabulated and summarized by 
visit/cycle at which these concentrations are collected. Descriptive statistics will include means, 
medians, ranges, and standard deviations, as appropriate. 
Additional PK analyses, including population PK analyses and exposure-response analyses 
(efficacy or safety endpoints) may be conducted as appropriate and the results of such analysis 
may be reported separately from the CSR. 
9.5. 
Immunogenicity Analyses  
Samples to assess anti-ociperlimab and anti-tislelizumab antibodies will be collected only in 
patients who receive study drugs and at sites that are able to adequately perform sampling, 
handling, and processing as outlined in the laboratory manual. 
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of patients who develop detectable ADAs. The incidence of positive ADAs and 
neutralizing ADAs will be reported for evaluable patients. The effect of immunogenicity on PK, 
efficacy, and safety may be evaluated if data allow. 


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9.6. 
Other Exploratory Analyses  
Summary statistics will be provided for exploratory biomarkers including but not limited to 
expression of PD-L1, TIGIT, CD226, CD155, and CD112 in tumor tissues, and TMB/gene 
mutation/MSI and GEP in tumor tissues and/or peripheral blood. 
An exploratory analysis on a potential correlation of these tumor tissue or blood-based 
biomarkers with response, resistance and prognosis will be performed to understand disease 
pathobiology and explore potential predictive biomarker. 
For QoL, EQ-5D-5L descriptive and VAS scores will be compared between the 2 arms. 
Descriptive statistics (mean, median standard deviation, and change of scores from baseline) will 
be used to show the changes from baseline in each arm. 
9.7. 
Sample Size Consideration  
The sample size calculation is based on the primary efficacy analysis of ORR between Arm A 
and Arm B in the ITT Analysis Set.   
With 120 randomized patients, the study has at least 80% power to detect a 24% difference in 
ORR (45% vs 21% in Arm A and Arm B, respectively) at a 1-sided type I error of 0.025. 
The sample size is calculated by EAST (version 6.4.1).  
9.8. 
Interim Analyses  
No formal interim analyses will be conducted. Summaries of efficacy and safety data may be 
generated to inform subsequent clinical development planning. 


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10. 
STUDY COMMITTEES AND COMMUNICATION  
10.1. 
Blinded Independent Review Committee  
A Blinded Independent Review (BIRC) committee will be established to perform an independent 
review of all radiological images for the efficacy analysis and to determine all instances of 
response and PD based on RECIST v1.1 criteria, in addition to the local investigator review of 
radiographs. The results from the investigator’s review of radiographic images will be used to 
determine whether patients should be enrolled or should continue the study treatment. The tumor 
assessment by the BIRC will be used for the reporting of the study results.  
All decisions made during the performance of the study will be based on the local investigator’s 
assessment of radiographic images, the patients’ clinical status, and relevant examination of the 
patients. Sites will submit specific radiographic image files to the centralized data review facility 
during the study on an ongoing basis or at the sponsor’s request. Detailed rules and guidelines 
for radiographic imaging and tumor assessments by the BIRC are outlined separately in the 
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11. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS  
The investigator must maintain adequate and accurate records to ensure that the conduct of the 
study may be fully documented. Such records include, but are not limited to, the protocol, 
protocol amendments, ICFs, and documentation of IRB/IEC and governmental approvals. In 
addition, at the end of the study, the investigator will receive patient data, which will include an 
audit trail containing a complete record of all changes to such data. 
11.1. 
Access to Information for Monitoring  
In accordance with ICH GCP guidelines, the study monitor must have direct access to the 
investigator’s source documentation to verify the data recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any patient records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected during these monitoring visits are resolved. 
11.2. 
Access to Information for Auditing or Inspections  
Representatives of regulatory authorities or of the sponsor may conduct inspections or audits any 
time during or after completion of this clinical study. If the investigator is notified of an 
inspection by a regulatory authority, the investigator agrees to notify the sponsor or its designee 
immediately. The investigator agrees to provide to representatives of a regulatory agency or the 
sponsor access to records, facilities, and personnel for the effective conduct of any inspection or 
audit. 


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12. 
QUALITY ASSURANCE AND QUALITY CONTROL  
12.1. 
Regulatory Authority Approval  
The sponsor will either obtain approval to conduct the study from the appropriate regulatory 
agency in accordance with any applicable country-specific regulatory requirements or file the 
protocol to the appropriate regulatory agency before the study is initiated at a study center in that 
country. 
12.2. 
Quality Assurance  
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection 
of this study. Such audits/inspections can occur at any time during or after completion of the 
study. If an audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and the time 
of his/her personnel to the auditor/inspector to discuss findings and any relevant issues. 
12.3. 
Study Site Inspections  
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines. 
Site audits may be performed periodically by the sponsor’s or the contract research 
organization’s qualified compliance auditing team, which is an independent function from the 
study team responsible for conduct of the study. 
Site visits will be conducted by the sponsor or an authorized representative to inspect study data, 
patients’ medical records, and eCRFs. The investigator is to permit national and local health 
authorities; sponsor study monitors, representatives, and collaborators; and IRB/IEC members to 
inspect all facilities and records relevant to this study. 
12.4. 
Drug Accountability  
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drugs. This includes acknowledgment of receipt of each shipment of 
study drugs (quantity and condition), patient drug dispensation records, and returned or 
destroyed study drugs. Dispensation records will document quantities received from the 
sponsor’s designated depot or its designee and quantities dispensed to patients, including 
batch/lot number, date dispensed, patient identifier number, and the initials of the person 
dispensing the medication. 
At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction to ensure that it complies with the requirements of the sponsor 
specified in the Pharmacy Manual. At appropriate timepoints during the conduct of the study or 
at the end of the study after the final drug inventory reconciliation by the medical monitor, the 
study site will dispose of and/or destroy all unused study drug supplies, including empty 
containers, according to these procedures. If the site cannot meet the sponsor’s requirements 
specified in the Pharmacy Manual for disposal, arrangements will be made between the site and 
the sponsor or its representative for destruction or return of unused study drug supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 


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13. 
ETHICS/PROTECTION OF HUMAN SUBJECTS  
13.1. 
Ethical Standard  
This study will be conducted by the principal investigator and the study center in full 
conformance with the ICH E6 guideline for GCP and the principles of the Declaration of 
Helsinki or the laws and regulations of the country in which the research is conducted, whichever 
affords the greater protection to the individual. The study will also comply with the requirements 
of the ICH E2A guideline (ICH E2A 1994). 
13.2. 
Institutional Review Board/Independent Ethics Committee  
This protocol, the ICFs, any information to be given to the patient, and relevant supporting 
information must be submitted, reviewed, and approved by the IRB/IEC before the study is 
initiated. In addition, any patient recruitment materials must be approved by the IRB/IEC. Copies 
of the IRB/IEC correspondence and approval of the amended ICF/other information and the 
approved amended ICF/other information must be forwarded to the sponsor promptly. 
The principal investigator is responsible for providing written summaries of the status of the 
study to the IRB/IEC annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC. Investigators are also responsible for promptly 
informing the IRB/IEC of any protocol amendments. In addition to the requirements for 
reporting all AEs to the sponsor, investigators must comply with requirements for reporting 
SAEs to the local health authority and IRB/IEC. Investigators may receive written 
Investigational New Drug 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/IEC and archived in the site’s study file. 
13.2.1. 
Protocol Amendments  
Any protocol amendments will be prepared by the sponsor. All protocol modifications must be 
submitted to competent authorities according to local requirements and to the IRB/IEC together 
with, if applicable, a revised model ICF in accordance with local requirements. Written 
documentation from competent authorities (according to local requirements) and from the 
IRB/IEC and required site approval must be obtained by the sponsor before changes can be 
implemented, except for changes necessary to eliminate an immediate hazard to patients or 
changes that involve logistical or administrative aspects only (eg, change in medical monitor or 
contact information). 
Information on any change in risk and/or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand, and sign each revised ICF 
confirming their willingness to remain in the study. 
13.3. 
Informed Consent  
The sponsor’s sample ICF will be provided to each site. If applicable, it will be provided in a 
certified translation of the local language. The final IRB/IEC-approved ICFs must be provided to 
the sponsor for health authority submission purposes according to local requirements. 


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The ICFs 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 before participation in the study. 
The ICFs will 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/IEC-approved consent forms must be provided to the sponsor for health 
authority submission purposes. 
Patients must be reconsented to the most current version of the ICFs (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/IEC policy) during 
their participation in the study. For any updated or revised ICFs, 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 ICFs for continued participation in the study. 
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative. All signed and dated ICFs 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. 
13.4. 
Patient and Data Confidentiality  
The principal investigator and sponsor will maintain confidentiality and privacy standards by 
following applicable data privacy laws covering the collection, storage, transmission, and 
processing of patients’ personal and medical information. 
The principal investigator shall code the medical information obtained during the study with a 
unique patient identification number assigned to each patient enrolled in the study. This approach 
ensures that patients’ names are not included in any data set transmitted to any sponsor location. 
Patient medical information obtained during this study is confidential and may be disclosed to 
third parties only as permitted by the signed ICF (or a separate authorization for the use and 
disclosure of personal health information that has been signed by the patient), unless permitted or 
required by law. 
In the event of a breach of the confidentiality of a patient’s personal and medical information, the 
principal investigator and sponsor, as appropriate, shall fulfill all mediation steps and reporting 
obligations under applicable data privacy laws. 
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. 
Data generated during this study must be available for inspection upon request by representatives 
of the China National Medical Products Administration and all other national and local health 
authorities; by sponsor monitors, representatives, and collaborators; and by the IRBs/IECs for 
each study site, as appropriate. 
The investigator must assure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. The investigator agrees that all information 
received from the sponsor, including but not limited to the Tislelizumab Investigator’s Brochure, 
Ociperlimab Investigator’s Brochure, this protocol, eCRFs, the information on the 


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investigational new drugs, and any other study information, remain the sole and exclusive 
property of the sponsor during the conduct of the study and thereafter. This information is not to 
be disclosed to any third party (except employees or agents directly involved in the conduct of 
the study or as required by law) without prior written consent from the sponsor. The investigator 
further agrees to take all reasonable precautions to prevent the disclosure by any employee or 
agent of the study site to any third party or otherwise into the public domain.  
If a written contract for the conduct of the study that includes confidentiality provisions 
inconsistent with this section is executed, that contract’s provisions shall apply to the extent they 
are inconsistent with this section. 
13.5. 
Financial Disclosure  
Investigators are required to provide the sponsor with sufficient accurate financial information in 
accordance with regulations to allow the sponsor to submit complete disclosure or certification to 
the absence of certain financial interest of clinical investigators and/or disclose those financial 
interests, as required, to the appropriate health authorities. This is intended to ensure that 
financial interests and arrangements of clinical investigators with the sponsor that could affect 
reliability of data submitted to health authorities are identified and disclosed by the sponsor. 
Investigators are responsible for providing information about their financial interests before 
participation in the study and to update this information if any relevant changes occur during the 
study and for 1 year after completion of the study (ie, last patient, last visit). 


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14. 
DATA HANDLING AND RECORD KEEPING  
14.1. 
Data Collection and Management Responsibilities  
14.1.1. 
Data Entry in the Electronic Case Report Form  
All study-related data collected or received by the investigator or study team shall be promptly 
entered into the eCRFs. In no event should the entry of the study data into the eCRF be later than 
what is stipulated in the site contract after the data is collected or received by the investigator or 
study team without prior communication with and approval by the sponsor. 
14.1.2. 
Data Collection  
Data required by the protocol will be entered into an electronic data capture (EDC) system. 
Data collection in the eCRF should follow the instructions described in the eCRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered in the eCRF.  The e-signature of the investigator or designee must be 
provided in the EDC system to attest to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of the sponsor and should not be made 
available in any form to third parties without prior written permission from the sponsor, except 
for authorized representatives of the sponsor or appropriate regulatory authorities. 
14.1.3. 
Data Management/Coding  
All final patient data, both eCRF and external data (eg, laboratory data), collected according to 
the protocol, will be stored by the sponsor at the end of the study. 
Standard procedures (including following data review guidelines, computerized validation to 
produce queries, and maintenance of an audit file that includes all database modifications) will 
be followed to support accurate data collection. Data will be reviewed for outliers, logic, data 
inconsistencies, and completeness. 
During the course of the study, a study monitor will make site visits to review protocol 
compliance, compare eCRFs against individual patient’s medical records, and ensure that the 
study is being conducted according to pertinent regulatory requirements. 
The eCRF entries will be verified with source documentation. The review of medical records 
will be performed in a manner to ensure that patient confidentiality is maintained. Checking the 
eCRFs for completeness, clarity, and cross-checking with source documents is required to 
monitor the progress of the study. Direct access to source data is also required for inspections 
and audits and will be carried out, giving due consideration to data protection and medical 
confidentiality. 
The AE verbatim descriptions (the investigator’s description from the eCRF) will be coded using 
MedDRA. AEs will be coded to MedDRA by Lower Level Term, Preferred Term, and primary 
System Organ Class. Concomitant medications will be coded using the World Health 
Organization Drug Dictionary. Concomitant diseases/medical history will be coded using 
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14.2. 
Data Integrity and In-house Blinding  
Functions/persons with access to the EDC system shall be prohibited from using the EDC system 
to generate unnecessary listings/summaries that may introduce unwanted bias or to share such 
outputs from the EDC system with other functions/persons who do not have access to the EDC.  
In addition, the central imaging vendor will perform the central imaging review without 
knowledge of treatment arm assignment. Analyses or summaries generated by randomized 
treatment assignment and actual treatment received will be limited and documented. 
14.3. 
Study Records Retention  
The investigator must maintain adequate and accurate records so that the conduct of the study 
can be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least 1 of the following 2 categories: the investigator’s study file or the 
patient clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC and governmental approval with correspondence, ICFs, drug records, staff curriculum 
vitae and authorization forms, and other appropriate documents and correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include, but not be limited to, 
documents such as the following: patient hospital/clinic records, physician’s and nurse’s notes, 
appointment book, original laboratory reports, ECG, electroencephalogram, x-ray, pathology and 
special assessment reports, consultant letters, and screening and enrollment log, etc. 
After closure of the study, the investigator must maintain all study records in a safe and secure 
location. The records must be maintained to allow easy and timely retrieval, when needed 
(eg, audit or inspection), and, whenever feasible, to allow any subsequent review of data in 
conjunction with assessment of the facility, supporting systems, and personnel. Where permitted 
by local laws/regulations or institutional policy, some or all of these records can be maintained in 
a format other than hard copy (eg, microfiche, scanned, electronic); however, caution needs to be 
exercised before such action is taken. The investigator must ensure that all reproductions are 
legible, are a true and accurate copy of the original, and meet accessibility and retrieval 
standards, including regenerating a hard copy, if required. Furthermore, the investigator must 
ensure that there is an acceptable backup of these reproductions and that an acceptable quality 
control process exists for making these reproductions. 
The sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that study center for the study, as dictated by any institutional 
requirements or local laws or regulations, or the sponsor’s standards/procedures; otherwise, the 
retention period will default to 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements including, 
but not limited to, the following: archival at an off-site facility or transfer of ownership of or 
responsibility for the records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and the sponsor to 


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store these in sealed containers at a separate location so that they can be sealed and returned to 
the investigator in case of a regulatory audit. When source documents are required for the 
continued care of the patient, appropriate copies should be made for storage outside of the site. 
At the conclusion of this study, biological samples may be retained as outlined in the agreement 
with the contract research organization managing the biological samples, for a period of up to 
10 years or as allowed by the IRB/IEC, whichever is shorter. 
14.4. 
Protocol Deviations  
The investigator is responsible for ensuring that the study is conducted in accordance with the 
procedures and evaluations described in this protocol. Investigators assert they will apply due 
diligence to avoid protocol deviations and shall report all protocol deviations to the sponsor. 
The investigator is to document and explain any deviations from the approved protocol. In 
accordance with established IRB/IEC policies and procedures, the investigator must promptly 
report any important deviations that might impact patient safety and/or data integrity to the 
sponsor and to the IRB/IEC. 
14.5. 
Study Report and Publications  
A clinical study report will be prepared and provided to the regulatory agency(ies). The sponsor 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3). An abbreviated report may be prepared in certain 
cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulatory guidance, and the need to protect the intellectual property of the sponsor, regardless of 
the outcome of the study. The data generated in this clinical study are the exclusive property of 
the sponsor and are confidential. For a multicenter study, the first publication or disclosure of 
study results shall be a complete, joint multicenter publication, or disclosure coordinated by the 
sponsor. Thereafter, any secondary publications will reference the original publication(s). 
Authorship will be determined by mutual agreement and all authors must meet the criteria for 
authorship established by the International Committee of Medical Journal Editors or stricter local 
criteria (International Committee of Medical Journal Editors 2022). 
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor for review before submission or presentation 
in accordance with the clinical study agreement. This allows the sponsors to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy. Each investigator agrees 
that, in accordance with the terms of the clinical study agreement, a further delay of the 
publication/presentation may be requested by the sponsor to allow for patent filings and/or 
protection in advance of the publication/presentation. 
14.6. 
Study and Study Center Closure  
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate: 


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• Return/provide all study data to the sponsor 
• Resolution and closure of all data queries 
• Accountability, reconciliation, and arrangements for unused study drugs 
• Review of study records for completeness 
• Collection of all study documents for the trial master file filing according to GCP and 
local regulation 
• Shipment of samples (including but not limited to those for PK, ADA, and 
biomarkers) to the assay laboratory for central laboratory analysis according to 
protocol and laboratory manual requirements 
In addition, the sponsor reserves the right to suspend the enrollment or prematurely discontinue 
this study either at a single study center or at all study centers at any time for any reasons. 
Potential reasons for suspension or discontinuation include but are not limited to safety or ethical 
issues or noncompliance with this protocol, GCP, the sponsor’s written instructions, the clinical 
study agreement, or applicable laws and regulations. If the sponsor determines such action is 
needed, the sponsor will discuss this with the investigator (including the reasons for taking such 
action) at that time. When feasible, the sponsor will provide advance notification to the 
investigator of the impending action before it takes effect. 
The sponsor will promptly inform all other investigators and/or institutions conducting the study 
if the study is suspended or terminated for safety reasons and will also inform the regulatory 
authorities of the suspension or termination of the study and the reason(s) for the action. If 
required by applicable regulations, the investigator must inform the IRB/IEC promptly and 
provide the reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must still be provided to the sponsor. In 
addition, arrangements will be made for all unused study drugs in accordance with the applicable 
sponsor procedures for the study. 
Financial compensation to investigators and/or institutions will be made in accordance with the 
clinical study agreement established between the investigator and/or institutions and the sponsor. 
14.7. 
Information Disclosure and Inventions  
All rights, title, and interests in any inventions, expertise, or other intellectual or industrial 
property rights that are conceived or reduced to practice by the study center personnel during the 
course of or as a result of the study are the sole property of the sponsor and are hereby assigned 
to the sponsor. 
If a written contract for the conduct of the study, which includes ownership provisions 
inconsistent with this statement, is executed between the sponsor and the study center that 
contract’s ownership provisions shall apply rather than this statement. 
All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) are the sole property of the 
sponsor and will be kept confidential by the investigator and other study center personnel.  


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This information and data will not be used by the investigator or other study center personnel for 
any purpose other than conducting the study without the prior written consent of the sponsor. 
These restrictions do not apply to: 
• Information that becomes publicly available through no fault of the investigator or 
study center personnel 
• Information that is necessary to disclose in confidence to an IRB/IEC solely for the 
evaluation of the study 
• Information that is necessary to disclose to provide appropriate medical care to a 
patient 
• Study results that may be published as described in Section 14.5. 
If a written contract for the conduct of the study, which includes provisions inconsistent with this 
statement is executed, that contract’s provisions shall apply rather than this statement. 


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15. 
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Haanen J, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO 
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He W, Zhang H, Han F, et al. CD155T/TIGIT signaling regulates CD8+ T cell metabolism and 
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International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human use. Clinical Safety Data Management: Definitions and Standards 
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Jiang P, Gu S, Pan D, et al. Signatures of T cell dysfunction and exclusion predict cancer 
immunotherapy response. Nat Med. 2018;24(10):1550-8.  
Johnston R, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor 
and antiviral CD8(+) T cell effector function. Cancer Cell. 2014;26:923-37.  
Joller N, Lozano E, Burkett P, et al. Treg cells expressing the coinhibitory molecule TIGIT 
selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity. 2014;40:569-81.  
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2019;20:1506-17.  
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advanced or recurrent esophageal cancer in patients who had previously received platinum-based 
chemotherapy. Cancer Chemother Pharmacol. 2011;67(6):1265-72.  
Kim SB, Doi T, Kato K, et al. Pembrolizumab vs chemotherapy in patients (pts) with 
advanced/metastatic adenocarcinoma (AC) or squamous cell carcinoma (SCC) of the esophagus 
as second-line (2L) therapy. Ann Oncol. 2019;30(Suppl_9):ix42-67  
Kong Y, Zhu L, Schell T, et al. T-cell immunoglobulin and ITIM domain (TIGIT) associates with 
CD8+ T-cell exhaustion and poor clinical outcome in AML patients. Clin Cancer Res. 
2016;22:3057-66.  
Kurtulus S, Sakuishi K., Ngiow SF, et al. TIGIT predominantly regulates the immune response 
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shows dual mechanism of action by restoration of T cell effector functions and preferential 
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2018; 2018 Apr 14-18, Chicago, IL.  
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Lordick F, Mariette C, Haustermans K, et al. Oesophageal cancer: ESMO clinical practice 
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16. 
Appendices  
 


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APPENDIX 1. SCHEDULE OF ASSESSMENTS  
Assessment 
Prescreeninga 
Screeninga 
Treatment Cycles 
EOT Visitb 
Safety Follow-up Visitsb 
Survival 
Follow-upc 
Days (Window) 
-56 to ~ -1 
-28 to ~ -1 
1 (±3) 
Within 7 
Days After 
EOT 
Decision 
30 (±7) 
After Last 
Dose 
(on-site) 
60 (±14) 
After 
Last 
Dose 
(Phone 
call) 
90 (±14) 
After 
Last 
Dose 
(Phone 
call) 
120 ± 14 
Days After 
last Dose 
(for 
pregnancy 
testing) 
Every 3 
Months 
(±14 days) 
Informed consent a 
x 
x 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
 
x 
 
 
 
 
 
 
 
Randomization d 
 
x 
 
 
 
 
 
 
 
Demographics/medical 
history/prior 
medications e 
 
x 
 
 
 
 
 
 
 
Vital signs/height and 
weight f 
 
x 
x 
x 
x 
 
 
 
 
Physical examination g 
 
x 
x 
x 
x 
 
 
 
 
ECOG PS 
 
x 
x 
x 
x 
 
 
 
 
12-lead ECG h 
 
x 
As clinically 
indicated 
x 
x 
 
 
 
 
Adverse events i 
 
x 
x 
x 
x 
x 
x 
 
 
Concomitant 
medications 
 
x 
x 
x 
x 
x 
x 
 
 
Hematology j 
 
xa 
x 
x 
x 
 
 
 
 
Serum chemistry 
j 
 
xa 
x 
x 
x 
 
 
 
 
Total CK and CK-MB j 
 
xa 
x 
x 
x 
 
 
 
 


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Assessment 
Prescreeninga 
Screeninga 
Treatment Cycles 
EOT Visitb 
Safety Follow-up Visitsb 
Survival 
Follow-upc 
Days (Window) 
-56 to ~ -1 
-28 to ~ -1 
1 (±3) 
Within 7 
Days After 
EOT 
Decision 
30 (±7) 
After Last 
Dose 
(on-site) 
60 (±14) 
After 
Last 
Dose 
(Phone 
call) 
90 (±14) 
After 
Last 
Dose 
(Phone 
call) 
120 ± 14 
Days After 
last Dose 
(for 
pregnancy 
testing) 
Every 3 
Months 
(±14 days) 
Coagulation 
parameters j 
 
x 
As clinically 
indicated 
x 
x 
 
 
 
 
Urinalysis j 
 
x 
As clinically indicated 
 
 
 
 
Pregnancy test k 
 
x 
x 
x 
x 
x 
x 
x 
 
Thyroid function l 
 
x1 
x (every 3 cycles) 
x 
x 
 
 
 
 
HBV/HCV tests m 
 
x 
Every 4 cycles and as clinically indicated 
 
 
 
 
Pulmonary function 
tests n 
 
 
As clinically indicated 
Pharmacokinetics o 
 
 
x (Cycles 1, 2, 5, 9, 
and 17) 
 
x 
 
 
 
 
Anti-drug antibodies p 
 
 
x (Cycles 1, 2, 5, 9, 
and 17) 
 
x 
 
 
 
 
Tumor assessment q 
 
x 
Every 6 weeks 
(± 7 days) for the 
first 54 weeks. 
Every 12 weeks 
(± 7 days) 
thereafter. 
 
 
 
 
 
x 
Archival/fresh tumor 
tissue r 
x 
 
 
x (optional) 
 
 
 
 
 
Blood biomarker 
(optional) s 
 
 
Baseline, first response, and 
confirmed PD as clinically 
indicated 
 
 
 
 
 


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Assessment 
Prescreeninga 
Screeninga 
Treatment Cycles 
EOT Visitb 
Safety Follow-up Visitsb 
Survival 
Follow-upc 
Days (Window) 
-56 to ~ -1 
-28 to ~ -1 
1 (±3) 
Within 7 
Days After 
EOT 
Decision 
30 (±7) 
After Last 
Dose 
(on-site) 
60 (±14) 
After 
Last 
Dose 
(Phone 
call) 
90 (±14) 
After 
Last 
Dose 
(Phone 
call) 
120 ± 14 
Days After 
last Dose 
(for 
pregnancy 
testing) 
Every 3 
Months 
(±14 days) 
Study drug 
administration t 
 
 
x 
 
 
 
 
 
 
EORTC QLQ-C30 u 
 
 
Every 2 cycles for 
the first 54 weeks. 
Every 4 cycles 
thereafter (Cycle 1 
as baseline). 
 
x 
 
 
 
 
EORTC QLQ-OES18 u 
 
 
Every 2 cycles for 
the first 54 weeks. 
Every 4 cycles 
thereafter (Cycle 1 
as baseline). 
 
x 
 
 
 
 
EQ-5D-5L u 
 
 
Every 2 cycles for 
the first 54 weeks. 
Every 4 cycles 
thereafter (Cycle 1 
as baseline). 
 
x 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
x 
Abbreviations: AE, adverse event; CNS, central nervous system; CK, creatine kinase; CK-MB, creatine kinase-muscle/brain; CT, computed tomography; ECG, 
electrocardiogram; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-OES18, European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire Oesophageal Carcinoma-18 Questions; EORTC QLQ-C30, European Organisation for Research and 
Treatment of Cancer Quality of Life Questionnaire-Core 30; EOT, end of treatment; EQ-5D-5L, European Quality of Life 5-Dimensional 5-Level; FFPE, 
formalin-fixed paraffin-embedded; HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis 
B virus; HCV, hepatitis C virus; imAE, immune-mediated adverse event; IRB, Institutional Review Board; IEC, Independent Ethics Committee; IRT, interactive 
response technology; MRI, magnetic resonance imaging; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; PD, 
progressive disease; PET, positron emission tomography; PK, pharmacokinetic; RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious adverse 
event; T3, triiodothyronine; T4, thyroxine; TSH, thyroid stimulating hormone; v, version. 


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a. 
Written informed consent is required before performing any study-specific tests or procedures. Results of standard of care tests or examinations performed 
before obtaining informed consent and within 28 days before the first dose of study drugs may be used for screening assessments rather than repeating such 
tests (only applicable if the same radiographic procedure will be used throughout the study). 
b. The Safety Follow-up Visit is required to be conducted 30 days (± 7 days) after the last dose of study treatment or before the initiation of a new anticancer 
treatment, whichever occurs first. In addition, telephone contacts with patients will be conducted to assess all imAEs and relevant concomitant medications (ie, 
associated with an imAE or is a new anticancer therapy) at 60 days and 90 days (±14 days) after the last dose of study treatment, regardless of whether the 
patient starts a new anticancer therapy. For women of childbearing potential (see Appendix 6), an additional visit to perform a pregnancy test will occur at 
approximately 120 days (± 14 days) after the last dose of study drugs. Visits are performed in clinic or over the phone, as needed based on assessments 
required. 
c. 
Survival Follow-up information will be collected via telephone calls, patient medical records, and/or clinic visits approximately every 3 months after the last 
Safety Follow-up Visit until death, loss to follow-up, withdrawal of consent, or study termination by the sponsor. All patients will be followed for survival and 
subsequent anticancer therapy information unless a patient requests to be withdrawn from follow-up. 
d. Patients will be randomized into either Arm A or Arm B via IRT in an investigator- and patient-blinded and sponsor-unblinded fashion. All patients are 
required to receive study treatment within 2 business days of randomization. 
e. 
Includes age or year of birth, sex, and self-reported race/ethnicity; history of treatment for the primary diagnosis, including prior medication, loco-regional 
treatment(s), and surgical treatment(s). Information on radiographic studies performed before study entry may be collected for review by the investigator. Pre-
existing AEs at baseline should be recorded as medical history. 
f.  
Vital signs collected on study include body temperature, pulse rate, respiratory rate, and blood pressure (systolic and diastolic) while the patient is in a seated 
position after resting for 10 minutes. The patient’s vital signs are required to be recorded within 60 minutes before, during, and 30 minutes after the first 
infusion of study drugs. For subsequent infusions, vital signs will be collected within 60 minutes before infusion and if clinically indicated, during and 
30 minutes after the infusion. Height should only be measured and recorded during screening. Weight will be measured before study drug administration in 
every cycle. 
g. During the Screening Visit, a complete physical examination will be conducted. At subsequent visits (and as clinically indicated), limited, symptom-directed 
physical examinations will be performed.  
h. The ECG recordings will be obtained during screening, at EOT Visit/on-site Safety Follow-up Visit, and as clinically indicated at other timepoints. Patients 
should be resting in semirecumbent supine position for ≥ 10 minutes before each ECG measurement. 
i.  
The AEs and laboratory abnormalities will be graded per NCI-CTCAE v5.0. All AEs will also be evaluated for seriousness. After the informed consent form 
has been signed, but before the administration of study drug, only SAEs should be reported. After the first dose of study drug, all AEs and SAEs, regardless of 
their assessed relationship to study drug, are to be reported until either 30 days after the last dose of study treatment or the initiation of new anticancer therapy, 
whichever occurs first. In addition, telephone contacts with patients should be conducted to assess immune-mediated AEs and concomitant medications (if 
appropriate, ie, associated with an immune-mediated AE or is a new anticancer therapy) at 60 days and 90 days (± 14 days) after the last dose of study 
treatment, regardless of whether the patient starts a new anticancer therapy. Immune-mediated AEs (serious or nonserious) will be reported until 90 days after 
the last dose of ociperlimab (or placebo) and/or tislelizumab, regardless of whether the patient starts a new anticancer therapy. The investigator should report 
any SAEs that are assessed as related to study drug(s), at any time after treatment discontinuation. 
j.  
Local and/or central laboratory assessments on serum chemistry, hematology, coagulation, and urinalysis will be conducted, of which certain elements will 
be collected as specified in Appendix 3. If laboratory tests at screening are not performed within 7 days before the first dose of study drugs, these tests should 
be repeated and reviewed before study drug administration. After Cycle 1, these laboratory tests are to be performed and reviewed within 48 hours before study 
drug administration. Urinalysis is to be conducted during the treatment period only if clinically warranted. Refer to Section 7.5.4 for additional information 
regarding clinical assessment and management of clinical laboratory abnormalities.   


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Serum CK and CK-MB testing is included in total CK and CK-MB assessment, which will be implemented for all patients at screening, predose on Day 1 of 
every cycle, at the EOT Visit, and at the on-site Safety Follow-up Visit. If CK-MB fractionation is not available, serum troponins (troponin I and/or T) 
measurements will be performed instead. 
k. Urine or Serum pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) must be performed and documented as 
negative within 7 days prior to randomization. Urine pregnancy test will be performed at each visit prior to study treatment, the EOT Visit, and each safety 
follow-up visit, including 120 days after the last dose of study drugs; a serum pregnancy test must be performed if the urine pregnancy test is positive or 
equivocal.  
l.  
Analysis of free T3, free T4, and TSH will be performed by a central laboratory or the local study site laboratory. Thyroid function tests will be performed at 
screening and every 3 cycles (ie, Day 1 of Cycles 4, 7, 10, etc), the EOT Visit, and the on-site Follow-up Visit. For sites where tests for free T3 or free T4 are 
not available, alternative tests can be considered after communication with medical monitor. 
m. Testing will be performed by a central laboratory and/or the local laboratory at screening and will include HBV/HCV serology (HBsAg, HBsAb, HBcAb, 
and HCV antibody) and viral load assessment (HBV DNA and HCV RNA), which will be assessed only when HBsAg or HCV antibody is positive, 
respectively. Patients who have detectable HBV DNA at screening will perform the respective viral load test every 4 cycles (ie, Day 1 of Cycle 5, 9, 13, etc) 
from Cycle 5 onwards. 
n. Pulmonary function testing includes spirometry and assessment of oxygenation, at a minimum pulse oximetry at rest and with exercise, or alternatively, 
assessment of diffusion capacity. Patient who are suspected of having serious/severe respiratory conditions, or who exhibit significant respiratory symptoms 
unrelated to the underlying cancer, or with a history of thoracic radiotherapy should be evaluated for the suitability on the study at screening. Tests may be 
repeated as clinically indicated while on study. Respective test results need to be submitted to the sponsor.  
o. Procedures for collection of PK samples are described in the Laboratory Manual. Predose (within 60 minutes before starting infusion) samples are required 
to be collected on Day 1 of Cycles 1, 2, 5, 9, and 17. A postdose (within 30 minutes after completing infusion) sample is required to be collected on Day 1 of 
Cycles 1 and 5. An additional PK sample is required to be collected at the on-site Safety Follow-up Visit. Should a patient present with any ≥ Grade 3 imAE, 
an additional blood PK sample may be taken to determine the serum concentration of tislelizumab and/or ociperlimab. These tests are required when it is 
allowed by local regulations/IRBs/IECs.  
p. For both arms, blood used to test for anti-tislelizumab/anti-ociperlimab antibodies should be collected within 60 minutes before beginning the Day 1 infusion 
of Cycles 1, 2, 5, 9, and 17 and at the on-site Safety Follow-up Visit. All samples should be drawn at the same time as blood collection for predose PK analysis. 
These tests are required when it is allowed by local regulations/IRBs/IECs.  
q. Radiological images captured as standard of care before obtaining written informed consent and within 28 days before randomization may be used rather 
than repeating tests, provided they meet the protocol specifications. All measurable and evaluable lesions are required to be assessed and documented at the 
Screening Visit and reassessed at each subsequent tumor evaluation. CT/MRI of the head at baseline is required for patients who are suspected to have CNS 
metastases; bone scan or PET is required if clinically indicated. The same radiographic procedure must be used throughout the study for each patient. 
The investigator must review radiograph results before dosing at the next cycle. Patients will undergo tumor assessments approximately every 6 weeks 
(± 7 days) for the first 54 weeks, and every 12 weeks (± 7 days) thereafter (based on RECIST v1.1 assessment). The investigator may perform additional scans 
or more frequent assessments if clinically indicated. Patients who discontinue from study treatment early for reasons other than PD (eg, toxicity) will continue 
to undergo tumor assessments following the original plan until the patient experiences PD, withdraws consent, dies, or until the study terminates, whichever 
occurs first. Patients who continue study treatment after radiographic PD will be monitored with a follow-up scan no more than 6 to 8 weeks after the initial 
diagnosis of radiographic PD before discontinuation of treatment. 
r.  
Patients are required to provide archival tumor tissues (FFPE blocks or approximately 15 [≥ 6] unstained slides) for biomarker analysis. Fresh biopsy: In the 
absence of archival tumor tissues, a fresh biopsy of a tumor lesion at baseline is mandatory. Prescreening samples will be subjected to PD-L1 testing centrally. 
An optional biopsy will be taken at the EOT Visit for patients with confirmed PD during the study.  


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s. 
An optional blood sample will be taken at baseline (predose on Cycle 1 Day 1), at the time of first tumor response (predose on Day 1 of the following cycle) 
and at EOT Visit after PD (10 mL each timepoint) to explore the association with response, resistance and prognosis. 
t.  
The first dose of study drug is to be administered within 2 business days after randomization. The initial infusions (Cycle 1 and Cycle 2, Day 1) will be 
delivered over 60 minutes for each dose of tislelizumab, ociperlimab, and placebo; if this is well tolerated, then the subsequent infusions may be administered 
over 30 minutes for each drug, which is the shortest period permissible for infusion. Treatment could continue after progression if clinical benefit is seen and 
treatment is tolerated per the investigator’s discretion. Patients should sign an additional informed consent form for continued treatment after PD per RECIST 
v1.1 (see Section 5.2).  
u. To be completed before any clinical activities during on-site visits. EORTC QLQ-C30, EORTC QLQ-OES18, and EQ-5D-5L will be completed before 
dosing on Day 1 of every other treatment cycle during the first 54 weeks, Day 1 of every 4 cycles thereafter, and at the on-site Safety Follow-up Visit.  


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APPENDIX 2. FLOWCHART FOR DETERMINING THE LINE OF 
TREATMENT IN ESOPHAGEAL SQUAMOUS CELL 
CARCINOMA  
 
Abbreviations: CRT, conformal radiation therapy; ESCC, esophageal squamous cell carcinoma; NCCN ESOPH, 
National Comprehensive Cancer Network Esophageal Neoplasms Practice Guidelines; TFI, treatment-free interval. 
a. This is a general guide to determine the line of therapy and cannot cover all possibilities; if you have questions, 
please consult the medical monitor. 
b. For the primary treatment, single drug regimen or regimens used for radiotherapy sensitization (the dose is lower 
than the NCCN treatment guidance recommended standard systematic treatment dose) should not be considered 
as one line of therapy.  
c. TFI is defined as the duration from the last day (administration day/infusion day) of prior treatment cycle to the 
date of PD. 
d. Patients with stage IV disease at first diagnosis are eligible for this study if their cancer has progressed after the 
first-line of systemic chemotherapy, regardless of the length of the TFI. 
e. Patients intolerant to most recent regimen due to Grade 4 hematologic toxicity or Grade 3 or 4 non-hematologic 
toxicity may also be eligible 
f. Patients must meet all inclusion and exclusion criteria to be enrolled into this study. 


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APPENDIX 3. CLINICAL LABORATORY ASSESSMENTS  
Clinical Chemistry 
Hematology 
Coagulation 
Urinalysis 
Alkaline phosphatase 
Hematocrit 
Prothrombin time 
pH 
ALT 
Hemoglobin 
Partial 
thromboplastin time 
or activated partial 
thromboplastin time 
Specific gravity 
AST 
Platelet counts 
International 
normalized ratio 
Glucose 
Albumin 
White blood cell count  
 
Protein 
Total bilirubin 
Neutrophil count 
 
Ketones 
Direct bilirubin 
Lymphocyte count 
 
 
Blood urea nitrogen or 
urea 
 
 
Blood 
Potassium 
 
 
24-hour proteina         
Sodium 
 
 
 
Calcium 
 
 
 
Phosphorus 
 
 
 
Magnesium  
 
 
 
Chloride 
 
 
 
Creatinine 
 
 
 
Glucose 
 
 
 
Lactate dehydrogenase 
 
 
 
Total protein 
 
 
 
Creatine kinase/CK-MB b  
 
 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK-MB, creatine 
kinase-muscle/brain. 
a On routine urinalysis, if urine protein is ≥ 2+ by dipstick then obtain a 24-hour urine sample for total protein or a 
random urine sample for total protein and creatinine to determine a protein-to-creatinine ratio. 
b Cardiac enzyme testing has been added to monitor for potential event of immune-mediated myocarditis. If CK-MB 
fractionation is not available, assess troponin I and/or troponin T instead. Investigators should make every effort to 
perform either CK-MB, troponin I and/or troponin T consistently at screening and at follow-up visits. 
 


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APPENDIX 4. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS  
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Source: Oken et al 1982. Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair. 


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APPENDIX 5. PRE-EXISTING IMMUNE DEFICIENCIES OR 
AUTOIMMUNE DISEASES  
Prospective patients should be carefully questioned to determine whether they have any history 
of an acquired or congenital immune deficiency or autoimmune disease. 
Contact the medical monitor regarding any uncertainty about immune deficiency/autoimmune 
disease exclusions. 
Acute disseminated encephalomyelitis 
Addison disease 
Ankylosing spondylitis 
Antiphospholipid antibody syndrome 
Aplastic anemia 
Autoimmune hemolytic anemia 
Autoimmune hepatitis 
Autoimmune hypoparathyroidism 
Autoimmune hypophysitis 
Autoimmune myocarditis 
Autoimmune oophoritis 
Autoimmune orchitis 
Autoimmune thrombocytopenic purpura 
Behcet disease 
Bullous pemphigoid 
Chronic inflammatory demyelinating polyneuropathy 
Chung-Strauss syndrome 
Crohn disease 
Dermatomyositis 
Dysautonomia  
Epidermolysis bullosa acquisita  
Gestational pemphigoid  
Giant cell arteritis  
Goodpasture syndrome  
Granulomatosis with polyangiitis  
Graves disease  
Guillain-Barré syndrome 
Hashimoto disease 
Immunoglobulin A (IgA) neuropathy 
Inflammatory bowel disease  
Interstitial cystitis  
Kawasaki disease  
Lambert-Eaton myasthenia syndrome  
Lupus erythematosus  
Lyme disease (chronic) 
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 cirrhosis  
Psoriasis  
Reiter syndrome  
Rheumatoid arthritis  
Sarcoidosis  
Sjögren syndrome  
Stiff person syndrome 
Takayasu arteritis 
Ulcerative colitis 
Vogt-Koyanagi-Harada disease 


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APPENDIX 6. CONTRACEPTION GUIDELINES AND DEFINITIONS 
OF “WOMEN OF CHILDBEARING POTENTIAL,” “NO 
CHILDBEARING POTENTIAL”  
Contraception Guidelines 
The Clinical Trials Facilitation Group’s recommendations related to contraception and 
pregnancy testing in clinical trials include the use of highly effective forms of birth control 
(Clinical Trials Facilitation Group 2020). These methods include the following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with the inhibition of ovulation (oral, intravaginal, or transdermal). 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation: 
− oral 
− injectable 
− implantable  
• Intrauterine device. 
• Intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 
• Vasectomized male partner, provided that the vasectomized partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the 
vasectomized partner has received medical assessment of surgical success. 
• Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of exposure associated with the study treatment). 
NOTE: Total sexual abstinence should only be used as a contraceptive method if it is in 
line with the patient’s usual and preferred lifestyle. 
Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation methods), 
declaration of abstinence for the duration of exposure to study drugs, and withdrawal are 
not acceptable methods of contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) 
is not considered a highly effective method of contraception and if used, this method must be 
combined with another acceptable method listed above. 
Definitions of “Women of Childbearing Potential,” “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant. 
Conversely, “women of no childbearing potential” are defined as female patients meeting any of 
the following criteria: 
• Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 


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• Postmenopausal, defined as: 
− FE 
Adapted from: Recommendations related to contraception and pregnancy testing in clinical trials 


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APPENDIX 7. NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION  
Class 
Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity 
causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at 
rest. If any physical activity is undertaken, discomfort increases. 
Adapted from Dolgin et al 1994. 
Original source: Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood Vessels.  
Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p 114. 


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APPENDIX 8. EORTC-QLQ-C30 QUESTIONNAIRE  
 
 


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APPENDIX 9. EORTC QLQ-OES18 QUESTIONNAIRE  
 


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APPENDIX 10. EQ-5D-5L QUESTIONNAIRE  
 


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APPENDIX 11. CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION  
In adults, the most widely-used equations for estimating glomerular filtration rate (GFR) from 
serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
(Levey et al 2009) equation and the Modification of Diet in Renal Disease Study equation. 
National Kidney Disease Education Program calculators rely on creatinine determinations which 
are isotope dilution mass spectrometry traceable. All laboratories should be using creatinine 
methods calibrated to be isotope dilution mass spectrometry traceable. 
The CKD-EPI equation calculator should be used when serum creatinine (Scr) reported in mg/dL. 
This equation is recommended when estimated GFR values above 60 mL/min/1.73 m2 are 
desired. 
GFR = 141 × min (Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr/κ or 1, and 
max indicates the maximum of Scr/κ or 1. 
The equation does not require weight because the results are reported normalized to 1.73 m2 
body surface area, which is an accepted average adult surface area. 
The online calculator for CKD-EPI can be found here: https://www.niddk.nih.gov/health-
information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-
calculators 


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APPENDIX 12. IMMUNE-MEDIATED ADVERSE EVENT EVALUATION 
AND MANAGEMENT  
The recommendations below for the diagnosis and management of any immune-mediated 
adverse event (imAE) are intended as guidance.  This document should be used in conjunction 
with expert clinical judgement (by specialist physicians experienced in the treatment of cancer 
using immunological agents) and individual institutional guidelines or policies. 
Criteria used to diagnose imAEs include blood tests, diagnostic imaging, histopathology, and 
microbiology assessments to exclude alternative causes such as infection, PD, and adverse 
effects of concomitant drugs.  In addition to the results of these tests, the following factors 
should be considered when making an imAE diagnosis: 
• What was the temporal relationship between initiation of study drugs and the AE? 
• How did the patient respond to withdrawal of study drugs? 
• Did the event recur when study drugs was/were reintroduced? 
• Was there a clinical response to corticosteroids? 
• Is the event an autoimmune endocrinopathy? 
• Is PD or an alternative diagnosis a more likely explanation? 
When alternative explanations to autoimmune toxicity have been excluded, the imAE field 
associated with the AE in the electronic case report form should be checked. 
Recommended Diagnostic Tests in the Management of Possible Immune-Mediated Adverse Events 
Immune-Mediated Toxicity 
Diagnostic Evaluation Guideline 
Thyroid disorders 
Scheduled and repeat thyroid function tests (TSH and T4).   
Hypophysitis 
Check visual fields and consider pituitary endocrine axis blood profile.  Perform 
pituitary and whole brain MRI in patients with headache, visual disturbance, 
unexplained fatigue, asthenia, weight loss, and unexplained constitutional 
symptoms. 
Consider consultation with an endocrinologist if an abnormality is detected. 
Pneumonitis 
All patients presenting with new or worsened pulmonary symptoms or signs, 
such as an upper respiratory infection, new cough, shortness of breath or hypoxia 
should be assessed by high-resolution CT.  Consider pulmonary function test 
including DLCO. 
Radiographic appearance is often nonspecific.  Depending on the location of the 
abnormality, bronchoscopy and bronchoalveolar lavage or lung biopsy may be 
considered.  Consult with a respiratory medicine physician for cases of uncertain 
cause.   
Neurological toxicity 
Perform a comprehensive neurological examination and brain MRI for all CNS 
symptoms; review alcohol history and other medications.  Conduct a diabetic 
screen, and assess blood B12/folate, HIV status, TFTs, and consider autoimmune 
serology.  Consider the need for brain/spine MRI/MRA and nerve conduction 
study for peripheral neuropathy.  Consult with a neurologist if there are abnormal 
findings. 
Colitis 
Review dietary intake and exclude steatorrhea.  Consider comprehensive testing, 
including the following: FBC, UEC, LFTs, CRP, TFTs, stool microscopy and 


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Recommended Diagnostic Tests in the Management of Possible Immune-Mediated Adverse Events 
Immune-Mediated Toxicity 
Diagnostic Evaluation Guideline 
culture, viral PCR, Clostridium difficile toxin, and cryptosporidia (drug-resistant 
organism). 
In case of abdominal discomfort, consider imaging, eg, X-ray, CT scan.  If a 
patient experiences bleeding, pain or distension, consider colonoscopy with 
biopsy and surgical intervention, as appropriate.   
Eye disorders 
If a patient experiences acute, new onset, or worsening of eye inflammation, 
blurred vision, or other visual disturbances, refer the patient urgently to an 
ophthalmologist for evaluation and management.   
Hepatitis 
Check ALT/AST/total bilirubin, INR/albumin; the frequency will depend on 
severity of the AE (eg, daily if ≥ 3-4; every 2-3 days if Grade 2, until recovering).  
Review medications (eg, statins, antibiotics) and alcohol history.  Perform liver 
screen including hepatitis A/B/C serology, hepatitis E PCR and assess anti-
ANA/SMA/LKM/SLA/LP/LCI, iron studies.  Consider imaging (eg, ultrasound 
scan for metastases or thromboembolism).  Consult with a hepatologist and 
consider liver biopsy.   
Renal toxicity 
Review hydration status and medication history.  Test and culture urine.  
Consider renal ultrasound scan, protein assessment (dipstick/24-hour urine 
collection), or phase-contrast microscopy.  Refer to nephrology for further 
management assistance.   
Dermatology 
Consider other causes by conducting a physical examination; consider 
dermatology referral for skin biopsy. 
Joint or muscle inflammation 
Conduct musculoskeletal history and perform complete musculoskeletal 
examination.  Consider joint X-ray and other imaging as required to exclude 
metastatic disease.  Perform autoimmune serology and refer to rheumatology for 
further management assistance. 
For suspected myositis/rhabdomyolysis/myasthenia include: CK, ESR, CRP, 
troponin I and consider a muscle biopsy. 
Myocarditis 
Perform ECG, echocardiogram, troponin I, and refer to a cardiologist. 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, aspartate 
aminotransferase; CK, creatine kinase; CNS, central nervous system; CRP, C-reactive protein; CT, computed 
tomography; DLCO, diffusing capacity for carbon monoxide; ECG, electrocardiogram; ESR, erythrocyte 
sedimentation rate; FBC, full blood count; INR, international normalized ratio; LCI, liver cytosolic antigen; 
LFT, liver function test; LKM, liver kidney microsomal antibody; LP, liver pancreas antigen; MRA, magnetic 
resonance angiogram; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; SLA, soluble liver 
antigen; SMA, smooth muscle antibody; T4, thyroxine; TFT, thyroid function tests; TSH, thyroid-stimulating 
hormone; UEC, urea electrolytes and creatinine. 
Treatment of Immune-mediated Adverse Events 
• Immune-mediated AEs can escalate quickly; study treatment interruption, close 
monitoring, timely diagnostic work-up, and treatment intervention, as appropriate, 
with patients is required 
• Immune-mediated AEs should improve promptly after introduction of 
immunosuppressive therapy.  If this does not occur, review the diagnosis, seek further 
specialist advice, and contact the medical monitor 


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• For some Grade 3 toxicities that resolve quickly, rechallenge with study drugs may be 
considered if there is evidence of a clinical response to study treatment after 
consultation with the medical monitor 
• Steroid dosages in the table below are for oral or intravenous (methyl)prednisolone.  
Equivalent dosages of other corticosteroids can be substituted.  For steroid-refractory 
imAEs, consider use of steroid-sparing agents (eg, mycophenolate mofetil [MMF]) 
• Consider prophylactic antibiotics for opportunistic infections if the patient is 
receiving long-term immunosuppressive therapy 
Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Thyroid 
disorders 
1-2 
Asymptomatic TFT 
abnormality or mild 
symptoms 
Replace thyroxine if hypothyroid, 
until TSH/T4 levels return to normal 
range. 
Thyrotoxic patients should be 
referred to an endocrinologist.  In 
cases with systemic symptoms: 
withhold study treatment, treat with a 
beta blocker and consider oral 
prednisolone 0.5 mg/kg/day for 
thyroid pain.  Taper corticosteroids 
over 2-4 weeks.  Monitor thyroid 
function regarding the need for 
hormone replacement. 
Continue study 
treatment or withhold 
treatment in cases with 
systemic symptoms. 
3-4 
Severe symptoms, 
hospitalization required 
Refer patient to an endocrinologist. 
If hypothyroid, replace with 
thyroxine 0.5-1.6 µg/kg/day (for the 
elderly or those with co-morbidities, 
the suggested starting dose is 
0.5 μg/kg/day).  Add oral 
prednisolone 0.5 mg/kg/day for 
thyroid pain.  Thyrotoxic patients 
require treatment with a beta blocker 
and may require carbimazole until 
thyroiditis resolves. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 
Hypophysitis 
1-2 
Mild symptoms 
Refer patient to an endocrinologist 
for hormone replacement.  Add oral 
prednisolone 0.5-1 mg/kg/day for 
patients with pituitary inflammation.  
Taper corticosteroids over at least 
1 month.  If there is no improvement 
in 48 hours, treat as Grade 3-4.  Taper 
corticosteroids over at least 1 month. 
Continue study 
treatment. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3-4 
Moderate-severe 
symptoms 
Refer patient to an endocrinologist 
for assessment and treatment.  Initiate 
pulse IV methylprednisolone 1 mg/kg 
for patients with headache/visual 
disturbance due to pituitary 
inflammation.  Convert to oral 
prednisolone and taper over at least 
1 month.  Maintain hormone 
replacement according to 
endocrinology advice.  Maintain 
hormone replacement according to 
endocrinology advice. 
Hold study treatment 
for patients with 
headache/visual 
disturbance due to 
pituitary inflammation 
until resolved/improved 
to Grade 2 or less.  
Discontinuation is 
usually not necessary. 
Pneumonitis 
1 
Radiographic changes 
only 
Monitor symptoms every 2-3 days. 
If appearance worsens, treat as 
Grade 2. 
Consider holding study 
treatment until 
appearance improves 
and cause is 
determined. 
2 
Symptomatic: exertional 
breathlessness 
Commence antibiotics if infection 
suspected.  Add oral prednisolone 
1 mg/kg/day if symptoms/appearance 
persist for 48 hours or worsen.  
Consider Pneumocystis infection 
prophylaxis.  Taper corticosteroids 
over ≥ 6 weeks. 
Consider prophylaxis for adverse 
steroid effects: eg, blood glucose 
monitoring, vitamin D/calcium 
supplement. 
Hold study treatment.  
Retreatment is 
acceptable if symptoms 
resolve completely or 
are controlled on 
prednisolone 
≤ 10 mg/day.  
Discontinue study 
treatment if symptoms 
persist with 
corticosteroid 
treatment. 
3-4 
Severe or life-threatening 
symptoms 
Breathless at rest 
Admit to a hospital and initiate 
treatment with IV 
methylprednisolone 2-4 mg/kg/day.  
If there is no improvement, or 
worsening after 48 hours, add 
infliximab 5 mg/kg (if no hepatic 
involvement).  Convert to oral 
prednisolone and taper over at least 
2 months.  Cover with empiric 
antibiotics and consider prophylaxis 
for Pneumocystis infection and other 
adverse steroid effects, eg, blood 
glucose monitoring, 
vitamin D/calcium supplement. 
Discontinue study 
treatment. 
Neurological 
toxicity 
1 
Mild symptoms 
– 
Continue study 
treatment. 
2 
Moderate symptoms 
Treat with oral prednisolone 0.5-
1 mg/kg/day.  Taper over at least 
4 weeks.  Obtain neurology 
consultation. 
Hold study treatment; 
resume when 
resolved/improved to 
Grade 0-1. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3-4 
Severe/life-threatening, 
Grade 3 or 4 
encephalitis, or Guillain-
Barré syndrome 
Initiate treatment with oral 
prednisolone or IV 
methylprednisolone 1-2 mg/kg/day, 
depending on symptoms.  Taper 
corticosteroids over at least 4 weeks. 
Consider azathioprine, MMF, 
cyclosporine if no response within 
72-96 hours. Guillain-Barré 
syndrome: Start intravenous 
immunoglobulin 0.4 g/kg/day for 5 
days or plasmapheresis. Consider 
corticosteroids (methylprednisolone 2 
to 4 mg/kg/day) followed by a slow 
taper. Monitor for concurrent 
autonomic dysfunction. 
Discontinue study 
treatment. 
Colitis/diarrhea 
1 
Mild symptoms: < 3 liquid 
stools per day over 
baseline and feeling well 
Symptomatic management: fluids, 
loperamide, avoid high fiber/lactose 
diet. 
If Grade 1 persists for > 14 days 
manage as a Grade 2 event. 
Continue study 
treatment. 
2 
Moderate symptoms: 4-
6 liquid stools per day 
over baseline, or 
abdominal pain, or blood 
in stool, or nausea, or 
nocturnal episodes 
Oral prednisolone 0.5 mg/kg/day 
(non-enteric coated). 
Do not wait for any diagnostic tests 
to start treatment.  Taper steroids over 
2-4 weeks, consider endoscopy if 
symptoms are recurring. 
Hold study treatment; 
resume when 
resolved/improved to 
baseline grade. 
3 
Severe symptoms: 
> 6 liquid stools per day 
over baseline, or if 
episodic within 1 hour of 
eating 
 
Initiate IV methylprednisolone 1-
2 mg/kg/day. 
Convert to oral prednisolone and 
taper over at least 4 weeks.  Consider 
prophylaxis for adverse steroid 
effects, eg, blood glucose monitoring, 
vitamin D/calcium supplement. 
If no improvement in 72 hours or 
symptoms worsen, consider 
infliximab 5 mg/kg; if no perforation, 
sepsis, TB, hepatitis, NYHA 
Grade III/IV CHF or other 
immunosuppressive treatment: MMF 
or tacrolimus. 
Consult gastroenterologist to conduct 
colonoscopy/sigmoidoscopy. 
Hold study treatment; 
retreatment may be 
considered when 
resolved/improved to 
baseline grade and after 
discussion with the 
study medical monitor. 
4 
Life-threatening 
symptoms 
Discontinue study 
treatment. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Skin reactions 
1 
Skin rash, with or without 
symptoms, < 10% BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Continue study 
treatment. 
2 
Rash covers 10%-30% of 
BSA 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Topical steroids (moderate strength 
cream once a day or potent cream 
twice a day) ± oral or topical 
antihistamines for itch.  Consider a 
short course of oral steroids. 
Consider holding study 
treatment and monitor 
weekly for 
improvement. If not 
resolved, interrupt 
treatment until 
improved to Grade 1. 
3 
Rash covers > 30% BSA 
or Grade 2 with substantial 
symptoms 
Avoid skin irritants and sun 
exposure; topical emollients 
recommended. 
Initiate steroids as follows based on 
clinical judgement: 
For moderate symptoms: oral 
prednisolone 0.5-1 mg/kg/day for 
3 days then taper over 2-4 weeks. 
For severe symptoms: IV 
methylprednisolone 0.5-1 mg/kg/day; 
convert to oral prednisolone and taper 
over at least 4 weeks. 
Hold study treatment. 
Re-treat when AE is 
resolved or improved to 
mild rash (Grade 1-2) 
after discussion with 
the study medical 
monitor. 
4 
Skin sloughing > 30% 
BSA with associated 
symptoms (eg, erythema, 
purpura, epidermal 
detachment) 
Initiate IV methylprednisolone 1-
2 mg/kg/day.  Convert to oral 
prednisolone and taper over at least 
4 weeks. 
Admit to a hospital and seek urgent 
dermatology consultation. 
Discontinue study 
treatment. 
Hepatitis 
1 
ALT or AST > ULN to 3X 
ULN 
Check LFTs within 1 week and 
before the next dose check LFTs to 
verify that there has been no 
worsening. 
If LFTs are worsening, recheck every 
48-72 hours until improvement is 
seen. 
Continue study 
treatment if LFTs are 
unchanged or 
improving. 
Hold study treatment if 
LFTs are worsening 
until improvement is 
seen. 
2 
ALT or AST 3-5X ULN 
Recheck LFTs every 48-72 hours: 
For persistent ALT/AST elevation: 
consider oral prednisolone 0.5-
1 mg/kg/day for 3 days then taper 
over 2-4 weeks. 
For rising ALT/AST: start oral 
prednisolone 1 mg/kg/day and taper 
over 2-4 weeks; re-escalate dose if 
LFTs worsen, depending on clinical 
judgement.   
Hold study treatment; 
treatment may be 
resumed when 
resolved/improved to 
baseline grade and 
prednisolone tapered to 
≤ 10 mg. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
3 
ALT or AST 5-20X ULN 
Immediately start methylprednisolone 
1 to 2 mg/kg (or equivalent). Monitor 
closely. If no improvement after 
3 days, consider additional treatment 
options (MMF or azathioprine).  
If ALT and AST 
≤ 10 x ULN: Hold 
study treatment until 
improved to baseline 
grade; reintroduce only 
after discussion with 
the medical monitor. 
If ALT or AST 
> 10 x ULN: 
Discontinue study 
treatment. 
4 
ALT or AST > 20X ULN 
Initiate IV methylprednisolone 
2 mg/kg/day.  Convert to oral 
prednisolone and taper over ≥ 
6 weeks.   
Discontinue study 
treatment. 
Worsening LFTs despite steroids: 
If on oral prednisolone, change to pulsed IV methylprednisolone 
If on IV, add MMF 500-1000 mg twice a day 
If worsens on MMF, consider addition of tacrolimus 
Duration and dose of steroid required will depend on severity of event 
Nephritis 
1 
Creatinine 1.5X baseline 
or > ULN to 1.5X ULN 
Repeat creatinine weekly. 
If symptoms worsen, manage as per 
criteria below. 
Continue study 
treatment. 
2 
Creatinine > 1.5X-3X 
baseline or > 1.5X-3X 
ULN 
Ensure hydration and review 
creatinine in 48-72 hours; if not 
improving, consider creatinine 
clearance measurement by 24-hour 
urine collection.  Discuss with 
nephrologist the need for kidney 
biopsy. 
If attributed to study drug, initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 2 weeks. 
Repeat creatinine/U&E every 48-
72 hours. 
Hold study treatment. 
If not attributed to drug 
toxicity, restart 
treatment. 
If attributed to study 
drug and 
resolved/improved to 
baseline grade: Restart 
study drug if tapered to 
< 10 mg prednisolone. 
3 
Creatinine > 3X baseline 
or > 3X-6X ULN 
Hospitalize patient for monitoring 
and fluid balance; repeat creatinine 
every 24 hours; refer to a 
nephrologist and discuss need for 
biopsy.  If worsening, initiate IV 
(methyl)prednisolone 1-2 mg/kg.  
Taper corticosteroids over at least 
4 weeks. 
Hold study treatment 
until the cause is 
investigated. 
If study drug suspected: 
Discontinue study 
treatment. 
4 
Creatinine > 6X ULN 
As per Grade 3, patient should be 
managed in a hospital where renal 
replacement therapy is available. 
Discontinue study 
treatment. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
Diabetes/ 
hyperglycemia 
1 
Fasting glucose value 
ULN to 160 mg/dL; ULN 
to 8.9 mmol/L 
Monitor closely and treat according 
to local guideline.  Check for 
C-peptide and antibodies against 
glutamic acid decarboxylase and islet 
cells are recommended. 
Continue study 
treatment. 
2 
Fasting glucose value 160-
250 mg/dL; 8.9-
13.9 mmol/L 
Obtain a repeat blood glucose level at 
least every week.  Manage according 
to local guideline. 
Continue study 
treatment  
3 
Fasting glucose value 250-
500 mg/dL; 13.9-27.8 
mmol/L 
Admit patient to hospital and refer to 
a diabetologist for hyperglycemia 
management.  Corticosteroids may 
exacerbate hyperglycemia and should 
be avoided. 
Hold study treatment 
until patient is 
hyperglycemia 
symptom-free, and 
blood glucose has been 
stabilized at baseline or 
Grade 0-1. 
4 
Fasting glucose value 
> 500 mg/dL; 
> 27.8 mmol/L 
Admit patient to hospital and institute 
local emergency diabetes 
management.  Refer the patient to a 
diabetologist for insulin maintenance 
and monitoring. 
Ocular toxicity 
1 
Asymptomatic eye 
exam/test abnormality 
Consider alternative causes and 
prescribe topical treatment as 
required. 
Continue study 
treatment. 
2 
Anterior uveitis or mild 
symptoms 
Refer patient to an ophthalmologist 
for assessment and topical 
corticosteroid treatment.  Consider a 
course of oral steroids. 
Continue study 
treatment or hold 
treatment if symptoms 
worsen or if there are 
symptoms of visual 
disturbance. 
3 
Posterior 
uveitis/panuveitis or 
significant symptoms 
Refer patient urgently to an 
ophthalmologist.  Initiate oral 
prednisolone 1-2 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1; reintroduce 
only after discussion 
with the study medical 
monitor. 
4 
Blindness (at least 20/200) 
in the affected eyes 
Initiate IV (methyl)prednisolone 
2 mg/kg/day.  Convert to oral 
prednisolone and taper over at least 
4 weeks. 
Discontinue study 
treatment. 
Pancreatitis 
2 
Asymptomatic, blood test 
abnormalities 
Monitor pancreatic enzymes. 
Continue study 
treatment. 
3 
Abdominal pain, nausea 
and vomiting 
Admit to hospital for urgent 
management.  Initiate IV 
(methyl)prednisolone 1-2 mg/kg/day.  
Convert to oral prednisolone when 
amylase/lipase improved to Grade 2, 
and taper over at least 4 weeks. 
 
Hold study treatment; 
reintroduce only after 
discussion with the 
study medical monitor. 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
4 
Acute abdominal pain, 
surgical emergency 
Admit to hospital for emergency 
management and appropriate referral.   
Discontinue study 
treatment. 
Arthritis 
1 
Mild pain with 
inflammation, swelling 
Management per local guideline.   
Continue study 
treatment. 
2 
Moderate pain with 
inflammation, swelling, 
limited instrumental (fine 
motor) activities 
Management as per local guideline.  
Consider referring patient to a 
rheumatologist.  If symptoms worsen 
on treatment manage as a Grade 3 
event. 
Continue treatment or, 
if symptoms continue 
worsens, hold study 
treatment until 
symptoms improve to 
baseline or Grade 0-1. 
3 
Severe pain with 
inflammation or 
permanent joint damage, 
daily living activity 
limited 
Refer patient urgently to a 
rheumatologist for assessment and 
management.  Initiate oral 
prednisolone 0.5-1 mg/kg and taper 
over at least 4 weeks. 
Hold study treatment 
unless improved to 
Grade 0-1; reintroduce 
only after discussion 
with the study medical 
monitor. 
Mucositis/ 
stomatitis 
1 
Test findings only or 
minimal symptoms 
Consider topical treatment or 
analgesia as per local guideline. 
Continue study 
treatment. 
2 
Moderate pain, reduced 
oral intake, limited 
instrumental activities 
As per local guidelines, treat with 
analgesics, topical treatments, and 
oral hygiene care.  Ensure adequate 
hydration.  If symptoms worsen or 
there is sepsis or bleeding, manage as 
a Grade 3 event. 
Continue study 
treatment. 
3 
Severe pain, limited food 
and fluid intake, daily 
living activity limited 
Admit to hospital for appropriate 
management.  Initiate IV 
(methyl)prednisolone 1-2 mg/kg/day.  
Convert to oral prednisolone when 
symptoms improved to Grade 2 and 
taper over at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1. 
4 
Life-threatening 
complications or 
dehydration 
Admit to hospital for emergency care.  
Consider IV corticosteroids if not 
contraindicated by infection. 
Discontinue study 
treatment. 
Myositis/ 
rhabdomyolysis 
1 
Mild weakness 
with/without pain 
Prescribe analgesics. 
If CK is significantly elevated and 
patient has symptoms, consider oral 
steroids and treat as Grade 2.   
Continue study 
treatment. 
2 
Moderate weakness 
with/without pain 
If CK is 3 X ULN or worse initiate 
oral prednisolone 0.5-1 mg/kg and 
taper over at least 4 weeks. 
Hold study treatment 
until improved to 
Grade 0-1. 
3-4 
Severe weakness, limiting 
self-care 
Admit to hospital and initiate oral 
prednisolone 1 mg/kg.  Consider 
bolus IV (methyl)prednisolone and 1-
2 mg/kg/day maintenance for severe 
activity restriction or dysphagia.  If 
Hold study treatment 
until improved to 
Grade 0-1.  
Discontinue if any 


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Autoimmune 
Toxicity 
Grade 
Treatment Guidelines (Subject to 
Clinical Judgement) 
Study Drug 
Management 
symptoms do not improve add 
immunosuppressant therapy. Taper 
oral steroids over at least 4 weeks. 
evidence of myocardial 
involvement. 
Myocarditis 
< 2 
Asymptomatic but 
significantly increased 
CK-MB or increased 
troponin OR clinically 
significant intraventricular 
conduction delay 
Admit to hospital and refer to a 
cardiologist. 
Transfer all patients with 
moderate/severe cardiac symptoms or 
any increase in cardiac serum 
markers to the coronary care unit. 
Initiate oral prednisolone or IV 
(methyl)prednisolone at 1-
2 mg/kg/day.  Manage symptoms of 
cardiac failure according to local 
guidelines. 
If no immediate response change to 
pulsed doses of (methyl)prednisolone 
1 g/day and add MMF, infliximab or 
anti-thymocyte globulin. 
Hold study treatment 
until completely 
resolved or myocarditis 
has been ruled out. 
2 
Symptoms on mild-
moderate exertion 
Discontinue study 
treatment unless 
cardiac involvement 
has been excluded and 
symptoms have 
completely resolved. 
3 
Severe symptoms with 
mild exertion 
4 
Life-threatening 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSA, body 
surface area; CK, creatine kinase; CK-MB, creatine kinase-muscle-brain; CHF, congestive heart failure; 
INR, international normalized ratio; IV, intravenous; LFT, liver function test; MMF, mycophenolate mofetil; 
NYHA, New York Heart Association; T4, thyroxine; TB, tuberculosis; TFT, thyroid function test; 
TSH, thyroid-stimulating hormone; U&E, urea and electrolytes; ULN, upper limit of normal. 


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APPENDIX 13. THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES, VERSION 1.1  
The text below was obtained from the following reference: Eisenhauer et al 2009. 
DEFINITIONS 
Response and progression will be evaluated in this trial using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1).  
Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are 
used in the RECIST criteria. 
Note: Lesions are either measurable or non-measurable using the criteria provided below.  The 
term “evaluable” in reference to measurability will not be used because it does not provide 
additional meaning or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the 
slice thickness and a minimum of 10 mm). 
• 10 mm caliper measurement by clinical examination (when superficial). 
• 20 mm by chest x-ray (if clearly defined and surrounded by aerated lung). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT or MRI scan (CT/MRI scan slice 
thickness recommended to be ≥ 5 mm).  At baseline and in follow-up, only the short axis will be 
measured and followed. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter ≥ 10 to < 15 mm 
with conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable 
disease.  Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all non-measurable. 
Bone lesions: 
• Bone scan, PET scan, or plain films are not considered adequate imaging techniques 
to measure 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 as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
• Blastic bone lesions are non-measurable. 


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Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
• Cystic lesions thought to represent cystic metastases can be considered as 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.  Trial protocols should detail the conditions 
under which such lesions would be considered measurable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organ, but in addition should be those that lend themselves to reproducible repeated 
measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥ 15 mm by CT or MRI 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.  Nodal size is normally reported as 2 dimensions in the plane in 
which the image is obtained (for CT scan, 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 which 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 
< 10 mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 


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Non-target Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required, and 
these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal 
progression” (more details to follow).  In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case record form (eg, “multiple enlarged 
pelvic lymph node” or “multiple liver metastases”). 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
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 follow-up.  Imaging-based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are accessible by clinical examination. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and P10 mm diameter as assessed using calipers (eg, skin nodules).  For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested.  As noted above, when lesions can be evaluated by both clinical examination and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the trial. 
• Chest x-ray: Chest CT is preferred over chest x-ray, particularly when progression is 
an important endpoint, because CT is more sensitive than x-ray, particularly in 
identifying new lesions.  However, lesions on chest x-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung. 
• CT, MRI: CT is the best currently available and reproducible method to measure 
lesions selected for response assessment.  This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less.  
When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable in 
certain situations (eg, for body scans). 
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.  Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identified by ultrasound in 
the course of the study, confirmation by CT or MRI is advised.  If there is concern 
about radiation exposure at CT, MRI may be used instead of CT in selected instances. 


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• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised.  However, they can be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials 
where recurrence following CR or surgical resection is an endpoint. 
• Tumor markers: Tumor markers alone cannot be used to assess objective tumor 
response.  If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in CR.  Because tumor markers are disease 
specific, instructions for their measurement should be incorporated into protocols on a 
disease specific basis.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and prostate-specific antigen response (in recurrent prostate cancer), 
have been published.  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line trials in ovarian cancer. 
• Cytology, histology: These techniques can be used to differentiate between partial 
response (PR) and CR in rare cases if required by protocol (for example, residual 
lesions in tumor types such as germ cell tumors, where known residual benign tumors 
can remain).  When effusions are known to be a potential adverse effect of treatment 
(eg, with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment can be considered if the measurable tumor has met criteria for response or 
stable disease to differentiate between response (or stable disease) and PD. 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
• CR: Disappearance of all target lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to < 10 mm. 
• PR: At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
• PD: At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  (Note: the appearance of 1 or 
more new lesions is also considered progression). 
• Stable disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
• 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 nodes regress to below 10 mm on study.  This 
means that when lymph nodes are included as target lesions, the “sum” of lesions 
may not be zero even if CR criteria are met, since a normal lymph node is defined as 
having a short axis of < 10 mm.  Case report recorded in a separate section where, to 
qualify for CR, each node must achieve a short axis < 10 mm.  For PR, stable disease, 


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and PD, the actual short axis measurement of the nodes is to be included in the sum of 
target lesions. 
• Target lesions that become “too small to measure.” While on study, all lesions (nodal 
and non-nodal) recorded at baseline should have their actual measurements recorded 
at each subsequent evaluation, even when very small (eg, 2 mm).  However, 
sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being “too small to measure.” 
• When this occurs, it is important that a value be recorded on the electronic case report 
form (eCRF).  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 (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 and is faintly seen but too small to measure, a default value of 5 mm should 
be assigned in this circumstance as well).  This default value is derived from the 
5 mm CT slice thickness (but should not be changed with varying CT slice thickness).  
The measurement of these lesions is potentially non-reproducible, therefore providing 
this default value will prevent false responses or progressions based upon 
measurement error.  To reiterate, however, if the radiologist is able to provide an 
actual measure, that should be recorded, even if it is below 5 mm. 
• Lesions that split or coalesce on treatment: When non-nodal lesions “fragment,” the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  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 maximal 
longest diameter for the “coalesced lesion.” 
Evaluation of Non-target Lesions 
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 protocol. 
• CR: Disappearance of all non-target lesions and normalization of tumor marker level.  
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• PD: Unequivocal progression (as detailed below) of existing non-target lesions.  
(Note: the appearance of 1 or more new lesions is also considered progression.) 
• Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
• When the patient also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of stable 


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disease or PR in target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy.  A modest “increase” in the size of 1 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 disease in the face of stable disease or PR of target disease will therefore 
be extremely rare. 
• When the patient has only non-measurable disease: This circumstance arises in some 
Phase 3 trials when it is not a criterion of trial entry to have measurable disease.  The 
same general concept applies here 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-target 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: ie, an increase in tumor burden representing an additional 
73% increase in “volume” (which is equivalent to a 20% increase diameter in a 
measurable lesion). 
• Examples include an increase in a pleural effusion from “trace” to “large,” an 
increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy.” 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 PD; 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: ie, 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 pre-existing lesions).  This is particularly important when the patient’s 
baseline lesions show partial or complete response.  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 on a follow-up trial in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate PD.  An example of this is the patient who has 
visceral disease at baseline and while on trial has a CT or MRI brain scan ordered that reveals 
metastases.  The patient’s brain metastases are considered to be evidence of PD even if he/she 
did not have brain imaging at baseline. 
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, then progression should be declared using the date of the initial scan. 


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While fluorine-18 [F-18] fluorodeoxyglucose (FDG)-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement 
CT scanning in assessment of progression (particularly possible “new” disease).  New lesions on 
the basis of FDG-PET imaging can be identified according to the following algorithm: 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up, is a sign of 
PD based on a new lesion.   
• No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of disease 
on CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a 
pre-existing site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
Evaluation of Best Overall Response 
The BOR is the best response recorded from the start of the study drug treatment until the end of 
treatment considering any requirement for confirmation.  On occasion a response may not be 
documented until after the end of therapy so protocols should be clear if post-treatment 
assessments are to be considered in determination of BOR.  Protocols must specify how any new 
therapy introduced before progression will affect best response designation.  The patient’s BOR 
assignment will depend on the findings of both target and non-target disease and will also take 
into consideration the appearance of new lesions.  Furthermore, depending on the nature of the 
trial and the protocol requirements, it may also require confirmatory measurement.  Specifically, 
in nonrandomized trials where response is the primary endpoint, confirmation of PR or CR is 
needed to deem either one the “BOR.” 
The BOR is determined once all the data for the patient is known.  Best response determination 
in trials where confirmation of complete or partial response IS NOT required: Best response in 
these trials is defined as the best response across all timepoints (for example, a patient who has 
stable disease at first assessment, PR at second assessment, and PD on last assessment has a 
BOR of PR).  When stable disease is believed to be best response, it must also meet the protocol 
specified minimum time from baseline.  If the minimum time is not met when stable disease is 
otherwise the best timepoint response, the patient’s best response depends on the subsequent 
assessments.  For example, a patient who has stable disease at first assessment, PD at second and 
does not meet minimum duration for stable disease, will have a best response of PD.  The same 
patient lost to follow-up after the first stable disease assessment would be considered 
inevaluable. 


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Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
Stable disease 
Non-PD or not all 
evaluated 
No 
Stable disease 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response. 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that patients with CR may 
not have a total sum of “zero” on the eCRF. 
In trials where confirmation of response is required, repeated ‘NE’ timepoint assessments may 
complicate best response determination.  The analysis plan for the trial must address how 
missing data/assessments will be addressed in determination of response and progression.  For 
example, in most trials it is reasonable to consider a patient with timepoint responses of PR-not 
evaluable-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of PD 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 trial therapy. 
Conditions that define “early progression, early death, and inevaluability” are trial specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of CR depends upon this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR.  FDG-PET 
may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a 
residual radiographic abnormality is thought to represent fibrosis or scarring.  The use of 
FDG-PET in this circumstance should be prospectively described in the protocol and supported 
by disease specific medical literature for the indication.  However, it must be acknowledged that 
both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 


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For equivocal findings of progression (eg, 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. 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
Confirmation 
In nonrandomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error.  This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials.  However, in all other circumstances, ie, in 
randomized trials (Phase 2 or 3) or trials where stable disease or progression are the primary 
endpoints, confirmation of response is not required since it will not add value to the 
interpretation of trial results.  However, elimination of the requirement for response confirmation 
may increase the importance of central review to protect against bias, in particular in trials which 
are not blinded. 
In the case of stable disease, measurements must have met the stable disease criteria at least once 
after trial entry at a minimum interval (in general not less than 6 weeks). 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent disease or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this is the 
reference for calculation of PD). 
The clinical relevance of the duration of stable disease varies in different studies and diseases.  If 
the proportion of patients achieving stable disease for a minimum period of time is an endpoint 
of importance in a particular trial, the protocol should specify the minimal time interval required 
between 2 measurements for determination of stable disease. 
Note: The DOR and stable disease as well as the PFS are influenced by the frequency of 
follow-up after baseline evaluation.  It is not in the scope of this guideline to define a standard 
follow-up frequency.  The frequency should consider many parameters including disease types 
and stages, treatment periodicity, and standard practice.  However, these limitations of the 
precision of the measured endpoint should be considered if comparisons between trials are to be 
made. 


Signature Page 
Approval with eSignature

SAP_001.pdf: 
AdvanTIG-203
BeiGene
Statistical Analysis Plan 1.0
27 February 2023
CONFIDENTIAL
Page 1
STATISTICAL ANALYSIS PLAN
Study Protocol Number:
BGB-A317-A1217-203 (AdvanTIG-203)
Study Protocol Title:
A Phase 2, Multicenter, Randomized, Placebo-Controlled 
Study to Compare the Efficacy of Anti-PD-1 Monoclonal 
Antibody Tislelizumab (BGB-A317) Plus Anti-TIGIT 
Monoclonal Antibody Ociperlimab (BGB-A1217) Versus 
Tislelizumab Plus Placebo as Second-Line Treatment in 
Patients With PD-L1 Tumor Area Positivity (TAP) Ŏ 10% 
Unresectable, Locally Advanced, Recurrent or Metastatic 
Esophageal Squamous Cell Carcinoma
Date:
27 February 2023
Version:
1.0
NCT Number:
NCT04732494


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................6 
1................. INTRODUCTION ........................................................................................................8 
2................. STUDY OVERVIEW ...................................................................................................8 
2.1.............. Study Design .................................................................................................................8 
2.2.............. Study Assessments......................................................................................................10 
3................. STUDY OBJECTIVES ..............................................................................................10 
3.1.............. Primary Objective .......................................................................................................10 
3.2.............. Secondary Objective ...................................................................................................10 
3.3.............. Exploratory Objective .................................................................................................11 
4................. DEFINITION OF ESTIMANDS ................................................................................11 
5................. STUDY ENDPOINTS ................................................................................................12 
5.1.............. Primary Endpoint(s) ....................................................................................................12 
5.2.............. Secondary Endpoints ..................................................................................................12 
5.3.............. Exploratory Endpoints ................................................................................................12 
6................. SAMPLE SIZE CONSIDERATIONS .......................................................................13 
7................. STATISTICAL METHODS .......................................................................................13 
7.1.............. Analysis Sets ...............................................................................................................13 
7.2.............. Multiplicity Adjustment..............................................................................................13 
7.3.............. Data Analysis General Considerations .......................................................................13 
7.3.1........... Definitions and Computations ....................................................................................13 
7.3.2........... Conventions ................................................................................................................14 
7.3.3........... Handling of Missing Data ...........................................................................................15 
7.4.............. Patient Characteristics ................................................................................................15 
7.4.1........... Patient Disposition ......................................................................................................15 
7.4.2........... Protocol Deviations ....................................................................................................15 
7.4.3........... Demographic and Other Baseline Characteristics ......................................................15 
7.4.4........... Disease History ...........................................................................................................16 
7.4.5........... Prior Anticancer Drug Therapies and Surgeries .........................................................16 
7.4.6........... Prior and Concomitant Medications ...........................................................................16 
7.4.7........... Medical History ..........................................................................................................17 
7.5.............. Efficacy Analysis ........................................................................................................17 


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7.5.1........... Primary Efficacy Endpoint(s) .....................................................................................17 
7.5.2........... Secondary Efficacy Endpoints ....................................................................................18 
7.5.3........... Subgroup Analyses .....................................................................................................24 
7.5.4........... Exploratory Efficacy Endpoints .................................................................................24 
7.5.5........... New Anticancer Therapy ............................................................................................25 
7.6.............. Safety Analyses ..........................................................................................................25 
7.6.1........... Extent of Exposure .....................................................................................................25 
7.6.2........... Adverse Events ...........................................................................................................26 
7.6.2.1........ Treatment Emergent Adverse Event ...........................................................................26 
7.6.2.2........ Immune-mediated Adverse Event ..............................................................................27 
7.6.2.3........ Infusion-related Adverse Event ..................................................................................28 
7.6.2.4........ Death ...........................................................................................................................28 
7.6.3........... Laboratory Values ......................................................................................................28 
7.6.4........... Vital Signs ..................................................................................................................29 
7.6.5........... Electrocardiograms (ECG) .........................................................................................30 
7.6.6........... Eastern Cooperative Oncology Group (ECOG) Performance Status .........................30 
7.7.............. Pharmacokinetic Analyses ..........................................................................................30 
7.7.1........... Reporting of Pharmacokinetic Concentrations for Descriptive Statistics ..................30 
7.8.............. Immunogenicity Analyses ..........................................................................................30 
8................. INTERIM ANALYSES ..............................................................................................31 
9................. CHANGES IN THE PLANNED ANALYSIS ...........................................................31 
10............... REFERENCES ...........................................................................................................32 
11............... APPENDIX.................................................................................................................33 
11.1............ Appendix 1: Imputation Rules for Partial Dates .........................................................33 
11.1.1......... Impute partial dates for concomitant medication .......................................................33 
11.1.2......... Impute partial dates for adverse events ......................................................................33 
11.1.3......... Impute partial dates for subsequent anticancer surgery/procedure as collected 
in the post-treatment page ...........................................................................................34 
11.1.4......... Impute partial dates for disease history and prior therapy (drug, 
surgery/procedure, radiotherapy) ................................................................................34 
11.2............ Appendix 2: Rules for Identifying Missing Tumor Assessments ...............................34 
 
 


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LIST OF TABLES 
Table 1:          Handling of Intercurrent Events and Missing Values for the Primary     
Analysis of ORR .........................................................................................................18 
Table 2:          Censoring Rules for Progression-Free Survival Per RECIST Version 1.1 ............20 
Table 3:          Scoring of QLQ-C30 ..............................................................................................22 
Table 4:          Scoring of QLQ-OES18 .........................................................................................23 
Table 5:          Clinical Laboratory Parameters ..............................................................................28 
Table 6:          Example of Scheduled Tumor Assessments With Time Window..........................35 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
Antidrug Antibody 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
CBR 
Clinical Benefit Rate 
CR 
Complete Response  
CV 
Coefficient of Variation 
DCR 
Disease Control Rate 
DOR 
Duration of Response 
ECG 
Electrocardiograms 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic case report form 
EORTC 
European Organization for Research and Treatment of Cancer 
EQ-5D-5L 
European Quality of Life 5-Dimensional 5-Level 
ESCC 
Esophageal Squamous Cell Carcinoma 
GHS 
Global Health Status  
HRQoL 
Health Related Quality of Life 
imAE 
Immune-mediated adverse event 
IRC 
Independent Review Committee 
INV 
Investigator  
IRR 
Infusion-Related Reactions 
IRT 
Interactive Response Technology 
ITT 
Intent to Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Event 
ORR 
Objective Response Rate  
OS 
Overall Survival 
PD 
Progressive disease 
PD-L1 
Programmed cell death protein-ligand 1 
PFS 
Progression-free survival 


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PK 
Pharmacokinetic 
PR 
Partial Response 
PRO 
Patient-reported outcomes 
PT 
Preferred Term  
QLQ-C30 
Quality of Life Questionnaire-Core 30 
QLQ-OES18 
Quality of Life Oesophageal Cancer Questionnaires 18 
QoL 
Quality of Life 
RECIST  
Response Evaluation Criteria in Solid Tumors  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SI 
Système International 
SOC 
System Organ Class 
TAP 
Tumor Area Positivity 
TCM 
Traditional Chinese Medication 
TEAE 
Treatment-Emergent Adverse Event 
TMB 
Tumor Mutation Burden 
TTR 
Time to Response 
VAS 
Visual Analog Scale 
WHO DD 
World Health Organization Drug Dictionary 
 


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1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for AdvanTIG-203: a Phase 2, multicenter, 
randomized, placebo-controlled study to compare the efficacy of anti-PD-1 monoclonal antibody 
tislelizumab (BGB-A317) plus anti-TIGIT monoclonal antibody ociperlimab (BGB-A1217) 
versus tislelizumab plus placebo as second-line treatment in patients with PD-L1 TAP ≥ 10% 
unresectable, locally advanced, recurrent or metastatic esophageal squamous cell carcinoma. This 
SAP is based on AdvanTIG-203 Protocol Amendment 2.0, dated on 27 February, 2023. The focus 
of this SAP is the planned final analysis specified in the study protocol. Separate analysis plans 
for Pharmacogenomics and Biomarker analyses that are not described within this SAP may be 
prepared as needed.  
2. 
STUDY OVERVIEW 
2.1. 
Study Design 
This is a multicenter, randomized, investigator-and patient-blinded, sponsor-unblinded, placebo-
controlled global Phase 2 study to compare the efficacy of anti-PD-1 monoclonal antibody 
tislelizumab plus anti-TIGIT monoclonal antibody ociperlimab versus tislelizumab plus placebo 
as second-line treatment in patients with PD-L1 TAP ≥ 10% unresectable, locally advanced, 
recurrent or metastatic Esophageal Squamous Cell Carcinoma (ESCC). After providing written 
informed consent, completing all prescreening and screening assessments, and being confirmed as 
eligible for study participation, approximately 120 patients will be randomized at a 1:1 ratio to 
receive 1 of the following treatment regimens: 
x Arm A: tislelizumab + ociperlimab 
x Arm B: tislelizumab + placebo 
Eligible patients will be stratified by the following factors: 
x ECOG PS score (0 versus 1) 
x Number of organs with metastases (≤1 versus ≥2) 
x Region (Asia versus non-Asia) 
Study drugs (including placebo) will be administered until PD per RECIST v1.1, unacceptable 
toxicity, or withdrawal of informed consent, whichever occurs first. 
No crossover between Arm A and Arm B will be allowed. 
The study design schema is in Figure 1. 
 


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Figure 1: Study Schema
Abbreviations: ADA, antidrug antibody; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern 
Cooperative Oncology Group Performance Status; ESCC, esophageal squamous cell carcinoma; HRQoL, Health 
Related Quality of Life; INV, investigator; IRC, Independent Review Committee; IV, intravenously; ORR, objective 
response rate; OS, overall survival; PD-L1, programmed cell death protein-ligand 1 (PD-L1); PFS, progression-free 
survival; PK, pharmacokinetics; Q3W, once every 3 weeks; RECIST v1.1, Response Evaluation Criteria in Solid 
Tumors version 1.1; TAP; Tumor Area Positivity.
Note: The initial infusion (Cycle 1 and Cycle 2, Day 1) will be administered over a period of 60 minutes. If this 
infusion is well tolerated, subsequent infusions may be administered over 30 minutes. After infusion, patients will be 
further monitored for at least 1 hour during Cycles 1 and 2. From Cycle 3 onward, a postinfusion monitoring period 
of at least 30 minutes will be required.
At the discretion of the investigator, patients may continue tislelizumab and ociperlimab or tislelizumab alone after 
PD under protocol defined conditions.
Key changes made from Original Protocol 0.0 (16 September 2020) to Protocol Amendment 1.0 
(03 June 2022) were as follows:
x
The expected number of randomized patients was revised from approximately 280 to 
approximately 120.
x
Overall survival (OS) was moved from a primary objective to secondary objective.
x
Study became single-blind versus double-blind (sponsor is unblinded but investigators, 
site staff, and patients remains blinded).
Key changes made from Protocol Amendment 1.0 (03 June 2022) to Protocol Amendment 2.0 (27
February 2023) were as follows:
x
Revised the percentage and number of the overall survival (OS) events from 70% (84 
deaths) of the total sample size to 60% (72 deaths) in the secondary efficacy analysis.
x
Revised the testing method of the null hypothesis of ORR from Miettinen and Nurminen 
test to Cochran-Mantel-Haenszel method.


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2.2. 
Study Assessments 
Tumor Assessment 
Tumor imaging will be performed at baseline (≤ 28 days before randomization).  During the study, 
tumor imaging will be performed approximately every 6 weeks (± 7 days) for the first 54 weeks 
and every 12 weeks (± 7 days) thereafter. Response will be assessed using RECIST v1.1.  A patient 
who discontinues study drugs early for reasons other than PD (eg, treatment toxicity) will continue 
to undergo tumor assessments according to the original plan until the patient experiences PD, 
withdraws consent, is lost to follow-up, dies, or until the study terminates, whichever occurs first.  
Patient-reported outcomes (PROs) will be collected using the EORTC QLQ-C30, EORTC QLQ-
OES18, and EQ-5D-5L before dosing on Day 1 of every other treatment cycle during the first 54 
weeks, Day 1 of every 4 cycles thereafter, and at the on-site safety follow-up visit. 
Safety Assessment 
Patients will be evaluated for any AEs and SAEs occurring up to 30 days after the last dose of 
study drugs (all severity grades, per NCI-CTCAE v5.0) or initiation of a new anticancer therapy, 
whichever occurs first, and immune-mediated AEs (imAEs) occurring up to 90 days after the last 
dose of study drugs regardless of initiation of a subsequent anticancer therapy. All drug-related 
SAEs will be recorded by the investigator after treatment discontinuation until patient death, 
withdrawal of consent, or loss to follow-up, whichever occurs first, and will be followed until they 
resolve to baseline or ≤ Grade 1, are assessed by the investigator as stable and unlikely to improve, 
or the patient is lost to follow-up, whichever occurs first. 
3. 
STUDY OBJECTIVES 
3.1. 
Primary Objective 
x 
To compare the objective response rate (ORR), as assessed by the investigator according to 
RECIST v1.1, of tislelizumab plus ociperlimab with tislelizumab plus placebo as second-line 
treatment in patients with PD-L1 TAP ≥ 10% unresectable, locally advanced, recurrent or 
metastatic ESCC in the Intent to Treat (ITT) Analysis Set.  
3.2. 
Secondary Objective 
x 
To compare the overall survival (OS) of tislelizumab plus ociperlimab with tislelizumab plus 
placebo as second-line treatment in patients with PD-L1 TAP ≥ 10% ESCC in the ITT 
Analysis Set. 
x 
To compare the following endpoints between tislelizumab plus ociperlimab and tislelizumab 
plus placebo based on tumor assessments per RECIST v1.1: 
 
Progression-free survival (PFS) assessed by both Independent Review Committee (IRC) 
and the investigator 
 
Duration of response (DOR), DCR, and clinical benefit rate (CBR) assessed by both the 
IRC and the investigator 
 
ORR assessed by the IRC 


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x 
To compare the safety and tolerability between tislelizumab plus ociperlimab and tislelizumab 
plus placebo. 
x 
To compare the health-related quality of life (HRQoL) via cancer-specific patient reported 
outcomes (PROs) between tislelizumab plus ociperlimab and tislelizumab plus placebo. 
3.3. 
Exploratory Objective 
x 
To characterize the PK of ociperlimab and tislelizumab. 
x 
To assess host immunogenicity to ociperlimab and tislelizumab. 
x 
To compare the quality of life (QoL) via a generic PRO between tislelizumab plus ociperlimab 
and tislelizumab plus placebo. 
4. 
DEFINITION OF ESTIMANDS  
Primary scientific question of interest: “Will tislelizumab plus ociperlimab versus tislelizumab 
plus placebo increases complete response (CR) or partial response (PR) rate prior to disease 
progression and any new anticancer therapy in patients with PD-L1 TAP ≥ 10% unresectable, 
locally advanced, recurrent or metastatic ESCC?” 
The primary estimand is described by the following attributes:  
1. Treatment of interest 
The study experimental treatment is tislelizumab + ociperlimab. The study control 
treatment for comparison is tislelizumab + placebo. 
2. Population 
Adult patients with PD-L1 TAP ≥ 10% unresectable, locally advanced, recurrent or 
metastatic ESCC who progressed or were intolerant to first-line treatment.  
3. Variable 
ORR, defined as the proportion of patients who have confirmed CR or PR prior to disease 
progression by the investigator’s review per RECIST v1.1. 
4. Handling of remaining intercurrent events 
x New anticancer therapy started prior to disease progression: patients starting any 
new anticancer therapy without achieving a confirmed CR or PR before will be 
considered as non-responders (composite strategy). 
x Discontinuation of treatment prior to disease progression: response assessment 
after discontinuation of treatment will be counted and used for analysis (treatment 
policy strategy) 
5. Population-level summary 
The ORR difference estimated by Mantel-Haenszel common risk difference stratified by, 
ECOG PS score [0 versus 1] and the number of organs with metastases [≤1 versus ≥2]). 


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5. 
STUDY ENDPOINTS 
5.1. 
Primary Endpoint(s) 
x 
ORR, defined as the proportion of patients who have confirmed CR or PR by the 
investigator’s review per RECIST v1.1 in the ITT Analysis Set. 
5.2. 
Secondary Endpoints 
x 
OS, defined as the time from the date of randomization until the date of death due to any 
cause in all randomized patients in the ITT Analysis Set. 
x 
ORR, defined as above and assessed by the IRC per RECIST v1.1 in the ITT Analysis 
Set. 
x 
PFS, defined as the time from the date of randomization to the date of first documentation 
of PD assessed by investigator (or IRC) per RECIST v1.1 or death, whichever occurs first 
in the ITT Analysis Set. 
x 
DOR, defined as the time from the first determination of an objective response until the 
first documentation of PD as assessed by investigator (or IRC) per RECIST v1.1, or death, 
whichever comes first in the ITT Analysis Set. 
x 
DCR, defined as the proportion of patients who have confirmed CR, confirmed PR, and 
stable disease assessed by investigator (or IRC) per RECIST v1.1 in the ITT Analysis Set. 
x 
CBR, defined as the proportion of patients who achieve confirmed CR, confirmed PR, 
and durable stable disease (stable disease ≥ 24 weeks).  
x 
HRQoL, assessed by changes from baseline in the scores of key PRO endpoints of Global 
Health Status (GHS)/QoL and Physical Function of European Organization for Research 
and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) 
and scores of Dysphagia, Eating, Reflux and Pain scales of EORTC Quality of Life 
Oesophageal Cancer Questionnaires 18 (QLQ-OES18). 
x 
AEs and SAEs as characterized by type, frequency, severity (as graded by National 
Cancer Institute Common Terminology Criteria for Adverse Event [NCI-CTCAE] 
version 5.0 [v5.0]), timing, seriousness, and relationship to study drugs, physical 
examinations, electrocardiograms (ECGs), and laboratory assessments.  
5.3. 
Exploratory Endpoints 
x 
Serum ociperlimab and tislelizumab concentrations at specified timepoints.  
x 
Immunogenic responses to ociperlimab and tislelizumab, evaluated through the detection 
of ADAs. 
x 
QoL, defined as assessment of the European Quality of Life 5-Dimensional 5-Level 
(EQ-5D-5L) via visual analog scale (VAS) in the ITT Analysis Set.  


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6. 
SAMPLE SIZE CONSIDERATIONS 
The sample size calculation is based on the primary efficacy analysis of ORR between Arm A and 
Arm B in the ITT Analysis Set. The number of patients was revised from 280 to 120 based on the 
Protocol Amendment 1.0.  
With 120 randomized patients, the study has at least 80% power to detect a 24% difference in ORR 
(45% vs 21% in Arm A and Arm B, respectively) at a 1-sided type I error of 0.025.The efficacy 
boundary of primary analysis of ORR is >16.3% ORR difference.  
The sample size is calculated by EAST (version 6.4.1). 
7. 
STATISTICAL METHODS 
7.1. 
Analysis Sets 
The Intent-to-Treat (ITT) Analysis Set includes all randomized patients. Patients will be analyzed 
according to their assigned treatment at randomization. This will be the primary analysis set for all 
efficacy analyses, including HRQoL analysis.  
The Safety Analysis Set includes all patients who received ≥ 1 dose of any component of study 
drugs. Patients will be analyzed according to their actual treatment received. This will be the 
primary analysis set for safety analyses. 
The PK Analysis Set includes all patients who received ≥ 1 dose of any component of study drugs 
per the protocol, and for whom any postdose PK data are available.  
The Immunogenicity Analysis Set includes all patients who received ≥ 1 dose of any component 
of study drugs and for whom both baseline antidrug antibody and at least 1 postbaseline antidrug 
antibody result are available. 
7.2. 
Multiplicity Adjustment 
The primary endpoint ORR will be tested at a 1-sided alpha of 0.025. If the null hypothesis for 
ORR in the ITT Analysis Set is rejected, the secondary endpoint OS in the ITT Analysis Set will 
be tested. 
7.3. 
Data Analysis General Considerations 
7.3.1. 
Definitions and Computations 
Study day 
Study day will be calculated in reference to the first dose date for safety analysis. For assessments 
conducted on or after the first dose date, study day will be calculated as (assessment date –first 
dose date + 1). For assessments conducted before first dose date, study day is calculated as 
(assessment date – first dose date). There is no study day 0. In the situation where the event date 
is partial or missing, the date will appear partial or missing in the listings. Study day and any 
corresponding durations will be presented based on the imputations specified in Appendix 1.  
To derive the duration of any efficacy endpoint, the reference date will be date of randomization. 


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Baseline Measurements 
x 
Efficacy evaluation except HRQoL  
A baseline value is defined as the last non-missing value collected prior to the 
randomization.  
x 
Safety and HRQoL 
A baseline value is defined as the last non-missing value prior to the first study drug 
administration. 
x 
Toxicity grade of certain laboratory tests 
Two baseline toxicity grades should be derived according to the directions (lower (Hypo) 
or higher (Hyper)). For example, a baseline hemoglobin with value between 10.0 g/dL 
and LLN, two baseline toxicity grades: Grade 1 for Hypo and Grade 0 for Hyper will be 
derived.  
Study Follow-up Duration 
Study follow-up duration is defined as the duration from the randomization date to the study 
discontinuation date (eg, death, consent withdrawal, lost to follow-up) or to cutoff date if a patient 
is still ongoing. 
All calculations and analyses will be conducted using SAS® Version 9.4 or higher. 
7.3.2. 
Conventions 
Unless otherwise specified, the following conventions will be applied to all analyses: 
x 
1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 
significant digit. 
x 
1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded up 
to 1 significant digit. 
x 
P-values will be rounded to 4 decimal places. P-values that is less than 0.0001 will be 
presented as '< 0.0001' and p-values that is larger than 0.9999 will be presented as 
'> 0.9999'.  
x 
Duration of image-based event endpoints (such as PFS) will be based on the actual date 
the radiograph was obtained rather than the associated visit date. 
x 
For laboratory results presented in numerical range, if lab results >= x or > x, then set it 
as x; if lab results <= x or < x, then set it as x/2. 
x 
For by-visit observed data analyses, percentages will be calculated based on the N unless 
it’s specified in the footnote. 
x 
For continuous endpoints, summary statistics will include n, mean, standard deviation, 
median, Q1, Q3 and range (minimum and maximum). 
x 
For discrete endpoints, summary statistics will include frequencies and percentages. 


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7.3.3. 
Handling of Missing Data 
Handling of missing data related to primary estimand will be further elaborated in Section 7.5.1. 
Missing dates or partially missing dates will be imputed conservatively for adverse events and 
prior/concomitant medications/procedures. Specific rules for the handling of missing or partially 
missing dates for adverse events and prior/concomitant medications/procedures are provided in  
Appendix 1. Other missing data will not be imputed unless otherwise specified elsewhere in this 
SAP. 
By-visit endpoints will be analyzed using observed data unless otherwise specified. For observed 
data analyses, missing data will not be imputed, and only the observed records will be included. 
7.4. 
Patient Characteristics 
7.4.1. 
Patient Disposition 
The number (percentage) of patients randomized, treated, discontinued from the study, reasons for 
discontinued from the study, and the duration of study follow-up will be summarized in the ITT 
analysis set. The patients who discontinued treatment and the primary reason for the end of 
treatment will be summarized among patients who were treated. The reasons for treatment/study 
discontinuation related to COVID-19 impact will also be summarized.  
7.4.2. 
Protocol Deviations 
Important protocol deviation criteria will be established, and patients with important protocol 
deviations will be identified and documented. Important protocol deviations will be summarized 
for all patients in the ITT analysis set. They will also be listed by each category. Patients with 
multiple important protocol deviations in each category/subcategory were counted only once at 
the category/subcategory level. 
Critical protocol deviation that significantly impacts efficacy or safety evaluation will be reviewed 
prior to database lock according to the criteria defined in protocol deviation specification.   
7.4.3. 
Demographic and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized using descriptive statistics in 
the ITT analysis set, including the following variables: 
x Age (continuously and by categories [≤65 or >65 years]) 
x Sex (Male, Female) 
x Race 
x Ethnicity 
x Country 
x Baseline Weight (kg) 
x Baseline BMI (kg/m2) 
In addition, the stratification factors per Interactive Response Technology (IRT) and per eCRF 
will be summarized using ITT analysis set: 


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x ECOG PS score (0 versus 1) 
x Number of organs with metastases (≤1 versus ≥2) 
x Region (Asia versus non-Asia) 
7.4.4. 
Disease History 
The number (percentage) of patients reporting a history of disease and characteristics, as recorded 
on the eCRF, will be summarized in the ITT analysis set. Disease characteristics include:  
x Stage at Initial Diagnosis (Stage I, II, III, IV, unknown) 
x Time from Initial Diagnosis to Study Entry (month) 
x Primary Site of Esophageal Cancer (cervical, upper, middle, and lower) 
x Histologic Grade (Gx, G1, G2, G3, not done) 
x Target lesions sum of diameter by investigator (mm) 
x Metastatic Disease Status at Study Entry (yes, no) 
x Time from Date of Metastatic Diagnosis to Study Entry (month) 
x Anatomic locations of metastases 
x Previous treatment (chemotherapy, radiation therapy, and surgery) 
7.4.5. 
Prior Anticancer Drug Therapies and Surgeries 
Prior anticancer drug therapies, prior anticancer radiotherapy, and prior anticancer surgeries will 
be summarized in the ITT analysis set. For prior anticancer drug therapies, the variables include 
number of patients with any prior anticancer therapy, number of prior lines, treatment setting, 
duration of prior anticancer therapy, reasons for discontinuation of last anticancer drug therapy, 
best overall response of the last prior anticancer drug therapy, time from the end of the last prior 
anticancer therapy to randomization, and time from last disease progression to randomization. For 
prior anticancer radiotherapy, the variables include number of patients with any prior radiotherapy, 
treatment intent, treatment setting, sites irradiated, and time from end of last radiotherapy to 
randomization. For prior anticancer surgeries, the variables include number of patients with any 
prior anticancer surgery, time from last anticancer surgery to randomization, and prior anticancer 
surgery location . The therapies and surgeries with the same sequence/regimen number are counted 
as one prior therapy/surgery. 
7.4.6. 
Prior and Concomitant Medications 
Prior medications will be defined as medications that stopped before the day of the first dose of 
study drugs. Concomitant medications will be defined as medications that 1) started before the 
first dose of study drugs and were continuing at the time of the first dose of study drugs, or 
2) started on or after the date of the first dose of study drugs up to 30 days after the patient’s last 
dose.   


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Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO DD) drug codes Version B3 March 2022 or higher and will be further classified 
to the appropriate Anatomical Therapeutic Chemical (ATC) code. 
The number (percentage) of patients reporting prior and concomitant medications will be 
summarized by ATC medication class and WHO DD preferred name in the safety analysis set.  
7.4.7. 
Medical History 
Medical history will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA) terminology available at the time of the analyses. The number (percentage) 
of patients reporting a history of any medical condition, as recorded on the eCRF, will be 
summarized by system organ class and preferred term in the ITT analysis set. A listing of medical 
history will be provided. 
7.5. 
Efficacy Analysis 
7.5.1. 
Primary Efficacy Endpoint(s) 
Primary estimand is defined in Section 4. Details of the statistical methods used in the derivation 
and analysis are provided in this section including pre-defined sensitivity analyses of the primary 
estimand. 
Variable 
ORR is defined as the proportion of patients who have confirmed CR or PR by the investigator per 
RECIST v1.1 in the ITT Analysis Set. Patients with no postbaseline response assessment (for any 
reason) will be considered non-responders. 
Primary Analysis for Primary Estimand  
The null hypothesis to be tested is: 
H0: ORR in Arm Aİ ORR in Arm B 
against the alternative: 
H1:  ORR in Arm A > ORR in Arm B 
The null hypothesis will be tested using the Cochran-Mantel-Haenszel method stratified by the 
selected stratification factors at randomization (ie, ECOG PS score [0 versus 1] and the number of 
organs with metastases [İ1 versus ı2]) at the one-sided significance level of 0.025. If the null 
hypothesis can be rejected, it will be concluded that the ORR in Arm A (Tislelizumab plus BGB-
A1217) is superior to the ORR in Arm B (Tislelizumab plus placebo). 
A Mantel-Haenszel common risk difference (Mantel and Haenszel, 1959) will be estimated, along 
with its 95% confidence interval constructed by a normal approximation and Sato's variance 
estimator (Sato, 1989) with the same stratification factors as described above. The Clopper Pearson 
95% CIs for the ORR within each arm will also be calculated. 
The final analysis of ORR is planned approximately 4 months after the randomization of the last 
patient.  


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Further derivation rules for the primary analysis of ORR are presented in Table 1. 
Table 1:          Handling of Intercurrent Events and Missing Values for the Primary 
Analysis of ORR 
 
Derivation rules 
Intercurrent events 
New anticancer therapy started 
prior to disease progression 
Patients starting any new anticancer therapy without 
achieving a confirmed CR or PR before will be 
considered as non-responders (composite strategy) 
Discontinuation of treatment prior 
to disease progression  
Response assessment after discontinuation of treatment 
will be counted and used for analysis (treatment policy 
strategy) 
Missing values not related to intercurrent events 
No post-baseline response 
assessment (regardless of the 
reason) 
Non-responders  
Sensitivity analyses  
Sensitivity analysis 1  
ORR assessed by the investigator’s review will be analyzed using an unstratified Cochran-Mantel-
Haenszel method. The crude rate difference along with its 95% CI will be provided. This analysis 
relaxes the assumption made by the primary analysis for the primary estimand that the baseline 
probabilities of achieving PR/CR is different among the strata (i.e., the stratification factors are 
confounding). 
Sensitivity analysis 2  
ORR assessed by the investigator’s review will be analyzed using a Cochran-Mantel-Haenszel 
method stratified by the actual value of selected stratification factors collected from eCRF (ie, 
ECOG PS score [0 versus 1] and the number of organs with metastases [≤1 versus ≥2]). 
Supplementary analysis  
This analysis targets an estimand which has the same attributes as the primary estimand except 
that the variable changed to unconfirmed ORR assessed by the investigator’s review. The same 
analysis methods as the one for the primary estimand will be used.  
7.5.2. 
Secondary Efficacy Endpoints 
Overall Survival  
Overall survival is defined as time from randomization date to the documented death date for 
patients who died prior to or on the clinical cutoff date. For patients who are alive by the clinical 
cutoff date, OS will be censored at the last known alive date. The last known alive date will be 
defined as either the clinical data cutoff date for patients who are still on treatment, or last available 
date showing patients alive or cut-off date whichever comes first for other alive patients.  


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Every effort should be made to ensure complete death dates. In the rare case, if day of death date 
is missing, death date is imputed as the max (last available date showing patient was alive + 1, first 
day of year/month of death date). The patient with imputed death date will be considered as an 
event for OS analysis.  
Primary analysis of Overall Survival 
The null hypothesis to be tested is:  
H0: OS in Arm A ≤ OS in Arm B 
against the alternative:  
H1: OS in Arm A > OS in Arm B 
The null hypothesis will be tested using a log-rank test stratified by the selected stratification 
factors at randomization (ie, ECOG PS score [0 versus 1] and the number of organs with metastases 
[≤1 versus ≥2]).  
The HR and its 2-sided 95% CI will be estimated from a stratified Cox regression model with the 
same stratification factors above. The distribution of OS, including median, Q1 and Q3, and event-
free rates at every 3 months, will be estimated using the Kaplan-Meier method for each treatment 
group. 95% CIs for median and Q1 and Q3 of OS will be estimated using the method of 
Brookmeyer and Crowley (Brookmeyer and Crowley, 1982). And 95% CIs for event-free rates 
will be estimated using Greenwood's formula (Greenwood, 1926). Kaplan-Meier survival 
probabilities over time for each arm will be plotted. 
The primary analysis of OS will take place when approximately 72 deaths (ie, 60% of the total 
sample size) have been observed. 
Sensitivity analysis 
Sensitivity analysis 1 
OS will be analyzed using a unstratified Cox model, and the treatment effect will be summarized 
by the hazard ratio with its 95% confidence interval. 
Sensitivity analysis 2 
OS will be analyzed using stratified Cox model and the distribution of OS will be compared 
between the treatment group using stratified log-rank test, with stratification factors obtained from 
the eCRF. 
Overall response rate by IRC 
ORR assessed by the IRC per RECIST v1.1 in the ITT Analysis Set will be analyzed similarly as 
the primary analysis of ORR assessed by the investigator. The Mantel-Haenszel common risk 
difference stratified by the selected stratification factors at randomization (ie, ECOG PS score [0 
versus 1] and the number of organs with metastases [≤1 versus ≥2]), along with its 95% confidence 
interval constructed by a normal approximation and Sato’s variance estimator (Sato, 1989)  will 
be estimated. The Clopper Pearson 95% CIs for the ORR within each arm will also be calculated. 
The Cochran-Mantel-Haenszel method stratified by the selected stratification factors at 
randomization (ie, ECOG PS score and the number of organs with metastases [≤1 versus ≥2]) will 


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be provided to show the magnitude of ORR difference, and are only used for descriptive purpose 
only. Unconfirmed ORR assessed by the IRC will also be analyzed.  
Progression Free Survival  
PFS is defined as the time from the date of randomization to the date of first documentation of PD 
assessed by investigator (or IRC) per RECIST v1.1 or death, whichever occurs first in the ITT 
Analysis Set. Progression-free survival censoring rule in handling intercurrent events and missing 
values are described in Table 2 , which follows United States (US) Food and Drug Administration 
(FDA) Guidance for Industry, Clinical Trial Endpoints for Approval of Cancer drugs and Biologics 
(2018). The algorithm to identify missing TAs are presented in Appendix 2.   
Table 2:          Censoring Rules for Progression-Free Survival Per RECIST Version 1.1 
 
Derivation rules 
Outcome 
No progression at the time of data 
cut-off or withdrawal from study or 
lost to follow up 
Date of last adequate radiologic 
assessment prior to or on date of data 
cut-off or withdrawal from study or 
lost to follow up 
Censored 
New anticancer therapy started prior 
to disease progression or death  
Last adequate radiological assessment 
before the new anticancer therapy 
(hypothetical strategy) 
Censored 
No baseline or post-baseline tumor 
assessments without death within 13 
weeks after randomization  
Date of randomization 
Censored 
No baseline or post-baseline tumor 
assessments with death within 13 
weeks after randomization  
Date of death 
Event 
Death or progression after more than 
one missed visit  
Date of last adequate radiologic 
assessment before missed tumor 
assessments 
Censored 
The distribution of PFS, including median, Q1, Q3, and event-free rates at every 3 months, will be 
estimated using the Kaplan-Meier method for each treatment group. 95% CIs for median, Q1, and 
Q3 of PFS will be estimated using the method of Brookmeyer and Crowley (Brookmeyer and 
Crowley, 1982). And 95% CIs for event-free rates will be estimated using Greenwood's formula 
(Greenwood, 1926). The treatment effect will be estimated by fitting a Cox regression model with 
treatment arm adjusted by the before mentioned stratification factors as strata. From this model, 
the HR of PFS will be estimated and presented with a 2-sided 95% CI. 
Duration of Response  
Duration of Response (DOR) is defined as the time from the first determination of an objective 
response until the first documentation of PD as assessed by investigator (or IRC) per RECIST 
v1.1, or death, whichever comes first in the ITT Analysis Set. All the censoring rules for PFS will 
be applied to DOR too. DOR will be analyzed in the responders only. The distribution of DOR, 
including median, Q1, Q3, and event-free rates at every 3 months, will be estimated using the 
Kaplan-Meier method for each treatment group. 95% CIs for median, Q1, and Q3 of DOR will be 
estimated using the method of Brookmeyer and Crowley (Brookmeyer and Crowley, 1982). And 


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95% CIs for event-free rates will be estimated using Greenwood's formula (Greenwood, 1926). 
No formal testing will be performed to compare DOR between two treatment group as it would be 
based on a non-randomized subgroup. Both confirmed and unconfirmed DOR will be analyzed.  
Disease control rate (DCR), clinical benefit rate (CBR)  
DCR, defined as the proportion of patients who have confirmed CR, confirmed PR, and stable 
disease assessed by investigator (or IRC) per RECIST v1.1 in the ITT Analysis Set. CBR, defined 
as the proportion of patients who achieve confirmed CR, confirmed PR and durable stable disease 
(stable disease≥ 24 weeks) assessed by investigator (or IRC) per RECIST v1.1 in the ITT Analysis 
Set. DCR and CBR will be analyzed similarly as the primary analysis of ORR in the ITT Analysis 
Set. The Mantel-Haenszel common risk difference, along with its 2-sided 95% CIs will be 
calculated, as will the Clopper-Pearson 95% CIs for the DCR and CBR within each arm. 
Unconfirmed DCR and CBR may be analyzed if needed.  
Waterfall plots will be provided for the maximum tumor shrinkage based on target lesions. The 
maximum tumor shrinkage based on target lesion used in the plots will be listed. These analyses 
will be performed based on RECIST1.1. 
Time to response (TTR) will be summarized using descriptive statistics, such as mean, median, 
and standard deviation. Only patients who have achieved objective response by investigators or 
IRC per RECIST v1.1 will be included in the analysis of TTR. 
Health -Related Quality of Life (HRQoL)  
The EORTC-QLQ-C30 consists of thirty questions that are associated with one global health 
status/QoL (GHS) scale (Aaronson NK, et al., 1993; Fayers PM, et al., 2001), five functional scales 
(physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea 
and vomiting), and six single item scales (dyspnoea, insomnia, appetite loss, constipation, diarrhea, 
and financial difficulties).  
The EORTC-QLQ-OES18 (Wen Y, et al., 2015) is the specific esophageal symptoms module of 
the QLQ-C30, and includes 18 questions: 6 single item subscales measuring saliva swallowing, 
choking, dry mouth, taste, coughing, and talking. It also includes 12 items grouped into 4 
subscales: dysphagia (3 items), eating (4 items), reflux (2 items), and pain (3 items). 
EORTC Scoring Derivation 
The principle for scoring applies to all scales/scores: Raw scores are calculated as the average of 
the items that contribute to the scale.  A linear transformation to standardize the raw scores is 
utilized, so that the scores are ranged from 0 to 100.  Increases in scores for functional domains 
(e.g., physical, role, social, emotional, etc.) are improvements while increases in scores for 
symptoms (e.g., fatigue, vomiting and nausea, diarrhea, pain, etc.) are deteriorations. 
If at least half of the items for a scale are answered, then all the completed items are used to 
calculate the scale score.  Otherwise, the scale score is set to missing. 
Raw Score (RS) 
For all scores, the raw score (RS) is the mean of the component items. 
RS = (I1+I2+…+ In)/n 


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Derived Scale (DS) 
The derived scales are obtained from the raw scores as defined in the EORTC manual. The derived 
scales have a more intuitive interpretation: larger function scale or global health status / QoL are 
improvements while larger symptom scales (e.g., pain, nausea, etc.) are deteriorations. The 
derivation formulas are as follows. 
For functional scales: 
DS = [1 - (RS-1)/range] ×100 
For symptom scales and global health status: 
DS = [(RS-1)/ range] ×100 
Refer Table 3 and Table 4 for EORTC -QLQ-C30 and EORTC-QLQ-OES18 scoring.  
Index Score 
The domain scores and single item scores are derived scales. Below is the index score formula.  
Index score = [∑(domain scores + single item scores)]÷ number of available domains and single 
items  
 
Table 3:          Scoring of QLQ-C30 
 
Scale 
Number of 
items 
Item range 
Item Numbers 
Global health status/ QoL 
Global health status/QOL 
QL2 
2 
6 
29,30 
Functional Scales 
 
 
 
 
Physical functioning  
PF2 
5 
3 
1, 2, 3, 4, 5  
Role functioning  
RF2 
2 
3 
6, 7  
Emotional functioning  
EF 
4 
3 
21, 22, 23, 24  
Cognitive functioning  
CF 
2 
3 
20, 25  
Social functioning  
SF 
2 
3 
26, 27  
Symptom Scales 
 
 
 
 
Fatigue 
FA 
3 
3 
10, 12, 18 
Nausea and vomiting 
NV 
2 
3 
14, 15 
Pain 
PA 
2 
3 
9, 19 
Single Items 
 
 
 
 
Dyspnoea 
DY 
1 
3 
8 
Insomnia 
SL 
1 
3 
11 


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Appetite loss 
AP 
1 
3 
13 
Constipation 
CO 
1 
3 
16 
Diarrhea 
DI 
1 
3 
17 
Financial Difficulties 
FI 
1 
3 
28 
 
Table 4:          Scoring of QLQ-OES18 
 
Scale 
Number of 
items 
Item range 
Item Numbers 
Symptom Scales 
 
 
 
 
Dysphagia 
DY 
3 
3 
31, 32, 33 
Eating 
EA 
4 
3 
36, 37, 38, 39 
Reflux 
RE 
2 
3 
44, 45 
Pain 
PA 
3 
3 
46, 47, 48 
Single Items 
 
 
 
 
Trouble swallowing saliva 
SA 
1 
3 
34 
Choked when swallowing 
SW 
1 
3 
35 
Dry mouth 
DM 
1 
3 
40 
Trouble with taste 
TA 
1 
3 
41 
Trouble with coughing 
CO 
1 
3 
42 
Trouble talking 
TA 
1 
3 
43 
 
All HRQoL measures will be summarized in ITT analysis set.  
A questionnaire module is considered complete if at least one derived scale is answered. The 
adjusted completion rate is defined as percentages of patients who completed the questionnaire at 
each visit divided by the number of patients still in treatment who were expected to complete the 
questionnaire. Completion rates and adjusted completion rates for the EORTC-QLQ-C30 and 
EORTC-QLQ-OES18 will be summarized separately at each visit.  
The derived scores (functional scales/symptom scales/single items and GHS/QoL scale) of 
EORTC-QLQ-C30 and EORTC-QLQ-OES18 and the index score of QLQ-OES18 will be 
summarized as well as change from baseline at each visit using descriptive statistics. The plots of 
the mean values and their standard errors at each visit over time for selected domains of EORTC-
QLQ-C30 and EORTC-QLQ-OES18 by treatment arm will be presented for both Arm A and Arm 
B.  
A mixed effect model analysis for assessing  differences  between the arms in changes post-
baseline will be performed for the PRO endpoints (GHS/QoL scale and physical function measured 


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by QLQ-C30;  and dysphagia, eating, reflux, pain measured by QLQ-OES18). Difference in 
change from baseline to the key clinical of cycle 5 and cycle 7 between treatment arms will be 
assessed. The model includes the PRO endpoint as dependent variable, baseline score, 
stratification factors, treatment arm, visit, and treatment arm by visit interaction as fixed effects 
and visit as a repeated measure with an unstructured covariance structure. LS mean change 
differences between arms at 95% CI with nominal p values will be reported. 
Time to deterioration analysis will be performed to compare the risk of experiencing a deterioration 
event in the PRO end points (GHS/QoL scale and physical function measured by QLQ-C30;  and 
dysphagia, eating, reflux, pain measured by QLQ-OES18) between two treatment arms. Time to 
deterioration is defined as changes ≥ 10 points (Osaba et al 1998) from baseline in the worsening 
direction. A deterioration is not counted as an event if a subsequent improvement returned to less 
than 10 points. If a patient does not have an deterioration event, they are censored at their last 
clinic visit at which HRQoL score is measured. The log-rank test and hazard ratio will be provided 
to show the magnitude of treatment effect and are only used for descriptive purpose only.  
7.5.3. 
Subgroup Analyses 
Subgroup analysis on ORR by the investigator’s review and OS will be conducted in ITT analysis 
set, to evaluate the uniformity of treatment effect across variety of subgroups. Subgroup variables 
may include, but not limited to,  
x Number of metastatic lesions (≤ 1 site versus ≥ 2 sites)  
x Geographic region: (Asia/Europe)  
x ECOG Performance status: (0, 1)  
x Age group: (< 65 years, >= 65 years)  
x Sex: (Male, Female)  
x Smoking status: (former/current smoker, non-smoker)  
x Race: (White, Asian, and Other)  
x Previous treatment (radiation therapy, surgery) 
For ORR by the investigator’s review, in each subgroup, a crude risk difference will be estimated, 
along with its 95% confidence interval . And the Clopper Pearson 95% CIs for the ORR within 
each arm will also be calculated. 
For OS, KM estimates by treatment arm, and the estimation of unstratified hazard ratio and their 
95% CI will be provided for the subgroups.  
7.5.4. 
Exploratory Efficacy Endpoints 
QoL 
The EQ-5D-5L comprises a descriptive module and an EQ Visual Analogue scale (EQ VAS). The 
EQ-5D-5L descriptive module comprises the following 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, 
slight problems, moderate problems, severe problems, and extreme problems. The EQ VAS 


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records the respondent’s self-rated health on a 0 to 100 scale, with 100 labelled ‘the best health 
you can imagine’ and 0 ‘the worst health you can imagine’.  Lower scores in descriptive dimension 
indicates better HRQoL and higher VAS score indicates better health state.  
EQ-5D-5L descriptive module will be summarized by visit and dimension in an ordinal scale using 
descriptive statistics. The EQ VAS and change from baseline will be summarized by visit in a 
continuous scale using descriptive statistics. Completion rates for EQ-5D-5L will be summarized 
at each visit. A questionnaire module is considered complete if at least one question is answered. 
7.5.5. 
Post and during-treatment Anticancer Therapy 
New anticancer therapy 
Separate flags of start date of new anticancer therapy for efficacy and safety analyses are derived 
individually. 
- 
As for efficacy analysis, the start date of new anticancer therapy will be the earliest date 
of prohibited anticancer therapy taken during treatment, date of the post-treatment 
systemic anticancer therapy and date of other anticancer therapy such as post-treatment 
surgery and radiotherapy as deemed appropriate. 
- 
For non-efficacy analysis, the start date of new anticancer therapy is always the first date 
of new systemic anticancer therapy taken after the last study treatment. 
Tumor response per RECIST or event driven endpoints have not been commonly used for the 
efficacy evaluation of Traditional Chinese Medication (TCM). ORR, PFS or OS benefit of Chinese 
herbal medicines or Chinese patent medicines has not yet been established. Therefore, they will 
not be taken into account as new anticancer therapy in the efficacy and safety analyses. 
Subsequent systemic anticancer therapy 
Subsequent systemic anticancer therapy is defined as the anticancer therapy started after the last 
dose of study drug(s). A summary of number and percentage of patients who received subsequent 
systematic anticancer therapy by therapy type (e.g. chemotherapy, immunotherapy, targeted 
therapy) will be provided by treatment arm based on ITT analysis set. 
7.6. 
Safety Analyses 
All safety analyses will be performed by treatment arms based on the safety analysis set. Safety 
and tolerability will be assessed, where applicable, by incidence, severity, and change from 
baseline values for all relevant parameters including AEs, laboratory values, vital signs, ECG 
findings and physical examination.  
7.6.1. 
Extent of Exposure 
The following measures of the extent of exposure will be summarized for ociperlimab/placebo and 
tislelizumab separately: 
x Duration of exposure (days): defined as last date of exposure – first dose date + 1.  
 If patients discontinue treatment (with non-missing EOT date), last date of exposure 
= min (last dose date + 20, death date, clinical data cutoff date)  


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 Otherwise, if patient has treatment ongoing, last date of exposure = clinical data 
cutoff date 
x Number of treatment cycles received: defined as the total number of cycles with non-
missing doses.  
x Total dose received per patient (mg): defined as the sum of all actual dosages per 
administration at all visits prior to the clinical data cutoff date. 
x Actual dose intensity (mg/cycle): defined as 21 × total dose received per patient (mg) / 
(last dose date prior to cutoff date + 21 – first dose date) 
x Relative dose intensity (%): defined as the ratio of the actual dose intensity and the 
planned dose intensity. The planned dose intensity is 200 mg/cycle for tislelizumab and 
900 mg/cycle for ociperlimab/placebo. 
The number of patients with dose modifications which includes dose missed, dose delays and 
infusion interruptions and their reasons will be summarized by counts and percentages according 
to study drug.  
Patient data listings will be provided for all dosing records, and for the above calculated summary 
statistics. 
7.6.2. 
Adverse Events  
AEs will be graded by the investigators using CTCAE version 5.0. The AE verbatim descriptions 
(investigator terms from the eCRF) will be classified into standardized medical terminology using 
MedDRA. Adverse events will be coded to the MedDRA (Version 25.0 or higher) lowest level 
term closest to the verbatim term, along with the linked MedDRA preferred term (PT) and primary 
system organ class (SOC). 
7.6.2.1 Treatment Emergent Adverse Event 
A treatment-emergent adverse event (TEAE) is defined as an AE that had an onset date or a 
worsening in severity from baseline (pretreatment) on or after the first dose of study drugs up to 
30 days of study drugs after last dose or initiation of subsequent anticancer therapy, whichever 
comes first. Only those AEs that were treatment emergent will be included in summary tables of 
TEAE.  All AEs, treatment emergent or otherwise, will be presented in patient data listings.  
An AE overview table, including the number and percentage of patients with TEAEs, treatment-
emergent serious adverse events (SAEs), TEAEs with Grade 3 or above, TEAEs that led to death, 
TEAEs that led to treatment discontinuation, TEAEs that led to dose delay, TEAEs that led to 
infusion interruption/rate decrease, treatment-related TEAEs, treatment-related version of any of 
the above categories, infusion-related reactions will be provided. Treatment-related AEs include 
those events considered by the investigator to be related to study drug or with a missing assessment 
of the causal relationship. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC and PT. A patient will be counted only once by the highest severity grade within an SOC and 
PT, even if the patient experienced more than 1 TEAE within a specific SOC and PT.  
The number (percentage) of patients with following TEAE will be provided: 


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x All TEAEs  
o TEAEs by SOC and PT (any grades and >= grade 3) 
o TEAE by PT (any grades and >= grade 3) 
o Treatment-related TEAEs by SOC and PT (any grades and >= grade 3) 
o Treatment-related TEAEs by PT (any grades and >= grade 3) 
o Tislelizumab-related TEAEs by SOC and PT (any grades and >= grade 3) 
o Ociperlimab/Placebo-related TEAEs by SOC and PT (any grades and >= grade 3) 
x Serious TEAEs  
o Serious TEAEs by SOC and PT 
o Serious TEAEs by PT 
o Serious treatment-related TEAEs by SOC and PT 
o Serious treatment-related TEAEs by PT 
o Serious tislelizumab -related TEAEs by SOC and PT 
o Serious ociperlimab/placebo -related TEAEs by SOC and PT 
x TEAEs leading to death  
o TEAEs leading to death excluding death due to disease under by SOC and PT 
o TEAEs leading to death excluding death due to disease under by PT 
o TEAEs leading to death including death due to disease under by SOC and PT 
o TEAEs leading to death including death due to disease under by PT 
o Treatment-related TEAEs leading to death excluding death due to disease by SOC 
and PT 
o Treatment-related TEAEs leading to death excluding death due to disease by PT 
x TEAEs leading to treatment discontinuation  
o TEAEs leading to treatment discontinuation by SOC and PT 
o TEAEs leading to treatment discontinuation by PT 
o TEAEs leading to tislelizumab discontinuation by SOC and PT 
o TEAEs leading to ociperlimab/placebo discontinuation by SOC and PT 
o Treatment-related TEAEs leading to treatment discontinuation by SOC and PT 
o Treatment-related TEAEs leading to treatment discontinuation by PT 
x TEAEs leading to treatment modification  
o TEAEs leading to treatment modification by SOC and PT 
o TEAEs leading to treatment modification by PT 
o TEAEs leading to treatment modification of tislelizumab by SOC and PT 
o TEAEs leading to treatment modification of ociperlimab/placebo by SOC and PT 
o Treatment-related TEAEs leading to treatment modification by SOC and PT 
o Treatment-related TEAEs leading to treatment modification by PT 
7.6.2.2 Immune-mediated Adverse Event 
ImAEs are of special interest and summarized by category within a pre-defined list. The 
identification of imAEs will be described in immune-mediated adverse events charter. All imAE 
up to 90 days of last dose of any study drug, regardless of whether the patient starts a new 
anticancer therapy, will be summarized. 
An overall summary table and separate summaries of the following incidence of imAEs will be 
provided: 
x ImAEs by category and PT (any grades and >= grade 3) 


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x ImAEs leading to death by category and PT 
x ImAEs leading to treatment discontinuation by category and PT 
x ImAEs leading to treatment modification by category and PT  
x ImAEs outcome, time to onset, and duration by category 
x ImAEs treated with systemic corticosteroids by category 
7.6.2.3 Infusion-related Adverse Event 
For IRRs and IRRs with NCI-CTCAE grade ≥3, a summary of incidence by SOC and PT be 
provided.  
7.6.2.4 Death 
All deaths and causes of death will be summarized by treatment group, including those occurred 
during the study treatment period and those reported during the survival follow-up period after 
treatment completion/discontinuation. 
7.6.3. 
Laboratory Values 
Laboratory safety tests will be evaluated for selected parameters described in Table 5, Abnormal 
laboratory values will be flagged and identified as those outside (above or below) the normal range. 
Reference (normal) ranges for laboratory parameters will be included in the CSR for this protocol.  
Laboratory results will be summarized/listed using Système International (SI) units, as appropriate. 
Hematology and serum chemistry laboratory parameters that are graded in NCI-CTCAE v.5.0 will 
be summarized by shifts from baseline NCI-CTCAE grade to maximum post-baseline grades. In 
the summary of laboratory parameters by NCI-CTCAE grade, parameters with NCI-CTCAE 
grading in both high and low directions (e.g., calcium, glucose, magnesium, potassium, sodium) 
will be summarized separately. The summary tables will report lab assessments up to 30 days of 
the last dose date.  
Laboratory parameters for potential Hy’s Law for liver injury and abnormal thyroid function will 
also be summarized. Box-whisker plots will be generated for parameters of interest. 
Patient data listings will be provided as appropriate. 
Table 5:          Clinical Laboratory Parameters 
Clinical 
Chemistry 
Hematology 
Coagulation 
Urinalysis 
Thyroid 
Function 
Alkaline 
phosphatase 
Hematocrit 
Prothrombin 
time 
pH 
TSH 
ALT 
Hemoglobin 
Partial 
thromboplastin 
time or activated 
partial 
thromboplastin 
time 
Specific gravity 
Free T3 


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Clinical 
Chemistry 
Hematology 
Coagulation 
Urinalysis 
Thyroid 
Function 
AST 
Platelet counts 
International 
normalized ratio 
Glucose 
Free T4 
Albumin 
White blood cell 
count  
 
Protein 
 
Total bilirubin 
Neutrophil count 
 
 
Ketones 
 
Direct bilirubin 
Lymphocyte 
count 
 
 
Blood 
 
Blood urea 
nitrogen or urea 
 
 
24-hour protein a  
Potassium 
 
 
 
 
Sodium 
 
 
 
 
Calcium 
 
 
 
 
Phosphorus 
 
 
 
 
Magnesium  
 
 
 
 
Chloride 
 
 
 
 
Creatinine 
 
 
 
 
Glucose 
 
 
 
 
Lactate 
dehydrogenase 
 
 
 
 
Total protein 
 
 
 
 
Creatine kinase/ 
CK-MB b 
 
 
 
 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK-MB, creatine kinase-
muscle/brain. 
a On routine urinalysis, if urine protein is ≥ 2+ by dipstick then obtain a 24-hour urine sample for total protein or a 
random urine sample for total protein and creatinine to determine a protein-to-creatinine ratio. 
b Cardiac enzyme testing has been added to monitor for potential event of immune-mediated myocarditis. If CK-MB 
fractionation is not available, assess troponin I and/or troponin T instead. Investigators should make every effort to 
perform either CK-MB, troponin I and/or troponin T consistently at screening and at follow-up visits. 
7.6.4. 
Vital Signs 
Vital signs will be listed by patient and visit.  


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7.6.5. 
Electrocardiograms (ECG) 
The number and percentage of patients satisfying the following abnormal QTcF conditions at any 
time post-baseline will be summarized by treatment group: 
x >450, > 480, or > 500 msec  
x > 30 msec increase from baseline, or > 60 msec increase from baseline  
7.6.6. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
A shift table from baseline to worst post-baseline in ECOG performance score will be summarized.  
7.7. 
Pharmacokinetic Analyses 
Pharmacokinetic samples will be collected in this study as outlined in Appendix 1 of Protocol. 
Placebo samples will be collected but not analyzed. 
The following analysis plan provides the framework for the summarization of the PK data from 
study AdvanTIG-203. The objective is to summarize available ociperlimab and tislelizumab PK 
concentrations following an IV administration. PK parameters will not be characterized as only 
sparse samples were collected. 
Additional PK analyses, including population PK analyses and exposure-response analyses 
(efficacy or safety endpoints) may be conducted as appropriate and the results of such analysis 
may be reported separately from the CSR. 
7.7.1. 
Reporting of Pharmacokinetic Concentrations for Descriptive Statistics 
The ociperlimab and tislelizumab serum concentration data will be listed and tabulated by 
visit/cycle at which these concentrations are collected per the study design. Descriptive statistics 
will include means, medians, ranges, standard deviations, geometric means, and geometric CV%, 
as appropriate.  
 
7.8. 
Immunogenicity Analyses 
Anti-drug antibodies (ADAs) samples will be collected in this study as outlined in Appendix 1 of 
Protocol. Placebo samples will be collected but not analyzed.  
The scope of ADAs calculations used for characterizing clinical immunogenicity depends on the 
incidence and kinetics of detected ADA. Therefore, not all parameters described below will be 
derived or additional parameters may be added. The effect of immunogenicity on PK, efficacy, 
and safety may be evaluated if data allows and will be reported separately from the CSR 
The immunogenicity results will be summarized using descriptive statistics by the number and 
percentage of subjects who develop detectable ADAs for ociperlimab and tislelizumab separately 
based on Immunogenicity Analysis set. The incidence of positive and neutralizing ADAs (as 
applicable) will be reported for ADA-evaluable subjects according to the following definitions: 
x ADA-evaluable subject: Number of subjects with reportable non-missing baseline result 
and at least one reportable sample taken after drug administration during the treatment or 


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follow-up observation period with reportable result (used for computing treatment induced 
ADA incidence). 
x Treatment-emergent ADA: The sum of both treatment-boosted and treatment-induced 
ADA-positive subjects as a proportion of the evaluable subject population. Synonymous 
with “ADA Incidence”. 
x Treatment-induced ADA: ADA-evaluable subjects that were ADA-negative at baseline 
and ADA-positive following administration of biologic product. 
x Treatment-boosted ADA: Baseline-positive ADA-evaluable subjects with significant 
increases (4-fold or higher) in ADA titer after biologic drug administration. Baseline-
positive ADA-evaluable subject is an ADA-evaluable subject with positive ADA result at 
baseline. 
x Persistent ADA: Treatment-induced ADA detected at two or more sampling time points 
during the treatment (including follow-up period if any), where the first and last ADA-
positive samples (irrespective of any negative samples in between) are separated by a 
period of 16 weeks or longer, or treatment induced ADA incidence only in the last sampling 
time point of the treatment study period or at a sampling time point with less than 16 weeks 
before an ADA-negative last sample. 
x Transient ADA: Treatment-induced ADA that is not considered as persistent ADA.  
x Neutralizing ADA: patients with positive NAb. 
The individual immunogenicity results will also be listed. 
8. 
INTERIM ANALYSES 
No formal interim analyses will be conducted, and no formal stopping rules have been specified 
per protocol for this study. Summaries of efficacy and safety data may be generated to inform 
subsequent clinical development planning. 
9. 
CHANGES IN THE PLANNED ANALYSISCHANGES IN THE PLANNED 
ANALYSIS 
If the SAP needs to be revised, the sponsor will determine how the revision impacts the study and 
how the revision should be implemented. The details of the revision will be documented and 
described in the clinical study report. 
 


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10. 
REFERENCES 
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, 
Fleishman SB, de Haes JC, et al. The European Organization for Research and Treatment of 
Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. 
J Natl Cancer Inst. 1993 Mar 3;85(5):365-76. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics. 
1982;38:29-41. 
Common Terminology Criteria for Adverse Events (CTCAE).  Version 5.0.  United States 
Department of Health and Human Services, National Institutes of Health, National Cancer 
Institute, Washington, DC, USA, Nov 27, 2017. 
Eisenhauer EA, Therasse P, Bogaerts J Schwartz LH, Sargent D, Ford R, et al.  New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).  Eur J Cancer. 
2009;45:228-47. 
Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A on behalf of the 
EORTC Quality of Life Group. EORTC QLQ-C30 Scoring Manual (3rd edition). Brussels: 
EORTC, 2001 
Greenwood M. The Natural Duration of Cancer. Reports on Public health and medical subjects. 
1926;33:1-26. 
ICH. Addendum on Estimands and Sensitivity Analyses in Clinical Trials to the Guideline on 
Statistical Principles for Clinical Trials: E9(R1). 2019. 
Mantel N, Haenszel W. Statistical Aspects of Analysis of Data from Retrospective Studies of 
Disease. Journal of the National Cancer Institute. 1959;22:719–748. 
Miettinen O, Nurminen M. Comparative analysis of two rates. Statistics in Medicine 1985; 4: 
213–226. 
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health related 
quality-of-life scores. J Clin Oncol. 1998;16(1):139–144.  
Sato T. On the Variance Estimator of the Mantel-Haenszel Risk Difference. Biometrics. 1989; 
45:1323–1324. 
US Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER). 
FDA guidance for industry: clinical trial endpoints for the approval of cancer drugs and 
biologics. 2018. Accessed August 18, 2020.  
Wen Y, Pan XF, Huang WZ, Zhao ZM, Wei WQ, Chen F, Lan H, Huang H, Yang CX, Qiao YL. 
Quality of Life for Patients with Esophageal/Gastric Cardia Precursor Lesions or Cancer: A One-
year Prospective Study. Asian Pacific Journal of Cancer Prevention, Vol 16: 45-51, 2015. 


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11. 
APPENDIX  
11.1. 
Appendix 1: Imputation Rules for Partial Dates 
11.1.1. 
 Impute partial dates for concomitant medication  
When the start date or end date of a medication/therapy/procedure is partially missing, the date 
will be imputed to determine whether the medication/therapy/procedure is prior or concomitant. 
The following rules will be applied to impute partial dates for medications.  
If start date of a medication/therapy/procedure is partially missing, impute as follows: 
x If both month and day are missing, then set to January 01 
x If only day is missing, then set to the first of the month 
x If the imputed start date > death date, then set to death date 
If end date of a medication/therapy/procedure is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to last day of the month 
x If the imputed end date > death date, then set to death date 
If the year of start date or year of end date of a medication/therapy/procedure is missing, or the 
start date or end date is completely missing, do not impute. 
11.1.2. 
Impute partial dates for adverse events 
If year of the start date is missing or start date is completely missing, do not impute. Impute AE 
end date first if both AE start date and end date are partially missing. 
If end date of an adverse event is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to last day of the month 
x If the imputed end date > min (death date, end of study date), then set to min (death 
date, end of study date) 
If year of the end date is missing or end date is completely missing, do not impute. 
If start date of an adverse event is partially missing, impute as follows: 
x If both month and day are missing and year = year of treatment start date, then set to 
treatment start date 
x If both month and day are missing and year ≠ year of treatment start date, then set to 
January 01 
x If day is missing and month and year = month and year of treatment start date, the set 
to treatment start date 
x If day is missing and month and year ≠ month and year of treatment start date, the set 
to first of the month 


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x If the imputed AE start date is after AE end date (maybe imputed), then update AE start 
date with AE end date as final imputed AE start date.  
11.1.3. 
Impute partial dates for subsequent anticancer surgery/procedure as 
collected in the post-treatment page 
If start date of subsequent anticancer therapy is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to last day of the month 
x If the imputed start date > min (death date, study discontinuation date, data cutoff date, 
start date of the subsequent anticancer therapy), then set to min (death date, study 
discontinuation date, data cutoff date, start date of the next subsequent therapy) 
x The imputed start date must be before or equal to the end date. 
If year of the start date is missing, do not impute. 
11.1.4. 
Impute partial dates for disease history and prior therapy (drug, 
surgery/procedure, radiotherapy) 
The following rules will be applied to impute partial dates such as initial diagnosis date, initial 
BCLC staging date, relapse date, therapy date (start/end date), or surgery date etc. 
Impute end date first. If end date is partially missing, impute as follows: 
x If both month and day are missing, then set to December 31 
x If only day is missing, then set to the last day of the month 
x If imputed end date > randomization date, then set to randomization date - 1 
 If start date is partially missing, impute as follows: 
x If both month and day are missing, then set to January 01 
x If only day is missing, then set to the first of the month 
x If the imputed start date > end date, then set to the end date 
If the year of start date or year of end date of a medication/therapy/procedure is missing, or the 
start date or end date is completely missing, do not impute. 
 
11.2. 
Appendix 2: Rules For Identifying Missing Tumor Assessments 
 
Identifying two missing tumor assessments 
1) Input scheduled TA visit list  
a. (6wk-12wk-18wk-24wk-30wk-36wk-42wk-48wk-54wk-66wk-78wk…) for this 
study with TA as every 6 weeks for the first 54 weeks, then every 12 weeks 
thereafter 
2) Identify last evaluable TA before PD or death (--LPTADT) and map it to the closest 
scheduled visit (--LPTADT_WK). 


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a. In the event of unscheduled TA, choose the closest scheduled visit number (e.g. 
6wk or 24wk) as –LPTADT_WK. It can be achieved programmatically by 
following the classification rule (e.g. defining thresholds) depicted in Table 6 
below.  (The team can consider to map all tumor visits if the scheduled visits code 
are uncleaned or questionable)  
b. Otherwise, assign the scheduled visit number (assuming it is coded correctly) to --
LPTADT_WK 
3) Find the 2nd TA visit after LPTADT_WK according to the list in step 1 (--
LPTADT_WK_2) 
a. If LPTADT_WK_2+1wk (assuming 1 wk TA window) < earliest of PD/death date, 
then censor PFS at the –LPTADT 
b. Otherwise, PFS event at the earliest of PD/death date 
Table 6 shows how to assign unscheduled TA to a schedule visit. The Threshold column is defined 
as the mid-point between current and next visit (except for baseline); it is the upper limit for 
LPTADT to be mapped to the prior scheduled assessment (step 2a above). For example, if 
LPTADT is Week 44 for an unscheduled visit, it will be mapped to Week 42 TA since it is within 
the Threshold for Week 42. Assuming it is SD and the subsequent TA of the patient is PD after 
Week 55, PFS will be censored at LPTADT (Week 44); had the PD occurred prior to Week 55, it 
would be counted as an PFS event. 
Table 6:          Example of Scheduled Tumor Assessments With Time Window 
Weeks 
Scheduled week 
-1 
Scheduled week Scheduled 
week+1 
Threshold  
Baseline 
  
Baseline 
  
  
Every 6 weeks 
for the first 54 
weeks 
  
  
  
Week 5 
Week6 
Week 7 
Week 9 
Week 11 
Week 12 
Week 13 
Week 15 
Week 17 
Week 18 
Week 19 
Week 21 
Week 23 
Week 24 
Week 25 
Week 27 
Week 29 
Week 30 
Week 31 
Week 33 
Week 35 
Week 36 
Week 37 
Week 39 
Week 41 
Week 42 
Week 43 
Week 45 
Week 47 
Week 48 
Week 49 
Week 51 
Week 53 
Week 54 
Week 55 
Week 60 
 Every 12 weeks 
thereafter 
  
Week 65 
Week 66 
Week 67 
Week 72 
 
 
 
 
Week 77 
Week 78 
Week 79 
Week 84 
Week 89 
Week 90 
Week 91 
…